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Pancreatic Neoplasms: HELP
Articles by Christoph W. Michalski
Based on 69 articles published since 2009
(Why 69 articles?)
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Between 2009 and 2019, C. Michalski wrote the following 69 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review The Sendai and Fukuoka consensus criteria for the management of branch duct IPMN - A meta-analysis on their accuracy. 2017

Heckler, Max / Michalski, Christoph W / Schaefle, Susanne / Kaiser, Jörg / Büchler, Markus W / Hackert, Thilo. ·Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address: thilo.hackert@med.uni-heidelberg.de. ·Pancreatology · Pubmed #28189431.

ABSTRACT: INTRODUCTION: The risk of malignancy in branch duct intraductal papillary mucinous neoplasia of the pancreas (BD-IPMN) is controversially debated. An increasing number of studies report on outcomes using the Sendai or Fukuoka consensus criteria for treatment decision-making. The objective of this work was to evaluate the diagnostic accuracy of the Sendai and Fukuoka criteria. METHODS: We systematically reviewed studies on Sendai or Fukuoka criteria-guided management of BD-IPMN. Pooled sensitivity, specificity and diagnostic odds ratios as compound measures of diagnostic accuracy were calculated from studies matching the inclusion criteria. The meta-analysis was performed using a random effects model. RESULTS: Fifteen studies with a total of 2710 patients were included. Twelve of these used the Sendai criteria. In these studies, 23% of Sendai-negative patients had a high grade dysplastic lesion or an invasive carcinoma in final histology. Pooled sensitivity was 56%, specificity was 74% and the diagnostic odds ratio for malignancy in Sendai-positive lesions was 7.45. When the results of follow-up examinations were included, diagnostic accuracy improved significantly (14.66, p < 0.001). Three studies were identified that used the Fukuoka criteria for decision making. Of 200 patients with Fukuoka-negative lesions who underwent surgery, 22 had a malignant lesion in final histology (11%). Pooled sensitivity was 83%, specificity was 53% and the diagnostic odds ratio was 8.76. CONCLUSION: The Fukuoka criteria have considerably improved sensitivity but still lack adequate specificity. For further reduction of a potential surgical overtreatment of BD-IPMN, the development of criteria with an increased specificity is required.

2 Review Reduced risk of pancreatic cancer associated with asthma and nasal allergies. 2017

Gomez-Rubio, Paulina / Zock, Jan-Paul / Rava, Marta / Marquez, Mirari / Sharp, Linda / Hidalgo, Manuel / Carrato, Alfredo / Ilzarbe, Lucas / Michalski, Christoph / Molero, Xavier / Farré, Antoni / Perea, José / Greenhalf, William / O'Rorke, Michael / Tardón, Adonina / Gress, Thomas / Barberà, Victor / Crnogorac-Jurcevic, Tatjana / Domínguez-Muñoz, Enrique / Muñoz-Bellvís, Luís / Alvarez-Urturi, Cristina / Balcells, Joaquim / Barneo, Luis / Costello, Eithne / Guillén-Ponce, Carmen / Kleeff, Jörg / Kong, Bo / Lawlor, Rita / Löhr, Matthias / Mora, Josefina / Murray, Lim / O'Driscoll, Damian / Peláez, Pablo / Poves, Ignasi / Scarpa, Aldo / Real, Francisco X / Malats, Núria / Anonymous6460850. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. · Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. · National Cancer Registry Ireland, Cork, Ireland, and Institute of Health & Society, Newcastle University, UK. · Hospital Madrid-Norte-Sanchinarro, Madrid, Spain. · Department of Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. · Technical University of Munich, Munich, Germany. · Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Department of Surgery, 12 de Octubre University Hospital, Madrid, Spain. · The Royal Liverpool University Hospital, Liverpool, UK. · Centre for Public Health, Queen's University Belfast, Belfast, UK. · Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital Giessen and Marburg, Marburg, Germany. · Laboratorio de Genética Molecular, Hospital General Universitario de Elche, Elche, Spain. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. · Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Cirugía General y del Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, Spain. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Gastrocentrum, Karolinska Institutet, Stockholm, Sweden. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ·Gut · Pubmed #26628509.

ABSTRACT: OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.

3 Review Strategies to improve the outcome in locally advanced pancreatic cancer. 2015

Späth, C / Nitsche, U / Müller, T / Michalski, C / Erkan, M / Kong, B / Kleeff, J. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany - christoph.spaeth@tum.de. ·Minerva Chir · Pubmed #25658301.

ABSTRACT: Pancreatic cancer is associated with the worst prognosis of all gastrointestinal malignancies. The major reasons for the dismal outcome are late diagnosis due to unspecific symptoms and aggressive tumor biology. Although highly effective chemotherapeutic options have emerged within the last decade, radical resection offers the only chance of cure. Only 10-20% of patients are resectable at presentation, and 30-40% present with borderline resectable or locally advanced/unresectable tumors. Even if resectable, the 5-year-survival rate after complete resections remains unsatisfactory, with less than 25%. This article gives an overview on current therapy standards as well as on new approaches especially for locally advanced tumors and outlines the importance of ongoing research to improve prognosis.

4 Review Update on surgical treatment of pancreatic neuroendocrine neoplasms. 2014

D'Haese, Jan G / Tosolini, Chiara / Ceyhan, Güralp O / Kong, Bo / Esposito, Irene / Michalski, Christoph W / Kleeff, Jörg. ·Jan G D'Haese, Chiara Tosolini, Güralp O Ceyhan, Bo Kong, Christoph W Michalski, Jörg Kleeff, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. ·World J Gastroenterol · Pubmed #25320524.

ABSTRACT: Pancreatic neuroendocrine neoplasms (PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential (neurendocrine tumors PNETs) or overt (neuroendocrine carcinomas PNECs) malignant, but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimally-invasive approaches which should be tailored to the individual patient. Generally, surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs, indications for tumor resection are much wider than for pancreatic adenocarcinoma, in many cases due to the relatively benign tumor biology. Thus, patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands, even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However, poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly single-center series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable, ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review, we summarize recent advances in the surgical treatment of PNENs.

5 Review The role of inflammation in pancreatic cancer. 2014

Hausmann, Simone / Kong, Bo / Michalski, Christoph / Erkan, Mert / Friess, Helmut. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany. ·Adv Exp Med Biol · Pubmed #24818722.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely poor prognosis. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. In genetically engineered mouse models, induction of pancreatitis accelerates PDAC development, and patients with chronic pancreatitis are known to have a higher risk of developing pancreatic cancer. In recent years, much effort has been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Many inflammatory pathways have been identified and inhibitors have been developed in order to prevent cancer development and progression. In this chapter, we discuss the role of inflammatory pathways in the initiation and progression of pancreatic cancer as well as the role of inhibitors used in treatment and prevention of pancreatic cancer.

6 Review The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. 2012

Erkan, Mert / Hausmann, Simone / Michalski, Christoph W / Fingerle, Alexander A / Dobritz, Martin / Kleeff, Jörg / Friess, Helmut. ·Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 12, 81675 Munich, Germany. m.mert.erkan@googlemail.com ·Nat Rev Gastroenterol Hepatol · Pubmed #22710569.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?

7 Review Energy metabolism and proliferation in pancreatic carcinogenesis. 2012

Regel, Ivonne / Kong, Bo / Raulefs, Susanne / Erkan, Mert / Michalski, Christoph W / Hartel, Mark / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. ·Langenbecks Arch Surg · Pubmed #22430298.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer entity with a high proliferative potential. Uncontrolled cell proliferation is mediated by a number of core signaling pathways. Recently, novel data of PDAC biology suggest that these core signal pathways affect cell proliferation and metabolism simultaneously. METHODS: Here, we reviewed the literature on core metabolic signaling pathways in pancreatic carcinogenesis. RESULTS: Results obtained from mouse genetics and in vitro experiments have demonstrated the significance of the Kras, p53, c-Myc, and Lkb1 networks in the proliferation of pancreatic epithelial and cancer cells. At the same time, these major pathways also affect energy metabolism by influencing glucose and glutamine utilization. In particular, Kras-mediated metabolic changes seem to be directly involved in carcinogenesis. However, there is a lack of solid evidence on how metabolism and proliferation are connected in pancreatic carcinogenesis. CONCLUSION: Understanding early and subtle changes in cellular metabolism of pancreatic epithelial-and specifically of acinar-cells, which accompany or directly influence malignant transformation and uncontrolled proliferation, will be paramount to define novel imaging and other modalities for earlier detection of PDAC.

8 Review The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. 2012

Erkan, Mert / Reiser-Erkan, Carolin / Michalski, Christoph W / Kong, Bo / Esposito, Irene / Friess, Helmut / Kleeff, Jorg. ·Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Germany. m.mert.erkan@googlemail.com ·Curr Mol Med · Pubmed #22272725.

ABSTRACT: Around 95% of patients diagnosed with pancreatic cancer will die of their disease within 5 years, three quarters within a year. The major hurdle in improving prognosis is the lack of a therapeutic time window. Early cancerous lesions are far beneath our threshold of detection. Therefore, at the time of diagnosis even early (T1) tumors can be metastatic and resistant to conventional treatments. Several therapies targeting epithelial tumor cells-all showing impressive results in vitro and in animal experiments-have failed to show relevant effects in clinical trials. This discrepancy between experimental data and clinical reality results mostly from the inefficiency of our current experimental setups in recreating the tumor microenvironment. Forming more than 80% of the tumor mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for the malignant cells but an active player in carcinogenesis. This component is mostly missing in the xeno-/allograft- mouse models. Although tumors are bigger if stellate cells are co-implanted, due to the disproportionate cancer/stromal cell ratio and -possibly- too rapid tumor growth, the stromal reaction is much smaller than in human pancreatic cancer. One the other hand, desmoplasia is present only in some of the genetically engineered mouse models. Clinically, stromal activity of the pancreatic ductal adenocarcinoma has as great an impact on patient prognosis as the lymph node status of the tumor. The exact molecular mechanisms behind this observation remain obscure. However, one possible fundamental biologic explanation could be that selective pressure applied by the stroma leads to the evolution of cancer cells. Consequently, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to this barrier, highlighting the importance of the fibrotic tumor microenvironment in the behavior of pancreatic cancer. In this review, the interaction of the epithelial tumor cells with the stroma in humans and in various animal models is scrutinized, and novel therapeutic options for uncoupling cancer-stroma interactions are discussed.

9 Review From tissue turnover to the cell of origin for pancreatic cancer. 2011

Kong, Bo / Michalski, Christoph W / Erkan, Mert / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #21750515.

ABSTRACT: The identity of the cell of origin for pancreatic ductal adenocarcinoma (PDAC) has long been debated. PDAC has a ductal morphology, but there is no formal proof that it originates from the ductal compartment. Targeting Kras expression to adult acinar or endocrine lineages induces the formation of tumors reminiscent of human PDAC, but only in the presence of concomitant inflammation. Apart from cells of the Pdx1-positive lineage in the adult pancreas, which can be transformed (albeit with low frequency), the cells susceptible to acquiring or retaining oncogenic mutations remain elusive. Hypothetically, a subset of cells that renew the adult organ physiologically or regenerate it upon severe tissue damage would be more susceptible to oncogenic transformation than mature, differentiated cells. Such a compartment could consist of putative pancreatic stem cells, progenitor cells, facultative stem cells or transdifferentiated bone marrow cells. An integrated approach combining techniques from stem cell and cancer biology will be necessary to define and map these cells.

10 Review Insulin-like growth factor signaling as a therapeutic target in pancreatic cancer. 2011

Rieder, Simon / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaninger Strasse 22, Munich, Germany. ·Anticancer Agents Med Chem · Pubmed #21492074.

ABSTRACT: Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.

11 Review Tumor microenvironment and progression of pancreatic cancer. 2010

Erkan, M / Reiser-Erkan, C / Michalski, C W / Kleeff, J. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, Munich 81675, Germany. erkan@chir.med.tu-muenchen.de ·Exp Oncol · Pubmed #21403605.

ABSTRACT: Pancreatic ductal adenocarcinoma is characterized by « tumor desmoplasia », a remarkable increase in connective tissue that penetrates and envelopes the neoplasm. It is becoming clear that this desmoplastic microenvironment of pancreatic cancer--which is forming approximately eighty percent of the tumor mass--is not a passive scaffold for the tumor cells but an active player in carcinogenesis. Several chemotherapeutic agents and novel molecular targeted therapies against epithelial tumor cells--although showing antitumor activity in cell culture and mouse experiments--have failed to show significant effects in the clinic. Thus, targeting pancreatic tumor cells alone seems unlikely to improve the dismal prognosis of pancreatic cancer. It has recently been shown that the activated stroma of pancreatic cancer is an independent prognostic marker with an impact on patient survival as much as the lymph node status of the cancer. Several primarily benign conditions associated with expansion of stromal and inflammatory components, such as chronic pancreatitis or hereditary pancreatitis are believed to increase the risk of pancreatic cancer. Similar observations have been made in other cancer types such as chronic hepatitis-liver cancer, Barrett dyplasia-esophageal cancer, and inflammatory bowel disease-colon cancer. The common denominator of all these conditions is; chronic inflammation leads to increased incidence of cancer. In this review the impact of the activated stroma on pancreatic carcinogenesis is discussed.

12 Review [Unresectable pancreatic cancer--palliative interventional and surgical treatment]. 2010

Hüser, N / Assfalg, V / Michalski, C W / Gillen, S / Kleeff, J / Friess, H. ·Klinikum rechts der Isar der Technischen Universität München, Chirurgische Klinik und Poliklinik, München, Deutschland. ·Zentralbl Chir · Pubmed #21154206.

ABSTRACT: In most cases pancreatic cancer appears in a non-curatively resectable stage at time the diagnosis is made. Thus, palliative treatment concepts come to the fore in these patients. Patients without metastases, but presenting with marginally resectable or locally non-resectable tumours should not be treated in a palliative therapeutic scheme. These patients should be enrolled in neoadjuvant radiochemotherapy trials. After finishing treatment and restaging, a potentially curative resection can be achieved in approximately one-third of these patients. Within the scope of the best possible palliative care, excision of metastases together with resection of the primary cancer represents a therapeutic option to be contemplated in selected cases. For distinct locally unresectable or metastasised advanced pancreatic cancer, treatment of bile duct or duodenal obstruction is an essential part of the comprehensive palliative therapy. However, both endoscopic / percutaneous stenting procedures and surgical bypass makeshifts constitute safe and highly effective therapeutic alternatives in this context. In the case of operative drainage of the biliary tract the prophylactic creation of a gastro-intestinal bypass (double bypass) is recommended. The decision on a surgical versus an endoscopic procedure for palliation depends considerably on the tumour stage and the estimated prognosis and has to be determined interdisciplinary and individually in each case.

13 Review Molecular mechanism of pancreatic cancer--understanding proliferation, invasion, and metastasis. 2010

Mihaljevic, André L / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg. ·Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany. ·Langenbecks Arch Surg · Pubmed #20237938.

ABSTRACT: INTRODUCTION: The purpose of this review is to highlight the molecular mechanisms leading to the development and progression of pancreatic ductal adenocarcinoma (PDAC) with particular emphasis on tumor cell proliferation, local invasion, and metastasis. Recent advances in the field of PDAC biology have shed light on the molecular events that trigger PDAC initiation and maintenance. RESULTS: It is now clear that apart from the genetic alterations within the tumor cells, interactions of the tumor with its environment are necessary for proliferation and invasion. Interestingly, a number of developmental signaling pathways are reactivated in PDAC. Progress has also been made in the understanding of the molecular events that govern the process of metastasis. CONCLUSION: Although our understanding of the mechanisms underlying PDAC pathobiology are more advanced than ever, little progress has been made in the clinical treatment of PDAC, and successful bench-to-bedside transfer of knowledge to boost new treatment options is still unsatisfying.

14 Review Confirmation of DNA microarray-derived differentially expressed genes in pancreatic cancer using quantitative RT-PCR. 2009

Streit, Sylvia / Michalski, Christoph W / Erkan, Mert / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Technische Universitat Munchen, Munich, Germany. ·Pancreatology · Pubmed #19657213.

ABSTRACT: The fact that pancreatic ductal adenocarcinoma (PDAC) is still an exceptionally lethal disease with an annual mortality almost equivalent to its annual incidence has stimulated intense research efforts directed at understanding the underlying molecular mechanisms. By enabling simultaneous expression analysis of thousands of genes, microarray technology has significantly contributed to illuminating the pathophysiology of PDAC. Gene expression profiling studies have been performed for molecular classification of clinically relevant tumor subtypes and have shed light on various signaling pathways associated with tumor progression. Altered expression levels of several genes have been identified as correlating with functional in vitro data as well as patient survival, indicating the potential clinical value of transcriptional profiling. However, broad clinical use of array techniques for patient characterization has been hampered by their cost intensity and by limited inter-study comparability. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), as the most sensitive technique for mRNA detection and quantification, will complement arrays for the confirmation of individual transcripts in larger sample cohorts. This review highlights recent studies that addressed gene expression analysis with both methodologies and that identified components of the TGF-beta signaling pathway, BNIP3, or periostin to be differentially expressed in PDAC. These studies demonstrated that the combination of microarray and RT-PCR technologies is a highly efficient and reliable approach for the identification of clinically important diagnostic and prognostic biomarkers, as well as for the discovery of novel therapeutic target candidates.

15 Review Systematic review and meta-analysis of prophylactic gastroenterostomy for unresectable advanced pancreatic cancer. 2009

Hüser, N / Michalski, C W / Schuster, T / Friess, H / Kleeff, J. ·Department of Surgery, Technische Universität München, Munich, Germany. ·Br J Surg · Pubmed #19526616.

ABSTRACT: BACKGROUND: The value of prophylactic gastroenterostomy (usually combined with a biliary bypass) in patients with unresectable cancer of the pancreatic head is controversial. METHODS: A systematic review of retrospective and prospective studies, and a meta-analysis of prospective studies, on the use of prophylactic gastroenterostomy for unresectable pancreatic cancer were performed. RESULTS: Analysis of retrospective studies did not reveal any advantage or disadvantage of prophylactic gastroenterostomy. Three prospective studies comparing prophylactic gastroenterostomy plus biliodigestive anastomosis with no bypass or a biliodigestive anastomosis alone were identified (altogether 218 patients). For patients who had prophylactic gastroenterostomy, the chance of gastric outlet obstruction during follow-up was significantly lower (odds ratio (OR) 0.06 (95 per cent confidence interval (c.i.) 0.02 to 0.21); P < 0.001). The rates of postoperative delayed gastric emptying were similar in both groups (OR 1.93 (95 per cent c.i. 0.57 to 6.53); P = 0.290), as were morbidity and mortality. The estimated duration of hospital stay after prophylactic gastroenterostomy was 3 days longer than for patients without bypass (weighted mean difference 3.1 (95 per cent c.i. 0.7 to 5.5); P = 0.010). CONCLUSION: Prophylactic gastroenterostomy should be performed during surgical exploration of patients with unresectable pancreatic head tumours because it reduces the incidence of long-term gastroduodenal obstruction without impairing short-term outcome.

16 Review Defining new pancreatic tumour entities by molecular analysis. 2009

Mihaljevic, A L / Esposito, I / Michalski, C W / Kleeff, J / Friess, H. ·Department of Surgery, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. ·Pancreatology · Pubmed #19451742.

ABSTRACT: Recent advances in molecular biology, biochemistry and genetics have broadened our understanding of tumourigenesis and of the maintenance and spread of pancreatic cancer far beyond traditional microscopic histopathological analysis. While the main focus of pancreatic cancer research has been on pancreatic ductal adenocarcinoma, molecular research has also led to a better understanding of rare tumours of the pancreas, as well as to the definition of previously unknown tumour entities that can only be identified through the application of molecular tools. Furthermore, molecular analysis increasingly reveals the genetic and cell biological heterogeneity of established tumour entities, making subclassification of tumours possible. Genetic and molecular approaches may, therefore, not only lead to a better understanding of the pathogenesis of pancreatic tumours, but also culminate in more precise diagnosis as well as individually tailored treatment strategies for affected patients.

17 Clinical Trial Sphincter of Oddi botulinum toxin injection to prevent pancreatic fistula after distal pancreatectomy. 2017

Hackert, Thilo / Klaiber, Ulla / Hinz, Ulf / Kehayova, Tzveta / Probst, Pascal / Knebel, Phillip / Diener, Markus K / Schneider, Lutz / Strobel, Oliver / Michalski, Christoph W / Ulrich, Alexis / Sauer, Peter / Büchler, Markus W. ·Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Interdisciplinary Center of Endoscopy, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address: markus.buechler@med.uni-heidelberg.de. ·Surgery · Pubmed #27865590.

ABSTRACT: BACKGROUND: Postoperative pancreatic fistula represents the most important complication after distal pancreatectomy. The aim of this study was to evaluate the use of a preoperative endoscopic injection of botulinum toxin into the sphincter of Oddi to prevent postoperative pancreatic fistula (German Clinical Trials Register number: DRKS00007885). METHODS: This was an investigator-initiated, prospective clinical phase I/II trial with an exploratory study design. We included patients who underwent preoperative endoscopic sphincter botulinum toxin injection (100 units of Botox). End points were the feasibility, safety, and postoperative outcomes, including postoperative pancreatic fistula within 30 days after distal pancreatectomy. Botulinum toxin patients were compared with a control collective of patients undergoing distal pancreatectomy without botulinum toxin injection by case-control matching in a 1:1 ratio. RESULTS: Between February 2015 and February 2016, 29 patients were included. All patients underwent successful sphincter of Oddi botulinum toxin injection within a median of 6 (range 0-10) days before operation. One patient had an asymptomatic, self-limiting (48 hours) increase in serum amylase and lipase after injection. Distal pancreatectomy was performed in 24/29 patients; 5 patients were not resectable. Of the patients receiving botulinum toxin, 7 (29%) had increased amylase levels in drainage fluid on postoperative day 3 (the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula grade A) without symptoms or need for reintervention. Importantly, no clinically relevant fistulas (International Study Group of Pancreatic Surgery grades B/C) were observed in botulinum toxin patients compared to 33% postoperative pancreatic fistula grade B/C in case-control patients (P < .004). CONCLUSION: Preoperative sphincter of Oddi botulinum toxin injection is a novel and safe approach to decrease the incidence of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. The results of the present trial suggest its efficacy in the prevention of clinically relevant postoperative pancreatic fistula and are validated currently in the German Federal Government-sponsored, multicenter, randomized controlled PREBOT trial.

18 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.

19 Article Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment. 2019

Cheng, Tao / Zhang, Zhiheng / Jian, Ziying / Raulefs, Susanne / Schlitter, Anna Melissa / Steiger, Katja / Maeritz, Nadja / Zhao, Yamin / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Friess, Helmut / Kleeff, Jörg / Michalski, Christoph W / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. · Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Int J Cancer · Pubmed #30412288.

ABSTRACT: Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras-driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein-induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction - which induces a more severe form of pancreatitis - by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative nonmucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of preneoplastic lesions. Lineage-tracing experiments revealed that these preneoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct-derived preneoplastic lesions show a high proliferative potential with persistent activation of tumour-promoting inflammatory pathways while the acinar-derived ones were less proliferative with persistent p53 activation. Furthermore, the duct-derived preneoplastic cells have a particularly high nuclear-to-cytoplasmic ratio. These data demonstrate that ductal obstruction promotes preneoplastic lesion formation from the pancreatic ductal compartment.

20 Article Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches. 2019

Gomez-Rubio, Paulina / Piñero, Janet / Molina-Montes, Esther / Gutiérrez-Sacristán, Alba / Marquez, Mirari / Rava, Marta / Michalski, Christoph W / Farré, Antoni / Molero, Xavier / Löhr, Matthias / Perea, José / Greenhalf, William / O'Rorke, Michael / Tardón, Adonina / Gress, Thomas / Barberá, Victor M / Crnogorac-Jurcevic, Tatjana / Muñoz-Bellvís, Luís / Domínguez-Muñoz, Enrique / Balsells, Joaquim / Costello, Eithne / Yu, Jingru / Iglesias, Mar / Ilzarbe, Lucas / Kleeff, Jörg / Kong, Bo / Mora, Josefina / Murray, Liam / O'Driscoll, Damian / Poves, Ignasi / Lawlor, Rita T / Ye, Weimin / Hidalgo, Manuel / Scarpa, Aldo / Sharp, Linda / Carrato, Alfredo / Real, Francisco X / Furlong, Laura I / Malats, Núria / Anonymous2321201. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center CNIO, Madrid, Spain. · Centro de Investigación Biomédica en Red en Oncología (CIBERONC), Enfermedades Hepáticas y Digestivas (CIBERHD), and Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. · Research Program on Biomedical Informatics (GRIB), Hospital del Mar Research Institute (IMIM), Universidad Pompeu Fabra (UPF), Barcelona, Spain. · Department of Surgery, Technical University of Munich, Munich, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Hospital Universitaru Vall d'Hebron, Exocrine Pancreas Research Unit and Vall d'Hebron Research Institute (VHIR), Barcelona, Spain. · Universitat Auntònoma de Barcelona, Campus de la UAB, Barcelona, Spain. · Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and University Hospital, Stockholm, Sweden. · Department of Surgery, University Hospital 12 de Octubre, Madrid, Spain. · Department of Molecular and Clinical Cancer Medicine, The Royal Liverpool University Hospital, Liverpool, United Kingdom. · Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom. · Department of Medicine, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, Germany. · Laboratorio de Genética Molecular, Hospital General Universitario de Elche, Elche, Spain. · Centre for Molecular Oncology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. · General and Digestive Surgery Department, Hospital Universitario de Salamanca, Salamanca, Spain. · Department of Gastroenterology, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Department of Gastroenterology, Hospital del Mar/Parc de Salut Mar, Barcelona, Spain. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, (Saale), Germany. · Cancer Data Registrars, National Cancer Registry Ireland, Cork, Ireland. · ARC-Net Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, University Hospital Trust of Verona, Verona, Italy. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Sweden. · Hospital Madrid-Norte-Sanchinarro and Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Rosenberg Clinical Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. · Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom. · Department of Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · PanGenEU Study Investigators (Additional file 1: Annex S1). ·Int J Cancer · Pubmed #30229903.

ABSTRACT: Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

21 Article Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma. 2018

Jian, Ziying / Cheng, Tao / Zhang, Zhiheng / Raulefs, Susanne / Shi, Kuangyu / Steiger, Katja / Maeritz, Nadja / Kleigrewe, Karin / Hofmann, Thomas / Benitz, Simone / Bruns, Philipp / Lamp, Daniel / Jastroch, Martin / Akkan, Jan / Jäger, Carsten / Huang, Peilin / Nie, Shuang / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Department of Nuclear Medicine, TUM, Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Bavarian Center for Biomolecular Mass Spectrometry, Freising, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU, Munich, Germany. · Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany. · Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany. · Division of Metabolic Diseases, TUM, Munich, Germany. · Department of Pathology, School of Medicine, Southeast University, Nanjing, China. · Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. ·Cell Mol Gastroenterol Hepatol · Pubmed #30258965.

ABSTRACT: Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown. Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients. Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1. Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.

22 Article Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives. 2018

Molina-Montes, E / Gomez-Rubio, P / Márquez, M / Rava, M / Löhr, M / Michalski, C W / Molero, X / Farré, A / Perea, J / Greenhalf, W / Ilzarbe, L / O'Rorke, M / Tardón, A / Gress, T / Barberà, V M / Crnogorac-Jurcevic, T / Domínguez-Muñoz, E / Muñoz-Bellvís, L / Balsells, J / Costello, E / Huang, J / Iglesias, M / Kleeff, J / Kong, Bo / Mora, J / Murray, L / O'Driscoll, D / Poves, I / Scarpa, A / Ye, W / Hidalgo, M / Sharp, L / Carrato, A / Real, F X / Malats, N / Anonymous601079. ·Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group, Madrid, and CIBERONC, Spain. · Karolinska Institutet and University Hospital, Gastrocentrum, Stockholm, Sweden. · Technical University of Munich, Department of Surgery, Munich, Germany. · University of Heidelberg, Department of Surgery, Heidelberg, Germany. · Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, and CIBEREHD, Spain. · Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology, Barcelona, Spain. · University Hospital 12 de Octubre, Department of Surgery, Madrid, Spain. · Royal Liverpool University Hospital, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK. · Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. · Queen's University Belfast, Centre for Public Health, Belfast, UK. · Instituto Universitario de Oncología del Principado de Asturias, Department of Medicine, Oviedo, and CIBERESP, Spain. · University Hospital of Giessen and Marburg, Department of Gastroenterology, Marburg, Germany. · General University Hospital of Elche, Molecular Genetics Laboratory, Elche, Spain. · Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of London, London, UK. · University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology, Santiago de Compostela, Spain. · Salamanca University Hospital, General and Digestive Surgery Department, Salamanca, Spain. · Martin-Luther-University Halle-Wittenberg, Department of Visceral, Vascular and Endocrine Surgery, Halle (Saale), Germany. · National Cancer Registry Ireland and HRB Clinical Research Facility, University College Cork, Cork, Ireland. · ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. · Madrid-Norte-Sanchinarro Hospital, Madrid, Spain. · Newcastle University, Institute of Health and Society, Newcastle upon Tyne, UK. · Ramón y Cajal University Hospital, Department of Oncology, IRYCIS, Alcala University, Madrid, and CIBERONC, Spain. · Spanish National Cancer Research Centre (CNIO), Epithelial Carcinogenesis Group, Madrid, Universitat Pompeu Fabra, Departament de Ciències Experimentals i de la Salut, Barcelona, and CIBERONC, Spain. ·Int J Epidemiol · Pubmed #29329392.

ABSTRACT: Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

23 Article International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. 2018

Isaji, Shuji / Mizuno, Shugo / Windsor, John A / Bassi, Claudio / Fernández-Del Castillo, Carlos / Hackert, Thilo / Hayasaki, Aoi / Katz, Matthew H G / Kim, Sun-Whe / Kishiwada, Masashi / Kitagawa, Hirohisa / Michalski, Christoph W / Wolfgang, Christopher L. ·Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Japan. Electronic address: shujiisaji1@mac.com. · Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Japan. · HBP/Upper GI Unit, Auckland City Hospital/Department of Surgery, University of Auckland, New Zealand. · Pancreas Surgery Unit, Pancreas Institute, Verona University Hospital, Verona, Italy. · Department of General and Gastrointestinal Surgery, Massachusetts General Hospital/Harvard Medical School, USA. · Department of Surgery, University of Heidelberg, Germany. · Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, USA. · Department of Surgery, Seoul National University Hospital, South Korea. · Department of Gastroenterologic Surgery, Toyama City Hospital/Department of Gastroenterological Surgery, Kanazawa University, Japan. · Department of Surgery, Johns Hopkins University School of Medicine, USA. ·Pancreatology · Pubmed #29191513.

ABSTRACT: This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19-9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.

24 Article Pylorus Resection Does Not Reduce Delayed Gastric Emptying After Partial Pancreatoduodenectomy: A Blinded Randomized Controlled Trial (PROPP Study, DRKS00004191). 2018

Hackert, Thilo / Probst, Pascal / Knebel, Phillip / Doerr-Harim, Colette / Bruckner, Thomas / Klaiber, Ulla / Werner, Jens / Schneider, Lutz / Michalski, Christoph W / Strobel, Oliver / Ulrich, Alexis / Diener, Markus K / Büchler, Markus W. ·Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Study Center of the German Surgical Society, University of Heidelberg, Heidelberg, Germany. · Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, Ludwig-Maximilians-University, Munich, Germany. ·Ann Surg · Pubmed #28885510.

ABSTRACT: OBJECTIVES: The aim of this study was to investigate the effect of pylorus resection on postoperative delayed gastric emptying (DGE) after partial pancreatoduodenectomy (PD). BACKGROUND: PD is the standard treatment for tumors of the pancreatic head. Preservation of the pylorus has been widely accepted as standard procedure. DGE is a common complication causing impaired oral intake, prolonged hospital stay, and postponed further treatment. Recently, pylorus resection has been shown to reduce DGE. METHODS: Patients undergoing PD for any indication at the University of Heidelberg were randomized to either PD with pylorus preservation (PP) or PD with pylorus resection and complete stomach preservation (PR). The primary endpoint was DGE within 30 days according to the International Study Group of Pancreatic Surgery definition. RESULTS: Ninety-five patients were randomized to PP and 93 patients to PR. There were no baseline imbalances between the groups. Overall, 53 of 188 patients (28.2%) developed a DGE (grade: A 15.5%; B 8.8%; C 3.3%). In the PP group 24 of 95 patients (25.3%) and in the PR group 29 of 93 patients (31.2%) developed DGE (odds ratio 1.534, 95% confidence interval 0.788 to 2.987; P = 0.208). Higher BMI, indigestion, and intraabdominal major complications were significant risk factors for DGE. CONCLUSIONS: In this randomized controlled trial, pylorus resection during PD did not reduce the incidence or severity of DGE. The development of DGE seems to be multifactorial rather than attributable to pyloric dysfunction alone. Pylorus preservation should therefore remain the standard of care in PD. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004191.

25 Article Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. 2018

Kong, Bo / Bruns, Philipp / Behler, Nora A / Chang, Ligong / Schlitter, Anna Melissa / Cao, Jing / Gewies, Andreas / Ruland, Jürgen / Fritzsche, Sina / Valkovskaya, Nataliya / Jian, Ziying / Regel, Ivonne / Raulefs, Susanne / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Mueller, Nikola S / Roth, Susanne / Hackert, Thilo / Esposito, Irene / Theis, Fabian J / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. · Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany. · Institute of Pathology, TUM, Munich, Germany. · Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany. · Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany. · German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. · Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany. · Chair of Experimental Genetics, Technische Universität München, Freising, Germany. · Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany. · Department of Surgery, Koc University, Istanbul, Turkey. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Mathematics, TUM, Munich, Germany. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. ·Gut · Pubmed #27646934.

ABSTRACT: OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.

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