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Pancreatic Neoplasms: HELP
Articles by Thilo Welsch
Based on 33 articles published since 2010
(Why 33 articles?)
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Between 2010 and 2020, T. Welsch wrote the following 33 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review [Early stage pancreatic cancer]. 2018

Kahlert, C / Distler, M / Aust, D / Gieldon, L / Weitz, J / Welsch, T. ·Klinik und Poliklinik für Viszeral‑, Thorax- und Gefäßchirurgie (VTG), Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland. · Institut für Pathologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Deutschland. · Tumor- und Normalgewebebank des Universitätskrebszentrums, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Deutschland. · Institut für Klinische Genetik, Universitätsklinikum Carl Gustav Carus an der Technische Universität Dresden, Dresden, Deutschland. · Klinik und Poliklinik für Viszeral‑, Thorax- und Gefäßchirurgie (VTG), Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland. Thilo.Welsch@uniklinikum-dresden.de. ·Chirurg · Pubmed #29264630.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth most common cause of cancer mortality and it is expected to become the second most common cause of cancer mortality by 2020 in the USA. OBJECTIVE: Which strategies for the detection and treatment of an early stage pancreatic adenocarcinoma and its precursor lesions are to be applied? RESULTS: Currently, there is no effective general screening program for pancreatic cancer due to the low incidence and the lack of an accurate and inexpensive diagnostic method; however, in patients with a positive history of hereditary pancreatic cancer or in patients with a known sporadic germline mutation that is associated with an increased risk of pancreatic cancer, frequent screening is highly recommended to detect and to treat early stage PDAC. Moreover, patients with a precursor lesion for pancreatic cancer (namely a mucinous pancreatic neoplasm) should undergo an oncological pancreatic resection to prevent the development of late stage pancreatic cancer. In future, additional biomarkers from a liquid biopsy, such as circulating tumor cells, exosomes or circulating tumor DNA may improve the early detection of pancreatic cancer. CONCLUSION: The early detection and treatment of pancreatic cancer and its precursor lesions can help to improve the dismal prognosis of this aggressive tumor type.

2 Review [Minimally invasive and robot-assisted surgery for pancreatic cystic tumors]. 2017

Welsch, T / Distler, M / Weitz, J. ·Klinik und Poliklinik für Viszeral‑, Thorax- und Gefäßchirurgie (VTG), Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Deutschland. thilo.welsch@uniklinikum-dresden.de. · Klinik und Poliklinik für Viszeral‑, Thorax- und Gefäßchirurgie (VTG), Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Deutschland. ·Chirurg · Pubmed #28842736.

ABSTRACT: BACKGROUND: The indications for resection of pancreatic cystic lesions (PCL) are often complex and the operative risk has to be balanced against the risk of malignant transformation. The aim of the study was to provide a synopsis of the current treatment results of minimally invasive surgery for PCL. METHODS: A systematic literature search was performed using the Medline database (PubMed). Subsequently, the retrieved literature was selectively reviewed. RESULTS: No published prospective randomized controlled trials have yet addressed the comparison of open and minimally invasive surgery of PCL; however, retrospective case studies have demonstrated the feasibility, safety and a comparable morbidity after minimally invasive distal pancreatectomy (DP), pancreatoduodenectomy (PD), central (CP) or total pancreatectomy and enucleation. Whereas most DPs are performed laparoscopically, the experience of minimally invasive PD has been consolidated for the robot-assisted approach but is concentrated in only a few centers. The number of published reports on minimally invasive organ-sparing pancreas procedures (e. g. CP or enucleation) for PCL is scarce; however, the available (selected) results are promising. CONCLUSION: Minimally invasive surgery for PCL has the potential to reduce the operative trauma to the patients, while at the same time causing comparable or less morbidity. This requires an increasing specialization of complex minimally invasive resections. The clinical use of robotic systems will grow for the latter cases. A prospective registry of the results should be mandatory for quality management.

3 Review Impact of preoperative diabetes on long-term survival after curative resection of pancreatic adenocarcinoma: a systematic review and meta-analysis. 2014

Walter, Ulrike / Kohlert, Tobias / Rahbari, Nuh N / Weitz, Juergen / Welsch, Thilo. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany. ·Ann Surg Oncol · Pubmed #24322532.

ABSTRACT: BACKGROUND: Diabetes mellitus (DM) is coupled to the risk and symptomatic onset of pancreatic ductal adenocarcinoma (PDAC). The important question whether DM influences the prognosis of resected PDAC has not been systematically evaluated in the literature. We therefore performed a systematic review and meta-analysis evaluating the impact of preoperative DM on survival after curative surgery. METHODS: The databases Medline, Embase, Web of Science, and the Cochrane Library were searched for studies reporting on the impact of preoperative DM on survival after PDAC resection. Hazard ratios and 95 % confidence intervals (CI) were extracted. The meta-analysis was calculated using the random-effects model. RESULTS: The data search identified 4,365 abstracts that were screened for relevant articles. Ten retrospective studies with a cumulative sample size of 4,471 patients were included in the qualitative review. The mean prevalence of preoperative DM was 26.7 % (1,067 patients), and all types of pancreatic resections were considered. The meta-analysis included 8 studies and demonstrated that preoperative DM is associated with a worse overall survival after curative resection of PDAC (hazard ratio 1.32, 95 % CI 1.46-1.60, P = 0.004). Only 2 studies reported separate data for new-onset and long-standing DM. CONCLUSIONS: To our knowledge, this is the first meta-analysis evaluating long-term survival after PDAC resection in normoglycemic and diabetic patients, demonstrating a significantly worse outcome in the latter group. The mechanism behind this observation and the question whether different antidiabetic medications or early control of DM can improve survival in PDAC should be evaluated in further studies.

4 Review [Intraductal papillary mucinous neoplasm of the pancreas (IPMN)--standards and new aspects]. 2014

Distler, M / Welsch, T / Aust, D / Weitz, J / Grützmann, R. ·Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Carl Gustav Carus an der TU Dresden, Deutschland. · Institut für Pathologie, Universitätsklinikum Carl Gustav Carus an der TU Dresden, Deutschland. ·Zentralbl Chir · Pubmed #24241954.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) of the pancreas belong to the heterogeneous group of cystic pancreatic lesions and have been diagnosed more frequently in recent years. Diagnosis and differentiation from other cystic lesions (pseudocysts, serous-cystic neoplasias [SCN], mucinous-cystic neoplasias [MCN], intraductal papillary-mucinous neoplasias [IPMN] and solid pseudopapillary neoplasias [SPN]) is often challenging. IPMN of the pancreas are considered as precursor lesions for the development of invasive pancreatic cancer. However, depending on the morphological (MD-IPMN, BD-IPMN) and histological subtype (intestinal, pancreatobiliary, oncocytic or gastric) the malignant potential of IPMNs varies significantly. Hence, early diagnosis and selection of the appropriate therapeutic strategy is necessary for optimal outcome and cure. There is a strong consensus for the resection of all MD-IPMN. Small BD-IPMN without signs of malignancy can be followed by observation. The increasing understanding of the histopathology and tumour biology of IPMN has led to an amendment of the 2006 International Association of Pancreatology (IAP) guidelines for the treatment of cystic pancreatic tumours. In consideration of recent data, recommendations for observation and/or follow-up of IPMN cannot be given definitely.

5 Article Results of portosystemic shunts during extended pancreatic resections. 2019

Oehme, Florian / Distler, Marius / Müssle, Benjamin / Kahlert, Christoph / Weitz, Jürgen / Welsch, Thilo. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. thilo.welsch@uniklinikum-dresden.de. ·Langenbecks Arch Surg · Pubmed #31446472.

ABSTRACT: PURPOSE: Patients with borderline resectable pancreatic cancer are increasingly explored after neoadjuvant treatment protocols. A complete resection, then, frequently includes the resection of the mesentericoportal axis. Portosystemic shunting for advanced tumours with infiltration of the splenic vein or cavernous transformation of the portal vein can enable complete tumour resection and prevent portovenous congestion of the intestine. The aim of this study was to report the results of this technique for selected patients. METHODS: Patients operated for pancreatic cancer at our department between September 2012 and December 2017 using intraoperative portosystemic shunting were included in this retrospective analysis. RESULTS: Some 11 patients with pancreatectomy and simultaneous portosystemic shunting were included. The median age was 65.1 years. A distal splenorenal shunt and a temporary mesocaval shunt were accomplished in 5 and 4 cases, respectively. Two patients were operated using persistent mesocaval shunts (from the coronary, splenic or inferior mesenteric veins). The median operating time was 9.43 h. All but one patient were resected with tumour-negative resection margins; 5 patients had relevant complicated postoperative courses. There was one case of in-hospital mortality but no further 30- or 90-day mortality or graft-associated complications. Five patients were alive after a median follow-up of 24.6 months. The median postoperative survival was 12 months. CONCLUSION: Portosystemic shunting at the time of extended pancreatectomy is technically challenging but feasible and enables complete tumour resection in cases in which standard vascular reconstruction is limited by cavernous transformation or to prevent sinistral portal hypertension with acceptable morbidity in selected cases. Considering the limited overall survival, the potential individual patient benefit needs to be weighed against the considerable morbidity of advanced tumour resections.

6 Article Detectability and structural stability of a liquid fiducial marker in fresh ex vivo pancreas tumour resection specimens on CT and 3T MRI. 2019

Schneider, Sergej / Aust, Daniela E / Brückner, Stefan / Welsch, Thilo / Hampe, Jochen / Troost, Esther G C / Hoffmann, Aswin L. ·Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. sergej.schneider@oncoray.de. · OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstraße 74, PF 41, 01307, Dresden, Germany. sergej.schneider@oncoray.de. · Institute of Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · Medical Department 1, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. · OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstraße 74, PF 41, 01307, Dresden, Germany. · Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. · National Center for Tumor Diseases (NCT), partner site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden; and Helmholtz Association/Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany. ·Strahlenther Onkol · Pubmed #31143995.

ABSTRACT: PURPOSE: To test the detectability of a liquid fiducial marker injected into ex vivo pancreas tumour tissue on magnetic resonance imaging (MRI) and computed tomography (CT). Furthermore, its injection performance using different needle sizes and its structural stability after fixation in formaldehyde were investigated. METHODS: Liquid fiducial markers with a volume of 20-100 µl were injected into freshly resected pancreas specimens of three patients with suspected adenocarcinoma. X‑ray guided injection was performed using different needle sizes (18 G, 22 G, 25 G). The specimens were scanned on MRI and CT with clinical protocols. The markers were segmented on CT by signal thresholding. Marker detectability in MRI was assessed in the registered segmentations. Marker volume on CT was compared to the injected volume as a measure of backflow. RESULTS: Markers with a volume ≥20 µl were detected as hyperintensity on X‑ray and CT. On T CONCLUSIONS: The liquid fiducial marker injected in ex vivo pancreatic resection specimen was visible as hyperintensity on kV X‑ray and CT and as hypointensity on MRI. The marker's size was stable in formaldehyde. A marker volume of ≥50 µL is recommended in clinically used MRI sequences. In vivo injection is expected to improve the markers sphericity due to persisting metabolism and thereby enhance detectability on MRI.

7 Article Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging. 2019

Casadonte, Rita / Kriegsmann, Mark / Perren, Aurel / Baretton, Gustavo / Deininger, Sören-Oliver / Kriegsmann, Katharina / Welsch, Thilo / Pilarsky, Christian / Kriegsmann, Jörg. ·Proteopath GmbH, Trier, 54296, Germany. · Institute of Pathology, University of Heidelberg, Heidelberg, 69120, Germany. · Institute of Pathology, University of Bern, Bern, 3012, Switzerland. · Institute of Pathology, University Hospital Carl Gustav Carus at the Technical University of Dresden, Dresden, 01307, Germany. · Bruker Daltonik, Bremen, 28359, Germany. · Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, 69120, Germany. · MVZ for Histology, Cytology and Molecular Diagnostics, Trier, 54296, Germany. ·Proteomics Clin Appl · Pubmed #30548962.

ABSTRACT: PURPOSE: To define proteomic differences between pancreatic ductal adenocarcinoma (pDAC) and pancreatic neuroendocrine tumor (pNET) by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). EXPERIMENTAL DESIGN: Ninety-three pDAC and 126 pNET individual tissues are assembled in tissue microarrays and analyzed by MALDI MSI. The cohort is separated in a training (52 pDAC and 83 pNET) and validation set (41 pDAC and 43 pNET). Subsequently, a linear discriminant analysis (LDA) model based on 46 peptide ions is performed on the training set and evaluated on the validation cohort. Additionally, two liver metastases and a whole slide of pDAC are analyzed by the same LDA algorithm. RESULTS: Classification of pDAC and pNET by the LDA model is correct in 95% (39/41) and 100% (43/43) of patients in the validation cohort, respectively. The two liver metastases and the whole slide of pDAC are also correctly classified in agreement with the histopathological diagnosis. CONCLUSION AND CLINICAL RELEVANCE: In the present study, a large dataset of pDAC and pNET by MALDI MSI is investigated, a class prediction model that allowed separation of both entities with high accuracy is developed, and differential peptide peaks with potential diagnostic, prognostic, and predictive values are highlighted.

8 Article Long-term tumor-free survival in a metastatic pancreatic carcinoma patient with FOLFIRINOX/Mitomycin, high-dose, fever inducing Viscum album extracts and subsequent R0 resection: A case report. 2018

Werthmann, Paul Georg / Inter, Pia / Welsch, Thilo / Sturm, Anne-Kathrin / Grützmann, Robert / Debus, Markus / Sterner, Martin-Günther / Kienle, Gunver Sophia. ·Institute for Applied Epistemology and Medical Methodology (IFAEMM) at the University of Witten/Herdecke, Freiburg i. Brsg. · Community practice for general medicine, Radebeul. · University Hospital Carl Gustav Carus. · Institute for pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden. · Department of Surgery, University hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg. · Department of Internal Medicine-Gastroenterology, Filderklinik, Filderstadt. · Department of Internal Medicine, Klinikum Niederlausitz, Senftenberg. · Institute for Applied Epistemology and Medical Methodology (IFAEMM) at the University of Witten/Herdecke, Freiburg i. Brsg., Germany. ·Medicine (Baltimore) · Pubmed #30544385.

ABSTRACT: RATIONALE: Metastatic pancreatic cancer has a dismal prognosis. Many patients seek integrative care as an add-on to their conventional cancer treatment. Viscum album extracts (VAE)-widely used as an adjunct to cancer treatment-have cytotoxic, apoptogenic, and immune stimulatory properties. A statistically significant survival benefit has been demonstrated for VAE in advanced pancreatic cancer. PATIENT CONCERNS AND DIAGNOSIS: A 28-year old patient presented with painless jaundice and was subsequently diagnosed as pancreatic adenocarcinoma with liver metastases. INTERVENTIONS: He was treated with FOLFIRINOX/Mitomycin, hyperthermia and fever-inducing VAE. OUTCOMES: Subsequently, the liver metastases regressed. Surgical intervention involved successful R0-resection of the primary tumor, as well as an atypical liver resection. A relapse was again treated with FOLFIRINOX/Mitomycin and hyperthermia. As of publication of this report, 49 months after initial diagnosis, the patient exhibits good condition, and is unrestricted in quality of life (till publication). LESSONS: This case demonstrates the favorable outcome of a patient with metastatic pancreatic cancer following treatment with chemotherapy, integrative medicine, and surgical excision. As other positive outcomes in pancreatic cancer patients are related to inflammatory events, we presume the immunologic effects of VAE to have contributed to the favorable outcome here. Based on this case, and the other positive results of VAE use in pancreatic cancer, further investigations seem highly worthwhile.

9 Article Validation of prognostic risk scores for patients undergoing resection for pancreatic cancer. 2018

Adamu, Mariam / Nitschke, Philipp / Petrov, Petar / Rentsch, Anke / Distler, Marius / Reissfelder, Christoph / Welsch, Thilo / Saeger, Hans-Detlev / Weitz, Juergen / Rahbari, Nuh N. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Germany. · University Cancer Center, Carl Gustav Carus, Technical University Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Germany. Electronic address: nuh.rahbari@umm.de. ·Pancreatology · Pubmed #29866508.

ABSTRACT: BACKGROUND/OBJECTIVES: A better stratification of patients into risk groups might help to select patients who might benefit from more aggressive therapy. The aim of this study was to validate five prognostic scores in patients resected for pancreatic ductal adenocarcinoma (PDAC). METHODS: Included were 307 PDAC patients who underwent resection with curative intent. Five clinical risk scores were selected and applied to our study population. Survival analyses were carried out using univariate and multivariate proportional hazards regression. RESULTS: Prognostic stratification was strong for the Heidelberg score (p < 0.001) and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (p = 0.001) and moderate for the Botsis score (p = 0.033). There was no significant prognostic value for the Early Mortality Risk Score (p = 0.126) and McGill Brisbane Symptom Score (p = 0.133). Positive resection margin (HR 1.53, 95% CI 1.08-2.16) and pain [pain (HR 1.40, CI 1.03-1.91), back pain (HR 1.67, 95% CI 1.08-2.57)] were independent prognostic factors on multivariate analysis. CONCLUSIONS: The Heidelberg score and MSKCC nomogram provided adequate risk stratification in our independent study cohort. Further studies in independent patient cohorts are required to achieve higher levels of validation.

10 Article Management of clinically relevant postpancreatectomy hemorrhage (PPH) over two decades - A comparative study of 1 450 consecutive patients undergoing pancreatic resection. 2017

Wolk, Steffen / Grützmann, Robert / Rahbari, Nuh N / Hoffmann, Ralf T / Plodeck, Verena / Weitz, Jürgen / Welsch, Thilo / Distler, Marius. ·Department of General, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany. · Institute of Radiology, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany. · Department of General, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany. Electronic address: marius.distler@uniklinikum-dresden.de. ·Pancreatology · Pubmed #29111264.

ABSTRACT: BACKGROUND/OBJECTIVES: PPH is the main cause of mortality (up to 50%) after pancreatic resection. Due to differences in time of onset, localization and clinical impairment, there is no consistent management algorithm. METHODS: Between 1994 and 2014 the occurrence of PPH in 115 out of 1 450 patients from a prospectively collected database was analyzed. The cohort was divided into two time periods: 1994-2009 and 2010-2014. The differences between the two groups were analyzed. RESULTS: The overall incidence of PPH was 7.9%. The main causes of hemorrhage were the pancreatic anastomosis (31.1%) and the splanchnic arteries (23.5%). In the first period, there were more anastomotic hemorrhages (40.0% vs. 20.4%, p = 0.02), while in the second period more hemorrhages from the splanchnic arteries occurred (12.3% vs. 37%, p = 0.002). Bleeding control was achieved by relaparotomy (45.7%), noninterventionally (22.8%), endoscopically (19.7%) and angiographically (13.4%). In the second period, the relevance of interventional angiography significantly increased (24.6% vs. 4.3%, p = 0.001), whereas endoscopy lost importance (7% vs. 30%, p = 0.001). The in-hospital case fatality rate after PPH was 27.4%, with higher case fatality rate following extraluminal hemorrhage (23.9% vs. 3.4%, p < 0.001). CONCLUSIONS: A shift in the management of PPH could be seen over the two periods. Interventional angiography has gained more importance in the treatment of severe extraluminal hemorrhage of the splanchnic arteries. Adequate treatment of PPH is crucial to improve the outcome.

11 Article Modulation of RAB5A early endosome trafficking in response to KRas mediated macropinocytic fluxes in pancreatic cancer cells. 2017

Teske, Christian / Schweitzer, Christine / Palamidessi, Andrea / Aust, Daniela E / Scita, Giorgio / Weitz, Jürgen / Welsch, Thilo. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. · Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139, Milan, Italy; Department of Hemato-Oncology (DIPO), University of Milan, Italy. · Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. Electronic address: thilo.welsch@uniklinikum-dresden.de. ·Biochem Biophys Res Commun · Pubmed #28867190.

ABSTRACT: KRAS is the key mutated gene in pancreatic ductal adenocarcinoma (PDAC). Emerging evidence indicates that KRas modulates endocytic uptake. The present study aimed to explore the fate of early endosomal trafficking under the control of KRas expression in PDAC. Surprisingly, PANC-1 cells lacking KRas exhibited significantly enlarged early and late endosomes containing internalized dextran and epidermal growth factor. Endosome enlargement was accompanied by reduced endosomal degradation. Both KRas silencing and lysosomal blockade caused an upregulation of the master regulator of early endosome biogenesis, RAB5A, which is likely responsible for the expansion of the early endosomal compartment, because simultaneous KRAS/RAB5A knockdown abolished endosome enlargement. In contrast, early endosome shrinkage was seen in MIA PaCa-2 cells despite RAB5A upregulation, indicating that distinct KRas-modulated responses operate in different metabolic subtypes of PDAC. In conclusion, mutant KRAS promotes endosomal degradation in PDAC cell lines, which is impaired by KRAS silencing. Moreover, KRAS silencing activates RAB5A upregulation and drives PDAC subtype-dependent modulation of endosome trafficking.

12 Article Para-aortic lymph node metastases in pancreatic cancer should not be considered a watershed for curative resection. 2017

Hempel, Sebastian / Plodeck, Verena / Mierke, Franz / Distler, Marius / Aust, Daniela E / Saeger, Hans-Detlev / Weitz, Jürgen / Welsch, Thilo. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. · Department of Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. · Institute for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. thilo.welsch@uniklinikum-dresden.de. ·Sci Rep · Pubmed #28794500.

ABSTRACT: No international consensus regarding the resection of the para-aortic lymph node (PALN) station Ln16b1 during pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) has been reached. The present retrospectively investigated 264 patients with PDAC who underwent curative pancreatoduodenectomy or total pancreatectomy between 2005-2015. In 95 cases, the PALN were separately labelled and histopathologically analysed. Metastatic PALN (PALN+) were found in 14.7% (14/95). PALN+ stage was associated with increased regional lymph node metastasis. The median overall survival (OS) of patients with metastatic PALN and with non-metastatic PALN (PALN-) was 14.1 and 20.2 months, respectively. Five of the PALN+ patients (36%) survived >19 months. The OS of PALN+ and those staged pN1 PALN- was not significantly different (P = 0.743). Patients who underwent surgical exploration or palliative surgery (n = 194) had a lower median survival of 8.8 (95% confidence interval: 7.3-10.1) months. PALN status could not be reliably predicted by preoperative computed tomography. We concluded that the survival data of PALN+ cases is comparable with advanced pN+ stages; one-third of the patients may expect longer survival after radical resection. Therefore, routine refusal of curative resection in the case of PALN metastasis is not indicated.

13 Article Clinical impact of duodenal pancreatic heterotopia - Is there a need for surgical treatment? 2017

Betzler, Alexander / Mees, Soeren T / Pump, Josefine / Schölch, Sebastian / Zimmermann, Carolin / Aust, Daniela E / Weitz, Jürgen / Welsch, Thilo / Distler, Marius. ·Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscher Str. 74, 01037, Dresden, Germany. · Institute for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Fetscher Str. 74, 01307, Dresden, Germany. · Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscher Str. 74, 01037, Dresden, Germany. Marius.Distler@uniklinikum-dresden.de. ·BMC Surg · Pubmed #28482873.

ABSTRACT: BACKGROUND: Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. METHODS: A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich's classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). RESULTS: A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. CONCLUSIONS: PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

14 Article Management of patients with pancreatic cystic lesions: A case-based survey. 2017

Müssle, B / Distler, M / Wolk, S / Shrikhande, S V / Aust, D E / Arlt, A / Weitz, J / Hackert, T / Welsch, T. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. · Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai, 400012, India. · Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. · Department of Internal Medicine I, Christian-Albrechts-University & UKSH Campus Kiel, Kiel, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. Electronic address: thilo.welsch@uniklinikum-dresden.de. ·Pancreatology · Pubmed #28456590.

ABSTRACT: BACKGROUND: Pancreatic cystic lesions (PCL), including intraductal papillary mucinous neoplasia (IPMN), harbor different malignant potential and the optimal management is often challenging. The present study aims to depict the compliance of experts with current consensus guidelines and the accuracy of treatment recommendations stratified by the medical specialty and hospital volume. METHODS: An international survey was conducted using a set of 10 selected cases of PCL that were presented to a cohort of international experts on pancreatology. All presented cases were surgically resected between 2004 and 2015 and histopathological examination was available. Accuracy of the treatment recommendations was based on the European and international consensus guideline algorithms, and the histopathological result. RESULTS: The response rate of the survey was 26% (46 of 177 contacted experts), consisting of 70% surgeons and 30% gastroenterologists/oncologists (GI/Onc). In the case of main-duct IPMN (MD-IPMN), surgeons preferred more often the surgical approach in comparison with the GI/Onc (55 versus 44%). The mean accuracy rate based on the European and international consensus guidelines, and the histopathological result, were 71/76/38% (surgeons), and 70/73/34% (GI/Onc), respectively. High-volume centers achieved insignificantly higher accuracy scores with regard to the histopathology. Small branch-duct IPMN with cysts <2 cm and malignant potential were not identified by the guideline algorithms. CONCLUSION: The survey underlines the complexity of treatment decisions for patients with PCL; less than 40% of the recommendations were in line with the final histopathology in this selected case panel. Experts and consensus guidelines may fail to predict malignant potential in small PCL.

15 Article Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer. 2017

Lerbs, Tristan / Bisht, Savita / Schölch, Sebastian / Pecqueux, Mathieu / Kristiansen, Glen / Schneider, Martin / Hofmann, Bianca T / Welsch, Thilo / Reissfelder, Christoph / Rahbari, Nuh N / Fritzmann, Johannes / Brossart, Peter / Weitz, Jürgen / Feldmann, Georg / Kahlert, Christoph. ·Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. · Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Bonn, Germany. · Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. · Department of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, Bonn, Germany. · Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. · Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. christoph.kahlert.079@googlemail.com. · Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. christoph.kahlert.079@googlemail.com. ·BMC Cancer · Pubmed #28388884.

ABSTRACT: BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis. Assessment of transcription factors involved in these two mechanisms can help to identify new targets for an oncological therapy. In this study, we focused on the evaluation of the transcription factor Six1 (Sine oculis 1). This protein is involved in embryologic development and its contribution to carcinogenesis has been described in several studies. METHODS: Immunohistochemistry against Six1 was performed on a tissue microarray containing specimens of primary pancreatic ductal adenocarcinomas (PDAC) of 139 patients. Nuclear and cytoplasmic expression was evaluated and correlated to histopathological parameters. Expression of Six1 was inhibited transiently by siRNA in Panc1 and BxPc3 cells and stably by shRNA in Panc1 cells. Expression analysis of CDH1 and Vimentin mRNA was performed and cell motility was tested in a migration assay. Panc1 cells transfected with Six1 shRNA or scrambled shRNA were injected subcutaneously into nude mice. Tumour growth was observed for four weeks. Afterwards, tumours were stained against Six1, CD24 and CD44. RESULTS: Six1 was overexpressed in the cytoplasm and cellular nuclei in malignant tissues (p < 0.0001). No correlation to histopathological parameters could be detected. Six1 down-regulation decreased pancreatic cancer cell motility in vitro. CDH1 and vimentin expression was decreased after inhibition of the expression of Six1. Pancreatic tumours with impaired expression of Six1 showed significantly delayed growth and displayed loss of the CD24 CONCLUSION: We show that Six1 is overexpressed in human PDAC and that its inhibition results in a decreased tumour progression in vitro and in vivo. Therefore, targeting Six1 might be a novel therapeutic approach in patients with pancreatic cancer.

16 Article [Robot-assisted pancreatic resection]. 2017

Müssle, B / Distler, M / Weitz, J / Welsch, T. ·Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie (VTG), Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstraße 74, 01307, Dresden, Deutschland. · Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie (VTG), Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstraße 74, 01307, Dresden, Deutschland. thilo.welsch@uniklinikum-dresden.de. ·Chirurg · Pubmed #28324155.

ABSTRACT: Although robot-assisted pancreatic surgery has been considered critically in the past, it is nowadays an established standard technique in some centers, for distal pancreatectomy and pancreatic head resection. Compared with the laparoscopic approach, the use of robot-assisted surgery seems to be advantageous for acquiring the skills for pancreatic, bile duct and vascular anastomoses during pancreatic head resection and total pancreatectomy. On the other hand, the use of the robot is associated with increased costs and only highly effective and professional robotic programs in centers for pancreatic surgery will achieve top surgical and oncological quality, acceptable operation times and a reduction in duration of hospital stay. Moreover, new technologies, such as intraoperative fluorescence guidance and augmented reality will define additional indications for robot-assisted pancreatic surgery.

17 Article Impact of Intraoperative Re-resection to Achieve R0 Status on Survival in Patients With Pancreatic Cancer: A Single-center Experience With 483 Patients. 2017

Nitschke, Philipp / Volk, Andreas / Welsch, Thilo / Hackl, Jonas / Reissfelder, Christoph / Rahbari, Mohammad / Distler, Marius / Saeger, Hans-Detlev / Weitz, Jürgen / Rahbari, Nuh N. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. ·Ann Surg · Pubmed #27280512.

ABSTRACT: OBJECTIVE: The aim of this study was to test the hypothesis that intraoperative frozen section (FS) and re-resection results to achieve R0 status are associated with different long-term outcomes in pancreatic cancer patients. BACKGROUND: Recent data have challenged the survival benefit of additional resection in patients with pancreatic cancer in case of positive FS to achieve clear pathological section (PS). METHODS: Patients who underwent surgery for exocrine pancreatic malignancy with curative intent were identified from a prospective database. Data were stratified by resection margin (group I: FS-R0 → PS-R0; group II: FS-R1 → PS-R0; group III: FS-R1 → PS-R1). Associations with survival were analyzed by univariate and multivariate analyses. RESULTS: A total of 483 patients met the inclusion criteria. Of these, 61 patients were excluded due to R2 or Rx status. Three hundred seventeen (75%) patients were allocated to margin group I, 32 (8%) to group II, and 73 (17%) to group III. Median overall survival in group I, II, and III was 29, 36, and 12 months (P < 0.001). There was no significant difference in survival between patients in Group I and II (P = 0.849), whereas patients in group III had significantly poorer outcome than group I (P < 0.001) and II (P = 0.039). The prognostic value of margin group status was confirmed on multivariate analysis (hazard ratio = 1.694, 95% confidence interval 1.175-2.442). CONCLUSIONS: FS analysis with intraoperative re-resection should be performed routinely in patients undergoing pancreatic cancer surgery with the aim to achieve a R0 resection.

18 Article Perioperative application of somatostatin analogs for pancreatic surgery-current status in Germany. 2016

Volk, Andreas / Nitschke, Philipp / Johnscher, Franziska / Rahbari, Nuh / Welsch, Thilo / Reißfelder, Christoph / Weitz, Jürgen / Distler, Marius / Mees, Soeren Torge. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fetscherstraße 74, 01307, Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Fetscherstraße 74, 01307, Dresden, Germany. soeren.mees@uniklinikum-dresden.de. ·Langenbecks Arch Surg · Pubmed #27628685.

ABSTRACT: BACKGROUND: The most common major complication after pancreatic resection is the postoperative pancreatic fistula (POPF). Somatostatin analogs can reduce POPF, but the use of somatostatin analogs is still controversial. The aim of this study was to assess treatment algorithms for pancreatic surgery in Germany with a special focus on the application of somatostatin analogs. METHODS: A questionnaire evaluating the perioperative management-especially the use of somatostatin analogs-and postoperative complications after pancreatic surgery was developed and sent to 209 German hospitals performing >12 pancreatoduodenectomies per year (the requirement for certification as a pancreas center). Statistical analysis was carried out using SPSS 21. RESULTS: The final response rate was 77 % (160/209), 14.5 % of hospitals never, 37 % always, and 45 % occasionally apply somatostatin analogs after pancreatic surgery. A (standard) drug of choice was defined in 64 % of hospitals. When standard and occasional usage was analyzed, it appeared that hospitals favored somatostatin (69 %) > sandostatin (50 %) > pasireotide (5 %). A relation between the usage of the different somatostatin analogs and morbidity (POPF) or mortality (84 and 16 % of hospitals reported <5 and 5-10 %, respectively) was not seen. Eighty-seven percent of hospitals were interested in participating in future studies analyzing somatostatin use. CONCLUSION: This is the first national survey in Germany evaluating the perioperative application of somatostatin analogs for pancreatic surgery. Despite controversial results in the literature, the majority of German pancreas surgeons apply somatostatin analogs perioperatively. The ideal drug to reduce POPF is still unclear. This uncertainty has aroused significant interest and prompted surgeons to participate in future studies in order to elucidate this issue.

19 Article Impact of Portal Vein Involvement from Pancreatic Cancer on Metastatic Pattern After Surgical Resection. 2016

Mierke, Franz / Hempel, Sebastian / Distler, Marius / Aust, Daniela E / Saeger, Hans-Detlev / Weitz, Jürgen / Welsch, Thilo. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. · Institute for Pathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. thilo.welsch@uniklinikum-dresden.de. ·Ann Surg Oncol · Pubmed #27554501.

ABSTRACT: BACKGROUND: The present study aims to evaluate the long-term outcome and metastatic pattern of patients who underwent resection of a pancreatic ductal adenocarcinoma (PDAC) with portal or superior mesenteric vein (PV/SMV) resection. METHODS: Patients who underwent a partial pancreatoduodenectomy or total pancreatectomy for PDAC between 2005 and 2015 were retrospectively analyzed. Three subgroups were generated, depending on PV/SMV resection (P RESULTS: The study cohort included 179 patients, 113 of whom underwent simultaneous PV/SMV resection. Thirty-six patients (31.9 %) had pathohistological tumor infiltration of the PV/SMV (P CONCLUSIONS: True invasion of the PV/SMV is an independent risk factor for overall survival, and is associated with a higher incidence of distant metastasis and shorter progressive-free survival. Radical vascular resection cannot compensate for aggressive tumor biology.

20 Article Role of TFEB-driven autophagy regulation in pancreatic cancer treatment. 2016

Klein, Kathrin / Werner, Kristin / Teske, Christian / Schenk, Miriam / Giese, Thomas / Weitz, Jürgen / Welsch, Thilo. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany. · Institute for Immunology, University of Heidelberg, D-69120 Heidelberg, Germany. ·Int J Oncol · Pubmed #27175909.

ABSTRACT: Autophagy pathways promote the growth of pancreatic ductal adenocarcinoma (PDAC), but the critical role is yet to be determined. Transcription factor EB (TFEB) centrally controls lysosomal and autophagy biogenesis. This study aimed to explore the role of TFEB for autophagy regulation in PDAC. We found that TFEB expression was significantly elevated in human PDAC samples (n=45), and localized to the cytoplasm and nucleus in 11 of 15 cases. In primary PDAC cell lines, TFEB nuclear expression was evident even under basal conditions, and further nuclear enrichment was achieved by starvation. Transient RNA interference reduced TFEB expression to 11-23%, but starvation-induced accumulation of the lipidated, autophagosome-associated LC3-II and the autophago-to-lysosome route was maintained after TFEB silencing. Likewise, gemcitabine treatment of the cancer cells augmented apoptosis and LC3-II as an indicator of autophagy, regardless of the TFEB expression levels. Moreover, the interplay of oncogenic KRAS with TFEB and autophagy was investigated. KRAS silencing caused PDAC cell apoptosis and a reciprocal increase in TFEB expression. This inverse correlation could be confirmed in published data sets of genetically engineered mouse models and human PDAC samples using the the Pubmed GEO and BioPortal databases, and was independent of KRAS mutation status. In conclusion, the central autophagy regulator TFEB is expressed and active in PDAC, but autophagy is sustained after TFEB knockdown, suggesting alternative bypass signaling. TFEB is dispensable for gemcitabine-induced cell death, but inversely correlated with KRAS expression.

21 Article Top-down approach to the superior mesenteric artery and the mesopancreas during pancreatoduodenectomy for pancreatic cancer. 2016

Welsch, Thilo / Bork, Ulrich / Distler, Marius / Weitz, Jürgen. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. ·J Surg Oncol · Pubmed #26898308.

ABSTRACT: Complete surgical resection with microscopically tumor-free resection margins (R0) is the most important survival determinant for patients with localized pancreatic cancer. The medial and posterior resection margins are the dominant sites of microscopic tumor involvement, and outline the so-called mesopancreas. In this study, we present a modified surgical approach to the superior mesenteric artery, celiac trunc, and mesopancreas during pancreatoduodenectomy, which enables a comfortable exposure and radical en bloc clearance of the mesopancreas and the tissue adjacent to the superior mesenteric artery. The dissection of the mesopancreas is directed from the ventral aspect of the portal vein downward along the superior mesenteric artery and the celiac trunc, before the transection of the duodenal mesentery is accomplished. The described technique complements the established surgical approaches to pancreatic head tumors, and is indicated in the absence of portal vein infiltration. J. Surg. Oncol. 2016;113:668-671. © 2016 Wiley Periodicals, Inc.

22 Article CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma. 2015

Teodorczyk, M / Kleber, S / Wollny, D / Sefrin, J P / Aykut, B / Mateos, A / Herhaus, P / Sancho-Martinez, I / Hill, O / Gieffers, C / Sykora, J / Weichert, W / Eisen, C / Trumpp, A / Sprick, M R / Bergmann, F / Welsch, T / Martin-Villalba, A. ·Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Apogenix GmbH, Heidelberg, Germany. · Institute of Pathology, University of Heidelberg, Heidelberg, Germany. · 1] Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH, Heidelberg, Germany. · 1] Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH, Heidelberg, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, Heidelberg, Germany. ·Cell Death Differ · Pubmed #25613377.

ABSTRACT: Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial-mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC.

23 Article Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity. 2015

Schenk, Miriam / Aykut, Berk / Teske, Christian / Giese, Nathalia A / Weitz, Juergen / Welsch, Thilo. ·Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. Electronic address: thilo.welsch@uniklinikum-dresden.de. ·Cancer Lett · Pubmed #25529011.

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

24 Article MHC class II expression in pancreatic tumors: a link to intratumoral inflammation. 2012

Gaida, Matthias M / Welsch, Thilo / Herpel, Esther / Tschaharganeh, Darjus F / Fischer, Lars / Schirmacher, Peter / Hänsch, G Maria / Bergmann, Frank. ·Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg, Germany. ·Virchows Arch · Pubmed #22120497.

ABSTRACT: Major histocompatibility complex class II antigens (MHC class II) are constitutively expressed by professional antigen presenting cells and present antigenic peptides to specific CD4+ T lymphocytes. MHC class II expression, however, can also be induced on epithelial cells and in a variety of solid tumors. We tested MHC class II expression on tissue samples derived from patients with pancreatic ductal adenocarcinoma (PDAC) and pancreatic endocrine tumors (PET). Immunohistochemistry revealed MHC class II expression in 86 of 112 (76.8%) PDAC samples and in 30 of 43 (70.0%) PET samples. In PDAC and PET, MHC class II expression correlated significantly with severity and activity of intratumoral inflammation, as well as with the infiltration of CD4+ T lymphocytes. High MHC class II expression significantly correlated with a better histological grade of differentiation in PDAC. In vitro MHC class II expression could be induced on PDAC tumor cell lines by interferon-γ. These cells were then able to present the staphylococci enterotoxin B superantigen to T lymphocytes, which resulted in T cell proliferation. Our findings suggest that MHC class II expression on pancreatic tumor cells is induced by the intratumoral inflammatory reaction in pancreatic tumors.

25 Article Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages. 2012

Welsch, Lena / Welsch, Thilo / Dovzhanskiy, Dmitriy I / Felix, Klaus / Giese, Nathalia A / Krysko, Dmitri V / Werner, Jens. ·Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. ·Int J Oncol · Pubmed #22020984.

ABSTRACT: Histone deacetylase inhibitors have been found to have potent anticancer activities, partly induced by tumour cell apoptosis. The clearance of apoptotic tumour cells is an important mechanism of antitumour immune surveillance. The aim of this study was to assess the impact of 4-phenylbutyrate (4-PB) and its immunological effects on the macrophage clearance of apoptotic pancreatic ductal adenocarcinoma (PDAC) cells. To this end, a co-culture system of human macrophages from donors and PDAC patients, and PDAC cell lines (T3M4, PANC-1 and AsPC-1) was established to study the effect of 4-PB. Apoptosis and phagocytic activity were analysed using flow cytometry, and phagocytosis was confirmed by confocal microscopy. Further, p21 expression was quantified by immunoblot analysis. 4-PB treatment (0-10 mM) resulted in a dose-dependent induction of tumour cell apoptosis in two of the cell lines (T3M4 and PANC-1), but it also induced human macrophage apoptosis. The apoptotic effect of gemcitabine on PDAC cells was further enhanced by 4-PB. Moreover, 4-PB led to a dose-dependent overexpression of the cell cycle regulator p21 in tumour cells. In co-culture, apoptotic PDAC cells were phagocytosed by donor macrophages and phagocytosis was increased through tumour cell exposure to 4-PB and/or gemcitabine, whereas phagocytosis of PANC-1 cells was reduced using macrophages of PDAC patients treated with 4-PB. The 4-PB treatment induced human macrophage expression of the pro-angiogenic IL-8 and simultaneously inhibited inflammatory cytokine release through modulation of IL-10 and TNFα after phagocytosis of apoptotic PDAC cells. In conclusion, the 4-PB treatment activated tumour cell death in PDAC cells, resulting in tumour cell phagocytosis by macrophages. The latter were characterized by an anti-inflammatory and pro-angiogenic cytokine response demonstrating adverse, tumour-promoting effects of macrophages on tumour cells. Thus, the potential of 4-PB as an anticancer agent against PDAC cannot be reliably assessed without taking into account the complex tumour microenvironment.

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