91 results on '"Gladhaug IP"'
Search Results
2. European experts consensus statement on cystic tumours of the pancreas
- Author
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Del Chiaro, Marco, primary, Verbeke, Caroline, additional, Salvia, Roberto, additional, Klöppel, Gunter, additional, Werner, Jens, additional, McKay, Colin, additional, Friess, Helmut, additional, Manfredi, Riccardo, additional, Van Cutsem, Eric, additional, Löhr, Matthias, additional, Segersvärd, Ralf, additional, Abakken, L, additional, Adham, M, additional, Albin, N, additional, Andren-Sandberg, Å, additional, Arnelo, U, additional, Bruno, M, additional, Cahen, D, additional, Cappelli, C, additional, Costamagna, G, additional, Del Chiaro, M, additional, Delle Fave, G, additional, Esposito, I, additional, Falconi, M, additional, Friess, H, additional, Ghaneh, P, additional, Gladhaug, IP, additional, Haas, S, additional, Hauge, T, additional, Izbicki, JR, additional, Klöppel, G, additional, Lerch, M, additional, Lundell, L, additional, Lüttges, J, additional, Löhr, M, additional, Manfredi, R, additional, Mayerle, J, additional, McKay, C, additional, Oppong, K, additional, Pukitis, A, additional, Rangelova, E, additional, Rosch, T, additional, Salvia, R, additional, Schulick, R, additional, Segersvärd, R, additional, Sufferlein, T, additional, Van Cutsem, E, additional, Van der Merwe, SW, additional, Verbeke, C, additional, Werner, J, additional, and Zamboni, G, additional
- Published
- 2013
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3. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma.
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Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, Clausen OP, Gladhaug IP, Westgaard, Arne, Tafjord, Svetlana, Farstad, Inger N, Cvancarova, Milada, Eide, Tor J, Mathisen, Oystein, Clausen, Ole Petter F, and Gladhaug, Ivar P
- Abstract
Background: Resectable adenocarcinomas in the pancreatic head, by definition "periampullary", originate from ampullary, duodenal, biliary, or ductal pancreatic epithelium. Typically, periampullary adenocarcinomas have either intestinal or pancreatobiliary type of differentiation, and the type of differentiation might be prognostically more important than the anatomic site of origin. The aim of the study was to determine whether the histologic type of differentiation is an independent prognostic factor in periampullary adenocarcinoma, and whether tumour origin predicts the prognosis in pancreatobiliary type carcinomas independently of resection margin involvement, tumour size, nodal involvement, perineural and vascular infiltration, and degree of differentiation.Methods: Histopathologic variables in 114 consecutively resected periampullary adenocarcinomas of pancreatobiliary (n = 67) and intestinal (n = 47) type differentiation were evaluated using a standardized, systematic protocol for evaluation of the resected specimen (study group). Histologic type of differentiation and tumour origin were compared as predictors of survival, and the results were validated by comparison with a historical control group consisting of 99 consecutive pancreaticoduodenectomies performed before standardization of histopathologic evaluation. Associations between histopathologic variables were evaluated by Chi-square and Mann-Whitney tests. Survival was estimated by the Kaplan-Meier method, comparing curves using log-rank test, and by univariate and multivariable Cox regression analysis.Results: Both in the study group (n = 114) and in the historical control group (n = 99), the histologic type of differentiation independently predicted survival, while tumour origin predicted survival only in univariate analysis. Independent adverse predictors of survival in the study group were pancreatobiliary type differentiation (p < 0.001; HR 3.1; CI 1.8-5.1), regional lymph node involvement (p < 0.001; HR 2.5; CI 1.5-4.4), vessel involvement (p = 0.012; HR 1.9; CI 1.2-3.1), and increasing tumour diameter (measured in cm, p = 0.011; HR 1.3; CI 1.1-1.5). For pancreatobiliary differentiated adenocarcinomas (n = 67), lymph node status, vessel involvement, and tumour diameter remained independent prognostic factors, while tumour origin did not independently predict the prognosis due to significant association with tumour size (p < 0.001) and lymph node involvement (p = 0.004).Conclusion: Pancreatobiliary versus intestinal type of differentiation independently predicts poor prognosis after pancreaticoduodenectomy for periampullary adenocarcinoma. Lymph node involvement, vessel infiltration, and increasing tumour diameter are adverse predictors of survival in tumours with pancreatobiliary differentiation. [ABSTRACT FROM AUTHOR]- Published
- 2008
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4. Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor.
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Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, Clausen OP, and Gladhaug IP
- Abstract
Background: The retroperitoneal margin is frequently microscopically tumour positive in non-curative periampullary adenocarcinoma resections. This margin should be evaluated by serial perpendicular sectioning. The aim of the study was to determine whether retroperitoneal margin involvement independently predicts survival after pancreaticoduodenectomy within a framework of standardized assessment of the resected specimens. Methods: 114 consecutive macroscopically margin-free periampullary adenocarcinomas were examined according to a prospective standardized protocol for histopathologic evaluation. The retroperitoneal margin was assessed by serial perpendicular sectioning. The periampullary cancer origin (pancreas, ampulla, distal bile duct or duodenum) was registered prospectively and reevaluated retrospectively. Associations between histopathologic factors were evaluated by Chi-square test, Fisher's exact test, Kruskal-Wallis test, and Mann-Whitney test, as appropriate. Survival curves were calculated by the Kaplan- Meier method and compared using the log-rank test. Associations between histopathologic factors and survival were also evaluated by unadjusted and adjusted Cox regression analysis, including stepwise variable selection, in order to identify factors that independently predict a poor prognosis after periampullary adenocarcinoma resections. Results: Microscopic resection margin involvement (R1 resection) was present in 40 tumours, of which 32 involved the retroperitoneal margin. Involvement of the retroperitoneal margin independently predicted a poor prognosis (p = 0.010; HR 1.89; CI 1.16-3.08) after presumed curative (R0 and R1) resection. In microscopically curative (R0) resections (n = 74), pancreatic tumour origin was the only factor that independently predicted a poor prognosis (p < 0.001; HR 4.71 for pancreatic versus ampullary; CI 2.13-10.4). Conclusion: Serial perpendicular sectioning of the retroperitoneal resection margin demonstrates that tumour involvement of this margin independently predicts survival after pancreaticoduodenectomy for adenocarcinoma. Periampullary tumour origin is the only histopathologic factor that independently predicts survival in microscopically curative (R0) resections. [ABSTRACT FROM AUTHOR]
- Published
- 2008
5. Global metabolomic profiling of tumor tissue and paired serum samples to identify biomarkers for response to neoadjuvant FOLFIRINOX treatment of human pancreatic cancer.
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Amrutkar M, Guttorm SJT, Finstadsveen AV, Labori KJ, Eide L, Rootwelt H, Elgstøen KBP, Gladhaug IP, and Verbeke CS
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- Humans, Male, Middle Aged, Female, Aged, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal blood, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Metabolome drug effects, Leucovorin therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms blood, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Irinotecan therapeutic use, Irinotecan pharmacology, Oxaliplatin therapeutic use, Oxaliplatin pharmacology, Neoadjuvant Therapy, Biomarkers, Tumor blood, Biomarkers, Tumor metabolism, Metabolomics methods, Fluorouracil therapeutic use
- Abstract
Neoadjuvant chemotherapy (NAT) is increasingly used for the treatment of non-metastatic pancreatic ductal adenocarcinoma (PDAC) and is established as a standard of care for borderline resectable and locally advanced PDAC. However, full exploitation of its clinical benefits is limited by the lack of biomarkers that assess treatment response. To address this unmet need, global metabolomic profiling was performed on tumor tissue and paired serum samples from patients with treatment-naïve (TN; n = 18) and neoadjuvant leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX)-treated (NAT; n = 17) PDAC using liquid chromatography mass spectrometry. Differentially abundant metabolites (DAMs) in TN versus NAT groups were identified and their correlation with various clinical parameters was assessed. Metabolomics profiling identified 40 tissue and five serum DAMs in TN versus NAT PDAC. In general, DAMs associated with amino acid and nucleotide metabolism were lower in NAT compared to TN. Four DAMs-3-hydroxybutyric acid (BHB), 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), glycochenodeoxycholate and citrulline-were common to both tissue and serum and showed a similar pattern of differential abundance in both groups. A strong positive correlation was observed between serum carbohydrate 19-9 antigen (CA 19-9) and tissue carnitines (C12, C18, C18:2) and N8-acetylspermidine. The reduction in CA 19-9 following NAT correlated negatively with serum deoxycholate levels, and the latter correlated positively with survival. This study revealed neoadjuvant-chemotherapy-induced changes in metabolic pathways in PDAC, mainly amino acid and nucleotide metabolism, and these correlated with reduced CA 19-9 following neoadjuvant FOLFIRINOX treatment., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2025
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6. Pancreatic duct occlusion with polychloroprene-based glue for the management of postoperative pancreatic fistula after pancreatoduodenectomy-an outdated approach?
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Yaqub S, Røsok B, Gladhaug IP, and Labori KJ
- Abstract
Background: Managing postoperative pancreatic fistula (POPF) presents a formidable challenge after pancreatoduodenectomy. Some centers consider pancreatic duct occlusion (PDO) in reoperations following pancreatoduodenectomy as a pancreas-preserving procedure, aiming to control a severe POPF. The aim of the current study was to evaluate the short- and long-term outcomes of employing PDO for the management of the pancreatic stump during relaparotomy for POPF subsequent to pancreatoduodenectomy., Methods: Retrospective review of consecutive patients at Oslo University Hospital undergoing pancreatoduodenectomy and PDO during relaparotomy. Pancreatic stump management during relaparotomy consisted of occlusion of the main pancreatic duct with polychloroprene Faxan-Latex, after resecting the dehiscent jejunal loop previously constituting the pancreaticojejunostomy., Results: Between July 2005 and September 2015, 826 pancreatoduodenectomies were performed. Overall reoperation rate was 13.2% ( n = 109). POPF grade B/C developed in 113 (13.7%) patients. PDO during relaparotomy was performed in 17 (2.1%) patients, whereas completion pancreatectomy was performed in 22 (2.7%) patients. Thirteen (76%) of the 17 patients had a persistent POPF after PDO, and the time from PDO until removal of the last abdominal drain was median 35 days. Of the PDO patients, 13 (76%) patients required further drainage procedures ( n = 12) or an additional reoperation ( n = 1). In-hospital mortality occurred in one patient (5.9%). Five (29%) patients developed new-onset diabetes mellitus, and 16 (94%) patients acquired exocrine pancreatic insufficiency., Conclusions: PDO is a safe and feasible approach for managing severe POPF during reoperation following pancreatoduodenectomy. A significant proportion of patients experience persistent POPF post-procedure, necessitating supplementary drainage interventions. The findings suggest that it is advisable to explore alternative pancreas-preserving methods before opting for PDO in the management of POPF subsequent to pancreatoduodenectomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Yaqub, Røsok, Gladhug and Labori.)
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- 2024
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7. Fatty acids abrogate the growth-suppressive effects induced by inhibition of cholesterol flux in pancreatic cancer cells.
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Li Y, Amrutkar M, Finstadsveen AV, Dalen KT, Verbeke CS, and Gladhaug IP
- Abstract
Background: Despite therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Metabolic reprogramming is increasingly recognized as a key contributor to tumor progression and therapy resistance in PDAC. One of the main metabolic changes essential for tumor growth is altered cholesterol flux. Targeting cholesterol flux appears an attractive therapeutic approach, however, the complex regulation of cholesterol balance in PDAC cells remains poorly understood., Methods: The lipid content in human pancreatic duct epithelial (HPDE) cells and human PDAC cell lines (BxPC-3, MIA PaCa-2, and PANC-1) was determined. Cells exposed to eight different inhibitors targeting different regulators of lipid flux, in the presence or absence of oleic acid (OA) stimulation were assessed for changes in viability, proliferation, migration, and invasion. Intracellular content and distribution of cholesterol was assessed. Lastly, proteome profiling of PANC-1 exposed to the sterol O-acyltransferase 1 (SOAT1) inhibitor avasimibe, in presence or absence of OA, was performed., Results: PDAC cells contain more free cholesterol but less cholesteryl esters and lipid droplets than HPDE cells. Exposure to different lipid flux inhibitors increased cell death and suppressed proliferation, with different efficiency in the tested PDAC cell lines. Avasimibe had the strongest ability to suppress proliferation across the three PDAC cell lines. All inhibitors showing cell suppressive effect disturbed intracellular cholesterol flux and increased cholesterol aggregation. OA improved overall cholesterol balance, reduced free cholesterol aggregation, and reversed cell death induced by the inhibitors. Treatment with avasimibe changed the cellular proteome substantially, mainly for proteins related to biosynthesis and metabolism of lipids and fatty acids, apoptosis, and cell adhesion. Most of these changes were restored by OA., Conclusions: The study reveals that disturbing the cholesterol flux by inhibiting the actions of its key regulators can yield growth suppressive effects on PDAC cells. The presence of fatty acids restores intracellular cholesterol balance and abrogates the alternations induced by cholesterol flux inhibitors. Taken together, targeting cholesterol flux might be an attractive strategy to develop new therapeutics against PDAC. However, the impact of fatty acids in the tumor microenvironment must be taken into consideration., (© 2023. The Author(s).)
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- 2023
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8. Pancreatic stellate cell-induced gemcitabine resistance in pancreatic cancer is associated with LDHA- and MCT4-mediated enhanced glycolysis.
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Amrutkar M, Berg K, Balto A, Skilbrei MG, Finstadsveen AV, Aasrum M, Gladhaug IP, and Verbeke CS
- Abstract
Background: Profound resistance to chemotherapy remains a major challenge in achieving better clinical outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). Recent studies indicate that gemcitabine (GEM) resistance is promoted both by pancreatic stellate cells (PSCs) and through increased glycolysis. However, it remains unknown whether PSCs affect GEM sensitivity via glycolytic regulation., Methods: Human pancreatic cancer cell (PCC) lines (BxPC-3, Capan-2, HPAF-II, Mia PaCa-2, Panc-1, SW-1990) were exposed to three different PSC-conditioned media (PSC-CM; PSC-1, PSC-2, HPaSteC), following either pre-treatment with glycolysis inhibitor NV-5440 or transfection for transient silencing of key glycolytic regulators (LDHA and MCT4). Proliferation, glucose transport, extracellular lactate, and GEM sensitivity were assessed. Protein expression was determined by Western blot and immunostaining. Moreover, secreted proteins in PSC-CMs were profiled by mass spectrometry (MS)., Results: While exposure to PSC-CMs did not affect glucose transport in PCCs, it increased their lactate release and proliferation, and reduced the sensitivity for GEM. Both NV-5440 treatment and transient silencing of LDHA and MCT4 inhibited these PSC-induced changes in PCCs. MS analysis identified 688 unique proteins with differential expression, of which only 87 were common to the three PSC-CMs. Most PSC-secreted proteins were extracellular matrix-related, including SPARC, fibronectin, and collagens. Moreover, exposure to PSC-CMs increased the phosphorylation of ERK in PCCs, but the treatment of PCCs with the MEK/ERK inhibitor PD98059 resulted in a reduction of PSC-CM-induced glycolysis and improved GEM sensitivity., Conclusions: The study findings suggest that PSC-secreted factors promote both glycolysis and GEM resistance in PCCs, and that glycolysis inhibition by NV-5440 and blocking of ERK phosphorylation by PD98059 protect PCCs from PSC-CM-induced loss of GEM sensitivity. Taken together, PSCs appear to promote GEM resistance in PDAC via glycolysis. Thus, targeting glycolysis may improve the effect of chemotherapy in PDAC., (© 2023. The Author(s).)
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- 2023
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9. Neoadjuvant chemotherapy is associated with an altered metabolic profile and increased cancer stemness in patients with pancreatic ductal adenocarcinoma.
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Amrutkar M, Verbeke CS, Finstadsveen AV, Dorg L, Labori KJ, and Gladhaug IP
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- Humans, Neoadjuvant Therapy, Proteomics, Metabolome, Retrospective Studies, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal pathology
- Abstract
The modest clinical benefits of neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) are associated with a lack of robust data on treatment-induced changes in the tumor. To this end, comparative proteomic profiling of tumor tissue samples from treatment-naïve (TN, n = 20) and NAT-treated (n = 22) PDACs was performed. Differentially expressed proteins were identified and correlation with overall survival (OS) was performed. Tumors were also examined for histopathological changes and expression of cancer stem cell (CSC) markers. Serum from 33 matched patients was analyzed for metabolic markers. Cytotoxicity, proliferation, and expression of CSC markers were assessed in chemoresistant Panc-1 and Mia PaCa-2 cells. Of the 2265 proteins identified, 227 and 144 proteins showed significantly altered expression and differential phosphorylation, respectively, in NAT compared with TN samples. The majority of these were metabolism-related proteins, and 14 of these correlated moderately with OS. NAT-treated tumors and chemoresistant cancer cells showed increased expression of CSC markers. Serum ALDH1A1 was higher in NAT compared with TN. Differentially phosphorylated proteins were mainly involved in cytoskeleton organization, cell locomotion, motility, and migration, and 17 of these showed a strong positive correlation with OS. This study provides evidence of the effects of NAT on PDAC metabolism at both the tumor and the systemic levels. NAT-treated tumors showed significantly lower expression of metabolic proteins, and patients who underwent NAT showed reduced serum lactate and high-density lipoprotein-cholesterol. Lastly, cancer cells that survived cytotoxic treatment expressed higher CSC markers, both in vivo and in vitro., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2023
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10. Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence.
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Sántha P, Lenggenhager D, Finstadsveen A, Dorg L, Tøndel K, Amrutkar M, Gladhaug IP, and Verbeke C
- Abstract
Inter- and intratumor heterogeneity is an important cause of treatment failure. In human pancreatic cancer (PC), heterogeneity has been investigated almost exclusively at the genomic and transcriptional level. Morphological heterogeneity, though prominent and potentially easily assessable in clinical practice, remains unexplored. This proof-of-concept study aims at demonstrating that morphological heterogeneity reflects structural and functional divergence. From the wide morphological spectrum of conventional PC, four common and distinctive patterns were investigated in 233 foci from 39 surgical specimens. Twenty-six features involved in key biological processes in PC were analyzed (immuno-)histochemically and morphometrically: cancer cell proliferation (Ki67) and migration (collagen fiber alignment, MMP14), cancer stem cells (CD44, CD133, ALDH1), amount, composition and spatial arrangement of extracellular matrix (epithelial proximity, total collagen, collagen I and III, fibronectin, hyaluronan), cancer-associated fibroblasts (density, αSMA), and cancer-stroma interactions (integrins α2, α5, α1; caveolin-1). All features differed significantly between at least two of the patterns. Stromal and cancer-cell-related features co-varied with morphology and allowed prediction of the morphological pattern. In conclusion, morphological heterogeneity in the cancer-cell and stromal compartments of PC correlates with structural and functional diversity. As such, histopathology has the potential to inform on the operationality of key biological processes in individual tumors.
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- 2021
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11. Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer.
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Amrutkar M and Gladhaug IP
- Abstract
Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma. PSCs are essential for extracellular matrix assembly and form a supportive niche for tumor growth. Various cytokines and growth factors induce activation of PSCs through autocrine and paracrine mechanisms, which in turn promote overall tumor growth and metastasis and induce chemoresistance. To maintain growth and survival in the nutrient-poor, hypoxic environment of PDAC, tumor cells fulfill their high energy demands via several unconventional ways, a process generally referred to as metabolic reprogramming. Accumulating evidence indicates that activated PSCs not only contribute to the therapy-resistant phenotype of PDAC but also act as a nutrient supplier for the tumor cells. However, the precise molecular links between metabolic reprogramming and an acquired therapy resistance in PDAC remain elusive. This review highlights recent findings indicating the importance of PSCs in aiding growth-permissive metabolic reprogramming and gemcitabine chemoresistance in PDAC.
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- 2021
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12. Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing.
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Amrutkar M, Vethe NT, Verbeke CS, Aasrum M, Finstadsveen AV, Sántha P, and Gladhaug IP
- Abstract
Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.
- Published
- 2020
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13. The thesis defence is part of the doctoral degree examination.
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Berg JP and Gladhaug IP
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- 2020
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14. Is there room for a nursing science community in a medical faculty?
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Engebretsen E and Gladhaug IP
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- Humans, Attitude of Health Personnel, Faculty, Medical
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- 2020
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15. Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor.
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Amrutkar M, Larsen EK, Aasrum M, Finstadsveen AV, Andresen PA, Verbeke CS, and Gladhaug IP
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- Adenocarcinoma genetics, Adenocarcinoma pathology, Alleles, Cell Movement drug effects, Cell Proliferation drug effects, Cell Proliferation genetics, Cell Shape drug effects, Cell Shape genetics, Culture Media, Conditioned pharmacology, DNA, Neoplasm biosynthesis, Humans, Mutation genetics, Pancreatic Neoplasms genetics, Pancreatic Stellate Cells drug effects, Phenotype, Proteome metabolism, Tumor Cells, Cultured, Pancreatic Neoplasms pathology, Pancreatic Stellate Cells pathology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored KRAS and TP53 mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology., Competing Interests: The authors declare no conflict of interest.
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- 2020
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16. Pancreatoduodenectomy with venous resection for ductal adenocarcinoma rarely achieves complete (R0) resection.
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Kleive D, Labori KJ, Line PD, Gladhaug IP, and Verbeke CS
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- Aged, Carcinoma, Pancreatic Ductal pathology, Female, Humans, Male, Margins of Excision, Mesenteric Veins pathology, Middle Aged, Neoplasm Invasiveness, Pancreatic Neoplasms pathology, Portal Vein pathology, Retrospective Studies, Treatment Outcome, Carcinoma, Pancreatic Ductal surgery, Mesenteric Veins surgery, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy, Portal Vein surgery
- Abstract
Background: Pancreatoduodenectomy with venous resection is considered standard of care for patients with tumour involvement of the superior mesenteric/portal vein (SMV/PV) and deemed justified if an R0-resection can be achieved. The aim of this study was to provide a detailed pathology assessment of the site and extent of margin involvement in specimens resulting from pancreatoduodenectomy with venous resection., Methods: Retrospective observational study including patients undergoing pancreatoduodenectomy with or without venous resection for pancreatic ductal adenocarcinoma between 2015 and 2017. Detailed histopathological mapping of the tumour and its relationship to the margins was undertaken., Results: 98 patients met the inclusion criteria. An R0-resection, based on 1 mm clearance, was achieved in 16 of 73 patients without venous resection and in 1 of 25 patients with venous resection (p = 0.063). The surface of the SMV-groove was the most frequently involved margin (23 of 25 patients with venous resection, 37 of 73 patients without venous resection; p < 0.001). The broad invasive tumour front as well as the absence of peripancreatic fat at the SMV-groove were the reasons for these findings., Conlusion: An R0-resection following pancreatoduodenectomy with venous resection for ductal adenocarcinoma can rarely be achieved due to microscopical involvement of the SMV-groove., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2020
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17. It is essential to fulfil the purpose of the trial lecture.
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Berg JP and Gladhaug IP
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- Humans, Research Personnel, Education, Medical
- Published
- 2019
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18. Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells.
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Amrutkar M, Aasrum M, Verbeke CS, and Gladhaug IP
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- Cell Line, Tumor, Cell Survival drug effects, Coculture Techniques, Deoxycytidine pharmacology, Dose-Response Relationship, Drug, Extracellular Matrix metabolism, Fibronectins antagonists & inhibitors, Flavonoids pharmacology, Humans, MAP Kinase Signaling System, Oligopeptides pharmacology, Phosphorylation, Proteome analysis, Proto-Oncogene Proteins c-akt metabolism, Gemcitabine, Carcinoma, Pancreatic Ductal pathology, Deoxycytidine analogs & derivatives, Drug Resistance, Neoplasm drug effects, Fibronectins metabolism, Pancreatic Neoplasms pathology, Pancreatic Stellate Cells metabolism
- Abstract
Background: Gemcitabine remains a cornerstone in chemotherapy of pancreatic ductal adenocarcinoma (PDAC) despite suboptimal clinical effects that are partly due to the development of chemoresistance. Pancreatic stellate cells (PSCs) of the tumor stroma are known to interact with pancreatic cancer cells (PCCs) and influence the progression of PDAC through a complex network of signaling molecules that involve extracellular matrix (ECM) proteins. To understand tumor-stroma interactions regulating chemosensitivity, the role of PSC-secreted fibronectin (FN) in the development of gemcitabine resistance in PDAC was examined., Methods: PSC cultures obtained from ten different human PDAC tumors were co-cultured with PCC lines (AsPC-1, BxPC-3, Capan-2, HPAF-II, MIA PaCa-2, PANC-1 and SW-1990) either directly, or indirectly via incubation with PSC-conditioned medium (PSC-CM). Gemcitabine dose response cytotoxicity was determined using MTT based cell viability assays. Protein expression was assessed by western blotting and immunofluorescence. PSC-CM secretome analysis was performed by proteomics-based LC-MS/MS, and FN content in PSC-CM was determined with ELISA. Radiolabeled gemcitabine was used to determine the capacity of PCCs to uptake the drug., Results: In both direct and indirect co-culture, PSCs induced varying degrees of resistance to the cytotoxic effects of gemcitabine among all cancer cell lines examined. A variable degree of increased phosphorylation of ERK1/2 was observed across all PCC lines upon incubation with PSC-CM, while activation of AKT was not detected. Secretome analysis of PSC-CM identified 796 different proteins, including several ECM-related proteins such as FN and collagens. Soluble FN content in PSC-CM was detected in the range 175-350 ng/ml. Neither FN nor PSC-CM showed any effect on PCC uptake capacity of gemcitabine. PCCs grown on FN-coated surface displayed higher resistance to gemcitabine compared to cells grown on non-coated surface. Furthermore, a FN inhibitor, synthetic Arg-Gly-Asp-Ser (RGDS) peptide significantly inhibited PSC-CM-induced chemoresistance in PCCs via downregulation of ERK1/2 phosphorylation., Conclusions: The findings of this study suggest that FN secreted by PSCs in the ECM plays a key role in the development of resistance to gemcitabine via activation of ERK1/2. FN-blocking agents added to gemcitabine-based chemotherapy might counteract chemoresistance in PDAC and provide better clinical outcomes.
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- 2019
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19. Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy.
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Bowitz Lothe IM, Kleive D, Pomianowska E, Cvancarova M, Kure E, Dueland S, Gladhaug IP, and Labori KJ
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- Adenocarcinoma pathology, Adenocarcinoma therapy, Adult, Aged, Aged, 80 and over, Duodenal Neoplasms classification, Duodenal Neoplasms pathology, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms classification, Pancreatic Neoplasms pathology, Survival, Adenocarcinoma classification, Antineoplastic Agents therapeutic use, Duodenal Neoplasms therapy, Neoplasm Recurrence, Local, Pancreatic Neoplasms therapy, Pancreaticoduodenectomy
- Abstract
Background: The clinical relevance of the classification of ampullary adenocarcinoma (AC) into pancreatobiliary (PB) or intestinal (Int) subtypes has not been resolved., Methods: Clinicopathological factors, survival, and localization and treatment of recurrence were investigated for patients with AC and duodenal adenocarcinoma (DC) treated by pancreatoduodenectomy from 2000 to 2015., Results: A total of 109 AC (45 PB, 64 Int) and 71 DC (all Int) were identified. Median overall survival (OS) for ACPB vs DC vs ACInt was 43.6 vs 51 vs 75 months, respectively. ACPB had significantly shorter OS than ACInt (p = 0.036). However, for AC stage (HR = 2.39; 95 %CI 1.23-4.64, p = 0.010) was the only factor associated with mortality risk in multivariate analysis. Localization of recurrence (n = 88) was predominantly distant (ACPB 81.5%; ACInt 92%; DC 91.7%, p = 0.371). Post-recurrence survival (PRS) for ACPB, ACInt and DC did not differ (6.9 vs 9.2 vs 7.5 months, p = 0.755). Best supportive care or palliative chemotherapy were offered for recurrent disease to 44.5%/48.1% for ACPB, 40%/56% for ACInt, and 41.7%/52.8% for DC (p = 0.947). The choice of chemotherapy regimen varied considerably. Five patients underwent surgical resection or ablation with curative intent. All deaths among ACPB were caused by recurrent disease, whereas 29.4% of ACInt and 23.1% of DC deaths was non-cancer related or caused by other specific cancer., Conclusion: ACPB, ACInt and DC have similar recurrence patterns and PRS. The difference in survival between ACPB and ACInt was not statistically significant when stratified by stage. The optimal chemotherapy in patients with recurrent AC remains undefined., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
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- 2019
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20. Commonly Used Pancreatic Stellate Cell Cultures Differ Phenotypically and in Their Interactions with Pancreatic Cancer Cells.
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Lenggenhager D, Amrutkar M, Sántha P, Aasrum M, Löhr JM, Gladhaug IP, and Verbeke CS
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- Animals, Cell Line, Tumor, Cell Movement, Cell Proliferation, Collagen metabolism, Humans, Phenotype, Transforming Growth Factor beta metabolism, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Pancreatic Stellate Cells metabolism, Pancreatic Stellate Cells pathology
- Abstract
Activated pancreatic stellate cells (PSCs) play a central role in the tumor stroma of pancreatic ductal adenocarcinoma (PDAC). Given the limited availability of patient-derived PSCs from PDAC, immortalized PSC cell lines of murine and human origin have been established; however, it is not elucidated whether differences in species, organ disease status, donor age, and immortalization alter the PSC phenotype and behavior compared to that of patient-derived primary PSC cultures. Therefore, a panel of commonly used PSC cultures was examined for important phenotypical and functional features: three primary cultures from human PDAC, one primary from normal human pancreas, and three immortalized (one from human, two from murine pancreas). Growth rate was considerably lower in primary PSCs from human PDAC. Basal collagen synthesis varied between the PSC cultures, and TGF-β stimulation increased collagen synthesis only in non-immortalized cultures. Differences in secretome composition were observed along with a divergence in the DNA synthesis, migration, and response to gemcitabine of PDAC cell lines that were grown in conditioned medium from the various PSC cultures. The findings reveal considerable differences in features and functions that are key to PSCs and in the interactions with PDAC. These observations may be relevant to researchers when selecting the most appropriate PSC culture for their experiments.
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- 2019
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21. Risk for hemorrhage after pancreatoduodenectomy with venous resection.
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Kleive D, Sahakyan M, Søreide K, Brudvik KW, Line PD, Gladhaug IP, and Labori KJ
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- Aged, Female, Humans, Male, Middle Aged, Operative Time, Retrospective Studies, Risk Factors, Veins surgery, Anticoagulants therapeutic use, Heparin, Low-Molecular-Weight therapeutic use, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy adverse effects, Postoperative Hemorrhage etiology
- Abstract
Purpose: No consensus exists on the optimal anticoagulation therapy after pancreatoduodenectomy with venous resection (PDVR). The aim of the study was to analyze perioperative outcomes of patients receiving low- vs high-dose anticoagulation therapy and to identify risk factors for postpancreatectomy hemorrhage in patients undergoing PDVR., Methods: Retrospective study of patients undergoing PDVR at a tertiary referral center between January 2006 and April 2017. Patients were investigated according to the dose of postoperative anticoagulation given (low- or high-dose low-molecular-weight heparin). Uni- and multivariate analysis were performed to assess risk factors for postpancreatectomy hemorrhage., Results: A total of 141 patients underwent PDVR. Low-dose anticoagulation was given to 45 (31.9%) patients. Operative time (428 min vs 398 min, p = 0.025) and the use of interposition grafts (27% vs 11%, P = 0.033) were significantly higher in the high-dose group. There was no difference in the rate of early portal vein thrombosis (4.4% vs 4.2%, p = 0.939) or postpancreatectomy hemorrhage (13.3% vs 16.7%, p = 0.611) between the low- and high-dose groups. On multivariate analysis, serum bilirubin ≥ 200 μmol/L and clinically relevant postoperative fistula were the only factors associated with postpancreatectomy hemorrhage (OR 10.28, 95% CI 3.51-30.07, P < 0.001, and OR 6.39, 95% CI 1.59-25.74, P = 0.009)., Conclusion: Preoperative hyperbilirubinemia and clinically relevant postoperative fistula are risk factors for postpancreatectomy hemorrhage after PDVR. Rates of postpancreatectomy hemorrhage did not differ between patients receiving high- vs low-dose low-molecular-weight heparin.
- Published
- 2018
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22. Portal vein reconstruction using primary anastomosis or venous interposition allograft in pancreatic surgery.
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Kleive D, Berstad AE, Sahakyan MA, Verbeke CS, Naper C, Haugvik SP, Gladhaug IP, Line PD, and Labori KJ
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- Aged, Allografts, Anastomosis, Surgical, Blood Loss, Surgical, Carcinoma, Pancreatic Ductal diagnostic imaging, Carcinoma, Pancreatic Ductal pathology, Computed Tomography Angiography, Female, Graft Occlusion, Vascular etiology, Graft Occlusion, Vascular physiopathology, Graft Rejection etiology, Humans, Iliac Vein diagnostic imaging, Iliac Vein immunology, Iliac Vein physiopathology, Isoantibodies blood, Male, Mesenteric Veins diagnostic imaging, Mesenteric Veins pathology, Mesenteric Veins physiopathology, Middle Aged, Operative Time, Pancreatectomy adverse effects, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms pathology, Phlebography methods, Portal Vein diagnostic imaging, Portal Vein pathology, Portal Vein physiopathology, Plastic Surgery Procedures adverse effects, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Ultrasonography, Vascular Patency, Vascular Surgical Procedures adverse effects, Carcinoma, Pancreatic Ductal surgery, Iliac Vein transplantation, Mesenteric Veins surgery, Pancreatectomy methods, Pancreatic Neoplasms surgery, Portal Vein surgery, Plastic Surgery Procedures methods, Vascular Surgical Procedures methods
- Abstract
Objective: Superior mesenteric vein/portal vein (SMV/PV) resection and reconstruction during pancreatic surgery are increasingly common. Several reconstruction techniques exist. The aim of this study was to evaluate characteristics of patients and clinical outcomes for SMV/PV reconstruction using interposed cold-stored cadaveric venous allograft (AG+) or primary end-to-end anastomosis (AG-) after segmental vein resections during pancreatic surgery., Methods: All patients undergoing pancreatic surgery with SMV/PV resection and reconstruction from 2006 to 2015 were identified. Clinical and histopathologic outcomes as well as preoperative and postoperative radiologic findings were assessed., Results: A total of 171 patients were identified. The study included 42 and 71 patients reconstructed with AG+ and AG-, respectively. Patients in the AG+ group had longer mean operative time (506 minutes [standard deviation, 83 minutes] for AG+ vs 420 minutes [standard deviation, 91 minutes] for AG-; P < .01) and more intraoperative bleeding (median, 1000 mL [interquartile range (IQR), 650-2200 mL] for AG+ vs 600 mL [IQR, 300-1000 mL] for AG-; P < .01). Neoadjuvant therapy was administered more frequently for patients in the AG+ group (23.8% vs 8.5%; P = .02). Patients with AG+ had a longer length of tumor-vein involvement (median, 2.4 cm [IQR, 1.6-3.0 cm] for AG+ vs 1.8 cm [IQR, 1.2-2.4 cm] for AG-; P = .01), and a higher number of patients had a tumor-vein interface >180 degrees (35.7% for AG+ vs 21.1% for AG-; P = .02). There was no difference in number of patients with major complications (42.9% for AG+ vs 36.6% for AG-; P = .51) or early failure at the reconstruction site (9.5% for AG+ vs 8.5% for AG-; P = 1). A subgroup analysis of 10 patients in the AG+ group revealed the presence of donor-specific antibodies in all patients., Conclusions: The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis. Graft rejection could be a contributing factor to severe stenosis in patients reconstructed with allograft., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)
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- 2018
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23. Pancreatic Cancer Chemoresistance to Gemcitabine.
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Amrutkar M and Gladhaug IP
- Abstract
Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
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24. Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy.
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Kleive D, Sahakyan MA, Berstad AE, Verbeke CS, Gladhaug IP, Edwin B, Fosby B, Line PD, and Labori KJ
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- Aged, Blood Loss, Surgical statistics & numerical data, Common Bile Duct Neoplasms surgery, Erythrocyte Transfusion statistics & numerical data, Female, Humans, Length of Stay statistics & numerical data, Male, Middle Aged, Operative Time, Pancreatic Neoplasms surgery, Postoperative Complications, Reoperation statistics & numerical data, Retrospective Studies, Mesenteric Veins surgery, Pancreaticoduodenectomy, Portal Vein surgery
- Abstract
Background: Pancreatoduodenectomy with superior mesenteric-portal vein resection has become a common procedure in pancreatic surgery. The aim of this study was to compare standard pancreatoduodenectomy with pancreatoduodenectomy plus venous resection at a high-volume centre, and to examine trends in management and outcome over a decade for the latter procedure., Methods: This retrospective observational study included all patients undergoing pancreatoduodenectomy with or without venous resection at Oslo University Hospital between January 2006 and December 2015. Trends were evaluated by assessing preoperative clinical and radiological characteristics, as well as perioperative outcomes in three time intervals (early, intermediate and late)., Results: A total of 784 patients had a pancreatoduodenectomy, of whom 127 (16·2 per cent) underwent venous resection. Venous resection resulted in a longer operating time (median 422 versus 312 min; P = 0·001) and greater estimated blood loss (EBL) (median 700 versus 500 ml; P = 0·004) than standard pancreatoduodenectomy. The rate of severe complications was significantly higher for pancreatoduodenectomy with venous resection (37·0 versus 26·3 per cent; P = 0·014). The overall burden of complications, evaluated using the Comprehensive Complication Index (CCI), did not differ (median score 8·7 versus 8·7; P = 0·175). Trends in venous resection over time showed a significant reduction in EBL (median 1050 versus 375 ml; P = 0·001) and duration of hospital stay (median 14 versus 9 days; P = 0·011) between the early and late periods. However, despite an improvement in the intermediate period, severe complication rates returned to baseline in the late period (18 of 43 versus 9 of 42 versus 20 of 42 patients in early, intermediate and late periods respectively; P = 0·032), as did CCI scores (median 20·9 versus 0 versus 20·9; P = 0·041)., Conclusion: Despite an initial improvement in severe complications for venous resection during pancreatoduodenectomy, this was not maintained over time. Every fourth patient with venous resection needed relaparotomy, most frequently for bleeding., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)
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- 2017
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25. Minneord: Johannes Setekleiv.
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Gladhaug IP, Skomedal T, Mørland J, Christoffersen T, and Osnes JB
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- 2017
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26. Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis.
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Haugvik SP, Basim Ibrahim I, Hedenström P, Valente R, Hayes AJ, Siuka D, Gladhaug IP, and Capurso G
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- Family Health, Humans, Intestinal Neoplasms genetics, Neuroendocrine Tumors genetics, Pedigree, Risk Assessment, Risk Factors, Alcohol Drinking adverse effects, Intestinal Neoplasms epidemiology, Medical History Taking, Neuroendocrine Tumors epidemiology, Smoking adverse effects
- Abstract
Objectives: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors for SI-NET and to further assess these by meta-analysis., Material and Methods: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement., Results: Seven studies evaluating six individual populations were included (study accrual period 1980-2012) in the meta-analysis, involving 765 (range 17-325) cases and 502,282 (range 52-498,376) controls. All studies were case-control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use and ever smoking. The pooled OR was 1.34 (95% CI: 1.12-1.60; p < .01; I
2 = 0.0%) for family history of any cancer, 1.43 (95% CI: 1.15-1.79; p < .01; I2 = 0.0%) for family history of colorectal cancer, 1.04 (95% CI: 0.63-1.72; p = .87; I2 = 65.0%) for ever alcohol use and 1.40 (95% CI: 1.06-1.86; p < .05; I2 = 49.3%) for ever smoking., Conclusions: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.- Published
- 2017
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27. Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells.
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Tjomsland V, Aasrum M, Christoffersen T, and Gladhaug IP
- Abstract
The pancreatic stellate cell (PSC) is the principal cell type of the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC). PSCs interact with cancer cells and influence the progression of the disease through a complex network of signaling molecules including hepatocyte growth factor (HGF). Functional heterogeneity of PSCs within a tumor might conceivably influence tumor progression. We investigated PSC populations isolated from different human PDACs and examined the effects of PSC-conditioned medium on BxPC-3 and AsPC-1 pancreatic cancer cells. The different PSC populations exhibited a wide range of variation (120-3,000 pg/ml) in their ability to secrete HGF. Media from high-HGF-producing PSCs stimulated phosphorylation of Met, Gab1, and ERK in the cancer cells and induced increases in DNA synthesis and migration which were blocked by the Met inhibitor SU11274, indicating a role of HGF as a mediator. HGF levels produced by PSCs and the effects of PSC media on the cancer cells were increased by IL-1α and inhibited by TGFβ. The functional heterogeneity of PSCs in terms of HGF-mediated tumor-stroma interactions suggests that inhibition of the HGF pathway as a novel treatment approach in PDAC might have different effects in different subsets of patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest related to this work.
- Published
- 2017
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28. Dissection of Pancreatic Resection Specimens.
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Verbeke CS and Gladhaug IP
- Subjects
- Humans, Pancreas anatomy & histology, Pancreaticoduodenectomy, Practice Guidelines as Topic, Tissue Fixation methods, Dissection methods, Pancreas pathology, Pancreatic Diseases pathology, Specimen Handling methods
- Abstract
Specimen grossing is a key step in the pathology examination of pancreatic resection specimens. Optimal display of pathologic changes and extensive tissue sampling are important determinants of the quality of pathology reporting. Divergence in macroscopic examination practice has led to considerable variation in the reporting of factors that are of clinical and prognostic significance. This article provides a detailed account of the macroscopic examination procedure with reference to current (inter-)national guidelines and recommendations., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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29. Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas.
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Johannessen LE, Panagopoulos I, Haugvik SP, Gladhaug IP, Heim S, and Micci F
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- Adult, Alleles, Chromosomes, Human, Pair 11 genetics, Exons genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor II biosynthesis, Insulinoma pathology, Male, Pancreas pathology, Polymorphism, Single Nucleotide, RNA Splicing genetics, Transcriptional Activation genetics, Insulin genetics, Insulin-Like Growth Factor II genetics, Insulinoma genetics, Protein Isoforms genetics
- Abstract
Fusion transcripts arising from the combination of exons residing on neighboring genes on the same chromosome may give rise to chimeric or novel proteins. Such read-through transcripts have been detected in different cancers where they may be of pathogenetic interest. In this study, we describe for the first time the expression of a read-through transcript in insulinomas, a functioning neuroendocrine pancreatic neoplasm. The read-through transcript INS-IGF2, composed of exons from the two genes proinsulin precursor (INS) and insulin‑like growth factor 2 (IGF2), both mapping to chromosomal subband 11p15.5, was highly expressed in the two insulinomas analyzed. More precisely, version 2 of the INS-IGF2 transcript was expressed, indicating possible expression of the chimeric INS-IGF2 protein. We further identified a novel splice variant of the INS-IGF2 read-through transcript in one of the insulinomas, composed of exon 1 of INS3 and exons of IGF2. In the same tumor, we found high expression of INS3 and the presence of the A allele at SNP rs689. SNP rs689 has been previously described to regulate splicing of the INS transcript, indicating that this regulatory mechanism also affects splicing of INS-IGF2. The identification of the INS-IGF2 read-through transcript specifically in tumor tissue but not in normal pancreatic tissue suggests that high expression of INS-IGF2 could be neoplasia‑specific. These results may have potential clinical applications given that the read-through transcript could be used as a biomarker in insulinoma patients.
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- 2016
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30. Transcriptomic Profiling of Tumor Aggressiveness in Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms.
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Haugvik SP, Vodák D, Haugom L, Hovig E, Gladhaug IP, Heim S, and Micci F
- Subjects
- Gene Expression, Gene Expression Profiling, Humans, Pancreatic Neoplasms, Up-Regulation, Neuroendocrine Tumors
- Abstract
Objectives: The aim of the study was to compare RNA sequencing data of sporadic nonfunctioning pancreatic neuroendocrine neoplasms (PNENs) to identify gene expression patterns that may be important for molecular differentiation of tumor aggressiveness., Methods: RNA sequencing was performed on samples of sporadic nonfunctioning PNENs, grouped as tumors with mild behavior (nonmetastatic and Ki67 < 5%) or aggressive behavior (metastatic and Ki67 ≥ 5%), on an Illumina Genome Analyzer II platform. Bioinformatic analyses were performed on the resulting data., Results: Of 22,810 identified transcripts from protein-coding genes, a set of 309 genes were significantly differentially expressed between the 2 groups, of which 166 were upregulated and 143 downregulated in the aggressive disease group. Among the top protein-coding upregulated genes, we found genes encoding proteins involved in DNA packaging, ability to taste, chromosome structuring, cytoskeleton structuring, and cell-cell signaling. Among the top protein-coding downregulated genes, we found genes encoding proteins involved in neuronal differentiation, cytoskeleton structuring, cell-cell signaling, and immunological processes., Conclusions: A higher degree of tumor aggressiveness in sporadic nonfunctioning PNENs seems to be associated with upregulation of genes involved in regulation of the cell cycle and cell division. Small sample size and lack of a replication set are limitations of this study.
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- 2016
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31. The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration.
- Author
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Tjomsland V, Sandnes D, Pomianowska E, Cizmovic ST, Aasrum M, Brusevold IJ, Christoffersen T, and Gladhaug IP
- Subjects
- Cell Communication, Cell Line, Tumor, Cell Movement, Cells, Cultured, Coculture Techniques, Gene Expression Regulation, Neoplastic, Humans, Interleukin-1alpha genetics, Pancreatic Neoplasms pathology, Pancreatic Stellate Cells metabolism, Receptors, Interleukin-1 Type I genetics, Receptors, Interleukin-1 Type I metabolism, Signal Transduction, Smad3 Protein genetics, Smad7 Protein genetics, Smad7 Protein metabolism, Interleukin-1alpha metabolism, Pancreatic Neoplasms metabolism, Pancreatic Stellate Cells cytology, Smad3 Protein metabolism, Transforming Growth Factor beta metabolism
- Abstract
Background: The most abundant cells in the extensive desmoplastic stroma of pancreatic adenocarcinomas are the pancreatic stellate cells, which interact with the carcinoma cells and strongly influence the progression of the cancer. Tumor stroma interactions induced by IL-1α/IL-1R1 signaling have been shown to be involved in pancreatic cancer cell migration. TGFβ and its receptors are overexpressed in pancreatic adenocarcinomas. We aimed at exploring TGFβ and IL-1α signaling and cross-talk in the stellate cell cancer cell interactions regulating pancreatic adenocarcinoma cell migration., Methods: Human pancreatic stellate cells were isolated from surgically resected pancreatic adenocarcinomas and cultured in the presence of TGFβ or pancreatic adenocarcinoma cell lines. The effects of TGFβ were blocked by inhibitors or amplified by silencing the endogenous inhibitor of SMAD signaling, SMAD7. Pancreatic stellate cell responses to IL-1α or to IL-1α-expressing pancreatic adenocarcinoma cells (BxPC-3) were characterized by their ability to stimulate migration of cancer cells in a 2D migration model., Results: In pancreatic stellate cells, IL-1R1 expression was found to be down-regulated by TGFβ and blocking of TGFβ signaling re-established the expression. Endogenous inhibition of TGFβ signaling by SMAD7 was found to correlate with the levels of IL-1R1, indicating a regulatory role of SMAD7 in IL-1R1 expression. Pancreatic stellate cells cultured in the presence of IL-1α or in co-cultures with BxPC-3 cells enhanced the migration of cancer cells. This effect was blocked after treatment of the pancreatic stellate cells with TGFβ. Silencing of stellate cell expression of SMAD7 was found to suppress the levels of IL-1R1 and reduce the stimulatory effects of IL-1α, thus inhibiting the capacity of pancreatic stellate cells to induce cancer cell migration., Conclusions: TGFβ signaling suppressed IL-1α mediated pancreatic stellate cell induced carcinoma cell migration. Depletion of SMAD7 upregulated the effects of TGFβ and reduced the expression of IL-1R1, leading to inhibition of IL-1α induced stellate cell enhancement of carcinoma cell migration. SMAD7 might represent a target for inhibition of IL-1α induced tumor stroma interactions.
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- 2016
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32. Cold-stored cadaveric venous allograft for superior mesenteric/portal vein reconstruction during pancreatic surgery.
- Author
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Kleive D, Berstad AE, Verbeke CS, Haugvik SP, Gladhaug IP, Line PD, and Labori KJ
- Subjects
- Aged, Allografts, Blood Loss, Surgical, Cadaver, Feasibility Studies, Female, Hospital Mortality, Humans, Iliac Vein diagnostic imaging, Male, Middle Aged, Operative Time, Organ Preservation adverse effects, Organ Preservation mortality, Pancreatectomy adverse effects, Pancreatectomy mortality, Pancreaticoduodenectomy adverse effects, Pancreaticoduodenectomy mortality, Phlebography methods, Reoperation, Retrospective Studies, Risk Factors, Time Factors, Tomography, X-Ray Computed, Treatment Outcome, Ultrasonography, Doppler, Vascular Patency, Cold Temperature adverse effects, Iliac Vein transplantation, Mesenteric Veins surgery, Organ Preservation methods, Pancreatectomy methods, Pancreaticoduodenectomy methods, Portal Vein surgery, Tissue Donors
- Abstract
Background: SMV/PV resection has become common practice in pancreatic surgery. The aim of this study was to evaluate the technical feasibility and surgical outcome of using cold-stored cadaveric venous allografts (AG) for superior mesenteric vein (SMV) and portal vein (PV) reconstruction during pancreatectomy., Methods: Patients who underwent pancreatic resection with concomitant vascular resection and reconstruction with AG between January 2006 and December 2014 were identified from our institutional prospective database. Medical records and pre- and postoperative CT-images were reviewed., Results: Forty-five patients underwent SMV/PV reconstruction with AG interposition (n = 37) or AG patch (n = 8). The median operative time and blood loss were 488 min (IQR: 450-551) and 900 ml (IQR: 600-2000), respectively. Major morbidity (Clavien ≥ III) occurred in 16 patients. Four patients were reoperated (thrombosis n = 2, graft kinking/low flow n = 2) and in-hospital mortality occurred in two patients. On last available CT scan, 3 patients had thrombosis, all of whom also had local recurrence. Estimated cumulative patency rate (reduction in SMV/PV luminal diameter <70% and no thrombosis) at 12 months was 52%., Conclusion: Cold-stored cadaveric venous AG for SMV/PV reconstruction during pancreatic surgery is safe and associated with acceptable long-term patency., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2016
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33. Profile of MMP and TIMP Expression in Human Pancreatic Stellate Cells: Regulation by IL-1α and TGFβ and Implications for Migration of Pancreatic Cancer Cells.
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Tjomsland V, Pomianowska E, Aasrum M, Sandnes D, Verbeke CS, and Gladhaug IP
- Subjects
- Cell Line, Tumor, Cell Movement, Enzyme Activation drug effects, Fluorescence Resonance Energy Transfer, Humans, Interleukin-1alpha metabolism, Pancreatic Ducts pathology, Tumor Suppressor Proteins metabolism, Carcinoma, Pancreatic Ductal pathology, Interleukin-1alpha pharmacology, Matrix Metalloproteinase 1 metabolism, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 3 metabolism, Pancreatic Neoplasms pathology, Pancreatic Stellate Cells metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism, Tissue Inhibitor of Metalloproteinase-2 metabolism, Tissue Inhibitor of Metalloproteinase-3 metabolism, Transforming Growth Factor beta pharmacology
- Abstract
Pancreatic ductal adenocarcinoma is characterized by a prominent fibroinflammatory stroma with both tumor-promoting and tumor-suppressive functions. The pancreatic stellate cell (PSC) is the major cellular stromal component and the main producer of extracellular matrix proteins, including collagens, which are degraded by metalloproteinases (MMPs). PSCs interact with cancer cells through various factors, including transforming growth factor (TGF)β and interleukin (IL)-1α. The role of TGFβ in the dual nature of tumor stroma, i.e., protumorigenic or tumor suppressive, is not clear. We aimed to investigate the roles of TGFβ and IL-1α in the regulation of MMP profiles in PSCs and the subsequent effects on cancer cell migration. Human PSCs isolated from surgically resected specimens were cultured in the presence of pancreatic cancer cell lines, as well as IL-1α or TGFβ. MMP production and activities in PSCs were quantified by gene array transcripts, mRNA measurements, fluorescence resonance energy transfer-based activity assay, and zymography. PSC-conditioned media and pancreatic cancer cells were included in a collagen matrix cell migration model. We found that production of IL-1α by pancreatic cancer cells induced alterations in MMP and tissue inhibitors of matrix metalloproteinase (TIMP) profiles and activities in PSCs, upregulated expression and activation of MMP1 and MMP3, and enhanced migration of pancreatic cancer cells in the collagen matrix model. TGFβ counteracted the effects of IL-1α on PSCs, reestablished PSC MMP and TIMP profiles and activities, and inhibited migration of cancer cells. This suggests that tumor TGFβ has a role as a suppressor of stromal promotion of tumor progression through alterations in PSC MMP profiles with subsequent inhibition of pancreatic cancer cell migration., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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34. Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study.
- Author
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Haugvik SP, Janson ET, Österlund P, Langer SW, Falk RS, Labori KJ, Vestermark LW, Grønbæk H, Gladhaug IP, and Sorbye H
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Neuroendocrine pathology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Staging, Pancreatic Neoplasms pathology, Prognosis, Retrospective Studies, Scandinavian and Nordic Countries, Survival Rate, Young Adult, Carcinoma, Neuroendocrine surgery, Pancreatic Neoplasms surgery
- Abstract
Background: This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery is uncertain., Methods: Data from patients with a diagnosis of hgPNEC determined between 1998 and 2012 were retrospectively registered at 10 Nordic university hospitals. Kaplan-Meier curves were used to compare the overall survival of different treatment groups, and Cox-regression analysis was used to evaluate factors potentially influencing survival., Results: The study registered 119 patients. The median survival period from the time of metastasis was 23 months for patients undergoing initial resection of localized nonmetastatic disease and chemotherapy at the time of recurrence (n = 14), 29 months for patients undergoing resection of the primary tumor and resection/radiofrequency ablation of synchronous metastatic liver disease (n = 12), and 13 months for patients with synchronous metastatic disease given systemic chemotherapy alone (n = 78). The 3-year survival rate after surgery of the primary tumor and metastatic disease was 69 %. Resection of the primary tumor was an independent factor for improved survival after occurrence of metastatic disease., Conclusions: Patients with resected localized nonmetastatic hgPNEC and later metastatic disease seemed to benefit from initial resection of the primary tumor. Patients selected for resection of the primary tumor and synchronous liver metastases had a high 3-year survival rate. Selected patients with both localized hgPNEC and metastatic hgPNEC should be considered for radical surgical treatment.
- Published
- 2016
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35. Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape.
- Author
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Haugvik SP, Kaemmerer D, Gaujoux S, Labori KJ, Verbeke CS, and Gladhaug IP
- Subjects
- Biomarkers, Tumor analysis, Carcinoma, Neuroendocrine metabolism, Carcinoma, Neuroendocrine pathology, Humans, Ki-67 Antigen analysis, Mitotic Index, Neoplasm Grading, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Prognosis, Survival Analysis, Treatment Outcome, Carcinoma, Neuroendocrine surgery, Pancreatic Neoplasms surgery
- Abstract
Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 5% of all pancreatic tumors. High-grade pancreatic neuroendocrine carcinomas (hgPNECs) represent about 5% of all PNENs. They show highly aggressive behavior with dismal prognosis. Throughout the last two decades, there has been a notable progress in basic and clinical research of PNENs and a therapeutic trend towards both more aggressive and minimally invasive surgery. Despite these advances, hgPNECs as a distinct clinical entity remains largely unexplored among surgeons. This review of current development in pathology reporting and surgical treatment of hgPNECs aims at increasing the awareness of an evolving field in pancreatic surgery.
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- 2016
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36. Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma - A population-based cohort study.
- Author
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Labori KJ, Katz MH, Tzeng CW, Bjørnbeth BA, Cvancarova M, Edwin B, Kure EH, Eide TJ, Dueland S, Buanes T, and Gladhaug IP
- Subjects
- Adenocarcinoma pathology, Adenocarcinoma therapy, Adult, Aged, Aged, 80 and over, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal therapy, Combined Modality Therapy, Disease Progression, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local therapy, Neoplasm Staging, Pancreatic Neoplasms pathology, Pancreatic Neoplasms therapy, Prognosis, Survival Rate, Adenocarcinoma mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Pancreatic Ductal mortality, Chemotherapy, Adjuvant mortality, Neoplasm Recurrence, Local mortality, Pancreatectomy mortality, Pancreatic Neoplasms mortality
- Abstract
Background: Multimodality treatment (MMT) improves survival for patients with pancreatic ductal adenocarcinoma (PDAC). The surgery-first (SF) strategy is the most universally accepted approach., Material and Methods: Population-based retrospective cohort study of all cases of resectable PDAC from 2006 to 2012. Patients were planned for adjuvant chemotherapy (AC) with the Nordic 5-fluorouracil/leucovorin regimen. Reasons for and rates of failure to complete AC, postoperative major complications (PMC), and overall survival (OS) were analysed., Results: Of 203 patients, 85 (41.9%) completed AC, 41 (20.2%) failed to complete AC, and 77 (37.9%) never initiated AC. Primary reasons for not initiating or completing AC were early disease progression (34.7%), postoperative complications/poor performance status (32.2%), and age > 75 years (24.6%). Median OS in the whole cohort was 17.0 months, and 20.0 months in patients who initiated AC. Median OS in patients who completed AC was higher than in patients who did not (25.0 months vs. 12.0 months, p < 0.001). PMC (n = 41) were associated with decreased initiation rate (p < 0.001) and completion rate (p = 0.007) of AC, and decreased median OS (11.0 months vs. 19.0 months, p = 0.028). Among patients with R1 resection, PMC again were associated with worse median OS (8.0 months vs. 16.0 months, p = 0.028). Multivariate analysis demonstrated that completion of MMT and tumour grade (G1/G2) were related to mortality rate (p < 0.001). Mortality risk for patients who completed AC was reduced also when adjusting for competing risk (SHR 0.426, p < 0.001)., Conclusions: MMT completion is strongly associated with reduced mortality risk in patients with resectable PDAC undergoing the SF approach. Early disease progression and PMC/poor performance status preclude MMT completion in more than one third of the patients. These reasons for failure to complete MMT underscore the need for strategies to improve patient selection and reduce surgical morbidity in patients with resectable PDAC.
- Published
- 2016
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37. Increased Serum Levels of LIGHT/TNFSF14 in Nonalcoholic Fatty Liver Disease: Possible Role in Hepatic Inflammation.
- Author
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Otterdal K, Haukeland JW, Yndestad A, Dahl TB, Holm S, Segers FM, Gladhaug IP, Konopski Z, Damås JK, Halvorsen B, and Aukrust P
- Abstract
Objectives: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism. We hypothesized that LIGHT could also have a pathogenic role in nonalcoholic fatty liver disease (NAFLD)., Methods: Serum levels of LIGHT in NAFLD patients and control subjects, as well as LIGHT and interleukin (IL)-8 released from Huh7 (human hepatoma cell line) hepatocytes, were determined by enzyme-linked immunosorbent assay. The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR., Results: (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes., Conclusion: We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction. Our findings should encourage further studies on the role of LIGHT in NAFLD development and progression.
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- 2015
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38. Information needs among patients and a surveillance strategy after surgery for pancreatic and periampullary cancer.
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Labori KJ, Verbeke CS, and Gladhaug IP
- Subjects
- Female, Humans, Male, Adenocarcinoma surgery, Attitude of Health Personnel, Clinical Competence, Duodenal Neoplasms surgery, Pancreatectomy standards, Pancreatic Neoplasms surgery, Qualitative Research
- Published
- 2015
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39. The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers.
- Author
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Vedeld HM, Andresen K, Eilertsen IA, Nesbakken A, Seruca R, Gladhaug IP, Thiis-Evensen E, Rognum TO, Boberg KM, and Lind GE
- Subjects
- Adult, Aged, Aged, 80 and over, Area Under Curve, Bile Duct Neoplasms genetics, Bile Duct Neoplasms metabolism, Bile Ducts, Intrahepatic metabolism, Biomarkers, Tumor metabolism, Case-Control Studies, Cell Line, Tumor, Cholangiocarcinoma genetics, Cholangiocarcinoma metabolism, Colorectal Neoplasms metabolism, Cysteine Dioxygenase metabolism, DNA-Binding Proteins metabolism, Gene Expression, Humans, Middle Aged, Neoplasm Proteins metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Promoter Regions, Genetic, ROC Curve, Sequence Analysis, DNA, Stomach Neoplasms genetics, Stomach Neoplasms metabolism, Young Adult, Biomarkers, Tumor genetics, Colorectal Neoplasms genetics, Cysteine Dioxygenase genetics, DNA Methylation, DNA-Binding Proteins genetics, Neoplasm Proteins genetics
- Abstract
We have previously shown that gastrointestinal cancers display similar epigenetic aberrations. In a recent study, we identified frequently methylated genes for cholangiocarcinoma (CDO1, DCLK1, SFRP1 and ZSCAN18), where one of these genes, DCLK1, was also confirmed to be highly methylated in colorectal cancer. The aim of the present study was to determine whether these four genes, in addition to one gene found to be methylated in colon cancer cell lines (ZNF331), are commonly methylated across gastrointestinal malignancies, as well as explore their role as potential biomarkers. Quantitative methylation specific PCR (qMSP) of colorectal cancer (n=164) and normal colorectal mucosa (n=106) samples showed that all genes were frequently methylated in colorectal cancer (71-92%) with little or no methylation in normal mucosa (0-3%). Methylation of minimum two of these five genes identified 95% of the tumors with a specificity of 98%, and an area under the receiver operating characteristics curve (AUC) of 0.98. For gastric (n=25) and pancreatic (n=20) cancer, the same panel detected 92% and 90% of the tumors, respectively. Seventy-four cancer cell lines were further analyzed by qMSP and real time RT-PCR. In addition to the previously reported DCLK1, a high negative correlation between promoter DNA methylation and gene expression was observed for CDO1, ZNF331 and ZSCAN18. In conclusion, the high methylation frequency of these genes in colorectal- as well as in gastric-, pancreatic- and bile duct cancer confirmed an epigenetic similarity between gastrointestinal cancer types, and simultaneously demonstrated their potential as biomarkers, particularly for colorectal cancer detection., (© 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.)
- Published
- 2015
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40. Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: a systematic review and meta-analysis.
- Author
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Haugvik SP, Hedenström P, Korsæth E, Valente R, Hayes A, Siuka D, Maisonneuve P, Gladhaug IP, Lindkvist B, and Capurso G
- Subjects
- Europe epidemiology, Humans, North America epidemiology, Risk Factors, Alcohol Drinking epidemiology, Diabetes Mellitus epidemiology, Neuroendocrine Tumors epidemiology, Pancreatic Neoplasms epidemiology, Smoking epidemiology
- Abstract
Background and Aims: Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs., Methods: MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement., Results: Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I(2) = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I(2) = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I(2) = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I(2) = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I(2) = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I(2) = 0.0%) for first-degree family history of cancer., Conclusions: Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET., (© 2015 S. Karger AG, Basel.)
- Published
- 2015
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41. Laparoscopic versus open pancreas resection for neuroendocrine tumours: need for evaluation of oncological outcomes.
- Author
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Haugvik SP, Gaujoux S, Røsok B, Gladhaug IP, Dousset B, and Edwin B
- Subjects
- Humans, Laparoscopy, Neuroendocrine Tumors surgery, Pancreatectomy methods, Pancreatic Neoplasms surgery
- Published
- 2014
- Full Text
- View/download PDF
42. Loss of 11p11 is a frequent and early event in sporadic nonfunctioning pancreatic neuroendocrine neoplasms.
- Author
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Haugvik SP, Gorunova L, Haugom L, Eibak AM, Gladhaug IP, Heim S, and Micci F
- Subjects
- Adult, Aged, Chromosome Deletion, Cytogenetic Analysis, DNA Copy Number Variations, Female, Genome, Human, Humans, Male, Middle Aged, Chromosomes, Human, Pair 11 genetics, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology
- Abstract
The pathogenesis of sporadic pancreatic neuroendocrine neoplasms (PNENs) is poorly understood. To gain insight into the genetic mechanisms underlying this tumor entity, we performed genome-wide screening of 16 surgical specimens from 15 patients with sporadic PNEN, combining G-band karyotyping and high resolution comparative genomic hybridization (HR-CGH). G-banding revealed abnormal karyotypes in 2 of 10 tumor samples analyzed. DNA copy number changes were detected in 13 samples, whereas three tumors showed a balanced genome. Gains were more frequent than losses in the nonfunctioning tumors (n=13). Common gains were scored at 5p12-13, 4q13-24, 5p15, 5q11-31, and 9q21-22. Common losses were scored at 11p11, 11p14-15, 11q23, 11p12-13, and 11q22. The average number of copy aberrations (ANCA index) was 12 for 13 nonfunctioning primary tumors, 4.8 for the nonfunctioning tumors with low Ki-67 (≥5%), 21.2 for the tumors with high Ki-67 (<5%), 2.5 for small tumors (<3.5 cm), and 17.8 for large tumors (≥3.5 cm). There was a statistically significant difference in the ANCA index between the groups defined by Ki-67 and tumor size. Nonfunctioning tumors with low Ki-67, no distant metastasis and small size had few aberrations detected by HR-CGH, but frequent loss of material from chromosomal band 11p11. The present study indicates the existence of distinct cytogenetic patterns in sporadic nonfunctioning PNEN. Loss of chromosomal band 11p11 might indicate a primary pathogenetic event in these tumors.
- Published
- 2014
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- View/download PDF
43. COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis.
- Author
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Pomianowska E, Schjølberg AR, Clausen OP, and Gladhaug IP
- Subjects
- Adenocarcinoma diagnosis, Adenocarcinoma surgery, Adult, Aged, Aged, 80 and over, Common Bile Duct Neoplasms genetics, Common Bile Duct Neoplasms mortality, Cyclooxygenase 2 metabolism, Female, Gene Expression, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms surgery, Prognosis, Tumor Burden, Adenocarcinoma genetics, Adenocarcinoma mortality, Cyclooxygenase 2 genetics, Pancreatic Neoplasms genetics, Pancreatic Neoplasms mortality
- Abstract
Background: Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas., Methods: The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed., Results: COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model., Conclusions: COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis.
- Published
- 2014
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44. Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma.
- Author
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Pomianowska E, Sandnes D, Grzyb K, Schjølberg AR, Aasrum M, Tveteraas IH, Tjomsland V, Christoffersen T, and Gladhaug IP
- Subjects
- Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, DNA Replication drug effects, Gene Expression, Humans, Immunohistochemistry, Pancreatic Neoplasms genetics, Collagen biosynthesis, Dinoprostone pharmacology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Pancreatic Stellate Cells drug effects, Pancreatic Stellate Cells metabolism
- Abstract
Background: Several studies have described an increased cyclooxygenase-2 (COX-2) expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis., Methods: Immunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin (αSMA). Pancreatic stellate cells (PSC) were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by [(3)H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [(3)H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR., Results: Immunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β (IL-1β), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-β1 (TGFβ). Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase (ERK). Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis., Conclusions: The present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors.
- Published
- 2014
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45. Pancreatic surgery with vascular reconstruction in patients with locally advanced pancreatic neuroendocrine tumors.
- Author
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Haugvik SP, Labori KJ, Waage A, Line PD, Mathisen Ø, and Gladhaug IP
- Subjects
- Aged, Feasibility Studies, Humans, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Neuroendocrine Tumors pathology, Pancreatic Neoplasms pathology, Retrospective Studies, Treatment Outcome, Vascular Neoplasms pathology, Vascular Surgical Procedures, Neuroendocrine Tumors surgery, Pancreatectomy methods, Pancreatic Neoplasms surgery, Vascular Neoplasms surgery
- Abstract
Introduction: Pancreatic neuroendocrine tumors (PNET) are rare neoplasms with better prognosis than most pancreatic malignancies. Surgery of locally advanced PNET remains controversial, and the role of vascular reconstruction in this patient group has yet to be defined. The aim of this study was to evaluate the feasibility and outcome of pancreatic resections with vascular reconstruction in patients with locally advanced PNET., Methods: Retrospective analysis of patients who underwent pancreatic surgery with vascular reconstruction for locally advanced PNET at a single institution. Furthermore, a review of the relevant literature on the topic was performed., Results: Seven patients who had undergone vascular reconstruction for locally advanced PNET were identified. Four patients had liver metastases at time of surgery. Postoperative complications developed in four patients with no mortality. Median follow-up time of all patients was 21 (range, 3-58) months. Three patients had disease in remission after 58, 42 and 3 months, respectively. One patient died 35 months postoperatively due to progressive disease, whereas three patients had progression of disease after 21, 9, and 4 months postoperatively., Conclusion: Pancreatic surgery with vascular reconstruction in patients with locally advanced PNET is feasible with acceptable outcome.
- Published
- 2013
- Full Text
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46. Liver transplantation for nonresectable liver metastases from colorectal cancer.
- Author
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Hagness M, Foss A, Line PD, Scholz T, Jørgensen PF, Fosby B, Boberg KM, Mathisen O, Gladhaug IP, Egge TS, Solberg S, Hausken J, and Dueland S
- Subjects
- Aged, Antineoplastic Agents therapeutic use, Chemotherapy, Adjuvant, Colorectal Neoplasms mortality, Female, Follow-Up Studies, Humans, Liver Neoplasms drug therapy, Liver Neoplasms mortality, Lung Neoplasms secondary, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Recurrence, Local, Pilot Projects, Prospective Studies, Survival Analysis, Treatment Outcome, Colorectal Neoplasms pathology, Liver Neoplasms secondary, Liver Neoplasms surgery, Liver Transplantation
- Abstract
Objective: The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs)., Background: Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5-year survival rate of about 50% after liver transplantation for CLMs could be anticipated., Methods: In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy., Results: Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8-60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors., Conclusions: OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453).
- Published
- 2013
- Full Text
- View/download PDF
47. Long-term outcome of laparoscopic surgery for pancreatic neuroendocrine tumors.
- Author
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Haugvik SP, Marangos IP, Røsok BI, Pomianowska E, Gladhaug IP, Mathisen O, and Edwin B
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Confidence Intervals, Disease-Free Survival, Female, Follow-Up Studies, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Laparoscopy mortality, Male, Middle Aged, Multivariate Analysis, Neoplasm Invasiveness pathology, Neoplasm Staging, Neuroendocrine Tumors pathology, Norway, Pancreatectomy mortality, Pancreatic Neoplasms pathology, Retrospective Studies, Risk Assessment, Splenectomy methods, Splenectomy mortality, Survival Analysis, Time Factors, Treatment Outcome, Young Adult, Laparoscopy methods, Neuroendocrine Tumors mortality, Neuroendocrine Tumors surgery, Pancreatectomy methods, Pancreatic Neoplasms mortality, Pancreatic Neoplasms surgery
- Abstract
Background: As most pancreatic neuroendocrine tumors (PNET) are relatively small and solitary, they may be considered well suited for removal by a minimally invasive approach. There are few large series that describe laparoscopic surgery for PNET. The primary aim of this study was to describe the feasibility, outcome, and histopathology associated with laparoscopic pancreatic surgery (LS) of PNET in a large series., Methods: All patients with PNET who underwent LS at a single hospital from March 1997 to April 2011 were included retrospectively in the study., Results: A total of 72 patients with PNET underwent 75 laparoscopic procedures, out of which 65 were laparoscopic resections or enucleations. The median operative time of all patients who underwent resections or enucleations was 175 (60-520) min, the median blood loss was 300 (5-2700) ml, and the median length of hospital stay was 7 (2-27) days. The overall morbidity rate was 42%, with a surgical morbidity rate of 21% and postoperative pancreatic fistula (POPF) formation in 21%. Laparoscopic enucleations were associated with a higher rate of POPF than were laparoscopic resections. Five-year disease-specific survival rate was 90%. The T stage, R stage, and a Ki-67 cutoff value of 5% significantly predicted 5-year survival., Conclusion: LS of PNET is feasible with acceptable morbidity and a good overall disease-specific long-term prognosis.
- Published
- 2013
- Full Text
- View/download PDF
48. Intestinal-type and pancreatobiliary-type adenocarcinomas: how does ampullary carcinoma differ from other periampullary malignancies?
- Author
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Westgaard A, Pomianowska E, Clausen OP, and Gladhaug IP
- Subjects
- Aged, Ampulla of Vater surgery, Common Bile Duct Neoplasms mortality, Common Bile Duct Neoplasms surgery, Duodenal Neoplasms mortality, Duodenal Neoplasms surgery, Female, Follow-Up Studies, Humans, Intestinal Neoplasms mortality, Intestinal Neoplasms surgery, Lymphatic Metastasis, Male, Neoplasm Staging, Pancreatic Neoplasms mortality, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy, Prognosis, Survival Rate, Ampulla of Vater pathology, Cell Differentiation, Common Bile Duct Neoplasms pathology, Duodenal Neoplasms pathology, Intestinal Neoplasms pathology, Pancreatic Neoplasms pathology
- Abstract
Background: Ampullary carcinomas typically have either intestinal or pancreatobiliary type of differentiation, histopathologically resembling carcinomas of its adjacent tissues (duodenum, bile duct, or pancreas). We evaluated whether the histologic type itself is more important for long-term survival than the fact that the tumor originated in the ampulla., Methods: Microscopic slides from 207 consecutive pancreatoduodenectomies were reviewed (72 pancreatic, 46 biliary, 61 ampullary, and 28 duodenal adenocarcinomas; 76 intestinal type, 131 pancreatobiliary type). Tumor size, nodal involvement, margin involvement, degree of differentiation, vascular involvement, and perineural growth, as well as overall survival, were compared between different origins of the same histologic type., Results: Intestinal-type ampullary adenocarcinomas had similar frequency of poor histopathologic factors compared to duodenal adenocarcinomas, and pancreatobiliary-type ampullary adenocarcinomas had similar frequency of poor histopathologic factors compared to pancreatobiliary-type biliary and pancreatic adenocarcinomas. Adjusting for tumor size and nodal involvement, there was no difference in long-term survival between patients with intestinal-type ampullary, duodenal, or biliary and pancreatic tumors (p = 0.79), and there was no difference in long-term survival between patients with pancreatobiliary-type ampullary, biliary, or pancreatic tumors (p = 0.41)., Conclusions: Long-term survival for patients with ampullary carcinomas equals pancreatic, biliary, and duodenal carcinomas when the same histologic type is compared. It can be questioned whether ampullary carcinomas should be regarded as a separate entity in classification of solid tumors. Clinical trials on adjuvant treatments for periampullary carcinomas should stratify by pancreatobiliary type versus intestinal type of histologic differentiation.
- Published
- 2013
- Full Text
- View/download PDF
49. Prognostic relevance of number and ratio of metastatic lymph nodes in resected pancreatic, ampullary, and distal bile duct carcinomas.
- Author
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Pomianowska E, Westgaard A, Mathisen Ø, Clausen OP, and Gladhaug IP
- Subjects
- Adenocarcinoma surgery, Adult, Aged, Aged, 80 and over, Bile Duct Neoplasms pathology, Bile Duct Neoplasms surgery, Common Bile Duct Neoplasms surgery, Confidence Intervals, Female, Humans, Kaplan-Meier Estimate, Lymph Node Excision, Lymphatic Metastasis, Male, Middle Aged, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Retrospective Studies, Adenocarcinoma secondary, Ampulla of Vater, Common Bile Duct Neoplasms pathology, Lymph Nodes pathology, Pancreatic Neoplasms pathology
- Abstract
Background: Lymph node ratio (LNR) may be more useful than nodal (N) status in prognostic subclassification of adenocarcinomas after pancreatoduodenectomy. Ampullary (AC), biliary (DBC), and pancreatic (PC) adenocarcinomas are biologically distinct, and nodal involvement may have different prognostic importance among these separate cancers., Methods: We included 179 consecutive pancreatoduodenectomies for PC, AC, or DBC, and performed standardized histopathologic evaluation, including prospective registration and retrospective reevaluation of the cancer origin. Associations between histopathologic variables and LNR, N status, and number of metastatic nodes were evaluated. Unadjusted and adjusted survival analysis was performed., Results: Overall 5 year survival was 6% for PC (n=72), 26% for DBC (n=46), and 46% for AC (n=61). Lymph node involvement was more frequent in PC (75%) than in AC (48%) and DBC (57%). In PC, N status did not discriminate between prognostic groups (N1 vs. N0; p=0.31). However, increasing LNR was associated with poorer survival in unadjusted analysis, as well as when adjusting for margin involvement, degree of differentiation, and tumor diameter (p=0.032; hazard ratio 1.87, 95% confidence interval 1.06-3.31). In AC and DBC, N status clearly discriminated between subgroups of patients with different long-term survival in unadjusted and adjusted survival analysis (N1 vs. N0; p<0.001), whereas number of metastatic nodes and LNR did not predict survival among node-positive resections., Conclusions: The predictive value of nodal involvement depends on the type of cancer within the pancreatic head. In AC and DBC, N status adequately discriminates between good and poor prognosis. In PC, LNR may be more powerful in prognostic subclassification.
- Published
- 2013
- Full Text
- View/download PDF
50. Authors' reply: Resection margin involvement and tumour origin in pancreatic head cancer (Br J Surg 2012; 99: 1036-1049).
- Author
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Verbeke CS and Gladhaug IP
- Subjects
- Humans, Bile Duct Neoplasms surgery, Pancreatic Neoplasms surgery
- Published
- 2013
- Full Text
- View/download PDF
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