Publications by authors named "Juergen Weitz"

38 Publications

The Hunger Games: Laparoscopic Performance in Novice Surgeons is Not Altered by Food Deprivation but Influenced by the Degree of Appetite - A Randomized Controlled Trial.

J Surg Educ 2020 Sep - Oct;77(5):1236-1243. Epub 2020 Jun 10.

Department for Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Dresden, Germany; Department of Surgery, University Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address:

Objectives: Food deprivation is a common condition for visceral surgeons and especially laparoscopic approaches require high levels of concentration. The current literature does not provide adequate answers whether intraoperative breaks, especially food intake, might influence the quality of the surgical skills. Thus, the primary aim of this trial was to analyze the influence of food deprivation on the laparoscopic performance.

Design Setting And Participants: 37 laparoscopic novices participated from 10/2017 to 04/2018 in this single center, prospective-randomized trial and were trained during laparoscopic training sessions until they reached a predefined level of proficiency. Subsequently, participants were randomized into 3 different groups: food deprivation of 8 hours, 4 hours, or carbohydrate loading directly prior to the laparoscopic exam. The exam comprised PEG-transfer, precise cutting, gallbladder resection and surgical knot.

Main Findings: Completion time for PEG-transfer, precise cutting, gallbladder resection and surgical knot was 63s, 139s, 192s and 272s respectively. Participants starving for 8 hours performed 3 of 4 tasks more slowly whilst participants starving for 4 hours performed 3 of 4 tasks faster than the average. Analyzing self-reported level of appetite revealed: Students with an intermediate level were significantly faster (p <0.05) during complex procedures compared to participants that reported hunger prior to performing these tasks (192s vs. 307s). Additionally, hungry students had been more inaccurate during the surgical knot (p <0.05) whilst students with intermediate appetite level tend to be most accurate (p - value 0.012).

Conclusions: The subjective level of appetite rather than the absolute number of fasting hours influences the laparoscopic performance most. Thus, any extreme level of appetite may be avoided and surgeons may achieve the best performance when they have an intermediate level of appetite. In consequence, heavy meals may be omitted immediately prior to demanding laparoscopic procedures and surgeons may have access to mini-breaks and refreshers during major procedures.
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http://dx.doi.org/10.1016/j.jsurg.2020.03.029DOI Listing
June 2020

A case study: impact of target surface mesh size and mesh quality on volume-to-surface registration performance in hepatic soft tissue navigation.

Int J Comput Assist Radiol Surg 2020 Aug 27;15(8):1235-1245. Epub 2020 Mar 27.

Division of Translational Surgical Oncology, National Center for Tumor Diseases (NCT), 01307, Dresden, Germany.

Purpose: Soft tissue deformation severely impacts the registration of pre- and intra-operative image data during computer-assisted navigation in laparoscopic liver surgery. However, quantifying the impact of target surface size, surface orientation, and mesh quality on non-rigid registration performance remains an open research question. This paper aims to uncover how these affect volume-to-surface registration performance.

Methods: To find such evidence, we design three experiments that are evaluated using a three-step pipeline: (1) volume-to-surface registration using the physics-based shape matching method or PBSM, (2) voxelization of the deformed surface to a [Formula: see text] voxel grid, and (3) computation of similarity (e.g., mutual information), distance (i.e., Hausdorff distance), and classical metrics (i.e., mean squared error or MSE).

Results: Using the Hausdorff distance, we report a statistical significance for the different partial surfaces. We found that removing non-manifold geometry and noise improved registration performance, and a target surface size of only 16.5% was necessary.

Conclusion: By investigating three different factors and improving registration results, we defined a generalizable evaluation pipeline and automatic post-processing strategies that were deemed helpful. All source code, reference data, models, and evaluation results are openly available for download: https://github.com/ghattab/EvalPBSM/ .
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http://dx.doi.org/10.1007/s11548-020-02123-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351822PMC
August 2020

Low level of exosomal long non-coding RNA is a prognostic biomarker in colorectal cancer.

RNA Biol 2019 10 7;16(10):1339-1345. Epub 2019 Jul 7.

Department for Visceral, Thoracic and Vascular Surgery, University Hospital Dresden , Dresden , Germany.

Molecular risk stratification of colorectal cancer can improve patient outcome. A panel of lncRNAs ( and ) derived from serum exosomes of patients with non-metastatic CRC and healthy donors was analyzed. Exosomes from healthy donors carried significantly more and transcripts in comparison to CRC patients. Correlation analysis between lncRNAs and clinical data revealed a statistical significance between low levels of exosomal and poor overall survival. This was confirmed by multivariate analysis that is an independent prognostic marker for overall survival (HR: 4.5, CI: 1.69-11.98, p = 0.0027). Here, poses to be a valid biomarker for patients with a CRC to predict post-surgical survival time.
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http://dx.doi.org/10.1080/15476286.2019.1637697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779381PMC
October 2019

Expression of Glypican 3 is an Independent Prognostic Biomarker in Primary Gastro-Esophageal Adenocarcinoma and Corresponding Serum Exosomes.

J Clin Med 2019 May 16;8(5). Epub 2019 May 16.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, D-01307 Dresden, Germany.

Exosomes are nano-sized membranous vesicles of endosomal origin that carry nucleic acids, lipids and proteins. The cargo of exosomes is cell origin specific and the release of these exosomes and uptake by an acceptor cell is seen as a vital element of cell-cell communication. Here, we sought to investigate the diagnostic and prognostic value of the expression of glypican 3 () on primary gastro-esophageal adenocarcinoma (GEA) tissue () and corresponding serum exosomes (). Circulating exosomes were extracted from serum samples of 49 patients with GEA and 56 controls. Extracted exosomes were subjected to flow cytometry for the expression of and expression on primary GEA tissue samples was determined by immunohistochemistry and correlated to clinicopathological parameters. We found decreased levels in GEA patients compared to healthy controls ( < 0.0001) and high expression. This was significantly associated with poor overall survival (high vs. low : 87.40 vs. 60.93 months, = 0.041, high vs. low : 58.03 vs. 84.70 months, = 0.044). Cox regressional analysis confirmed as an independent prognostic biomarker for GEA ( = 0.02) and expression was validated in two independent cohorts. Our findings demonstrate that and can be used as potential diagnostic and prognostic biomarkers for GEA.
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http://dx.doi.org/10.3390/jcm8050696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572603PMC
May 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.
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http://dx.doi.org/10.1136/gutjnl-2018-317619DOI Listing
May 2019

Correction to: FDG-PET/MRI in patients with pelvic recurrence of rectal cancer: first clinical experiences.

Eur Radiol 2019 02;29(2):1064

Institut und Poliklinik fuer Radiologische Diagnostik, Universitaetsklinikum Carl Gustav Carus, Fetscherstrasse 74, 01307, Dresden, Germany.

The original version of this article, published on 6 July 2018, unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00330-018-5677-7DOI Listing
February 2019

FDG-PET/MRI in patients with pelvic recurrence of rectal cancer: first clinical experiences.

Eur Radiol 2019 Jan 6;29(1):422-428. Epub 2018 Jul 6.

Institut und Poliklinik fuer Radiologische Diagnostik, Universitaetsklinikum Carl Gustav Carus, Fetscherstrasse 74, 01307, Dresden, Germany.

Objectives: To determine the value of F-FDG-PET/MRI in the diagnosis and management of patients with pelvic recurrence of rectal cancer.

Methods: Forty-four patients (16 women, 28 men) with a history of rectal cancer who received FDG-PET/MRI between June 2011 and February 2017 at our institution were retrospectively enrolled. Three patients received two FDG-PET/MRIs; thus a total of 47 examinations were included. Pelvic recurrence was confirmed either with histology (n = 27) or imaging follow-up (n = 17) (> 4 months). Two readers (one radiologist, one nuclear medicine physician) interpreted the images in consensus. Pelvic lesions were assessed regarding FDG uptake and morphology. Sensitivity, specificity, positive and negative predictive values as well as accuracy of PET/MRI in detecting recurrence were determined.

Results: In 47 FDG-PET/MRIs 30 suspicious pelvic lesions were identified, 29 of which were malignant. Two patients underwent resection and had histologically proven pelvic recurrence without showing suspicious findings on FDG-PET/MRI. Changes in management due to FDG-PET/MRI findings had been implemented in eight patients. Eighty per cent (16/20) of resected patients had histologically negative resection margins (R0), one patient had uncertain resection margins. Sensitivity of FDG-PET/MRI in detecting recurrence was 94%, specificity 94%, positive/negative predictive value and accuracy were 97%, 90% and 94%, respectively.

Conclusions: FDG-PET/MRI is a valuable tool in the diagnosis and staging of pelvic recurrence in patients with rectal cancer.

Key Points: • Metabolic information obtained from PET coupled with excellent soft tissue contrast from MRI could facilitate detection of rectal cancer recurrence and assist in treatment planning. • PET/MRI demonstrates high sensitivity and specificity for the diagnosis of local recurrence of rectal cancer • PET/MRI led to alterations in management in 18.2% of patients.
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http://dx.doi.org/10.1007/s00330-018-5589-6DOI Listing
January 2019

Validation of prognostic risk scores for patients undergoing resection for pancreatic cancer.

Pancreatology 2018 Jul 21;18(5):585-591. Epub 2018 May 21.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Germany. Electronic address:

Background/objectives: A better stratification of patients into risk groups might help to select patients who might benefit from more aggressive therapy. The aim of this study was to validate five prognostic scores in patients resected for pancreatic ductal adenocarcinoma (PDAC).

Methods: Included were 307 PDAC patients who underwent resection with curative intent. Five clinical risk scores were selected and applied to our study population. Survival analyses were carried out using univariate and multivariate proportional hazards regression.

Results: Prognostic stratification was strong for the Heidelberg score (p < 0.001) and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (p = 0.001) and moderate for the Botsis score (p = 0.033). There was no significant prognostic value for the Early Mortality Risk Score (p = 0.126) and McGill Brisbane Symptom Score (p = 0.133). Positive resection margin (HR 1.53, 95% CI 1.08-2.16) and pain [pain (HR 1.40, CI 1.03-1.91), back pain (HR 1.67, 95% CI 1.08-2.57)] were independent prognostic factors on multivariate analysis.

Conclusions: The Heidelberg score and MSKCC nomogram provided adequate risk stratification in our independent study cohort. Further studies in independent patient cohorts are required to achieve higher levels of validation.
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http://dx.doi.org/10.1016/j.pan.2018.05.005DOI Listing
July 2018

Transferability of laparoscopic skills using the virtual reality simulator.

Surg Endosc 2018 10 30;32(10):4132-4137. Epub 2018 Mar 30.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Fetscherstraße 74, 01307, Dresden, Germany.

Background: Skill transfer represents an important issue in surgical education, and is not well understood. The aim of this randomized study is to assess the transferability of surgical skills between two laparoscopic abdominal procedures using the virtual reality simulator in surgical novices.

Methods: From September 2016 to July 2017, 44 surgical novices were randomized into two groups and underwent a proficiency-based basic training consisting of five selected simulated laparoscopic tasks. In group 1, participants performed an appendectomy training on the virtual reality simulator until they reached a defined proficiency. They moved on to the tutorial procedural tasks of laparoscopic cholecystectomy. Participants in group 2 started with the tutorial procedural tasks of laparoscopic cholecystectomy directly. Finishing the training, participants of both groups were required to perform a complete cholecystectomy on the simulator. Time, safety and economy parameters were analysed.

Results: Significant differences in the demographic characteristics and previous computer games experience between the two groups were not noted. Both groups took similar time to complete the proficiency-based basic training. Participants in group 1 needed significantly less movements (388.6 ± 98.6 vs. 446.4 ± 81.6; P < 0.05) as well as shorter path length (810.2 ± 159.5 vs. 945.5 ± 187.8 cm; P < 0.05) to complete the cholecystectomy compared to group 2. Time and safety parameters did not differ significantly between both groups.

Conclusion: The data demonstrate a positive transfer of motor skills between laparoscopic appendectomy and cholecystectomy on the virtual reality simulator; however, the transfer of cognitive skills is limited. Separate training curricula seem to be necessary for each procedure for trainees to practise task-specific cognitive skills effectively. Mentoring could help trainees to get a deeper understanding of the procedures, thereby increasing the chance for the transfer of acquired skills.
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http://dx.doi.org/10.1007/s00464-018-6156-6DOI Listing
October 2018

Impaired laparoscopic performance of novice surgeons due to phone call distraction: a single-centre, prospective study.

Surg Endosc 2017 12 8;31(12):5312-5317. Epub 2017 Jun 8.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Dresden, Fetscherstraße 74, 01307, Dresden, Germany.

Background: Distractions such as phone calls during laparoscopic surgery play an important role in many operating rooms. The aim of this single-centre, prospective study was to assess if laparoscopic performance is impaired by intraoperative phone calls in novice surgeons.

Methods: From October 2015 to June 2016, 30 novice surgeons (medical students) underwent a laparoscopic surgery training curriculum including two validated tasks (peg transfer, precision cutting) until achieving a defined level of proficiency. For testing, participants were required to perform these tasks under three conditions: no distraction (control) and two standardised distractions in terms of phone calls requiring response (mild and strong distraction). Task performance was evaluated by analysing time and accuracy of the tasks and response of the phone call.

Results: In peg transfer (easy task), mild distraction did not worsen the performance significantly, while strong distraction was linked to error and inefficiency with significantly deteriorated performance (P < 0.05). Precision cutting (difficult task) was not slowed down by mild distraction, but surgical and cognitive errors were significantly increased when participants were distracted (P < 0.05). Compared to mild distraction, participants reported a more severe subjective disturbance when they were diverted by strong distraction (P < 0.05).

Conclusion: Our data reveals that phone call distractions result in impaired laparoscopic performance under certain circumstances. To ensure patient safety, phone calls should be avoided as far as possible in operating rooms.
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http://dx.doi.org/10.1007/s00464-017-5609-7DOI Listing
December 2017

Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival.

Oncoimmunology 2017;6(3):e1286436. Epub 2017 Feb 23.

Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.

On a broader scale, T cell density and localization in colorectal cancer liver metastases have prognostic and predictive implications. As T cell distribution at higher resolutions has not been fully investigated, a detailed resolution analysis of T cell distribution was performed. Patient tissues were divided into 10 µm distance classes between the tumor border and adjacent normal liver. Thereby, distinct density patterns of T cell localization in relation to the malignant tissue could be detected. At a distance of 20 to 30 µm to the tumor, a decrease of CD3 T cells is common. Within this area, cytotoxic Granzyme B and CD8 T cells were found to be significantly reduced as well as CD163 macrophages were increased and identified to be in close contact with T cells. Our data suggests a physical or functional border within this region. Survival analysis revealed improved overall survival in patients with high T cells numbers at the direct tumor border. Interestingly, the decreased T cells in the 20 to 30 µm region were also found to be significantly associated with improved survival. Consequently, the detailed localization of T cells, despite blockade, could be associated with improved clinical outcome. The high-resolution analysis represents new insights into relevant heterogenous T cell distributions especially related to clinical responses. As the paradoxical observation of localization-dependent prognostic relevance of T cell densities is only detectable by detailed spatial analyses, this investigation of spatial profiles at higher resolutions is suggested as a new biomarker for survival and response to therapies.
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http://dx.doi.org/10.1080/2162402X.2017.1286436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384380PMC
February 2017

Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients.

BMC Cancer 2016 07 18;16:494. Epub 2016 Jul 18.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Matrixmetalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases which are involved in angiogenesis, tumor invasion and metastatic formation. Up to date, the prognostic relevance of MMPs in serum of patients with colon cancer remains unknown. Thus, we wanted to assess an expression pattern of MMPs in a homogenous cohort of colon cancer patients to assess their potential as prognostic biomarkers.

Methods: Differences in the expression pattern of MMP7, MMP10 and MMP12 in 78 serum specimens of patients with an adenocarcinoma of the colon and serum specimens of a healthy control group were assessed using Luminex-100 technologies. Subsequently, we correlated these results with histopathological and clinical data of the patients.

Results: Luminex based expression analysis revealed a significant overexpression of MMP7 and an overexpression of MMP10 and MMP12 in the sera of colon cancer patients compared to the healthy control group. Patients with vascular invasion showed a significantly higher MMP12 expression than V0-staged patients. Moreover overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera displayed a significantly impaired overall survival. Multivariate analysis revealed high MMP10 serum levels to be an independent adverse prognostic marker in colon cancer patients.

Conclusions: Expression patterns of MMP7, MMP10 and MMP12 in colon cancer patients´ sera are different compared to serum specimens of healthy individuals. Furthermore, overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera correlates with a dismal prognosis and may help to stratify patients into different risk groups.
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http://dx.doi.org/10.1186/s12885-016-2515-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950722PMC
July 2016

Exosomes: novel implications in diagnosis and treatment of gastrointestinal cancer.

Langenbecks Arch Surg 2016 Dec 24;401(8):1097-1110. Epub 2016 Jun 24.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Background: Amongst all cancer subtypes, gastrointestinal tumours are responsible for most cancer-related deaths. In most of the cases, the limitation of the prognosis of patients with malignant gastrointestinal tumours can be attributed to delayed diagnosis of the disease. In the last decade, secondary prevention strategies, in particular tumour screenings, have been identified to significantly improve the identification of patients with early-stage disease, leading to more effective therapeutic interventions. Therefore, new screening methods and further innovative treatment approaches may lead to an increase in progression-free and overall survival rates.

Purpose: Exosomes are small microvesicles with a size of 50-150 nm. They are formed in the endosomal system of many different cell types, where they are packed with nucleotides and proteins from the parental cell. After their release into the extracellular space, exosomes can deliver their cargo into recipient cells. By this mechanism, tumour cells can recruit and manipulate the adjacent and systemic microenvironment in order to support invasion and dissemination. Cancer-derived exosomes in the blood may provide detailed information about the tumour biology of each individual patient. Moreover, tumour-derived exosomes can be used as targetable factors and drug delivery agents in clinical practice.

Conclusion: In this review, we summarise new aspects about novel implications in the diagnosis and treatment of gastrointestinal cancer and show how circulating exosomes have come into the spotlight of research as a high potential source of 'liquid biopsies'.
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http://dx.doi.org/10.1007/s00423-016-1468-2DOI Listing
December 2016

Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients.

Cancer Cell 2016 Apr;29(4):587-601

Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.

The immune response influences the clinical course of colorectal cancer (CRC). Analyzing the invasive margin of human CRC liver metastases, we identified a mechanism of immune cell exploitation by tumor cells. While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5. CCR5 blockade in patient-derived functional in vitro organotypic culture models showed a macrophage repolarization with anti-tumoral effects. These anti-tumoral effects were then confirmed in a phase I trial with a CCR5 antagonist in patients with liver metastases of advanced refractory CRC. Mitigation of tumor-promoting inflammation within the tumor tissue and objective tumor responses in CRC were observed.
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http://dx.doi.org/10.1016/j.ccell.2016.03.005DOI Listing
April 2016

Prolyl Hydroxylase 3 Attenuates MCL-1-Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells.

Cancer Res 2016 04 26;76(8):2219-30. Epub 2016 Feb 26.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219-30. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1474DOI Listing
April 2016

Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.

Nature 2015 Jul 24;523(7559):177-82. Epub 2015 Jun 24.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.

Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
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http://dx.doi.org/10.1038/nature14581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825698PMC
July 2015

Expressional STAT3/STAT5 Ratio is an Independent Prognostic Marker in Colon Carcinoma.

Ann Surg Oncol 2015 Dec 13;22 Suppl 3:S1548-55. Epub 2015 Mar 13.

Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: Signal transducer and activator of transcription proteins (STATs) are crucial regulators of cell growth and differentiation; however, their specific prognostic impact in human colon cancer has only been studied to limited extent. We aimed to assess the prognostic significance of specific STAT expression patterns in colon carcinoma.

Methods: Protein expression patterns of activated STAT1, STAT3, STAT4, and STAT5 in human colon carcinoma tissue and corresponding healthy mucosa (n = 104) were assessed using multiplex bead-based immunoassay technologies. Expression patterns were correlated with clinical and survival data. Immunohistochemistry was performed to assess spatial expression of STAT3 and STAT5.

Results: STAT3 was underexpressed whereas STAT4 and STAT5 were overexpressed in colon carcinoma tissue. Primary tumors from patients with distant metastases (M1) displayed significantly increased expression of STAT1 and STAT3 but decreased expression of STAT4 and STAT5. Increased tumor expression of STAT1 or STAT3 was associated with impaired patient survival, whereas increased expression of STAT4 or STAT5 correlated with improved survival. Multivariate analysis identified an increased STAT3/STAT5 expressional ratio as an adverse prognostic marker in colon cancer patients.

Conclusions: The tumor progression-associated transcription factors STAT3, STAT4, and STAT5 are differently expressed in colon carcinoma tissue and colon mucosa. Moreover, the STAT3/STAT5 expression ratio is an independent prognostic marker in colon cancer patients.
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http://dx.doi.org/10.1245/s10434-015-4485-4DOI Listing
December 2015

Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity.

Cancer Lett 2015 Mar 18;358(2):161-169. Epub 2014 Dec 18.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive growth, early metastasis and high resistance to chemotherapy. Salinomycin is a promising compound eliminating cancer stem cells and retarding cancer cell migration. The present study investigated the effectiveness of salinomycin against PDAC in vivo and elucidated the mechanism of PDAC growth inhibition. Salinomycin treatment was well tolerated by the mice and significantly reduced tumor growth after 19 days compared to the control group (each n = 16). There was a trend that salinomycin also impeded metastatic spread to the liver and peritoneum. Whereas salinomycin moderately induced apoptosis and retarded proliferation at 5-10 µM, it strongly inhibited cancer cell migration that was accompanied by a marked loss of actin stress fibers after 6-9 h. Salinomycin silenced RhoA activity, and loss of stress fibers could be reversed by Rho activation. Moreover, salinomycin dislocated fascin from filopodia and stimulated Rac-associated circular dorsal ruffle formation. In conclusion, salinomycin is an effective and promising compound against PDAC. Besides its known stem cell-specific cytotoxic effects, salinomycin blocks cancer cell migration by disrupting stress fiber integrity and affecting the mutual Rho-GTPase balance.
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http://dx.doi.org/10.1016/j.canlet.2014.12.037DOI Listing
March 2015

Prognostic impact of a compartment-specific angiogenic marker profile in patients with pancreatic cancer.

Oncotarget 2014 Dec;5(24):12978-89

Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany.

Pancreatic cancer consists of a heterogenous bulk of tumor cells and stroma cells which contribute to tumor progression by releasing angiogenic factors. Those factors can be detected as circulating serum factors. We performed a compartment-specific analysis of tumor-derived and stroma-derived angiogenic factors to identify biomarkers and molecular targets for the treatment of pancreatic cancer. Kryo-frozen tissue from primary ductal adenocarcinomas (n = 51) was laser-microdissected to isolate tumor and stroma tissue. Expression of 17 angiogenic factors (angiopoietin-2, follistatin, GCSF, HGF, interleukin-8, leptin, PDGF-BB, PECAM-1, VEGF, matrix metalloproteinase -1, -2, -3, -7, -9, -10, -12, and -13) was analyzed using a multiplex elisa assay for tissue-derived proteins and corresponding serum. Our study reveals a compartment-specific expression profile for several angiogenic factors and matrix metalloproteinases. ROC analysis of corresponding serum samples reveals MMP-7 and MMP-12 as strong classifiers for the diagnosis of patients with pancreatic cancer vs. healthy control donors. High expression of tumor-derived PDGF-BB and MMP-1 correlates with prolonged survival in univariate and multivariate analysis. In conclusion, a distinct expression patterns for angiogenic cytokines and MMPs in pancreatic cancer and surrounding stroma may implicate them as novel targets for cancer treatment. Tumor-derived PDGF-BB and MMP-1 are significant and independent prognostic markers for poor survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350362PMC
http://dx.doi.org/10.18632/oncotarget.2651DOI Listing
December 2014

Prospective evaluation of the International Study Group for Liver Surgery definition of bile leak after a liver resection and the role of routine operative drainage: an international multicentre study.

HPB (Oxford) 2015 Jan 24;17(1):46-51. Epub 2014 Jul 24.

Flinders Medical Centre, Bedford Park, SA, Australia; Flinders University of South Australia, Bedford Park, SA, Australia.

Background: The International Study Group for Liver Surgery (ISGLS) proposed a definition for bile leak after liver surgery. A multicentre international prospective study was designed to evaluate this definition.

Methods: Data collected prospectively from 949 consecutive patients on specific datasheets from 11 international centres were collated centrally.

Results: Bile leak occurred in 69 (7.3%) of patients, with 31 (3.3%), 32 (3.4%) and 6 (0.6%) classified as grade A, B and C, respectively. The grading system of severity correlated with the Dindo complication classification system (P < 0.001). Hospital length of stay was increased when bile leak occurred, from a median of 7 to 15 days (P < 0.001), as was intensive care stay (P < 0.001), and both correlated with increased severity grading of bile leak (P < 0.001). 96% of bile leaks occurred in patients with intra-operative drains. Drain placement did not prevent subsequent intervention in the bile leak group with a 5-15 times greater risk of intervention required in this group (P < 0.001).

Conclusion: The ISGLS definition of bile leak after liver surgery appears robust and intra-operative drain usage did not prevent the need for subsequent drain placement.
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http://dx.doi.org/10.1111/hpb.12322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266440PMC
January 2015

Peritoneal dissemination of a gastric API2-MALT1-positive MALT lymphoma.

J Clin Pathol 2014 Aug 18;67(8):746-8. Epub 2014 Jun 18.

Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany.

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http://dx.doi.org/10.1136/jclinpath-2014-202297DOI Listing
August 2014

Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer.

J Biol Chem 2014 Feb 7;289(7):3869-75. Epub 2014 Jan 7.

From the Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.

Exosomes are small vesicles (50-150 nm) of endocytic origin that are released by many different cell types. Exosomes in the tumor microenvironment may play a key role in facilitating cell-cell communication. Exosomes are reported to predominantly contain RNA and proteins. In this study, we investigated whether exosomes from pancreatic cancer cells and serum from patients with pancreatic ductal adenocarcinoma contain genomic DNA. Our results provide evidence that exosomes contain >10-kb fragments of double-stranded genomic DNA. Mutations in KRAS and p53 can be detected using genomic DNA from exosomes derived from pancreatic cancer cell lines and serum from patients with pancreatic cancer. In addition, using whole genome sequencing, we demonstrate that serum exosomes from patients with pancreatic cancer contain genomic DNA spanning all chromosomes. These results indicate that serum-derived exosomes can be used to determine genomic DNA mutations for cancer prediction, treatment, and therapy resistance.
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http://dx.doi.org/10.1074/jbc.C113.532267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924256PMC
February 2014

Impact of preoperative diabetes on long-term survival after curative resection of pancreatic adenocarcinoma: a systematic review and meta-analysis.

Ann Surg Oncol 2014 Apr 10;21(4):1082-9. Epub 2013 Dec 10.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.

Background: Diabetes mellitus (DM) is coupled to the risk and symptomatic onset of pancreatic ductal adenocarcinoma (PDAC). The important question whether DM influences the prognosis of resected PDAC has not been systematically evaluated in the literature. We therefore performed a systematic review and meta-analysis evaluating the impact of preoperative DM on survival after curative surgery.

Methods: The databases Medline, Embase, Web of Science, and the Cochrane Library were searched for studies reporting on the impact of preoperative DM on survival after PDAC resection. Hazard ratios and 95 % confidence intervals (CI) were extracted. The meta-analysis was calculated using the random-effects model.

Results: The data search identified 4,365 abstracts that were screened for relevant articles. Ten retrospective studies with a cumulative sample size of 4,471 patients were included in the qualitative review. The mean prevalence of preoperative DM was 26.7 % (1,067 patients), and all types of pancreatic resections were considered. The meta-analysis included 8 studies and demonstrated that preoperative DM is associated with a worse overall survival after curative resection of PDAC (hazard ratio 1.32, 95 % CI 1.46-1.60, P = 0.004). Only 2 studies reported separate data for new-onset and long-standing DM.

Conclusions: To our knowledge, this is the first meta-analysis evaluating long-term survival after PDAC resection in normoglycemic and diabetic patients, demonstrating a significantly worse outcome in the latter group. The mechanism behind this observation and the question whether different antidiabetic medications or early control of DM can improve survival in PDAC should be evaluated in further studies.
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http://dx.doi.org/10.1245/s10434-013-3415-6DOI Listing
April 2014

Intraoperative Electron Radiation Therapy (IOERT) in the management of locally recurrent rectal cancer.

BMC Cancer 2012 Dec 11;12:592. Epub 2012 Dec 11.

Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.

Background: To evaluate disease control, overall survival and prognostic factors in patients with locally recurrent rectal cancer after IOERT-containing multimodal therapy.

Methods: Between 1991 and 2006, 97 patients with locally recurrent rectal cancer have been treated with surgery and IOERT. IOERT was preceded or followed by external beam radiation therapy (EBRT) in 54 previously untreated patients (median dose 41.4 Gy) usually combined with 5-Fluouracil-based chemotherapy (89%). IOERT was delivered via cylindric cones with doses of 10-20 Gy. Adjuvant CHT was given only in a minority of patients (34%). Median follow-up was 51 months.

Results: Margin status was R0 in 37%, R1 in 33% and R2 in 30% of the patients. Neoadjuvant EBRT resulted in significantly increased rates of free margins (52% vs. 24%). Median overall survival was 39 months. Estimated 5-year rates for central control (inside the IOERT area), local control (inside the pelvis), distant control and overall survival were 54%, 41%, 40% and 30%. Resection margin was the strongest prognostic factor for overall survival (3-year OS of 80% (R0), 37% (R1), 35% (R2)) and LC (3-year LC 82% (R0), 41% (R1), 18% (R2)) in the multivariate model. OS was further significantly affected by clinical stage at first diagnosis and achievement of local control after treatment in the univariate model. Distant failures were found in 46 patients, predominantly in the lung. 90-day postoperative mortality was 3.1%.

Conclusion: Long term OS and LC can be achieved in a substantial proportion of patients with recurrent rectal cancer using a multimodality IOERT-containing approach, especially in case of clear margins. LC and OS remain limited in patients with incomplete resection. Preoperative re-irradiation and adjuvant chemotherapy may be considered to improve outcome.
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http://dx.doi.org/10.1186/1471-2407-12-592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557137PMC
December 2012

Expression analysis of aldehyde dehydrogenase 1A1 (ALDH1A1) in colon and rectal cancer in association with prognosis and response to chemotherapy.

Ann Surg Oncol 2012 Dec 10;19(13):4193-201. Epub 2012 Aug 10.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been described as a cancer stem cell marker and as a regulator of cellular chemoresistance. Therefore, ALDH1A1 has been suggested as potential biomarker to stratify patients into different risk categories for a "personalized" therapy approach. We have investigated the prognostic role of ALDH1A1 in primary colorectal cancer and its value in predicting response to chemotherapy in metastatic colorectal cancer.

Methods: Immunostaining against ALDH1A1 was performed on a paraffin-embedded tissue microarray including 659 primary colon cancer samples and 338 rectal cancer samples. Likewise, tissue of 44 palliatively resected colorectal liver metastases on whole-mount tissue slides was immunostained against ALDH1A1. Cytoplasmic, nuclear, and stromal expression of ALDH1A1 was assessed and merged with histopathological and clinical data.

Results: Univariate and multivariate analysis revealed that cytoplasmic and stromal expression of ALDH1A1 is not significantly associated with prognosis either in colon or in rectal cancer. Furthermore, cytoplasmic expression of ALDH1A1 does not predict response to palliative chemotherapy in patients with metastatic diseases. Intriguingly, as a novel finding, nuclear expression of ALDH1A1 was observed in a small subgroup of patients with colon cancer and rectal cancer. In colon cancer, nuclear expression was significantly associated with shortened overall survival by univariate and multivariate analysis.

Conclusions: Immunohistochemical expression analysis of ALDH1A1 in colon cancer is useful for the detection of nuclear expression in a small subpopulation of patients and is associated with shorter survival. Cytoplasmic expression fails to be of clinical relevance as prognostic or predictive marker in colorectal cancer.
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http://dx.doi.org/10.1245/s10434-012-2518-9DOI Listing
December 2012

A clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma.

BMC Cancer 2012 Jul 12;12:287. Epub 2012 Jul 12.

Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered.

Methods/design: The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50-56 Gy) followed by surgery and IORT (10-12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population.

Discussion: The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity.

Trial Registration: NCT01566123.
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http://dx.doi.org/10.1186/1471-2407-12-287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495760PMC
July 2012

Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy.

Cancer Res 2011 Sep 16;71(17):5670-7. Epub 2011 Aug 16.

Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany.

Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-0268DOI Listing
September 2011

Technical and clinical outcome of transjugular intrahepatic portosystemic stent shunt: bare metal stents (BMS) versus viatorr stent-grafts (VSG).

Eur J Radiol 2012 Sep 23;81(9):2273-80. Epub 2011 Jul 23.

Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg, Germany.

Purpose: To compare retrospectively angiographical and clinical results in patients undergoing transjugular intrahepatic portosystemic stent-shunt (TIPS) using BMS or VSG.

Materials And Methods: From February 2001 to January 2010, 245 patients underwent TIPS. From those, 174 patients matched the inclusion criteria with elective procedures and institutional follow-up. Group (I) consisted of 116 patients (mean age, 57.0±11.1 years) with BMS. Group (II) consisted of 58 patients with VSG (mean age, 53.5±16.1 years). Angiographic and clinical controls were scheduled at 3, 6 and 12 months, followed by clinical controls every 6 months. Primary study goals included hemodynamic success, shunt patency as well as time to and number of revisions. Secondary study goals included clinical success.

Results: Hemodynamic success was 92.2% in I and 91.4% in II (n.s.). Primary patency was significantly higher in II compared to I (53.8% after 440.4±474.5 days versus 45.8% after 340.1±413.8 days; p<0.05). The first TIPS revision was performed significantly later in II compared to I (288.3±334.7 days versus 180.1±307.0 days; p<0.05). In the first angiographic control, a portosystemic pressure gradient ≥15 mmHg was present in 73.9% in I and in 39.4% in II (p<0.05). Clinical success was 73.7-86.2% after 466.3±670.1 days in I and 85.7-90.5% after 617.5±642.7 days in II (n.s.). Hepatic encephalopathy was 37.5% in I and 36.5% in II (n.s.).

Conclusion: VSG increased primary shunt patency as well as decreased time to and number of TIPS revisions. There was a trend of higher clinical success in VSG without increased hepatic encephalopathy.
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http://dx.doi.org/10.1016/j.ejrad.2011.06.037DOI Listing
September 2012

Invasion front-specific expression and prognostic significance of microRNA in colorectal liver metastases.

Cancer Sci 2011 Oct 4;102(10):1799-807. Epub 2011 Aug 4.

Department of Surgery, University of Heidelberg, Heidelberg, Germany.

The tumor edge of colorectal cancer and its adjacent peritumoral tissue is characterized by an invasion front-specific expression of genes that contribute to angiogenesis or epithelial-to-mesenchymal transition. Dysregulation of these genes has a strong impact on the invasion behavior of tumor cells. However, the invasion front-specific expression of microRNA (miRNA) still remains unclear. Therefore, the aim of the present study was to investigate miRNA expression patterns at the invasion front of colorectal liver metastases. Laser microdissection of colorectal liver metastases was performed to obtain separate tissue compartments from the tumor center, tumor invasion front, liver invasion front and pure liver parenchyma. Microarray expression analysis revealed 23 miRNA downregulated in samples from the tumor invasion front with respect to the same miRNA in the liver, the liver invasion front or the tumor center. By comparing samples from the liver invasion front with samples from pure liver parenchyma, the tumor invasion front and the tumor center, 13 miRNA were downregulated. By quantitative RT-PCR, we validated the liver invasion front-specific downregulation of miR-19b, miR-194, let-7b and miR-1275 and the tumor invasion front-specific downregulation of miR-143, miR- 145, let-7b and miR-638. Univariate analysis demonstrated that enhanced expression of miR-19b and miR-194 at the liver invasion front, and decreased expression of let-7 at the tumor invasion front, is an adverse prognostic marker of tumor recurrence and overall survival. In conclusion, the present study suggests that invasion front-specific downregulation of miRNA in colorectal liver metastases plays a pivotal role in tumor progression.
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http://dx.doi.org/10.1111/j.1349-7006.2011.02023.xDOI Listing
October 2011