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  • 51.
    Granberg, Dan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Clinical Chemistry.
    Seensalu, Rein
    Eriksson, Barbro
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Plasma Chromogranin A In Patients with Multiple Endocrine Neoplasia Type 11999In: Journal of Clinical Endocrinology and Metabolism, Vol. 84, no 8, p. 2712-2717Article in journal (Refereed)
  • 52.
    Granberg, Dan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Department of Oncology, Radiology and Clinical Immunology.
    Tiensuu Janson, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Westlin, Jan-Erik
    Octreoscan in patients with bronchial carcinoid tumours.2003In: Clin Endocrinol (Oxf), ISSN 0300-0664, Vol. 59, no 6, p. 793-9Article in journal (Refereed)
  • 53.
    Granberg, Dan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Wilander, Erik
    Department of Genetics and Pathology. Department of Genetics and Pathology.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Expression of tyrosine kinase receptors in lung carcinoids.2006In: Tumour Biol, ISSN 1010-4283, Vol. 27, no 3, p. 153-7Article in journal (Refereed)
  • 54.
    Granberg, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granerus, Göran
    Skogseid, Britt
    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.
    Clinical symptoms, hormone profiles, treatment, and prognosis in patients with gastric carcinoids1998In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 43, no 2, p. 223-228Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Type 1 gastric carcinoids are associated with hypergastrinaemia and chronic atrophic gastritis, type 2 occur in patients with multiple endocrine neoplasia type 1 combined with Zollinger-Ellison syndrome, and type 3 lack any relation to hypergastrinaemia. Type 1 tumours are usually benign whereas type 3 are highly malignant. AIMS: To identify possible tumour markers in patients with gastric carcinoids. PATIENTS/METHOD: Nine patients with type 1, one with type 2, and five with type 3 were evaluated with regard to symptoms, hormone profile, and prognosis. RESULTS: Plasma chromogranin A was increased in all patients but was higher (p < 0.01) in those with type 3 than those with type 1 carcinoids. All patients with type 3 carcinoids died from metastatic disease, but none of the type 1 patients died as a result of their tumours. One type 1 patient with a solitary liver metastasis received interferon alpha and octreotide treatment. Nine months later, the metastasis was no longer detectable. She is still alive eight years after diagnosis, without recurrent disease. This represents the only reported case of foregut carcinoid with an unresectable liver metastasis that seems to be have been cured by biotherapy. CONCLUSIONS: Plasma chromogranin A appears to be a valuable tumour marker for all types of gastric carcinoid. Combination therapy with interferon alpha and octreotide may be beneficial in patients with metastasising type 1 gastric carcinoids.

  • 55. Grander, D
    et al.
    Oberg, K
    Uppsala University.
    Lundqvist, M L
    Tiensuu Janson, E
    Uppsala University.
    Eriksson, B
    Uppsala University.
    Einhorn, S
    Interferon-induced enhancement of 2',5'-oligoadenylate synthetase in mid-gut carcinoid tumours.1990In: Lancet, ISSN 0140-6736, Vol. 336, no 8711, p. 337-40Article in journal (Refereed)
  • 56. Grimaldi, Franco
    et al.
    Fazio, Nicola
    Attanasio, Roberto
    Frasoldati, Andrea
    Papini, Enrico
    Angelini, Francesco
    Baldelli, Roberto
    Berretti, Debora
    Bianchetti, Sara
    Bizzarri, Giancarlo
    Caputo, Marco
    Castello, Roberto
    Cremonini, Nadia
    Crescenzi, Anna
    Davi, Maria Vittoria
    D'Elia, Angela Valentina
    Faggiano, Antongiulio
    Pizzolitto, Stefano
    Versari, Annibale
    Zini, Michele
    Rindi, Guido
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms2014In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 37, no 9, p. 875-909Article in journal (Refereed)
  • 57. Grimaldi, Franco
    et al.
    Fazio, Nicola
    Attanasio, Roberto
    Frasoldati, Andrea
    Papini, Enrico
    Cremonini, Nadia
    Davi, Mariavittoria
    Funicelli, Luigi
    Massironi, Sara
    Spada, Francesca
    Toscano, Vincenzo
    Versari, Annibale
    Zini, Michele
    Falconi, Massimo
    Öberg, Kjell
    Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms2018In: Endocrine, Metabolic & Immune Disorders - Drug Targets, ISSN 1871-5303, E-ISSN 2212-3873, Vol. 18Article in journal (Refereed)
    Abstract [en]

    Well-established criteria for evaluating the response to treatment and the appropriate follow-up of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs.

  • 58.
    Hellman, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Lundstrom, T
    Ohrvall, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, B
    Department of Medical Sciences.
    Skogseid, B
    Department of Medical Sciences.
    Oberg, K
    Department of Medical Sciences.
    Tiensuu Janson, E
    Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases.2002In: World J Surg, Vol. 26, p. 991-Article in journal (Refereed)
  • 59.
    Hoersch, D.
    et al.
    Zentralklin Bad Berka, Dept Internal Med, Bad Berka, Germany..
    Kulke, M. H.
    Dana Farber Canc Inst, Div Med Oncol Solid Tumor Oncol, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England..
    Anthony, L.
    Univ Kentucky, Div Med Oncol, Chandler Med Ctr, Lexington, KY USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, Hereditary GI Canc Prevent Program, San Francisco, CA USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Warner, R. R. P.
    Icahn Sch Med Mt Sinai, Div Gastroenterol, New York, NY 10029 USA..
    Kunz, P.
    Stanford Univ, Med Ctr, Div Oncol, Stanford, CA 94305 USA..
    Grande Pulido, E.
    Hosp Univ Ramon y Cajal, Dept Med Oncol, Madrid, Spain..
    Valle, J. W.
    Univ Manchester, Dept Med Oncol, Christie, Manchester, Lancs, England..
    Dillon, J. S.
    Univ Iowa, Dept Internal Med Endocrinol & Metab, Iowa City, IA USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, Lexicon Pharmaceut, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut Inc, Lexicon Pharmaceut, The Woodlands, TX USA..
    Jackson, S.
    Lexicon Pharmaceut Inc, Lexicon Pharmaceut, The Woodlands, TX USA..
    Pavel, M.
    Charite, Dept Gastroenterol & Hepatol Endocrinol & Metab D, Berlin, Germany..
    Efficacy and safety of telotristat ethyl in patients with carcinoid syndrome inadequately controlled by somatostatin analogs: Analysis of the completed TELESTAR extension period2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S5, article id 440PDArticle in journal (Other academic)
  • 60.
    Hrsch, D.
    et al.
    Zent Klin Bad Berka, Bad Berka, Germany..
    Kulke, M.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, London, England..
    Anthony, L.
    Univ Kentucky, Lexington, KY 40506 USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    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, Endocrine oncology.
    Warner, R.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, C.
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, P.
    Stanford Univ, Palo Alto, CA 94304 USA..
    Valle, J.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England..
    Fleming, D.
    Ipsen BioSci, Cambridge, MA USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Pavel, M.
    Charite, Berlin, Germany..
    Efficacy and Safety of Telotristat Etiprate in Patients with Carcinoid Syndrome Not Adequately Controlled by Somatostatin Analog Therapy: Analysis of the Ongoing TELESTAR Extension Period2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 88-88Article in journal (Refereed)
  • 61.
    Hörsch, Dieter
    et al.
    Zent Klin Bad Berka, Bad Berka, Germany.
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA, USA.
    Caplin, Martyn E.
    Royal Free Hosp, ENETS Ctr Excellence, London, England.
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA.
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Warner, Richard R. P.
    Icahn Sch Med Mt Sinai, New York, NY, USA.
    Kunz, Pamela L.
    Stanford Univ, Stanford, CA, USA.
    Grande, Enrique
    Hosp Ramon & Cajal, Madrid, Spain.
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England.
    Dillon, Joseph S.
    Univ Iowa, Iowa City, IA USA.
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX, USA.
    Banks, Phillip
    Lexicon Pharmaceut Inc, The Woodlands, TX, USA.
    Jackson, Shanna
    Lexicon Pharmaceut Inc, The Woodlands, TX, USA.
    Pavel, Marianne
    Charite, Berlin, Germany.;Friedrich Alexander Univ, Nurnberg, Germany..
    Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period2018In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 341-342Article in journal (Other academic)
  • 62.
    Imam, Hassan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lukinius, Agneta
    Tiensuu Janson, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindgren, PG
    Department of Oncology, Radiology and Clinical Immunology.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Induction of apoptosis in neuroendocrine tumors of digestive system during treatment with somatostatin analogs.1997In: Acta Oncol., Vol. 36, p. 60714-Article in journal (Refereed)
  • 63.
    Kalkner, Karl Mikael
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tiensuu Janson, Eva
    Department of Medical Sciences.
    Nilsson, S
    Carlsson, S
    Oberg, Kjell
    Department of Medical Sciences.
    Westlin, Jan Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Somatostatin receptor scintigraphy in patients with carcinoid tumors: Comparison between radioligand uptake and tumor markers.1995In: Cancer Research, Vol. 55, p. 5801-Article in journal (Refereed)
  • 64. Kanakis, G.
    et al.
    Kaltsas, G.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Papaioannou, D.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Unusual Complication of a Pancreatic Neuroendocrine Tumor Presenting with Malignant Hypercalcemia2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 4, p. E627-E631Article in journal (Refereed)
    Abstract [en]

    Context:

    Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia but has only been described in a few cases of neuroendocrine tumors (NET).

    Objective:

    The aim of this case report is to describe the clinical syndrome, complex therapeutic interventions, and unusual complications caused by persistent PTHrP hypersecretion in a patient with a pancreatic NET.

    Case Illustration:

    A 58-yr-old male patient presented with nonspecific abdominal pain and was found to have severe hypercalcemia secondary to a well-differentiated NET of the pancreas associated with extensive liver metastases. Elevated ionized calcium levels accompanied by low serum PTH and remarkably elevated PTHrP concentrations were consistent with PTHrP-related hypercalcemia that proved to be resistant to various chemotherapeutic regimens and supportive therapy. Partial control of the humoral syndrome was obtained only after the application of cytoreductive interventions and the introduction of various molecular targeted therapies. Due to persistent PTHrP action, bone disease emerged in the form of brown tumors.

    Discussion:

    The manifestation of paraneoplastic syndrome due to PTHrP hypersecretion, despite its rareness in NET, should be considered in the differential diagnosis of hypercalcemia in such tumors. Moreover, the appearance of bone lesions in this setting may be in the context of metabolic bone disease and could be misdiagnosed as bone metastases.

  • 65. Kanakis, George
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Spathis, Athanasios
    Tringidou, Rodoula
    Rassidakis, George Z.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Kaltsas, Gregory
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, no 3, p. 211-222Article in journal (Refereed)
    Abstract [en]

    Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

  • 66. Karadeniz, Cemile
    et al.
    Köse, Fatih
    Abali, Hüseyin
    Sümbül, Ahmet Taner
    Oğuzkurt, Levent
    Karabacak, Tuba
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Severe systemic vasoconstriction starting with acute limb ischemia leading to death in a patient with well-differentiated pulmonary neuroendocrine carcinoma: a new paraneoplastic syndrome?2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 124-127Article in journal (Refereed)
  • 67.
    Kidd, Mark
    et al.
    Yale Univ, Dept Surg, Sch Med, 333 Cedar St, New Haven, CT 06519 USA.
    Modlin, Irvin
    Yale Univ, Dept Surg, Sch Med, 333 Cedar St, New Haven, CT 06519 USA.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms.2016In: Nature Reviews Clinical Oncology, ISSN 1759-4774, E-ISSN 1759-4782, Vol. 13, no 11, p. 691-705Article, review/survey (Refereed)
    Abstract [en]

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a heterogeneous group of tumours associated with variable clinical presentations, growth rates, and prognoses. To improve the management of GEP-NENs, the WHO developed a classification system that enables tumours to be graded based on markers of cell proliferation in biopsy specimens. Indeed, histopathology has been a mainstay in the diagnosis of GEP-NENs, and the WHO grading system facilitates therapeutic decision-making; however, considerable intratumoural heterogeneity, predominantly comprising regional variations in proliferation rates, complicates the evaluation of tumour biology. The use of molecular imaging modalities to delineate the most-aggressive cell populations is becoming more widespread. In addition, molecular profiling is increasingly undertaken in the clinical setting, and genomic studies have revealed a number of chromosomal alterations in GEP-NENs, although the 'drivers' of neoplastic development have not been identified. Thus, our molecular understanding of GEP-NENs remains insufficient to inform on patient prognosis or selection for treatments, and the WHO classification continues to form the basis for management of this disease. Nevertheless, our increasing understanding of the molecular genetics and biology of GEP-NENs has begun to expose flaws in the WHO classification. We describe the current understanding of the molecular characteristics of GEP-NENs, and discuss how advances in molecular profiling measurements, including assays of circulating mRNAs, are likely to influence the management of these tumours.

  • 68.
    Kindmark, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dunder, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    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.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years2007In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 24, no 3, p. 330-337Article in journal (Refereed)
    Abstract [en]

    Background  Glucagon-secreting endocrine pancreatic tumor is a rare disease, hence controlled studies on clinical management are lacking. In an attempt to assess the efficacy of diagnostic and therapeutic measures in patients with glucagonoma, a retrospective study was performed using the archives of a tertiary care center. Patients and methods  Records from 340 patients with endocrine pancreatic tumors were reassessed and 23 patients with malignant endocrine pancreatic tumor and elevated plasma glucagon levels were identified. Results  About 7% of patients with histologically verified tumors fullfilled our criteria for glucagonoma. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma. Seventy eight percent had metastatic disease to the liver at diagnosis. Necrolytic migratory erythema was diagnosed or clinically suspected in 52%. Somatostatin receptor scintigraphy was positive in 95%. Nineteen patients received chemotherapy at some point, in 18 cases streptozotocin and 5 FU. With this treatment, objective radiological responses were seen in 50% of evaluable patients. Other treatment modalities used were interferon, somatostatin analogs, hepatic artery embolization, radio-frequency ablation of liver metastases, and radiolabeled somatostatin analogs. During the study period, 11 patients died at a median of 80 months from diagnosis whereas 11 patients are still alive after a median follow up of 52 months. One patient was lost to follow-up. Conclusions  Glucagonomas represent 7% of our comprehensive referal material of endocrine pancreatic tumors. Necrolytic migratory erythema was a common finding (52%) and diabetes less frequent at presentation than previously reported. Tumors were positive on somatostatin receptor scintigraphy and objective responses were seen to chemotherapy.

  • 69.
    Koumarianou, Anna
    et al.
    Attikon Univ Hosp, Hematol Oncol Unit, Dept Internal Med 4, GR-12462 Athens, Greece..
    Kaltsas, Gregory
    Natl Tech Univ Athens, Dept Pathophysiol, Endocrine Unit, Athens, Greece..
    Kulke, Matthew H.
    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Strosberg, Jonathan R.
    Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA..
    Spada, Francesca
    European Inst Oncol, Gastrointestinal Med Oncol & Neuroendocrine Tumor, IT-20141 Milan, Italy..
    Galdy, Salvatore
    European Inst Oncol, Gastrointestinal Med Oncol & Neuroendocrine Tumor, IT-20141 Milan, Italy..
    Barberis, Massimo
    European Inst Oncol, Div Pathol, IT-20141 Milan, Italy..
    Fumagalli, Caterina
    European Inst Oncol, Div Pathol, IT-20141 Milan, Italy..
    Berruti, Alfredo
    Univ Brescia, Dipartimento Specialita Med Chirurg Sci Radiol &, Azienda Osped Spedali Civili, Brescia, Italy..
    Fazio, Nicola
    European Inst Oncol, Gastrointestinal Med Oncol & Neuroendocrine Tumor, IT-20141 Milan, Italy..
    Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, no 4, p. 274-288Article in journal (Refereed)
    Abstract [en]

    Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the CP-nnethylguanineDNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response. 

  • 70.
    Kulke, M. H.
    et al.
    Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA..
    Hoersch, D.
    Zent Klin Bad Berka, Ctr Neuroendocrine Tumors, Bad Berka, Germany..
    Caplin, M.
    Royal Free Hosp, Ctr Gastroenterol, London NW3 2QG, England..
    Anthony, L.
    Univ Kentucky, Med Ctr, Dept Med, Div Med Oncol, Lexington, KY 40536 USA..
    Bergsland, E.
    Univ Calif San Francisco, Med Ctr, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Warner, R.
    Mt Sinai Hosp, Dept Med Gastroenterol, New York, NY 10029 USA..
    Lombard-Bohas, C.
    Hosp Civils Lyon, Hop Edouard Herriot, Med Oncol, Lyon, France..
    Kunz, P.
    Stanford Univ, Sch Med Med Oncol, Palo Alto, CA 94304 USA..
    Grande, E.
    Hosp Univ Ramon y Cajal, Dept Med Oncol, Madrid, Spain..
    Valle, J.
    Christie NHS Fdn Trust, Med Oncol, London, England..
    Fleming, D.
    Ipsen BioSci, Clin Dev, Cambridge, MA USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, Clin Dev, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut Inc, Clin Dev, The Woodlands, TX USA..
    Jackson, S.
    Lexicon Pharmaceut Inc, Clin Dev, The Woodlands, TX USA..
    Wheeler, D.
    Lexicon Pharmaceut Inc, Med Affairs, The Woodlands, TX USA..
    Zambrowicz, B.
    Lexicon Pharmaceut Inc, Res & Dev, The Woodlands, TX USA..
    Sands, A.
    Lexicon Pharmaceut Inc, Res & Dev, The Woodlands, TX USA..
    Pavel, M.
    Charite, Dept Gastroenterol & Hepatol, D-13353 Berlin, Germany..
    Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial)2015In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 51, no S3, p. S728-S728Article in journal (Other academic)
  • 71.
    Kulke, M.
    et al.
    Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA..
    Hoersch, D.
    Zent Klin Bad Berka GmbH, Ctr Neuroendocrine Tumors Bad Berka, Gastroenterol & Endocrinol, Bad Berka, Germany..
    Caplin, M.
    Royal Free Hosp, Sch Med, Gastroenterol & Neuroendocrine Tumours, London, England..
    Anthony, L.
    Univ Kentucky, Med Oncol, Lexington, KY USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, Hematol Oncol, San Francisco, CA USA..
    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, Endocrine oncology.
    Warner, R.
    Mt SInai Med Coll, Gastroenterol, New York, NY USA..
    Bohas, C. Lombard
    Hop Edouard Herriot, Med Oncol, Pav E Bis, Lyon, France..
    Kunz, P. L.
    Stanford Univ, Sch Med, Med Oncol, Palo Alto, CA 94304 USA..
    Grande, E.
    Hosp Univ Ramon & Cajal, Med Oncol, Madrid, Spain..
    Valle, J. W.
    Univ Manchester, Christie NHS Fdn Trust, Med Oncol, Manchester, Lancs, England..
    Lapuerta, P.
    Lexicon Pharmaceut, Med Affairs, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut, Med Affairs, The Woodlands, TX USA..
    Jackson, S.
    Lexicon Pharmaceut Inc, Clin Operat, The Woodlands, TX USA..
    Jiang, W.
    Lexicon Pharmaceut, Med Affairs, The Woodlands, TX USA..
    Biran, T.
    Lexicon Pharmaceut Inc, Clin Operat, The Woodlands, TX USA..
    Pavel, M.
    Charite, Endocrinol, Berlin, Germany..
    Integrated placebo-controlled safety analysis from clinical studies of telotristat ethyl for the treatment of carcinoid syndrome2016In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, no suppl. 6, article id 422PDArticle in journal (Refereed)
  • 72.
    Kulke, Matthew H.
    et al.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Hoersch, Dieter
    Zentralklin Bad Berka, Bad Berka, Germany..
    Caplin, Martyn
    Royal Free Hosp, Pond St, London NW3 2QG, England..
    Anthony, Lowell
    Univ Kentucky, Lexington, KY USA..
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    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, Endocrine Oncology. Uppsala Univ, Uppsala, Sweden..
    Warner, Richard
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, Catherine
    Hos Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, Pamela
    Stanford Univ, Palo Alto, CA 94304 USA..
    Grande, Enrique
    Hosp Univ Ramon & Cajal, Madrid, Spain..
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdon Trust, Manchester, Lancs, England..
    Fleming, Douglas
    Ipsen BioSci, Cambridge, MA USA..
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Banks, Phillip
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Jackson, Shanna
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Wheeler, Darren
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Zambrowicz, Brian
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Sands, Arthur
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Pavel, Marianne
    Charite, D-13353 Berlin, Germany..
    Telotristat Etiprate Shows Benefit in Treating Patients With Carcinoid Syndrome That is Inadequately Controlled by Somatostatin Analog Therapy in the Phase 3 TELESTAR Clinical Trial2016In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 3, p. 478-478Article in journal (Other academic)
  • 73.
    Kulke, Matthew H.
    et al.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Hoersch, Dieter
    Zentralklinik Bad Berka, Bad Berka, Germany..
    Caplin, Martyn E.
    Royal Free Hosp, London, England..
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA..
    Bergsland, Emily
    Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA..
    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.
    Warner, Richard R. P.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, Pamela L.
    Stanford Univ, Palo Alto, CA 94304 USA..
    Grande, Enrique
    Hosp Univ Ramon y Cajal, Madrid, Spain..
    Valle, Juan W.
    Univ Manchester, Christie Natl Hlth Serv Fdn Trust, Manchester, Lancs, England..
    Fleming, Douglas
    Ipsen Biosci, Cambridge, MA USA..
    Lapuerta, Pablo
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Banks, Phillip
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Jackson, Shanna
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Zambrowicz, Brian
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Sands, Arthur T.
    Lexicon Pharmaceut, The Woodlands, TX USA..
    Pavel, Marianne
    Charite, Berlin, Germany..
    Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome2017In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 35, no 1, p. 14-23Article in journal (Refereed)
    Abstract [en]

    Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1: 1: 1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg (P < .001) and -0.69 for telotristat ethyl 500 mg (P,.001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction >= 30% from baseline for >= 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 (P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

  • 74. Kvols, Larry K
    et al.
    Öberg, Kjell E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    O'Dorisio, Thomas M
    Mohideen, Pharis
    de Herder, Wouter W
    Arnold, Rudolf
    Hu, Ke
    Zhang, Yilong
    Hughes, Gareth
    Anthony, Lowell
    Wiedenmann, Bertram
    Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study2012In: Endocrine-related cancer, ISSN 1479-6821, Vol. 19, no 5, p. 657-66Article in journal (Refereed)
    Abstract [en]

    Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst(1,2,3)) and sst(5). Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.

  • 75.
    Lapuerta, P.
    et al.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Kulke, M. H.
    Dana Farber Canc Inst, Gastrointestinal Canc Treatment Ctr, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, Hereditary GI Canc Prevent Program, San Francisco, CA USA..
    Anthony, L.
    Univ Kentucky, Chandler Med Ctr, Div Med Oncol, Lexington, KY USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Pavel, M.
    Charite, Dept Gastroenterol & Hepatol Endocrinol & Metab D, Berlin, Germany..
    Hoersch, D.
    Zentralklin Bad Berka, Dept Internal Med, Bad Berka, Germany..
    O'Dorisio, T. M.
    Univ Iowa, Dept Internal Med Endocrinol & Metab, Iowa City, IA USA..
    Dillon, J. S.
    Univ Iowa, Dept Internal Med Endocrinol & Metab, Iowa City, IA USA..
    Kassler-Taub, K.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Jiang, W.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Long-term survival of patients with carcinoid syndrome in clinical trials of telotristat ethyl2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S5, article id 442PArticle in journal (Other academic)
  • 76.
    Larsson, Dhana E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Öberg, Kjell
    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.
    The Cytotoxic Effect of Emetine and CGP-74514A Studied with the Hollow Fiber Model and ArrayScan Assay in Neuroendocrine Tumors In Vitro2012In: ANTI-CANCER AGENT ME, ISSN 1871-5206, Vol. 12, no 7, p. 783-790Article in journal (Refereed)
    Abstract [en]

    Emetine and CGP-74514A have previously shown antitumor activity in neuroendocrine tumor cell lines. The aim of this study was to investigate the cytotoxic activity of the drugs in a three-dimensional model and to study if the mechanism of the cytotoxic activity was induction of apoptosis. An in vitro hollow fiber model was used to study the cytotoxic effect and a multiparametric high-content screening assay was used for measurement of apoptosis. The human pancreatic carcinoid cell line, BON-1 and the human typical and atypical bronchial carcinoid cell lines NCI-H727 and NCI-H720 were tested. Emetine and CGP-74514A showed higher antitumor activity on NCI-H720 compared to NCI-H727 and 3 day cultures were more sensitive than the 14 day cultures. A time-and dose-dependent activation of caspase-3 and increase in nuclear fragmentation and condensation were observed for the drugs in NCI-H727 and BON-1 using a multiparametric apoptosis assay. These results were confirmed with nuclear morphological examinations on microscopic slides. Emetine and CGP-74514A showed antitumor activity and induced caspase-3 activation with modest changes in nuclear morphology, indicating induction of apoptosis.

  • 77.
    Larsson, Dhana E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Identification and evaluation of potential anti-cancer drugs on human neuroendocrine tumor cell lines2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 6B, p. 4125-4129Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate drug sensitivity in neuroendocrine tumor cell lines. Materials and Methods: In vitro drug sensitivity screening was performed using the fluorometric microculture cytotoxicity assay in one human pancreatic carcinoid and two human bronchial carcinoid cell lines. In addition, a normal human retinal pigment epithelial cell line was used for comparison. A total of 18 drugs with different mechanisms of action were tested. Results: The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC50 values < 1 μM in all four cell lines. In addition, the three tumor cell lines showed sensitivity for sanguinarine, Bay11-7085, mitoxantrone, doxorubicin, β-lapachone, NSC 95397 and CGP-74514A. Conclusion: The cell lines were sensitive for several drugs acting in different ways, covering a broad spectrum of mechanisms of action. Some of these compounds may possibly be used in clinical trials and show therapeutic effect in patients with neuroendocrine tumors.

  • 78.
    Larsson, Gunnel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. 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, Caring Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Importance-satisfaction discrepancies are associated with health-related quality of life in five-year survivors of endocrine gastrointestinal tumours1999In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 10, no 11, p. 1321-1327Article in journal (Refereed)
    Abstract [en]

    Background: Little is known about the health-related-quality of life (HRQoL) of patients with endocrine gastrointestinal tumours. In this study, HRQoL was investigated in long-term survivors of endocrine GI tumours.

    Patients and methods: A questionnaire including the EORTC QLQ-C30 and ratings of importance of and satisfaction with a variety of HRQoL aspects was mailed to patients with carci-noid tumours (n = 64), or endocrine pancreatic tumours (EPT, n = 55). Median time since diagnosis was 120 months (range 60–360). The majority of patients (77 of 119) had ongoing treatment.

    Results: The EORTC QLQ-C30 ratings suggest that in spite of a long disease duration and treatment, patients perceived their HRQoL as relatively good. There were no major differences in HRQoL ratings between patients with carcinoid tumours and those with EPT. Patients whose ratings of importance was higher than their ratings of satisfaction with a specific HRQoL aspect also evidenced a low HRQoL for that aspect.

    Conclusions: The results indicate that survivors of endocrine GI tumours enjoy a relatively good HRQoL and suggest that importance < satisfaction discrepancies identify patients with a low quality of life.

  • 79.
    Leja, Justyna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Dzojic, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    A novel chromogranin-A promoter-driven oncolytic adenovirus for midgut carcinoid therapy2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 8, p. 2455-2462Article in journal (Refereed)
    Abstract [en]

    Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene.

    Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases.

    Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes.

    Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.

  • 80.
    Leja, Justyna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hakkarainen, Tanja
    University of Helsinki, Finnish Institute for Molecular Medicine.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells2011In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 18, no 11, p. 1052-1062Article in journal (Refereed)
    Abstract [en]

    We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5 while it transduces normal hepatocytes at about 50% of Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systematic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.

  • 81.
    Li, Su-Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Essaghir, Ahmed
    Martijn, Cécile
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Lloyd, Ricardo V
    Demoulin, Jean-Baptiste
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors.2013In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 5, p. 685-696Article in journal (Refereed)
    Abstract [en]

    Well-differentiated small intestinal neuroendocrine tumors are rare malignancies. They arise from enterochromaffin cells and very little is known about differential microRNA (miRNA) expression. The aim of this study was to identify the miRNA profile of well-differentiated small intestinal neuroendocrine tumors, which may have a critical role in tumor development, progression and potentially develop miRNAs as novel clinical biomarkers. Specimens from two test groups, 24 small intestinal neuroendocrine tumor specimens at different stages of malignancy, are included in this study. Total RNA from the first test group, five primary tumors, five mesentery metastases and five liver metastases was hybridized onto the Affymetrix Genechip miRNA arrays to perform a genome-wide profile. The results were validated by using quantitative real-time PCR (QRT-PCR) and northern blot analyses. We then expanded the investigation to laser capture microdissected small intestinal neuroendocrine tumor cells and immuno-laser capture microdissected normal enterochromaffin cells of the first test group. Furthermore, a second test group, three primary tumors, three mesentery metastases and three liver metastases, was included in the study. Thus, two independent test groups validated the data by QRT-PCR. Moreover, we characterized nine miRNAs, five (miR-96, -182, -183, -196a and -200a), which are upregulated during tumor progression, whereas four (miR-31, -129-5p, -133a and -215) are downregulated. Several online software programs were used to predict potential miRNA target genes to map a number of putative target genes for the aberrantly regulated miRNAs, through an advanced and novel bioinformatics analysis. Our findings provide information about pivotal miRNAs, which may lead to further insights into tumorigenesis, progression mechanisms and novel therapeutic targets recognition.

  • 82.
    Li, Su-Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Khan, M. S.
    Caplin, M.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Meyer, T.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    MicroRNA Expression in Serum of Small Intestine Neuroendocrine Tumor Patients and miR-196a Biological Function in Neuroendocrine Tumor Cells2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 228-228Article in journal (Other academic)
  • 83.
    Li, Su-Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Khan, Mohid
    Caplin, Martyn
    Meyer, Tim
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Circulating microRNA detection in small intestinal neuroendocrine tumor patients treated with somatostatin analogs2014Article in journal (Refereed)
  • 84.
    Li, Su-Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Khan, Mohid
    Caplin, Martyn
    Meyer, Tim
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0125553Article in journal (Refereed)
    Abstract [en]

    We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients' microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression.

  • 85.
    Li, Su-Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Martijn, Cecile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Essaghir, Ahmed
    Lloyd, Ricardo V.
    Demoulin, Jean-Baptiste
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    B12Global MicroRNA Profiling of Small Intestine Neuroendocrine Tumors (SI-NETs) and Establishment of a Method to Study Serum MicroRNA Expression From the Same Tumors2013In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 42, no 2, p. 377-377Article in journal (Other academic)
  • 86.
    Li, Su-Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cui, Tao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Essaghir, Ahmed
    Luque, Raúl M.
    Demoulin, Jean-Baptiste
    Castaño, Justo P.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    The Somatostatin Analogue Octreotide Inhibits Growth of Small Intestine Neuroendocrine Tumour Cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e48411-Article in journal (Refereed)
    Abstract [en]

    Octreotide is a widely used synthetic somatostatin analogue that significantly improves the management of neuroendocrine tumours (NETs). Octreotide acts through somatostatin receptors (SSTRs). However, the molecular mechanisms leading to successful disease control or symptom management, especially when SSTRs levels are low, are largely unknown. We provide novel insights into how octreotide controls NET cells. CNDT2.5 cells were treated from 1 day up to 16 months with octreotide and then were profiled using Affymetrix microarray analysis. Quantitative real-time PCR and western blot analyses were used to validate microarray profiling in silico data. WST-1 cell proliferation assay was applied to evaluate cell growth of CNDT2.5 cells in the presence or absence of 1 μM octreotide at different time points. Moreover, laser capture microdissected tumour cells and paraffin embedded tissue slides from SI-NETs at different stages of disease were used to identify transcriptional and translational expression. Microarrays analyses did not reveal relevant changes in SSTR expression levels. Unexpectedly, six novel genes were found to be upregulated by octreotide: annexin A1 (ANXA1), rho GTPase-activating protein 18 (ARHGAP18), epithelial membrane protein 1 (EMP1), growth/differentiation factor 15 (GDF15), TGF-beta type II receptor (TGFBR2) and tumour necrosis factor (ligand) superfamily member 15 (TNFSF15). Furthermore, these novel genes were expressed in tumour tissues at transcript and protein levels. We suggest that octreotide may use a potential novel framework to exert its beneficial effect as a drug and to convey its action on neuroendocrine cells. Thus, six novel genes may regulate cell growth and differentiation in normal and tumour neuroendocrine cells and have a role in a novel octreotide mechanism system.

  • 87. Li, Su-Chen
    et al.
    Shi, Hao
    Khan, Mohid
    Caplin, Martyn
    Meyer, Tim
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Roles of miR-196a on gene regulation of neuroendocrine tumor cells2015In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 412, no C, p. 131-139Article in journal (Refereed)
    Abstract [en]

    This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETS) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells. We show that the four target genes were significantly upregulated at transcriptional level in silenced NET cells. HOXA9, HOXB7, LRP4 and RSPO2 encoded proteins are also upregulated at translational level in miR-196a silenced NET cells. miR-196a downstream genes BMP4, ETS1, CTNNB1, FZD5, LEP5 and LRP6 were significantly upregulated at transcriptional level in miR-196a silenced CNDT2.5 and NCI-H727 cells. In addition, miR-196a clearly does not play a role in NET cell growth control.

  • 88.
    Lindholm, Daniel P
    et al.
    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.
    Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 12, p. 832-837Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

  • 89. Liu, Eric
    et al.
    Marincola, Paula
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations2013In: Therapeutic Advances in Gastroenterology, ISSN 1756-283X, E-ISSN 1756-2848, Vol. 6, no 5, p. 412-419Article in journal (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 (p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy.

  • 90.
    Liu, Minghui
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Imam, Hassan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Zhou, Yinghua
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Gene Transfer of Vasostatin, a Calreticulin Fragment, into Neuroendocrine Tumor Cells Results in Enhanced Malignant Behavior.2005In: Neuroendocrinology, ISSN 0028-3835, Vol. 82, no 1, p. 1-10Article in journal (Refereed)
  • 91.
    Liu, Minghui
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Kilarski, Witold W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gerwins, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Zhou, Yinghua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Efficient human interferon-alpha gene transfer to neuroendocrine tumor cells with long-term and stable expression2005In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 82, no 5-6, p. 264-73Article in journal (Refereed)
    Abstract [en]

    Interferon (IFN)-alpha has been used in the treatment of neuroendocrine (NE) tumors; however, the feasibility of IFN-alpha gene therapy has not been evaluated in NE tumor cells. In this study, human IFN-alpha2 (hIFN-alpha2) gene has been transferred into a NE tumor cell line BON. hIFN-alpha2-expressing BON cells were subcutaneously inoculated in nude mice. The results demonstrated that hIFN-alpha2 exerted significant antiproliferative effects on NE tumor cell lines (BON and LCC18) and other tumor cell lines (CA46 and SW480) as well as porcine aorta cell line. Furthermore, hIFN-alpha2 demonstrated its antineovascular activity in mice tumor and a direct antiangiogenic effect in chicken chorioallantoic membrane assay. hIFN-alpha2-expressing BON cells had a stable and long-term expression. Mice implanted with hIFN-alpha2-expressing BON cells showed a lower incidence, a delayed development and a significantly longer doubling time of the tumor compared to both wild-type (WT) and vector group. In addition, IFN-alpha significantly inhibited cell adhesion of WT BON cells. hIFN-alpha2-expressing BON tumors had a high level of hIFN-alpha2 protein. Finally, mice implanted with a mixture of WT and hIFN-alpha2-expressing BON cells (1:1) presented a delayed tumor development and had an even lower incidence of tumors than those implanted with hIFN-alpha2-expressing BON cells only. The doubling time of tumor was also longest in the mixture group. Our data suggest that hIFN-alpha2 gene therapy might be possible to be used as a new treatment for NE tumor patients. Further studies on the regulation of hIFN-alpha expression are needed, especially in combination with other cytokines, which could lead to a better understanding and improvements of hIFN-alpha gene therapy.

  • 92.
    Liu, Minghui
    et al.
    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.
    Zhou, Yinghua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression and function of vinculin in neuroendocrine tumors2007In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 28, no 4, p. 196-204Article in journal (Refereed)
    Abstract [en]

    Transfection of chicken vinculin into highly malignant neuroendocrine tumor cells, vasostatin-transformed (vaso-transformed) Bon cells which expressed low levels of vinculin protein, reversed their malignant behavior and restored expression of tumor suppressor genes. Conversely, small interfering RNA (siRNA)-mediated knockout of vinculin resulted in fast cell growth and augmentation of colony formation in wild-type cells. Moreover, expression of a tight junction protein, claudin 4 (CLD4), was found to be associated with vinculin expression. In the vaso-transformed Bon cells, CLD4 expression was reduced, whereas a significantly increased CLD4 expression was observed in the cells with vinculin overexpression. Furthermore, vinculin knockout brought about CLD4 downregulation in wild-type cells. However, vinculin and CLD4 expression was inversely correlated in neuroendocrine tumors, respectively. Based on these findings, we hypothesize that vinculin plays a role in growth regulation of neuroendocrine tumors. Further studies are necessary to analyze the relationship between the course of the disease, and vinculin and CLD4 expression in large tumor samples.

  • 93.
    Ludvigsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Taylor, John
    Culler, Michael
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 138, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Somatostatin is an inhibitor of hormone secretion through specific receptors (sst1-5). The aim of this study was to investigate the putative regulatory role of somatostatin analogues on the secretion of insulin and glucagon by rat pancreatic islets. After 48 h exposure only the non-selective agonists (somatostatin, octreotide and SOM-230) inhibited insulin accumulation. The inhibition of insulin secretion was accompanied by increased islet insulin contents. None of the analogues showed a consistent effect on the glucagon accumulation in the medium after 48 h. Since we observed a difference in the regulatory effect between the non-selective and selective analogues, combinations of selective analogues were studied. Combination of sst2 + sst5 agonists inhibited the medium insulin accumulation, while combination of sst1 + sst2 analogues caused a decrease in glucagon accumulation. After removal of somatostatin a rebound effect with increased insulin secretion were observed. This effect was reversed after 6 h. For SOM-230 insulin secretion continued to be suppressed even after the analogue was removed and returned to control values after 3 h. As for glucagon secretion there was an initial decline after culture with octreotide, while the other substances failed to induce any changes. In summary, non-selective somatostatin analogues or combinations of receptor selective analogues may cause inhibition of hormone secretion from rat pancreatic islets. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively may exert this effects. Thus, our data suggest that more than one sst must be involved to down-regulate islet glucagon and insulin secretion.

  • 94.
    Ludvigsen, Eva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Stridsberg, Mats
    Department of Medical Sciences. Clinical Chemstry.
    Taylor, John E
    Culler, Michael D
    Öberg, Kjell
    Department of Medical Sciences. Onkologisk endokrinologi.
    Tiensuu Janson, Eva
    Department of Medical Sciences. Onkologisk endokrinologi.
    Subtype Selective Interactions of Somatostatin and Somatostatin Analogs with sst1, sst2, and sst5 in BON-1 Cells.2004In: Med Oncol, ISSN 1357-0560, Vol. 21, no 3, p. 285-96Article in journal (Refereed)
  • 95.
    Lukinius, Agneta
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Ohrvall, U
    Department of Surgical Sciences.
    Westlin, Jan Eric
    Department of Oncology, Radiology and Clinical Immunology.
    Oberg, Kjell
    Department of Medical Sciences.
    Tiensuu Janson, E
    Department of Medical Sciences.
    In vivo cellular distribution and endocytosis of the somatostatin receptor-ligand complex1999In: Acta Oncol., Vol. 38, p. 383-Article in journal (Refereed)
  • 96.
    Makridis, C
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Theodorsson, E
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Öberg, Kjell
    Department of Medical Sciences.
    Knutson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Increased intestinal non-substance P tachykinin concentrations in malignant midgut carcinid disease1999In: J Gastroenterol Hepatol, Vol. 14, no 5, p. 500-507Article in journal (Refereed)
  • 97.
    Makridis, Charlie
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Rastad, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Oberg, K
    Department of Medical Sciences. Onkologisk endokrinologi.
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Progression of metastases and symptom improvement from laparotomy in midgut carcinoid tumors1996In: World J Surg, Vol. 20, p. 900-Article in journal (Refereed)
  • 98. Modlin, Irvin
    et al.
    Drozdov, Ignat
    Gustafsson, Björn I
    Öberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Endokrin onkologi.
    Kidd, Mark
    Rectal neuroendocrine tumors: Diagnosis and treatment2007In: A Century of Advances in Neuroendocrine tumor biology and treatment, Felsenstein , 2007, p. 124-133Chapter in book (Refereed)
  • 99. Modlin, Irvin M
    et al.
    Öberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    A century of advances in neuroendocrine tumor biology and treatment: A tribute to Siegried Oberndorfer2007Book (Refereed)
  • 100. Modlin, Irvin M.
    et al.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Taylor, Andrew
    Drozdov, Ignat
    Bodei, Lisa
    Kidd, Mark
    Neuroendocrine Tumor Biomarkers: Current Status and Perspectives2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 100, no 4, p. 265-277Article in journal (Refereed)
    Abstract [en]

    The identification of accurate harbingers of disease status and therapeutic efficacy are critical requirements in precise diagnosis and effective management. Initially, tissue analysis was regarded as ideal but invasive strategies represent risk compared with peripheral blood sampling. Thus far, most biomarkers, whether in tissue or blood/urine, have been single analytes with varying degrees of sensitivity and specificity. Some analytes have not exhibited robust metrics or have lacked methodological rigor. Neuroendocrine disease represents an area of dire biomarker paucity since the individual biomarkers (gastrin, insulin, etc.) are not widely applicable to the diverse types of neuroendocrine neoplasia. Broad-spectrum markers such as chromogranin A have limitations in sensitivity, specificity and reproducibility. Mono-analytes cannot define the multiple variables (proliferation, metabolic activity, invasive potential, metastatic propensity) that constitute tumor growth. The restricted status of the neuroendocrine neoplasia field has resulted in a lack of comprehensive knowledge of the molecular and cellular biology of the disease, with tardy application of innovative technology. This overview examines limitations in current practice and describes contemporary viable strategies under evaluation, including the identification of novel analytes ( gene transcripts, microRNA), circulating tumor cells and metabolic imaging agents that identify disease. Novel requirements are necessary to develop biomathematical algorithms for synchronous calibration of multiple molecular markers and predictive nomograms that interface biological variables to delineate disease progress or treatment efficacy. Optimally, the application of novel techniques and amalgamations of multianalyte assessment will provide a personalized molecular disease signature extrapolative of neuroendocrine neoplasia status and likelihood of progression and predictive of therapeutic opportunity.

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