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  • SpringerLink Open Access  (5)
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  • 1
    Language: English
    In: International Journal of Colorectal Disease, 2013, Vol.28(3), pp.385-398
    Description: Byline: Thomas C. Wehler (1), Swaantje Hamdi (2), Annett Maderer (2), Claudine Graf (1), Ines Gockel (3), Irene Schmidtmann (4), Michael Hainz (5), Martin R. Berger (6), Matthias Theobald (1), Peter R. Galle (2), Markus Moehler (2), Carl C. Schimanski (2,7) Keywords: Colorectal cancer; TKI; Sorafenib Abstract: Background We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. Methods The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. Results In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib+5-FU irinotecan) and disadvantageous in others (sorafenib+oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45[beta]. In resistant cell lines, pp53 and GADD45[beta] levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFR[beta] expression intensity. Conclusions In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect. Author Affiliation: (1) Third Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz, Mainz, Germany (2) First Department of Internal Medicine, Johannes Gutenberg University Hospital of Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany (3) Department of General and Abdominal Surgery, Johannes Gutenberg University Hospital of Mainz, Mainz, Germany (4) Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg University Hospital of Mainz, Mainz, Germany (5) Institute of Pathology, Johannes Gutenberg University Hospital of Mainz, Mainz, Germany (6) Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany (7) Department of Internal Medicine, Marienhospital, 64285, Darmstadt, Germany Article History: Registration Date: 25/07/2012 Accepted Date: 25/07/2012 Online Date: 15/09/2012 Article note: This study was presented at the 22nd EORTC-NCI-AACR Symposium on "Molecular Targets and Cancer Therapeutics," 2010, in a poster presentation.
    Keywords: Colorectal cancer ; TKI ; Sorafenib
    ISSN: 0179-1958
    E-ISSN: 1432-1262
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  • 2
    Language: English
    In: Journal of Cancer Research and Clinical Oncology, 2013, Vol.139(10), pp.1667-1672
    Description: Byline: Thomas C. Wehler (1), Claudine Graf (1), Markus Mohler (2), Jutta Herzog (5), Martin R. Berger (3), Ines Gockel (4), Hauke Lang (4), Matthias Theobald (1), Peter R. Galle (2), Carl C. Schimanski (2,5) Keywords: Skin; Rash; Exanthema; EGFR; Cetuximab; Therapy reactive Abstract: Purpose Treatment with cetuximab is accompanied by the development of an acneiform follicular skin exanthema in more than 80 % of patients. Severe exanthema (grade III/IV) develops in about 9--19 % of patients with the necessity of cetuximab dose reduction or cessation. Methods The study presented was a retrospective analysis of 50 gastrointestinal cancer patients treated with cetuximab in combination with either FOLFIRI or FOLFOX. One cohort of 15 patients received an in-house reactive skin protocol upon development of an exanthema. A second cohort of 15 patients received a skin prophylaxis starting with the first dose of cetuximab before clinical signs of toxicity. A third historic group of 20 patients had received no skin prophylaxis or reactive treatment. Results 19/20 patients of the historic group developed a skin exanthema. Grade III/IV exanthema was observed six times. Forty percent discontinued cetuximab therapy. The average time to exanthema onset was 14.7 days. Applying the reactive skin protocol after the first occurrence of an exanthema, the exanthema was downgraded as follows: No patients developed grade IVdeg exanthema, and two patients developed a grade II/III exanthema. In the majority of cases, the reactive skin protocol controlled the exanthema (grade 0--Ideg). No dose reductions in cetuximab were necessary. Applying the prophylactic skin protocol starting at the beginning of cetuximab application was not superior to the reactive skin protocol. Conclusions Cetuximab-induced skin exanthema can be coped with a reactive protocol equally effective as compared to a prophylactic skin treatment. A prospective study with higher patient numbers is planned. Author Affiliation: (1) Third Department of Internal Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany (2) First Department of Internal Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany (3) Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany (4) Department of General and Abdominal Surgery, Johannes Gutenberg University of Mainz, Mainz, Germany (5) Department of Internal Medicine, Marienhospital Darmstadt, Martinspfad 72, 64285, Darmstadt, Germany Article History: Registration Date: 19/07/2013 Received Date: 11/07/2013 Accepted Date: 19/07/2013 Online Date: 07/08/2013 Article note: Thomas C. Wehler and Claudine Graf have contributed equally to this work.
    Keywords: Skin ; Rash ; Exanthema ; EGFR ; Cetuximab ; Therapy reactive
    ISSN: 0171-5216
    E-ISSN: 1432-1335
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  • 3
    Language: English
    In: Gastric Cancer, 2015, Vol.18(3), pp.550-563
    Description: Byline: Markus Moehler (1,17), Christoph T. H. Baltin (5), Matthias Ebert (2), Wolfgang Fischbach (3), Ines Gockel (1), Lars Grenacher (4), Arnulf H. Holscher (5), Florian Lordick (6), Peter Malfertheiner (7), Helmut Messmann (8), Hans-Joachim Meyer (9), Anne Palmqvist (1), Christoph Rocken (10), Christoph Schuhmacher (11), Michael Stahl (12), Martin Stuschke (13), Michael Vieth (14), Christian Wittekind (15), Dorothea Wagner (16), Stefan P. Monig (5) Keywords: Guidelines; Esophageal cancer; Gastric cancer; Perioperative therapy; Diagnosis Abstract: Background Clinical guidelines are essential in implementing and maintaining nationwide stage-specific diagnostic and therapeutic standards. In 2011, the first German expert consensus guideline defined the evidence for diagnosis and treatment of early and locally advanced esophagogastric cancers. Here, we compare this guideline with other national guidelines as well as current literature. Methods The German S3-guideline used an approved development process with de novo literature research, international guideline adaptation, or good clinical practice. Other recent evidence-based national guidelines and current references were compared with German recommendations. Results In the German S3 and other Western guidelines, adenocarcinomas of the esophagogastric junction (AEG) are classified according to formerly defined AEG I--III subgroups due to the high surgical impact. To stage local disease, computed tomography of the chest and abdomen and endosonography are reinforced. In contrast, laparoscopy is optional for staging. Mucosal cancers (T1a) should be endoscopically resected "en-bloc" to allow complete histological evaluation of lateral and basal margins. For locally advanced cancers of the stomach or esophagogastric junction (a[yen]T3N+), preferred treatment is preoperative and postoperative chemotherapy. Preoperative radiochemotherapy is an evidence-based alternative for large AEG type I--II tumors (a[yen]T3N+). Additionally, some experts recommend treating T2 tumors with a similar approach, mainly because pretherapeutic staging is often considered to be unreliable. Conclusions The German S3 guideline represents an up-to-date European position with regard to diagnosis, staging, and treatment recommendations for patients with locally advanced esophagogastric cancer. Effects of perioperative chemotherapy versus chemoradiotherapy are still to be investigated for adenocarcinoma of the cardia and the lower esophagus. Author Affiliation: (1) University Medical Center Mainz, Mainz, Germany (2) University Medical Center Mannheim, Mannheim, Germany (3) Klinikum Aschaffenburg, Aschaffenburg, Germany (4) Heidelberg University Hospital, Heidelberg, Germany (5) University Hospital of Cologne, Cologne, Germany (6) Klinikum Braunschweig, Braunschweig, Germany (7) University Clinic Magdeburg, Magdeburg, Germany (8) Klinikum Augsburg, Augsburg, Germany (9) Stadtisches Klinikum Solingen, Solingen, Germany (10) Charite Universitatsmedizin Berlin, Berlin, Germany (11) University Hospital Klinikum Rechts der Isar, Munich, Germany (12) Kliniken Essen-Mitte, Essen, Germany (13) Essen University Hospital, Essen, Germany (14) Klinikum Bayreuth, Bayreuth, Germany (15) Universitatsmedizin Leipzig, Leipzig, Germany (16) Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland (17) Medizinische Klinik und Poliklinik, Johannes-Gutenberg-Universitat, Langenbeckstra[sz]e, 155101, Mainz, Germany Article History: Registration Date: 16/07/2014 Received Date: 07/10/2013 Accepted Date: 13/07/2014 Online Date: 07/09/2014 Article note: M. Moehler and C.T.H. Baltin contributed equally. Electronic supplementary material The online version of this article (doi: 10.1007/s10120-014-0403-x) contains supplementary material, which is available to authorized users.
    Keywords: Guidelines ; Esophageal cancer ; Gastric cancer ; Perioperative therapy ; Diagnosis
    ISSN: 1436-3291
    E-ISSN: 1436-3305
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  • 4
    Language: English
    In: Surgical Endoscopy, 2019, Vol.33(8), pp.2720-2720
    Description: In the original version, Ines Gockel was omitted as a coauthor. The complete author listing is corrected here.
    Keywords: Ischemia – Analysis;
    ISSN: 0930-2794
    E-ISSN: 1432-2218
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  • 5
    Language: English
    In: Gastric Cancer, 2019, Vol.22(1), pp.172-189
    Description: Perioperative complications can affect outcomes after gastrectomy for cancer, with high mortality and morbidity rates ranging between 10 and 40%. The absence of a standardized system for recording complications generates wide variation in evaluating their impacts on outcomes and hinders proposals of quality-improvement projects. The aim of this study was to provide a list of defined gastrectomy complications approved through international consensus. The Gastrectomy Complications Consensus Group consists of 34 European gastric cancer experts who are members of the International Gastric Cancer Association. A group meeting established the work plan for study implementation through Delphi surveys. A consensus was reached regarding a set of standardized methods to define gastrectomy complications. A standardized list of 27 defined complications (grouped into 3 intraoperative, 14 postoperative general, and 10 postoperative surgical complications) was created to provide a simple but accurate template for recording individual gastrectomy complications. A consensus was reached for both the list of complications that should be considered major adverse events after gastrectomy for cancer and their specific definitions. The study group also agreed that an assessment of each surgical case should be completed at patient discharge and 90 days postoperatively using a Complication Recording Sheet. The list of defined complications (soon to be validated in an international multicenter study) and the ongoing development of an electronic datasheet app to record them provide the basic infrastructure to reach the ultimate goals of standardized international data collection, establishment of benchmark results, and fostering of quality-improvement projects.
    Keywords: Perioperative complications ; Gastric cancer ; Gastrectomy ; International consensus ; Clavien–Dindo classification ; Comprehensive Complications Index
    ISSN: 1436-3291
    E-ISSN: 1436-3305
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