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Pancreatic Neoplasms: HELP
Articles by Julia Mayerle
Based on 42 articles published since 2010
(Why 42 articles?)
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Between 2010 and 2020, J. Mayerle wrote the following 42 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline [S3-guideline exocrine pancreatic cancer]. 2013

Seufferlein, T / Porzner, M / Becker, T / Budach, V / Ceyhan, G / Esposito, I / Fietkau, R / Follmann, M / Friess, H / Galle, P / Geissler, M / Glanemann, M / Gress, T / Heinemann, V / Hohenberger, W / Hopt, U / Izbicki, J / Klar, E / Kleeff, J / Kopp, I / Kullmann, F / Langer, T / Langrehr, J / Lerch, M / Löhr, M / Lüttges, J / Lutz, M / Mayerle, J / Michl, P / Möller, P / Molls, M / Münter, M / Nothacker, M / Oettle, H / Post, S / Reinacher-Schick, A / Röcken, C / Roeb, E / Saeger, H / Schmid, R / Schmiegel, W / Schoenberg, M / Siveke, J / Stuschke, M / Tannapfel, A / Uhl, W / Unverzagt, S / van Oorschot, B / Vashist, Y / Werner, J / Yekebas, E / Anonymous260779 / Anonymous270779 / Anonymous280779. ·Klinik für Innere Medizin I, Universitätsklinikum Ulm. · Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Kiel. · Klinik für Radioonkologie und Strahlentherapie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Institut für Allgemeine Pathologie, Klinikum rechts der Isar, TU München. · Strahlenklinik, Universitätsklinikum Erlangen. · Leitlinienprogramm Onkologie, Deutsche Krebsgesellschaft e. V., Berlin. · I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz. · Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen. · Klinik für Allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes Homburg/Saar. · Klinik für Gastroenterologie, Endokrinologie und Stoffwechsel, Universitätsklinikum Gießen und Marburg. · Medizinischen Klinik und Poliklinik III, Klinikum der Universität München LMU. · Chirurgische Klinik, Universitätsklinikum Erlangen. · Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg. · Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf. · Klinik für Allgemeine Chirurgie, Thorax-, Gefäß- und Transplantationschirurgie, Universitätsmedizin Rostock. · AWMF-Institut für Medizinisches Wissensmanagement, Marburg. · Medizinische Klinik I, Klinikum Weiden. · Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Martin-Luther-Krankenhaus Berlin. · Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald. · Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm. · Institut für Pathologie, Marienkrankenhaus Hamburg. · Medizinische Klinik - Schwerpunkt Gastroenterologie, Endokrinologie, Infektiologie, Caritasklinikum Saarbrücken. · Institut für Pathologie, Universitätsklinikum Ulm. · Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie, Klinikum rechts der Isar, TU München. · Klinik für Strahlentherapie und Radioonkologie, Klinikum Stuttgart. · AWMF-Institut für Medizinisches Wissensmanagement, Berlin. · Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Universitätsmedizin Berlin. · Chirurgische Klinik, Universitätsmedizin Mannheim. · Abt. für Hämatologie und Onkologie, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Pathologie, Universitätsklinikum Kiel. · Medizinische Klinik II, SP Gastroenterologie, Universitätsklinikum Gießen und Marburg. · Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Dresden. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU München. · Medizinische Klinik, Klinikum der Ruhr-Universität Bochum. · Klinik für Chirurgie, Rotkreuzklinikum München. · Klinik für Strahlentherapie, Universitätsklinikum Essen. · Institut für Pathologie, Ruhr-Universität Bochum. · Chirurgische Klinik, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum. · Institut für Medizinische Epidemiologie, Biometrie und Informatik, Martin-Luther-Universität Halle-Wittenberg. · Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Würzburg. · Klinik für Allgemeine, Viszerale und Transplantationschirurgie, Universitätsklinikum Heidelberg. · Klinik für Allgemein-, Thorax- und Viszeralchirurgie, Klinikum Darmstadt. ·Z Gastroenterol · Pubmed #24338757.

ABSTRACT: -- No abstract --

2 Review Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies. 2018

Auernhammer, Christoph J / Spitzweg, Christine / Angele, Martin K / Boeck, Stefan / Grossman, Ashley / Nölting, Svenja / Ilhan, Harun / Knösel, Thomas / Mayerle, Julia / Reincke, Martin / Bartenstein, Peter. ·Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany. Electronic address: christoph.auernhammer@med.uni-muenchen.de. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 3, Ludwig-Maximilians-University of Munich, Munich, Germany. · Neuroendocrine Tumour Centre, Royal Free Hospital, London, UK. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany. · Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 2, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Munich, Germany. ·Lancet Diabetes Endocrinol · Pubmed #29229497.

ABSTRACT: In this Review, we discuss clinical developments and controversies in the treatment of neuroendocrine tumours (NETs) that are relevant for clinicians and clinical researchers. We describe advances in genetics, blood-based biomarkers, functional imaging, and systemic therapy of advanced NETs and discuss results of recent phase 3 studies, systemic treatment of advanced disease with peptide receptor radionuclide therapy, biotherapy, chemotherapy, and molecularly targeted therapy, and the potential role of immunotherapy in the treatment of NETs. Suggested treatment algorithms for NETs of ileal or jejunal origin and of pancreatic origin are presented.

3 Review Nutrition in Pancreatic Cancer: A Review. 2016

Gärtner, Simone / Krüger, Janine / Aghdassi, Ali A / Steveling, Antje / Simon, Peter / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. ·Gastrointest Tumors · Pubmed #27403414.

ABSTRACT: BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related mortality in both genders. More than 80% of patients suffer from significant weight loss at diagnosis and over time develop severe cachexia. Early nutritional support is therefore essential. SUMMARY: This review evaluates the different nutritional therapies, such as enteral nutrition, parenteral nutrition and special nutritional supplements, on nutritional status, quality of life and survival. KEY MESSAGE: Due to the high prevalence of malnutrition and the rapid development of anorexia-cachexia-syndrome, early nutritional intervention is crucial and supported by clinical data. PRACTICAL IMPLICATIONS: Enteral nutrition should be preferred over parenteral nutrition. Omega-3 fatty acids and l-carnitine are promising substances for the prevention of severe cachexia, but further randomized controlled trials are needed to establish generally accepted guidelines on nutrition in pancreatic cancer.

4 Review Pancreatic cancer in 2015: Precision medicine in pancreatic cancer--fact or fiction? 2016

Seufferlein, Thomas / Mayerle, Julia. ·Ulm University Medical Center, Department of Internal Medicine I, Albert Einstein Allee 23, D-89081 Ulm, Germany. · Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Ferdinand-Sauerbruchstrasse, 17475 Greifswald, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #26758788.

ABSTRACT: Late diagnosis and an inability to personalize treatment are major problems preventing reductions in pancreatic cancer mortality. In 2015, the identification of a highly discriminatory exosomal biomarker, culture systems that recapitulate human disease and new methods of analysing large data sets to identify prognostic markers have improved the future outlook for patients with this cancer.

5 Review [Intraductal papillary mucinous neoplasia: which findings support observation?]. 2012

Mayerle, J / Kraft, M / Menges, P / Simon, P / Ringel, J / Partecke, L I / Heidecke, C D / Lerch, M M. ·Klinik für Innere Medizin A, Universitätsmedizin der Ernst-Moritz-Arndt-Universität, Friedrich-Loeffler-Strasse 23a, Greifswald, Germany. ·Chirurg · Pubmed #22271054.

ABSTRACT: On abdominal CT scans asymptomatic cystic lesions of the pancreas are accidentally detected in 1-2% of patients. Congenital cysts and pancreatic pseudocysts account for two thirds of these lesions. Pancreatic pseudocysts are a frequent complication of acute and chronic pancreatitis. Among resected cystic neoplasms serous cystic adenoma accounts for 30%, mucinous cystic neoplasms for 45% and intraductal papillary mucinous neoplasms for 25%. The diagnosis of a cystic pancreatic lesion is usually made by diagnostic imaging. Symptomatic lesions require definitive therapeutic treatment after appropriate diagnostic work-up. In the diagnosis of asymptomatic cystic lesions several factors are important, among them whether the cyst is connected to the pancreatic duct (as in IPMN and pseudocysts), the size of lesion (for treatment indications) and whether nodules form in the wall of the cyst (a sign of potential malignancy). EUS-guided fine needle aspiration of the cyst fluid adds to the discrimination between benign, premalignant and malignant cystic lesions. Measuring lipase activity, CEA, viscosity and mucin as well as cytology can help in differentiating cystic lesions. An algorithm is discussed for the differential diagnosis and for selection of the appropriate treatment for pancreatic cystic lesions, most of which never require surgery.

6 Review [Pancreatic diseases: update 2011]. 2011

Ringel, J / Lerch, M M / Mayerle, J. ·Klinik für Innere Medizin A, Universitätsmedizin der Ernst-Moritz-Arndt-Universität, Greifswald. ·Dtsch Med Wochenschr · Pubmed #21960335.

ABSTRACT: -- No abstract --

7 Review Environmental risk factors for chronic pancreatitis and pancreatic cancer. 2011

Nitsche, Claudia / Simon, Peter / Weiss, F Ulrich / Fluhr, Gabriele / Weber, Eckhard / Gärtner, Simone / Behn, Claas O / Kraft, Matthias / Ringel, Jörg / Aghdassi, Ali / Mayerle, Julia / Lerch, Markus M. ·Department of Medicine A, Klinikum der Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany. ·Dig Dis · Pubmed #21734390.

ABSTRACT: Chronic pancreatitis has long been thought to be mainly associated with immoderate alcohol consumption. The observation that only ∼10% of heavy drinkers develop chronic pancreatitis not only suggests that other environmental factors, such as tobacco smoke, are potent additional risk factors, but also that the genetic component of pancreatitis is more common than previously presumed. Either disease-causing or protective traits have been indentified for mutations in different trypsinogen genes, the gene for the trypsin inhibitor SPINK1, chymotrypsinogen C, and the cystic fibrosis transmembane conductance regulator (CFTR). Other factors that have been proposed to contribute to pancreatitis are obesity, diets high in animal protein and fat, as well as antioxidant deficiencies. For the development of pancreatic cancer, preexisting chronic pancreatitis, more prominently hereditary pancreatitis, is a risk factor. The data on environmental risk factors for pancreatic cancer are, with the notable exception of tobacco smoke, either sparse, unconfirmed or controversial. Obesity appears to increase the risk of pancreatic cancer in the West but not in Japan. Diets high in processed or red meat, diets low in fruits and vegetables, phytochemicals such as lycopene and flavonols, have been proposed and refuted as risk or protective factors in different trials. The best established and single most important risk factor for cancer as well as pancreatitis and the one to clearly avoid is tobacco smoke.

8 Clinical Trial Early Parenteral Nutrition in Patients with Biliopancreatic Mass Lesions, a Prospective, Randomized Intervention Trial. 2016

Krüger, Janine / Meffert, Peter J / Vogt, Lena J / Gärtner, Simone / Steveling, Antje / Kraft, Matthias / Mayerle, Julia / Lerch, Markus M / Aghdassi, Ali A. ·Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. · cts Vinzentius Krankenhaus, Landau, Germany. ·PLoS One · Pubmed #27861546.

ABSTRACT: PURPOSE: Patients with biliopancreatic tumors frequently suffer from weight loss and cachexia. The in-hospital work-up to differentiate between benign and malignant biliopancreatic lesions requires repeated pre-interventional fasting periods that can aggravate this problem. We conducted a randomized intervention study to test whether routine in-hospital peripheral intravenous nutrition on fasting days (1000 ml/24 h, 700 kcal) has a beneficial effect on body weight and body composition. MATERIAL AND METHODS: 168 patients were screened and 100 enrolled in the trial, all undergoing in-hospital work-up for biliopancreatic mass lesions and randomized to either intravenous nutrition or control. Primary endpoint was weight loss at time of hospital discharge; secondary endpoints were parameters determined by bioelectric impedance analysis and quality of life recorded by the EORTC questionnaire. RESULTS: Within three months prior to hospital admission patients had a median self-reported loss of 4.0 kg (25*th: -10.0 kg and 75*th* percentile: 0.0kg) of body weight. On a multivariate analysis nutritional intervention increased body weight by 1.7 kg (95% CI: 0.204; 3.210, p = 0.027), particularly in patients with malignant lesions (2.7 kg (95% CI: 0.71; 4.76, p < 0.01). CONCLUSIONS: In a hospital setting, patients with suspected biliopancreatic mass lesions stabilized their body weight when receiving parenteral nutrition in fasting periods even when no total parenteral nutrition was required. Analysis showed that this effect was greatest in patients with malignant tumors. Further studies will be necessary to see whether patient outcome is affected as well. TRIAL REGISTRATION: ClinicalTrials.gov NCT02670265.

9 Clinical Trial Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. 2014

Valle, Juan W / Palmer, Daniel / Jackson, Richard / Cox, Trevor / Neoptolemos, John P / Ghaneh, Paula / Rawcliffe, Charlotte L / Bassi, Claudio / Stocken, Deborah D / Cunningham, David / O'Reilly, Derek / Goldstein, David / Robinson, Bridget A / Karapetis, Christos / Scarfe, Andrew / Lacaine, Francois / Sand, Juhani / Izbicki, Jakob R / Mayerle, Julia / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Lind, Pehr A / Middleton, Mark R / Anthoney, Alan / Sumpter, Kate / Carter, Ross / Büchler, Markus W. ·Juan W. Valle, Derek O'Reilly, Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester · Richard Jackson, Trevor Cox, John P. Neoptolemos, Paula Ghaneh, Charlotte L. Rawcliffe, Liverpool Cancer Research UK Centre and the National Institute for Health Research Pancreas Biomedical Research Unit, University of Liverpool, Liverpool · Daniel Palmer, the Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust · Deborah D. Stocken, the Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham · David Cunningham, Royal Marsden Hospital Foundation Trust, Sutton · Mark R. Middleton, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford · Alan Anthoney, The Leeds Teaching Hospital Trust, Leeds · Kate Sumpter, Freeman Hospital, Newcastle upon Tyne · Ross Carter, Glasgow Royal Infirmary, Glasgow, United Kingdom · Claudio Bassi, Giovanni Butturini, University of Verona, Verona, Italy · David Goldstein, Bridget A. Robinson, Christos Karapetis, the Australasian Gastro-Intestinal Trials Group, Camperdown, Australia · Andrew Scarfe, University of Alberta, Edmonton, Canada · Francois Lacaine, Hôpital TENON, Assistance Publique Hôpitaux de Paris, Universite Pierre Et Marie Curie, Paris, France · Juhani Sand, Tampere University Hospital, Tampere, Finland · Jakob R. Izbicki, University of Hamburg, Hamburg · Julia Mayerle, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald · Markus W. Büchler, University of Heidelberg, Heidelberg, Germany · Christos Dervenis, the Agia Olga Hospital, Athens, Greece · Attila Oláh, the Petz Aladar Hospital, Gyor, Hungary · Pehr A. Lind, Karolinska-Stockholm Söder Hospital, Stockholm, Sweden. ·J Clin Oncol · Pubmed #24419109.

ABSTRACT: PURPOSE: Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. PATIENTS AND METHODS: Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer-3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. RESULTS: There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). CONCLUSION: Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

10 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.

11 Article Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis. 2019

Benitz, Simone / Straub, Tobias / Mahajan, Ujjwal Mukund / Mutter, Jurik / Czemmel, Stefan / Unruh, Tatjana / Wingerath, Britta / Deubler, Sabrina / Fahr, Lisa / Cheng, Tao / Nahnsen, Sven / Bruns, Philipp / Kong, Bo / Raulefs, Susanne / Ceyhan, Güralp O / Mayerle, Julia / Steiger, Katja / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W / Regel, Ivonne. ·Department of Medicine II, University Hospital, LMU Munich, Munich, Germany. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA. · Bioinformatic Unit, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany. · Quantitative Biology Center, University of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany. · Department of Surgery, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany. · Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. ·Gut · Pubmed #30954952.

ABSTRACT: BACKGROUND AND AIMS: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. DESIGN: With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. RESULTS: The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. CONCLUSIONS: Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

12 Article The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma. 2019

Ghaneh, Paula / Kleeff, Jorg / Halloran, Christopher M / Raraty, Michael / Jackson, Richard / Melling, James / Jones, Owain / Palmer, Daniel H / Cox, Trevor F / Smith, Chloe J / O'Reilly, Derek A / Izbicki, Jakob R / Scarfe, Andrew G / Valle, Juan W / McDonald, Alexander C / Carter, Ross / Tebbutt, Niall C / Goldstein, David / Padbury, Robert / Shannon, Jennifer / Dervenis, Christos / Glimelius, Bengt / Deakin, Mark / Anthoney, Alan / Lerch, Markus M / Mayerle, Julia / Oláh, Attila / Rawcliffe, Charlotte L / Campbell, Fiona / Strobel, Oliver / Büchler, Markus W / Neoptolemos, John P / Anonymous291017. ·Liverpool Cancer Research U.K. Cancer Trials Unit, University of Liverpool, Liverpool, United Kingdom University of Liverpool, Liverpool, UK. · The Department of Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · Department of Surgery, Manchester Royal Infirmary, Manchester, UK. · Department of Surgery, University of Hamburg Medical institutions UKE, Hamburg, Germany. · Department of Oncology Division of Medical Oncology 2228 Cross Cancer Institute and University of Alberta, Canada. · Department of Medical Oncology , The Christie, Manchester, UK. · Department of Medical Oncology, The Beatson West of Scotland Cancer Centre, Glasgow, Scotland, UK. · Department of Surgery, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Department of Medical Oncology, Austin Health, Melbourne, Australia. · Department of Medical Oncology, Prince of Wales hospital and Clinical School University of New South Wales, Australia. · Department of Surgery, Flinders Medical Centre, Adelaide, South Australia. · Department of Medical Oncology, Nepean Cancer Centre and University of Sydney, Australia. · Department of Surgery, The Agia Olga Hospital, Athens, Greece. · Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala Clinical Research Center, Uppsala, Sweden. · Department of Surgery, University Hospital, North Staffordshire, UK. · Division of Oncology at the University of Leeds, St James's University Hospital, Leeds, UK. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Surgery, The Petz Aladar Hospital, Gyor, Hungary. · Department of Pathology, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · The Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Ann Surg · Pubmed #29068800.

ABSTRACT: OBJECTIVE AND BACKGROUND: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. METHODS: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. RESULTS: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence. CONCLUSIONS: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

13 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.

14 Article [Pancreatic Cancer in the Year 2018 - Room for Precision Medicine?] 2018

Simon, Ole / Beyer, Georg / Mahajan, Ujjwal M / Mayerle, Julia. ·Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum München, Ludwig-Maximilians-Universität, München. ·Dtsch Med Wochenschr · Pubmed #30060283.

ABSTRACT: In Germany, an estimated 19 000 people will develop pancreatic carcinoma in 2018. The 5-year survival rate of all pancreatic carcinoma patients is very low at around 6 %, and the potentially curative operation is only possible in 15 - 20 % of patients. More frequent use and combination of systemic chemotherapeutic agents has led to improved life expectancy in recent years. In this article we will summarize recent therapeutic strategies depending on tumor status and current approaches to personalized medicine in pancreatic carcinoma.

15 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.

16 Article Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy. 2018

Elander, N O / Aughton, K / Ghaneh, P / Neoptolemos, J P / Palmer, D H / Cox, T F / Campbell, F / Costello, E / Halloran, C M / Mackey, J R / Scarfe, A G / Valle, J W / McDonald, A C / Carter, R / Tebbutt, N C / Goldstein, D / Shannon, J / Dervenis, C / Glimelius, B / Deakin, M / Charnley, R M / Anthoney, A / Lerch, M M / Mayerle, J / Oláh, A / Büchler, M W / Greenhalf, W / Anonymous591038. ·Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. · Cross Cancer Institute and University of Alberta, Edmonton, Canada. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, UK. · Glasgow Royal Infirmary, Glasgow, UK. · Austin Health, Melbourne, VIC, Australia. · Prince of Wales hospital and Clinical School, University of New South Wales, Sydney, NSW, Australia. · Nepean Cancer Centre and University of Sydney, Camperdown, NSW, Australia. · The Agia Olga Hospital, Athens, Greece. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · University Hospital, North Staffordshire, Staffordshire, UK. · Freeman Hospital, Newcastle upon Tyne, UK. · St James's University Hospital, Leeds, UK. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany. · The Petz Aladar Hospital, Gyor, Hungary. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. greenhaf@liv.ac.uk. ·Br J Cancer · Pubmed #29523831.

ABSTRACT: BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

17 Article Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer. 2018

Elander, N O / Aughton, K / Ghaneh, P / Neoptolemos, J P / Palmer, D H / Cox, T F / Campbell, F / Costello, E / Halloran, C M / Mackey, J R / Scarfe, A G / Valle, J W / McDonald, A C / Carter, R / Tebbutt, N C / Goldstein, D / Shannon, J / Dervenis, C / Glimelius, B / Deakin, M / Charnley, R M / Anthoney, Alan / Lerch, M M / Mayerle, J / Oláh, A / Büchler, M W / Greenhalf, W / Anonymous1050939. ·From the Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. · The Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Cross Cancer Institute and University of Alberta, Alberta, Canada. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, Scotland, UK. · Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Austin Health, Melbourne, Australia. · Prince of Wales hospital and Clinical School University of New South Wales, New South Wales, Australia. · Nepean Cancer Centre and University of Sydney, Sydney, Australia. · The Agia Olga Hospital, Athens, Greece. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · University Hospital, North Staffordshire, UK. · Freeman Hospital, Newcastle upon Tyne, UK. · St James's University Hospital, Leeds, UK. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital of the Ludwig-Maximilians-University, Munich, Germany. · The Petz Aladar Hospital, Gyor, Hungary. · From the Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. greenhaf@liv.ac.uk. ·Br J Cancer · Pubmed #29515256.

ABSTRACT: BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

18 Article Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. 2018

Mueller, Sebastian / Engleitner, Thomas / Maresch, Roman / Zukowska, Magdalena / Lange, Sebastian / Kaltenbacher, Thorsten / Konukiewitz, Björn / Öllinger, Rupert / Zwiebel, Maximilian / Strong, Alex / Yen, Hsi-Yu / Banerjee, Ruby / Louzada, Sandra / Fu, Beiyuan / Seidler, Barbara / Götzfried, Juliana / Schuck, Kathleen / Hassan, Zonera / Arbeiter, Andreas / Schönhuber, Nina / Klein, Sabine / Veltkamp, Christian / Friedrich, Mathias / Rad, Lena / Barenboim, Maxim / Ziegenhain, Christoph / Hess, Julia / Dovey, Oliver M / Eser, Stefan / Parekh, Swati / Constantino-Casas, Fernando / de la Rosa, Jorge / Sierra, Marta I / Fraga, Mario / Mayerle, Julia / Klöppel, Günter / Cadiñanos, Juan / Liu, Pentao / Vassiliou, George / Weichert, Wilko / Steiger, Katja / Enard, Wolfgang / Schmid, Roland M / Yang, Fengtang / Unger, Kristian / Schneider, Günter / Varela, Ignacio / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany. · Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Institute of Pathology, Technische Universität München, 81675 Munich, Germany. · The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Comparative Experimental Pathology, Technische Universität München, 81675 Munich, Germany. · Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians Universität, 82152 Martinsried, Germany. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. · Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), 33193 Oviedo, Spain. · Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain. · Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33011 Oviedo, Spain. · Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, 33940 El Entrego, Spain. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, 81377 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC), 39012 Santander, Spain. ·Nature · Pubmed #29364867.

ABSTRACT: The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras

19 Article Plasma protein profiling of patients with intraductal papillary mucinous neoplasm of the pancreas as potential precursor lesions of pancreatic cancer. 2018

Ilies, Maria / Sappa, Praveen Kumar / Iuga, Cristina Adela / Loghin, Felicia / Gesell Salazar, Manuela / Weiss, Frank Ulrich / Beyer, Georg / Lerch, Markus M / Völker, Uwe / Mayerle, Julia / Hammer, Elke. ·Department of Pharmaceutical Analysis, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, no. 6 Louis Pasteur st., 400349 Cluj-Napoca, Romania; Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: ilies.maria@umfcluj.ro. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: praveen.kumar@uni-greifswald.de. · Department of Pharmaceutical Analysis, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, no. 6 Louis Pasteur st., 400349 Cluj-Napoca, Romania; Department of Proteomics and Metabolomics, MedFuture Research Center for Advanced Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, no. 4-6 Louis Pasteur st., 400349 Cluj-Napoca, Romania. Electronic address: iugac@umfcluj.ro. · Department of Toxicology, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, no. 6 Louis Pasteur st., 400349 Cluj-Napoca, Romania. Electronic address: floghin@umfcluj.ro. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: gesell@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany. Electronic address: ulrich.weiss@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany; Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377 München, Germany. Electronic address: georg.beyer@med.uni-muenchen.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany. Electronic address: lerch@uni-greifswald.de. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: voelker@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Sauerbruchstr., 17475 Greifswald, Germany; Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377 München, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. · Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, F.-L.-Jahn-Str. 15a, 17475 Greifswald, Germany. Electronic address: hammer@uni-greifswald.de. ·Clin Chim Acta · Pubmed #29221926.

ABSTRACT: Efforts for the early diagnosis of the pancreatic ductal adenocarcinoma (PDAC) have recently been driven to one of the precursor lesions, namely intraductal papillary mucinous neoplasm of the pancreas (IPMN). Only a few studies have focused on IPMN molecular biology and its overall progression to cancer. Therefore, IPMN lacks comprehensive characterization which makes its clinical management controversial. In this study, we characterized plasma proteins in the presence of IPMNs in comparison to healthy controls, chronic pancreatitis, and PDAC by a proteomics approach using data-independent acquisition based mass spectrometry. We describe several protein sets that could aid IPMN diagnosis, but also differentiation of IPMN from healthy controls, as well as from benign and malignant diseases. Among all, high levels of carbonic anhydrases and hemoglobins were characteristic for the IPMN group. By employing ELISA based quantification we validated our results for human tissue inhibitor of metalloproteinase inhibitor 1 (TIMP-1). We consider IPMN management directed towards an early potential cancer development a crucial opportunity before PDAC initiation and thus its early detection and cure.

20 Article Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study. 2018

Kromrey, Marie-Luise / Bülow, Robin / Hübner, Jenny / Paperlein, Christin / Lerch, Markus M / Ittermann, Till / Völzke, Henry / Mayerle, Julia / Kühn, Jens-Peter. ·Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany. · Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany. · Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Medizinische Klinik und Poliklinik II, Universitätsklinikum der Ludwig-Maximilians-Universität München, Greifswald, Germany. · Department of Radiology, Universitätsklinikum Dresden, Carl Gustav Carus University Dresden, Greifswald, Germany. ·Gut · Pubmed #28877981.

ABSTRACT: OBJECTIVE: To analyse the prevalence, incidence and clinical relevance of pancreatic cysts detected as incidental finding in a population-based longitudinal study. DESIGN: A total of 1077 participants (521 men, mean age 55.8±12.8 years) of 2333 participants from the population-based Study of Health in Pomerania (SHIP) underwent magnetic resonance cholangiopancreaticography (MRCP) at baseline (2008-2012). MRCP was analysed for pancreatic cysts with a diameter ≥2 mm. 676/1077 subjects received a 5-year follow-up (2014-2016). The prevalence and incidence of pancreatic cysts (weighted for study participation) were assessed in association to age, gender and suspected epidemiological risk factors. Mortality follow-up was performed in 2015 for all SHIP participants (mean follow-up period 5.9 years, range 3.2-7.5 years). RESULTS: At baseline pancreatic cysts had a weighted prevalence of 49.1%, with an average number of 3.9 (95% CI 3.2 to 4.5) cysts per subject in the subgroup harbouring cysts. Cyst size ranged from 2 to 29 mm. Prevalence (p<0.001), number (p=0.001) and maximum size (p<0.001) increased significantly with age. The 5-year follow-up revealed a weighted incidence of 12.9% newly detected pancreatic cysts. 57.1% of the subjects initially harbouring pancreatic cysts showed an increase in number and/or maximum cyst size. Of all subjects undergoing MRCP, no participant died of pancreatic diseases within mortality follow-up. CONCLUSION: The prevalence of pancreatic cysts in the general population is unexpectedly high, and their number and size increase with age. Overall, no pancreatic cancer was observed in this collective during a 5-year follow-up. Nevertheless, prospective follow-up imaging showed minimal progress in more than 50%. Only about 6% of cysts and 2.5% of the study group initially presented with cysts of more than 1 cm and thus might be clinically meaningful.

21 Article Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. 2018

Mayerle, Julia / Kalthoff, Holger / Reszka, Regina / Kamlage, Beate / Peter, Erik / Schniewind, Bodo / González Maldonado, Sandra / Pilarsky, Christian / Heidecke, Claus-Dieter / Schatz, Philipp / Distler, Marius / Scheiber, Jonas A / Mahajan, Ujjwal M / Weiss, F Ulrich / Grützmann, Robert / Lerch, Markus M. ·Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, München, Germany. · Section for Molecular Oncology, Institut for Experimental Cancer Research (IET), UKSH, Kiel, Germany. · Metanomics Health GmbH, Berlin, Germany. · metanomics GmbH, Berlin, Germany. · Department of Surgery, University Hospital, Erlangen, Germany. · Department of General, Visceral, Thoracic and Vascular Surgery University Medicine Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany. · Clinic and Outpatient Clinic for Visceral-, Thorax- and Vascular Surgery, Medizinische Fakultät, TU Dresden, Dresden, Germany. ·Gut · Pubmed #28108468.

ABSTRACT: OBJECTIVE: Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. DESIGN: For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. RESULTS: A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. CONCLUSIONS: In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.

22 Article Newcastle disease virus mediates pancreatic tumor rejection via NK cell activation and prevents cancer relapse by prompting adaptive immunity. 2017

Schwaiger, Theresa / Knittler, Michael R / Grund, Christian / Roemer-Oberdoerfer, Angela / Kapp, Joachim-Friedrich / Lerch, Markus M / Mettenleiter, Thomas C / Mayerle, Julia / Blohm, Ulrike. ·Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany. · Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. · Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Greifswald-Insel Riems, Germany. · Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany. · Senheimerstr. 25A, Berlin, 13465. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, Munich, Germany. ·Int J Cancer · Pubmed #28857157.

ABSTRACT: Pancreatic cancer is the 8th most common cause of cancer-related deaths worldwide and the tumor with the poorest prognosis of all solid malignancies. In 1957, it was discovered that Newcastle disease virus (NDV) has oncolytic properties on tumor cells. To study the oncolytic properties of NDV in pancreatic cancer a single dose was administered intravenously in a syngeneic orthotopic tumor model using two different murine pancreatic adenocarcinoma cell lines (DT6606PDA, Panc02). Tumor growth was monitored and immune response was analyzed. A single treatment with NDV inhibited DT6606PDA tumor growth in mice and prevented recurrence for a period of three months. Tumor infiltration and systemic activation of NK cells, cytotoxic and helper T-cells was enhanced. NDV-induced melting of Panc02 tumors until d7 pi, but they recurred displaying unrestricted tumor growth, low immunogenicity and inhibition of tumor-specific immune response. Arrest of DT6606PDA tumor growth and rejection was mediated by activation of NK cells and a specific antitumor immune response via T-cells. Panc02 tumors rapidly decreased until d7 pi, but henceforth tumors characterized by the ability to perform immune-regulatory functions reappeared. Our results demonstrated that NDV-activated immune cells are able to reject tumors provided that an adaptive antitumor immune response can be initiated. However, activated NK cells that are abundant in Panc02 tumors lead to outgrowth of nonimmunogenic tumor cells with inhibitory properties. Our study emphasizes the importance of an adaptive immune response, which is initiated by NDV to mediate long-term tumor surveillance in addition to direct oncolysis.

23 Article Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges. 2017

Maertin, Sandrina / Elperin, Jason M / Lotshaw, Ethan / Sendler, Matthias / Speakman, Steven D / Takakura, Kazuki / Reicher, Benjamin M / Mareninova, Olga A / Grippo, Paul J / Mayerle, Julia / Lerch, Markus M / Gukovskaya, Anna S. ·Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. · Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California. · Department of Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany. · Department of Medicine, University of Illinois-Chicago, Chicago, Illinois; and. · Department of Medicine II, University Hospital, Ludwig-Maximilian-University, Munich, Germany. · Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; agukovsk@ucla.edu. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #28705806.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC.

24 Article 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer. 2017

Lutz, Manfred P / Zalcberg, John R / Ducreux, Michel / Aust, Daniela / Bruno, Marco J / Büchler, Markus W / Delpero, Jean-Robert / Gloor, Beat / Glynne-Jones, Rob / Hartwig, Werner / Huguet, Florence / Laurent-Puig, Pierre / Lordick, Florian / Maisonneuve, Patrick / Mayerle, Julia / Martignoni, Marc / Neoptolemos, John / Rhim, Andrew D / Schmied, Bruno M / Seufferlein, Thomas / Werner, Jens / van Laethem, Jean-Luc / Otto, Florian. ·CaritasKlinikum St. Theresia, Saarbrücken, Germany. Electronic address: m.lutz@caritasklinikum.de. · Department of Epidemiology and Preventive Medicine, School of Public Health, Monash University, The Alfred Centre, Melbourne, Australia. · Institut Gustave Roussy, Villejuif, France. · Department of Pathology, Universitätsklinikum Carl Gustav Carus, Dresden, Germany. · Department of Gastroenterology & Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, The Netherlands. · Chirurgische Universitätsklinik, Heidelberg, Germany. · Department of Surgery, Institut Paoli Calmettes, Marseille, France. · Klinik für Viszerale und Transplantationschirurgie, Inselspital, Bern, Switzerland. · Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK. · Department of General, Visceral and Transplantation Surgery, Klinikum der Universität München, Munich, Germany. · Radiooncology Service, Hôpital Tenon (Hôpitaux Universitaires Est Parisien), Paris Cedex 20, France. · Université René Descartes, UFR Biomédicale des Saints-Pères, Paris, France. · University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Germany. · Istituto Europeo di Oncologia, Divisione di Epidemiologia e Biostatistica, Milan, Italy. · Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin, Greifswald, Germany; Medizinische Klinik und Poliklinik II, Klinikum der Universität München, Munich, Germany. · Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, TU München, Munich, Germany. · Department of Surgery, Liverpool University, Liverpool, UK. · University of Michigan, Ann Arbor, MI, USA. · Klinik für Chirurgie, Kantonsspital St. Gallen, St. Gallen, Switzerland. · Department of Internal Medicine I, Ulm University, Ulm, Germany. · Hopital Erasme, Anderlecht, Belgium. · Tumor- und Brustzentrum ZeTuP, St. Gallen, Switzerland. ·Eur J Cancer · Pubmed #28460245.

ABSTRACT: The primary treatment of pancreatic cancer was the topic of the 3rd St. Gallen Conference 2016. A multidisciplinary panel reviewed the current evidence and discussed controversial issues in a moderated consensus session. Here we report on the key expert recommendations. It was generally accepted that radical surgical resection followed by adjuvant chemotherapy offers the only evidence-based treatment with a chance for cure. Initial staging should classify localised tumours as resectable or unresectable (i.e. locally advanced pancreatic cancer) although there remains a large grey-zone of potentially resectable disease between these two categories which has recently been named as borderline resectable, a concept which was generally accepted by the panel members. However, the definition of these borderline-resectable (BR) tumours varies between classifications due to their focus on either (i) technical hurdles (e.g. the feasibility of vascular resection) or (ii) oncological outcome (e.g. predicting the risk of a R1 resection and/or occult metastases). The resulting expert discussion focussed on imaging standards as well as the value of pretherapeutic laparoscopy. Indications for biliary drainage were seen especially before neoadjuvant therapy. Following standard resection, the panel unanimously voted for the use of adjuvant chemotherapy after R0 resection and considered it as a reasonable standard of care after R1 resection, even though the optimal pathologic evaluation and the definition of R0/R1 was the issue of an ongoing debate. The general concept of BR tumours was considered as a good basis to select patients for preoperative therapy, albeit its current impact on the therapeutic strategy was far less clear. Main focus of the conference was to discuss the limits of surgical resection and to identify ways to standardise procedures and to improve curative outcome, including adjuvant and perioperative treatment.

25 Article Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFα in a murine pancreatic cancer model. 2017

Partecke, Lars Ivo / Käding, André / Trung, Dung Nguyen / Diedrich, Stephan / Sendler, Matthias / Weiss, Frank / Kühn, Jens-Peter / Mayerle, Julia / Beyer, Katharina / von Bernstorff, Wolfram / Heidecke, Claus-Dieter / Keßler, Wolfram. ·Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany. · Department of Internal Medicine A, University Medicine, Greifswald, Germany. · Department of Experimental Radiology, University Medicine, Greifswald, Germany. · Department of General, Visceral and Vascular Surgery, Charité-University Medicine, Campus Benjamin Franklin, Berlin, Germany (current address). ·Oncotarget · Pubmed #28160574.

ABSTRACT: This study analyses the effects of vagotomy on tumor growth and survival in a murine, pancreatic cancer model in wild-type and TNFα-knockout (-/-) mice.Throughout many operative procedures in the upper gastrointestinal tract the partial or complete transection of the vagus nerve or its local nerve fibers is unavoidable. Thereby its anti-inflammatory effects in residual tumor tissue may get lost. This effect may be mediated by tumor-associated macrophages (TAM) secreting TNFα.In an orthotopic murine pancreatic cancer model subdiaphragmatic vagotomy versus sham surgery was performed. The impact on tumor growth was monitored in wild type and TNFα -/- mice using MRI. TAMs as well as expression levels of TNFα were analyzed using immunohistochemistry. The role of TNFα on tumor growth and migration was examined in vitro. Vagotomised mice showed increased tumor growth with macroscopic features of invasive growth and had a shorter survival time. The loss of vagal modulation led to significantly increased TNFα levels in tumors and considerably elevated numbers of TAMs. In vitro TNFα significantly stimulated growth (p < 0.05) and migration (p < 0.05) of pancreatic cancer cells. TNFα -/- mice survived significantly longer after tumor implantation (p < 0.05), with vagotomy not affecting the prognosis of these animals (p > 0.05).Vagotomy can increase tumor growth and worsen survival in a murine pancreatic cancer model mediated through TAMs and TNFα. Hence, the suppression of TAMs and the modulation of TNFα dependent pathways could offer new perspectives in immunotherapies of pancreatic cancer patients especially with remaining vital tumor cells and lost vagal modulation.

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