Is surgical quality more important than radicality? Long-term outcomes of stage I-III colon cancer (SAKK 40/00).

BACKGROUND: To prospectively determine the influence of variations of surgical radicality and surgical quality on long-term outcome in patients with stage I-III colon cancer. METHODS: From a prospective multicenter cohort study including 1040 patients undergoing surgery for colorectal cancer from 09/2001 to 06/2005 in nine Swiss and one German hospital, 423 patients with stage I-III colon cancer were selected and analyzed. Surgeons and pathologists filled in standardized forms prospectively assessing items of oncosurgical radicality and quality. Patients had standardized follow-up according to national guidelines. RESULTS: Follow-up was median 6.2 years (range 0.3-10.4) showing a 5-year disease-free survival/overall survival of 83 %/87 % in stage I (n = 85), 69 %/77 % in stage II (n = 187), and 53 %/61 % in stage III (n = 151) colon cancer. Despite remarkable variations of oncosurgical radicality and quality, the multivariate model revealed that mainly quality items correlated significantly with disease-free survival (surgical tumor lesion HR 2.12, p = 0.036, perioperative blood transfusion HR 1.67, p = 0.018, emergency resection HR 1.74, p = 0.035) and overall survival (early venous ligation HR 0.66, p = 0.023, surgical tumor lesion HR 2.28, p = 0.027, perioperative blood transfusion HR1.79, p = 0.010, emergency resection HR 1.88, p = 0.026), while radicality parameters (length of specimen, distance of the tumor to nearest bowel resection site, number of lymph nodes, height of resected mesocolon and of central vascular dissection) did not. CONCLUSION: Surgical quality seems to have a stronger impact on oncologic long-term outcome in stage I - III colon cancer than surgical radicality.

Abdominoplasty in a Patient With Type 3 von Willebrand Disease: A Case Report.

ABSTRACT: von Willebrand disease (vWD) is an inherited bleeding disorder that is characterized by a quantitative or qualitative deficiency of the von Willebrand factor (vWF). Type 3 is the most severe form of vWD with a near-complete absence of vWF and a significantly increased risk of excessive bleeding and hematoma during a surgical procedure. To date, no data on surgical and hemostatic management of a type 3 vWD patient undergoing body-contouring surgery has been published. We report the case of a 47-year-old woman with type 3 vWD requiring medically indicated abdominoplasty after massive weight loss due to bariatric surgery. The case was successfully managed with individualized bodyweight-adapted substitution of recombinant vWF vonicog alfa and tranexamic acid under close monitoring of vWF and factor VIII activity. For further risk stratification, we propose the multidisciplinary treatment of patients with severe vWF undergoing elective plastic surgery in specialized centers providing around-the-clock laboratory testing and access to a blood bank. In addition, strict hemostasis during surgery and early postoperative mobilization with fitted compression garments are recommended to further reduce the risk of bleeding and thromboembolic complications.

Acute and long-term exercise adaptation of adipose tissue and skeletal muscle in humans: a matched transcriptomics approach after 8-week training-intervention.

BACKGROUND: Exercise exerts many health benefits by directly inducing molecular alterations in physically utilized skeletal muscle. Molecular adaptations of subcutaneous adipose tissue (SCAT) might also contribute to the prevention of metabolic diseases. AIM: To characterize the response of human SCAT based on changes in transcripts and mitochondrial respiration to acute and repeated bouts of exercise in comparison to skeletal muscle. METHODS: Sedentary participants (27 ± 4 yrs) with overweight or obesity underwent 8-week supervised endurance exercise 3×1h/week at 80% VO2peak. Before, 60 min after the first and last exercise bout and 5 days post intervention, biopsies were taken for transcriptomic analyses and high-resolution respirometry (n = 14, 8 female/6 male). RESULTS: In SCAT, we found 37 acutely regulated transcripts (FC > 1.2, FDR < 10%) after the first exercise bout compared to 394, respectively, in skeletal muscle. Regulation of only 5 transcripts overlapped between tissues highlighting their differential response. Upstream and enrichment analyses revealed reduced transcripts of lipid uptake, storage and lipogenesis directly after exercise in SCAT and point to ß-adrenergic regulation as potential major driver. The data also suggest an exercise-induced modulation of the circadian clock in SCAT. Neither term was associated with transcriptomic changes in skeletal muscle. No evidence for beigeing/browning was found in SCAT along with unchanged respiration. CONCLUSIONS: Adipose tissue responds completely distinct from adaptations of skeletal muscle to exercise. The acute and repeated reduction in transcripts of lipid storage and lipogenesis, interconnected with a modulated circadian rhythm, can counteract metabolic syndrome progression toward diabetes.

E40 glutenase detoxification capabilities of residual gluten immunogenic peptides in in vitro gastrointestinal digesta of food matrices made of soft and durum wheat.

Gluten degrading enzymes, which are commonly referred to as "glutenases," represent attractive candidates for the development of a pharmacological treatment of gluten related disorders, such as coeliac disease (CeD). Endoprotease-40 (E40), a novel glutenase secreted by the actinomycete Actinoallomurus A8 and recombinantly produced in S. lividans TK24, was shown to be active at pH 3 to 6 (optimum pH 5), resistant to pepsin and trypsin degradation, able to destroy immunotoxicity of both gliadin 33-mer peptide and whole proteins and to strongly reduce the response of specific T cells when added to gliadin in in vitro gastrointestinal digestion. This study aims to functionally assess the capabilities of Endoprotease-40 (E40) to detoxify residual gluten immunogenic peptides in gastrointestinal digesta of food matrices made of soft and durum wheat. The INFOGEST harmonized protocols were applied to the multicompartmental model of simulated human gastrointestinal digestion, for the quantitative assessment of residual gluten in liquid (beer) and solid (bread and pasta) foods, made of either soft or durum wheat. Proteomic and immunological techniques, and functional assays on intestinal T cell lines from celiac disease patients were used to identify gluten-derived immunogenic peptide sequences surviving in gastric and gastrointestinal digesta after the addition of E40 at increasing enzyme: wheat proteins ratios. During the gastric phase (2 h incubation time), the addition of E40 demonstrated an extensive (≥ 95%) dose-dependent detoxification of whole gluten in real food matrices. Overall, the residual gluten content was found at, or even below, the 20 ppm gluten-free threshold for soft and durum wheat-based food. Furthermore, unlike in untreated gastrointestinal digesta, none of the immunodominant α-gliadin peptides survived in E40-treated digesta. Traces of ω- and γ-gliadin derived immunogenic peptides were still detected in E40-treated digesta, but unable to stimulate celiac-intestinal T cells. In conclusion, E40 is a promising candidate for the oral enzymatic therapy of CeD, as a stand-alone enzyme being efficient along the complete gastrointestinal digestion of gluten.

Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.

The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

Saliva Samples as A Tool to Study the Effect of Meal Timing on Metabolic And Inflammatory Biomarkers.

: Meal timing affects metabolic regulation in humans. Most studies use blood samples for their investigations. Saliva, although easily available and non-invasive, seems to be rarely used for chrononutritional studies. In this pilot study, we tested if saliva samples could be used to study the effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until 13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated saliva samples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones and inflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports in blood and showing significant correlations with blood levels. The rhythm patterns were similar for both diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolic and inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for the non-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies.

Shotgun Lipidomics Discovered Diurnal Regulation of Lipid Metabolism Linked to Insulin Sensitivity in Nondiabetic Men.

CONTEXT: Meal timing affects metabolic homeostasis and body weight, but how composition and timing of meals affect plasma lipidomics in humans is not well studied. OBJECTIVE: We used high throughput shotgun plasma lipidomics to investigate effects of timing of carbohydrate and fat intake on lipid metabolism and its relation to glycemic control. DESIGN: 29 nondiabetic men consumed (1) a high-carb test meal (MTT-HC) at 09.00 and a high-fat meal (MTT-HF) at 15.40; or (2) MTT-HF at 09.00 and MTT-HC at 15.40. Blood was sampled before and 180 minutes after completion of each MTT. Subcutaneous adipose tissue (SAT) was collected after overnight fast and both MTTs. Prior to each investigation day, participants consumed a 4-week isocaloric diet of the same composition: (1) high-carb meals until 13.30 and high-fat meals between 16.30 and 22:00 or (2) the inverse order. RESULTS: 12 hour daily lipid patterns showed a complex regulation by both the time of day (67.8%) and meal composition (55.4%). A third of lipids showed a diurnal variation in postprandial responses to the same meal with mostly higher responses in the morning than in the afternoon. Triacylglycerols containing shorter and more saturated fatty acids were enriched in the morning. SAT transcripts involved in fatty acid synthesis and desaturation showed no diurnal variation. Diurnal changes of 7 lipid classes were negatively associated with insulin sensitivity, but not with glucose and insulin response or insulin secretion. CONCLUSIONS: This study identified postprandial plasma lipid profiles as being strongly affected by meal timing and associated with insulin sensitivity.

Meal Timing, Aging, and Metabolic Health.

A growing body of evidence suggests that meal timing is an important factor for metabolic regulation and that the circadian clock tightly interacts with metabolic functions. The proper functioning of the circadian clock is critical for maintaining metabolic health. Therefore, chrononutrition, a novel discipline which investigates the relation between circadian rhythms, nutrition, and metabolism, has attracted increasing attention in recent years. Circadian rhythms are strongly affected by obesity, type 2 diabetes, and other dietary-induced metabolic diseases. With increasing age, the circadian system also undergoes significant changes which contribute to the dysregulation of metabolic rhythms. Metabolic diseases are a major health concern, particularly in light of a growing aging population, and effective approaches for their prevention and treatment are urgently needed. Recently, animal studies have impressively shown beneficial effects of several dietary patterns (e.g., caloric restriction or time-restricted feeding) on circadian rhythms and metabolic outcomes upon nutritional challenges. Whether these dietary patterns show the same beneficial effects in humans is, however, less well studied. As indicated by recent studies, dietary approaches might represent a promising, attractive, and easy-to-adapt strategy for the prevention and therapy of circadian and metabolic disturbances in humans of different age.

Diurnal distribution of carbohydrates and fat affects substrate oxidation and adipokine secretion in humans.

Background: A diet in which fat is mainly eaten in the morning and carbohydrates mainly in the evening (compared with the reverse order) was recently shown to worsen glycemic control in people with prediabetes. Objective: We investigated the effects of these dietary patterns on energy metabolism, and on the daily profiles of circulating lipids, adipokines, and inflammatory markers. Design: In a randomized controlled crossover trial, 29 nonobese men (with normal glucose tolerance, n = 18; or impaired fasting glucose/glucose tolerance, n = 11) underwent 2 isocaloric 4-wk diets: 1) carbohydrate-rich meals until 1330 and fat-rich meals between 1630 and 2200 (HC/HF); or 2) the inverse sequence of meals (HF/HC). During a 12-h clinical investigation day after each intervention period, 2 meal tolerance tests were performed, at 0900 and 1540, respectively. Substrate oxidation and concentrations of circulating lipids, adipokines, and cytokines were assessed pre- and postprandially. The postprandial inflammatory response in leukocytes was analyzed ex vivo. Results: Fasting carbohydrate oxidation decreased (P = 0.004) and lipid oxidation increased (P = 0.012) after the HC/HF diet. Fasting concentrations of blood markers did not differ between diets. The diets modulated the daily profiles of carbohydrate oxidation, lipid oxidation, and ß-hydroxybutyrate, although the average daily values of these parameters showed no difference between the diets, and no interaction between diet and glucose tolerance status. Diurnal patterns of triglycerides, low-density lipoprotein cholesterol, leptin, visfatin, and of LPS-induced cytokine secretion in blood leukocytes were also modulated by the diets. Average daily concentrations of leptin (P = 0.017) and visfatin (P = 0.041) were lower on the HF/HC diet than on the HC/HF diet. Conclusions: Diurnal distribution of carbohydrates and fat affects the daily profiles of substrate oxidation, circulating lipids, and cytokine secretion, and alters the average daily concentrations of adipokine secretion in nonobese nondiabetic humans. The study was registered at clinicaltrials.gov as NCT02487576.

The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial.

Diurnal carbohydrate and fat distribution modulates glycaemic control in rodents. In humans, the optimal timing of both macronutrients and its effects on glycaemic control after prolonged consumption are not studied in detail. In this cross-over trial, 29 non-obese men were randomized to two four-week diets: (1) carbohydrate-rich meals until 13.30 and fat-rich meals between 16.30 and 22.00 (HC/HF) versus (2) inverse sequence of meals (HF/HC). After each trial period two meal tolerance tests were performed, at 09.00 and 15.40, respectively, according to the previous intervention. On the HF/HC diet, whole-day glucose level was increased by 7.9% (p = 0.026) in subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT, n = 11), and GLP-1 by 10.2% (p = 0.041) in normal glucose-tolerant subjects (NGT, n = 18). Diet effects on fasting GLP-1 (p = 0.009) and PYY (p = 0.034) levels were observed in IFG/IGT, but not in NGT. Afternoon decline of glucose tolerance was more pronounced in IFG/IGT and associated with a stronger decrease of postprandial GLP-1 and PYY levels, but not with changes of cortisol rhythm. In conclusion, the HF/HC diet shows an unfavourable effect on glycaemic control in IFG/IGT, but not in NGT subjects. Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism.

Prospective multicenter registration study of colorectal cancer: significant variations in radicality and oncosurgical quality-Swiss Group for Clinical Cancer Research Protocol SAKK 40/00.

PURPOSE: This study aimed to investigate in a multicenter cohort study the radicality of colorectal cancer resections, to assess the oncosurgical quality of colorectal specimens, and to compare the performance between centers. METHODS: One German and nine Swiss hospitals agreed to prospectively register all patients with primary colorectal cancer resected between September 2001 and June 2005. The median number of eligible patients with one primary tumor included per center was 95 (range 12-204). RESULTS: The following variations of median values or percentages between centers were found: length of bowel specimen 20-39 cm (25.8 cm), maximum height of mesocolon 6.5-12.5 cm (9.0 cm), number of examined lymph nodes 9-24 (16), distance to nearer bowel resection margin in colon cancer 4.8-12 cm (7 cm), and in rectal cancer 2-3 cm (2.5 cm), central ligation of major artery 40-97 % (71 %), blood loss 200-500 ml (300 ml), need for perioperative blood transfusion 5-40 % (19 %), tumor opened during mobilization 0-11 % (5 %), T4-tumors not en-bloc resected 0-33 % (4 %), inadvertent perforation of mesocolon/mesorectum 0-8 % (4 %), no-touch isolation technique 36-86 % (67 %), abdominoperineal resection for rectal cancer 0-30 % (17 %), rectal cancer specimen with circumferential margin ≤1 mm 0-19 % (10 %), in-hospital mortality 0-6 % (2 %), anastomotic leak or intra-abdominal abscess 0-17 % (7 %), re-operation 0-17 % (8 %). CONCLUSION: In colorectal cancer, surgery considerable variations between different centers were found with regard to radicality and oncosurgical quality, suggesting a potential for targeted improvement of surgical technique.

Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice.

BACKGROUND: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. OBJECTIVES: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. METHODS: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-µg silicon/g feed), silicon-replete in feed (+Si-feed; 100-µg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-µg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). RESULTS: The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. CONCLUSIONS: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model.

Changes of Dietary Fat and Carbohydrate Content Alter Central and Peripheral Clock in Humans.

CONTEXT: The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE: We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN: Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS: The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS: Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.

Diagnostic accuracy of magnetic resonance imaging: a prospective evaluation of patients with suspected appendicitis (diamond).

PURPOSE: To show the effect of standard magnetic resonance imaging (MRI) in patients with suspected appendicitis on negative laparotomy and perforation rate. Moreover, the economic impact on hospital resources was evaluated. MATERIALS AND METHODS: In all, 52 patients (21 female; mean age 44.7 years) were prospectively included in this Institutional Review Board (IRB)-approved study. Abdominal MRI including coronal inversion recovery, axial T2-weighted, and contrast-enhanced axial T1-weighted sequences was performed. MRI results were compared to final clinical outcome determined by follow-up or histopathology. Change of treatment was evaluated according to the final clinical outcome. Economic impact was evaluated by comparing the costs of MRI to the savings due to a change in treatment after MRI. Negative laparotomy and perforation rate as well as sensitivity and specificity were derived. RESULTS: Negative laparotomy and perforation rate were 0% (0/52) and 8% (1/13). Sensitivity and specificity for detecting acute appendicitis were 85% (11/13) and 97% (38/39). In 40% of patients therapy changed due to the MRI. The overall effect on the use of hospital resources was a net saving of €2,335. CONCLUSION: Abdominal MRI in the evaluation of patients with suspected appendicitis and equivocal clinical findings is safe, reliable, and cost-effective. It should be considered an important alternative to computed tomography.

Surgeon-performed sonographic findings in a traumatic trans-anal rectal perforation.

Early diagnosis and active management of trans-anal rectal injuries is essential for a favorable outcome. Intraperitoneal free air (IFA) is usually diagnosed by an erect Chest X-ray. Point-of-care ultrasound has been recently used to detect IFA. We report a 45-year-old male who presented to the Emergency Department with lower abdominal peritonitis. Surgeon-performed portable point-of-care ultrasound as an extension of the abdominal examination revealed an inflamed omentum with hypoechoic stranding, thickened non compressible small bowel, and free fluid in the pelvis. A transverse abdominal section of the right upper quadrant showed free intraperitoneal air. Rectal examination revealed a longitudinal rectal tear. Laparotomy has confirmed the sonographic findings. There was a 12 cm intraperitoneal tear of the anterior wall of the rectum which was necrotic. This case clearly demonstrates that portable point-of-care ultrasound gives very useful detailed information even when performed by a non radiologist. Surgeons should be encouraged to use point-of-care ultrasound after appropriate training.