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Pancreatic Neoplasms: HELP
Articles by Steffen Ormanns
Based on 29 articles published since 2010
(Why 29 articles?)
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Between 2010 and 2020, S. Ormanns wrote the following 29 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review [Personalized cancer medicine : Biomarkers for molecular therapy stratification in pancreatic carcinoma]. 2018

Ormanns, S. ·Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, München, Deutschland. steffen.ormanns@med.uni-muenchen.de. ·Pathologe · Pubmed #30361776.

ABSTRACT: Ductal adenocarcinoma of the pancreas has a very poor prognosis and a rising incidence. Even after curative intent resection, which is possible in a minority of patients, most patients relapse, whereas the majority is diagnosed with inoperable or metastatic disease. That's why palliative systemic chemotherapy is the current therapeutic mainstay. Biomarker-based tumor characterization could identify potential therapy targets and enable a personalized cancer medicine. Although potentially targetable alterations occur at very low frequencies, the possible impact on patient outcome can be significant. This article summarizes some of the contributions to these aspects and gives an outlook on their clinical meaning.

2 Review Prevailing over T cell exhaustion: New developments in the immunotherapy of pancreatic cancer. 2016

Bauer, Christian / Kühnemuth, Benjamin / Duewell, Peter / Ormanns, Steffen / Gress, Thomas / Schnurr, Max. ·Division of Gastroenterology, Endocrinology, Infectiology and Metabolism, University Hospital Giessen and Marburg, Campus Marburg, Philipps University Marburg, Baldingerstraße, Marburg 35043, Germany. · Division of Clinical Pharmacology & Center for Integrated Protein Science Munich (CIPSM), Klinikum der Universität München, Ludwig-Maximilians-University, Lindwurmstraße 2a, Munich 80337, Germany. · Institute of Pathology, Ludwig-Maximilians-University, Thalkirchner Strasse 36, Munich 80337, Germany. · Division of Gastroenterology, Endocrinology, Infectiology and Metabolism, University Hospital Giessen and Marburg, Campus Marburg, Philipps University Marburg, Baldingerstraße, Marburg 35043, Germany. Electronic address: gress@med.uni-marburg.de. ·Cancer Lett · Pubmed #26968250.

ABSTRACT: Pancreatic cancer is one of the most aggressive malignancies and has been considered poorly immunogenic for decades. However, this characterization might be over-simplistic. A more sophisticated approach is needed in order to develop new treatment strategies. In this review, we will focus on T cell exhaustion as a phenomenon of immune failure that is a useful paradigm to characterize immunosuppressive effects. Cancer creates an environment of constant antigen exposure and inflammation. In this setting, T cells transform into a differentiation state that has been termed T cell exhaustion, which is characterized by upregulation of inhibitory receptors, resulting in loss of effector function. The discovery of receptor-mediated immune checkpoints, which prevent uncontrolled T cell reactions, led to the development of a new class of antibodies termed checkpoint inhibitors. Unprecedented results in patients with metastatic melanoma and lung cancer have renewed interest in the immunotherapy of other solid tumor entities, including pancreatic cancer. Data on the efficacy of checkpoint inhibitors in pancreatic cancer are still sparse and indicate limited efficacy as single agents. Combination of checkpoint inhibitors with other immune-activating strategies or cytotoxic drugs might be a way to overcome therapy resistance in the treatment of pancreatic cancer.

3 Review Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. 2014

Kruger, Stephan / Haas, Michael / Ormanns, Steffen / Bächmann, Sibylle / Siveke, Jens T / Kirchner, Thomas / Heinemann, Volker / Boeck, Stefan. ·Stephan Kruger, Michael Haas, Sibylle Bächmann, Volker Heinemann, Stefan Boeck, Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. ·World J Gastroenterol · Pubmed #25152580.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified chemotherapy regimen folinic acid, irinotecan and oxaliplatin, the epidermal growth factor receptor inhibitor erlotinib or the recently FDA-approved nab-paclitaxel. Up to date, no established approach for prediction of treatment response or specific treatment allocation exists. Translational research was able to identify a number of potential biomarkers that might help to improve the dismal prognosis of PDA by facilitating upfront treatment allocation. This topic highlight is focused on current evidence on potential biomarkers for tumor biology, prognosis and prediction of treatment efficacy.

4 Clinical Trial The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy. 2017

Ormanns, Steffen / Haas, Michael / Remold, Anna / Kruger, Stephan / Holdenrieder, Stefan / Kirchner, Thomas / Heinemann, Volker / Boeck, Stefan. ·Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany. steffen.ormanns@med.uni-muenchen.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. michael.haas@med.uni-muenchen.de. · Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany. annaremold@yahoo.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. annaremold@yahoo.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. stephan.kruger@med.uni-muenchen.de. · Institute of Laboratory Medicine, German Heart Centre Munich, Technische Universität München, 80333 Munich, Germany. holdenrieder@dhm.mhn.de. · Institute of Clinical Chemistry and Clinical Pharmacology, Universitätsklinikum Bonn, 53127 Bonn, Germany. holdenrieder@dhm.mhn.de. · Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany. thomas.kirchner@med.uni-muenchen.de. · Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. thomas.kirchner@med.uni-muenchen.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. volker.heinemann@med.uni-muenchen.de. · Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. volker.heinemann@med.uni-muenchen.de. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany. stefan.boeck@med.uni-muenchen.de. · Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. stefan.boeck@med.uni-muenchen.de. ·Int J Mol Sci · Pubmed #28534865.

ABSTRACT: The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (

5 Clinical Trial pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. 2014

Ormanns, Steffen / Siveke, Jens T / Heinemann, Volker / Haas, Michael / Sipos, Bence / Schlitter, Anna Melissa / Esposito, Irene / Jung, Andreas / Laubender, Rüdiger P / Kruger, Stephan / Vehling-Kaiser, Ursula / Winkelmann, Cornelia / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Gauler, Thomas C / Märten, Angela / Geissler, Michael / Greten, Tim F / Kirchner, Thomas / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, München, Germany. stefan.boeck@med.uni-muenchen.de. ·BMC Cancer · Pubmed #25164437.

ABSTRACT: BACKGROUND: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. METHODS: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. RESULTS: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. CONCLUSION: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash. TRIAL REGISTRATION: NCT00440167 (registration date: February 22, 2007).

6 Clinical Trial Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody. 2014

Ormanns, Steffen / Heinemann, Volker / Raponi, Mitch / Isaacson, Jeff / Laubender, Rüdiger P / Haas, Michael / Kruger, Stephan / Kleespies, Axel / Mann, Elaina / Bartosiewicz, Mike / Kirchner, Thomas / Boeck, Stefan. ·Department of Pathology, Ludwig-Maximilians-University of Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. · Clovis Oncology Inc., San Francisco, CA, USA. · German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. · Department of Pathology, Ludwig-Maximilians-University of Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. Electronic address: stefan.boeck@med.uni-muenchen.de. ·Eur J Cancer · Pubmed #24857044.

ABSTRACT: BACKGROUND: The role of human equilibrative nucleoside transporter 1 (hENT1) as a predictive biomarker for gemcitabine efficacy in advanced pancreatic cancer remains unclear to date. PATIENTS AND METHODS: AIO-PK0104 was a German multicenter phase III trial comparing gemcitabine/erlotinib followed by capecitabine (GEC) with capecitabine/erlotinib followed by gemcitabine (CEG) in advanced pancreatic cancer. Archival tumour tissue from 169 of the 274 eligible study patients was available for a central and standardised immunohistochemistry staining for hENT1 expression using the SP120 rabbit monoclonal anti-hENT1 antibody. Within a retrospective translational subgroup analysis, biomarker data were correlated with efficacy end-points. RESULTS: Thirty-nine out of 130 fresh-cut slides were scored as hENT1(high) (30%), whereas 91 samples were classified as hENT1(low) (70%). For the 62 patients randomised to CEG median overall survival was estimated with 6.4 months in the hENT1(low) compared to 6.9 months in the hENT1(high) subgroup (Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.48-1.61, p=0.67). For the 68 patients randomised to GEC survival was 5.7 months in the hENT1(low) compared to 4.4 months in the hENT1(high) subgroup (HR 1.16, 95% CI 0.69-1.96, p=0.57). In 101 patients receiving gemcitabine at any time during study treatment (either within the 1st- or 2nd-line setting) hENT1(low) cases had a median overall survival of 7.5 months and hENT1(high) patients an overall survival of 4.4 months (HR 1.30, 95% CI 0.84-2.03, p=0.24), respectively. CONCLUSION: Within this subgroup analysis from Arbeitsgemeinschaft Internistische Onkologie-pancreatic cancer (AIO-PK0104), no evidence supporting the use of hENT1 as a predictive biomarker for gemcitabine efficacy in patients with advanced pancreatic cancer was found.

7 Clinical Trial Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. 2013

Poplin, Elizabeth / Wasan, Harpreet / Rolfe, Lindsey / Raponi, Mitch / Ikdahl, Tone / Bondarenko, Ihor / Davidenko, Irina / Bondar, Volodymyr / Garin, August / Boeck, Stefan / Ormanns, Steffen / Heinemann, Volker / Bassi, Claudio / Evans, T R Jeffrey / Andersson, Roland / Hahn, Hejin / Picozzi, Vince / Dicker, Adam / Mann, Elaina / Voong, Cynthia / Kaur, Paramjit / Isaacson, Jeff / Allen, Andrew. ·Elizabeth Poplin, Cancer Institute of New Jersey, New Brunswick, NJ · Mitch Raponi, Elaina Mann, Cynthia Voong, and Andrew Allen, Clovis Oncology, San Francisco, CA · Hejin Hahn and Vince Picozzi, Virginia Mason Medical Center, Seattle, WA · Adam Dicker, Radiation Therapy Oncology Group, Philadelphia, PA · Jeff Isaacson, Clovis Oncology, Boulder, CO · Harpreet Wasan, Hammersmith Hospital, London · Lindsey Rolfe and Paramjit Kaur, Clovis Oncology UK, Cambridge · T.R. Jeffrey Evans, University of Glasgow, Glasgow, United Kingdom · Tone Ikdahl, Oslo Universitetssykehus, Oslo, Norway · Ihor Bondarenko, Dnipropetrovsk State Medical Academy, Dnipropetrovsk · Volodymyr Bondar, Donetsk Regional Antitumor Center, Donetsk, Ukraine · Irina Davidenko, Clinical Oncology Center 1, Krasnodar · August Garin, Blokhin Russian Cancer Research Center, Moscow, Russia · Stefan Boeck, Steffen Ormanns, and Volker Heinemann, Ludwig-Maximilians-University of Munich, Munich, Germany · Claudio Bassi, Ospedale Policlinico G.B. Rossi, Verona, Italy · and Roland Andersson, Lund University, Lund, Sweden. ·J Clin Oncol · Pubmed #24220555.

ABSTRACT: PURPOSE: Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. PATIENTS AND METHODS: Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. RESULTS: Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). CONCLUSION: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.

8 Clinical Trial KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. 2013

Boeck, Stefan / Jung, Andreas / Laubender, Rüdiger P / Neumann, Jens / Egg, Rosalind / Goritschan, Clara / Ormanns, Steffen / Haas, Michael / Modest, Dominik P / Kirchner, Thomas / Heinemann, Volker. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany. stefan.boeck@med.uni-muenchen.de ·J Gastroenterol · Pubmed #23435671.

ABSTRACT: BACKGROUND: It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC). METHODS: AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). RESULTS: KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc. CONCLUSION: This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.

9 Article Prolonged time to treatment initiation in advanced pancreatic cancer patients has no major effect on treatment outcome: a retrospective cohort study controlled for lead time bias and waiting time paradox. 2020

Kruger, Stephan / Schirle, Karoline / Haas, Michael / Crispin, Alexander / Schirra, Jörg / Mayerle, Julia / D'Haese, Jan G / Kunz, Wolfgang G / Ricke, Jens / Ormanns, Steffen / Kirchner, Thomas / Kobold, Sebastian / Ilmer, Matthias / Gebauer, Leonie / Westphalen, Christoph B / von Bergwelt-Baildon, Michael / Werner, Jens / Heinemann, Volker / Boeck, Stefan. ·Department of Medicine III, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany. stephan.kruger@med.uni-muenchen.de. · Division of Clinical Pharmacology and Center for Integrated Protein Science Munich (CIPSM), University Hospital, LMU Munich, Munich, Germany. stephan.kruger@med.uni-muenchen.de. · Department of Medicine III, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, LMU Munich, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Munich, Germany. · Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany. · Department of Radiology, University Hospital, LMU Munich, Munich, Germany. · Institute of Pathology, LMU Munich, Munich, Germany. · Division of Clinical Pharmacology and Center for Integrated Protein Science Munich (CIPSM), University Hospital, LMU Munich, Munich, Germany. ·J Cancer Res Clin Oncol · Pubmed #31642961.

ABSTRACT: PURPOSE: A prolonged time to treatment initiation (TTI) correlates with an adverse prognosis in different cancer types including resectable pancreatic cancer (PC). Only limited evidence on the correlation between TTI and prognosis in advanced PC exists. METHODS: Consecutive PC patients (n = 368) who were diagnosed or treated at our high-volume comprehensive cancer center were included in a prospectively maintained database. We retrospectively analyzed time from first imaging showing advanced PC to initiation of palliative first-line chemotherapy. Lead time bias and waiting time paradox were addressed by landmark analysis and correlation of tumor burden with TTI. RESULTS: Two hundred and ninety-seven patients met the pre-specified in- and exclusion criteria of our study. Median TTI was 29 days (range: 1-124 days). Most common reasons for prolonged TTI (> 21 days) were referral from an external treatment center (39%) and a second biopsy (31%). A TTI above the median-, 75th or 90th percentile (43 or 60 days, respectively) had no impact on overall survival. Furthermore, no correlation between levels of carbohydrate antigen 19-9 (CA 19-9) at time of treatment initiation and TTI was observed. CONCLUSION: While a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.

10 Article Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer. 2018

Kruger, S / Heinemann, V / Ross, C / Diehl, F / Nagel, D / Ormanns, S / Liebmann, S / Prinz-Bravin, I / Westphalen, C B / Haas, M / Jung, A / Kirchner, T / von Bergwelt-Baildon, M / Boeck, S / Holdenrieder, S. ·Department of Medicine III, University Hospital, LMU, Munich, Germany. · Sysmex Inostics, Hamburg, Germany. · Institute of Laboratory Medicine, University Hospital, LMU, Munich, Germany. · Institute of Pathology, LMU, Munich, Germany. · Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. · Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany. ·Ann Oncol · Pubmed #30346475.

ABSTRACT: Background: The presence of mutated KRAS (mutKRAS ctDNA) in plasma samples has been consistently shown to be a negative prognostic indicator in pancreatic cancer (PC). Only small pilot studies have evaluated the value of serial mutKRAS ctDNA-measurements in PC. Patients and methods: The aim of the present study was to explore the potential of repeated mutKRAS ctDNA measurements for response prediction and therapy monitoring in advanced PC patients. We used the BEAMing technology to determine levels of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 in 284 plasma samples of 54 patients with advanced PC receiving gemcitabine-based chemotherapy. Absolute levels and kinetics of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 were correlated to radiological response, progression-free and overall survival. Results: mutKRAS ctDNA was present in a majority of advanced PC patients (n = 36/54, 67%) and indicated tissue KRAS mutation status with a high sensitivity (75%) and specificity (100%). The presence of mutKRAS ctDNA, as well as higher levels of CA 19-9, CEA and CYFRA 21-1 before initiation of the first-line chemotherapy, was significantly correlated to an adverse overall survival. During therapy, changes in mutKRAS ctDNA levels were more rapid and pronounced than changes in protein-based tumor markers. A decrease in mutKRAS ctDNA levels during therapy was an early indicator of response to therapy, while there was no significant correlation between kinetics of CA 19-9, CEA or CYFRA 21-1 and response to chemotherapy during the first four weeks of treatment. Repeated mutKRAS ctDNA measurements during follow-up appeared to be superior to protein-based tumor markers in detecting progressive disease (sensitivity: 83%, specificity: 100%). Conclusion: mutKRAS ctDNA kinetics appear to be a powerful and highly specific tool in early response prediction and therapy monitoring of advanced PC patients receiving chemotherapy.

11 Article POLE gene hotspot mutations in advanced pancreatic cancer. 2018

Guenther, Michael / Veninga, Vivien / Kumbrink, Joerg / Haas, Michael / Westphalen, C Benedikt / Kruger, Stephan / Heinemann, Volker / Kirchner, Thomas / Boeck, Stefan / Jung, Andreas / Ormanns, Steffen. ·Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Thalkirchner Str. 36, 80337, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Comprehensive Cancer Center Munich (CCCM), Munich, Germany. · Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Thalkirchner Str. 36, 80337, Munich, Germany. steffen.ormanns@med.uni-muenchen.de. ·J Cancer Res Clin Oncol · Pubmed #30194485.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, lacking relevant prognostic and predictive biomarkers. DNA polymerase epsilon (POLE) has important functions in the maintenance of genetic stability during DNA replication and has previously been associated with favorable prognosis in endometrial and colorectal cancer. However, its relevance in advanced pancreatic cancer (aPDAC) has not been examined to date. METHODS: Using pyrosequencing on tumoral DNA extracted from 60 samples from the AIO-PK0104 study as well as 55 samples from completed translational trials, we examined POLE hotspot mutations in exon 9 (P286R) and exon 13 (V411R/L/M) in the POLE gene exonuclease domain. DNA extracted from 37 endometrial carcinomas were tested as positive controls. Publically available sequencing databases were searched for POLE mutations in PDAC samples. RESULTS: Fifty-three patients (pts) were men, 62 pts were women, median age was 61.2 years. Median overall survival (OS) was 7.4 months and median progression free survival (PFS) was 4.0 months. In four of the 37 endometrial carcinomas POLE mutations were detected in exon 9 (10.8%) and none in exon 13. In none of the overall 115 aPDAC tumors POLE gene hotspot mutations could be detected. CONCLUSION: Mutations in the hotspot regions of exon 9 and 13 of the POLE gene are very rare events in advanced pancreatic cancer. Thus, it is unlikely that POLE gene mutations contribute to genetic instability in the vast majority of aPDAC. POLE mutation does not serve as a relevant biomarker and should not be tested on a regular basis in PDAC.

12 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

13 Article [Chronic Pancreatitis and Pancreatic Cancer - Tumor Risk and Screening]. 2018

Beyer, Georg / D'Haese, Jan G / Ormanns, Steffen / Mayerle, Julia. · ·Dtsch Med Wochenschr · Pubmed #29898491.

ABSTRACT: Chronic pancreatitis is a fibroinflammatory syndrome of the exocrine pancreas, which is characterized by an increasing incidence, high morbidity and lethality. Common etiologies besides alcohol and nicotine consumption include genetic causes and risk factors. The life time risk for the development of pancreatic cancer is elevated 13- to 45-fold depending on the underlying etiology. In patients with chronic pancreatitis clinical, laboratory and imaging surveillance for early detection of complications, including pancreatic cancer, is recommended, although the available methods lack the desired sensitivity and specificity. In this article we review the epidemiology, etiologies and risk factors for chronic pancreatitis and pancreatic cancer and discuss current recommendations for screening and management of patients at risk for tumor development.

14 Article Development of a reliable and accurate algorithm to quantify the tumor immune stroma (QTiS) across tumor types. 2017

Miksch, Rainer Christoph / Hao, Jingcheng / Schoenberg, Markus Bo / Dötzer, Katharina / Schlüter, Friederike / Weniger, Maximilian / Yin, Shuai / Ormanns, Steffen / D'Haese, Jan Goesta / Guba, Markus Otto / Werner, Jens / Mayer, Barbara / Bazhin, Alexandr V. ·Department of General, Visceral and Transplantation Surgery, Ludwig-Maximilians University, Munich, Germany. · Department of Pathology, Ludwig-Maximilians University, Munich, Germany. · German Cancer Consortium (DKTK), Partner Site Munich, Germany. ·Oncotarget · Pubmed #29383131.

ABSTRACT: The tumor microenvironment plays an important role in the tumor biology. Overall survival of tumor patients after resection is influenced by tumor-infiltrating lymphocytes (TILs) as a component of the tumor stroma. However, it is not clear how to assess TILs in the tumor stroma due to heterogeneous methods in different cancer types. Therefore, we present a novel Quantification of the Tumor immune Stroma (QTiS) Algorithm to reliably and accurately quantify cells in the tumor stroma. Immunohistochemical staining of CD3 and CD8 cells in sections of metastatic colorectal cancer (mCRC), ovarian cancer (OvCa), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC), alltogether

15 Article Incidence, outcome and risk stratification tools for venous thromboembolism in advanced pancreatic cancer - A retrospective cohort study. 2017

Kruger, Stephan / Haas, Michael / Burkl, Carolin / Goehring, Peter / Kleespies, Axel / Roeder, Falk / Gallmeier, Eike / Ormanns, Steffen / Westphalen, Christoph Benedikt / Heinemann, Volker / Rank, Andreas / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Institute of Laboratory Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany. · Department of General, Visceral, Transplantation, Vascular, and Thoracic Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany. · Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Molecular Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. · Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, Marburg, Germany. · Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany. · Department of Hematology and Oncology, Klinikum Augsburg, Augsburg, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. Electronic address: stefan.boeck@med.uni-muenchen.de. ·Thromb Res · Pubmed #28675831.

ABSTRACT: INTRODUCTION: Venous thromboembolism (VTE) is frequent in advanced pancreatic cancer (APC). Recent studies demonstrated that the Khorana score - an established risk stratification tool for VTE in cancer - performs poorly in identifying pancreatic cancer patients at high risk for VTE. MATERIALS AND METHODS: We performed a retrospective cohort study in order to define incidence, treatment and outcome of VTE as well as the performance of VTE risk stratification tools (Khorana score, CONKO score and aPTT ratio) in a "real life" clinical cohort of APC patients undergoing palliative chemotherapy. RESULTS AND CONCLUSIONS: One hundred and seventy-two eligible APC patients from our comprehensive cancer center were identified. VTE after start of palliative chemotherapy was diagnosed in 71 patients (41.3%). Most VTE events were asymptomatic (n=50, 29.1%) with only 21 symptomatic events (12.2%). On multivariate analysis - including age, performance status and carbohydrate antigen 19-9 (CA 19-9) - symptomatic VTE was an independent risk factor for death (hazard ratio [HR]: 2.22, 95% CI: 1.05-2.60, p<0.05). Khorana score, CONKO score and aPTT ratio alone were not able to predict the risk for symptomatic VTE. High risk patients could only be identified by using a combination of either Khorana or CONKO score with aPTT ratio (30% vs. 10% symptomatic VTE events in high vs. low risk patients, p<0.05). The combination of Khorana or CONKO score with aPTT thus may represent a novel risk stratification tool for symptomatic VTE in APC and should further be validated within prospective clinical trials.

16 Article Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer. 2017

Kruger, Stephan / Legenstein, Marie-Louise / Rösgen, Verena / Haas, Michael / Modest, Dominik Paul / Westphalen, Christoph Benedikt / Ormanns, Steffen / Kirchner, Thomas / Heinemann, Volker / Holdenrieder, Stefan / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · DKTK, German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany. · Institute of Laboratory Medicine, German Heart Centre Munich, Technical University of Munich, Munich, Germany. · Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. ·Oncoimmunology · Pubmed #28638732.

ABSTRACT: Up to now, the efficacy of programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade in pancreatic cancer (PC) remains uncertain. Serum levels of soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have been reported to be independent prognostic factors in solid tumors susceptible to checkpoint blockade. Provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer are poorly understood. To the best of our knowledge, sPD-1 and sPD-L1 have not been measured conjointly in any cancer type yet. In contrast to other tumor entities, sPD-1/sPD-L1 levels did not indicate an adverse outcome in a cohort of 41 patients with advanced PC. We observed a close positive correlation of sPD-L1 levels with sPD-1 in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. Higher sPD-L1 levels were present in patients with elevated C-reactive protein or strong tumoral T cell infiltration, while no correlation of sPD-L1 levels with tumoral PD-L1 expression was found. Our findings indicate that sPD-1 and sPD-L1 are markers of systemic inflammation in (pancreatic) cancer. In a subset of PC patients, elevation in sPD-L1 levels might be caused by an inflammatory tumor type - independent of tumoral PD-L1 expression.

17 Article Switch in KRAS mutational status during an unusual course of disease in a patient with advanced pancreatic adenocarcinoma: implications for translational research. 2017

Baechmann, Sibylle / Ormanns, Steffen / Haas, Michael / Kruger, Stephan / Remold, Anna / Modest, Dominik Paul / Kirchner, Thomas / Jung, Andreas / Werner, Jens / Heinemann, Volker / Boeck, Stefan. ·Institute of Pathology, Ludwig-Maximilians University of Munich, Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr. 15, 81377, Munich, Germany. · DKTK, German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of General, Visceral, Vascular and Transplantation Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr. 15, 81377, Munich, Germany. stefan.boeck@med.uni-muenchen.de. ·BMC Cancer · Pubmed #28549417.

ABSTRACT: BACKGROUND: Despite the introduction of novel effective treatment regimens like gemcitabine plus nab-paclitaxel and FOLFIRINOX, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive epithelial tumors. Among the genetic alterations frequently found in PDAC, mutations in the KRAS gene might play a prognostic role regarding overall survival and may also have the potential to predict the efficacy of anti-EGFR treatment. CASE PRESENTATION: We report the clinical case of a 69 year old Caucasian female that was diagnosed with histologically confirmed locally advanced PDAC with lymph node involvement in August 2010. At the time of first diagnosis, tumor tissue obtained from an open regional lymph node biopsy showed a poorly differentiated adenocarcinoma with a wild type sequence within exon 2 (codon 12/13) of the KRAS gene. The patient initially received single-agent gemcitabine and a subsequent 5-FU-based chemoradiotherapy with a sequential maintenance chemotherapy with oral capecitabine resulting in a long term disease control. Local disease progression occurred in May 2014 and the patient underwent pancreaticoduodenectomy in September 2014. A novel KRAS gene mutation (c.35G > T, p.G12 V) in exon 2 (codon 12) was detected within the surgical specimen. As of January 2016 the patient is still alive and without evidence of the underlying disease. CONCLUSIONS: Specifically in the context of clinical trials and translational research in PDAC a re-assessment of molecular biomarkers, i. e. KRAS, at defined time points (e. g. relapse, disease progression, unusual clinical course) may be indicated in order to detect a potential switch in biomarker status during the course of disease.

18 Article Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer. 2017

Haas, Michael / Ormanns, Steffen / Baechmann, Sibylle / Remold, Anna / Kruger, Stephan / Westphalen, Christoph B / Siveke, Jens T / Wenzel, Patrick / Schlitter, Anna Melissa / Esposito, Irene / Quietzsch, Detlef / Clemens, Michael R / Kettner, Erika / Laubender, Ruediger P / Jung, Andreas / Kirchner, Thomas / Boeck, Stefan / Heinemann, Volker. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, Munich 81377, Germany. · Institute of Pathology, Ludwig-Maximilians-University of Munich, Germany and German Cancer Consortium (DKTK), Partner Site Munich, Thalkirchner Str. 36, Munich 80377, Germany. · 2nd Medical Department, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. · Division of Solid Tumour Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, University Hospital Essen, Hufelandstr. 55, Essen 45147, Germany. · Institute of Pathology, Technical University of Munich, Trogerstr. 18, Munich 81675, Germany. · Institute of Pathology, Heinrich Heine University of Duesseldorf, Moorenstr. 5, Duesseldorf 40225, Germany. · Department of Internal Medicine II, Klinikum Chemnitz gGmbH, Flemmingstr. 2, Chemnitz 09116, Germany. · Department of Hematology and Oncology, Mutterhaus der Boromaeerinnen, Feldstr. 16, Trier 54290, Germany. · Department of Hematology and Oncology, Klinikum Magdeburg, Birkenallee 34, Magdeburg 39130, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, Munich 81377, Germany. ·Br J Cancer · Pubmed #28449008.

ABSTRACT: BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. RESULTS: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2-4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). CONCLUSIONS: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.

19 Article Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells. 2017

Hütz, Katharina / Zeiler, Julian / Sachs, Lena / Ormanns, Steffen / Spindler, Volker. ·Department I, Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany. · Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany. ·Mol Carcinog · Pubmed #28277619.

ABSTRACT: The ability to maintain cell-cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents contributes to cancer progression through altered cell signaling pathways. Here, we focused on the desmosomal adhesion molecules Desmoglein 2 (Dsg2) and Desmocollin 2 (Dsc2), and their contribution to migration and invasion in pancreatic cancer cells. Silencing of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration, and invasion of pancreatic adenocarcinoma cells. To identify potential pathways regulated by Dsg2, we performed kinase arrays and detected the activity of ERK and growth factor receptors to be significantly enhanced in Dsg2-deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells normalized migration. Loss of Dsg2 resulted in reduced levels of the desmosomal adapter protein and transcriptional regulator Plakoglobin (PG) in an ERK-dependent manner, whereas other desmosomal molecules were not altered. Overexpression of PG rescued enhanced migration induced by silencing of Dsg2. These results identify a novel pro-migratory pathway of pancreatic cancer cells in which loss of Dsg2 reduces the levels of PG via deregulated MAPK signaling.

20 Article Impact of SPARC expression on outcome in patients with advanced pancreatic cancer not receiving nab-paclitaxel: a pooled analysis from prospective clinical and translational trials. 2016

Ormanns, Steffen / Haas, Michael / Baechmann, Sibylle / Altendorf-Hofmann, Annelore / Remold, Anna / Quietzsch, Detlef / Clemens, Michael R / Bentz, Martin / Geissler, Michael / Lambertz, Helmut / Kruger, Stephan / Kirchner, Thomas / Heinemann, Volker / Boeck, Stefan. ·Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Strasse 36, D-80337 Munich, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistrasse 15, D-81377 Munich, Germany. · Department of Surgery, Jena University Hospital, Jena, Germany. · Department of Internal Medicine II, Klinikum Chemnitz gGmbH, Chemnitz, Germany. · Department of Hematology and Oncology, Mutterhaus der Boromaeerinnen, Trier, Germany. · Department of Internal Medicine III, Klinikum Karlsruhe, Karlsruhe, Germany. · Department of Gastroenterology and Oncology, Klinikum Esslingen, Esslingen, Germany. · Department of Hematology and Oncology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany. ·Br J Cancer · Pubmed #27802454.

ABSTRACT: BACKGROUND: Conflicting results on the role of secreted protein acidic and rich in cysteins (SPARC) expression have been reported in resected pancreatic ductal adenocarcinoma (PDAC), and its prognostic and/or predictive role in advanced PDAC (aPDAC) has not been extensively investigated yet. This study was designed to evaluate SPARC expression as a biomarker in aPDAC patients (pts) not receiving nab-paclitaxel. METHODS: Using immunohistochemistry, we examined the stromal as well as the tumoral (i.e., cytoplasmic) SPARC expression in tumour tissue (primary tumours and metastases) of 134 aPDAC pts participating in completed prospective clinical and biomarker trials. The SPARC expression levels were correlated to the pts' clinicopathological parameters and survival times. RESULTS: Sixty-seven per cent of the analysed tumours showed high stromal SPARC expression, which was not associated with overall survival (OS, median 9.1 vs 7.6 months, P=0.316). A positive cytoplasmic SPARC expression was detected in 55% of the tumours and correlated significantly with inferior progression-free survival (PFS, 6.2 vs 8.6 months, P=0.004) and OS (7.8 vs 8.4 months, P=0.032). This association was strongest for pts, where primary tumour tissue was examined (PFS: 6.7 vs 10.8 months, P=0.004; OS: 7.9 vs 11.9 months, P=0.030), whereas no significant correlation was detected for pts, where only metastatic tissue was available (PFS: 5.8 vs 6.6 months, P=0.502; OS: 7.0 vs 7.8 months, P=0.452). In pts receiving gemcitabine-based chemotherapy cytoplasmic SPARC expression was significantly associated with an inferior PFS and OS (PFS: 6.2 vs 9.2 months, P=0.002; OS 7.3 vs 9.9 months, P=0.012), whereas no such association was detected for stromal SPARC expression or for pts receiving fluoropyrimidine-based chemotherapy. CONCLUSION: We identified cytoplasmic SPARC expression in the primary tumour as a biomarker associated with inferior PFS and OS in aPDAC. Cytoplasmic SPARC expression may furthermore act as a negative predictive biomarker in pts treated with gemcitabine-based chemotherapy.

21 Article Acinar cell carcinoma of the pancreas: a rare disease with different diagnostic and therapeutic implications than ductal adenocarcinoma. 2016

Kruger, Stephan / Haas, Michael / Burger, Philipp Johannes / Ormanns, Steffen / Modest, Dominik Paul / Westphalen, Christoph Benedikt / Kleespies, Axel / Angele, Martin Kurt / Hartwig, Werner / Bruns, Christiane Josephine / Kirchner, Thomas / Werner, Jens / Heinemann, Volker / Boeck, Stefan. ·Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany. · Institute of Pathology, Ludwig-Maximilians-University of Munich, 81377, Munich, Germany. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, 81377, Munich, Germany. · Department of General, Visceral and Tumor Surgery, University of Cologne, 50937, Köln-Lindenthal, Germany. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany. stefan.boeck@med.uni-muenchen.de. ·J Cancer Res Clin Oncol · Pubmed #27629876.

ABSTRACT: PURPOSE: Acinar cell carcinoma (ACC) of the pancreas is a very rare cancer, constituting 1 % of all malignant non-endocrine pancreatic tumors. Only very limited data exist to guide treatment in patients with advanced ACC. METHODS: Between 2000 and 2015, 15 patients with ACC were diagnosed and/or treated at our high-volume comprehensive cancer center. Medical records and correlating serum levels of the potential serum tumor markers CA 19-9, CEA and lipase were analyzed retrospectively. RESULTS: A substantial antitumor activity was observed for treatment regimens containing 5-FU and oxaliplatin with partial responses or prolonged disease stabilizations (>12 months) observed in 6 out of 7 patients (86 %). Activity was also observed for single-agent 5-FU and its oral prodrugs. Serum lipase levels were elevated in 7 of 12 patients with advanced disease (58 %), whereas CEA and CA 19-9 seemed to be of minor importance for ACC (elevated pre-treatment levels in 4/12 and 3/12 cases, respectively). In selected patients, repeated serum lipase measurements were available and accurately predicted response to chemotherapy and relapse after surgery. CONCLUSIONS: 5-FU- and oxaliplatin-containing regimens are active in advanced ACC. Lipase kinetics may be a useful novel tool to monitor the course of disease as well as treatment effects in ACC.

22 Article Isolated pulmonary metastases define a favorable subgroup in metastatic pancreatic cancer. 2016

Kruger, Stephan / Haas, Michael / Burger, Philipp Johannes / Ormanns, Steffen / Modest, Dominik Paul / Westphalen, Christoph Benedikt / Michl, Marlies / Kleespies, Axel / Angele, Martin Kurt / Hartwig, Werner / Bruns, Christiane Josephine / Niyazi, Maximilian / Roeder, Falk / Kirchner, Thomas / Werner, Jens / Heinemann, Volker / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. · Institute of Pathology, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. · Department of General, Abdominal and Vascular Surgery, Otto-von-Guericke-University, D-39120 Magdeburg, Germany. · Department of Radiation Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. · Department of Radiation Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany; Department of Molecular Radiation Oncology, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany. · Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, D-81377 Munich, Germany. Electronic address: stefan.boeck@med.uni-muenchen.de. ·Pancreatology · Pubmed #27067420.

ABSTRACT: PURPOSE: Liver metastasis represents the first site of dissemination in >80% of metastatic pancreatic cancer (PC) patients. Pulmonary metastasis as first site of dissemination in PC is a rare event and might define a biologically distinct subgroup in metastatic PC. METHODS: Consecutive PC patients who were diagnosed or treated with isolated pulmonary metastases at our high-volume comprehensive cancer center were included in a prospectively maintained database between 2002 and 2015. Medical records and correlating computed tomography findings (CT) were retrospectively analyzed. RESULTS: A total of 40 PC patients with isolated pulmonary metastases were identified. Pulmonary metastases represented disease recurrence after initial resection of PC in 22 patients and disease progression of locally advanced pancreatic cancer in 5 patients. 14 out of 27 PC patients (56%) had received chemoradiotherapy for localized disease prior to pulmonary metastasis. Data on 1st-line treatment for pulmonary metastases was available for 38 patients: most patients (71%) received a gemcitabine-based chemotherapy regimen, 5 patients (13%) received best supportive care. After a median follow-up of 37.3 months, median survival after diagnosis of pulmonary metastasis was estimated with 25.5 months (95% CI 19.1-31.8); a significantly improved survival after diagnosis of pulmonary metastasis was observed for patients with less than 10 lung metastases (31.3 vs 18.7 months, p = 0.003) and for an unilateral localization of lung involvement (31.3 vs 21.8 months, p = 0.03). CONCLUSIONS: Our results suggest a favorable outcome of PC patients with isolated pulmonary metastases. Further research is warranted to elucidate the specific molecular characteristics of this rare subgroup.

23 Article Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. 2016

Westphalen, C Benedikt / Takemoto, Yoshihiro / Tanaka, Takayuki / Macchini, Marina / Jiang, Zhengyu / Renz, Bernhard W / Chen, Xiaowei / Ormanns, Steffen / Nagar, Karan / Tailor, Yagnesh / May, Randal / Cho, Youngjin / Asfaha, Samuel / Worthley, Daniel L / Hayakawa, Yoku / Urbanska, Aleksandra M / Quante, Michael / Reichert, Maximilian / Broyde, Joshua / Subramaniam, Prem S / Remotti, Helen / Su, Gloria H / Rustgi, Anil K / Friedman, Richard A / Honig, Barry / Califano, Andrea / Houchen, Courtney W / Olive, Kenneth P / Wang, Timothy C. ·Department of Internal Medicine III, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, 40128 Bologna, Italy. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology, Hospital of the University of Munich D-81377, Munich, Germany. · Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA. · Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany; Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA. · Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cell Stem Cell · Pubmed #27058937.

ABSTRACT: The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

24 Article Desmogleins as prognostic biomarkers in resected pancreatic ductal adenocarcinoma. 2015

Ormanns, Steffen / Altendorf-Hofmann, Annelore / Jackstadt, Rene / Horst, David / Assmann, Gerald / Zhao, Yue / Bruns, Christiane / Kirchner, Thomas / Knösel, Thomas. ·Institute of Pathology, Ludwig-Maximilians-University, Thalkirchner Strasse 36, Munich 80337, Germany. · Department of General, Visceral and Vascular Surgery, Jena University Hospital, Erlanger Allee 101, Jena 07747, Germany. · Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK. · Department of Surgery, University Hospital Magdeburg, Leipziger Strasse 44, Magdeburg 39120, Germany. ·Br J Cancer · Pubmed #26469831.

ABSTRACT: BACKGROUND: Frequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell-cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date. This study evaluated desmoglein expression as a biomarker in PDAC. METHODS: Using immunohistochemistry, we examined desmoglein 1 (DSG1), desmoglein 2 (DSG2) and desmoglein 3 (DSG3) expression in the tumour tissue of 165 resected PDAC cases. Expression levels were correlated to the patients' clinicopathological parameters and postoperative survival times. We confirmed these results in two independent gene expression data sets. RESULTS: A total of 36% of the tumours showed high DSG3 expression that correlated significantly with shorter patient survival (P=0.011) and poor tumour differentiation (P<0.001), whereas no such association was detected for DSG1 or DSG2. In RNA-Seq data and in microarray expression data, high DSG3 expression correlated significantly with poor survival (P=0.000356 and P=0.00499). CONCLUSIONS: We identify DSG3 as a negative prognostic biomarker in resected PDAC, as high DSG3 expression is associated with poor overall survival and poor tumour-specific survival. These findings suggest DSG3 and its downstream signalling pathways as possible therapeutic targets in DSG3-expressing PDAC.

25 Article Assessing novel prognostic serum biomarkers in advanced pancreatic cancer: the role of CYFRA 21-1, serum amyloid A, haptoglobin, and 25-OH vitamin D3. 2015

Haas, Michael / Kern, Christoph / Kruger, Stephan / Michl, Marlies / Modest, Dominik P / Giessen, Clemens / Schulz, Christoph / von Einem, Jobst C / Ormanns, Steffen / Laubender, Rüdiger P / Holdenrieder, Stefan / Heinemann, Volker / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany, michael.haas@med.uni-muenchen.de. ·Tumour Biol · Pubmed #25472579.

ABSTRACT: The present prospective single-center study investigated the prognostic role of novel serum biomarkers in advanced pancreatic cancer (PC). Patients (pts) with locally advanced or metastatic PC treated with first-line palliative chemotherapy were included. Among others, the serum markers CYFRA 21-1, haptoglobin, serum-amyloid A (SAA), and 25-OH vitamin D3 were determined at baseline and categorized by pre-defined cut-offs [median values (MV), upper limits of normal (ULN), lower limits of normal (LLN), or the natural logarithm (ln)] and correlated with overall survival (OS). Among the 59 pts included, pre-treatment CYFRA 21-1 levels showed a strong correlation with OS independent of the applied cut-off (MV 4.9 ng/ml-14.2 vs. 4.2 months, HR 0.18, p = 0.001; ULN 3.3 ng/ml-14.2 vs. 4.4 months, HR 0.28, p = 0.003; [ln] CYFRA 21-1-HR 0.77, p = 0.013). Lower values of haptoglobin were additionally associated with an improvement in OS (categorized by LLN of 2.05 g/l-10.4 vs. 5.5 months, HR 0.46, p = 0.023; [ln] haptoglobin-HR 0.51, p = 0.036). Pts with baseline SAA values below the MV of 22 mg/l also had a prolonged OS (10.4 vs. 5.0 months, HR 0.47, p = 0.036). For 25-OH vitamin D3 levels, no significant correlation with OS was found. In multivariate analyses, pre-treatment CYFRA 21-1 levels (categorized by MV-HR 0.15, p = 0.032) as well as [ln] haptoglobin (HR 0.30, p = 0.006) retained their independent prognostic significance for OS. CYFRA 21-1, haptoglobin, and SAA might provide useful prognostic information in advanced PC. An external multicenter validation of these results is necessary.

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