Radiogenomic Analysis of F-18-Fluorodeoxyglucose Positron Emission Tomography and Gene Expression Data Elucidates the Epidemiological Complexity of Colorectal Cancer Landscape.

PURPOSE: Transcriptomic profiling has enabled the neater genomic characterization of several cancers, among them colorectal cancer (CRC), through the derivation of genes with enhanced causal role and informative gene sets. However, the identification of small-sized gene signatures, which can serve as potential biomarkers in CRC, remains challenging, mainly due to the great genetic heterogeneity of the disease. METHODS: We developed and exploited an analytical framework for the integrative analysis of CRC datasets, encompassing transcriptomic data and positron emission tomography (PET) measurements. Profiling data comprised two microarray datasets, pertaining biopsy specimen from 30 untreated patients with primary CRC, coupled by their F-18-Fluorodeoxyglucose (FDG) PET values, using tracer kinetic analysis measurements. The computational framework incorporates algorithms for semantic processing, multivariate analysis, data mining and dimensionality reduction. RESULTS: Transcriptomic and PET data feature sets, were evaluated for their discrimination performance between primary colorectal adenocarcinomas and adjacent normal mucosa. A composite signature was derived, pertaining 12 features: 7 genes and 5 PET variables. This compact signature manifests superior performance in classification accuracy, through the integration of gene expression and PET data. CONCLUSIONS: This work represents an effort for the integrative, multilayered, signature-oriented analysis of CRC, in the context of radio-genomics, inferring a composite signature with promising results for patient stratification.

[Diverticular disease - timing of surgery in demand]. / Divertikelkrankheit - Wann ist der Chirurg gefragt?

In preparation for operations of patients with diverticular disease an adequate medical indication has to be performed. The new classification of sigmoid diverticulitis corresponding to the German guidelines for diverticular disease classification (GGDDC) enables an appropriate strategy for evaluating the indications and selection of the time for surgery. New is, that the uncomplicated form of diverticulitis indicates an operation in exceptional case only. Furthermore the frequency of diverticulitis-exacerbation does not influence the indication for surgery any more.

Dynamic PET with (18)F-Deoxyglucose (FDG) and quantitative assessment with a two-tissue compartment model reflect the activity of glucose transporters and hexokinases in patients with colorectal tumors.

Dynamic PET (dPET) with (18)F-Deoxyglucose (FDG) provides quantitative information about distribution of the tracer in a predefined volume over time. A two-tissue compartment model can be used to obtain quantitative data regarding transport of FDG into and out of the cells, phosphorylation and dephosphorylation rate of intracellular FDG, and fractional blood volume in the target volume, also named vessel density. Aim of the study was the correlation of glucose transporters expression and hexokinases with the corresponding compartment parameters.Patients with colorectal tumors were examined with dynamic PET prior to surgery. Afterwards, tumor samples were obtained during surgery and gene expression was assessed using gene arrays. The dynamic PET data were evaluated to quantify the parameters of a two tissue compartment model for colorectal tumors using a Volume-of-Interest (VOI) technique. A multiple correlation/regression analysis was performed using glucose transporters as independent variables and k1 as the dependent variable. A correlation of r=0.7503 (p=0.03) was obtained for the transporters SLC2A1, SLC2A2, SLC2A4, SLC2A8, SLC2A9, SLC2A10 and k1. The correlation of r=0.7503 refers to an explained variance of data of 56.30 %, therefore more than 50 % of data changes are associated with the gene expression. An analysis of the hexokinases HK1-HK3 and k3 revealed a correlation coefficient of r=0.6093 (p=0.04), which is associated with an explained variance of 37.12 %. Therefore, parameters k1 and k3 reflect gene activity. The results demonstrate that k1 and k3 of the two-tissue compartment model are correlated with glucose transporters and hexokinases.

Diversion stoma after colorectal surgery: loop colostomy or ileostomy?

BACKGROUND: The total rate as well as the clinical outcome of anastomotic leakage in colorectal and coloanal anastomosis necessitates a loop stoma for fecal diversion. The aim of this study was to determine the outcome of loop transverse colostomy compared to loop ileostomy as a temporary defunctioning stoma following colorectal surgery with colorectal or coloanal anastomosis. METHODS: Data of 200 patients between January 2003 and January 2009 were analyzed in this two-center study to determine the surgical outcome in patients with loop colostomy (n = 100) in comparison to loop ileostomy (n = 100) for fecal diversion including outcome of stoma creation and complication rates during stoma reversal. RESULTS: During stoma placement, dermatitis and renal insufficiency occurred significantly more often in the loop ileostomy group than in the loop transverse colostomy group (15% vs. 0%; p < 0.001 and 10% vs. 1%; p = 0.005). During stoma reversal, wound infection occurred significantly more often in the loop transverse colostomy group than in the loop ileostomy group (27% vs. 8%; p < 0.001). Time to first defecation was significantly shorter in the loop ileostomy group after both placement and reversal (4 ± 2 vs. 2 ± 1; p < 0.001 and 3 ± 2 vs. 2 ± 1; p < 0.001). Hospital stay was significantly shorter in the loop ileostomy group than in the loop transverse colostomy group after stoma closure (18 ± 15 vs. 13 ± 6; p < 0.001). CONCLUSIONS: Both methods provide a good operative outcome with low complication rates. We do recommend the loop ileostomy in all patients in which dehydration is not to be expected since wound infection rate is lower and hospital stay is shorter during stoma reversal.

Impact of cell-proliferation-associated gene expression on 2-deoxy-2-[(18)f]fluoro-D-glucose (FDG) kinetics as measured by dynamic positron emission tomography (dPET) in colorectal tumors.

INTRODUCTION: Glucose transporters and hexokinases determine the kinetics of 2-deoxy-2-[(18)F]fluoro-D: -glucose (FDG). However, the genes controlling these proteins are not independent and may be modulated from other biological processes, e.g., like angiogenesis and proliferation. The impact of cell-proliferation-related genes on the FDG kinetics was assessed in colorectal tumors in this study. METHODS: Patients with primary colorectal tumors (n = 25) were examined with positron emission tomography and FDG within 2 days prior to surgery. Tissue specimens were obtained from the colorectal tumor and the normal colon by surgery and gene expression was assessed using gene arrays. RESULTS: Overall, an increase of the expression of proliferation associated genes was observed by a factor of 2-5.3 for the colorectal tumors as compared with the normal colon. Correlation analysis revealed an impact of cdk2 on K1, thus directing to a modulation of the FDG uptake into the cells. The correlations were generally higher for the FDG influx as compared with the standardized uptake value (SUV). The influx was mainly correlated with proliferation inhibiting genes (cyclin G2, cdk inhibitor 1 C, cdk inhibitor 2B). It was possible to predict the expression of cyclin D2 using a multiple linear regression function and the parameters of the FDG kinetics with r = 0.67. Using a group based analysis it was possible to demonstrate, that tumors with an SUV >12 are associated with a high expression of cyclin D2 in the colorectal tumors. If the gene expression data for cyclin D1, cyclin G2, cdk2, cdk6 and cdk inhibtor 2B were used, the overall FDG uptake as measured by the SUV could be predicted with r = 0.75. CONCLUSIONS: The results suggest that the FDG kinetics is modulated by proliferation associated genes. Especially K1, the parameter for the FDG transport into the cells, is modulated by cdk2. Tumors with a SUV exceeding 12 have usually a higher expression of cyclin D2. The parameters of the FDG kinetics can be used to predict the expression of proliferation associated genes individually.

Haemorrhoids are related to changes of cell function in mucosa and submucosa.

PURPOSE: Epidemiology and risk factors of haemorrhoidal disease are not well defined. This study tried to evaluate if the appearance of haemorrhoids is related to a disturbed remodelling of the soft tissue of rectal mucosa and submucosa. Therefore, immunohistochemical expression profiles of five parameters as potential mediators in neoangiogenesis (EGFR), in inflammatory cell activity (COX-2), and in cell migration, differentiation, and wound healing (notch-3, c-myc, and beta-Catenin) were analysed (Saed et al., Fertil Steril 83(Suppl 1):1216-1219, 1; Saed et al., Fertil Steril 79:1404-1408, 2; Stojadinovic et al., Am J Pathol 167:59-69, 3). METHODS: Haemorrhoidal tissue specimens were collected from 44 patients. Healthy rectal mucosa was obtained from 16 non-fixed fresh cadavers and served as control. Histological and immunohistochemical markers like EGFR, COX-2, notch-3, c-myc, and beta-Catenin were analysed semi-quantitatively, separately for mucosal and submucosal layer. RESULTS: Significantly increased expressions were found for EGFR, COX-2, and notch-3 in the mucosal and submucosal layer of haemorrhoidal tissue in comparison to normal rectal tissue. CONCLUSIONS: This finding confirms that haemorrhoidal disease may be regarded as a manifestation of a soft tissue disease.

Impact of angiogenesis-related gene expression on the tracer kinetics of 18F-FDG in colorectal tumors.

UNLABELLED: 18F-FDG kinetics are primarily dependent on the expression of genes associated with glucose transporters and hexokinases but may be modulated by other genes. The dependency of 18F-FDG kinetics on angiogenesis-related gene expression was evaluated in this study. METHODS: Patients with primary colorectal tumors (n = 25) were examined with PET and 18F-FDG within 2 days before surgery. Tissue specimens were obtained from the tumor and the normal colon during surgery, and gene expression was assessed using gene arrays. RESULTS: Overall, 23 angiogenesis-related genes were identified with a tumor-to-normal ratio exceeding 1.50. Analysis revealed a significant correlation between k1 and vascular endothelial growth factor (VEGF-A, r = 0.51) and between fractal dimension and angiopoietin-2 (r = 0.48). k3 was negatively correlated with VEGF-B (r = -0.46), and a positive correlation was noted for angiopoietin-like 4 gene (r = 0.42). A multiple linear regression analysis was used for the PET parameters to predict the gene expression, and a correlation coefficient of r = 0.75 was obtained for VEGF-A and of r = 0.76 for the angiopoietin-2 expression. Thus, on the basis of these multiple correlation coefficients, angiogenesis-related gene expression contributes to about 50% of the variance of the 18F-FDG kinetic data. The global 18F-FDG uptake, as measured by the standardized uptake value and influx, was not significantly correlated with angiogenesis-associated genes. CONCLUSION: 18F-FDG kinetics are modulated by angiogenesis-related genes. The transport rate for 18F-FDG (k1) is higher in tumors with a higher expression of VEGF-A and angiopoietin-2. The regression functions for the PET parameters provide the possibility to predict the gene expression of VEGF-A and angiopoietin-2.

Fecal incontinence after radical perineal prostatectomy: a prospective study.

OBJECTIVES: To assess, in a prospective study, the incidence of fecal incontinence after radical perineal prostatectomy. METHODS: Bowel symptoms were evaluated with questionnaires mailed to 132 patients preoperatively and 6 months postoperatively, and annually thereafter. All patients had undergone extrafascial perineal prostatectomy for Stage cT1-cT3N0M0 prostate cancer. The data of 116 patients (88%), who answered at least the preoperative and 12-month questionnaires, were analyzed. Reduced sensibility, reduced discrimination, urgency, or stool smearing were symptoms indicative of fecal incontinence. Patients with one symptom of fecal incontinence were evaluated further with a structured telephone interview. RESULTS: Daily stool smearing was reported preoperatively by 4% of the patients. Two symptoms related to fecal incontinence were present preoperatively in 6% of the patients. At 12 months postoperatively, 15 patients (13%) reported at least two symptoms of fecal incontinence. The structured telephone interview revealed that 6 of these 15 patients had symptoms of fecal incontinence that were related to the perineal prostatectomy; 9 patients had newly developed symptoms not related to surgery or symptoms due to tumor recurrence or radiotherapy. Patients with the presence of at least one symptom of fecal incontinence before surgery had an almost fourfold increased risk of developing at least two symptoms of fecal incontinence postoperatively compared with patients without any symptom of fecal incontinence. CONCLUSIONS: Significant fecal incontinence after radical extrafascial perineal prostatectomy is a rare event. The results of questionnaires should be supplemented by additional interviews to obviate wrong interpretations.

Anal sphincter injury during vaginal delivery--an argument for cesarean section on request?

AIMS: Fear of damage to the pelvic floor from vaginal delivery and long-term sequelae (urinary and anal incontinence) sometimes being cited as an indication for cesarean section on request. The aim of the present study was to compare the effects of vaginal delivery versus elective cesarean section on anal sphincter function. MATERIAL AND METHODS: We studied 71 consecutive women six weeks before delivery, 52 of them 4-6 weeks after delivery, and all patients with occult sphincter lesions 3 months after delivery. A bowel function questionnaire was completed, and anal endosonography, manometry, and measurement of the pudendal-nerve terminal motor latency were performed. RESULTS: Forty-two (80.8 percent) patients were delivered vaginally, ten (19.2 percent) by elective cesarean section at term. Clinically recognized anal sphincter injuries occurred in 9.5 percent (4) of patients, two of them developed incontinence for gas. The overall incidence of anal incontinence after vaginal delivery was 4.8 percent. Occult sphincter defects were identified endosonographically in 19 percent (8) of women, there was no reported case of any anal incontinence 3 months after delivery. No woman delivered by cesarean section had altered anal continence or any significant change in anal pressures, rectal sensibility, and PNTML. CONCLUSION: Severe sphincter tear is the single most important factor leading to anal incontinence in women, whereas occult sphincter defects are rarely associated with short-term sequelae, but may predispose to the development of anal incontinence later on in life. Elective cesarean section should be recommended for women at increased risk for anal incontinence.

Morphological and functional adaptation of the small intestine after colectomy and ileal pouch-anal anastomosis in rats.

BACKGROUND AND AIMS: This study investigated morphological and functional changes in the small bowel after colectomy and ileal pouch-anal anastomosis (IPAA). METHODS AND MATERIALS: In 15 rats electrolyte, glucose, and water absorption was determined by in vivo single-pass perfusion of the proximal and distal small intestine 15 weeks after IPAA. Afterwards the small intestine was resected for morphometric evaluation. Controls were 15 identically treated rats without operation. RESULTS: IPAA led to a significant increase in the small intestinal diameter and a significant increase in villus length and density, which was more apparent in ileum than in jejunum. Therefore the mucosal surface per unit serosa increased significantly by 59% in the jejunum and by 76% in the ileum. In the pouch there was a significant increase in goblet cell density, crypt depth, and diameter of the muscularis which was not detectable in the segments proximal from the pouch. Due to the increase in mucosal surface there was a significant increase in total glucose and electrolyte and sorption in the ileum while absorption rates per unit mucosa were unchanged, with the exception of an increase in mucosal sodium absorption. Jejunal absorption and ileal absorption of water remained unchanged. CONCLUSION: Adaptation of the small intestine after IPAA leads to colonic metaplasia in the pouch and intestinal hyperplasia proximal from the pouch. The loss of colonic absorption is compensated by the increase in ileal mucosal surface with subsequently elevated electrolyte and glucose absorption. Changes in intestinal permeability may be responsible for additional water depletion, which is compensated by the upregulation of enteric water and sodium absorption.