The DGAV risk calculator: development and validation of statistical models for a web-based instrument predicting complications of colorectal cancer surgery.

PURPOSE: The purpose of this study is to provide a web-based calculator predicting complication probabilities of patients undergoing colorectal cancer (CRC) surgery in Germany. METHODS: Analyses were based on records of first-time CRC surgery between 2010 and February 2017, documented in the database of the Study, Documentation, and Quality Center (StuDoQ) of the Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV), a registry of CRC surgery in hospitals throughout Germany, covering demography, medical history, tumor features, comorbidity, behavioral risk factors, surgical procedures, and outcomes. Using logistic ridge regression, separate models were developed in learning samples of 6729 colon and 4381 rectum cancer patients and evaluated in validation samples of sizes 2407 and 1287. Discrimination was assessed using c statistics. Calibration was examined graphically by plotting observed versus predicted complication probabilities and numerically using Brier scores. RESULTS: We report validation results regarding 15 outcomes such as any major complication, surgical site infection, anastomotic leakage, bladder voiding disturbance after rectal surgery, abdominal wall dehiscence, various internistic complications, 30-day readmission, 30-day reoperation rate, and 30-day mortality. When applied to the validation samples, c statistics ranged between 0.60 for anastomosis leakage and 0.85 for mortality after rectum cancer surgery. Brier scores ranged from 0.003 to 0.127. CONCLUSIONS: While most models showed satisfactory discrimination and calibration, this does not preclude overly optimistic or pessimistic individual predictions. To avoid misinterpretation, one has to understand the basic principles of risk calculation and risk communication. An e-learning tool outlining the appropriate use of the risk calculator is provided.

Impact of staged surgery on quality of life in refractory ulcerative colitis.

INTRODUCTION: Coloproctomucosectomy (CPM) with ileopouchanal anastomosis (IPAA), as the procedure of choice for surgical management of ulcerative colitis (UC), is commonly performed either as a 2- or 3-staged procedure. For patients with considerable immunosuppression, reduced nutritional or general health status, and as part of emergency treatment, a 3-staged (3S) procedure is recommended by guidelines to minimize perioperative complication rates compared to 2-staged (2S) procedure. However, the necessity of additional hospitalization and surgery is suspect to affect quality of life (QoL). In this prospective, observational study, we evaluate the long-term QoL after 2- and 3-staged interventions of CPM with IPAA for patients with UC. PATIENTS AND METHODS: Between 1997 and 2011, a total of 233 patients underwent CPM and had a 2- or 3-staged procedure. In 108 patients, surgical procedure was completed, and evaluation of QoL was performed by specific questionnaires (IBDQ, FIQoL, SF-12, CCS) up to 20 years after ileostomy closure. Data were collected within the framework of a prospective study. RESULTS: Observing a total of 84 patients (2S: n = 59; 3S: n = 25), QoL measured by IBDQ was higher after CPM, compared to preoperative (2S: 15 â†’ 31; 3S: 17 â†’ 28; p < 0.01), with no differences between 2S or 3S procedures (p > 0.05). Specific QoL assessment concerning incontinence and stool frequency (CCS, FIQoL) did not differ either (CCS: 2S:3S = 12:15; p > 0.05). General health-related QoL, determined by SF-12 score, did not differ between 2S or 3S procedures. CONCLUSION: The indication for a 2-staged or 3-staged procedure should be adjusted to the severity of the underlying disease, nutritional status of the patient, and the extent of immunosuppression at the time of surgery. It should not be affected by the fear of complications or a reduced quality of life by additional surgery in 3-staged versus 2-staged procedures.

Dendritic cells from human mesenteric lymph nodes in inflammatory and non-inflammatory bowel diseases: subsets and function of plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDC) in mesenteric lymph nodes (MLN) may be important regulators of both inflammatory and non-inflammatory mucosal immune responses but human studies are rare. Here we compare pDC from human MLN and peripheral blood (PB) by phenotype and function. MLN from patients with or without inflammatory bowel disease (IBD) undergoing colon surgery and PB from patients with IBD and from controls were used to isolate mononuclear cells. The pDC were analysed by flow cytometry for the expression of CD40, CD80, CD83, CD86, CCR6, CCR7, CX3CR1, CD103 and HLA-DR. Purified pDC from MLN and PB were stimulated with staphylococcus enterotoxin B (SEB), CpG-A, interleukin-3 (IL-3), SEB + IL-3, CpG-A + IL-3 or left unstimulated, and cultured alone or with purified allogeneic CD4(+) CD45RA(+) HLA-DR- T cells. Subsequently, concentrations of IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, interferon-α (IFN-α), IFN-γ and tumour necrosis factor-α (TNF-α) in culture supernatants were determined by multiplex bead array. The PB pDC from IBD patients exhibited an activated and matured phenotype whereas MLN pDC and control PB pDC were less activated. CpG-A and CpG-A + IL-3-stimulated MLN pDC secreted less IL-6 and TNF-α compared with PB pDC from controls. Compared with co-cultures of naive CD4 T cells with PB pDC, co-cultures with MLN pDC contained more IL-2, IL-10 and IFN-γ when stimulated with SEB and SEB + IL-3, and less IFN-α when stimulated with CpG-A. MLN pDC differ phenotypically from PB pDC and their pattern of cytokine secretion and may contribute to specific outcomes of mucosal immune reactions.

Recombinant human beta 2-defensin fusion proteins as a tool to investigate defensin structure and function in small human intestinal tissue samples.

OBJECTIVE: Effects of immune cells on the beta 2 (ß2)-defensin (HBD2) expression and its antibacterial activity in the intestinal mucosa of patients with inflammatory bowel diseases remains unclear. The small size of these proteins presents a major challenge in localizing antibacterial activities in human intestinal tissue. In this study, we evaluated the detection limits at mRNA and protein level by approaching HBD2 from small tissue samples. METHODS: HT-29 colonic epithelial cells were incubated with proinflammatory cytokines before HBD2 mRNA was investigated by quantitative polymerase chain reaction. The HBD2 protein was assessed by Western blot analysis using HBD2 fused with enhanced green fluorescent protein (HBD2-EGFP). Purified HBD2 fused with the glutathione-S-transferase (GST-HBD2) was used to detect antibacterial activity in a densitometric assay. RESULTS: Interleukin (IL)-1ß induced HBD2 mRNA in HT-29 cells; however, tumor necrosis factor-α, IL-6 and IL-17 did not. The Western blot had a sensitivity of 1.5 pmol to detect recombinant HBD2, but did not detect HBD2 in either human intestinal or IL-1ß-treated HT-29 cells. HBD2-EGFP was detected by HBD2-specific Western blot within cell lysates and culture supernants of transfected HT-29 and primary cells. In nanomolar ranges, GST-HBD2 reduced bacterial growth. The HBD2 bioactivity depended on solution conditions, but not on the size of the fusion partner. CONCLUSION: The established fusion proteins provide excellent tools to evaluate expression patterns and antibacterial effects of HBD2 in human intestinal tissue samples.

Educational and training aspects of new surgical techniques: experience with the endoscopic­laparoscopic interdisciplinary training entity (ELITE) model in training for a natural orifice translumenal endoscopic surgery (NOTES) approach to appendectomy.

BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) is a new surgical concept that requires training before it is introduced into clinical practice. The endoscopic­laparoscopic interdisciplinary training entity (ELITE) is a training model for NOTES interventions. The latest research has concentrated on new materials for organs with realistic optical and haptic characteristics and the possibility of high-frequency dissection. This study aimed to assess both the ELITE model in a surgical training course and the construct validity of a newly developed NOTES appendectomy scenario. METHODS: The 70 attendees of the 2010 Practical Course for Visceral Surgery (Warnemuende, Germany) took part in the study and performed a NOTES appendectomy via a transsigmoidal access. The primary end point was the total time required for the appendectomy, including retrieval of the appendix. Subjective evaluation of the model was performed using a questionnaire. Subgroups were analyzed according to laparoscopic and endoscopic experience. RESULTS: The participants with endoscopic or laparoscopic experience completed the task significantly faster than the inexperienced participants (p = 0.009 and 0.019, respectively). Endoscopic experience was the strongest influencing factor, whereas laparoscopic experience had limited impact on the participants with previous endoscopic experience. As shown by the findings, 87.3% of the participants stated that the ELITE model was suitable for the NOTES training scenario, and 88.7% found the newly developed model anatomically realistic. CONCLUSIONS: This study was able to establish face and construct validity for the ELITE model with a large group of surgeons. The ELITE model seems to be well suited for the training of NOTES as a new surgical technique in an established gastrointestinal surgery skills course.

Is there a weekend effect in emergency surgery for colorectal carcinoma? Analysis from the German StuDoQ registry.

BACKGROUND: Higher postoperative mortality has been observed among patients who received emergency colorectal surgery on the weekend compared to during the week. The aim of this study was to determine whether the weekday of emergency surgery affects the 30-day mortality and postoperative course in emergency colorectal surgery. METHODS: Prospectively acquired data from the 2010-2017 German StuDoQ|Colorectal surgery registries were analysed. Differences in 30-day mortality, transfer and length of stay (MTL30) (primary endpoints), postoperative complications, length of stay and pathological results of resected specimens (secondary endpoints) were assessed. Multivariable analysis was performed to identify independent risk factors for postoperative outcome. RESULTS: In total, 1,174 patients were included in the analysis. Major postoperative complications and the need for reoperation were observed more frequently for emergency colorectal surgery performed during the week compared to the weekend (23.01 vs. 15.28%, p = 0.036 and 17.96% vs. 11.11%, p = 0.040, respectively). In contrast, patients who received emergency surgery on the weekend presented with significantly higher UICC tumour stages (UICC III 44.06 vs. 34.15%, p = 0.020) compared to patients with emergency colorectal surgery on a weekday. Emergency surgery performed during the week was an independent risk factor for the development of severe postoperative complications (OR 1.69 [1.04-2.74], p = 0.033) and need for reoperation (OR 1.79 [1.02-3.05], p = 0.041) in the multivariable analysis. CONCLUSION: Emergency surgery for colorectal carcinoma in Germany is performed with equal postoperative MTL30 and mortality throughout the entire week. However, emergency surgery during the week seems to be associated with a higher rate of severe postoperative complications and reoperation.

Molecular profiles and clinical outcome of stage UICC II colon cancer patients.

PURPOSE: Published multigene classifiers suggesting outcome prediction for patients with stage UICC II colon cancer have not been translated into a clinical application so far. Therefore, we aimed at validating own and published gene expression signatures employing methods which enable their reconstruction in routine diagnostic specimens. METHODS: Immunohistochemistry was applied to 68 stage UICC II colon cancers to determine the protein expression of previously published prognostic classifier genes (CDH17, LAT, CA2, EMR3, and TNFRSF11A). RNA from macrodissected tumor samples from 53 of these 68 patients was profiled on Affymetrix GeneChips (HG-U133 Plus 2.0). Prognostic signatures were generated by "nearest shrunken centroids" with cross-validation. Previously published gene signatures were applied to our data set using "global tests" and leave-one-out cross-validation RESULTS: Correlation of protein expression with clinical outcome failed to separate patients with disease-free follow-up (group DF) and relapse (group R). Although gene expression profiling allowed the identification of differentially expressed genes ("DF" vs. "R"), a stable classification/prognosis signature was not discernable. Furthermore, the application of previously published gene signatures to our data was unable to predict clinical outcome (prediction rate 75.5% and 64.2%; n.s.). T-stage was the only independent prognostic factor for relapse with established clinical and pathological parameters including microsatellite status (multivariate analysis). CONCLUSIONS: Our protein and gene expression analyses do not support application of molecular classifiers for prediction of clinical outcome in current routine diagnostic as a basis for patient-orientated therapy in stage UICC II colon cancer. Further studies are needed to develop prognosis signatures applicable in patient care.

In vivo validation of a therapy planning system for laser-induced thermotherapy (LITT) of liver malignancies.

PURPOSE: In situ ablation is increasingly being used for the treatment of liver malignancies. The application of these techniques is limited by the lack of a precise prediction of the destruction volume. This holds especially true in anatomically difficult situations, such as metastases in the vicinity of larger liver vessels. We developed a three-dimensional (3D) planning system for laser-induced thermotherapy (LITT) of liver tumors. The aim of the study was to validate the system for calculation of the destruction volume. METHODS: LITT (28 W, 20 min) was performed in close contact to major hepatic vessels in six pigs. After explantation of the liver, the coagulation area was documented. The liver and its vascular structures were segmented from a pre-interventional CT scan. Therapy planning was carried out including the cooling effect of adjacent liver vessels. The lesions in vivo and the simulated lesions were compared with a morphometric analysis. RESULTS: The volume of lesions in vivo was 6,568.3 ± 3,245.9 mm(3), which was not different to the simulation result of 6,935.2 ± 2,538.5 mm(3) (P = 0.937). The morphometric analysis showed a sensitivity of the system of 0.896 ± 0.093 (correct prediction of destructed tissue). The specificity was 0.858 ± 0.090 (correct prediction of vital tissue). CONCLUSIONS: A 3D computer planning system for the prediction of thermal lesions in LITT was developed. The calculation of the directional cooling effect of intrahepatic vessels is possible for the first time. The morphometric analysis showed a good correlation under clinical conditions. The pre-therapeutic calculation of the ablation zone might be a valuable tool for procedure planning.

Surveillance colonoscopy in patients with inflammatory bowel disease: comparison of random biopsy vs. targeted biopsy protocols.

BACKGROUND: Endoscopic surveillance in patients with long-standing inflammatory bowel disease (IBD) improves early detection of intraepithelial neoplasia (IEN). We aimed to compare three different endoscopic surveillance strategies in the detection of IEN. METHODS: One hundred fifty surveillance colonoscopies (ulcerative colitis, UC n = 141; Crohn's disease, CD n = 9) were carried out. Random quadrant biopsies were taken (group I, n = 50). Chromoendoscopy with indigo carmine was performed and subsequently quadrant biopsies were collected (group II, n = 50). Patients in group III (n = 50) underwent confocal endomicroscopy (CEM), and CEM-guided as well as random quadrant biopsies were taken (group III, n = 50). The findings of CEM were correlated to conventional histology. Patients with high-grade IEN underwent surgery or strict follow-up by patients' request. RESULTS: In group I (1531 biopsies), no IEN was detected by histology. In group II (1,811 biopsies), chromoendoscopy-guided biopsies revealed high-grade IEN in two patients (4% detection rate). In four patients of group III (1477 biopsies), areas with high-grade IEN were clearly visible by CEM and confirmed by histology (8% detection rate, p < 0.05). Of six patients with high-grade IEN, five patients underwent proctocolectomy. Colorectal cancer was detected in one out of five patients. CONCLUSION: Targeted biopsy protocols guided by either chromoendoscopy or CEM led to higher detection rates of IEN and are thus mandatory for surveillance colonoscopies in patients with long-standing UC. Random biopsy protocols should be replaced by chromoendoscopy-guided protocols.

A novel antiangiogenic approach for adjuvant therapy of pancreatic carcinoma.

INTRODUCTION: Surgical therapy remains the only curative option for pancreatic ductal adenocarcinoma. But even after complete resection, almost all patients suffer from local tumor recurrence. Current standard adjuvant therapy with gemcitabine does not impressively affect the recurrence rate. The aim of this study was to evaluate a novel anti-angiogenic adjuvant treatment strategy by targeting the vascular endothelial growth factor receptor (VEGFR). We assayed the effects of a novel VEGFR inhibitor (ZK261991) on pancreatic carcinoma. ZK261991 is a highly selective and potent VEGFR-kinase inhibitor, which is orally available. METHODS: We used a previously established nude mouse orthotopic pancreatic cancer resection model. Subcutaneous donor tumor fragments (1 mm(3)) derived from human pancreatic cancer cell lines HPAF-2 and AsPC-1 were implanted in the pancreatic tail of 48 nude mice. Fourteen days afterwards, all mice underwent a histologically confirmed curative tumor resection followed by daily adjuvant oral therapy with ZK261991 (50 mg/kg; n = 24) vs. placebo (n = 24). The mice were sacrificed after 12 weeks of therapy or in case of defined endpoints. All sacrificed mice underwent autopsy. A dissemination score (local and systemic tumor spread), size of recurrent tumor mass, survival, and weight loss/gain were surveyed. RESULTS: Kaplan-Meier analysis of survival showed a significant benefit for mice treated with ZK261991 after HPAF-2 tumor resection: 83.8 days (95% CI 73.9-93.6) vs. 60.9 days (95% CI 48.9-73.0), p = 0.006. Adjuvant treatment with ZK261991 of AsPC-1-derived tumors showed a tendency towards a benefit compared to control but no significant difference: 75.8 days (95% CI 59.7-91.9) vs. 65.7 days (95% CI 51.6-79.7). There were no significant differences in dissemination score and size of recurrent tumor mass between the treatment groups. CONCLUSION: Adjuvant anti-angiogenic therapy with the novel VEGFR-inhibitor ZK261991 resulted in a significant survival benefit after curative tumor resection in a clinically relevant orthotopic animal model of pancreatic cancer. Combination of anti-angiogenic treatment with cytotoxic agents may further improve the results of adjuvant therapy.

Safety of anastomoses in colorectal cancer surgery in octogenarians: a prospective cohort study with propensity score matching.

BACKGROUND: Up to 20 per cent of all operations for patients with colorectal cancer (CRC) are performed in octogenarians. Anastomotic leakage is a leading cause of morbidity and death after resection for CRC. The aim of this study was to assess the rate of anastomosis creation, the risk of anastomotic leakage and death in surgery for left-sided CRC in elderly patients. METHODS: This prospective cohort study compared patients less than 80 and 80 or more years with left-sided CRC resection performed between 2013 and 2019. Data were provided from a risk-adjusted surgical quality-assessment system with 219 participating centres in Germany. Outcome measures were the rate of anastomoses, anastomotic leakages, death at 30 days and 2-year overall survival (OS). Propensity score matching was used to control for selection bias and compare subgroups of patients of less than 80 and 80 or more years. RESULTS: Out of 18 959 patients, some 3169 (16.7 per cent) were octogenarians. Octogenarians were less likely to receive anastomoses (82.0 versus 92.9 per cent, P < 0.001; odds ratio 0.50 (95 per cent c.i. 0.44 to 0.58), P < 0.001). The rate of anastomotic leakages did not differ between age groups (8.6 versus 9.7 per cent, P = 0.084), but 30-day mortality rate after leakage was significantly higher in octogenarians (15.8 versus 3.5 per cent, P < 0.001). Overall, anastomotic leakage was the strongest predictor for death (odds ratio 4.95 (95 per cent c.i. 3.66 to 6.66), P < 0.001). In the subgroup with no leakage, octogenarians had a lower 2-year OS rate than younger patients (71 versus 87 per cent, P < 0.001), and in the population with anastomotic leakage, the 2-year OS was 80 per cent in younger and 43 per cent in elderly patients (P < 0.001). After propensity score matching, older age remained predictive for not receiving an anastomosis (odds ratio 0.54 (95 per cent c.i. 0.46 to 0.63), P < 0.001) and for death (odds ratio 2.60 (95 per cent c.i. 1.78 to 3.84), P < 0.001), but not for the occurrence of leakages (odds ratio 0.94 (95 per cent c.i. 0.76 to 1.15), P = 0.524). CONCLUSION: Anastomotic leakage is not more common in octogenarians, but an age of 80 years or older is an independent factor for not receiving an anastomosis in surgery for left-sided CRC. The mortality rate in the case of leakage in octogenarians was reported to exceed 15 per cent.

Capsule endoscopy in small-bowel surveillance of patients with hereditary polyposis syndromes.

PURPOSE: Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS) are hereditary polyposis syndromes with a high risk for benign small-bowel polyps and cancer. The aim of this study was to assess the prevalence of small-bowel polyps beyond the duodenum in patients with FAP and PJS and to examine the clinical value and the optimal interval of capsule endoscopy (CE) for the surveillance of small-bowel polyps in patients with FAP. METHODS: Between 2002 and 2009, standard gastroscopy, duodenoscopy, and CE were performed on 19 consecutive patients with hereditary polyposis syndromes (FAP n=15; PJS n=4). The number, size, and location of polyps detected by CE were assessed. Five FAP patients had repeated CEs in intervals of 2-7 years. RESULTS: In 13 of the 15 (87%) FAP patients, small-bowel polyps were detected by CE ranging from estimated <5 mm to >10 mm in size. Thereof, in four patients, medium-sized (5-10 mm) or large-sized (>10 mm) polyps were seen-all of them located in the proximal jejunum. In three FAP patients with repeated CEs, the latest CE displayed medium- and large-sized polyps in the proximal jejunum, whereas previous CEs had detected only small-sized (<5 mm) polyps. In three of the four PJS patients, large-sized small-bowel polyps were visualized by CE which could then be removed by double-balloon enteroscopy (DBE) or surgical resection. CONCLUSION: CE is an effective and safe method for small-bowel surveillance in FAP and PJS.

Comparison of strictureplasty and endoscopic balloon dilatation for stricturing Crohn's disease--review of the literature.

BACKGROUND: Stricturing Crohn's disease is accompanied by a high-risk for bowel resection and subsequent short bowel syndrome. Strictureplasty (SP) and endoscopic balloon dilatation (EBD) have been developed to prevent, or at least delay, the requirement for resection. The goal of this study was to compare the outcome of these two procedures with regard to complications and disease recurrence. METHODS: We conducted a MEDLINE literature search to give a current overview about the safety and efficacy of EBD and SP. RESULTS: The initial search yielded 744 articles. Case reports, reviews and meta-analyses were excluded. Finally, 63 articles (SP, 40 articles; EBD, 23 articles) were used for the review. None of the studies compared the two methods directly. A total of 2,532 patients (SP, n = 1,958; EBD, n = 574) were included. The incidence of perioperative complications after SP was 11% and the incidence of major complications was 5%. The median surgical recurrence rate was 24% after a median follow-up of 46 months. The median technical success for EBD was 90%. Major complications occurred in 3% of the cases. According to an intention-to-treat protocol, the median surgical recurrence rate was 27.6%. Per-protocol analysis revealed a median surgical recurrence rate of 21.4% after a median follow-up of 21 months. CONCLUSION: Due to the lack of comparable data, there is currently no reliable information on whether one treatment option is superior to the other. Regarding the limited applicability of EBD in strictures of the small bowel, only a controlled trial would provide evidence as a basis for clinical decision making in CD strictures that are potentially treatable by EBD and SP.

Pilot study of bipolar radiofrequency-induced anastomotic thermofusion-exploration of therapy parameters ex vivo.

PURPOSE: Vessel sealing has been well-established in surgical practice in recent years. Bipolar radiofrequency-induced thermofusion (BIRTH) of intestinal tissue might replace traditionally used staples or sutures in the near future. In this experimental study, the influence of compressive pressure, fusion temperature, and duration of heating on the quality of intestinal anastomosis was investigated to obtain the relevant major parameters for the in vivo use of this system. METHODS: An experimental setup for a closed-loop temperature-controlled bipolar radiofrequency-induced thermofusion of porcine intestinal tissue was developed. Twenty-four colon samples were harvested from nine different Saalower-Kräuter pigs and then anastomosed altering compressive pressure on five different levels to explore its influence on anastomotic bursting pressure. RESULTS: The anastomotic bursting strength depends on the compressive pressure applied to the colonic fusion site. An optimal interval of compressive pressure (CP = 1.125 N/mm(2)) in respect of a high amount of burst pressure was detected. A correlation (r = 0.54, p = 0.015) of burst pressure to delta compression indicated that increasing colonic wall thickness probably strengthens the anastomotic fusion. CONCLUSION: This study is a first step to enlighten the major parameters of tissue fusion, though effects and interactions of various main parameters of bipolar radiofrequency-induced thermofusion of colonic tissue remain unclear. Further studies exploring the main effects and interactions of tissue and process parameters to the quality of the fusion site have to follow.

The Effect of Day of the Week on Morbidity and Mortality From Colorectal and Pancreatic Surgery.

BACKGROUND: A number of studies have revealed higher postoperative mortality after operations that were performed toward the end of the week. It is not yet known whether a day-of-the-week effect exists after visceral surgical procedures for cancer in Germany. METHODS: Data on resections of carcinomas of the colon, rectum (2010-2017), and head of the pancreas (2014-2017) (n = 19 703) that had been prospectively acquired by the Study, Documentation, and Quality Center of the German Society for General and Visceral Surgery were analyzed in relation to the day of the week on which the operation was performed. The primary endpoint was postoperative 30-day mortality; the secondary endpoints were complications, length of hospital stay, and MTL30 (a combined outcome criterion that is positive if the patient has died, is still in the hospital, or has been transferred to another acute care hospital 30 days after the index procedure). RESULTS: Resections of colon carcinomas that were performed on Mondays were associated with more advanced tumor stages (T4: 18.4% vs. 15.7%, p <0.001), higher 30-day mortality (3.5% vs. 2.3%, p = 0.004), and a more frequently positive MTL30 (10.5% vs. 8.5%, p = 0.004). Among patients who underwent pancreatic head resections, those whose procedures were on Tuesday had higher mortality (6.2% vs. 3.8%; p = 0.021). Among those who underwent surgery for rectal carcinoma, the day of the week on which the procedure was performed had no effect on postoperative morality. Multivariate analysis revealed that the independent risk factors for postoperative mortality were colonic resection on a Monday (odds ratio [OR]: 1.45; 95% confidence interval [1.11; 1.92], p = 0.008) and pancreatic head resection on a Tuesday (OR: 1.88 [1.18; 2.91], p = 0.006). CONCLUSION: Elective surgery for carcinoma of the colon or pancreatic head is associated with slightly higher mortality if per - formed toward the beginning of the week. On the other hand, the day of the week has no effect on the outcome of surgery for rectal carcinoma.

Combination of p53 expression and p21 loss has an independent prognostic impact on sporadic colorectal cancer.

There is no clear evidence on the prognostic and predictive value of abnormal p53 expression in colorectal cancer. The major downstream protein, p21, a cell cycle inhibitor, is transcriptionally regulated by p53. The prognostic impact of p21 expression in colorectal carcinomas is still under debate. In this study, we investigated the expression of p21 and p53 in a prospective cohort of 116 sporadic colorectal carcinomas at UICCII/III stage. We observed an expression of p21 in 26% and p53 in 63% of the carcinomas by immunohistochemistry. Patients with p21-negative colorectal carcinomas had a significant better recurrence-free and overall survival than patients with p21-positive carcinomas (p=0.02 and p=0.005). Expression of p53 was related to a better overall survival (p=0.048). The combination of p21-negative/p53-positive expression was significantly related to better recurrence-free and overall survival (p=0.007 and p=0.0001) and gained independent prognostic significance (HR: 3.4, p=0.01). Moreover, patients with combined p21-/p53+ expression had a remarkable benefit in overall survival after adjuvant chemotherapy as compared to the p21-/p53- subgroup (HR: 3.6, p=0.027). Our data suggest that the assessment of both p53 and p21 expression may provide prognostic information in colorectal cancer patients. This combination might be helpful to identify patients who could benefit from chemotherapy.

Expression of catalytic proteasome subunits in the gut of patients with Crohn's disease.

BACKGROUND AND PURPOSE: Activation of the transcription factor NF-kappaB by proteasomes and subsequent nuclear translocation of cytoplasmatic complexes play a crucial role in the intestinal inflammation. Proteasomes have a pivotal function in NF-kappaB activation by mediating degradation of inhibitory IkappaB proteins and processing of NF-kappaB precursor proteins. This study aims to analyze the expression of the human proteasome subunits in colonic tissue of patients with Crohn's disease. MATERIALS AND METHODS: Thirteen patients with Crohn's disease and 12 control patients were studied. The expression of immunoproteasomes and constitutive proteasomes was examined by Western blot analysis, immunoflourescence and quantitative real-time PCR. For real-time PCR, AK2C was used as housekeeping gene. RESULTS: The results indicate the influence of the intestinal inflammation on the expression of the proteasomes in Crohn's disease. Proteasomes from inflamed intestine of patients with Crohn's disease showed significantly increased expression of immunosubunits on both protein and mRNA levels. Especially, the replacement of the constitutive proteasome subunit beta1 by inducible immunosubunit beta1i was observed in patients with active Crohn's disease. In contrast, relatively low abundance of immunoproteasomes was found in control tissue. CONCLUSIONS: Our data demonstrate that in contrast to normal colonic tissue, the expression of immunoproteasomes was evidently increased in the inflamed colonic mucosa of patients with Crohn's disease. Thus, the chronic intestinal inflammation process in Crohn's disease leads to significant alterations of proteasome subsets.

Influence of change in surgical practice for benign thyroid disease on postsurgical outcome-Single-center experience in 1400 patients.

PURPOSE: To evaluate the rate of surgical complications during the change from subtotal resection to hemithyroidectomy or thyroidectomy over a period of 17 years. METHODS: All operations for benign goiter at our hospital were analyzed for the periods 1996-2002 (Group 1) and 2003-2012 (Group 2). The groups were compared for recurrent laryngeal nerve damage, hypocalcemia, and other surgical complications directly postoperatively. RESULTS: In total, 1462 patients were operated on for goiter between 1996 and 2012. There were 1219 patients who underwent a primary thyroid operation, whereas 50 patients had surgery for recurrence. Postoperative histology revealed thyroid cancer in 193 patients (13.2%). In Group 1, 42.7% of all operated lobes were performed as lobectomies and 57.3% as subtotal resections; in Group 2, 74.4% were performed as lobectomies and 25.6% as subtotal resections. No differences were found for reduced vocal cord function (2.4% vs. 1.9%, p = 0.746) and recurrent laryngeal nerve paralysis in the postoperative laryngoscopy (2.9% vs. 1.8%, p = 0.675). Postoperative hypoparathyroidism was detected in 13.66% in Group 1 and in 19.80% in Group 2 after bilateral resections (p = 0.037). There was no difference in the rate of reoperations for cancer between both groups (43.4% vs. 52.1%, p = 0.182). CONCLUSION: Surgical practice changed from subtotal to lobectomies for benign goiter over a period of 17 years without change in laryngeal nerve damage but with increasing rates of postoperative hypocalcemia.

Genome-wide expression patterns of invasion front, inner tumor mass and surrounding normal epithelium of colorectal tumors.

Colorectal tumors have characteristic genome-wide expression patterns that allow their distinction from normal colon epithelia and facilitate clinical prognosis. The expression heterogeneity within a primary colorectal tumor has not been studied on a genome scale yet. Here we investigated three compartments of colorectal tumors, the invasion front, the inner tumor mass, and surrounding normal epithelial tissue by microdissection and microarray-based expression profiling. In both tumor compartments many genes were differentially expressed when compared to normal epithelium. The sets of significantly deregulated genes in both compartments overlapped to a large extent and revealed various interesting known and novel pathways that could have contributed to tumorigenesis. Cells from the invasion front and inner tumor mass, however, did not show significant differences in their expression profile, neither on the single gene level nor on the pathway level. Instead, gene expression differences between individuals are more pronounced as all patient-matched tumor samples clustered in close proximity to each other. With respect to invasion front and inner tumor mass we conclude that the specific tumor cell micro-environment does not have a strong influence on expression patterns: largely similar genome-wide expression programs operate in the invasion front and interior compartment of a colorectal tumor.

A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer.

BACKGROUND: Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. RESULTS: We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes) are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. CONCLUSION: An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin) also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.