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  • 151.
    Strosberg, Jonathan R.
    et al.
    Univ S Florida, H Lee Moffitt Canc Ctr, Dept Med, Tampa, FL 33682 USA..
    Yao, James C.
    Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Div Canc Med, Houston, TX 77030 USA..
    Bajetta, Emilio
    Policlin Monza, Ist Oncol, Monza, Italy..
    Aout, Mounir
    Novartis Int AG, Basel, Switzerland..
    Bakker, Bert
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hainsworth, John D.
    Sarah Cannon Res Inst, Nashville, TN USA..
    Ruszniewski, Philippe B.
    Univ Paris 07, Paris, France.;Hop Beaujon, Paris, France..
    Van Cutsem, Eric
    Univ Hosp Gasthuisberg, Digest Oncol, Leuven, Belgium.;KULeuven, Leuven, Belgium..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pavel, Marianne E.
    Charite, Campus Virchow Klinikum, Dept Gastroenterol & Hepatol, D-13353 Berlin, Germany..
    Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis2015In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 6, p. 933-940Article in journal (Refereed)
    Abstract [en]

    Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). Apost hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NETwere considered for present analysis. Of these, 41 patients were SSA-treatment naive and 155 had received SSA therapy before study entry. For SSA-naive patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2-22.7) months. For SSA-naive patients with midgut NET (nZ24), median PFS was 22.2 (95% CI 8.3-29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4-14.3) months. Among the SSA-pretreated patients who had midgut NET (nZ119), the median PFS was 12.0 (95% CI 8.4-19.3) months. Median OS was 35.8 (95% CI 32.5-48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 -not reached) months for SSA-naive patients and 33.5 (95% CI 27.5-44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.

  • 152.
    Strosberg, Jonathan
    et al.
    H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA.
    Wolin, Edward
    Montefiore Einstein Ctr Canc Care, Bronx, NY USA.
    Chasen, Beth
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Kulke, Matthew
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Bushnell, David
    Univ Iowa, Iowa City, IA USA.
    Caplin, Martyn
    Royal Free Hosp, London, England.
    Baum, Richard P.
    Zentralklinik, Bad Berka, Germany.
    Kunz, Pamela
    Stanford Univ, Med Ctr, Stanford, CA 94305 USA.
    Hendifar, Andrew
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA.
    Hobday, Timothy
    Mayo Clin, Coll Med, Rochester, MN USA.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sierra, Maribel Lopera
    Adv Accelerator Applicat, Geneva, Switzerland.
    Thevenet, Thomas
    Adv Accelerator Applicat, Geneva, Switzerland.
    Margalet, Ines
    Adv Accelerator Applicat, Geneva, Switzerland.
    Ruszniewski, Philippe
    Paris Diderot Univ, Clichy, France;Hop Beaujon, Clichy, France.
    Krenning, Eric
    Erasmus MC, Rotterdam, Netherlands.
    Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With Lu-177-Dotatate in the Phase III NETTER-1 Trial2018In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 25, p. 2578-2584Article in journal (Refereed)
    Abstract [en]

    Purpose

    Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of Lu-177-Dotatate treatment on time to deterioration in health-related QoL.

    Methods

    The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with Lu-177-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date.

    Results

    TTD was significantly longer in the Lu-177-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning.

    Conclusion

    This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, Lu-177-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.

  • 153.
    Strosberg, Jonathan
    et al.
    H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA.
    Wolin, Edward
    Montefiore Med Ctr, New York, NY USA.
    Chasen, Beth
    Univ Texas MD Anderson Canc Ctr, Houston, TX, USA.
    Kulke, Matthew
    Dana Farber Canc Inst, Boston, MA, USA.
    Bushnell, David
    Univ Iowa, Iowa City, IA USA.
    Caplin, Martyn
    Royal Free Hosp, London, England.
    Baum, Richard P.
    Zent Klin Bad Berka, Bad Berka, Germany.
    Kunz, Pamela
    Stanford Univ, Med Ctr, Stanford, CA, USA.
    Hobday, Timothy
    Mayo Clin, Coll Med, Rochester, MN, USA.
    Hendifar, Andrew
    Cedars Sinai Med Ctr, Los Angeles, CA, USA.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sierra, Maribel Lopera
    Adv Accelerator Applicat, St Genis Pouilly, France.
    Ruszniewski, Philippe
    Hop Beaujon, Clichy, France.
    Krenning, Eric
    Erasmus MC, Rotterdam, Netherlands.
    QOL Improvements in NETTER-1 Phase III Trial in Patients With Progressive Midgut Neuroendocrine Tumors2018In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 355-355Article in journal (Other academic)
  • 154.
    Strosberg, Jonathan
    et al.
    Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA..
    Wolin, Edward
    Univ Kentucky, Markey Canc Ctr, Lexington, KY USA..
    Chasen, Beth
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Kulke, Matthew
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Bushnell, David
    Univ Iowa, Iowa City, IA USA..
    Caplin, Martyn
    Royal Free Hosp, Pond St, London NW3 2QG, England..
    Baum, Richard P.
    Zentralklin, Bad Berka, Germany..
    Mittra, Erik
    Stanford Univ, Med Ctr, Stanford, CA 94305 USA..
    Hobday, Timothy
    Mayo Clin, Coll Med, Rochester, MN USA..
    Hendifar, Andrew
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sierra, Maribel Lopera
    Adv Accelerator Applicat, New York, NY USA..
    Kwekkeboom, Dik
    Erasmus MC, Rotterdam, Netherlands..
    Ruszniewski, Philippe
    Hop Beaujon, Clichy, France..
    Krenning, Eric
    Erasmus MC, Rotterdam, Netherlands..
    177-Lu-Dotatate Significantly Improves Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors: Results of the Phase III NETTER-1 Trial2016In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 3, p. 483-483Article in journal (Other academic)
  • 155.
    Stålberg, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lopez-Egido, J R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wang, S
    Gobl, A
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Skogseid, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Differentially expressed cDNAs in PLCbeta3-induced tumor suppression in a human endocrine pancreatic tumor cell line: activation of the human mismatch repair protein 3 gene.2001In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 281, no 1, p. 227-31Article in journal (Refereed)
  • 156.
    Stålberg, Peter
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Granberg, Dan
    Department of Medical Sciences.
    Carling, Tobias
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Wilander, Erik
    Department of Genetics and Pathology.
    Eriksson, Barbro
    Department of Medical Sciences.
    Gobl, Anders
    Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Rastad, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Modlin, Irvin M
    Oberg, Kjell
    Department of Medical Sciences.
    Skogseid, Britt
    Department of Medical Sciences.
    In Situ RNA-RNA Hybridization of Phospholipase C β3 Shows Lack of Expression in Neuroendocrine Tumours2003In: Anticancer Research, Vol. 23, no 3B, p. 2227-2232Article in journal (Refereed)
  • 157.
    Stålberg, Peter
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Endokrin tumörbiologi.
    Grimfjärd, Per
    Department of Medical Sciences.
    Santesson, Mårten
    Department of Medical Sciences.
    Zhou, Yinghua
    Department of Medical Sciences. Onkologisk endokrinologi.
    Lindberg, Daniel
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gobl, Anders
    Department of Medical Sciences.
    Öberg, Kjell
    Department of Medical Sciences. Onkologisk endokrinologi.
    Westin, Gunnar
    Rastad, Jonas
    Wang, Shu
    Department of Medical Sciences. Endokrin tumörbiologi.
    Skogseid, Britt
    Department of Medical Sciences. Endokrin tumörbiologi.
    Transfection of the multiple endocrine neoplastia type 1 gene to a human endocrine pancreatic tumor cell line inhibits cell growth and affects expression of junD, delta-like protein 1/preadipocyte factor-1, proliferating cell nuclear antigen and QM/Jif-12004In: The journal of clinical endocrinology & metabolism, Vol. 5, p. 2326-2337Article in journal (Refereed)
  • 158.
    Sundin, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Bergström, Mats
    Uppsala University Petcentre (Imanet).
    Långström, Bengt
    Uppsala University Petcentre (Imanet).
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    PET in the diagnosis of neuroendocrine tumors2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1014, p. 246-257Article in journal (Refereed)
    Abstract [en]

    For general oncological imaging, positron emission tomography (PET) using [18F]fluoro-deoxy-glucose (FDG) has evolved as a powerful functional imaging modality. Unfortunately, FDG-PET has not been as advantageous for imaging gastropancreatic neuroendocrine tumors, and only tumors with high proliferative activity and low differentiation have shown an increased FDG uptake. Therefore, the 11C-labeled amine precursors L-dihydroxyphenylalanine and 5-hydroxy-L-tryptophan (5-HTP) were developed for PET imaging of these tumors. Because of the higher tumor uptake of the latter tracer in a study of patients with endocrine pancreatic tumors, 11C-5-HTP was chosen for further evaluation. In comparative studies of patients with carcinoids and endocrine pancreatic tumors, 5-HTP-PET proved better than CT and somatostatin receptor scintigraphy for tumor visualization, and many small, previously overlooked lesions were diagnosed by 11C-5-HTP-PET. The strong correlation found during medical treatment between the changes in the transport rate constant at repeated PET and those of U-HIAA indicates the possible use of 11C-5-HTP-PET also for therapy monitoring. By premedication of patients with Carbidopa orally before PET examination, in order to block the aromatic amino acid decarboxylase enzyme, the decarboxylation rate of 11C-5-HTP was decreased, leading to a higher tumor uptake and a considerably lower urinary radioactivity concentration.

  • 159. Tamagno, G.
    et al.
    Crespo, G.
    Fierro Maya, E.
    Fossmark, R.
    Igaz, P.
    Rinke, A.
    Vitale, G.
    Walenkamp, A.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Meyer, T.
    Phase 1 and Phase 2 Clinical Trials Investigating Targets Against the Molecular Hallmarks of Gastroenteropancreatic Neuroendocrine Tumors2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 280-281Article in journal (Other academic)
  • 160. Tartaglia, Andreas
    et al.
    Portela-Gomes, Guida M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Oberg, Kjell
    Department of Medical Sciences. Onkologisk endokrinologi.
    Vezzadini,
    Foschini,
    Stridsberg, Mats
    Department of Medical Sciences. Clinical Chemistry.
    Chromogranin A in gastric neuroendocrine tumours: an immunohistochemical and biochemical study with region-specific antibodies.2006In: Virchows Arch, ISSN 0945-6317, p. 1-8Article in journal (Refereed)
  • 161.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Gobl, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Kalkner, M
    Department of Oncology, Radiology and Clinical Immunology.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    A comparison between the efficacy of somatostatin receptor scintigraphy and in situ hybridization for somatostatin receptor subtype 2 mRNA to predict therapeutic outcome in carcinoid patients1996In: Cancer Research, Vol. 56, p. 2561-Article in journal (Refereed)
  • 162.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Carcinoid tumours1996In: Clinical Gastroenterology, 1996Chapter in book (Other scientific)
  • 163.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Clinical GastroenterologyCarcinoid tumours.1996Chapter in book (Other scientific)
  • 164.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Malignant neuroendocrine tumors.2002In: Cancer Chemother Biol Response Modif, 2002, p. 463-Chapter in book (Other scientific)
  • 165.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Somatostatin receptor ligands and their use in the treatment of endocrine disorders1999In: Curr Pharm Des, Vol. 1, p. 693-Article in journal (Refereed)
  • 166. Tiensuu Janson, E
    et al.
    Stridsberg, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Gobl, A
    Westlin, J E
    Oberg, K
    Determination of somatostatin receptor subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies.1998In: Cancer Res, ISSN 0008-5472, Vol. 58, no 11, p. 2375-8Article in journal (Other scientific)
  • 167.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Westlin, JE
    Department of Oncology, Radiology and Clinical Immunology.
    Öhrvall, U
    Department of Surgical Sciences.
    Öberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lukinius, A
    Department of Genetics and Pathology.
    Nuclear localization of 111In after intravenous injection of 111In-DTPA-D-Phe-1-octreotide to patients with neuroendocrine tumors.2000In: J Nuclear Medicine, Vol. 41, p. 1514-Article in journal (Refereed)
  • 168.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Öberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    The carcinoid syndrome2005In: Gastroenterology and Hepatology: the Modern Clinician's Guide, Weinstein WM, Hawkey CJ and Bosch J , 2005, p. 823-830Chapter in book (Other scientific)
  • 169.
    Tiensuu Janson, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Öberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Neuroendocrine tumors--somatostatin receptor expression and somatostatin analog treatment.2003In: Cancer Chemother Biol Response Modif, ISSN 0921-4410, Vol. 21, p. 535-46Article in journal (Refereed)
  • 170.
    Tiensuu Janson, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Theodorsson, E
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center1997In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 8, no 7, p. 685-690Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors.

    PATIENTS AND METHODS:

    We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival.

    RESULTS:

    Survival was significantly shorter in midgut carcinoid patients with > or = 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 micrograms/l were independent predictors of overall survival.

    CONCLUSIONS:

    Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut, carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 micrograms/l. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.

  • 171.
    Tiensuu Janson, Eva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Öberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Neuroendocrine tumors-Somatostatin receptors and treatment2004In: Austral-Asian Journal of Cancer, ISSN 0972-2556, Vol. 3, no 1, p. 51-59Article, book review (Other (popular scientific, debate etc.))
  • 172. Torén, A
    et al.
    Öberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lembke, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Enlund, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Rask-Andersen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Tractor-driving hours and their relation to self-reported low-back and hip symptoms.2002In: Appl Ergon, ISSN 0003-6870, Vol. 33, no 2, p. 139-46Article in journal (Other scientific)
    Abstract [en]

    Tractor driving might be one causal risk factor in the incidence of low-back and hip symptoms among farmers. Information on the annual exposure to tractor driving and its distribution among different work operations is scarce. The purpose of this study was to quantify the total and the annual time driving tractors among Swedish farmers and its distribution into different work operations, and to investigate the risk of low-back and hip symptoms in relation to tractor driving within different work operations. The data were collected from a questionnaire study sent to all farms with acreage more than 10 ha in a county in Sweden. Farmers having farming and/or forestry as their main occupation in 1995 were included in the analysis. The annual tractor-driving time and the percentage distribution within different work operations were calculated for females, males, the total group and four production groups. The risk calculations for low-back and hip symptoms from the variables related to tractor driving were performed on the total group. The results showed that the mean annual tractor-driving time was 472 h. Ploughing was the single most time-consuming work operation but it had no influence on the risk for low-back or hip pain. The results showed that some of the variables investigated related to tractor driving influenced the risk for low-back and hip symptoms.

  • 173. Toumpanakis, Christos
    et al.
    Kim, Michelle K.
    Rinke, Anja
    Bergestuen, Deidi S.
    Thirlwell, Christina
    Khan, Mohid S.
    Salazar, Ramon
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Combination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine Tumors2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 2, p. 63-74Article in journal (Refereed)
    Abstract [en]

    Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 (Ga-68)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 (C-11)-5-hydroxy-L-tryptophan (5-HTP) PET and F-18-dihydroxyphenylalanine (F-18-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of Ga-68-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 (F-18)-fluorodeoxyglucose (F-18-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, F-18-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values > 10%. According to limited data, F-18-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. F-18-FDG PET and Ga-68-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.  

  • 174.
    Van Leeuwaarde, R.
    et al.
    UMC Utrecht, Utrecht, Netherlands.
    Spada, F.
    European Inst Oncol, Milan, Italy.
    Cheung, W.
    Tom Baker Canc Clin, Calgary, AB, Canada.
    Gonzalez-Clavijo, A.
    Univ Nacl Colombia, Bogota, Colombia.
    Pracht, M.
    Ctr Eugene Marquis, Rennes, France.
    Emelianova, G.
    Natl Med Res Ctr Oncol NN Blokhin, Moscow, Russia.
    Thirlwell, C.
    UCL, London, England.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Is the EORTC QLQ-QNET21 Optimal for Patients with Neuroendocrine Tumors?2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 122-122Article in journal (Other academic)
  • 175.
    Vikman, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cunningham, Janet L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gene expression in midgut carcinoid tumors: potential targets for immunotherapy2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 1, p. 32-40Article in journal (Refereed)
    Abstract [en]

    Classical midgut carcinoids are serotonin-secreting tumors derived from enterochromaffin cells in the gut. Metastatic disease represents a therapeutic challenge and immunotherapy implies a novel approach for treatment. In order to define antigens suitable for T-cell therapy with a preferential expression in midgut carcinoid tissue a broad screening of genes with preferential neuroendocrine restriction, genes described as over-expressed in various malignancies, and genes encoding cancer-testis associated antigens was performed. The expression of 32 genes was analyzed by reverse transcription polymerase chain reaction (RT-PCR) in 28 midgut carcinoid specimens, in the cell line BON and in normal tissues. Immunohistochemistry (IHC) was used to evaluate protein expression. Expression is shown of genes that have previously not been observed in midgut carcinoid tumors, such as Survivin and GAGEs. Also the expression is confirmed of genes that encode pivotal proteins in enterochromaffin cells, such as TPH1 and VMAT1, and their tissue-restricted expression is indicated. In addition, gene expression of IA-2 and CDX-2 in normal gastrointestinal (GI) tract and in tumor is shown. Protein expression of TPH, VMAT1, and Survivin was detected in tumor tissue. This study elucidates that TPH1, VMAT1, and Survivin should be further investigated as potential target antigens for T cell-mediated immunotherapy of midgut carcinoids.

  • 176. Vilar, Eduardo
    et al.
    Salazar, Ramón
    Pérez-García, Jose
    Cortes, Javier
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tabernero, Josep
    Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors2007In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 14, no 2, p. 221-232Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) of the digestive tract are a heterogeneous group of rare malignancies. Three major subgroups can be defined: pancreatic endocrine tumors, carcinoid tumors, and poorly differentiated gastroenteropancreatic NETs. Classically, digestive NETS have been considered to have an indolent course characterized for prolonged stabilizations or slow progressions, but there are clear differences in terms of aggressiveness, clinical course, and response to treatment among them. Retrospective studies have identified several clinicopathological and immunohistochemical factors as angioinvasion and proliferative index assessed by Ki-67 expression, which predict biological behavior and correlate with survival. Chemotherapy regimens based on the combination of several active drugs such as streptozocin, doxorubicin, 5-fluorouracil, dacarbazine, and temozolomide show low response rates, which sets the need to improve the results of the medical treatment of these malignancies. This review will analyze the role of Ki-67 in digestive NETs under a clinical perspective and will suggest future fields for development of this approach that enable a better patient selection for chemotherapy. Also a comprehensive review of the literature about chemotherapy in NETs is presented.

  • 177.
    Von Essen, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Larsson, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjödén, Per-Olow
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    'Satisfaction with care': associations with health-related quality of life and psychosocial function among Swedish patients with endocrine gastrointestinal tumours2002In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 11, no 2, p. 91-99Article in journal (Refereed)
    Abstract [en]

    The aims of this study were to investigate ‘satisfaction with care’ and its possible relationships to hope, health-related quality of life, anxiety and depression. Eighty-five patients with endocrine gastrointestinal (GI) tumours responded to questionnaires a few days after a hospital visit. ‘Satisfaction with care’ was assessed by the Comprehensive Assessment of Satisfaction with Care (CASC), health-related quality of life by the EORTC QLQ C-30 and anxiety and depression by the Hospital Anxiety and Depression Scale (HADS). Patients’ highest satisfaction scores were obtained for ‘general satisfaction’ and ‘nurses’ and doctors’ technical skills’. The lowest satisfaction was expressed for ‘doctors’ interpersonal skills’, ‘nurses’ communication skills’ and ‘care organization’. Patients reporting a clinically relevant level of anxiety were less satisfied with several care aspects than those reporting less anxiety. Satisfaction with ‘nurses’ communication skills’ and ‘doctors’ interpersonal skills’ was associated with several aspects of health-related quality of life, whereas satisfaction with ‘doctors’ information’, ‘nurses’ technical skills’ and ‘general satisfaction’ was not. Satisfaction with psychosocial aspects of care is related to the psychosocial function of patients with endocrine GI tumours.

  • 178. von Marschall, Zofia
    et al.
    Scholz, Arne
    Cramer, Thorsten
    Schäfer, Georgia
    Schirner, Michael
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wiedenmann, Bertram
    Höcker, Michael
    Rosewicz, Stefan
    Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis.2003In: J Natl Cancer Inst, ISSN 0027-8874, Vol. 95, no 6, p. 437-48Article in journal (Refereed)
  • 179.
    Waldum, Helge L.
    et al.
    Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7491 Trondheim, Norway;St Olavs Univ Hosp, Dept Gastroenterol & Hepatol, Trondheim, Norway.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sördal, Öystein F.
    St Olavs Univ Hosp, Dept Gastroenterol & Hepatol, Trondheim, Norway.
    Sandvik, Arne K.
    Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7491 Trondheim, Norway;St Olavs Univ Hosp, Dept Gastroenterol & Hepatol, Trondheim, Norway.
    Gustafsson, Björn I.
    Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7491 Trondheim, Norway;St Olavs Univ Hosp, Dept Gastroenterol & Hepatol, Trondheim, Norway.
    Mjönes, Patricia
    Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7491 Trondheim, Norway;St Olavs Univ Hosp, Dept Pathol, Trondheim, Norway.
    Fossmark, Reidar
    Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7491 Trondheim, Norway;St Olavs Univ Hosp, Dept Gastroenterol & Hepatol, Trondheim, Norway.
    Not only stem cells, but also mature cells, particularly neuroendocrine cells, may develop into tumours: time for a paradigm shift2018In: Therapeutic Advances in Gastroenterology, ISSN 1756-283X, E-ISSN 1756-2848, Vol. 11, article id UNSP 1756284818775054Article, review/survey (Refereed)
    Abstract [en]

    Stem cells are considered the origin of neoplasms in general, and malignant tumours in particular, and the stage at which the stem cells stop their differentiation determines the degree of malignancy. However, there is increasing evidence supporting an alternative paradigm. Tumours may develop by dedifferentiation from mature cells able to proliferate. Studies of gastric carcinogenesis demonstrate that mature neuroendocrine (NE) cells upon long-term overstimulation may develop through stages of hyperplasia, dysplasia, and rather benign tumours, into highly malignant carcinomas. Dedifferentiation of cells may change the histological appearance and impede the identification of the cellular origin, as seen with gastric carcinomas, which in many cases are dedifferentiated neuroendocrine tumours. Finding the cell of origin is important to identify risk factors for cancer, prevent tumour development, and tailor treatment. In the present review, we focus not only on gastric tumours, but also evaluate the role of neuroendocrine cells in tumourigenesis in two other foregut-derived organs, the lungs and the pancreas, as well as in the midgut-derived small intestine.

  • 180. Walenkamp, Annemiek
    et al.
    Crespo, Guillermo
    Fierro Maya, Felipe
    Fossmark, Reidar
    Igaz, Peter
    Rinke, Anja
    Tamagno, Gianluca
    Vitale, Giovanni
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Meyer, Tim
    Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 6, p. R445-R460Article, review/survey (Refereed)
    Abstract [en]

    In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.

  • 181. Walsh, Kyle M.
    et al.
    Choi, Murim
    Öberg, Kjell E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kulke, Matthew H.
    Yao, James C.
    Wu, Chengqing
    Jurkiewicz, Magdalena
    Hsu, Ling-I
    Hooshmand, Susanne M.
    Hassan, Manal
    Janson, Eva T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vosburgh, Evan
    Sackler, Richard S.
    Lifton, Richard P.
    Dewan, Andrew T.
    Hoh, Josephine
    A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum2011In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 18, no 1, p. 171-180Article in journal (Refereed)
    Abstract [en]

    Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10−7) at a Bonferroni-corrected level (<1.62×10−7). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ∼1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0–77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.

  • 182.
    Wang, S
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lukinius, A
    Department of Genetics and Pathology.
    Zhou, Y
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stålberg, P
    Department of Surgical Sciences.
    Gobl, A
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Subcellular distribution of phospholipase C isoforms in rodent pancreas and gastric mucosa.2000In: Endocrinology, ISSN 0013-7227, Vol. 141, no 7, p. 2589-93Article in journal (Refereed)
  • 183.
    Wang, Shu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gebre-Medhin, Samuel
    Betsholtz, Christer
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Zhou, Yinghua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Larsson, Catharina
    Weber, Gunther
    Feinstein, Ricardo
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Targeted disruption of the mouse phospholipase C β3 gene results in early embryonic lethality1998In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 441, no 2, p. 261-265Article in journal (Other academic)
    Abstract [en]

    In order to investigate the biological function of phosphatidylinositol-specific phospholipase C (PLC) we generated mutant mice by gene targeting. Homozygous inactivation of PLCbeta3 is lethal at embryonic day 2.5. These mutants show poor embryonic organization as well as reduced numbers of cells. Identical phenotypes were recorded in homozygous mutants generated from two independently targeted embryonic stem cell clones. Heterozygous mutant mice, however, are viable and fertile for at least two generations. We also showed that mouse PLCbeta3 is expressed in unfertilized eggs, 3-cell and egg cylinder stages of embryos. In conclusion, these results indicate that PLCbeta3 expression is essential for early mouse embryonic development.

  • 184.
    Wang, Shu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zhou, Yinghua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Subcellular distribution of phospholipase C isoforms in rodent pancreas and gastric mucosa2000In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 141, no 7, p. 2589-2593Article in journal (Refereed)
    Abstract [en]

    Phosphoinositide-specific phospholipase C (PLC) has been implicated as a participant in cell proliferation as well as enzyme and hormone secretion. Defining the subcellular distribution of PLC isoforms would possibly contribute to further understanding of their function. We investigated the intracellular distribution of four PLCs (β1, β2, β3, and γ1) in mouse pancreatic cells as well as mouse and rat gastric mucosa cells by ultrastructural immunocytochemistry. In pancreatic acinar cells, PLCβ1 and PLCγ1 were demonstrated in the zymogen granules while PLCβ2 was present in the granulae as well as the endoplasmic reticulum (ER), and PLCβ3 was prominent in the ER. In the endocrine pancreas, PLCβ2 immunolabeling was expressed in the secretory granulae of α, β, δ, and pancreatic polypeptide cells. PLCβ3 showed a slight labeling in the nucleus and ER of all four pancreatic endocrine cell types while PLCγ1 was prominent in α cell granulae. In the gastric mucosa cells, PLCβ2 was highly expressed in the heterochromatin areas and in the ER of parietal, chief, mucous, and enterochromaffin-like cells. PLCβ3 were expressed in a manner similar to PLCβ2 in those cells; however, no immunoreaction was seen in the ER of parietal cell. PLCγ1 was demonstrated in the chief cell granulae. One possible, although yet speculative, interpretation of our results is that the studied PLC isoforms may be involved in processing in pancreatic secretory granulae and that nuclear PLCβ2 and PLCβ3 signaling pathways may be operative in the cells of the gastric mucosa.

  • 185.
    Weickert, Martin O.
    et al.
    Univ Hosp Coventry, ENETS Ctr Excellence, ARDEN NET Ctr, Coventry CV2 2DX, W Midlands, England;Warwickshire Natl Hlth Serv Trust, Coventry CV2 2DX, W Midlands, England.
    Kaltsas, Gregory
    Univ Hosp Coventry, ENETS Ctr Excellence, ARDEN NET Ctr, Coventry CV2 2DX, W Midlands, England;Warwickshire Natl Hlth Serv Trust, Coventry CV2 2DX, W Midlands, England.
    Hörsch, Dieter
    Zent Klin Bad Berka, Bad Berka, Germany.
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Pavel, Marianne
    Friedrich Alexander Univ Erlangen Nurnberg, Erlangen, Germany;Charite, Berlin, Germany.
    Valle, Juan W.
    Univ Manchester, Christie Natl Hlth Serv Fdn Trust, Manchester, Lancs, England.
    Caplin, Martyn E.
    Royal Free Hosp, European Neuroendocrine Tumor Soc Ctr Excellence, Neuroendocrine Tumour Unit, London, England.
    Bergsland, Emily
    Univ Calif San Francisco, San Francisco, CA 94143 USA.
    Kunz, Pamela L.
    Stanford Univ, Sch Med, Stanford, CA USA.
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA.
    Grande, Enrique
    MD Anderson Int Canc Ctr, Madrid, Spain.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France.
    Ramage, John K.
    Kings Coll Hosp London, Kings Hlth Partners European Neuroendocrine Tumor, London, England.
    Kittur, Ashwin
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Yang, Qi M.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome2018In: Clinical Therapeutics, ISSN 0149-2918, E-ISSN 1879-114X, Vol. 40, no 6, p. 952-962Article in journal (Refereed)
    Abstract [en]

    Purpose: In the placebo-controlled Phase III TELE-STAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and >= 4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m(2)) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

    Methods: Assessment of the occurrence of weight change >= 3% at week 12 was prespecified in the statistical analysis plan.

    Findings: In 120 patients with weight data available, weight gain >= 3% was observed in 2 of 39 patients (5.1%) taking placebo [1.1), 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss >= 3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status.

  • 186.
    Weickert, Martin O.
    et al.
    Univ Hosp Coventry & Warwickshire NHS Trust, Coventry, W Midlands, England.
    Kaltsas, Gregory
    Univ Hosp Coventry & Warwickshire NHS Trust, Coventry, W Midlands, England.
    Hörsch, Dieter
    Zent Klin Bad Berka, Bad Berka, Germany.
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Pavel, Marianne
    Charite, Berlin, Germany.;Friedrich Alexander Univ, Nurnberg, Germany.
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England.
    Caplin, Martyn E.
    Royal Free Hosp, London, England.
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
    Kunz, Pamela L.
    Stanford Univ, Stanford, CA USA.
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA.
    Grande, Enrique
    Hosp Univ Ramon y Cajal, Madrid, Spain.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Warner, Richard R. P.
    Icahn Sch Med Mt Sinai, New York, NY USA.
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France.
    Fleming, Rosanna
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Kittur, Ashwin
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Arnold, Karie
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Yang, Qi M.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA USA.
    Weight Change Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome2018In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 357-358Article in journal (Other academic)
  • 187.
    Welin, Staffan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Lavenius, Erik
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    High-dose treatment with a long-acting somatostatin analogue in patients with advanced midgut carcinoid tumours2004In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 151, no 1, p. 107-112Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    High-dose somatostatin analogue treatment has shown an antiproliferative effect in one study including patients with neuroendocrine tumours. To explore this therapeutic strategy further, we have studied the effect of a high-dose formula of octreotide, octreotide pamoate, in midgut carcinoid patients.

    DESIGN AND METHODS:

    Twelve patients with advanced midgut carcinoid tumours with a median duration of disease of more than 5 years were included. All were in a progressive state despite several previous treatment modalities. Octreotide pamoate (160 mg) was given as an intramuscular injection every 2 weeks for 2 months and then monthly. Radiological and biochemical responses were monitored.

    RESULTS:

    Tumour size and biochemical markers were stabilised for a median of 12 months in 75% of the patients. Ten patients had symptomatic improvement of flush and diarrhoea.

    CONCLUSION:

    In this group of patients with advanced midgut carcinoid tumours and progressive disease, octreotide pamoate managed to improve symptoms, and stabilise hormone production and tumour growth in 75% of the patients. We believe that high-dose treatment with somatostatin analogues can be an important addition to the therapeutic arsenal for patients with advanced progressive midgut carcinoid tumours.

  • 188.
    Welin, Staffan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sorbye, Halfdan
    Sebjornsen, Sigrunn
    Knappskog, Stian
    Busch, Christian
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy2011In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 117, no 20, p. 4617-4622Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first-line palliative chemotherapy. There are, however, no published studies concerning second-line treatment of the disease. Temozolomide has shown clinical effect in well-differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first-line treatment.

    METHODS: Twenty-five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively.

    RESULTS: One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression-free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation.

    CONCLUSIONS: Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first-line chemotherapy. These results indicated that temozolomide may be used as second-line treatment in PDEC.

  • 189.
    Welin, Staffan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Elevated Plasma Chromogranin A is the First Indication of Recurrence in Radically Operated Midgut Carcinoid Tumours2009In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 89, no 3, p. 302-307Article in journal (Refereed)
    Abstract [en]

    Background:

    Patients with malignant midgut carcinoids are occasionally diagnosed with limited tumor spread, and surgery with radical intention is performed. Despite curative intent, recurrences occur frequently, motivating long-term biochemical and radiological follow-up. This study aimed to compare the usefulness of various methods in detecting such recurrences.

    Methods:

    This retrospective study included 56 patients with radically operated midgut carcinoids referred to our University Hospital for evaluation and follow-up between 1985 and 2004. Patients were monitored 1-3 times per year using plasma-chromogranin A (P-CgA), urinary 5-hydroxyindoleacetic acid (U-5HIAA) concentrations as well as radiological examinations, including ultrasonography, computerized tomography or magnetic resonance investigation. In a subset of cases, somatostatin receptor scintigraphy and/or positron emission tomography with 5-hydroxytryptophan was performed. Time from operation until established recurrence was recorded.

    Results:

    Tumor recurrence was established in 33 of 56 patients after a median of 32 months (range 6-217). Elevated P-CgA was the first marker to become pathologically elevated in 28 of these 33 patients (85%). In 3 of these 28 patients, radiology was simultaneously positive for a recurrence.

    Conclusion:

    P-CgA was the first marker to indicate tumor recurrence in the majority of radically operated midgut carcinoid patients. To avoid unnecessary and costly examinations in asymptomatic patients, we suggest that follow-up should comprise measurements of P-CgA twice a year and annual ultrasonography until P-CgA is elevated or clinical symptoms occur, at which time all efforts should be made to identify recurrent tumor lesions in order to give the patient the best possible treatment which, if possible, should be surgical removal of the recurrence.

  • 190. Whitman, Hendricks H
    et al.
    Fishman, Elliot K
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Wildman, Joseph M
    Long, Andrea L
    Catecholamine-secreting metastatic carcinoid as differential diagnosis in pheochromocytoma: clinical, laboratory, and imaging clues in the search for the lurking neuroendocrine tumor (NET).2006In: Annals of the New York Academy of Sciences: Pheochromocytoma: First International Symposium, ISSN 0077-8923, Vol. 1073, p. 59-78Article in journal (Refereed)
  • 191.
    Wolin, Edward M.
    et al.
    Univ Kentucky, Markey Canc Ctr, Lexington, KY 40536 USA..
    Jarzab, Barbara
    Maria Sklodowska Curie Mem Canc Ctr, Dept Nucl Med & Endocrine Oncol, Gliwice, Poland.;Inst Oncol, Gliwice Branch, Gliwice, Poland..
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Walter, Thomas
    Hop Edouard Herriot, Dept Med Oncol, Lyon, France..
    Toumpanakis, Christos
    Royal Free Hosp, Gastroenterol & Neuroendocrine Tumours, London NW3 2QG, England..
    Morse, Michael A.
    Duke Univ, Med Ctr, Dept Med Oncol, Durham, NC USA..
    Tomassetti, Paola
    Univ Hosp St Orsola, Dept Med & Surg Sci, Bologna, Italy..
    Weber, Matthias M.
    Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, D-55122 Mainz, Germany..
    Fogelman, David R.
    Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA..
    Ramage, John
    North Hampshire Hosp, Gastroenterol Unit, Basingstoke, Hants, England..
    Poon, Donald
    Raffles Hosp, Dept Med Oncol, Singapore, Singapore.;Duke NUS Grad Med Sch, Singapore, Singapore..
    Gadbaw, Brian
    Novartis Pharmaceut, E Hanover, NJ USA..
    Li, Jiang
    Novartis Pharmaceut, E Hanover, NJ USA..
    Pasieka, Janice L.
    Foothills Prov Gen Hosp, Surg & Oncol Fac Med, Calgary, AB T2N 2T9, Canada..
    Mahamat, Abakar
    CHU Nice, Hop Archet, Dept Gastrointestinal Oncol, F-06202 Nice, France..
    Swahn, Fredrik
    Karolinska Univ Sjukhuset, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Newell-Price, John
    Univ Sheffield, Sch Med & Biomed Sci, Dept Human Metab, Sheffield, S Yorkshire, England.;Sheffield Teaching Hosp NHS Fdn Trust, Sheffield, S Yorkshire, England..
    Mansoor, Wasat
    Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues2015In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 9, p. 5075-5086Article in journal (Refereed)
    Abstract [en]

    In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

  • 192. Wolin, Edward M.
    et al.
    Jarzab, Barbara
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Walter, Thomas
    Toumpanakis, Christos
    Morse, Michael
    Tomassetti, Paola
    Weber, Matthias
    Fogelman, David
    Ramage, John
    Poon, Donald
    Huang, Jerry
    Hudson, Michelle
    Li, Jiang
    Pasieka, Janice L.
    Mahamat, Abakar
    Swahn, Fredrik
    Newell-Price, John
    Mansoor, Was
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A Multicenter, Randomized, Blinded, Phase 3 Study of Pasireotide LAR vs Octreotide LAR in Patients with Metastatic Neuroendocrine Tumors (NET) with Disease-Related Symptoms Inadequately Controlled by Somatostatin Analogs2014In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 43, no 3, p. 508-508Article in journal (Other academic)
  • 193.
    Yao, James C.
    et al.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Pavel, Marianne
    Charite, Berlin, Germany..
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Van Cutsem, Eric
    Univ Hosp Gasthuisberg, Leuven, Belgium.;Univ Hosp Leuven, Leuven, Belgium.;Katholieke Univ Leuven, Leuven, Belgium..
    Voi, Maurizio
    Novartis, E Hanover, NJ USA..
    Brandt, Ulrike
    Novartis Pharma AG, Basel, Switzerland..
    He, Wei
    Novartis, E Hanover, NJ USA..
    Chen, David
    Novartis, E Hanover, NJ USA..
    Capdevila, Jaume
    Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Barcelona, Spain..
    de Vries, Elisabeth G. E.
    Univ Groningen, UMCG, Groningen, Netherlands..
    Tomassetti, Paola
    Univ Bologna, Bologna, Italy..
    Hobday, Timothy
    Mayo Clin, Coll Med, Rochester, MN USA..
    Pommier, Rodney
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 32, p. 3906-3913Article in journal (Refereed)
    Abstract [en]

    Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low-or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to openlabel everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

  • 194. Yao, James C
    et al.
    Pavel, Marianne
    Phan, Alexandria T
    Kulke, Matthew H
    Hoosen, Sakina
    St Peter, Jessica
    Cherfi, Azzeddine
    Öberg, Kjell E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chromogranin A and Neuron-Specific Enolase as Prognostic Markers in Patients with Advanced pNET Treated with Everolimus2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 12, p. 3741-3749Article in journal (Refereed)
    Abstract [en]

    Context:Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors.

    Objective:The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus.

    Patients and Methods:Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels.

    Results:In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study.

    Conclusions:Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

  • 195. Yao, James C.
    et al.
    Öberg, Kjell E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hainsworth, John D.
    Lam, Du
    Stergiopolos, Sotirios G.
    Rouyrre, Nicolas
    Peeters, Marc
    Baudin, Eric
    Gross, David
    Pavel, Marianne E.
    Everolimus Plus Octreotide Long-Acting Repeatable (LAR) for the Treatment of Advanced Neuroendocrine Tumors (NET) Associated with Carcinoid Syndrome: Updated Overall Survival Results from RADIANT-2 Study2014In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 43, no 3, p. 508-509Article in journal (Other academic)
  • 196.
    Yu, Di
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Leja, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 1, p. 54-66Article in journal (Refereed)
    Abstract [en]

    Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately, 73-fold higher concentration of AdVince is needed to induce similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET.

  • 197.
    Zhou, Y
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wang, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Yue, BG
    Gobl, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Effects of interferon alpha on the expression of p21cip1/waf1 and cellcycle distribution in carcinoid tumors.2002In: Cancer Invest, Vol. 20, p. 348-Article in journal (Refereed)
    Abstract [en]

    Interferon alpha (IFN-alpha) has been shown to produce antitumor effects in 50-80% of carcinoid tumor patients and has demonstrated anti-proliferative effects in carcinoid tumor cells, but the mechanism is not well established. This study presents evidence that in a carcinoid tumor cell line, Bon1, IFN-alpha increases the expression of p21 and promotes nuclear translocation of endogenous p21. Furthermore, immunoprecipitation experiments demonstrated that p21 formed immuno-complexes with Stat1 and Stat2 in the nucleus of cells. Interferon alpha can decrease G1- and G2-phase cells, but increase S-phase population. The p21 mRNA expression is inversely correlated to the G1 population (r = -0.933, P < 0.05) and positively correlated to the S-phase population (r = 0.901, P < 0.05). In addition, IFN-alpha inhibited cyclin dependent kinases (CDK), CDK2-, CDK3-, CDK4-, and cyclin E- but not cyclin A-associated kinase activities. Immunodepletion of p21 resulted in a significant enhancement of CDK3 kinase activity (approximately 1.6-fold increase). These results suggest that the mechanism of antitumor and cell cycle regulation of IFN-alpha in carcinoid tumors may, at least in part, be p21-dependent. Based on these results, we conclude that IFN-alpha exerts antitumor effects by increased p21 expression in neuroendocrine tumors.

  • 198.
    Zhou, Yinghua
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Gobl, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wang, Shu
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Jacobsen, M B
    Tiensuu Janson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Haines, G K
    Radosevich, J A
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Expression of p68 protein kinase and its prognostic significance during IFN-a therapy in patients with carcinoid tumors1998In: Eur J Cancer, Vol. 34, p. 2046-Article in journal (Refereed)
  • 199.
    Öberg, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Neuroendocrine tumors2002In: Tumor markers: physiology, pathobiology, technology and clinical applications, 2002, p. 339-349Chapter in book (Other scientific)
  • 200.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Advances in Neuroendocrine Tumor Management2011Collection (editor) (Refereed)
123456 151 - 200 of 253
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