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Pancreatic Neoplasms: HELP
Articles by Uwe A. Wittel
Based on 25 articles published since 2010
(Why 25 articles?)
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Between 2010 and 2020, U. Wittel wrote the following 25 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Elevating pancreatic cystic lesion stratification: Current and future pancreatic cancer biomarker(s). 2020

Carmicheal, Joseph / Patel, Asish / Dalal, Vipin / Atri, Pranita / Dhaliwal, Amaninder S / Wittel, Uwe A / Malafa, Mokenge P / Talmon, Geoffrey / Swanson, Benjamin J / Singh, Shailender / Jain, Maneesh / Kaur, Sukhwinder / Batra, Surinder K. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA. · Department of General- and Visceral Surgery, University of Freiburg Medical Center, Faculty of Medicine, Freiburg, Germany. · Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: skaur@unmc.edu. · Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: sbatra@unmc.edu. ·Biochim Biophys Acta Rev Cancer · Pubmed #31676330.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an incredibly deadly disease with a 5-year survival rate of 9%. The presence of pancreatic cystic lesions (PCLs) confers an increased likelihood of future pancreatic cancer in patients placing them in a high-risk category. Discerning concurrent malignancy and risk of future PCL progression to cancer must be carefully and accurately determined to improve survival outcomes and avoid unnecessary morbidity of pancreatic resection. Unfortunately, current image-based guidelines are inadequate to distinguish benign from malignant lesions. There continues to be a need for accurate molecular and imaging biomarker(s) capable of identifying malignant PCLs and predicting the malignant potential of PCLs to enable risk stratification and effective intervention management. This review provides an update on the current status of biomarkers from pancreatic cystic fluid, pancreatic juice, and seromic molecular analyses and discusses the potential of radiomics for differentiating PCLs harboring cancer from those that do not.

2 Review Carcinosarcoma of the Pancreas: Case Report With Comprehensive Literature Review. 2017

Ruess, Dietrich A / Kayser, Claudia / Neubauer, Jakob / Fichtner-Feigl, Stefan / Hopt, Ulrich T / Wittel, Uwe A. ·From the *Department of Surgery, †Institute for Surgical Pathology, and ‡Department of Radiology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany. ·Pancreas · Pubmed #28902796.

ABSTRACT: Carcinosarcomas are rare biphasic neoplasms with distinct malignant epithelial and mesenchymal components. Most commonly, carcinosarcomas arise in the uterus as malignant mixed müllerian tumors, but also infrequently appear in other organs such as the ovaries and breast, the prostate and urinary tract, the lungs, or in the gastrointestinal system, among others. Pancreatic carcinosarcomas are exceedingly rare; only a few cases are reported in the English literature. Their pathogenesis remains to be fully clarified. We present here the case of a pancreatic carcinosarcoma with evidence for monoclonality via determination of Kras mutational status after microdissection and suggest a common origin of the 2 tumor components. Comprehensive review of the available literature allows the conclusion that most pancreatic carcinosarcomas appear to be of monoclonal origin and seem to have arisen from a carcinoma via metaplastic transformation of 1 part or subclone of the tumor, probably by epithelial-mesenchymal transition. All reported patients were treated with surgery. Adjuvant therapy, if administered, consisted predominantly of gemcitabine. Prognosis for this neoplasm occurs to be similar or even worse compared with classic pancreatic ductal adenocarcinoma. Despite the lack of evidence-based recommendations for its treatment, resection should be performed, if possible.

3 Review [Complications of minimally invasive pancreas resection for pancreatic neuroendocrine tumors]. 2015

Wittel, U A / Hopt, U T. ·Department Chirurgie, Klinik für Allgemein- und Visceralchirurgie, Universitätsklinikum Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland, uwe.wittel@uniklinik-freiburg.de. ·Chirurg · Pubmed #25492242.

ABSTRACT: BACKGROUND: Laparoscopic pancreas resections are performed with increasing frequency for pancreatic neuroendocrine tumors and other benign and malignant diseases. OBJECTIVES: This article describes the complications arising from laparoscopic resection of pancreatic neuroendocrine tumors and compares them to complications arising from similar open procedures. METHODS: Case series, reports, trials and meta-analyses were analyzed and the results are described and discussed. RESULTS: The types and the frequencies of complications are comparable for laparoscopic and open resection of pancreatic neuroendocrine tumors. The lack of the ability to perform an intraoperative examination of the pancreas to detect the tumors can be alleviated by laparoscopic ultrasound examination or in the case of tumors expressing somatostatin receptors by preoperative DOTATATE positron emission tomography (PET) computed tomography (CT) scanning. CONCLUSION: The complications arising from the resection of pancreatic neuroendocrine tumors do not justify a recommendation for a laparoscopic or open approach.

4 Review Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis. 2012

Momi, Navneet / Kaur, Sukhwinder / Ponnusamy, Moorthy P / Kumar, Sushil / Wittel, Uwe A / Batra, Surinder K. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. ·Carcinogenesis · Pubmed #22623649.

ABSTRACT: Despite continuous research efforts directed at early diagnosis and treatment of pancreatic cancer (PC), the status of patients affected by this deadly malignancy remains dismal. Its notoriety with regard to lack of early diagnosis and resistance to the current chemotherapeutics is due to accumulating signaling abnormalities. Hoarding experimental and epidemiological evidences have established a direct correlation between cigarette smoking and PC risk. The cancer initiating/promoting nature of cigarette smoke can be attributed to its various constituents including nicotine, which is the major psychoactive component, and several other toxic constituents, such as nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and polycyclic aromatic hydrocarbons. These predominant smoke-constituents initiate a series of oncogenic events facilitating epigenetic alterations, self-sufficiency in growth signals, evasion of apoptosis, sustained angiogenesis, and metastasis. A better understanding of the molecular mechanisms underpinning these events is crucial for the prevention and therapeutic intervention against PC. This review presents various interconnected signal transduction cascades, the smoking-mediated genotoxicity, and genetic polymorphisms influencing the susceptibility for smoking-mediated PC development by modulating pivotal biological aspects such as cell defense/tumor suppression, inflammation, DNA repair, as well as tobacco-carcinogen metabolization. Additionally, it provides a large perspective toward tumor biology and the therapeutic approaches against PC by targeting one or several steps of smoking-mediated signaling cascades.

5 Review The pathobiological impact of cigarette smoke on pancreatic cancer development (review). 2012

Wittel, Uwe A / Momi, Navneet / Seifert, Gabriel / Wiech, Thorsten / Hopt, Ulrich T / Batra, Surinder K. ·Department of General- and Visceral Surgery, Universitätsklinik Freiburg, Freiburg, Germany. uwe.wittel@uniklinik-freiburg.de ·Int J Oncol · Pubmed #22446714.

ABSTRACT: Despite extensive efforts, pancreatic cancer remains incurable. Most risk factors, such as genetic disposition, metabolic diseases or chronic pancreatitis cannot be influenced. By contrast, cigarette smoking, an important risk factor for pancreatic cancer, can be controlled. Despite the epidemiological evidence of the detrimental effects of cigarette smoking with regard to pancreatic cancer development and its unique property of being influenceable, our understanding of cigarette smoke-induced pancreatic carcinogenesis is limited. Current data on cigarette smoke-induced pancreatic carcinogenesis indicate multifactorial events that are triggered by nicotine, which is the major pharmacologically active constituent of tobacco smoke. In addition to nicotine, a vast number of carcinogens have the potential to reach the pancreatic gland, where they are metabolized, in some instances to even more toxic compounds. These metabolic events are not restricted to pancreatic ductal cells. Several studies show that acinar cells are also greatly affected. Furthermore, pancreatic cancer progenitor cells do not only derive from the ductal epithelial lineage, but also from acinar cells. This sheds new light on cigarette smoke-induced acinar cell damage. On this background, our objective is to outline a multifactorial model of tobacco smoke-induced pancreatic carcinogenesis.

6 Clinical Trial Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT. 2017

Gkika, E / Adebahr, S / Kirste, S / Schimek-Jasch, T / Wiehle, R / Claus, R / Wittel, U / Nestle, U / Baltas, D / Grosu, A L / Brunner, T B. ·Department of Radiation Oncology, University Medical Center Freiburg, Robert-Koch-Str. 3, 79106, Freiburg im Breisgau, Germany. eleni.gkika@uniklinik-freiburg.de. · Department of Radiation Oncology, University Medical Center Freiburg, Robert-Koch-Str. 3, 79106, Freiburg im Breisgau, Germany. · German Cancer Consortium (DKTK), Heidelberg (partner site Freiburg), Germany. · Division of Medical Physics, Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany. · Department of Hematology, Oncology and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany. · Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany. · Faculty of Medicine, University of Freiburg, Freiburg, Germany. ·Strahlenther Onkol · Pubmed #28138949.

ABSTRACT: BACKGROUND: Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. MATERIALS AND METHODS: According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a 4 mm expansion of the internal target volume. In C2, a subvolume was additionally created, a simultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed a reduced dose. RESULTS: In all, 18 patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23 lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8 months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12 months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12 months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1 patient in C1 experienced a grade ≥3 late toxicity. CONCLUSION: The SIP approach is a useful prescription method for abdominal SBRT with a favorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

7 Article Adjuvant chemotherapy after surgery for pancreatic ductal adenocarcinoma: retrospective real-life data. 2019

Chikhladze, Sophia / Lederer, Ann-Kathrin / Kousoulas, Lampros / Reinmuth, Marilena / Sick, Olivia / Fichtner-Feigl, Stefan / Wittel, Uwe A. ·Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg im Breisgau, Germany. sophia.chikhladze@uniklinik-freiburg.de. · Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg im Breisgau, Germany. · Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Straße 115b, 79106, Freiburg im Breisgau, Germany. ·World J Surg Oncol · Pubmed #31706323.

ABSTRACT: BACKGROUND: The recommendation for postoperative chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is based on prospective randomized trials. However, patients included in clinical trials do not often reflect the overall patient population treated in clinical practice. MATERIALS AND METHODS: A retrospective review of all patients undergoing pancreas resection for PDAC between 2001 and 2013 was performed. Follow-up data from oncologists, general practitioners, or hospital patient files were available for 92% of patients. RESULTS: A total of 251 patients were included in our analysis. Chemotherapy was recommended for 223 patients, but 86 patients did not follow the recommendation. The application of the recommended chemotherapy, consisting of 6 cycles of gemcitabine, was only applied to 45 patients. Forty patients received the recommended number of cycles with dose reduction or prolonged intervals between cycles, and adjuvant chemotherapy was terminated prior to the intended completion of all 6 cycles in 54 patients. Survival of patients after adjuvant chemotherapy was increased compared to that of patients without chemotherapy (with recurrence 25.6 vs. 14.3 months, p = 0.001, and without recurrence 27.4 vs. 14.3 months, p <  0.001). Terminating chemotherapy prior to completion (p = 0.009) as well as a lower number of chemotherapy cycles (p = 0.026) was associated with a decreased survival. CONCLUSION: Adjuvant chemotherapy improves overall and disease-free survival after curative pancreatic resection, but only a small fraction of patients completes the recommended 6 cycles of adjuvant chemotherapy. Our data indicates that performance status of patients after pancreas resections for PDAC requires not only highly biologically active but also well-tolerated adjuvant chemotherapy regimens.

8 Article Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial. 2019

Wittel, U A / Lubgan, D / Ghadimi, M / Belyaev, O / Uhl, W / Bechstein, W O / Grützmann, R / Hohenberger, W M / Schmid, A / Jacobasch, L / Croner, R S / Reinacher-Schick, A / Hopt, U T / Pirkl, A / Oettle, H / Fietkau, R / Golcher, H. ·Department for General- und Visceral Surgery, Medical Center and Faculty of Medicine University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany. uwe.wittel@unikklinik-freiburg.de. · Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. · Department of General, Visceral and Pediatric Surgery, Medical Center Georg-August-University Göttingen, Göttingen, Germany. · Department of Surgery, St. Josef Hospital Ruhr-University Bochum, Bochum, Germany. · Department of General and Visceral Surgery, Frankfurt University Hospital and Clinics, Frankfurt, Germany. · Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. · Department of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. · Private Practice, Hematology/Oncology, Dresden, Germany. · Department of Surgery, University Hospital Magdeburg, Magdeburg, Germany. · Department for Hematology, Oncology and Palliative Care, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany. · Department for General- und Visceral Surgery, Medical Center and Faculty of Medicine University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany. · Medical Centre for Information and Communication Technology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. · Outpatient Department Hematology/Oncology, Friedrichshafen, Germany. ·BMC Cancer · Pubmed #31640628.

ABSTRACT: BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).

9 Article Indications for resection and perioperative outcomes of surgery for pancreatic neuroendocrine neoplasms in Germany: an analysis of the prospective DGAV StuDoQ|Pancreas registry. 2019

Mintziras, Ioannis / Keck, Tobias / Werner, Jens / Fichtner-Feigl, Stefan / Wittel, Uwe / Senninger, Norbert / Vowinkel, Thorsten / Köninger, Jörg / Anthuber, Matthias / Geißler, Bernd / Bartsch, Detlef Klaus / Anonymous1391084. ·Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ioannis.mintziras@uk-gm.de. · Clinic for Surgery, University Clinic Schleswig-Holstein, UKSH Campus Lübeck, Lübeck, Germany. · Department of General, Visceral, Vascular and Transplant Surgery, Klinikum Der Universität München, Munich, Germany. · Department of General and Visceral Surgery, University Clinic Freiburg, Freiburg, Germany. · Department of General and Visceral Surgery, University Clinic Münster, Münster, Germany. · Department of General and Visceral Surgery, Klinikum Oldenburg, Oldenburg, Germany. · Department of General-, Visceral- and Vascular Surgery, St. Josefskrankenhaus, Freiburg, Germany. · Department of General, Visceral, Thoracic and Transplant Surgery, Katharinenhospital, Stuttgart, Germany. · Department of General, Visceral and Transplant Surgery, Klinikum Augsburg, Augsburg, Germany. · Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ·Surg Today · Pubmed #31240463.

ABSTRACT: PURPOSE: Pancreatic neuroendocrine neoplasms (pNENs) are rare, and their surgical management is complex. This study evaluated the current practice of pNEN surgery across Germany, including its adherence with guidelines and its perioperative outcomes. METHODS: Patients who underwent surgery for pNENs (April 2013-June 2017) were retrieved from the prospective StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery and retrospectively analyzed. RESULTS: A total of 287 patients (53.7% male) with a mean age of 59.2 ± 14.2 years old underwent pancreatic resection for pNENs. Tumors were localized in the pancreatic head (40.4%), body (23%), or tail (36.6%). A total of 239 (83.3%) patients underwent formal resection with lymphadenectomy, 40 (14%) parenchyma-sparing resection, and 8 (2.8%) only exploration. Fifty (17.4%) patients underwent a minimally invasive approach. Among the 245 patients with complete pathological information, 42 (17.1%) had distant metastases, 78 (31.8%) had stage I tumors, 74 (30.2%) stage II, and 51 (20.8%) stage III. A total of 112 (45.7%) patients had G1 tumors, 101 (41.2%) G2, and 24 (9.8%) G3. Nodal involvement on imaging was an independent predictor of lymph node metastasis according to the multivariable analysis (odds ratio: 0.057; 95% confidence interval: 0.016-0.209; p < 0.01). R0 resection was reported in 240 (83.6%) patients. The 30- and 90-day mortality rates were 2.8% and 4.2%, respectively. CONCLUSION: In Germany the rate of potential curative resection for pNEN is high. However, formal pancreatic resection seems to be overrepresented, while minimally invasive resection is underrepresented.

10 Article Unraveling altered RNA metabolism in pancreatic cancer cells by liquid-chromatography coupling to ion mobility mass spectrometry. 2019

Lagies, Simon / Schlimpert, Manuel / Braun, Lukas M / Kather, Michel / Plagge, Johannes / Erbes, Thalia / Wittel, Uwe A / Kammerer, Bernd. ·Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, Habsburgerstr. 49, 79104, Freiburg, Germany. · Institute of Biology II, Albert-Ludwigs-University Freiburg, Schänzlestr. 1, 79104, Freiburg, Germany. · Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Albertstr. 19A, 79104, Freiburg, Germany. · Department of General- and Visceral Surgery, University of Freiburg Medical Center, Hugstetter Str. 55, 79106, Freiburg, Germany. · Faculty of Chemistry and Pharmacy, Albert-Ludwigs-University Freiburg, Hebelstr. 27, 79104, Freiburg, Germany. · Hermann Staudinger Graduate School, University of Freiburg, Hebelstr. 27, 79104, Freiburg, Germany. · Department of Gynecology and Obstetrics, Faculty of Medicine and Medical Center, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. · Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, Habsburgerstr. 49, 79104, Freiburg, Germany. Bernd.Kammerer@zbsa.uni-freiburg.de. · BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestr. 16, 79104, Freiburg, Germany. Bernd.Kammerer@zbsa.uni-freiburg.de. ·Anal Bioanal Chem · Pubmed #31037374.

ABSTRACT: Ion mobility coupling to mass spectrometry facilitates enhanced identification certitude. Further coupling to liquid chromatography results in multi-dimensional analytical methods, especially suitable for complex matrices with structurally similar compounds. Modified nucleosides represent a large group of very similar members linked to aberrant proliferation. Besides basal production under physiological conditions, they are increasingly excreted by transformed cells and subsequently discussed as putative biomarkers for various cancer types. Here, we report a method for modified nucleosides covering 37 species. We determined collisional cross-sections with high reproducibility from pure analytical standards. For sample purification, we applied an optimized phenylboronic acid solid-phase extraction on media obtained from four different pancreatic cancer cell lines. Our analysis could discriminate different subtypes of pancreatic cancer cell lines. Importantly, they could clearly be separated from a pancreatic control cell line as well as blank medium. m1A, m27G, and Asm were the most important features discriminating cancer cell lines derived from well-differentiated and poorly differentiated cancers. Eventually, we suggest the analytical method reported here for future tumor-marker identification studies. Graphical abstract.

11 Article Implementation of Current ENETS Guidelines for Surgery of Small (≤2 cm) Pancreatic Neuroendocrine Neoplasms in the German Surgical Community: An Analysis of the Prospective DGAV StuDoQ|Pancreas Registry. 2019

Mintziras, Ioannis / Keck, Tobias / Werner, Jens / Fichtner-Feigl, Stefan / Wittel, Uwe / Senninger, Norbert / Vowinkel, Thorsten / Köninger, Jörg / Anthuber, Matthias / Geißler, Bernd / Bartsch, Detlef Klaus / Anonymous6310957. ·Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ioannis.mintziras@uk-gm.de. · Clinic for Surgery, University Clinic Schleswig-Holstein, UKSH Campus Lübeck, Lübeck, Germany. · Department of General, Visceral, Vascular and Transplant Surgery, Klinikum der Universität München, Munich, Germany. · Department of General and Visceral Surgery, University Clinic Freiburg, Freiburg, Germany. · Department of General and Visceral Surgery, University Clinic Münster, Münster, Germany. · Department of General and Visceral Surgery, Katharinenhospital, Stuttgart, Germany. · Department of General, Visceral and Transplant Surgery, Klinikum Augsburg, Augsburg, Germany. · Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. ·World J Surg · Pubmed #30097704.

ABSTRACT: BACKGROUND: ENETS guidelines recommend parenchyma-sparing procedures without formal lymphadenectomy, ideally with a minimally invasive laparoscopic approach for sporadic small pNENs (≤2 cm). Non-functioning (NF) small pNENs can also be observed. The aim of the study was to evaluate how these recommendations are implemented in the German surgical community. METHODS: Data from the prospective StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery were analyzed regarding patient's demographics, tumor characteristics, surgical procedures, histology and perioperative outcomes. RESULTS: Eighty-four (29.2%) of 287 patients had sporadic pNENs ≤2 cm. Forty-three (51.2%) patients were male, and the mean age at diagnosis was 58.8 ± 15.6 years. Twenty-five (29.8%) pNENs were located in the pancreatic head. The diagnosis pNEN was preoperatively established in 53 (65%) of 84 patients. Sixty-two (73.8%) patients had formal pancreatic resections, including partial pancreaticoduodenectomy or total pancreatectomy (21.4%). Only 22 (26.2%) patients underwent parenchyma-sparing resections and 23 (27.4%) patients had minimally invasive procedures. A lymphadenectomy was performed in 63 (75.4%) patients, and lymph node metastases were diagnosed in 6 (7.2%) patients. Eighty-two (97.7%) patients had an R0 resection. Sixty (72%) tumors were classified G1, 24 (28%) tumors G2. Twenty-seven (32.2%) of 84 patients had postoperative relevant Clavien-Dindo grade ≥3 complications. Thirty- and 90-day mortalities were 2.4% and 3.6%. CONCLUSIONS: ENETS guidelines for surgery of small pNENs are yet not well accepted in the German surgical community, since the rate of formal resections with standard lymphadenectomy is high and the minimally invasive approach is underused. The attitude to operate small NF tumors seems to be rather aggressive.

12 Article Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA): A Pan-European Propensity Score Matched Study. 2019

van Hilst, Jony / de Rooij, Thijs / Klompmaker, Sjors / Rawashdeh, Majd / Aleotti, Francesca / Al-Sarireh, Bilal / Alseidi, Adnan / Ateeb, Zeeshan / Balzano, Gianpaolo / Berrevoet, Frederik / Björnsson, Bergthor / Boggi, Ugo / Busch, Olivier R / Butturini, Giovanni / Casadei, Riccardo / Del Chiaro, Marco / Chikhladze, Sophia / Cipriani, Federica / van Dam, Ronald / Damoli, Isacco / van Dieren, Susan / Dokmak, Safi / Edwin, Bjørn / van Eijck, Casper / Fabre, Jean-Marie / Falconi, Massimo / Farges, Olivier / Fernández-Cruz, Laureano / Forgione, Antonello / Frigerio, Isabella / Fuks, David / Gavazzi, Francesca / Gayet, Brice / Giardino, Alessandro / Groot Koerkamp, Bas / Hackert, Thilo / Hassenpflug, Matthias / Kabir, Irfan / Keck, Tobias / Khatkov, Igor / Kusar, Masa / Lombardo, Carlo / Marchegiani, Giovanni / Marshall, Ryne / Menon, Krish V / Montorsi, Marco / Orville, Marion / de Pastena, Matteo / Pietrabissa, Andrea / Poves, Ignaci / Primrose, John / Pugliese, Raffaele / Ricci, Claudio / Roberts, Keith / Røsok, Bård / Sahakyan, Mushegh A / Sánchez-Cabús, Santiago / Sandström, Per / Scovel, Lauren / Solaini, Leonardo / Soonawalla, Zahir / Souche, F Régis / Sutcliffe, Robert P / Tiberio, Guido A / Tomazic, Aleš / Troisi, Roberto / Wellner, Ulrich / White, Steven / Wittel, Uwe A / Zerbi, Alessandro / Bassi, Claudio / Besselink, Marc G / Abu Hilal, Mohammed / Anonymous5620925. ·Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, the Netherlands. · Department of Surgery, Southampton University Hospital NHS Foundation Trust, Southampton, United Kingdom. · Department of Surgery, San Raffaele Hospital, Milan, Italy. · Department of Surgery, Morriston Hospital, Swansea, United Kingdom. · Department of Surgery, Virginia Mason Medical Center, Seattle, United States. · Department of Surgery, Karolinska Institute, Stockholm, Sweden. · Department of General and HPB surgery and liver transplantation, Ghent University Hospital, Ghent, Belgium. · Department of Surgery, Linköping University, Linköping, Sweden. · Department of Surgery, Universitá di Pisa, Pisa, Italy. · Department of Surgery, Pederzoli Hospital, Peschiera, Italy. · Department of Surgery, S. Orsola-Malpighi Hospital, Bologna, Italy. · Department of Surgery, Universitätsklinikum Freiburg, Freiburg, Germany. · Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands. · Department of Surgery, Pancreas Institute, Verona University Hospital, Verona, Italy. · Department of Surgery, Hospital of Beaujon, Clichy, France. · Department of Surgery, Oslo University Hospital and Institute for Clinical Medicine, Oslo, Norway. · Department of Surgery, Erasmus MC, Rotterdam, the Netherlands. · Department of Surgery, Hopital Saint Eloi, Montpellier, France. · Department of Surgery, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Surgery, Niguarda Ca' Granda Hospital, Milan, Italy. · Department of Surgery, Institut Mutualiste Montsouris, Paris, France. · Department of Surgery, Humanitas University Hospital, Milan, Italy. · Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. · Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, United Kingdom. · Clinic for Surgery, UKSH Campus Lübeck, Lübeck, Germany. · Department of Surgery, Moscow Clinical Scientific Center, Moscow, Russian Federation. · Department of Surgery, University Medical Center Ljubljana, Ljubljana, Slovenia. · Department of Surgery, King's College Hospital NHS Foundation Trust, London, United Kingdom. · Department of Surgery, University hospital Pavia, Pavia, Italy. · Department of Surgery, Hospital del Mar, Barcelona, Spain. · Department of Surgery, University Hospital Birmingham, Birmingham, United Kingdom. · Surgical Clinic, Department of clinical and experimental sciences, University of Brescia, Brescia, Italy. · Department of Surgery, The Freeman Hospital Newcastle Upon Tyne, Newcastle, United Kingdom. ·Ann Surg · Pubmed #29099399.

ABSTRACT: OBJECTIVE: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. METHODS: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. RESULTS: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60-400) vs 300 mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929). CONCLUSIONS: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

13 Article Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. 2018

Ettrich, Thomas J / Berger, Andreas W / Perkhofer, Lukas / Daum, Severin / König, Alexander / Dickhut, Andreas / Wittel, Uwe / Wille, Kai / Geissler, Michael / Algül, Hana / Gallmeier, Eike / Atzpodien, Jens / Kornmann, Marko / Muche, Rainer / Prasnikar, Nicole / Tannapfel, Andrea / Reinacher-Schick, Anke / Uhl, Waldemar / Seufferlein, Thomas. ·Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. · Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité University Medicine Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. · Department of Oncology/Hematology, Fulda Hospital, Pacelliallee 4, 36043, Fulda, Germany. · Department of General and Visceral Surgery, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. · Department of Hematology and medical oncology, Johannes-Wesling-Klinikum Minden, Hans-Nolte-Straße 1, 32429, Minden, Germany. · Department of Internal Medicine, Oncology/Hematology, Gastroenterology, Esslingen Hospital, Hirschlandstr. 97, 73730 Esslingen, Esslingen, Germany. · Department of Internal Medicine II, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. · Department of Gastroenterology and Endocrinology, University of Marburg, Baldingerstraße, 35043, Marburg, Germany. · Department of Medical Oncology and Hematology, Niels-Stensen-Kliniken, Alte Rothenfelder Str. 23, 49124, Georgsmarienhütte, Germany. · Department of General and Visceral Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. · Institute of Epidemiology and Medical Biometry, University of Ulm, Schwabstrasse 13, 89081, Ulm, Germany. · Department of Oncologie, Asklepios Klinik Barmbek, Rübenkamp 220, 22291, Hamburg, Germany. · Department of Pathology, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. · Department of Internal Medicine, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. · Department of Surgery, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. · Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. thomas.seufferlein@uniklinik-ulm.de. ·BMC Cancer · Pubmed #30594153.

ABSTRACT: BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.

14 Article Oncological outcome of laparoscopically assisted pancreatoduodenectomy for ductal adenocarcinoma in a retrospective cohort study. 2018

Kuesters, Simon / Chikhladze, Sophia / Makowiec, Frank / Sick, Olivia / Fichtner-Feigl, Stefan / Hopt, Ulrich T / Wittel, Uwe A. ·Department of General- and Visceral Surgery, University of Freiburg Medical Center, Faculty of Medicine, Freiburg, Germany. · Department of General- and Visceral Surgery, University of Freiburg Medical Center, Faculty of Medicine, Freiburg, Germany. Electronic address: uwe.wittel@uniklinik-freiburg.de. ·Int J Surg · Pubmed #29807171.

ABSTRACT: INTRODUCTION: Laparoscopic resections of the pancreatic head are increasingly performed. Several studies show that they are comparable to open operations in terms of postoperative morbidity. However, since a substantial proportion of pancreatic head resections are necessary for pancreatic adenocarcinoma the oncologic safety and outcome of minimally invasive operations is of interest. In this study we evaluated oncologic outcome and survival after laparoscopically assisted pancreatic head resection for ductal adenocarcinoma. METHODS: Perioperative and oncological outcome of sixty-two laparoscopically assisted pancreatic head resections for pancreatic ductal adenocarcinoma performed between 2010 and 2016 was compared to outcome of 278 open resections between 2001 and 2016 in a retrospective study. Data was continuously collected in a prospectively maintained database. RESULTS: Operation time was significantly longer in the laparoscopic group (477 vs. 428 min. p < 0.001). Tumor size, lymph node yield and lymph node state and need of portal vein resection were comparable. There was a higher rate of free resection margins in the laparoscopic group (87% vs. 71%, p < 0.01). There was no difference in postoperative mortality and morbidity. Patients with laparoscopic resection stayed in hospital significantly shorter (median 14 vs. 16 days, p < 0.003). Postoperative survival after 5 years was not different in both groups. CONCLUSION: Laparoscopically assisted resection of adenocarcinoma of the pancreatic head is equal to open resection concerning oncologic outcome and actuarial survival. However, minimally invasive resection shortened the hospital stay. However, further evaluations with a longer follow up time are needed.

15 Article The Indications for Laparoscopic Pancreatectomy. 2017

Siech, Marco / Strauss, Peter / Huschitt, Stephanie / Bartsch, Detlef K / Wittel, Uwe / Keck, Tobias. ·Department of Surgery I, Ostalb Klinikum Aalen; Department of General and Visceral Surgery, Medical Center-University of Freiburg; Department of Visceral, Thoracic and Vascular Surgery University of Marburg; Department of Surgery, University Medical Center-UKSH, Lübeck. ·Dtsch Arztebl Int · Pubmed #28468714.

ABSTRACT: BACKGROUND: Laparoscopic pancreatectomy is not yet established as a routine procedure everywhere in Germany or in other countries. Few data are available on its short- and long-term outcomes. METHODS: From 2008 onward, a working group initiated by 10 centers and currently comprising 34 centers has gathered data on all cases of laparoscopic pancreatectomy. Procedures in which laparoscopy was converted to open surgery are also included. RESULTS: The registry now contains 550 data sets representing 267 cases of benign disease, 244 malignancies, and 39 borderline tumors. The most common procedure was laparoscopic left pancreatectomy, followed by resection of the head of the pancreas and tumor enucleation. The most common intraoperative complication was hemorrhage, with a frequency of 3%. The rate of conversion to open surgery was 35%; if minilaparotomies are excluded, the conversion rate was only 16%. 39% of patients developed a pancreatic fistula after surgery (usually grade A or B, with 1.5% grade C) and 3% underwent reoperation because of postoperative hemorrhage. The procedure-related mortality was 1.3%. 91% of the patients reported only very mild postoperative pain. 6.7% newly developed diabetes mellitus after the procedure. CONCLUSION: The patient cohort in the registry consists of persons who were selected to undergo laparoscopic pancreatectomy by the participating hospital teams, and the data are thus inherently affected by selection bias. The operative procedures that they underwent reflect the current practice of laparoscopic pancreatectomy in Germany. The complication rates are similar to those of open surgery. Selection bias can be avoided only by a randomized trial.

16 Article Histopathological tumor invasion of the mesenterico-portal vein is characterized by aggressive biology and stromal fibroblast activation. 2017

Lapshyn, Hryhoriy / Bolm, Louisa / Kohler, Ilona / Werner, Martin / Billmann, Franck G / Bausch, Dirk / Hopt, Ulrich T / Makowiec, Frank / Wittel, Uwe A / Keck, Tobias / Bronsert, Peter / Wellner, Ulrich F. ·Clinic for General and Visceral Surgery, University Medical Center Freiburg, Germany; Clinic for Surgery, University Clinic Schleswig-Holstein, Campus Lübeck, Germany. · Clinic for Surgery, University Clinic Schleswig-Holstein, Campus Lübeck, Germany. · Institute of Surgical Pathology, University Medical Center Freiburg, Germany. · Institute of Surgical Pathology, University Medical Center Freiburg, Germany; Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, Germany; German Cancer Consortium (DKTK) and Cancer Research Center (DKFZ), Heidelberg, Germany. · Clinic for General and Visceral Surgery, University Medical Center Freiburg, Germany; Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, Germany. Electronic address: ulrich.hopt@uniklinik-freiburg.de. · Clinic for General and Visceral Surgery, University Medical Center Freiburg, Germany; Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, Germany. · Clinic for General and Visceral Surgery, University Medical Center Freiburg, Germany. ·HPB (Oxford) · Pubmed #27825542.

ABSTRACT: BACKGROUND: Mesenterico-portal vein resection (PVR) during pancreatoduodenectomy for pancreatic head cancer was established in the 1990s and can be considered a routine procedure in specialized centers today. True histopathologic portal vein invasion is predictive of poor prognosis. The aim of this study was to examine the relationship between mesenterico-portal venous tumor infiltration (PVI) and features of aggressive tumor biology. METHODS: Patients receiving PVR for pancreatic ductal adenocarcinoma of the pancreatic head were identified from a prospectively maintained database. Immunohistochemical staining of tumor tissue was performed for the markers of epithelial-mesenchymal transition (EMT) E-Cadherin, Vimentin and beta-Catenin. Morphology of cancer-associated fibroblasts (CAFs) was assessed as inactive or activated. Statistical calculations were performed with MedCalc software. RESULTS: In total, 41 patients could be included. Median overall survival was 25 months. PVI was found in 17 patients (41%) and was significantly associated with loss of membranous E-Cadherin in tumor buds (p = 0.020), increased Vimentin expression (p = 0.03), activated CAF morphology (p = 0.046) and margin positive resection (p = 0.005). CONCLUSION: Our findings suggest that PVI is associated with aggressive tumor biology and disseminated growth less amenable to margin-negative resection.

17 Article Laparoscopic versus open distal pancreatectomy-a propensity score-matched analysis from the German StuDoQ|Pancreas registry. 2017

Wellner, Ulrich Friedrich / Lapshyn, Hryhoriy / Bartsch, Detlef K / Mintziras, Ioannis / Hopt, Ulrich Theodor / Wittel, Uwe / Krämling, Hans-Jörg / Preissinger-Heinzel, Hubert / Anthuber, Matthias / Geissler, Bernd / Köninger, Jörg / Feilhauer, Katharina / Hommann, Merten / Peter, Luisa / Nüssler, Natascha C / Klier, Thomas / Mansmann, Ulrich / Keck, Tobias / Anonymous5440886. ·Clinic for Surgery, University Clinic Schleswig-Holstein, UKSH Campus Lübeck, 23538, Lübeck, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany. · Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany. · Department of General, Visceral and Vascular Surgery, Evangelical Hospital of Düsseldorf, Düsseldorf, Germany. · Department of General, Visceral and Transplantation Surgery,, Clinic Augsburg, Augsburg, Germany. · Department of General, Visceral, Thoracic, and Transplantation Surgery, Katharinenhospital, Clinic Stuttgart, Stuttgart, Germany. · Department of General and Visceral Surgery, Central Clinic Bad Berka, Bad Berka, Germany. · Department of General and Visceral Surgery, Endocrine Surgery and Coloproctology,, Clinic Neuperlach, Munich, Germany. · Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Clinic for Surgery, University Clinic Schleswig-Holstein, UKSH Campus Lübeck, 23538, Lübeck, Germany. tobias.keck@uksh.de. ·Int J Colorectal Dis · Pubmed #27815701.

ABSTRACT: PURPOSE: The aim of this study was to assess intraoperative, postoperative, and oncologic outcome in patients undergoing laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for benign and malignant lesions of the pancreas. METHODS: Data from patients undergoing distal pancreatic resection were extracted from the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. After propensity score case matching, groups of LDP and ODP were compared regarding demography, comorbidities, operative details, histopathology, and perioperative outcome. RESULTS: At the time of data extraction, the StuDoQ|Pancreas registry included over 3000 pancreatic resections from over 50 surgical departments in Germany. Data from 353 patients undergoing ODP (n = 254) or LDP (n = 99) from September 2013 to February 2016 at 29 institutions were included in the analysis. Baseline data showed a strong selection bias in LDP patients, which disappeared after 1:1 propensity score matching. A comparison of the matched groups disclosed a significantly longer operation time, higher rate of spleen preservation, more grade A pancreatic fistula, shorter hospital stay, and increased readmissions for LDP. In the small group of patients operated for pancreatic cancer, a lower lymph node yield with a lower lymph node ratio was apparent in LDP. CONCLUSIONS: LDP needed more time but potential advantages include increased spleen preservation and shorter hospital stay, as well as a trend for less transfusion, ventilation, and mortality. LDP for pancreatic cancer was performed rarely and will need critical evaluation in the future. Data from a prospective randomized registry trial is needed to confirm these results.

18 Article Inducing a humoral immune response to pancreatic cancer antigen. 2016

Seifert, Michael / Seifert, Gabriel / Wolff-Vorbeck, Guido / Langenmair, Elia / Hopt, Ulrich T / Wittel, Uwe A. ·Department of General and Visceral Surgery, Universitätsklinik Freiburg, Freiburg, Germany. Electronic address: michael.seifert@uniklinik-freiburg.de. · Department of General and Visceral Surgery, Universitätsklinik Freiburg, Freiburg, Germany. ·Cell Immunol · Pubmed #27663207.

ABSTRACT: BACKGROUND: Patients with pancreatic carcinoma have a grim prognosis. Here, we examine the induction of an in vitro antibody response of human B cells to pancreatic carcinoma antigens. MATERIAL AND METHODS: Cells of five cultured pancreatic ductal adenocarcinoma lines were lysed and their plasma membrane fragments isolated in an aqueous two-phase-system. The plasma membrane fragments were then added to cultures of isolated peripheral blood mononuclear cells from healthy volunteers for 14 days to act as a tumor antigen. Also, we added combinations of IL-2, IL-4, IL-21, anti-CD40 mAb and varying protein concentrations of the plasma membrane fragments to these cultures. We then tested characteristics and binding of resulting IgG and IgM against aforementioned tumor plasma membrane fragments and their respective cells using ELISAs. RESULTS: The combination of IL-2, IL-4 and anti-CD40 mAb elicited IgM production showing significant binding (p<0.05) to plasma membrane fragments. PANC-1 antigen and the combination of IL-4, IL-21 and anti-CD40 mAb was able to produce a significant and specific IgG formation against PANC-1 plasma membrane fragments (p<0.05). Tumor antigen, interleukins and anti-CD40 mAb had a significant impact on the binding capacity of these antibodies (p<0.05). IgG binding pancreatic carcinoma cells was observed when the tumor antigen concentration was increased during stimulation (p<0.05). BxPC3 plasma membrane fragments showed inhibitory effects on IgG binding BxPC3 antigens (p<0.05). CONCLUSIONS: A human anti-tumor antibody formation can be induced in vitro using PANC-1 antigens and B cell stimulating agents. This response has the potential to generate antibodies specific to PANC-1 antigens. PRéCIS: The concept presented is novel and a promising approach to eliciting a specific B cell response to tumor antigen. The method may prove useful in understanding and developing anti-tumor immunity.

19 Article Prognostic Role of Log Odds of Lymph Nodes After Resection of Pancreatic Head Cancer. 2016

Riediger, Hartwig / Kulemann, Birte / Wittel, Uwe / Adam, Ulrich / Sick, Olivia / Neeff, Hannes / Höppner, Jens / Hopt, Ulrich T / Makowiec, Frank. ·Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany. · Department of Surgery, Vivantes-Humboldt-Klinikum, Berlin, Germany. · Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany. frank.makowiec@uniklinik-freiburg.de. ·J Gastrointest Surg · Pubmed #27384432.

ABSTRACT: INTRODUCTION: Nodal status is a strong prognostic factor after resection of pancreatic cancer. The lymph node ratio (LNR) has been shown to be superior to the pN status in several studies. The role of log odds of the ratio between positive and negative nodes (LODDS) as a suggested new indicator of prognosis, however, has been hardly evaluated in pancreatic cancer. METHODS: Prognostic factors for overall survival after resection for cancer of the pancreatic head were evaluated in 409 patients from two institutions (prospectively maintained databases). The lymph node status, LNR, and LODDS were separately analyzed and independently compared in multivariate survival analysis. RESULTS: The median numbers of examined and positive lymph nodes were 16 and 2, respectively. Actuarial 3- and 5-year survival rates were 29 and 16 %. All three classifications of nodal disease significantly predicted survival in the entire group (n = 409), in patients with free resection margins (n = 297), and in patients with <12 examined nodes. In multivariate analysis, however, both LNR and LODDS were equally superior to the nodal status. In node-negative patients (n = 110), LODDS could not identify subgroups with different prognosis. CONCLUSION: Both LNR and LODDS are superior to the classical nodal status in predicting prognosis in resected pancreatic cancer. However, LODDS has not shown any advantage over LNR in our series, neither in the entire patient group nor in the subgroups with free margins, negative nodes or a low number of examined nodes. Therefore, the use of LODDS to predict the outcome after resection of pancreatic head cancer cannot be recommended.

20 Article Prognostic factors after pancreatoduodenectomy with en bloc portal venous resection for pancreatic cancer. 2016

Lapshyn, Hryhoriy / Bronsert, Peter / Bolm, Louisa / Werner, Martin / Hopt, Ulrich T / Makowiec, Frank / Wittel, Uwe A / Keck, Tobias / Wellner, Ulrich F / Bausch, Dirk. ·Clinic for General and Visceral Surgery, University Medical Center Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany. · Clinic for Surgery, University Clinic Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. · Institute of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany. · Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, Freiburg, Germany. · German Cancer Consortium (DKTK) and Cancer Research Center (DKFZ), Heidelberg, Germany. · Clinic for General and Visceral Surgery, University Medical Center Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany. ulrich.hopt@uniklinik-freiburg.de. · Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, Freiburg, Germany. ulrich.hopt@uniklinik-freiburg.de. ·Langenbecks Arch Surg · Pubmed #26739620.

ABSTRACT: PURPOSE: Pancreatoduodenectomy (PD) with superior mesenteric/portal venous resection (PVR) for pancreatic ductal adenocarcinoma (PDAC) is performed routinely in case of tumor adhesion to the superior mesenteric or portal vein. True histopathological portal vein invasion (PVI) is found in a subgroup of patients. Even though this procedure has become routine in most centers for pancreatic surgery, data on prognostic factors in this situation is limited. The aim of this study was to identify prognostic factors after PD with PVR for PDAC. METHODS: Retrospective analysis was performed on the basis of a prospectively maintained database, and paraffin-embedded formalin-fixed tissue slides stained for hematoxylin-eosin were re-evaluated by two independent pathologists. Statistical analysis was conducted using MedCalc software. RESULTS: From 2001 to 2012, 86 cases of PD with PVR for PDAC with long-term follow-up and sufficient tissue for re-assessment were identified. Histopathological re-review disclosed PVI in 39 resection specimens and adhesion without infiltration in 47. Overall median survival in all patients was 22 months. Patients with PVI versus no PVI showed comparable baseline demographic and standard histopathological parameters; however, PVI was associated with microscopic hemangiosis (p = 0.001) and positive margin status (p = 0.001). Median survival in patients with PVI was 14 months versus 25 months in patients without PVI (p = 0.042). Only lymph node ratio and PVI were independent predictors of survival after resection. CONCLUSION: The only independent factors influencing overall survival after PD with PVR for PDAC were lymph node ratio and PVI. PVI might indicate aggressive tumor biology, but the available data remains controversial.

21 Article The prognostic influence of intrapancreatic tumor location on survival after resection of pancreatic ductal adenocarcinoma. 2015

Ruess, Dietrich A / Makowiec, Frank / Chikhladze, Sophia / Sick, Olivia / Riediger, Hartwig / Hopt, Ulrich T / Wittel, Uwe A. ·Department of Surgery, University of Freiburg, Freiburg, Germany. · Department of Surgery, Vivantes-Humboldt-Clinic, Berlin, Germany. · Department of Surgery, University of Freiburg, Freiburg, Germany. uwe.wittel@uniklinik-freiburg.de. ·BMC Surg · Pubmed #26615588.

ABSTRACT: BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is worse when the tumor is located in the pancreatic body or tail, compared to being located in the pancreatic head. However, for localized, resectable tumors survival seems to be at least similar. METHODS: We analyzed and compared the outcome after pancreatoduodenectomy (PD) and distal pancreatectomy (DP) for PDAC at our institution. Clinical, pathological and survival data from patients undergoing pancreatic resection for PDAC 1994-2014 were explored retrospectively, accessing a prospective pancreatic database. Patients receiving primary total pancreatectomy were excluded. RESULTS: Four hundred and thirteen patients were treated for PDAC: 347 (84%) underwent PD and 66 (16%) DP. Tumors located in the pancreatic body and tail were significantly larger than their counterparts located in the head (30.6 mm vs. 41.2 mm; p < 0.001). However, distal tumors had significantly less nodal involvement (71% vs. 57%; p = 0.03). Portal-vein resection (PVR) was performed more often in PD, multivisceral resection (MVR) was more frequent in DP (37% vs. 14% and 4% vs. 29%; p < 0.001). Rates for negative resection margins and tumor grading were similar. Postoperative complication rates including morbidity, rates of re-operation and mortality were comparable. Long-term outcome revealed no significant difference between PD and DP with 5-year survival rates of 17.8 and 22% respectively (p = 0.284). Multivariate analysis confirmed positive resection margin, positive nodal status, extended resection (PVR, MVR) and lack of adjuvant/additive chemotherapy as independent risk factors for poor survival after pancreatic resection. CONCLUSION: Patients with resectable pancreatic ductal adenocarcinoma located in the body and tail of the pancreas display a similar postoperative oncological outcome despite larger tumors when compared to patients with resectable tumors located in the pancreatic head.

22 Article Retrospective analyses of trends in pancreatic surgery: indications, operative techniques, and postoperative outcome of 1,120 pancreatic resections. 2015

Wittel, Uwe A / Makowiec, Frank / Sick, Olivia / Seifert, Gabriel J / Keck, Tobias / Adam, Ulrich / Hopt, Ulrich T. ·Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. uwe.wittel@uniklinik-freiburg.de. · Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. frank.makowiec@uniklinik-freiburg.de. · Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. olivia.sick@uniklinik-freiburg.de. · Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. gabriel.seifert@uniklinik-freiburg.de. · Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. tobias.keck@uksh.de. · Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. ulrich.adam@vivantes.de. · Clinic of General and Visceral Surgery, Department of Surgery, Universitätsklinik Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. ulrich.hopt@uniklinik-freiburg.de. ·World J Surg Oncol · Pubmed #25880929.

ABSTRACT: BACKGROUND: Hospital volume, surgeons' experience, and adequate management of complications are factors that contribute to a better outcome after pancreatic resections. The aim of our study was to analyze trends in indications, surgical techniques, and postoperative outcome in more than 1,100 pancreatic resections. METHODS: One thousand one hundred twenty pancreatic resections were performed since 1994. The vast majority of operations were performed by three surgeons. Perioperative data were documented in a pancreatic database. For the purpose of our analysis, the study period was sub-classified into three periods (A 1994 to 2001/n = 363; B 2001 to 2006/n = 305; C since 2007 to 2012/n = 452). RESULTS: The median patient age increased from 51 (A) to 65 years (C; P < 0.001). Indications for surgery were pancreatic/periampullary cancer (49%), chronic pancreatitis (CP; 33%), and various other lesions (18%). About two thirds of the operations were pylorus-preserving pancreaticoduodenectomies. The frequency of mesenterico-portal vein resections increased from 8% (A) to 20% (C; P < 0.01). The overall mortality was 2.4% and comparable in all three periods (2.8%, 2.0%, 2.4%; P = 0.8). Overall complication rates increased from 42% (A) to 56% (C; P < 0.01). CONCLUSIONS: Mortality remained low despite a more aggressive surgical approach to pancreatic disease. An increased overall morbidity may be explained by more clinically relevant pancreatic fistulas and better documentation.

23 Article Perioperative and long-term outcome after standard pancreaticoduodenectomy, additional portal vein and multivisceral resection for pancreatic head cancer. 2015

Kulemann, Birte / Hoeppner, Jens / Wittel, Uwe / Glatz, Torben / Keck, Tobias / Wellner, Ulrich F / Bronsert, Peter / Sick, Olivia / Hopt, Ulrich T / Makowiec, Frank / Riediger, Hartwig. ·Department of Surgery, University of Freiburg, Hugstetter Str. 55, D-79106, Freiburg, Germany, birte.kulemann@gmail.com. ·J Gastrointest Surg · Pubmed #25567663.

ABSTRACT: INTRODUCTION: The value of extended resection (portal vein, multivisceral) in patients with pancreatic adenocarcinoma (PDAC) is not well defined. We analyzed the outcome after standard resection (standard pancreaticoduodenectomy (SPR)), additional portal vein (PV) and multivisceral (MV) resection in PDAC patients. METHODS: Clinicopathologic, perioperative, and survival data of patients undergoing pancreatic head resection (PHR) for PDAC 1994-2014 were reviewed from a prospective database. RESULTS: Three hundred fifty nine patients had PHR for PDAC: 208 (58 %) underwent SPR, 131 (36 %) additional PV, and 20 (6 %) MV. The postoperative complication rate in MV (65 %) was slightly higher than in PV (56 %) or SPR (50 %; p = 0.32). MV patients had higher in-hospital mortality (10 %) than SPR (3.8 %) and PV (1.5 %) patients (p = 0.12). Nodal status was comparable, whereas more patients in PV and MV had final R0 resection (p = 0.02). Five-year survival was 7 % after MV versus 17 % in patients without MV (p = 0.07). Multivariate survival analysis identified resection margin, nodal disease, blood transfusions, and MV are set as independent risk factors for overall survival. CONCLUSION: Multivisceral pancreatic head resections for PDAC are associated with increased perioperative morbidity and mortality, without improving oncologic outcome. Portal vein resection can be performed safely to reach R0 resection and its survival benefits.

24 Article Potentials of plasma NGAL and MIC-1 as biomarker(s) in the diagnosis of lethal pancreatic cancer. 2013

Kaur, Sukhwinder / Chakraborty, Subhankar / Baine, Michael J / Mallya, Kavita / Smith, Lynette M / Sasson, Aaron / Brand, Randall / Guha, Sushovan / Jain, Maneesh / Wittel, Uwe / Singh, Shailender K / Batra, Surinder K. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. ·PLoS One · Pubmed #23383312.

ABSTRACT: Pancreatic cancer (PC) is lethal malignancy with very high mortality rate. Absence of sensitive and specific marker(s) is one of the major factors for poor prognosis of PC patients. In pilot studies using small set of patients, secreted acute phase proteins neutrophil gelatinase associated lipocalin (NGAL) and TGF-β family member macrophage inhibitory cytokine-1 (MIC-1) are proposed as most potential biomarkers specifically elevated in the blood of PC patients. However, their performance as diagnostic markers for PC, particularly in pre-treatment patients, remains unknown. In order to evaluate the diagnostic efficacy of NGAL and MIC-1, their levels were measured in plasma samples from patients with pre-treatment PC patients (n = 91) and compared it with those in healthy control (HC) individuals (n = 24) and patients with chronic pancreatitis (CP, n = 23). The diagnostic performance of these two proteins was further compared with that of CA19-9, a tumor marker commonly used to follow PC progression. The levels of all three biomarkers were significantly higher in PC compared to HCs. The mean (± standard deviation, SD) plasma NGAL, CA19-9 and MIC-1 levels in PC patients was 111.1 ng/mL (2.2), 219.2 U/mL (7.8) and 4.5 ng/mL (4.1), respectively. In comparing resectable PC to healthy patients, all three biomarkers were found to have comparable sensitivities (between 64%-81%) but CA19-9 and NGAL had a higher specificity (92% and 88%, respectively). For distinguishing resectable PC from CP patients, CA19-9 and MIC-1 were most specific (74% and 78% respectively). CA19-9 at an optimal cut-off of 54.1 U/ml is highly specific in differentiating resectable (stage 1/2) pancreatic cancer patients from controls in comparison to its clinical cut-off (37.1 U/ml). Notably, the addition of MIC-1 to CA19-9 significantly improved the ability to distinguish resectable PC cases from CP (p = 0.029). Overall, MIC-1 in combination with CA19-9 improved the diagnostic accuracy of differentiating PC from CP and HCs.

25 Article Pathobiological implications of MUC16 expression in pancreatic cancer. 2011

Haridas, Dhanya / Chakraborty, Subhankar / Ponnusamy, Moorthy P / Lakshmanan, Imayavaramban / Rachagani, Satyanarayana / Cruz, Eric / Kumar, Sushil / Das, Srustidhar / Lele, Subodh M / Anderson, Judy M / Wittel, Uwe A / Hollingsworth, Michael A / Batra, Surinder K. ·Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. ·PLoS One · Pubmed #22066010.

ABSTRACT: MUC16 (CA125) belongs to a family of high-molecular weight O-glycosylated proteins known as mucins. While MUC16 is well known as a biomarker in ovarian cancer, its expression pattern in pancreatic cancer (PC), the fourth leading cause of cancer related deaths in the United States, remains unknown. The aim of our study was to analyze the expression of MUC16 during the initiation, progression and metastasis of PC for possible implication in PC diagnosis, prognosis and therapy. In this study, a microarray containing tissues from healthy and PC patients was used to investigate the differential protein expression of MUC16 in PC. MUC16 mRNA levels were also measured by RT-PCR in the normal human pancreatic, pancreatitis, and PC tissues. To investigate its expression pattern during PC metastasis, tissue samples from the primary pancreatic tumor and metastases (from the same patient) in the lymph nodes, liver, lung and omentum from Stage IV PC patients were analyzed. To determine its association in the initiation of PC, tissues from PC patients containing pre-neoplastic lesions of varying grades were stained for MUC16. Finally, MUC16 expression was analyzed in 18 human PC cell lines. MUC16 is not expressed in the normal pancreatic ducts and is strongly upregulated in PC and detected in pancreatitis tissue. It is first detected in the high-grade pre-neoplastic lesions preceding invasive adenocarcinoma, suggesting that its upregulation is a late event during the initiation of this disease. MUC16 expression appears to be stronger in metastatic lesions when compared to the primary tumor, suggesting a role in PC metastasis. We have also identified PC cell lines that express MUC16, which can be used in future studies to elucidate its functional role in PC. Altogether, our results reveal that MUC16 expression is significantly increased in PC and could play a potential role in the progression of this disease.