Publications by authors named "Sebastian Hinz"

37 Publications

Longitudinal Analysis of Circulating Tumor Cells in Colorectal Cancer Patients by a Cytological and Molecular Approach: Feasibility and Clinical Application.

Front Oncol 2021 28;11:646885. Epub 2021 Jun 28.

Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus, Kiel, Kiel, Germany.

Introduction: Liquid biopsies allowing for individualized risk stratification of cancer patients have become of high significance in individualized cancer diagnostics and treatment. The detection of circulating tumor cells (CTC) has proven to be highly relevant in risk prediction, e.g., in colorectal cancer (CRC) patients. In this study, we investigate the clinical relevance of longitudinal CTC detection over a course of follow-up after surgical resection of the tumor and correlate these findings with clinico-pathological characteristics.

Methods: In total, 49 patients with histologically proven colorectal carcinoma were recruited for this prospective study. Blood samples were analyzed for CTC presence by two methods: first by marker-dependent immunofluorescence staining combined with automated microscopy with the NYONE cell imager and additionally, indirectly, by semi-quantitative Cytokeratin-20 (CK20) RT-qPCR. CTC quantification data were compared and correlated with the clinico-pathological parameters.

Results: Detection of CTC over a post-operative time course was feasible with both applied methods. In patients who were pre-operatively negative for CTCs with the NYONE method or below the cut-off for relative CK20 mRNA expression after analysis by PCR, a statistically significant rise in the immediate post-operative CTC detection could be demonstrated. Further, in the cohort analyzed by PCR, we detected a lower CTC load in patients who were adjuvantly treated with chemotherapy compared to patients in the follow-up subgroup. This finding was contrary to the same patient subset analyzed with the NYONE for CTC detection.

Conclusion: Our study investigates the occurrence of CTC in CRC patients after surgical resection of the primary tumor and during postoperative follow-up. The resection of the tumor has an impact on the CTC quantity and the longitudinal CTC analysis supports the significance of CTC as a prognostic biomarker. Future investigations with an even more extended follow-up period and larger patient cohorts will have to validate our results and may help to define an optimal longitudinal sampling scheme for liquid biopsies in the post-operative monitoring of cancer patients to enable tailored therapy concepts for precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.646885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273730PMC
June 2021

Intraoperative Assessment of Gastric Sleeve Oxygenation Using Hyperspectral Imaging in Esophageal Resection: A Feasibility Study.

Visc Med 2021 Jun 7;37(3):165-170. Epub 2020 Aug 7.

Department of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock, Germany.

Introduction: Sufficient tissue oxygenation is essential for anastomotic healing in visceral surgery. Hyperspectral imaging (HSI) is a noncontact, noninvasive technique for clinical assessment of tissue oxygenation in real time.

Methods: In this case series, HSI was used in 4 patients who were admitted for either esophageal cancer or cardiac carcinoma (AEG type I or II). Thoraco-abdominal surgical esophageal resection was performed after staging and neoadjuvant therapy. Intraoperative oxygenation of superficial (StO) and underlying tissue (NIR perfusion index) of the gastric sleeve were studied intrathoracic by means of the TIVITA® Tissue HSI camera. This was performed prior to esophagogastric anastomosis. The postoperative course, especially in view of surgical complications, was recorded.

Results: Assessment of StO and NIR perfusion index was performed in 4 regions of interest per gastric sleeve, aboral and oral of the clinically determined resection line. It allowed the fast quantification of gastric oxygenation prior gastroesophageal anastomosis. Median StO aboral of the determined resection line was 69%, while median StO in the oral part of the gastric sleeve was found at 53%. In contrast, the median NIR perfusion index was similar aboral (80) and oral (82) of the resection line. In none of the 4 studied patients, an anastomotic failure appeared.

Discussion/conclusion: This report suggests that HSI is a feasible technique for intraoperative assessment of tissue oxygenation before gastroesophageal anastomosis and might reduce the incidence of anastomotic failure in the gastrointestinal tract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000509304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237785PMC
June 2021

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

Gut 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-323868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292596PMC
April 2021

The Digital Abutment Check: An Improvement of the Fully Digital Workflow.

Case Rep Dent 2020 24;2020:8831862. Epub 2020 Oct 24.

Department of Prosthodontics, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Magdeburger Straße 16, 06112 Halle (Saale), Germany.

By using modern digitalization techniques, an existing denture can be digitized and aid the provision of a new implant-supported denture according to a fully digital workflow. This includes fully navigated implant surgery and results in an immediately provided prosthetic restoration. However, even with the current digital workflow, it is challenging to achieve a definitive prosthetic restoration in a single treatment session. In order to achieve a definitive denture in as few treatment sessions as possible, we have implemented the digital abutment test. This test modified the existing data set and determined the final restoration. In the present case, the preexisting maxillary removable complete denture was converted into a fixed immediate restoration using the fully digital workflow. The workflow is divided into two treatment phases, each with three treatment sessions, where part of the second phase involves an innovative digital abutment check. The illustrated case shows an effective use of current digital possibilities. Special attention was also paid to a minimally invasive course of therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8831862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604591PMC
October 2020

Isolation and Enumeration of CTC in Colorectal Cancer Patients: Introduction of a Novel Cell Imaging Approach and Comparison to Cellular and Molecular Detection Techniques.

Cancers (Basel) 2020 Sep 16;12(9). Epub 2020 Sep 16.

Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building U30 Entrance 1, 24105 Kiel, Germany.

Circulating tumour cells (CTC) were proven to be prognostically relevant in cancer treatment, e.g., in colorectal cancer (CRC). This study validates a molecular detection technique through using a novel cell imaging approach for CTC detection and enumeration, in comparison to a size-based cellular and correlated the data to clinico-pathological characteristics. Overall, 57 CRC patients were recruited for this prospective study. Blood samples were analysed for CTCs by three methods: (1) Epithelial marker immunofluorescence staining combined with automated microscopy using the NYONE cell imager; (2) isolation by size using membrane filtration with the ScreenCell Cyto IS device and immunofluorescence staining; (3) detection by semi-quantitative Cytokeratin-20 RT-qPCR. Enumeration data were compared and correlated with clinic-pathological parameters. CTC were detected by either approach; however, with varying positivity rates: NYONE 36.4%, ScreenCell 100%, and PCR 80.5%. All methods revealed a positive correlation of CTC presence and higher tumour burden, which was most striking using the ScreenCell device. Generally, no intercorrelation of CTC presence emerged amongst the applied techniques. Overall, enumeration of CTC after isolation by size demonstrated to be the most reliable strategy for the detection of CTC in CRC patients. Ongoing studies will have to unravel the prognostic value of this finding, and validate this approach in a larger cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563529PMC
September 2020

Loss of hepatic Mboat7 leads to liver fibrosis.

Gut 2021 May 26;70(5):940-950. Epub 2020 Jun 26.

Department of General, Visceral, Vascular and Transplantation Surgery, University of Rostock, Rostock, Mecklenburg-Vorpommern, Germany.

Objective: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.

Design: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.

Results: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7 mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p0.05), hydroxyproline content (p0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7 mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7 livers and human rs641738TT carriers were similar.

Conclusion: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-320853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040158PMC
May 2021

Stage IV Colorectal Cancer Patients with High Risk Mutation Profiles Survived 16 Months Longer with Individualized Therapies.

Cancers (Basel) 2020 Feb 8;12(2). Epub 2020 Feb 8.

Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA.

Personalized treatment vs. standard of care is much debated, especially in clinical practice. Here we investigated whether overall survival differences in metastatic colorectal cancer patients are explained by tumor mutation profiles or by treatment differences in real clinical practice. Our retrospective study of metastatic colorectal cancer patients of confirmed European ancestry comprised 54 Americans and 54 gender-matched Germans. The Americans received standard of care, and on treatment failure, 35 patients received individualized treatments. The German patients received standard of care only. Tumor mutations, tumor mutation burden and microsatellite status were identified by using the FoundationOne assay or the IDT Pan-Cancer assay. High-risk patients were identified according to the mutational classification by Schell and colleagues. : Kaplan-Meier estimates show the high-risk patients to survive 16 months longer under individualized treatments than those under only standard of care, in the median ( < 0.001). Tumor mutation profiles stratify patients by risk groups but not by country. : High-risk patients appear to survive significantly longer ( < 0.001) if they receive individualized treatments after the exhaustion of standard of care treatments. Secondly, the tumor mutation landscape in Americans and Germans is congruent and thus warrants the transatlantic exchange of successful treatment protocols and the harmonization of guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12020393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072525PMC
February 2020

Clinical performance of non-precious metal double crowns with friction pins in severely reduced dentitions.

Clin Oral Investig 2020 Oct 1;24(10):3567-3575. Epub 2020 Feb 1.

Department of Prosthetic Dentistry, University School of Dental Medicine, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 16, 06112, Halle, Germany.

Objectives: Several in vitro studies have investigated the retention of double crowns with friction pins (DCP); however, clinical data on their long-term success have not been reported. We sought to evaluate the 5-year survival rate of DCPs in patients with severely reduced dentition (SRD) and not severely reduced dentition (NSRD).

Materials And Methods: A total of 158 patients were treated with 182 dentures on 520 abutment teeth between 2006 and 2016. The SRD group included 144 dentures that had been inserted on 314 abutment teeth. We evaluated the influence of age, sex, jaw, number, tooth vitality, and abutment teeth localization (according to Steffel's classification) on the 60-month survival rates of dentures and abutment teeth using the Kaplan-Meier estimator, logrank test, and Cox regression.

Results: The cumulative 60-month survival rate was 84.3% (CI 77.1-91.5%) for all dentures; however, the survival rate in the SRD group (80.3%; CI 71.5-89.1%) was significantly lower than in the NSRD group (100%; p = 0.04). Dentures classified in Steffel's class A had the lowest survival rate (51.5%; CI 30.9-72.1%). Number, location, and vitality of the abutment teeth had a significant impact on survival rate.

Conclusions: DCP dentures showed comparable clinical long-term success to double crown systems that have been previously reported in the literature. The number, localization, and vitality of abutment teeth had the greatest influence on the survival rates of denture and abutment teeth.

Clinical Relevance: DCP dentures have an acceptable 5-year survival rate. Clinical treatment planning must take into account key factors associated with the prognosis of the abutment teeth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00784-020-03228-1DOI Listing
October 2020

Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy.

BMC Med Genet 2020 01 3;21(1). Epub 2020 Jan 3.

Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany.

Background: Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients.

Case Presentation: In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19-9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed.

Conclusion: As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-019-0941-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942307PMC
January 2020

Shotgun lipidomics-based characterization of the landscape of lipid metabolism in colorectal cancer.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 03 30;1865(3):158579. Epub 2019 Nov 30.

Center for Regenerative Therapies Dresden, Technische Universität (TU) Dresden, Dresden, Germany; Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Dresden, Germany. Electronic address:

Solid tumors are characterized by global metabolic alterations which contribute to their growth and progression. Altered gene expression profiles and plasma lipid composition suggested a role for metabolic reprogramming in colorectal cancer (CRC) development. However, a conclusive picture of CRC-associated lipidome alterations in the tumor tissue has not emerged. Here, we determined molar abundances of 342 species from 20 lipid classes in matched biopsies of CRC and adjacent normal mucosa. We demonstrate that in contrast to previous reports, CRC shows a largely preserved lipidome composition that resembles that of normal colonic mucosa. Important exceptions include increased levels of lyso-phosphatidylinositols in CRC and reduced abundance of ether phospholipids in advanced stages of CRC. As such, our observations challenge the concept of widespread alterations in lipid metabolism in CRC and rather suggest changes in the cellular lipid profile that are limited to selected lipids involved in signaling and the scavenging of reactive oxygen species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2019.158579DOI Listing
March 2020

Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.

Nat Med 2019 12 2;25(12):1885-1893. Epub 2019 Dec 2.

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-019-0660-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899159PMC
December 2019

Complications of endodontically treated abutment teeth after restoration with non-precious metal double crowns.

Clin Oral Investig 2020 Aug 15;24(8):2809-2817. Epub 2019 Nov 15.

Department of Prosthodontics, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 16, 06112, Halle, Germany.

Objectives: This study aimed to evaluate the effects of endodontic treatment on the complication rate in abutment teeth following double crown treatment.

Materials And Methods: Data of 233 patients supplied with 278 prostheses on 773 teeth were retrospectively analyzed. The 60-month cumulative complication rate for vital, root filled, and post and core reconstructed abutment teeth is calculated using the Kaplan-Meier method. Cox regression is performed to evaluate factors including age, sex, jaw, and tooth number.

Results: After 60 months, the cumulative complication rate for all abutment teeth was 24.1% (CI: 19.7-28.5%). A significantly higher cumulative fracture rate (log-rank test, p < 0.001) was found for devital (51.7%; CI: 35.3-68.1%) compared to vital abutment teeth (20.6%; CI: 16.2-25%). Devital teeth restored with post and core reconstructions (46.3%; CI: 26.1-66.5%) showed a lower cumulative fracture rate than abutment teeth with only root fillings (60.9%; CI: 33.5-88.3%). Abutment teeth in severely reduced dentitions (≤ 3 teeth) were found to have significantly lower survival rates than abutment teeth in not severely reduced dentitions (≥ 4 teeth, p = 0.031, HR = 0.609).

Conclusion: Lower abutment teeth survival rates were associated with non-vitality and a reduced number of abutment teeth. Devital teeth with post and core reconstructions showed higher survival rates than root filled devital teeth.

Clinical Relevance: After 5 years, devital teeth with double crowns have a fracture rate twice as high as vital teeth. This prognosis should be taken into account during treatment planning, especially in the severely reduced dentition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00784-019-03145-yDOI Listing
August 2020

Copy number variants in lipid metabolism genes are associated with gallstones disease in men.

Eur J Hum Genet 2020 02 4;28(2):264-273. Epub 2019 Sep 4.

Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile.

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10-20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency < 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 × 10; OR = 2.76; CI 95% = 1.53-4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-019-0501-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974590PMC
February 2020

Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry.

Sci Rep 2019 01 28;9(1):772. Epub 2019 Jan 28.

Departmento de Gastroenterología, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 × 10 in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 × 10, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10, OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-35852-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349870PMC
January 2019

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

Gut 2019 05 19;68(5):854-865. Epub 2019 Jan 19.

University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.

Objective: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.

Design: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.

Results: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near with a p value of 2.3×10 and 0.002 (OR=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, (OR 1.32, 95% CI 1.12 to 1.56), (OR 1.21, 95% CI 1.04 to 1.42), (OR 1.17, 95% CI 1.03 to 1.33) and (OR 1.17, 95% CI 1.03 to 1.33).

Conclusion: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2018-317619DOI Listing
May 2019

EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video).

Gastrointest Endosc 2019 02 1;89(2):311-319.e1. Epub 2018 Sep 1.

Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.

Background And Aims: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce.

Methods: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis.

Results: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10).

Conclusions: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gie.2018.08.046DOI Listing
February 2019

[Acute Cholecystitis].

Zentralbl Chir 2018 Aug 22;143(4):392-399. Epub 2018 Aug 22.

Klinik für Allgemeine-, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Deutschland.

Acute cholecystitis is inflammation of the gallbladder and is triggered by cholelithiasis in about 90% of cases. Gallstone-associated diseases are among the most expensive in the field of gastroenterology and are therefore of great economic importance. Development of gallstones is multifactorial. The risk of gallstone disease increases with age. In particular, the carbohydrate- and fat-rich diet and the lack of physical activity in the Western world are involved in the formation of gallstones. Another important risk factor is genetic variants in cholesterol transporters. Diagnosis is based on the combination of the medical history, the physical examination, abdominal ultrasound and infection parameters in clinical chemistry. Typical symptoms include colic-like upper abdominal pain lasting more than six hours, fever or leukocytosis, and ultrasound gallbladder wall oedema in combination with a positive Murphy sign. The treatment of choice is early laparoscopic cholecystectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0631-9463DOI Listing
August 2018

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
June 2019

Evolutionary Distance Predicts Recurrence After Liver Transplantation in Multifocal Hepatocellular Carcinoma.

Transplantation 2018 10;102(10):e424-e430

Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Germany.

Background: Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome-wide single-nucleotide polymorphism data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC.

Methods: In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping.

Results: Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (P = 0.04) and in the replication data sets (P = 0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined P = 0.0002). In a univariate analysis, evolutionary distance (P = 7.4 × 10) and microvascular invasion (P = 1.31 × 10) were significantly associated with survival in a Cox regression analysis.

Conclusions: Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598094PMC
October 2018

Identifying patients with an unfavorable prognosis in early stages of colorectal carcinoma.

Oncotarget 2018 Jun 8;9(44):27423-27434. Epub 2018 Jun 8.

Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: In recent years, the concept of liquid biopsy diagnostics in detection and progress monitoring of malignant diseases gained significant awareness. We here report on a semi-quantitative real-time cytokeratin 20 RT-PCR-based assay, for detecting circulating tumor cells within a fraction of peripheral blood mononuclear cells in colorectal cancer patients.

Methods: In total, 381 patients were included. Prior to surgical tumor resection, a peripheral blood sample was drawn. Mononuclear cells were isolated by Ficoll centrifugation and a cytokeratin 20 qRT-PCR assay was performed. Quantitative PCR data was assessed regarding histopathological characteristics and patients´ clinical outcome.

Results: A cut-off value was determined at ≥ 2.77 [EU]. Stratifying patients by this cut-off, it represents a statistically highly significant prognostic marker for both the overall and disease-free survival in the entire cohort UICC I-IV (both p<0.001) and in early tumor stages UICC I+II (overall survival p=0.003 and disease-free survival p=0.005). In multivariate analysis, the cut-off value stands for an independent predictor of significantly worse overall and disease-free survival (p=0.035 and p=0.047, respectively).

Conclusion: We successfully established a highly sensitive real-time qRT-PCR assay by which we are able to identify colorectal cancer patients at risk for an unfavorable prognosis in UICC I and II stages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007960PMC
June 2018

Detection of circulating tumor cells with CK20 RT-PCR is an independent negative prognostic marker in colon cancer patients - a prospective study.

BMC Cancer 2017 01 13;17(1):53. Epub 2017 Jan 13.

Division Molecular Oncology, Institute for Experimental Cancer Research, Cancer Center North, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller Str. 7, 24105, Kiel, Germany.

Background: Detection of circulating (CTC) or disseminated tumor cells (DTC) has been associated with negative prognosis and outcome in patients with colorectal cancer, though testing for these cells is not yet part of clinical routine. There are several different methodological approaches to detect tumor cells but standardized detection assays are not implemented so far.

Methods: In this prospective monocentric study 299 patients with colon cancer were included. CTC and DTC were detected using CK20 RT-PCR as well as immunocytochemistry staining with anti-pan-keratin and anti-EpCAM antibodies. The primary endpoints were: Evaluation of CTC and DTC at the time of surgery and correlation with main tumor characteristics and overall (OS) and disease free survival (DFS).

Results: Patients with detectable CTC had a 5-year OS rate of 68% compared to a 5-year OS rate of 85% in patients without detectable CTC in the blood (p = 0.002). Detection of DTC in the bone marrow with CK20 RT-PCR was not associated with a worse OS or DFS. Detection of pan-cytokeratin positive DTC in the bone marrow correlated with a significantly reduced 5-year OS rate (p = 0.048), but detection of DTC in the bone marrow with the anti-EpCAM antibody did not significantly influence the 5-year OS rate (p = 0.958). By multivariate analyses only detection of CTC with CK20 RT-PCR in the blood was revealed to be an independent predictor of worse OS (HR1.94; 95% CI 1.0-3.7; p = 0.04) and DFS (HR 1.94; 95% CI 1.1-3.7; p = 0.044).

Conclusions: Detection of CTC with CK20 RT-PCR is a highly specific and independent prognostic marker in colon cancer patients. Detection of DTC in the bone marrow with CK20 RT-PCR or immunohistochemistry with anti-EpCAM antibody is not associated with a negative prognostic influence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-016-3035-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237158PMC
January 2017

Cytokeratin 20 positive circulating tumor cells are a marker for response after neoadjuvant chemoradiation but not for prognosis in patients with rectal cancer.

BMC Cancer 2015 Dec 16;15:953. Epub 2015 Dec 16.

Division Molecular Oncology, Institute for Experimental Cancer Research, Cancer Center North, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller Str. 7, 24105, Kiel, Germany.

Background: Several studies have shown, that circulating tumor cells (CTC) have a negative prognostic value in colorectal cancer patients. Aim of this study was to evaluate the role of CTC in specifically rectal cancer patients regarding the influence on overall survival and to elucidate the impact of CTC in predicting response after chemoradiation (RCTX).

Methods: In this prospective monocentric study 267 patients with rectal cancer were included. Patients with locally advanced tumors were treated with RCTX followed by surgery. The primary endpoints were: Evaluation of CTC at the time of surgery and correlation with main tumor characteristics, response to neoadjuvant RCTX and overall survival (OS). CTC were detected in the blood using CK20 RT-PCR.

Results: Sixty-three patients were treated with neoadjuvant RCTX. In 46.8% of the patients receiving neoadjuvant RCTX CTC were detected, which was significantly higher than in the group without RCTX (p=0.002). Histopathologic regression after RCTX was evident in 27.8% of the patients. In the subgroup of responders after RCTX we found CTC at a significantly lower rate than in non-responders (p=0.03). No significant association was found between CTC detection and tumor characteristics and OS. The OS was significantly improved for responders compared to non-responders (p=0.007).

Conclusions: Responders after neoadjuvant RCTX had a lower incidence of CTC compared to non-responders, which might be a result of effective systemic and local treatment prior to surgery. Interestingly, detection of CTC did not correlate with tumor stage and OS, which is in contrast to previous reports of patients with colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-015-1989-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682277PMC
December 2015

Profile of serum factors and disseminated tumor cells before and after radiofrequency ablation compared to resection of colorectal liver metastases - a pilot study.

Anticancer Res 2015 May;35(5):2961-7

Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.

Background/aim: The degree of systemic response after hepatic radiofrequency ablation (RFA) has not been well-compared to liver resection so far. This pilot study was designed to examine whether RFA, compared to liver resection, significantly varies concerning dissemination of circulating tumor cells and induction of different pro-inflammatory markers and liver-specific growth factors.

Patients And Methods: Patients with colorectal liver metastases were treated with RFA, a combination of RFA and resection or liver resection only. Blood samples of 18 patients were obtained at different time points and interleukin (IL)-6, hepatocyte growth factor (HGF) and 70-kD heat shock protein (HSP70) serum levels were determined by ELISA. Circulating tumor cells were detected with reverse transcription-polymerase chain reaction (RT-PCR) amplification of cytokeratin 20 (CK20) mRNA (CK20 RT-PCR).

Results: The detection of circulating tumor cells was not significantly different, but in two patients RFA induced tumor cell dissemination. Serum levels of IL-6 were strongly elevated after the operation without any significant differences between the treatment groups. The HGF ratio was significantly higher after RFA+resection compared to resection-alone and the HSP70 ratio also showed significantly higher values after RFA compared to resection alone. High postoperative IL-6 and HGF levels negatively influenced overall survival (OS) independently of the treatment group.

Conclusion: This pilot study demonstrates that RFA might influence tumor cell dissemination. There exist detectable differences in serum factors between RFA and liver resection after the operation but this did not influence the overall survival of the patients. For all patients, high postoperative IL-6 and HGF levels are negative prognostic markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
May 2015

Postdiagnosis body mass index and risk of mortality in colorectal cancer survivors: a prospective study and meta-analysis.

Cancer Causes Control 2014 Oct 19;25(10):1407-18. Epub 2014 Jul 19.

Institute of Epidemiology, Christian-Albrechts University of Kiel, Campus UKSH, Arnold-Heller-Str. 3, Haus 1, 24105, Kiel, Germany,

Purpose: Aim of this study was to investigate the association between postdiagnosis body mass index (BMI) and all-cause mortality in colorectal cancer (CRC) survivors in a prospective study and meta-analysis.

Methods: We conducted a prospective cohort study on 2,143 CRC survivors in Germany. Participants were recruited to the study on average 4 years after diagnosis, and postdiagnosis BMI was assessed at recruitment using a self-administered questionnaire. CRC survivors were followed up for a mean time of 3.5 years. The association between BMI and all-cause mortality was investigated using multivariable Cox proportional hazards models. Additionally, we performed a meta-analysis of studies on postdiagnosis BMI and all-cause mortality (n = 5, including this study) by applying random-effects models.

Results: In the prospective analysis, 349 participants died. BMI was not statistically significantly associated with all-cause mortality. Compared to normal weight survivors, the hazard ratios (HRs) [95% confidence interval (CI)] for all-cause mortality in underweight, overweight and obese survivors were 1.65 (0.79-3.45), 0.80 (0.62-1.03) and 0.84 (0.62-1.14), respectively. In the meta-analysis, individuals with underweight were at increased risk for all-cause mortality [HR (95% CI) 1.72 (1.18-2.49)], whereas individuals with overweight had a lower risk [HR (95% CI) 0.79 (0.71-0.88)], compared to normal weight subjects. For obesity, the risk of mortality was also reduced with only borderline significance [HR (95% CI) 0.88 (0.77-1.00)].

Conclusions: While the present study as well as single previously published studies showed that overweight was associated with a non-significant reduced risk for all-cause mortality, our meta-analysis indicated a decreased mortality risk among overweight CRC survivors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10552-014-0435-xDOI Listing
October 2014

Lifestyle factors and health-related quality of life in colorectal cancer survivors.

Cancer Causes Control 2014 Jan 25;25(1):99-110. Epub 2013 Oct 25.

Institute of Epidemiology, Christian-Albrechts University of Kiel, Campus Kiel, UKSH, Arnold-Heller-Str. 3, Haus 1, 24105, Kiel, Germany,

Purpose: This study investigates the association between a postdiagnosis lifestyle score and health-related quality of life (HrQol) in long-term colorectal cancer (CRC) survivors.

Methods: A cross-sectional study of 1,389 long-term CRC survivors in Northern Germany was analyzed. On average 7.2 years after CRC diagnosis, HrQol was assessed with the EORTC QLQ-C30, and lifestyle factors, including weight, height, diet, physical activity, and smoking were obtained using self-administered questionnaires. A lifestyle score (BMI <30 kg/m², healthy diet, recreationally active, and not smoking) was applied. Participants were categorized in adhering to at most one, two, three, or all recommended lifestyle factors, categorizing unfavorable behaviors with 0 and favorable with 1 point. Multivariable logistic regression models were used to investigate the association between the lifestyle score and HrQol as a binary variable.

Results: Approximately 10 % had at most one, 30 % two, 38 % three, and 23 % all favorable factors. Compared to participants with one or zero factors, the odds ratio (OR) for a low global HrQol (gHrQol) decreased with stronger adherence to the score. The OR (95% CI) for a low gHrQol was 0.50 (0.33-0.76) for participants with all favorable lifestyle factors compared to participants with one or zero. Clinical and socio-demographic factors had little impact on these associations, with exception of living arrangement which showed a statistically significant interaction. Associations were stronger for functioning domains, representing mobility rather than mental health.

Conclusions: Favorable lifestyle behaviors might be associated with HrQol in CRC long-term survivors. More research in prospective studies is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10552-013-0313-yDOI Listing
January 2014

Functional TLR5 genetic variants affect human colorectal cancer survival.

Cancer Res 2013 Dec 23;73(24):7232-42. Epub 2013 Oct 23.

Authors' Affiliations: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle; Department of Pediatrics I; Institute for Medical Microbiology and Hygiene, University Hospital Tübingen, Tübingen, Germany; Division of Molecular Genetic Epidemiology; Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein; Department of General Internal Medicine; POPGEN Biobank Project, Christian-Albrechts University, Kiel, Germany; and Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.

Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1β mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-13-1746DOI Listing
December 2013

Metabolic signature of electrosurgical liver dissection.

PLoS One 2013 13;8(9):e72022. Epub 2013 Sep 13.

Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.

Background And Aims: High frequency electrosurgery has a key role in the broadening application of liver surgery. Its molecular signature, i.e. the metabolites evolving from electrocauterization which may inhibit hepatic wound healing, have not been systematically studied.

Methods: Human liver samples were thus obtained during surgery before and after electrosurgical dissection and subjected to a two-stage metabolomic screening experiment (discovery sample: N = 18, replication sample: N = 20) using gas chromatography/mass spectrometry.

Results: In a set of 208 chemically defined metabolites, electrosurgical dissection lead to a distinct metabolic signature resulting in a separation in the first two dimensions of a principal components analysis. Six metabolites including glycolic acid, azelaic acid, 2-n-pentylfuran, dihydroactinidiolide, 2-butenal and n-pentanal were consistently increased after electrosurgery meeting the discovery (p<2.0 × 10(-4)) and the replication thresholds (p<3.5 × 10(-3)). Azelaic acid, a lipid peroxidation product from the fragmentation of abundant sn-2 linoleoyl residues, was most abundant and increased 8.1-fold after electrosurgical liver dissection (preplication = 1.6 × 10(-4)). The corresponding phospholipid hexadecyl azelaoyl glycerophosphocholine inhibited wound healing and tissue remodelling in scratch- and proliferation assays of hepatic stellate cells and cholangiocytes, and caused apoptosis dose-dependently in vitro, which may explain in part the tissue damage due to electrosurgery.

Conclusion: Hepatic electrosurgery generates a metabolic signature with characteristic lipid peroxidation products. Among these, azelaic acid shows a dose-dependent toxicity in liver cells and inhibits wound healing. These observations potentially pave the way for pharmacological intervention prior liver surgery to modify the metabolic response and prevent postoperative complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072022PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772850PMC
June 2014

Disseminated tumor cells in the bone marrow negatively influence survival after resection of colorectal liver metastases.

Ann Surg Oncol 2012 Aug 7;19(8):2539-46. Epub 2012 Mar 7.

Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.

Background: Despite all efforts in extending the resectability rates of colorectal liver metastases, thus improving the prognosis of the patients, tumor recurrence occurs in many patients. Occult dissemination of tumor cells might reflect a minimal residual disease that is not eliminated by primary surgery. Because the prognostic effect of disseminated tumor cells (DTC) is still uncertain in this clinical setting, we analyzed these cells in the peripheral blood and bone marrow of patients undergoing hepatic resection of colorectal liver metastases.

Methods: In 108 patients with colorectal liver metastases, the presence of DTC in the peripheral blood and bone marrow was detected with CK20 RT-PCR. Clinical data were prospectively collected, and multiple variables were analyzed regarding their influence on overall survival.

Results: DTC in the peripheral blood were detected in 40% of the patients. In 25% of the patients, DTC were detected in the bone marrow. The median follow-up was 34 months. Fifty-nine of 108 patients died from tumor relapse. Multivariate analysis determined detection of DTC in the bone marrow to be an independent prognostic factors for overall survival (P = 0.038).

Conclusions: This large series of patients with hepatic resection of colorectal liver metastases demonstrated that detection of CK20-positive DTC via RT-PCR in the bone marrow compartment negatively influences overall survival. The evidence of DTC in the bone marrow might serve as an additional individual marker to select patients for adjuvant treatment after liver metastases resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-012-2291-9DOI Listing
August 2012

Evaluation of the POSSUM score in surgical treatment of cholangiocarcinoma.

Hepatogastroenterology 2010 May-Jun;57(99-100):403-8

Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 7, 24105 Kiel, Germany.

Background/aims: The surgical treatment for cholangiocarcinoma (CCC) is still a challenge. The aim of this study was to evaluate the POSSUM scoring system for preoperative physiological risk adjustment and for the operative risk of postoperative morbidity and mortality.

Methodology: The operative notes and hospital files of 171 patients with CCC were analyzed retrospectively. The POSSUM scoring system was used to predict morbidity and mortality rates after surgery. The physiological sub score and the operative sub score of the POSSUM score were analyzed with regard to their ability to predict major postoperative complications.

Results: The overall complication rate was 40.9% and the mortality was 11.2%. The morbidity predicted by POSSUM was 63.5% and the prediction for postoperative mortality was 23.7%. Both rates are much higher than the observed morbidity and mortality. High operative severity sub scores correlate with the occurrence of major complications.

Conclusion: The POSSUM scoring system over predicts morbidity and mortality in surgery for CCC. Operative severity and intraoperative parameters have a greater influence on postoperative mortality and morbidity rates than the physiological parameters represented in the POSSUM physiological score. Prospective studies will have to show whether POSSUM can be modified or whether it is necessary to develop a new score for assessing morbidity and mortality in surgery for CCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2010

Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer.

BMC Gastroenterol 2009 Oct 20;9:79. Epub 2009 Oct 20.

Department of General Internal Medicine Christian-Albrechts-University, Kiel, Germany.

Background: Variation in genes involved in the innate immune response may play a role in the predisposition to colorectal cancer (CRC). Several polymorphisms of the CARD15 gene (caspase activating recruitment domain, member 15) have been reported to be associated with an increased susceptibility to Crohn disease. Since the CARD15 gene product and other CARD proteins function in innate immunity, we investigated the impact of germline variation at the CARD4, CARD8 and CARD15 loci on the risk for sporadic CRC, using a large patient sample from Northern Germany.

Methods: A total of 1044 patients who had been operated with sporadic colorectal carcinoma (median age at diagnosis: 59 years) were recruited and compared to 724 sex-matched, population-based control individuals (median age: 68 years). Genetic investigation was carried out following both a coding SNP and haplotype tagging approach. Subgroup analyses for N = 143 patients with early manifestation of CRC (
Results: No significant differences were observed between the patient and control allelic or haplotypic spectra of the three genes under study for the total cohort (N = 1044 patients). None of the analysed SNPs was significantly associated with either tumour location or yielded significant association in the familial or non-familial CRC patient subgroups. However, in a patient subgroup (
Conclusion: Variation in the innate immunity genes CARD4, CARD8 and CARD15 is unlikely to play a major role in the susceptibility to CRC in the German population. But, we report a significant disease contribution of CARD15 for CRC patients with very early disease manifestation, mainly driven by variant R702W.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-230X-9-79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776017PMC
October 2009
-->