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Pancreatic Neoplasms: HELP
Articles by Ivar Prydz Gladhaug
Based on 37 articles published since 2010
(Why 37 articles?)
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Between 2010 and 2020, I. P. Gladhaug wrote the following 37 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Dissection of Pancreatic Resection Specimens. 2016

Verbeke, Caroline Sophie / Gladhaug, Ivar Prydz. ·Institute of Clinical Medicine, University of Oslo, Postboks 1171, Blindern, Oslo 0318, Norway; Department of Pathology, Oslo University Hospital, Sognsvannsveien 20, Oslo 0372, Norway; Department of Pathology, Karolinska University Hospital, F42, Stockholm 14186, Sweden. Electronic address: c.s.verbeke@medisin.uio.no. · Institute of Clinical Medicine, University of Oslo, Postboks 1171, Blindern, Oslo 0318, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Sognsvannsveien 20, Oslo 0372, Norway. ·Surg Pathol Clin · Pubmed #27926357.

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.

2 Review Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape. 2016

Haugvik, Sven-Petter / Kaemmerer, Daniel / Gaujoux, Sebastien / Labori, Knut Jørgen / Verbeke, Caroline Sophie / Gladhaug, Ivar Prydz. ·Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Postbox 4950, Nydalen, 0424, Oslo, Norway. svhaug@ous-hf.no. · Institute of Clinical Medicine, University of Oslo, Postbox 1171, Blindern, 0318, Oslo, Norway. svhaug@ous-hf.no. · Department of Surgery, Drammen Hospital, Vestre Viken Hospital Trust, Postbox 800, 3004, Drammen, Norway. svhaug@ous-hf.no. · Department of General and Visceral Surgery, Zentralklinik Bad Berka, Robert-Koch-Allee 9, Bad Berka, 99437, Germany. · Department of Digestive and Endocrine Surgery, Cochin Hospital, APHP, Université Paris Descartes, 27, rue du Faubourg Saint Jacques, 74014, Paris, France. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Postbox 4950, Nydalen, 0424, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Postbox 1171, Blindern, 0318, Oslo, Norway. · Department of Pathology, Oslo University Hospital, Rikshospitalet, Postbox 4956, Nydalen, 0424, Oslo, Norway. ·Curr Oncol Rep · Pubmed #26984415.

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.

3 Review Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: a systematic review and meta-analysis. 2015

Haugvik, Sven-Petter / Hedenström, Per / Korsæth, Emilie / Valente, Roberto / Hayes, Alastair / Siuka, Darko / Maisonneuve, Patrick / Gladhaug, Ivar Prydz / Lindkvist, Björn / Capurso, Gabriele. ·Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. ·Neuroendocrinology · Pubmed #25613442.

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.

4 Review Pancreatic surgery with vascular reconstruction in patients with locally advanced pancreatic neuroendocrine tumors. 2013

Haugvik, Sven-Petter / Labori, Knut Jørgen / Waage, Anne / Line, Pål-Dag / Mathisen, Øystein / Gladhaug, Ivar Prydz. ·Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, 0372, Oslo, Norway. svhaug@ous-hf.no ·J Gastrointest Surg · Pubmed #23670519.

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.

5 Review Surgical treatment of sporadic pancreatic neuroendocrine tumors: a state of the art review. 2012

Haugvik, Sven-Petter / Labori, Knut Jørgen / Edwin, Bjørn / Mathisen, Øystein / Gladhaug, Ivar Prydz. ·Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. svhaug@ous-hf.no ·ScientificWorldJournal · Pubmed #23304085.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms. They are clinically diverse and divided into functioning and nonfunctioning disease, depending on their ability to produce symptoms due to hormone production. Surgical resection is the only curative treatment and remains the cornerstone therapy for this patient group, even in patients with advanced disease. Over the last decade there has been a noticeable trend towards more aggressive surgery as well as more minimally invasive surgery in patients with PNETs. This has resulted in improved long-term survival in patients with locally advanced and metastatic disease treated aggressively, as well as shorter hospital stays and comparable long-term outcomes in patients with limited disease treated minimally invasively. There are still controversies related to issues of surgical treatment of PNETs, such as to what extent enucleation, lymph node sampling, and vascular reconstruction are beneficial for the oncologic outcome. Histopathologic tumor classification is of high clinical importance for treatment planning and prognostic evaluation of patients with PNETs. A constant challenge, which relates to the treatment of PNETs, is the lack of an internationally accepted histopathological classification system. This paper reviews current issues on the surgical treatment of sporadic PNETs with specific focus on surgical approaches and tumor classification.

6 Review Resection margin involvement and tumour origin in pancreatic head cancer. 2012

Verbeke, C S / Gladhaug, I P. ·Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden. ·Br J Surg · Pubmed #22517199.

ABSTRACT: BACKGROUND: Assessment of the origin of adenocarcinoma in pancreatoduodenectomy specimens (pancreatic, ampullary or biliary) and resection margin status is not performed in a consistent manner in different centres. The aim of this review was to identify the impact of such variations on patient outcome. METHODS: A systematic literature search for articles on pancreatic, ampullary, distal bile duct and periampullary cancer was performed, with special attention to data on resection margin status, pathological examination and outcome. RESULTS: The frequent reclassification of tumour origin following slide review, and the wide variation in published incidence of pancreatic (33-89 per cent), ampullary (5-42 per cent) and distal bile duct (5-38 per cent) cancers indicate that the histopathological distinction between the three cancer groups is less accurate than generally believed. Recent studies have shown that the wide range of rates of microscopic margin involvement (R1) in pancreatoduodenectomy specimens (18-85, 0-27 and 0-72 per cent respectively for pancreatic, ampullary and distal bile duct cancers) is mainly caused by differences in pathological assessment rather than surgical practice and patient selection. As a consequence of the existing inconsistency in reporting of these data items, the clinical significance of microscopic margin involvement in each of the three cancer groups remains unclear. CONCLUSION: Inaccurate and inconsistent distinction between pancreatic, ampullary and distal bile duct cancer, combined with inaccuracies in resection margin assessment, results in obfuscation of key clinicopathological data. Specimen dissection technique plays a key role in the quality of the assessment of both tumour origin and margin status. Unless the pathological examination is meticulous and standardized, comparison of results between centres and observations in multicentre trials will remain of limited value.

7 Clinical Trial Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. 2011

Wedén, Synne / Klemp, Marianne / Gladhaug, Ivar P / Møller, Mona / Eriksen, Jon Amund / Gaudernack, Gustav / Buanes, Trond. ·Faculty of Medicine, University of Oslo. ·Int J Cancer · Pubmed #20473937.

ABSTRACT: K-ras mutations are frequently found in adenocarcinomas of the pancreas and can elicit mutation-specific immune responses. Targeting the immune system against mutant Ras may thus influence the clinical course of the disease. Twenty-three patients who were vaccinated after surgical resection for pancreatic adenocarcinoma (22 pancreaticoduodenectomies, one distal resection), in two previous Phase I/II clinical trials, were followed for more than 10 years with respect to long-term immunological T-cell reactivity and survival. The vaccine was composed of long synthetic mutant ras peptides designed mainly to elicit T-helper responses. Seventeen of 20 evaluable patients (85%) responded immunologically to the vaccine. Median survival for all patients was 27.5 months and 28 months for immune responders. The 5-year survival was 22% and 29%, respectively. Strikingly, 10-year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a cohort of nonvaccinated patient treated in the same period. Three patients mounted a memory response up to 9 years after vaccination. The present observation of long-term immune response together with 10-year survival following surgical resection indicates that K-ras vaccination may consolidate the effect of surgery and represent an adjuvant treatment option for the future.

8 Article Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells. 2019

Amrutkar, Manoj / Aasrum, Monica / Verbeke, Caroline S / Gladhaug, Ivar P. ·Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316, Oslo, Norway. manoj.amrutkar@medisin.uio.no. · Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, PO Box 1171, Blindern, 0318, Oslo, Norway. manoj.amrutkar@medisin.uio.no. · Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316, Oslo, Norway. · Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316, Oslo, Norway. · Department of Pathology, Oslo University Hospital Rikshospitalet, Nydalen, 0424, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, PO Box 1171, Blindern, 0318, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital Rikshospitalet, Nydalen, 0424, Oslo, Norway. ·BMC Cancer · Pubmed #31208372.

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.

9 Article Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy. 2019

Bowitz Lothe, Inger Marie / Kleive, Dyre / Pomianowska, Ewa / Cvancarova, Milada / Kure, Elin / Dueland, Svein / Gladhaug, Ivar P / Labori, Knut Jørgen. ·Department of Pathology, Oslo University Hospital, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Norway. · Department of Surgery, Baerum Hospital, Vestre Viken Hospital Trust, Norway. · Faculty of Health Sciences, Department of Nursing and Health Promotion, Oslo Metropolitan University, Oslo, Norway. · Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. · Department of Oncology, Oslo University Hospital, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Norway. Electronic address: uxknab@ous-hf.no. ·Pancreatology · Pubmed #30713128.

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.

10 Article Commonly Used Pancreatic Stellate Cell Cultures Differ Phenotypically and in Their Interactions with Pancreatic Cancer Cells. 2019

Lenggenhager, Daniela / Amrutkar, Manoj / Sántha, Petra / Aasrum, Monica / Löhr, Johannes-Matthias / Gladhaug, Ivar P / Verbeke, Caroline S. ·Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway. Daniela.Lenggenhager@usz.ch. · Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway. Daniela.Lenggenhager@usz.ch. · Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Schmelzbergstrasse 12, 8091 Zürich, Switzerland. Daniela.Lenggenhager@usz.ch. · Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway. manoj.amrutkar@medisin.uio.no. · Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway. manoj.amrutkar@medisin.uio.no. · Department of Pathology, Oslo University Hospital Rikshospitalet, Nydalen, 0424 Oslo, Norway. petra.santha@medisin.uio.no. · Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway. monica.aasrum@medisin.uio.no. · Department of Clinical Science, Intervention and Technology, Karolinska Institutet, K 53, 141 86 Stockholm, Sweden. matthias.lohr@ki.se. · Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway. i.p.gladhaug@medisin.uio.no. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital Rikshospitalet, Nydalen, 0424 Oslo, Norway. i.p.gladhaug@medisin.uio.no. · Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway. c.s.verbeke@medisin.uio.no. · Department of Pathology, Oslo University Hospital Rikshospitalet, Nydalen, 0424 Oslo, Norway. c.s.verbeke@medisin.uio.no. ·Cells · Pubmed #30621293.

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.

11 Article Risk for hemorrhage after pancreatoduodenectomy with venous resection. 2018

Kleive, Dyre / Sahakyan, Mushegh / Søreide, Kjetil / Brudvik, Kristoffer W / Line, Pål-Dag / Gladhaug, Ivar P / Labori, Knut Jørgen. ·Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Nydalen, 0424, Oslo, Norway. dyrkle@ous-hf.no. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. dyrkle@ous-hf.no. · Department of Surgery N1, Yerevan State Medical University after M. Heratsi, Yerevan, Armenia. · The Intervention Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway. · Clinical Surgery, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, UK. · Department of Clinical Medicine, University of Bergen, Bergen, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Nydalen, 0424, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Institute of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. ·Langenbecks Arch Surg · Pubmed #30397778.

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.

12 Article Portal vein reconstruction using primary anastomosis or venous interposition allograft in pancreatic surgery. 2018

Kleive, Dyre / Berstad, Audun Elnaes / Sahakyan, Mushegh A / Verbeke, Caroline S / Naper, Christian / Haugvik, Sven Petter / Gladhaug, Ivar P / Line, Pål-Dag / Labori, Knut Jørgen. ·Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: dyrkle@ous-hf.no. · Department of Radiology, Oslo University Hospital, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway; The Intervention Centre, Oslo University Hospital, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital, Oslo, Norway. · Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway; Department of Surgery, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. ·J Vasc Surg Venous Lymphat Disord · Pubmed #29128301.

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.

13 Article Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells. 2017

Tjomsland, Vegard / Aasrum, Monica / Christoffersen, Thoralf / Gladhaug, Ivar P. ·Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway. ·Oncotarget · Pubmed #29069737.

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.

14 Article Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy. 2017

Kleive, D / Sahakyan, M A / Berstad, A E / Verbeke, C S / Gladhaug, I P / Edwin, B / Fosby, B / Line, P-D / Labori, K J. ·Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Intervention Centre, Oslo University Hospital, Oslo, Norway. · Department of Radiology, Oslo University Hospital, Oslo, Norway. · Department of Pathology, Oslo University Hospital, Oslo, Norway. · Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway. ·Br J Surg · Pubmed #28815556.

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.

15 Article Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas. 2016

Johannessen, Lene E / Panagopoulos, Ioannis / Haugvik, Sven-Petter / Gladhaug, Ivar Prydz / Heim, Sverre / Micci, Francesca. ·Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, 0372 Oslo, Norway. ·Oncol Rep · Pubmed #27667266.

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.

16 Article The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration. 2016

Tjomsland, Vegard / Sandnes, Dagny / Pomianowska, Ewa / Cizmovic, Smiljana Torbica / Aasrum, Monica / Brusevold, Ingvild Johnsen / Christoffersen, Thoralf / Gladhaug, Ivar P. ·Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. vegard.tjomsland@medisin.uio.no. · Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. vegard.tjomsland@medisin.uio.no. · Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · Department of Oral Biology, University of Oslo, Oslo, Norway. · Department of Pediatric Dentistry and Behavioral Science, Faculty of Dentistry, University of Oslo, Oslo, Norway. ·J Exp Clin Cancer Res · Pubmed #27473228.

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.

17 Article 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. 2016

Tjomsland, Vegard / Pomianowska, Eva / Aasrum, Monica / Sandnes, Dagny / Verbeke, Caroline Sophie / Gladhaug, Ivar Prydz. ·Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: vegard.tjomsland@medisin.uio.no. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. ·Neoplasia · Pubmed #27435927.

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.

18 Article Transcriptomic Profiling of Tumor Aggressiveness in Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms. 2016

Haugvik, Sven-Petter / Vodák, Daniel / Haugom, Lisbeth / Hovig, Eivind / Gladhaug, Ivar Prydz / Heim, Sverre / Micci, Francesca. ·From the *Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital; †Institute of Clinical Medicine, University of Oslo; ‡Department of Tumor Biology, Institute for Cancer Research, and §Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital; and ∥Centre for Cancer Biomedicine and ¶Department of Informatics, University of Oslo, Oslo, Norway. ·Pancreas · Pubmed #26918873.

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.

19 Article Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study. 2016

Haugvik, Sven-Petter / Janson, Eva Tiensuu / Österlund, Pia / Langer, Seppo W / Falk, Ragnhild Sørum / Labori, Knut Jørgen / Vestermark, Lene Weber / Grønbæk, Henning / Gladhaug, Ivar Prydz / Sorbye, Halfdan. ·Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway. sphaugvik@yahoo.de. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. sphaugvik@yahoo.de. · Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. · Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. · Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. · Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway. · Department of Oncology, Odense University Hospital, Odense C, Denmark. · Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Oncology, Haukeland University Hospital, Bergen, Norway. ·Ann Surg Oncol · Pubmed #26678407.

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.

20 Article 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. 2016

Labori, Knut J / Katz, Matthew H / Tzeng, Ching W / Bjørnbeth, Bjørn A / Cvancarova, Milada / Edwin, Bjørn / Kure, Elin H / Eide, Tor J / Dueland, Svein / Buanes, Trond / Gladhaug, Ivar P. ·a Department of Hepato-Pancreato-Biliary Surgery , Oslo University Hospital , Oslo , Norway. · b Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston, Texas , USA. · c Department of Surgery , University of Kentucky , Lexington, Kentucky , USA. · d Department of Oncology , National Resource Center for Late Effects, Oslo University Hospital , Oslo , Norway. · e Intervention Centre, Rikshospitalet, Oslo University Hospital , Oslo , Norway. · f Institute of Clinical Medicine, University of Oslo , Oslo , Norway. · g Department of Genetics , Institute for Cancer Research, Oslo University Hospital , Oslo , Norway. · h Department of Pathology , Oslo University Hospital , Oslo , Norway. · i Department of Oncology , Oslo University Hospital , Oslo , Norway. ·Acta Oncol · Pubmed #26213211.

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.

21 Article The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers. 2015

Vedeld, Hege Marie / Andresen, Kim / Eilertsen, Ina Andrassy / Nesbakken, Arild / Seruca, Raquel / Gladhaug, Ivar P / Thiis-Evensen, Espen / Rognum, Torleiv O / Boberg, Kirsten Muri / Lind, Guro E. ·Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital- Norwegian Radium Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway. ·Int J Cancer · Pubmed #24948044.

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.

22 Article Loss of 11p11 is a frequent and early event in sporadic nonfunctioning pancreatic neuroendocrine neoplasms. 2014

Haugvik, Sven-Petter / Gorunova, Ludmila / Haugom, Lisbeth / Eibak, Anne Mette / Gladhaug, Ivar Prydz / Heim, Sverre / Micci, Francesca. ·Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, 0372 Oslo, Norway. · Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0372 Oslo, Norway. · Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway. ·Oncol Rep · Pubmed #25018013.

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.

23 Article COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis. 2014

Pomianowska, Ewa / Schjølberg, Aasa R / Clausen, Ole Petter F / Gladhaug, Ivar P. ·Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. ewa.pomianowska@medisin.uio.no. ·BMC Cancer · Pubmed #24950702.

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.

24 Article Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. 2014

Pomianowska, Ewa / Sandnes, Dagny / Grzyb, Krzysztof / Schjølberg, Aasa R / Aasrum, Monica / Tveteraas, Ingun H / Tjomsland, Vegard / Christoffersen, Thoralf / Gladhaug, Ivar P. ·Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. ewa.pomianowska@medisin.uio.no. ·BMC Cancer · Pubmed #24912820.

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.

25 Article Long-term outcome of laparoscopic surgery for pancreatic neuroendocrine tumors. 2013

Haugvik, Sven-Petter / Marangos, Irina Pavlik / Røsok, Bård Ingvald / Pomianowska, Ewa / Gladhaug, Ivar Prydz / Mathisen, Oystein / Edwin, Bjørn. ·Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, 0372, Oslo, Norway. svhaug@ous-hf.no ·World J Surg · Pubmed #23263686.

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.

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