Ivar Prydz Gladhaug

• Amrutkar, Manoj; Vefferstad, Anette; Labori, Knut Jørgen; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2026). Proteomic characterization of primary pancreatic fibroblasts derived from neoadjuvant chemotherapy treated versus treatment-naïve PDAC. Journal of Proteomics. ISSN 1874-3919. 328. doi: 10.1016/j.jprot.2026.105660. Full text in Research Archive
• Amrutkar, Manoj; Guttorm, Sander Johannes Thorbjørnsen; Labori, Knut Jørgen; Rootwelt, Helge; Elgstøen, Katja B. Prestø & Gladhaug, Ivar Prydz [Show all 7 contributors for this article] (2026). Reduced lipid metabolite abundance in human pancreatic cancer and matched serum samples following neoadjuvant FOLFIRINOX treatment | Metabolomics | Springer Nature Link. Metabolomics. ISSN 1573-3882. 22. doi: 10.1007/s11306-025-02388-z. Full text in Research Archive Show summary

  Introduction Exploiting the full potential of neoadjuvant treatment (NAT) in pancreatic ductal adenocarcinoma (PDAC) is hampered by the lack of biomarkers for treatment response. Dysregulated lipid metabolism has been suggested to promote PDAC growth and resistance to therapy. Objectives To investigate lipid metabolic changes in PDAC following NAT. Methods Cross-sectional study of mass spectrometry-based global lipidomic profiling of tumour tissue (n = 35) and paired serum samples (n = 35) from treatment-naïve (TN; n = 18) and neoadjuvant FOLFIRINOX-treated (NAT; n = 17) PDAC patients was conducted. Pre- and post-treatment CA 19–9 levels were available from 15 NAT patients. Differentially abundant lipids (DALs) in NAT versus TN were assessed for correlation with various clinical parameters and the performance of all serum DALs to distinguish NAT from TN samples was explored using receiver operating characteristic analysis. Results A total of 40 tissue and 35 serum DALs were identified, which mainly belonged to glycerophospholipids and sphingolipids in tissue and glycerolipids, glycerophospholipids, and fatty acyls in serum. All 19 serum glycerolipids were less abundant in NAT and 18 of these were triacylglycerols. The abundance of 26 tissue and 11 serum DALs correlated moderately with % reduction in serum CA 19–9 following NAT. The top five of 23 serum DALs with moderate discriminatory potential (AUC = 0.66–0.87) ‒ PI(18:0_20:3), AcCa(13:0), PC(O-42:6), TG(49:6), TG(66:14), performed better together (AUC = 0.93 and 95% CI = 0.79‒1) and combined with CA 19–9 (AUC = 0.99 and 95% CI = 0.81‒1). Conclusions Both tumour tissue and serum samples from PDAC patients showed lower abundance of lipid metabolites following neoadjuvant FOLFIRINOX treatment. Moreover, a biomarker panel of CA 19–9 together with five serum DALs could potentially be used to assess NAT response in PDAC but requires further validation.

• Amrutkar, Manoj; Li, Yuchuan; Vefferstad, Anette; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2025). Proteomic Characterization of Primary Human Pancreatic Cancer Cell Lines Following Long-Term Exposure to Gemcitabine. Proteomes. 13(4), p. 1–22. doi: 10.3390/proteomes13040048. Full text in Research Archive Show summary

  Background: Gemcitabine (GEM) remains a cornerstone in the treatment of pancreatic cancer. Upon exposure to GEM, pancreatic cancer cells (PCCs) tend to adapt quickly to outcompete drug-induced cytotoxicity, thereby contributing to treatment failure. Thus, understanding GEM-induced molecular changes in PCCs is important. Methods: Three primary PCC lines (PCC-1, PCC-2, PCC-7) and Mia PaCa-2 cultured for 40 passages (p) in the absence (control) or presence of GEM (GemR) were assessed for phenotypic changes. Proteome profiles for all PCCs at p10, p20, p25, p30, p35, and p40 were obtained using mass spectrometry (MS). Protein expression was determined using immunoblotting. Differentially abundant proteins (DAPs) were evaluated for enrichment of functional and biological attributes and protein–protein interactions. Results: GEM sensitivity and growth were both reduced in GemR versus paired controls for all four PCC lines. MS mapped > 7000 proteins in each PCC line, and the abundance of 70–83% of these was found to be significantly altered when comparing all sample groups. Proteomic changes in GemR versus paired controls differed remarkably among the PCCs and were affected by passaging and treatment duration. DAPs at p40 were mostly related to metabolic pathways, including nucleotide metabolism and diverse cell growth processes. Several closely related DAPs and multiple hub proteins in each PCC line were identified. Conclusions: Overall, this study revealed cell-line-specific, heterogeneous changes in proteome profiles of PCCs following their long-term exposure to GEM, and these were likely affected by treatment duration, dosage, and passaging.

• Amrutkar, Manoj; Guttorm, Sander; Vefferstad, Anette; Labori, Knut Jørgen; Eide, Lars & Rootwelt, Helge [Show all 9 contributors for this article] (2024). Global metabolomic profiling of tumor tissue and paired serum samples to identify biomarkers for response to neoadjuvant FOLFIRINOX treatment of human pancreatic cancer. Molecular Oncology. ISSN 1574-7891. 19(2), p. 391–411. doi: 10.1002/1878-0261.13759. Full text in Research Archive Show summary

  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.

• Yakub, Sheraz; Røsok, Bård Ingvald; Gladhaug, Ivar Prydz & Labori, Knut Jørgen (2024). Pancreatic duct occlusion with polychloroprene-based glue for the management of postoperative pancreatic fistula after pancreatoduodenectomy—an outdated approach? Frontiers in Surgery. 11. doi: 10.3389/fsurg.2024.1386708. Full text in Research Archive Show summary

  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.

• Amrutkar, Manoj; Berg, Kjersti; Balto, Aina; Skilbrei, Miguel Garcia; Finstadsveen, Anette Vefferstad & Aasrum, Monica [Show all 8 contributors for this article] (2023). Pancreatic stellate cell-induced gemcitabine resistance in pancreatic cancer is associated with LDHA- and MCT4-mediated enhanced glycolysis. Cancer Cell International. 23, p. 1–17. doi: 10.1186/s12935-023-02852-7. Full text in Research Archive Show summary

  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.

• Li, Yuchuan; Amrutkar, Manoj; Finstadsveen, Anette V.; Dalen, Knut Tomas; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2023). Fatty acids abrogate the growth-suppressive effects induced by inhibition of cholesterol flux in pancreatic cancer cells. Cancer Cell International. 23. doi: 10.1186/s12935-023-03138-8. Full text in Research Archive Show summary

  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.

• Amrutkar, Manoj; Verbeke, Caroline Sophie; Vefferstad, Anette; Dorg, Linda Trobe; Labori, Knut Jørgen & Gladhaug, Ivar Prydz (2022). Neoadjuvant chemotherapy is associated with an altered metabolic profile and increased cancer stemness in patients with pancreatic ductal adenocarcinoma. Molecular Oncology. ISSN 1574-7891. 17(1), p. 59–81. doi: 10.1002/1878-0261.13344. Full text in Research Archive Show summary

  he 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.

• Amrutkar, Manoj & Gladhaug, Ivar Prydz (2021). Stellate cells aid growth‐permissive metabolic reprogramming and promote gemcitabine chemoresistance in pancreatic cancer. Cancers. 13:601(4), p. 1–21. doi: 10.3390/cancers13040601. Full text in Research Archive Show summary

  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.

• Santha, Petra; Lenggenhager, Daniela; Vefferstad, Anette; Dorg, Linda Trobe; Tøndel, Kristin & Amrutkar, Manoj [Show all 8 contributors for this article] (2021). Morphological heterogeneity in pancreatic cancer reflects structural and functional divergence. Cancers. 13(4). doi: 10.3390/cancers13040895. Full text in Research Archive Show summary

  Pancreatic cancer has a poor prognosis, which is largely due to resistance to treatment. Tumor heterogeneity is a known cause for treatment failure and has been studied at the molecular level. Morphological heterogeneity is common but has not been investigated, despite the fact that pathology examination is an integral part of clinical diagnostics. This study assessed whether morphological heterogeneity reflects structural and functional diversity in key cancer biological processes. Using archival tissues from resected pancreatic cancer, we selected four common and distinct morphological phenotypes and demonstrated that these differed significantly for a panel of 26 structural and functional features of the cancer-cell and stromal compartments. The strong link between these features and morphological phenotypes allowed prediction of the latter based on the results for the panel of features. The findings of this study indicate that morphological heterogeneity reflects biological diversity and that its assessment may potentially provide clinically relevant information.

• Amrutkar, Manoj; Vethe, Nils Tore; Verbeke, Caroline Sophie; Aasrum, Monica; Vefferstad, Anette & Santha, Petra [Show all 7 contributors for this article] (2020). Differential gemcitabine sensitivity in primary human pancreatic cancer cells and paired stellate cells is driven by heterogenous drug uptake and processing. Cancers. 12:3628(12), p. 1–18. doi: 10.3390/cancers12123628. Full text in Research Archive Show summary

  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.

• Engebretsen, Eivind & Gladhaug, Ivar Prydz (2020). Er det plass til et sykepleievitenskapelig fagmiljø på et medisinsk fakultet? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(9), p. 1–3. doi: 10.4045/tidsskr.20.0311. Full text in Research Archive
• Amrutkar, Manoj; Larsen, Emma Kristine; Aasrum, Monica; Finstadsveen, Anette Vefferstad; Andresen, Per Arne & Verbeke, Caroline Sophie [Show all 7 contributors for this article] (2020). Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor. Cells. 9:227(1), p. 1–18. doi: 10.3390/cells9010227. Full text in Research Archive Show summary

  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.

• Amrutkar, Manoj; Aasrum, Monica; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2019). Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells. BMC Cancer. 19(596). doi: 10.1186/s12885-019-5803-1. Full text in Research Archive Show summary

  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.

• Kleive, Dyre; Labori, Knut Jørgen; Line, Pål Dag; Gladhaug, Ivar Prydz & Verbeke, Caroline Sophie (2019). Pancreatoduodenectomy with venous resection for ductal adenocarcinoma rarely achieves complete (R0) resection. HPB. ISSN 1365-182X. 22(1), p. 50–57. doi: 10.1016/j.hpb.2019.05.005. Full text in Research Archive Show summary

  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.

• Lothe, Inger Marie Bowitz; Kleive, Dyre; Pomianowska, Ewa; Småstuen, Milada Cvancarova; Kure, Elin Wenche Hegland & Dueland, Svein [Show all 8 contributors for this article] (2019). Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy. Pancreatology (Print). ISSN 1424-3903. 19(2), p. 316–324. doi: 10.1016/j.pan.2019.01.019. Full text in Research Archive Show summary

  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.

• Lenggenhager, Daniela; Amrutkar, Manoj; Santha, Petra; Aasrum, Monica; Löhr, Johannes-Matthias & Gladhaug, Ivar Prydz [Show all 7 contributors for this article] (2019). Commonly Used Pancreatic Stellate Cell Cultures Differ Phenotypically and in Their Interactions With Pancreatic Cancer Cells. Cells. 8:E23(1), p. 1–18. doi: 10.3390/cells8010023. Full text in Research Archive Show summary

  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.

• Kleive, Dyre; Sahakyan, Mushegh; Søreide, Kjetil; Brudvik, Kristoffer Watten; Line, Pål Dag & Gladhaug, Ivar Prydz [Show all 7 contributors for this article] (2018). Risk for hemorrhage after pancreatoduodenectomy with venous resection. Langenbeck's Archives of Surgery. ISSN 1435-2443. p. 1–9. doi: 10.1007/s00423-018-1721-y. Full text in Research Archive
• Kleive, Dyre; Berstad, Audun Elnæs; Sahakyan, Mushegh; Verbeke, Caroline Sophie; Naper, Christian & Haugvik, Sven-Petter [Show all 9 contributors for this article] (2017). Portal vein reconstruction using primary anastomosis or venous interposition allograft in pancreatic surgery. Journal of Vascular Surgery: Venous and Lymphatic Disorders (JVS-VL). ISSN 2213-333X. 6(1), p. 66–74. doi: 10.1016/j.jvsv.2017.09.003. Full text in Research Archive
• Haugvik, Sven-Petter; Basim, Ibrahim; Hedenström, Per; Valente, Roberto; Hayes, Alastair J. & Siuka, Darko [Show all 8 contributors for this article] (2017). Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 52(8), p. 797–802. doi: 10.1080/00365521.2017.1310290. Full text in Research Archive
• Amrutkar, Manoj & Gladhaug, Ivar Prydz (2017). Pancreatic cancer chemoresistance to gemcitabine. Cancers. 9(11:157), p. 1–23. doi: 10.3390/cancers9110157. Full text in Research Archive
• Tjomsland, Vegard; Aasrum, Monica; Christoffersen, Thoralf & Gladhaug, Ivar Prydz (2017). Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells. OncoTarget. 8(42), p. 71672–71684. doi: 10.18632/oncotarget.17800. Full text in Research Archive
• Kleive, Dyre; Sahakyan, Mushegh; Berstad, Audun Elnæs; Verbeke, Caroline Sophie; Gladhaug, Ivar Prydz & Edwin, Bjørn [Show all 9 contributors for this article] (2017). Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy. British Journal of Surgery. ISSN 0007-1323. 104(11), p. 1558–1567. doi: 10.1002/bjs.10603. Full text in Research Archive
• Haugvik, Sven-Petter; Kaemmerer, Daniel; Gaujoux, Sebastien; Labori, Knut Jørgen; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2016). Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape. Current Oncology Reports. ISSN 1523-3790. 18(5). doi: 10.1007/s11912-016-0518-9. Full text in Research Archive
• Haugvik, Sven-Petter; Vodak, Daniel; Haugom, Lisbeth; Hovig, Johannes Eivind; Gladhaug, Ivar Prydz & Heim, Sverre [Show all 7 contributors for this article] (2016). Transcriptomic Profiling of Tumor Aggressiveness in Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms. Pancreas. ISSN 0885-3177. 45(8), p. 1196–1203. doi: 10.1097/MPA.0000000000000610. Full text in Research Archive
• Labori, Knut Jørgen; H, Katz Matthew; Tzeng, Ching; Bjørnbeth, Bjørn Atle; Småstuen, Milada Cvancarova & Edwin, Bjørn [Show all 11 contributors for this article] (2016). 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. Acta Oncologica. ISSN 0284-186X. 55(3), p. 265–277. doi: 10.3109/0284186X.2015.1068445. Full text in Research Archive
• Tjomsland, Vegard; Pomianowska, Ewa; Aasrum, Monica; Sandnes, Dagny Lise; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2016). Profile of MMP and TIMP expression in human pancreatic stellate cells: regulation by IL-1? and TGF? and implications for migration of pancreatic cancer cells. Neoplasia. ISSN 1522-8002. 18(7), p. 447–456. doi: 10.1016/j.neo.2016.06.003. Full text in Research Archive
• Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2016). Dissection of Pancreatic Resection Specimens. Surgical Pathology Clinics. ISSN 1875-9181. 9(4), p. 523–538. doi: 10.1016/j.path.2016.05.001. Full text in Research Archive
• Kleive, Dyre; Berstad, Audun Elnæs; Verbeke, Caroline Sophie; Haugvik, Sven-Petter; Gladhaug, Ivar Prydz & Line, Pål Dag [Show all 7 contributors for this article] (2016). Cold-stored cadaveric venous allograft for superior mesenteric/portal vein reconstruction during pancreatic surgery. HPB. ISSN 1365-182X. 18(7), p. 615–622. doi: 10.1016/j.hpb.2016.05.010. Full text in Research Archive Show summary

  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.

• Tjomsland, Vegard; Sandnes, Dagny Lise; Pomianowska, Ewa; Cizmovic, Smiljana Torbica; Aasrum, Monica & Brusevold, Ingvild Johnsen [Show all 8 contributors for this article] (2016). The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration. Journal of Experimental & Clinical Cancer Research. 35:122, p. 1–12. doi: 10.1186/s13046-016-0400-5. Full text in Research Archive Show summary

  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.

• Haugvik, Sven-Petter; Janson, Eva Tiensuu; Osterlund, Pia; Langer, Seppo W; Falk, Ragnhild Sørum & Labori, Knut Jørgen [Show all 10 contributors for this article] (2016). Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study. Annals of Surgical Oncology. ISSN 1068-9265. 23(5), p. 1721–1728. doi: 10.1245/s10434-015-5013-2. Full text in Research Archive
• Johannessen, Lene Elisabeth; Panagopoulos, Ioannis; Haugvik, Sven-Petter; Gladhaug, Ivar Prydz; Heim, Sverre & Micci, Francesca (2016). Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas. Oncology Reports. ISSN 1021-335X. 36(5), p. 2653–2662. doi: 10.3892/or.2016.5132. Full text in Research Archive
• Otterdal, Kari; Haukeland, John Willy; Yndestad, Arne; Dahl, Tuva Børresdatter; Holm, Sverre & Segers, Filip [Show all 11 contributors for this article] (2015). Increased serum levels of LIGHT/TNFSF14 in nonalcoholic fatty liver disease: Possible role in hepatic inflammation. Clinical and Translational Gastroenterology. 6:e95. doi: 10.1038/ctg.2015.23. Full text in Research Archive Show summary

  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.

• Haugvik, Sven-Petter; Hedenström, Per; Korsæth, Emilie; Valente, Roberto; Hayes, Alastair & Siuka, Darko [Show all 10 contributors for this article] (2015). Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: A systematic review and meta-analysis. Neuroendocrinology. ISSN 0028-3835. 101(2), p. 133–142. doi: 10.1159/000375164. Full text in Research Archive
• Pomianowska, Ewa; Schjølberg, Aasa Rambæk; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2014). COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis. BMC Cancer. 14458. doi: 10.1186/1471-2407-14-458. Full text in Research Archive Show summary

  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.

• Haugvik, Sven-Petter; Gorunova, Ludmila; Haugom, Lisbeth; Eibak, Anne Mette E.; Gladhaug, Ivar Prydz & Heim, Sverre [Show all 7 contributors for this article] (2014). Loss of 11p11 is a frequent and early event in sporadic nonfunctioning pancreatic neuroendocrine neoplasms. Oncology Reports. ISSN 1021-335X. p. 906–912. doi: 10.3892/or.2014.3328. Full text in Research Archive
• Pomianowska, Ewa; Sandnes, Dagny Lise; Grzyb, Krzysztof; Schjølberg, Aasa Rambæk; Aasrum, Monica & Tveteraas, Ingun Heiene [Show all 9 contributors for this article] (2014). Inhibitory effects of prostaglandin E&lt;sub&gt;2&lt;/sub&gt; on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer. 14(1). doi: 10.1186/1471-2407-14-413. Full text in Research Archive
• Vedeld, Hege Marie; Andresen, Kim; Eilertsen, Ina Andrassy; Nesbakken, Arild; Seruca, Raquel & Gladhaug, Ivar Prydz [Show all 10 contributors for this article] (2014). The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers. International Journal of Cancer. ISSN 0020-7136. 136(4), p. 844–853. doi: 10.1002/ijc.29039. Full text in Research Archive
• Hagness, Morten; Foss, Aksel; Line, Pål Dag; Scholz, Tim; Jørgensen, Pål Foyn & Fosby, Bjarte [Show all 13 contributors for this article] (2013). Liver Transplantation for Nonresectable Liver Metastases From Colorectal Cancer. Annals of Surgery. ISSN 0003-4932. 257(5), p. 800–806. doi: 10.1097/SLA.0b013e3182823957. Full text in Research Archive
• Haugvik, Sven-Petter; Labori, Knut Jørgen; Waage, Anne; Line, Pål Dag; Mathisen, Øystein & Gladhaug, Ivar Prydz (2013). Pancreatic Surgery with Vascular Reconstruction in Patients with Locally Advanced Pancreatic Neuroendocrine Tumors. Journal of Gastrointestinal Surgery. ISSN 1091-255X. 17(7), p. 1224–1232. doi: 10.1007/s11605-013-2221-6. Full text in Research Archive
• Pomianowska, Ewa; Westgaard, Arne; Mathisen, Øystein; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2013). Prognostic Relevance of Number and Ratio of Metastatic Lymph Nodes in Resected Pancreatic, Ampullary, and Distal Bile Duct Carcinomas. Annals of Surgical Oncology. ISSN 1068-9265. 20(1), p. 233–241. doi: 10.1245/s10434-012-2592-z. Full text in Research Archive
• Chiaro, Marco Del; Verbeke, Caroline Sophie; Salvia, Roberto; Klöppel, Gunter; Werner, Jens & McKay, Colin [Show all 39 contributors for this article] (2013). European experts consensus statement on cystic tumours of the pancreas. Digestive and Liver Disease. ISSN 1590-8658. 45(9), p. 703–711. doi: 10.1016/j.dld.2013.01.010. Full text in Research Archive
• Haugvik, Sven-Petter; Marangos, Irina Pavlik; Røsok, Bård Ingvald; Pomianowska, Ewa; Gladhaug, Ivar Prydz & Mathisen, Øystein [Show all 7 contributors for this article] (2013). Long-Term Outcome of Laparoscopic Surgery for Pancreatic Neuroendocrine Tumors. World Journal of Surgery. ISSN 0364-2313. 37(3), p. 582–590. doi: 10.1007/s00268-012-1893-5. Full text in Research Archive
• Westgaard, Arne; Pomianowska, Ewa; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2013). Intestinal-type and Pancreatobiliary-type Adenocarcinomas: How Does Ampullary Carcinoma Differ from Other Periampullary Malignancies? Annals of Surgical Oncology. ISSN 1068-9265. 20(2), p. 430–439. doi: 10.1245/s10434-012-2603-0. Full text in Research Archive
• Pomianowska, Ewa; Grzyb, Krzysztof; Westgaard, Arne; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2012). Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer. European Journal of Surgical Oncology. ISSN 0748-7983. 38(11), p. 1043–1050. doi: 10.1016/j.ejso.2012.07.113. Full text in Research Archive
• Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2012). Resection margin involvement and tumour origin in pancreatic head cancer. British Journal of Surgery. ISSN 0007-1323. 99(8), p. 1036–1049. doi: 10.1002/bjs.8734. Full text in Research Archive
• Haukeland, John Willy; Dahl, Tuva Børresdatter; Yndestad, Arne; Gladhaug, Ivar Prydz; Løberg, Else Marit & Haaland, Therese Kristina [Show all 13 contributors for this article] (2012). Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies. European Journal of Endocrinology (EJE). ISSN 0804-4643. 166(3), p. 503–510. doi: 10.1530/EJE-11-0864. Full text in Research Archive
• Marangos, Irina Pavlik; Buanes, Trond; Røsok, Bård Ingvald; Kazaryan, Airazat M.; Rosseland, Arne Retvedt & Grzyb, Krzysztof [Show all 10 contributors for this article] (2012). Laparoscopic resection of exocrine carcinoma in central and distal pancreas results in a high rate of radical resections and long postoperative survival. Surgery. ISSN 0039-6060. 151(5), p. 717–723. doi: 10.1016/j.surg.2011.12.016. Full text in Research Archive
• Haugvik, Sven-Petter; Labori, Knut Jørgen; Edwin, Bjørn; Mathisen, Øystein & Gladhaug, Ivar Prydz (2012). Surgical Treatment of Sporadic Pancreatic Neuroendocrine Tumors: A State of the Art Review. Scientific World Journal. Article ID 357475, p. 9–sider. doi: 10.1100/2012/357475. Full text in Research Archive
• Verbeke, Caroline Sophie; Knapp, Johannes & Gladhaug, Ivar Prydz (2011). Tumour growth is more dispersed in pancreatic head cancers than in rectal cancer: implications for resection margin assessment. Histopathology. ISSN 0309-0167. 59(6), p. 1111–1121. doi: 10.1111/j.1365-2559.2011.04056.x. Full text in Research Archive
• Weden, Synne L. S.; Klemp, Marianne; Gladhaug, Ivar Prydz; Møller, Mona; Eriksen, Jon Amund & Gaudernack, Gustav [Show all 7 contributors for this article] (2011). Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. International Journal of Cancer. ISSN 0020-7136. 128(5), p. 1120–1128. doi: 10.1002/ijc.25449. Full text in Research Archive
• Westgaard, Arne; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2011). Survival estimates after pancreatoduodenectomy skewed by non-standardized histopathology reports. APMIS - Journal of Pathologiy, Microbiology and Immunology. ISSN 0903-4641. 119(10), p. 689–700. doi: 10.1111/j.1600-0463.2011.02783.x. Full text in Research Archive
• Dahl, Tuva Børresdatter; Haukeland, John Willy; Yndestad, Arne; Ranheim, Trine; Gladhaug, Ivar Prydz & Damås, Jan Kristian [Show all 16 contributors for this article] (2010). Intracellular Nicotinamide Phosphoribosyltransferase Protects against Hepatocyte Apoptosis and Is Down-Regulated in Nonalcoholic Fatty Liver Disease. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 95(6), p. 3039–3047. doi: 10.1210/jc.2009-2148. Full text in Research Archive
• Gladhaug, Ivar Prydz; Westgaard, Arne; Schjølberg, Aasa Rambæk; Auensen, Espen; Pomianowska, Ewa & Clausen, Ole Petter Fraas (2010). Spindle proteins in resected pancreatic head adenocarcinomas: BubR1 is an independent prognostic factor in pancreatobiliary-type tumours. Histopathology. ISSN 0309-0167. 56(3), p. 345–355. doi: 10.1111/j.1365-2559.2010.03489.x. Full text in Research Archive
• Pomianowska, Ewa; Gladhaug, Ivar Prydz; Grzyb, Krzysztof; Røsok, Bård Ingvald; Edwin, Bjørn & Bergestuen, Deidi Ann [Show all 7 contributors for this article] (2010). Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 45(7-8), p. 971–979. doi: 10.3109/00365521003782363. Full text in Research Archive
• Westgaard, Arne; Larønningen, Siri; Mellem, Christine; Eide, Tor Jacob; Clausen, Ole Petter Fraas & Møller, Bjørn [Show all 7 contributors for this article] (2009). Are survival predictions reliable? Hospital volume versus standardisation of histopathologic reporting for accuracy of survival estimates after pancreatoduodenectomy for adenocarcinoma. European Journal of Cancer. ISSN 0959-8049. 45(16), p. 2850–2859. doi: 10.1016/j.ejca.2009.03.019. Full text in Research Archive
• Westgaard, Arne; Schjølberg, Aasa Rambæk; Cvancarova, Milada; Eide, Tor Jacob; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2009). Differentiation markers in pancreatic head adenocarcinomas: MUC1 and MUC4 expression indicates poor prognosis in pancreatobiliary differentiated tumours. Histopathology. ISSN 0309-0167. 54(3), p. 337–347. doi: 10.1111/j.1365-2559.2009.03227.x. Full text in Research Archive
• Westgaard, Arne; Tafjord, S; Farstad, IN; Cvancarova, M; Eide, TJ & Mathisen, O [Show all 8 contributors for this article] (2008). Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC Cancer. 8. doi: 10.1186/1471-2407-8-170. Full text in Research Archive Show summary

  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.

• Frich, Lars; Brabrand, Knut; Aaløkken, Trond Mogens; Edwin, Bjørn & Gladhaug, Ivar Prydz (2008). Radiofrekvensablasjon av kolorektale levermetastaser. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 128(1), p. 57–60. Full text in Research Archive
• Westgaard, Arne; Tafjord, S; Farstad, IN; Cvancarova, M; Eide, TJ & Mathisen, O [Show all 8 contributors for this article] (2008). Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor. BMC Cancer. 8. doi: 10.1186/1471-2407-8-5. Full text in Research Archive Show summary

  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.

• Frich, L; Halvorsen, PS; Skulstad, H; Damas, JK & Gladhaug, Ivar Prydz (2007). Microbubbles in the pulmonary artery generated during experimental hepatic radiofrequency increased ablation is correlated with pulmonary arterial pressure. Journal of Vascular and Interventional Radiology. ISSN 1051-0443. 18. doi: 10.1016/j.jvir.2006.12.010. Full text in Research Archive
• Frich, L; Hagen, G; Brabrand, K; Edwin, B; Mathisen, O & Aalokken, TM [Show all 7 contributors for this article] (2007). Local tumor progression after Radiofrequency ablation of colorectal liver metastases: Evaluation of ablative margin and three-dimensional volumetric analysis. Journal of Vascular and Interventional Radiology. ISSN 1051-0443. 18, p. 1134–1140. doi: 10.1016/j.jvir.2007.06.007. Full text in Research Archive
• Frich, L; Mala, T & Gladhaug, Ivar Prydz (2006). Hepatic radiofrequency ablation using perfusion electrodes in a pig model: Effect of the Pringle manoeuvre. European Journal of Surgical Oncology. ISSN 0748-7983. 32, p. 527–532. Full text in Research Archive
• Frich, Lars Inge; Bjørnland, Kristin; Pettersen, Solveig; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2006). Increased Activity of Matrix Metalloproteinase 2 and 9 After Hepatic Radiofrequency Ablation. Journal of Surgical Research. ISSN 0022-4804. p. 297–304. Full text in Research Archive
• Frich, Lars Inge; Hol, Per Kristian; Roy, Sumit; Mala, Tom; Edwin, Bjørn & Clausen, Ole Petter F. [Show all 7 contributors for this article] (2006). Experimental hepatic radiofrequency ablation using wet electrodes: electrode-to-vessel distance is a significant predictor for delayed portal vein thrombosis. European Radiology. ISSN 0938-7994. 16, p. 1990–1999. Full text in Research Archive
• Mala, Tom; Edwin, Bjørn; Rosseland, Arne Retvedt; Gladhaug, Ivar Prydz; Fosse, Erik & Mathisen, Øystein (2005). Laparoscopic liver resection: experience of 53 procedures at a single center. Journal of Hepato-Biliary-Pancreatic Surgery. ISSN 0944-1166. 12(4), p. 298–303. Full text in Research Archive
• Frich, Lars; Edwin, Bjørn; Brabrand, Knut; Rosseland, Arne Retvedt; Mala, Tom & Mathisen, Øystein [Show all 7 contributors for this article] (2005). Gastric perforation after percutaneous radiofrequency ablation of a colorectal liver metastasis in a patient with adhesions in the peritoneal cavity. American Journal of Roentgenology. ISSN 0361-803X. 184, p. 120–122. Full text in Research Archive
• Mala, Tom; Edwin, Bjørn; Mathisen, Øystein; Tillung, Terje; Fosse, Erik & Bergan, Anstein Bjørnar [Show all 8 contributors for this article] (2004). Cryoablation of colorectal liver metastases: Minimally invasive tumour control. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 39, p. 571–578. Full text in Research Archive
• Frich, Lars Inge; Bjørnerud, Atle; Fossheim, Sigrid Lise; Tillung, Terje & Gladhaug, Ivar Prydz (2004). Experimental application of thermosensitive paramagnetic liposomes for monitoring magnetic resonance imaging guided thermal ablation. Magnetic Resonance in Medicine. ISSN 0740-3194. 52(6), p. 1302–1309. doi: 10.1002/mrm.20289. Full text in Research Archive
• Stensvold, E; Aass, Nina Kathrine; Gladhaug, Ivar Prydz; Stenwig, Anna Elisabeth; Clausen, Ole Petter Fraas & Fosså, Sophie Dorothea (2004). Erroneous diagnosis of pancreatic cancer after radiotherapy of testicular cancer. European Journal of Surgical Oncology. ISSN 0748-7983. 30(3), p. 352–355. doi: 10.1016/j.ejso.2003.09.003. Full text in Research Archive
• Mala, Tom; Aurdal, Lars; Frich, Lars Inge; Samset, Eigil; Hol, Per Kristian & Edwin, Bjørn [Show all 8 contributors for this article] (2004). Liver tumor cryoablation: a commentary on the need of improved procedural monitoring. Technology in Cancer Research & Treatment (TCRT). ISSN 1533-0346. 3(1), p. 85–91. Full text in Research Archive
• Edwin, Bjørn; Mala, Tom; Mathisen, Øystein; Gladhaug, Ivar Prydz; Buanes, Trond & Lunde, O.C. [Show all 9 contributors for this article] (2004). Laparoscopic resection of the pancreas: a feasibility study of the short-term outcome. Surgical Endoscopy. ISSN 0930-2794. 18(3), p. 407–411. Full text in Research Archive
• Samset, Eigil; Mala, Tom; Ellingsen, Reinold; Gladhaug, Ivar Prydz; Søreide, O & Fosse, Erik (2001). Temperature measurement in soft tissue using a distributed fibre Bragg-grating sensor system. MITAT. Minimally invasive therapy & allied technologies. ISSN 1364-5706. 10(2), p. 83–93. doi: 10.1080/13645700152601379. Full text in Research Archive

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• Rosvold, Elin Olaug & Gladhaug, Ivar Prydz (2022). Opptaksprøve på medisinstudiet? Full text in Research Archive
• Engebretsen, Eivind & Gladhaug, Ivar Prydz (2020). Er det plass til et sykepleievitenskapelig fagmiljø på et medisinsk fakultet? Full text in Research Archive
• Gladhaug, Ivar Prydz & Engebretsen, Eivind (2020). Unyansert oppgjør med fortiden. Full text in Research Archive
• Berg, Jens Petter & Gladhaug, Ivar Prydz (2020). Disputasen er en del av doktorgradsproven. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(9), p. 1–3. doi: 10.4045/tidsskr.20.0328. Full text in Research Archive
• Berg, Jens Petter & Gladhaug, Ivar Prydz (2019). Viktig at prøveforelesningens hensikt blir oppfylt. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(16), p. 1534–1534. doi: 10.4045/tidsskr.19.0646. Full text in Research Archive
• Labori, Knut Jørgen; Verbeke, Caroline Sophie & Gladhaug, Ivar Prydz (2015). Information needs among patients and a surveillance strategy after surgery for pancreatic and periampullary cancer. HPB Surgery. ISSN 0894-8569. 17(7), p. 659–659. doi: 10.1111/hpb.12411. Full text in Research Archive
• Haugvik, Sven-Petter; Gaujoux, Sebastien; Røsok, Bård Ingvald; Gladhaug, Ivar Prydz; Dousset, Bertrand & Edwin, Bjørn (2014). Laparoscopic versus open pancreas resection for neuroendocrine tumours: Need for evaluation of oncological outcomes. HPB Surgery. ISSN 0894-8569. 16(9), p. 871–871. doi: 10.1111/hpb.12254. Full text in Research Archive
• Haugvik, Sven-Petter; Marangos, Irina Pavlik; Røsok, Bård Ingvald; Mathisen, Øystein; Pomianowska, Ewa & Gladhaug, Ivar Prydz [Show all 7 contributors for this article] (2012). Laparoscopic Surgery of Pancreatic Neuroendocrine Tumors: Results From a Tertiary Care Institution. Neuroendocrinology. ISSN 0028-3835. 96, p. 34–35. Full text in Research Archive
• Hagness, Morten; Foss, Aksel; Line, Pål Dag; Scholz, Tim; Jørgensen, Pål Foyn & Fosby, Bjarte [Show all 13 contributors for this article] (2012). Liver Transplantation for Non-Resectable Liver Metastases from Colorectal Cancer. Liver transplantation. ISSN 1527-6465. 18, p. S140–S140. Full text in Research Archive
• Haukeland, John Willy; Zbigniew, Konopski; AASHEIM, ERLEND T.; Johansen, Odd Erik; Løberg, Else Marit & Haaland, T. [Show all 12 contributors for this article] (2010). ELEVATED LEVELS OF FETUIN A IN NONALCOHOLIC FATTY LIVER DISEASE. Journal of Hepatology. ISSN 0168-8278. 52, p. S143–S144. Full text in Research Archive
• Westgaard, Arne; Laronningen, S; Clausen, Ole Petter Fraas; Mellem, C; Eide, Tor Jacob & Mathisen, O [Show all 8 contributors for this article] (2009). Standardized histopathologic reporting after pancreatoduodenectomy for adenocarcinoma is necessary to determine tumour origin, nodal and margin status, and assures prognostic validity. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 44, p. 36–36. Full text in Research Archive
• Westgaard, Arne; Laronningen, S; Mellem, C; Eide, Tor Jacob; Clausen, Ole Petter Fraas & Moller, B [Show all 7 contributors for this article] (2009). Standardized histopathologic reporting improves survival estimates: A population-based nationwide study of pancreatic head resections for adenocarcinoma from the Norwegian Cancer Registry. APMIS - Journal of Pathologiy, Microbiology and Immunology. ISSN 0903-4641. 117(3), p. 235–236. Full text in Research Archive
• Gladhaug, Ivar Prydz; Westgaard, Arne; Schjolberg, AR; Burum-Auensen, E; Pomianowska, Ewa & Clausen, Ole Petter Fraas (2009). Spindle proteins in resected pancreatic head adenocarcinomas: BUB1B is an independent prognostic factor in pancreatobiliary-differentiated tumours. APMIS - Journal of Pathologiy, Microbiology and Immunology. ISSN 0903-4641. 117(3), p. 237–238. Full text in Research Archive
• Westgaard, Arne; Schjolberg, A; Cvancarova, M; Eide, Tor Jacob; Clausen, Ole Petter Fraas & Gladhaug, Ivar Prydz (2008). Histological and immunohistochemical classification and prognosis of resected periampullary adenocarcinomas. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 43, p. 33–34. Full text in Research Archive
• Westgaard, Arne; Tafjord, Svetlana; Farstad, Inger Nina; Cvancarova, Milada; Eide, Tor Jacob & Mathisen, Øystein [Show all 8 contributors for this article] (2007). Histologisk type er en uavhengig prognostisk faktor etter pankreatikoduodenektomi for periampullært adenokarsinom. Full text in Research Archive
• Westgaard, Arne; Tafjord, Svetlana; Farstad, Inger Nina; Eide, Tor Jacob; Mathisen, Øystein & Clausen, Ole Petter Fraas [Show all 7 contributors for this article] (2006). Retroperitoneale reseksjonsrand er en uavhengig prognostisk faktor ved pankreatikoduodenektomi for periampullært adenokarsinom. Full text in Research Archive Show summary

  BAKGRUNN Pasienter antatt kurativt operert for adenokarsinom i pancreashodet får ofte residiv. En årsak til dette kan være ikke-erkjent tumorinfiltrasjon i retroperitoneale reseksjonsflate. Vi har benyttet en standardisert, systematisk protokoll med særlig henblikk på snittuttak fra denne reseksjonsflaten og undersøkt histopatologiske faktorers betydning for overlevelse etter pankreatikoduodenektomi a.m. Whipple. PASIENTER OG METODE Fra 1998 er alle whipplereseksjoner utført på Kirurgisk avdeling Rikshospitalet blitt undersøkt på Avdeling for patologi Rikshospitalet etter en standardisert systematisk protokoll for snittuttak og mikroskopisk undersøkelse, spesielt med henblikk på retroperitoneale reseksjonsflate. Vi har revurdert alle histologiske snitt fra perioden 1998–2004 (n=161) og registrert histopatologiske data for pasienter som er makroskopisk tumorfritt operert (R0/R1) for primære duktale adenokarsinomer i pancreashodet (n=114). Dette inkluderer svulster utgått fra pancreas (n=40), ampulla Vateri (n=41), intrapankreatiske del av ductus choledochus (n=17) og peri-vateriske duodenum (n=16). RESULTATER Førti av 114 (35 %) reseksjoner hadde mikroskopisk infiltrasjon i en eller flere av reseksjonsrendene (R1-reseksjoner), hvorav 32 (32/40) hadde infiltrasjon i retroperitoneale reseksjonsrand. I univariat analyse hadde følgende histopatologiske faktorer prognostisk betydning: tumors utgangspunkt, differensieringsgrad, størrelse, infiltrasjon i retroperitoneale reseksjonsrand, vaskulær infiltrasjon og perinevral infiltrasjon, samt regional lymfeknutemetastasering (p<0,01 for hver faktor). Multippel analyse viste at følgende faktorer har uavhengig betydning for overlevelse: lymfeknutestatus (p=0,025), perinevral infiltrasjon (p=0,012), samt retroperitoneale reseksjonsflate (p=0,016). Grensesignifikante faktorer var differensieringsgrad (p=0,059) og tumordiameter (p=0,068). KONKLUSJON Systematisk undersøkelse av whippleresektatet med særlig henblikk på retroperitoneale reseksjonsflate er essensielt for å identifisere kurative reseksjoner og for å oppnå pålitelige histopatologiske prognostiske data ved pankreatikoduodenektomi for periampullært adenokarsinom. Lymfeknutestatus, perinevral infiltrasjon og reseksjonsstatus for retroperitoneale rand er uavhengige prognostiske faktorer.

• Westgaard, Arne; Tafjord, Svetlana; Farstad, Inger Nina; Eide, Tor Jacob; Mathisen, Øystein & Clausen, Ole Petter Fraas [Show all 7 contributors for this article] (2006). Histologisk type er en uavhengig prognostisk faktor ved pankreatikoduodenektomi for periampullært adenokarsinom. Full text in Research Archive Show summary

  BAKGRUNN: Adenokarsinomer i pancreashodet operert ved pankreatikoduodenektomi a.m. Whipple kan utgå fra duktalt pancreasvev, ampulla Vateri, intrapankreatiske del av ductus choledochus eller duodenalt epitel. Utgangspunktet har betydning for prognosen, men kan være vanskelig å fastslå nøyaktig. Svulster utgått fra ampullen deles inn etter differensieringsretning i intestinal eller pankreatobiliær histologisk type, men vi har tidligere vist at også svulster i pancreashodet med annet utgangspunkt enn ampullen kan klassifiseres på denne måten. Vi har nå sett nærmere på om histologisk type er en uavhengig prognostisk faktor for svulster i pancreashodet, vurdert etter en systematisk protokoll for beskjæring og histopatologisk vurdering av whippleresektater. PASIENTER OG METODE: Fra 1998 har Avdeling for patologi ved Rikshospitalet hatt en standardisert, systematisk protokoll for histopatologisk undersøkelse av whippleresektater. I perioden 1998–2004 ble det på Kirurgisk avdeling utført 114 makroskopisk tumorfrie whipplereseksjoner for primært adenokarsinom, hvorav 41 svulster utgikk fra ampulla Vateri. Vi har klassifisert alle disse 114 svulstene som enten intestinale eller pankreatobiliære. Vi har deretter gjort overlevelsesanalyse etter Kaplan-Meier-metoden, samt univariat og multippel Cox-analyse, for å estimere betydningen av histologisk type og øvrige histopatologiske faktorer for overlevelse. RESULTATER: For alle whipplereseksjoner sett under ett (n=114) fordelte histologisk type seg på 67 pankreatobiliære og 47 intestinale, med henholdsvis 16,4 % og 52,8 % femårs aktuarisk overlevelse (p<0,001). Ampullesvulstene (n=41) bestod av 13 pankreatobiliære og 28 intestinale, med henholdsvis 23,1 % og 60,5 % femårs aktuarisk overlevelse (p=0,013). Multippel analyse viste at følgende faktorer har uavhengig betydning for overlevelse ved adenokarsinom i pancreashodet (n=114): lymfeknutestatus (p=0,002), karinfiltrasjon (p=0,033), diameter (p=0,015), samt histologisk type (p<0,001). For undergruppen ampullære svulster (n=41) kommer histologisk type (p=0,009), lymfeknutestatus (p<0,001) og tumordiameter (p=0,004) ut som uavhengige faktorer for overlevelse, mens karinfiltrasjon ikke lenger oppnår statistisk signifikans. KONKLUSJON: Adenokarsinomer i pancreashodet kan uavhengig av anatomisk utgangspunkt inndeles i ”intestinal” og ”pankreatobiliær” type. Histologisk type er en uavhengig prognostisk faktor etter whippleoperasjon for adenokarsinom i caput pancreatis.

• Westgaard, Arne; Tafjord, Svetlana; Farstad, Inger Nina; Cvancarova, Milada; Eide, Tor Jacob & Mathisen, Øystein [Show all 8 contributors for this article] (2006). Histologisk type er en uavhengig prognostisk faktor etter pankreatikoduodenektomi for adenokarsinom i pancreashodet. Full text in Research Archive Show summary

  BAKGRUNN: Adenokarsinomer i pancreashodet operert ved pankreatikoduodenektomi a.m. Whipple kan utgå fra duktalt pancreasvev, ampulla Vateri, intrapankreatiske del av ductus choledochus eller duodenalt epitel. Utgangspunktet har betydning for prognosen, men kan være vanskelig å fastslå nøyaktig. Svulster utgått fra ampullen deles inn etter differensieringsretning i intestinal eller pankreatobiliær histologisk type, men vi har tidligere vist at også svulster i pancreashodet med annet utgangspunkt enn ampullen kan klassifiseres på denne måten. Vi har nå sett nærmere på om histologisk type er en uavhengig prognostisk faktor for svulster i pancreashodet, vurdert etter en systematisk protokoll for beskjæring og histopatologisk vurdering av whippleresektater. PASIENTER OG METODE: Fra 1998 har Avdeling for patologi ved Rikshospitalet hatt en standardisert, systematisk protokoll for histopatologisk undersøkelse av whippleresektater. I perioden 1998–2004 ble det på Kirurgisk avdeling utført 114 makroskopisk tumorfrie whipplereseksjoner for primært adenokarsinom, hvorav 41 svulster utgikk fra ampulla Vateri. Vi har klassifisert alle disse 114 svulstene som enten intestinale eller pankreatobiliære. Vi har deretter gjort overlevelsesanalyse etter Kaplan-Meier-metoden, samt univariat og multippel Cox-analyse, for å estimere betydningen av histologisk type og øvrige histopatologiske faktorer for overlevelse. RESULTATER: For alle whipplereseksjoner sett under ett (n=114) fordelte histologisk type seg på 67 pankreatobiliære og 47 intestinale, med henholdsvis 16,4 % og 52,8 % femårs aktuarisk overlevelse (p<0,001). Ampullesvulstene (n=41) bestod av 13 pankreatobiliære og 28 intestinale, med henholdsvis 23,1 % og 60,5 % femårs aktuarisk overlevelse (p=0,013). Multippel analyse viste at følgende faktorer har uavhengig betydning for overlevelse ved adenokarsinom i pancreashodet (n=114): lymfeknutestatus (p=0,002), karinfiltrasjon (p=0,033), diameter (p=0,015), samt histologisk type (p<0,001). For undergruppen ampullære svulster (n=41) kommer histologisk type (p=0,009), lymfeknutestatus (p<0,001) og tumordiameter (p=0,004) ut som uavhengige faktorer for overlevelse, mens karinfiltrasjon ikke lenger oppnår statistisk signifikans. KONKLUSJON: Adenokarsinomer i pancreashodet kan uavhengig av anatomisk utgangspunkt inndeles i ”intestinal” og ”pankreatobiliær” type. Histologisk type er en uavhengig prognostisk faktor etter whippleoperasjon for adenokarsinom i caput pancreatis.

• Westgaard, Arne; Tafjord, Svetlana; Farstad, Inger Nina; Eide, Tor Jacob; Mathisen, Øystein & Clausen, Ole Petter Fraas [Show all 7 contributors for this article] (2006). Whipple-operasjon for adenokarsinom, Rikshospitalet 1998-2004: Retroperitoneale reseksjonsflate og histologisk type. Full text in Research Archive
• Tafjord, Svetlana; Westgaard, Arne; Farstad, Inger Nina; Eide, Tor Jacob; Mathisen, Øystein & Clausen, Ole Petter Fraas [Show all 7 contributors for this article] (2006). Retroperitoneale reseksjonsrand er en uavhengig prognostisk faktor ved pankreatikoduodenektomi for periampullært adenokarsinom. Full text in Research Archive Show summary

  BAKGRUNN Pasienter antatt kurativt operert for adenokarsinom i pancreashodet får ofte residiv. En årsak til dette kan være ikke-erkjent tumorinfiltrasjon i retroperitoneale reseksjonsflate. Vi har benyttet en protokoll med særlig henblikk på snittuttak fra denne reseksjonsflaten og undersøkt histopatologiske faktorers betydning for overlevelse etter pankreatikoduodenektomi a.m. Whipple. PASIENTER OG METODE Fra 1998 er alle whipplereseksjoner utført på Kirurgisk avdeling Rikshospitalet blitt undersøkt på Avdeling for patologi Rikshospitalet etter en standardisert systematisk protokoll for snittuttak og mikroskopisk undersøkelse, spesielt med henblikk på retroperitoneale reseksjonsflate. Vi har revurdert hele vårt materiale i perioden 1998–2004 (n=161) og registrert histopatologiske data for pasienter som er makroskopisk tumorfritt operert (R0/R1) for primære duktale adenokarsinomer i pancreashodet (n=114). Dette inkluderer svulster utgått fra pancreas (n=40), ampulla Vateri (n=41), intrapankreatiske del av ductus choledochus (n=17) og peri-ampullære duodenum (n=16). RESULTATER Førti av 114 (35 %) reseksjoner hadde mikroskopisk infiltrasjon i en eller flere av reseksjonsrendene (R1-reseksjoner), hvorav 32 (32/40) hadde infiltrasjon i retroperitoneale reseksjonsrand. Både univariat og multifaktor analyse viste at tumorinfiltrasjon i bakre reseksjonsrand hadde signifikant betydning for overlevelse etter Whipples operasjon for periampullære adenokarsinomer. KONKLUSJON Systematisk undersøkelse av Whippleresektatet med særlig henblikk på retroperitoneale reseksjonsflate er essensielt for å identifisere kurative reseksjoner og for å oppnå pålitelige histopatologiske prognostiske data ved pankreatikoduodenektomi for periampullært adenokarsinom. Tumorinfiltrasjon i bakre reseksjonsrand er uavhengig prognostisk faktor etter Whipples operasjon for periampullære adenokarsinomer.

• Øyen, Ole; Eskild, Winnie; Attramadal, Håvard; Gladhaug, Ivar Prydz; Levy, Finn Olav & Knutsen, G. [Show all 9 contributors for this article] (1986). Cyclic AMP increases the mRNA levels for the regulatory subunit (R-II51) of type II cAMP-dependent protein kinase in rat Sertoli cells. Full text in Research Archive
• Øyen, Ole; Eskild, Winnie; Attramadal, Håvard; Gladhaug, Ivar Prydz; Knutsen, G. & Richards, JoAnne S. [Show all 8 contributors for this article] (1986). Hormonal regulation of mRNA for the regulatory subunit (R-II51) of type II cAMP-dependent protein kinase in rat Sertoli cells. Full text in Research Archive
• Søreide, Jon Arne; Grønbech, Jon Erik; Lassen, Kristoffer; Dueland, Svein; Smaaland, Rune & Gladhaug, Ivar Prydz [Show all 12 contributors for this article] (2014). Nasjonalt handlingsprogram med retningslinjer for diagnostikk, behandling og oppfølging av pasienter med pancreaskreft. Helsedirektoratet. ISSN 9788280812964. Full text in Research Archive
• Westgaard, Arne & Gladhaug, Ivar Prydz (2010). Standardised histopathologic evaluation after pancreatoduodenectomy for adenocarcinoma : Resection margins, tumour origin, and survival. Universitetet i Oslo. Full text in Research Archive Show summary

  Pancreatic cancer is a lethal disease, and even after assumed margin-free pancreatoduodenectomy, most patients die within few years. The aims were to evaluate the importance of standardised histopathologic assessment for adequacy of reporting and survival estimates, and to report on prognostic factors in a setting of standardised histopathologic assessment. We performed immunohistochemical evaluation, slide review, and review of histopathologic reports from all pancreatoduodenectomies at Rikshospitalet University Hospital in 1980–2004. Reports from 1998-2004 at this institution were compared with reports from all other Norwegian institutions in the same period. Standardised histopathologic assessment and reporting was found necessary to avoid underestimation of poor prognostic factors, and to avoid misdiagnosis of tumours originating from non-pancreatic tissue (ampulla, distal bile duct, duodenum). Standardised histopathology was more important than surgical volume for completeness of reporting and for reliability of survival estimates, particularly with respect to lymph node evaluation. Immunostaining for MUC1 and MUC4 identified a subgroup of patients with particularly poor prognosis. Standardised histopathologic evaluation should be a first prerequisite to assure adequate histopathology after pancreatoduodenectomy. Immunostaining may identify tumour markers potentially targetable in future adjuvant treatments for pancreatic cancer.

• Frich, Lars Inge & Gladhaug, Ivar Prydz (2007). Radiofrequency ablation of liver tumors : an experimental and clinical study. Universitetet i Oslo. ISSN 9788280726933. Full text in Research Archive

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