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| 1 | m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment显示文摘AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection model.METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.RESULTS: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor(TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors(HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatmentwith the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight(75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin(TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.CONCLUSION: mT OR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways. | Suomi MG Fouraschen Petra E de Ruiter Jaap Kwekkeboom Ron WF de Bruin Geert Kazemier Herold J Metselaar Hugo W Tilanus Luc JW van der Laan Jeroen de Jonge | 2013 | World Journal of Transplantation2013，3，3： | 6 |
| 2 | FOLFIRINOX and translational studies: Towards personalized therapy in pancreatic cancer显示文摘Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase Ⅲ trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARClevels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microR NAs as predictive biomarkers. | Chiara Caparello Laura L Meijer Ingrid Garajova Alfredo Falcone Tessa Y Le Large Niccola Funel Geert Kazemier Godefridus J Peters Enrico Vasile Elisa Giovannetti | 2016 | World Journal of Gastroenterology2016，22，31： | 4 |
| 3 | Increased incidence of early de novo cancer in liver graft recipients treated with cyclosporine: An association with C显示文摘 | Angela S. W. Tjon Jerome Sint Nicolaas Jaap Kwekkeboom Robert A. de Man Geert Kazemier Hugo W. Tilanus Bettina E. Hansen Luc J. W. van der Laan Thanyalak Tha‐In Herold J. Metselaar | 2010 | Liver Transpl2010，，7： | 2 |
| 4 | Retroperitoneal Adrenalectomy: Open or Endoscopic?显示文摘 | H. Jaap Bonjer Erwin van der Harst Ewout W. Steyerberg Wouter W. de Herder Geert Kazemier Robert S.A. Mohammedamin Hajo A. Bruining | 1998 | World Journal of Surgery1998，，12： | 1 |
| 5 | Serum miR-1290 as a Marker of Pancreatic Cancer—Letter显示文摘 | Adam E. Frampton Jonathan Krell Geert Kazemier Elisa Giovannetti | 2013 | Clinical Cancer Research2013，，18： | 1 |
| 6 | A prospective group sequential study evaluating a new type of fully covered self-expandable metal stent for the treatment of benign biliary strictures (with video)显示文摘 | Jan-Werner Poley Djuna L. Cahen Herold J. Metselaar Henk R. van Buuren Geert Kazemier Casper H.J. van Eijck Jelle Haringsma Ernst J. Kuipers Marco J. Bruno | 2012 | Gastrointestinal Endoscopy2012，，4： | 1 |
| 7 | Management in patients with liver cirrhosis and an umbilical hernia显示文摘 | Hendrik A. Marsman Joos Heisterkamp Jens A. Halm Hugo W. Tilanus Herold J. Metselaar Geert Kazemier | 2007 | Surgery2007，，： | 1 |
| 8 | Closing Emergency Operating Rooms Improves Efficiency显示文摘 | Gerhard Wullink Mark Houdenhoven Erwin W. Hans Jeroen M. Oostrum Marieke Lans Geert Kazemier | 2007 | Journal of Medical Systems2007，，6： | 1 |
| 9 | Clinical outcomes of patients with duodenal adenocarcinoma and intestinal-type papilla of Vater adenocarcinoma显示文摘BACKGROUND Duodenal adenocarcinoma(DA)and intestinal-type papilla of Vater adenocarcinoma(it-PVA)are rare malignancies of the gastrointestinal tract.Current therapeutic options are translated nowadays from treatment strategies for patients with colorectal cancer due to histopathological similarities.AIM To retrospectively investigate the clinical outcome of patients with DA and it-PVA.METHODS All patients with DA and it-PVA diagnosed between 2000 and 2017 were included at two academic centers in the Netherlands.All patients with histopathologically-confirmed DA or it-PVA were eligible for inclusion.Clinical outcome was compared between DA and it-PVA per disease stage.In the subgroup of stage IV disease,survival after local treatment of oligometastases was compared with systemic therapy or supportive care.RESULTS In total,155 patients with DA and it-PVA were included.Patients with it-PVA more often presented with stage I disease,while DA was more often diagnosed at stage IV(P<0.001).Of all patients,79%were treated with curative intent.The median survival was 39 mo,and no difference in survival was found for patients with DA and it-PVA after stratification for disease stage.Seven(23%)of 31 patients with synchronous stage IV disease underwent resection of the primary tumor,combined with local treatment of oligometastases.Local treatment of metastases was associated with an overall survival of 37 mo,compared to 14 and 6 mo for systemic therapy and supportive care,respectively.CONCLUSION Survival of patients with DA and it-PVA is comparable per disease stage.These results suggest a potential benefit for local treatment strategies in selected patients with oligometastases,although additional prospective studies are needed. | Laura L Meijer Marin Strijker Jacob K de Bakker Jurgen GJ Toennaer Barbara M Zonderhuis Hans J van der Vliet Hanneke Wilmink Joanne Verheij Freek Daams Olivier R Busch Nicole CT van Grieken Marc G Besselink Geert Kazemier | 2020 | World Journal of Gastrointestinal Oncology2020，12，3： | 1 |
| 10 | Laparoscopic appendectomy: State of the art. Tailored approach to the application of laparoscopic appendectomy?显示文摘 | Ramon R. Gorter Hugo A. Heij Hasan H. Eker Geert Kazemier | 2013 | Best Practice & Research Clinical Gastroenterology2013，，： | 1 |
| 11 | A prospective group sequential study evaluating a new type of fully covered self-expandable metal stent for the treatment of benign biliary strictures (with video)显示文摘 | Jan-Werner Poley Djuna L. Cahen Herold J. Metselaar Henk R. van Buuren Geert Kazemier Casper H.J. van Eijck Jelle Haringsma Ernst J. Kuipers Marco J. Bruno | 2012 | Gastrointestinal Endoscopy2012，，4： | 1 |
| 12 | Fatigue After Liver Transplantation: Effects of a Rehabilitation Program Including Exercise Training and Physical Activity Counseling显示文摘 | van den Berg-Emons Rita J G van Ginneken Berbke T J Nooijen Carla F J Metselaar Herold J Tilanus Huug W Kazemier Geert Stam Henk J | 2014 | Physical Therapy2014，，6： | 1 |
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