Publications by authors named "Gabriel Seifert"

41 Publications

Obesity Surgery–Weight Loss, Metabolic Changes, Oncological Effects, and Follow-up.

Dtsch Arztebl Int 2022 02 4(Forthcoming). Epub 2022 Feb 4.

Background: In 2017, the prevalence of obesity (BMI ≥ 30 kg/m2) in Germany was approximately 16%. Obesity increases an individual's risk of developing type 2 diabetes (T2DM) and arterial hypertension; it also increases overall mortality. Consequently, effective treatment is a necessity. Approximately 20 000 bariatric operations are performed in Germany each year.

Methods: This review is based on pertinent publications retrieved by a selective search in the PubMed and Cochrane databases and on current German clinical practice guidelines.

Results: The types of obesity surgery most commonly performed in Germany, Roux-en-Y gastric bypass and sleeve gastrectomy, lead to an excess weight loss of 27-69% ≥ 10 years after the procedure. In obese patients with T2DM, the diabetes remission rate ≥ 10 years after these procedures ranges from 25% to 62%. Adjusted regression analyses of data from large registries have shown that the incidence of malignancies is 33% lower in persons who have undergone obesity surgery compared to control subjects with obesity (unadjusted incidence 5.6 versus 9.0 cases per 1000 person-years). The operation can cause vitamin deficiency, surgical complications, gastroesophageal reflux, and dumping syndrome. Therefore, lifelong follow-up is necessary.

Conclusion: In view of an increasing number of patients undergoing bariatric surgery, it will probably not be feasible in the future for lifelong follow-up to be provided exclusively in specialized centers.
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http://dx.doi.org/10.3238/arztebl.m2021.0359DOI Listing
February 2022

Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice.

Arterioscler Thromb Vasc Biol 2021 10 5;41(10):2563-2574. Epub 2021 Aug 5.

Department of Cardiology, Medical University of Graz, Austria (N.A.M., H.B., A.Z.).

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNF[alpha], MIP (macrophage inflammatory protein)-1[alpha], MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.
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http://dx.doi.org/10.1161/ATVBAHA.121.316677DOI Listing
October 2021

Leg Volume in Patients with Lipoedema following Bariatric Surgery.

Visc Med 2021 Jun 22;37(3):206-211. Epub 2020 Oct 22.

European Center for Lymphology Black Forest Germany, Specialist Clinic for Lymphology, Hinterzarten, Germany.

Introduction: Lipoedema is characterized as subcutaneous lipohypertrophy in association with soft-tissue pain affecting female patients. Recently, the disease has undergone a paradigm shift departing from historic reiterations of defining lipoedema in terms of classic edema paired with the notion of weight loss-resistant leg volume towards an evidence-based, patient-centered approach. Although lipoedema is strongly associated with obesity, the effect of bariatric surgery on thigh volume and weight loss has not been explored.

Material And Methods: In a retrospective cohort study, thigh volume and weight loss of 31 patients with lipoedema were analyzed before and 10-18 and ≥19 months after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Fourteen patients, with distal leg lymphoedema (i.e., with healthy thighs), who had undergone bariatric surgery served as controls. Statistical analysis was performed using a linear mixed-effects model adjusted for patient age and initial BMI.

Results: Adjusted initial thigh volume in patients with lipoedema was 23,785.4 mL (95% confidence interval [CI] 22,316.6-25,254.1). Thigh volumes decreased significantly in lipoedema and control patients (baseline vs. 1st follow-up, < 0.0001 and = 0.0001; baseline vs. 2nd follow-up, < 0.0001 and = 0.0013). Adjusted thigh volume reduction amounted to 33.4 and 37.0% in the lipoedema and control groups at the 1st follow-up, and 30.4 and 34.7% at the 2nd follow-up, respectively (lipoedema vs. control > 0.999 for both). SG and RYGB led to an equal reduction in leg volume (operation type × time, = 0.83). Volume reduction was equally effective in obese and superobese patients (weight category × time, = 0.43).

Conclusion: SG and RYGB lead to a significant thigh volume reduction in patients with lipoedema.
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http://dx.doi.org/10.1159/000511044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237786PMC
June 2021

Auto-aggressive CXCR6 CD8 T cells cause liver immune pathology in NASH.

Nature 2021 04 24;592(7854):444-449. Epub 2021 Mar 24.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer. The accumulation of metabolites leads to cell stress and inflammation in the liver, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.
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http://dx.doi.org/10.1038/s41586-021-03233-8DOI Listing
April 2021

Banded Versus Nonbanded Sleeve Gastrectomy: A Randomized Controlled Trial With 3 Years of Follow-up.

Ann Surg 2020 11;272(5):690-695

Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Objective: The aim of this study was to compare silicone-banded sleeve gastrectomy (BSG) to nonbanded sleeve gastrectomy (SG) regarding weight loss, obesity-related comorbidities, and complications.

Summary Background Data: As a primary bariatric procedure, SG leads to excellent weight loss, yet weight regain is a relevant issue in mid- to long-term follow-up. Retrospective analyses suggest that banding a sleeve using a silicone ring may decrease weight regain and improve weight loss.

Methods: The banded versus nonbanded sleeve gastrectomy single-center, randomized controlled trial was conducted from January 2015 to August 2019. The primary endpoint was defined as excess weight loss 3 years after surgery. Secondary endpoints included the surgery's impact on obesity-related comorbidities, quality of life, and complications. The study was registered under DRKS00007729.

Results: Among 94 patients randomized, 97% completed 3-year follow-up. Mean initial body mass index was 50.9 kg/m [95% confidence interval (CI), 49.6-52.2]. Mean adjusted excess weight loss 3 years after SG amounted to 62.3% (95% CI, 56.2-68.5) and 73.9% ( 95% CI, 67.8-80.0) after BSG (difference 11.6%, P = 0.0073). Remission of type 2 diabetes occurred in 66.7% (4/6) after SG and in 91.0% (10/11) following BSG (P = 0.21). Three years after surgery, ring implantation correlated with decreased frequency of symptomatic reflux episodes (P = 0.01) but increased frequency of regurgitation (P = 0.03). The rate of major complications was not different between the study groups (BSG, n = 3; SG, n = 2; P = 0.63). Quality of life was better following BSG (P = 0.001).

Conclusions: BSG provided better weight loss than nonbanded SG 3 years after surgery. Regurgitation was the main clinically relevant negative effect after BSG.
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http://dx.doi.org/10.1097/SLA.0000000000004174DOI Listing
November 2020

Reply to the letter to the editor: to band or not to band: is that the question… or the answer for sleeve gastrectomy?

Surg Obes Relat Dis 2019 09 20;15(9):1644-1645. Epub 2019 Jul 20.

Centre for Surgery, Department of General and Visceral Surgery, Centre for Obesity and Metabolic Surgery, Medical Centre, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1016/j.soard.2019.07.011DOI Listing
September 2019

Putting the Hindgut Hypothesis to the Test in a Diabetic Zucker Rat Model.

Obes Surg 2019 12;29(12):4000-4007

Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.

Background: The hindgut theory hypothesizes a key role of differential hindgut stimulation following metabolic procedures in ameliorating diabetes mellitus. We used two strategies to remove the hindgut from intestinal continuity in order to analyze its impact on diabetes mellitus.

Methods: Loop duodeno-jejunostomy (DJOS) with exclusion of one-third of total intestinal length was performed in 3 groups of 9-week-old Zucker diabetic fatty rats. In group 1, no further alteration of the intestinal tract was made. Group 2 received additional ileal exclusion (IE). Group 3 underwent additional resection of 50% of the ileum with side-to-side ileocecal anastomosis (IR). One, 2, and 4 months after surgery, fasting blood glucose levels, oral glucose tolerance tests (OGTT), and glucose-stimulated hormone analyses were conducted, and bile acid blood levels were compared. Body weight was documented weekly.

Results: In relation to DJOS, glucose control was not impaired in IR or IE. On the contrary, only IR could maintain preOP glucose values until 4 months. There were no significant weight differences between the groups. Confirming effective ileal diversion, bile acid blood levels were significantly higher in the DJOS group compared with both IR and IE (p = 0.0025 and p = 0.0047). Operative interventions had no impact on GLP-1 levels at any time point (ANOVA p > 0.05 for all). Insulin secretion was preserved in all groups.

Conclusion: This data supports the hypothesis that the mechanisms driving amelioration of diabetes mellitus are complex and cannot be reduced to the ileum.
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http://dx.doi.org/10.1007/s11695-019-04079-wDOI Listing
December 2019

Banded versus nonbanded sleeve gastrectomy: 5-year results of a matched-pair analysis.

Surg Obes Relat Dis 2019 08 24;15(8):1233-1238. Epub 2019 May 24.

Centre for Surgery, Department of General and Visceral Surgery, Centre for Obesity and Metabolic Surgery, Medical Centre, University of Freiburg, Freiburg, Germany.

Background: Laparoscopic sleeve gastrectomy (SG) achieves excellent weight loss, yet recent reports indicate weight regain in a substantial number of patients.

Objectives: Inserting a nonadjustable gastric band may improve weight loss after SG.

Setting: University Hospital, Germany.

Methods: In a retrospective matched-pair analysis 51 patients who underwent banded SG (BSG) using a silicone ring between November 2010 and May 2017 were compared with patients who underwent conventional SG regarding weight loss, complications, and co-morbidity. Median follow-up was 5 years.

Results: Total weight loss was equal in the early follow-up (P = .118 and P = .111) but significantly better in BSG 3 and 5 years after surgery (BSG versus SG at 3 yr 38.7% ± 7.8, n = 33 versus 31.9 ± 10.7, n = 33, P = .002; BSG versus SG at 5 yr 37.6% ± 8.5, n = 27 versus 29.5 ± 12.9, n = 23, P = .008). Ring placement had no significant impact on clinical reflux signs (Fisher's exact test P > .999), yet 37 % of BSG patients reported ≥1 regurgitation per week (Fisher's exact test P = .013, odds ratio 12.4).

Conclusion: BSG leads to better weight loss than nonbanded SG 5 years after surgery. This comes at the expense of a higher rate of regurgitation. At a time in which weight loss limitations of a stand-alone SG are becoming a clinical problem, banding the sleeve may be a strategy to improve weight loss with this procedure.
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http://dx.doi.org/10.1016/j.soard.2019.05.023DOI Listing
August 2019

Recurring Anastomotic Leak-A Prospective Clinicopathological Investigation of a Distinct Disease Pattern.

J Surg Res 2019 Jul 6;239:201-207. Epub 2019 Mar 6.

Department of General and Visceral Surgery, Medical Center - University of Freiburg, Center for Surgery, Freiburg, Germany.

Background: Intestinal anastomotic insufficiency (AI) is a common problem in visceral surgery associated with overexpression of matrix metalloproteinases (MMPs). In some patients it occurs more than once. The etiology of recurring anastomotic insufficiency (RAI) is not understood yet and should be addressed as an independent disease entity.

Materials And Methods: Thirty nine consecutive patients with AI were treated at our university center and were included in this prospective study. Clinical data were evaluated by correlative statistical analysis to identify independent risk factors for RAI. Patients were divided in two groups: 18 patients had a single operative revision until restoration (group SAI), and 21 patients had two or more revisions (group RAI). Anastomotic tissue samples as well as untouched bowel wall were collected during reoperations for analysis of MMPs and tissue inhibitor of metalloproteinases (TIMP2). Clinical data were correlated with pathological observations.

Results: Significant differences of clinical and molecular pathological data were found between the two groups. Transfusion of red blood cells until the first reoperation and alcohol abuse led to RAI and were the only independent risk factors for RAI in multivariate analysis. Overexpression of MMP-8, -9, and -13 in anastomotic tissue correlated with the administration of red blood cells during initial operation. Reduced expression of TIMP2 was frequent in nearly all patients without differences throughout the subgroups.

Conclusions: RAI seems to have an independent disease pattern. Transfusion of blood products is not only a known risk factor for AI but seems to significantly disturb the anastomotic healing process leading to RAI.
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http://dx.doi.org/10.1016/j.jss.2019.02.013DOI Listing
July 2019

Bio-absorbable sealants for reinforcing the pancreatic stump after distal pancreatectomy are critical.

J Hepatobiliary Pancreat Sci 2019 Mar 10;26(3):96-103. Epub 2019 Feb 10.

Department of Surgery, Faculty of Medicine, Clinic for Generalund Visceral Surgery, University of Freiburg Medical Center, Hugstetter Straße 55, D-79106 Freiburg, Germany.

Background: Bio-absorbable sealants are widely used to reduce the rate and severity of postoperative pancreatic fistulas after distal pancreatectomy. However, numerous clinical trials have failed to demonstrate their clinical benefit. We therefore investigated stability and bio-compatibility of absorbable sealants in vitro and in vivo.

Methods: In vitro, polymerized compounds were incubated in pancreatic juice before their stability was tested. In vivo, two compounds were used to seal the pancreatic stump after distal pancreatectomy in nine pigs. Burst pressure of the pancreatic stump, surgical outcome, histology of the pancreatic stump, systemic inflammation, and drain fluid was examined.

Results: Products based on fibrin or collagen were unstable in the presence of active pancreatic enzymes and completely dissolved within 2 h. Sealants using chemical cross-linking of proteins showed improved stability for 7 days. In vivo, application of polyethylenglycol-based sealant leads to complete closure of the pancreatic duct after 5 days, while a glutaraldehyde-based sealant prevented physiological closure of the pancreatic main duct.

Conclusions: Many compounds used clinically to reinforce the pancreatic stump after distal pancreatectomy are inadequate due to instability in the presence of pancreatic enzymes. While selected bio-absorbable sealants inhibited the natural healing of the pancreatic stump, polyethylenglycol-based sealants should be tested in further clinical trials.
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http://dx.doi.org/10.1002/jhbp.604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593819PMC
March 2019

The effect of pasireotide on intestinal anastomotic healing with and without whole-body irradiation in a rat model.

Int J Colorectal Dis 2019 Feb 27;34(2):337-345. Epub 2018 Nov 27.

Department of General and Visceral Surgery, Medical Centre - University of Freiburg, Faculty of Medicine, University Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.

Objective: To examine pasireotide's effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation.

Material And Methods: Forty-five male Wistar rats received an ileoileal end-to-end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined.

Results: Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R-SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R-SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups.

Conclusion: Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect.
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http://dx.doi.org/10.1007/s00384-018-3193-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331742PMC
February 2019

Left Gastric Artery Embolization for Weight Loss-a Dead-End Procedure.

Obes Surg 2018 11;28(11):3623-3624

Center for Surgery, Department of General and Visceral Surgery, Center for Bariatric and Metabolic Surgery, Medical Center - University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

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http://dx.doi.org/10.1007/s11695-018-3427-1DOI Listing
November 2018

Duodenal Exclusion but Not Sleeve Gastrectomy Preserves Insulin Secretion, Making It the More Effective Metabolic Procedure.

Obes Surg 2018 05;28(5):1408-1416

Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.

Introduction: There is an ongoing debate on which procedure provides the best treatment for type 2 diabetes. Furthermore, the pathomechanisms of diabetes improvement of partly anatomically differing operations is not fully understood.

Methods: A loop duodenojejunostomy (DJOS) with exclusion of one third of intestinal length, a sleeve gastrectomy (SG), or a combination of DJOS + SG was performed in 8-week-old male ZDF rats. One, three, and six months after surgery, an oral glucose tolerance test and measurements of GLP-1, GIP, insulin, and bile acids were conducted.

Results: After an initial (4 weeks) equal glucose control, DJOS and DJOS + SG showed significantly lower glucose levels than SG 3 and 6 months after surgery. There was sharp decline of insulin levels in SG animals over time, whereas insulin levels in DJOS and DJOS + SG were preserved. GIP levels were significantly larger in both groups containing a sleeve at all three time points, whereas GLP-1 was equal in all groups at all time. Bile acid levels were significantly higher in the DJOS compared to the SG group at all time points. Interestingly, the additional SG in the DJOS + SG group led to lower bile acid levels 1 and 6 months postoperatively.

Conclusion: The effect of SG on glucose control was transient, whereas a duodenal exclusion was the more effective procedure in this model due to a sustained pancreatic function with a preserved insulin secretion.
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http://dx.doi.org/10.1007/s11695-017-3045-3DOI Listing
May 2018

Antidepressants Rescue Stress-Induced Disruption of Synaptic Plasticity via Serotonin Transporter-Independent Inhibition of L-Type Calcium Channels.

Biol Psychiatry 2018 07 19;84(1):55-64. Epub 2017 Oct 19.

Department of Biomedicine, University of Basel, Basel, Switzerland.

Background: Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear.

Methods: We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca) channels in heterologous expression systems were used to determine the modulation of Ca channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and in the absence of SERT.

Results: SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca channels and was independent of SERT. Furthermore, SSRIs protected both wild-type and SERT knockout mice from behavioral despair induced by chronic stress. Finally, long-term depression was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment.

Conclusions: These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca channels and synaptic plasticity independent of SERT. Thus, L-type Ca channels might constitute an important signaling hub for stress response and for pathophysiology and treatment of depression.
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http://dx.doi.org/10.1016/j.biopsych.2017.10.008DOI Listing
July 2018

Author Correction: Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations.

Sci Rep 2017 10 27;7(1):14631. Epub 2017 Oct 27.

Center for Surgery, Department of General and Visceral Surgery, Medical Center University of Freiburg, Freiburg, Germany.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-017-14870-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666001PMC
October 2017

Murine genotype impacts pancreatitis severity and systemic inflammation: An experimental study.

Ann Med Surg (Lond) 2017 Dec 28;24:8-14. Epub 2017 Sep 28.

Department of General and Visceral Surgery, Medical Center - University of Freiburg, Freiburg, Germany.

Background: Little is known regarding the impact of host response in acute pancreatitis. Here, we induce murine necrotizing pancreatitis in 9 different mouse strains.

Materials And Methods: We examined 9 different mouse strains: Balb/CB4J, C3H/HEJ, NOD/SHILT, A/J, AKR/J, C57BI/6J, DBA/2J, FVB/NJ, 129S1/SvlmJ. 10 animals per strain were randomly allotted to two groups. Sterile necrotizing pancreatitis was induced by injection of taurocholate into the common bile duct. Control animals were injected with saline. Every 6 h, clinical parameters were examined and scored. After 24 h, animals were sacrificed to examine and compare serum enzymes, histology, bronchoalveolar lavage fluid, and serum IL-6.

Results: Histologically, taurocholate treated animals scored significantly higher than control animals. Concordantly, serum lipase and amylase were significantly elevated in pancreatitis animals in all strains. NOD/SHILT and AKR/J mice had the highest enzyme activity. 24 h after induction, there were no signs of increased pulmonary vascular leak in taurocholate animals. Remarkably, interleukin 6 was not increased at all in C57BL/6J, C3H/HeJ, and 129S1/SvlmJ mice compared to all other strains.

Conclusion: The genetic strain has an impact on pancreatitis severity and systemic inflammatory response in a murine taurocholate induction model. Analogous differences in humans may partially account for the disparity in post-ERCP pancreatitis.
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http://dx.doi.org/10.1016/j.amsu.2017.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645008PMC
December 2017

Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations.

Sci Rep 2017 07 3;7(1):4510. Epub 2017 Jul 3.

Center for Surgery, Department of General and Visceral Surgery, Medical Center University of Freiburg, Freiburg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation. We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p < 0.001). Patients with >3 CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3–3 CTC/ml (P = 0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRAS G12V mutation in their CTC (n = 14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P = 0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 “tumor-CTC-pairs” (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P = 0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology.
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http://dx.doi.org/10.1038/s41598-017-04601-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495768PMC
July 2017

Survival outcome and prognostic factors after pancreatoduodenectomy for distal bile duct carcinoma: a retrospective multicenter study.

Langenbecks Arch Surg 2017 Aug 13;402(5):831-840. Epub 2017 Jun 13.

Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.

Purpose: Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma.

Methods: Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival.

Results: N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51-19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13-12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25-14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12-14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29-3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13-2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13-2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21-5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04-2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis.

Conclusion: Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.
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http://dx.doi.org/10.1007/s00423-017-1590-9DOI Listing
August 2017

Common Channel Length in Bypass Surgery Does Not Impact T2DM in Diabetic Zucker Rats.

Obes Surg 2017 08;27(8):2090-2098

Department of General and Visceral Surgery, Albert-Ludwigs-University, Hugstetter Straße 55, 79106, Freiburg, Germany.

Introduction: Metabolic surgery is known to impact glucose tolerance but the exact mechanism is still unclear. Based on recently-published data, especially the role of the hindgut may require redefinition.

Methods: Either a loop duodeno-jejunostomy (DJOS) with exclusion of one third of total intestinal length, a loop duodeno-ileostomy (DiOS, exclusion of two thirds), or SHAM operation was performed in 9-week-old Zucker diabetic fatty rats. One, 3, and 6 months after surgery, an oral glucose tolerance test (OGTT) and glucose-stimulated hormone analyses were conducted. Body weight was documented weekly.

Results: DJOS and DiOS animals showed significantly better glucose control in all OGTTs than the SHAM group (two-way ANOVA p < 0.0001). Body weight developed largely parallel in both intervention groups; SHAM animals had gained significantly less weight after 6 months (Mann-Whitney DJOS/DiOS vs. SHAM p < 0.05, DJOS vs. DiOS p > 0.05). Operative interventions had no impact on GLP-1 and GIP levels at any time point (Mann-Whitney p > 0.05 for all). DJOS/DiOS operations could preserve insulin production up to 6 months, while there was already a sharp decline of insulin levels in the SHAM group (Mann-Whitney: DJOS/DiOS vs. SHAM p < 0.05 for all time points). Additionally, insulin sensitivity was improved significantly 1 month postoperative in both intervention groups compared to SHAM (Mann-Whitney DJOS/DiOS vs. SHAM p < 0.05).

Conclusion: The data of the current study demonstrate a sharp amelioration of glucose control after duodenal exclusion with unchanged levels of GLP-1 and GIP. Direct or delayed hindgut stimulation had no impact on glucose control in our model.
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http://dx.doi.org/10.1007/s11695-017-2611-zDOI Listing
August 2017

Banding the Sleeve Improves Weight Loss in Midterm Follow-up.

Obes Surg 2017 04;27(4):1098-1103

Department of General, Visceral and Transplant Surgery, Centre for Metabolic Surgery, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

Introduction: Laparoscopic sleeve gastrectomy (LSG) can achieve excellent weight loss, yet sleeve dilatation with concomitant weight regain proves to be a relevant issue. Hence, additional restriction might improve results after LSG.

Methods: In a retrospective matched-pair analysis, 42 patients who underwent banded LSG (BLSG) using a MiniMizer® ring between January 2012 and October 2014 were analysed regarding weight loss, complications and comorbidity. Median follow-up was 3 years. Forty-two patients who had undergone conventional LSG were selected as matched pairs.

Results: Mean preoperative BMI was 54.93 ± 7.42 kg/m for BLSG and 53.46 ± 6.69 kg/m for LSG (Mann-Whitney P = 0.540). Total weight loss (%TWL) was significantly greater in the BLSG group 3 years after surgery (BLSG 38.22% ± 7.26; n = 26 vs. LSG 32.69 ± 9.47; n = 26; P = 0.0154). Ring placement had no relevant impact on new-onset reflux (Fisher's exact test P = 1.0) but a tendency towards reflux improvement when reflux pre-existed (odds ratio 1.96). The major side effect of ring implantation was regurgitation with over 44% of patients presenting with regurgitation >1 per week (Fisher's exact test P = 0.0019, odds ratio 18.07).

Conclusion: BLSG is a safe procedure showing similar comorbidity to conventional LSG. However, BLSG leads to a higher rate of postoperative regurgitation. Weight loss is significantly improved 3 years after surgery. Hence, additional ring implantation might be an option for increased restriction in LSG surgery.
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http://dx.doi.org/10.1007/s11695-017-2610-0DOI Listing
April 2017

Inducing a humoral immune response to pancreatic cancer antigen.

Cell Immunol 2016 12 6;310:150-155. Epub 2016 Sep 6.

Department of General and Visceral Surgery, Universitätsklinik Freiburg, Freiburg, Germany.

Background: Patients with pancreatic carcinoma have a grim prognosis. Here, we examine the induction of an in vitro antibody response of human B cells to pancreatic carcinoma antigens.

Material And Methods: Cells of five cultured pancreatic ductal adenocarcinoma lines were lysed and their plasma membrane fragments isolated in an aqueous two-phase-system. The plasma membrane fragments were then added to cultures of isolated peripheral blood mononuclear cells from healthy volunteers for 14 days to act as a tumor antigen. Also, we added combinations of IL-2, IL-4, IL-21, anti-CD40 mAb and varying protein concentrations of the plasma membrane fragments to these cultures. We then tested characteristics and binding of resulting IgG and IgM against aforementioned tumor plasma membrane fragments and their respective cells using ELISAs.

Results: The combination of IL-2, IL-4 and anti-CD40 mAb elicited IgM production showing significant binding (p<0.05) to plasma membrane fragments. PANC-1 antigen and the combination of IL-4, IL-21 and anti-CD40 mAb was able to produce a significant and specific IgG formation against PANC-1 plasma membrane fragments (p<0.05). Tumor antigen, interleukins and anti-CD40 mAb had a significant impact on the binding capacity of these antibodies (p<0.05). IgG binding pancreatic carcinoma cells was observed when the tumor antigen concentration was increased during stimulation (p<0.05). BxPC3 plasma membrane fragments showed inhibitory effects on IgG binding BxPC3 antigens (p<0.05).

Conclusions: A human anti-tumor antibody formation can be induced in vitro using PANC-1 antigens and B cell stimulating agents. This response has the potential to generate antibodies specific to PANC-1 antigens. PRéCIS: The concept presented is novel and a promising approach to eliciting a specific B cell response to tumor antigen. The method may prove useful in understanding and developing anti-tumor immunity.
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http://dx.doi.org/10.1016/j.cellimm.2016.09.002DOI Listing
December 2016

Validation of undergraduate medical student script concordance test (SCT) scores on the clinical assessment of the acute abdomen.

BMC Surg 2016 Aug 17;16(1):57. Epub 2016 Aug 17.

Center for Medical Biometry and Medical Informatics, University of Freiburg, Stefan-Meier-Str. 26, 79104, Freiburg, Germany.

Background: Health professionals often manage medical problems in critical situations under time pressure and on the basis of vague information. In recent years, dual process theory has provided a framework of cognitive processes to assist students in developing clinical reasoning skills critical especially in surgery due to the high workload and the elevated stress levels. However, clinical reasoning skills can be observed only indirectly and the corresponding constructs are difficult to measure in order to assess student performance. The script concordance test has been established in this field. A number of studies suggest that the test delivers a valid assessment of clinical reasoning. However, different scoring methods have been suggested. They reflect different interpretations of the underlying construct. In this work we want to shed light on the theoretical framework of script theory and give an idea of script concordance testing. We constructed a script concordance test in the clinical context of "acute abdomen" and compared previously proposed scores with regard to their validity.

Methods: A test comprising 52 items in 18 clinical scenarios was developed, revised along the guidelines and administered to 56 4(th) and 5(th) year medical students at the end of a blended-learning seminar. We scored the answers using five different scoring methods (distance (2×), aggregate (2×), single best answer) and compared the scoring keys, the resulting final scores and Cronbach's α after normalization of the raw scores.

Results: All scores except the single best answers calculation achieved acceptable reliability scores (>= 0.75), as measured by Cronbach's α. Students were clearly distinguishable from the experts, whose results were set to a mean of 80 and SD of 5 by the normalization process. With the two aggregate scoring methods, the students' means values were between 62.5 (AGGPEN) and 63.9 (AGG) equivalent to about three expert SD below the experts' mean value (Cronbach's α : 0.76 (AGGPEN) and 0.75 (AGG)). With the two distance scoring methods the students' mean was between 62.8 (DMODE) and 66.8 (DMEAN) equivalent to about two expert SD below the experts' mean value (Cronbach's α: 0.77 (DMODE) and 0.79 (DMEAN)). In this study the single best answer (SBA) scoring key yielded the worst psychometric results (Cronbach's α: 0.68).

Conclusion: Assuming the psychometric properties of the script concordance test scores are valid, then clinical reasoning skills can be measured reliably with different scoring keys in the SCT presented here. Psychometrically, the distance methods seem to be superior, wherein inherent statistical properties of the scales might play a significant role. For methodological reasons, the aggregate methods can also be used. Despite the limitations and complexity of the underlying scoring process and the calculation of reliability, we advocate for SCT because it allows a new perspective on the measurement and teaching of cognitive skills.
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http://dx.doi.org/10.1186/s12893-016-0173-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989333PMC
August 2016

Mesopancreatic Stromal Clearance Defines Curative Resection of Pancreatic Head Cancer and Can Be Predicted Preoperatively by Radiologic Parameters: A Retrospective Study.

Medicine (Baltimore) 2016 Jan;95(3):e2529

From the Clinic for Surgery, UKSH Campus Lübeck, Lübeck (UFW, HL, LB, DB, TK); Clinic for Radiology (TK, ML); Institute of Pathology (AC, ST, MW, PB); Clinic for General and Visceral Surgery, University Medical Center Freiburg (BK, JH, SK, GS, FM, UTH); Institute for Molecular Medicine and Cell Research, University of Freiburg, Freiburg (OS); Department of Surgery, University Hospital Hamburg-Eppendorf (UKE), Hamburg (YKV); Institute of Medical Biometry and Informatics (IMBI), University of Heidelberg, Heidelberg (TB); Comprehensive Cancer Center Freiburg, Freiburg (ML, FM, UTH, MW, PB); and German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany (OS, MW, PB).

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong fibrotic stromal reaction and diffuse growth pattern. Peritumoral fibrosis is often evident during surgery but only distinguishable from tumor by microscopic examination. The aim of this study was to investigate the role of clearance of fibrotic stromal reaction at the mesopancreatic resection margin as a criterion for radical resection and preoperative assessment of resectability.Mesopancreatic stromal clearance status (S-status) was defined as the presence or absence (S+/S0) of fibrotic stromal reaction at the mesopancreatic resection margin. Detailed retrospective clinicopathologic re-evaluation of margin status and preoperative cross-sectional imaging was performed in a cohort of 91 patients operated for pancreatic head PDAC from 2001 to 2011.Conventional margin positive resection (R+, tumor cells directly at the margin) was found in 36%. However, S-status further divided the margin negative (R0) group into patients with median survival of 14 months versus 31 months (S+ versus S0, P = 0.005). Overall rate of S+ was 53%. S-status and lymph node ratio constituted the only independent predictors of survival. Stranding of the superior mesenteric artery fat sheath was the only independent radiologic predictor of S+ resection, and achieved a 71% correct prediction of S-status.Mesopancreatic stromal clearance is a major determinant of curative resection in PDAC, and preoperative prediction by cross-sectional imaging is possible, setting the basis for a new definition of borderline resectability.
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http://dx.doi.org/10.1097/MD.0000000000002529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998270PMC
January 2016

The degree of local inflammatory response after colonic resection depends on the surgical approach: an observational study in 61 patients.

BMC Surg 2015 Oct 6;15:108. Epub 2015 Oct 6.

Department of General and Visceral Surgery, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany.

Background: Clinical data indicate that laparoscopic surgery reduces postoperative inflammatory response and benefits patient recovery. Little is known about the mechanisms involved in reduced systemic and local inflammation and the contribution of reduced trauma to the abdominal wall and the parietal peritoneum.

Methods: Included were 61 patients, who underwent elective colorectal resection without intraabdominal complications; 17 received a completely laparoscopic, 13 a laparoscopically- assisted procedure and 31 open surgery. Local inflammatory response was quantified by measurement of intraperitoneal leukocytes and IL-6 levels during the first 4 days after surgery.

Results: There was no statistical difference between the groups in systemic inflammatory parameters and intraperitoneal leukocytes. Intraperitoneal interleukin-6 was significantly lower in the laparoscopic group than in the laparoscopically-assisted and open group on postoperative day 1 (26.16 versus 43.25 versus 40.83 ng/ml; p = 0.001). No difference between the groups was recorded on POD 2-4. Intraperitoneal interleukin-6 showed a correlation with duration of hospital stay on POD 1 (0.233, p = 0.036), but not on POD 2-4. Patients who developed a surgical wound infection showed higher levels of intraperitoneal interleukin-6 on postoperative day 2-4 (POD 2: 42.56 versus 30.02 ng/ml, p = 0.03), POD 3: 36.52 versus 23.62 ng/ml, p = 0.06 and POD 4: 34.43 versus 19.99 ng/ml, p = 0.046). Extraabdominal infections had no impact.

Conclusion: The analysis shows an attenuated intraperitoneal inflammatory response on POD 1 in completely laparoscopically-operated patients, associated with a quicker recovery. This effect cannot be observed in patients, who underwent a laparoscopically-assisted or open procedure. Factors inflicting additional trauma to the abdominal wall and parietal peritoneum promote the intraperitoneal inflammation process.
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http://dx.doi.org/10.1186/s12893-015-0097-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596306PMC
October 2015

Organ-specific monocyte activation in necrotizing pancreatitis in mice.

J Surg Res 2015 Aug 31;197(2):374-81. Epub 2015 Mar 31.

Department of General and Visceral Surgery, Universitätsklinik Freiburg, Freiburg, Germany. Electronic address:

Background: Acute necrotizing pancreatitis (NAP) induces a systemic inflammatory response syndrome. We investigated the underlying changes of monocytes using different activation markers.

Materials And Methods: A retrograde injection of 2 mL/kg bodyweight of sodium taurocholate into the common bile duct of BALB/c mice induced NAP, whereas sham-operated animals (SOP) were treated with saline. After 6, 12, 24, and 48 h, histologic alterations, pancreatic enzymes, and interleukin 6 in serum, albumin, and myeloperoxidase (MPO) in bronchoalveolar lavage fluid were examined. Isolation of mononuclear cells from the blood, spleen, and liver and the subsequent determination of macrophages (F4/80) and their activation marker CD121b and MHCII (1Ad) were performed by fluorescence-activated cell sorting (FACS analyses).

Results: After pancreatitis induction, pancreatic enzymes (amylase: SOP 7008 U/L, NAP 37,044 U/L, P < 0.001) and histologic pancreatic damage (SOP 0.80 ± 1.92, NAP 19.6 ± 0.64, P < 0.001) developed instantly. Pulmonary vascular damage and MPO were detected between 6 and 12 h after onset (6 h albumin SOP 132.0 ± 12.0 μg/mL, NAP 267.2 ± 49.6 μg/mL; P < 0.05; MPO SOP 0.23 ± 0.20 ng/mL, NAP 11.29 ± 3.12 ng/mL, P < 0.01). Blood levels of interleukin 6 increased after 12-24 h (12 h SOP 584 ± 300 pg/mL; NAP 2169 ± 942 pg/mL, P < 0.05), whereas monocytes increased fourfold within 48 h (P < 0.05). Furthermore, pancreatitis increased the percentage of activated monocytes in the blood (6 h and/or 48 h: MHCII (1Ad) 2196%/5.65%; CD121b 51,654%/82,146%). Similar observations were made for monocytes from the liver and spleen.

Conclusions: Although inflammatory mediators increased during 24 h after pancreatitis induction, monocyte activation lasted for at least 48 h. The latter is not limited to blood but also detected in isolated liver and spleen monocytes.
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http://dx.doi.org/10.1016/j.jss.2015.03.075DOI Listing
August 2015

Retrospective analyses of trends in pancreatic surgery: indications, operative techniques, and postoperative outcome of 1,120 pancreatic resections.

World J Surg Oncol 2015 Mar 12;13:102. Epub 2015 Mar 12.

Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.

Background: Hospital volume, surgeons' experience, and adequate management of complications are factors that contribute to a better outcome after pancreatic resections. The aim of our study was to analyze trends in indications, surgical techniques, and postoperative outcome in more than 1,100 pancreatic resections.

Methods: One thousand one hundred twenty pancreatic resections were performed since 1994. The vast majority of operations were performed by three surgeons. Perioperative data were documented in a pancreatic database. For the purpose of our analysis, the study period was sub-classified into three periods (A 1994 to 2001/n = 363; B 2001 to 2006/n = 305; C since 2007 to 2012/n = 452).

Results: The median patient age increased from 51 (A) to 65 years (C; P < 0.001). Indications for surgery were pancreatic/periampullary cancer (49%), chronic pancreatitis (CP; 33%), and various other lesions (18%). About two thirds of the operations were pylorus-preserving pancreaticoduodenectomies. The frequency of mesenterico-portal vein resections increased from 8% (A) to 20% (C; P < 0.01). The overall mortality was 2.4% and comparable in all three periods (2.8%, 2.0%, 2.4%; P = 0.8). Overall complication rates increased from 42% (A) to 56% (C; P < 0.01).

Conclusions: Mortality remained low despite a more aggressive surgical approach to pancreatic disease. An increased overall morbidity may be explained by more clinically relevant pancreatic fistulas and better documentation.
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http://dx.doi.org/10.1186/s12957-015-0525-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364492PMC
March 2015

The chemokine ligand CXCL16 is an indicator of bacterial infection in necrotizing pancreatitis.

Pancreatology 2015 Mar-Apr;15(2):124-30. Epub 2015 Jan 23.

Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.

Objectives: Current guidelines tell us that intervention in severe necrotizing pancreatitis ought to be performed as late as possible. However, when pancreatic necrosis becomes infected, the necrotic tissue needs to be removed. Unfortunately, bacterial infection can only be proven by invasive methods.

Methods: Necrotizing pancreatitis with sterile or infected necrosis was induced in mice. Mice serum samples were examined by antibody-based protein array. After identifying candidate proteins that showed strong regulation, the serum concentration of these proteins was examined by sandwich ELISA. Then, human serum samples were collected from patients with mild pancreatitis, severe pancreatitis with and without pancreatic necrosis and patients with microbiologically proven infection of pancreatic necrosis. These serum samples were then analyzed by sandwich ELISA.

Results: In mice 6 proteins were strongly up-regulated and were further investigated by ELISAs. Of these proteins, CXCL16 and TRANCE (RANKL) concentrations were analyzed in human serum samples. CXCL16 and TRANCE were increased in patients with pancreatic necrosis and abdominal infection. Receiver operated characteristics showed that CXCL16 was superior in predicting infected pancreatic necrosis when compared to C-reactive protein and TRANCE.

Conclusions: Serum CXCL16 is increased in severe pancreatitis with infected pancreatic necrosis and identifies patients who benefit from surgical necrosectomy.
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http://dx.doi.org/10.1016/j.pan.2015.01.004DOI Listing
December 2015

A prospective clinical study evaluating the development of bowel wall edema during laparoscopic and open visceral surgery.

J Gastrointest Surg 2014 Dec 18;18(12):2149-54. Epub 2014 Oct 18.

Department of General and Digestive Surgery, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany,

Background: To examine bowel wall edema development in laparoscopic and open major visceral surgery.

Methods: In a prospective study, 47 consecutively operated patients with gastric and pancreatic resections were included. Twenty-seven patients were operated in a conventional open procedure (open group) and 20 in a laparoscopic fashion (lap group). In all procedures, a small jejunal segment was resected during standard preparation, of which we measured the dry-wet ratio. Furthermore, HE staining was performed for measuring of bowel wall thickness and edema assessment.

Results: Mean value (±std) of dry-wet ratio was significantly lower in the open than in the lap group (0.169 ± 0.017 versus 0.179 ± 0.015; p = 0.03) with the same amount of fluid administration in both groups and a longer infusion interval during laparoscopic surgery. Subgroup analyses (only pancreatic resections) still showed similar results. Histologic examination depicted a significantly larger bowel wall thickness in the open group.

Conclusions: Laparoscopic surgery does not seem to lead to the bowel wall edema observed to occur in open surgery regardless of the degree of intravenous fluid administration, thus supporting its use even in major visceral surgery.
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http://dx.doi.org/10.1007/s11605-014-2681-3DOI Listing
December 2014

Searching for the molecular benchmark of physiological intestinal anastomotic healing in rats: an experimental study.

Eur Surg Res 2014 13;53(1-4):73-85. Epub 2014 Aug 13.

Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany.

Purpose: This investigation focuses on the physiological characteristics of gene transcription of intestinal tissue following anastomosis formation.

Methods: In eight rats, end-to-end ileo-ileal anastomoses were performed (n = 2/group). The healthy intestinal tissue resected for this operation was used as a control. On days 0, 2, 4 and 8, 10-mm perianastomotic segments were resected. Control and perianastomotic segments were examined with an Affymetrix microarray chip to assess changes in gene regulation. Microarray findings were validated using real-time PCR for selected genes. In addition to screening global gene expression, we identified genes intensely regulated during healing and also subjected our data sets to an overrepresentation analysis using the Gene Ontology (GO) and Kyoto Encyclopedia for Genes and Genomes (KEGG).

Results: Compared to the control group, we observed that the number of differentially regulated genes peaked on day 2 with a total of 2,238 genes, decreasing by day 4 to 1,687 genes and to 1,407 genes by day 8. PCR validation for matrix metalloproteinases-3 and -13 showed not only identical transcription patterns but also analogous regulation intensity. When setting the cutoff of upregulation at 10-fold to identify genes likely to be relevant, the total gene count was significantly lower with 55, 45 and 37 genes on days 2, 4 and 8, respectively. A total of 947 GO subcategories were significantly overrepresented during anastomotic healing. Furthermore, 23 overrepresented KEGG pathways were identified.

Conclusion: This study is the first of its kind that focuses explicitly on gene transcription during intestinal anastomotic healing under standardized conditions. Our work sets a foundation for further studies toward a more profound understanding of the physiology of anastomotic healing.
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http://dx.doi.org/10.1159/000365751DOI Listing
June 2015
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