K Oberg

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (273)1375.7 Total impact

  • No preview · Conference Paper · Jan 2015

  • No preview · Conference Paper · Jan 2014
  • Eric Liu · Paula Marincola · Kjell Oberg
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    ABSTRACT: 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.
    No preview · Article · Sep 2013 · Therapeutic Advances in Gastroenterology
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    ABSTRACT: Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors.
    Preview · Article · Aug 2013 · Journal of Molecular Endocrinology
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    ABSTRACT: The treatment landscape and biological understanding of neuroendocrine tumors (NETs) has shifted dramatically in recent years. Recent studies have shown that somatostatin analogs have the potential to not only control symptoms of hormone hypersecretion, but also have the ability to slow tumor growth in patients with advanced carcinoid. The results of clinical trials have further shown that the vascular endothelial growth factor (VEGF) pathway inhibitor sunitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus have efficacy in patients with advanced pancreatic NETs. The efficacy of these targeted therapies in NET suggests that the molecular characterization of NETs may provide an avenue to both predict which patients may most benefit from treatment and to overcome potential drug resistance. Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. These observations offer the potential for new therapeutic and diagnostic advances for patients with NET.
    Full-text · Article · Mar 2013 · Clinical Cancer Research
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    ABSTRACT: Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET has increased greatly in the past three decades. However, during this time progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology, along with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally absent. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of patients with NET, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Professor Kjell Öberg at the University of Uppsala, Uppsala, Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This manuscript describes the symposium presentations and resulting discussions.
    No preview · Article · Feb 2013 · Neuroendocrinology
  • Kjell Oberg
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    ABSTRACT: Unlabelled: Biological treatment for GI neuroendocrine tumours (NETs) includes treatment with somatostatin analogues and alpha interferons. Both of these therapies were developed in the early 1980's and initially for treatment of a carcinoid syndrome in patients with small intestinal NETs. Later on tumour biology studies indicated that well differentiated NETs (G1-tumours) benefit from treatment with somatostatin analogues and alpha interferons. Both agents give symptomatic improvement in patients with functioning tumours in 40-60% of the patients, biochemical responses in 50-70% of the patients and significant tumour shrinkage in 5-10% of the patients. Combination therapy with somatostatin analogues and alpha interferon has demonstrated some clinical benefit. In conclusion: Somatostatin analogues and alpha interferons are still playing an important role and considered to be first-line treatment in functioning and in non-functioning well-differentiated NETs, (G1-tumours) and somatostatin analogues might also be applied to control clinical symptoms in G2-tumours with higher proliferation.
    No preview · Article · Dec 2012 · Best practice & research. Clinical gastroenterology
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    ABSTRACT: Objective: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker. Design: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor. Results: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor. Conclusion: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.
    Preview · Article · Nov 2012 · European Journal of Endocrinology
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    K. Oberg · U. Knigge · D. Kwekkeboom · A. Perren

    Preview · Article · Sep 2012 · Annals of Oncology
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    ABSTRACT: 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.
    No preview · Article · Jul 2012 · Endocrine Related Cancer
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    Kjell Oberg
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    ABSTRACT: Neuroendocrine tumors (NETs) possess unique features including expression of peptide hormone receptors as well as the capacity to concentrate and take up precursor forms of amines and peptides making hormones that are stored in secretory granules within the tumor cells (APUD). The expression of somatostatin receptors on tumor cells have been widely explored during the last two decades starting with (111)In-DTPA-Octreotide as an imaging agent followed by (68)Ga-DOTATOC/TATE positron emission tomography scanning. The new generation of treatment includes (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE/DOTANOC treatment of various subtypes of NETs. The objective response rate by these types of PRRT is in the range of 30-45% objective responses with 5-10% grade 3/4 toxicity mainly hematologic and renal toxicity. The APUD mechanism is another unique feature of NETs which have generated an interest over the last two decades to develop specific tracers including (11)C-5HTP, (18)F-DOPA and (11)C-hydroxyefedrin. These radioactive tracers have been developed in centres with specific interest in NETs and are not available everywhere. (111)In-DTPA-Octreotide is still the working horse in diagnosis and staging of metastatic NETs, but will in the future be replaced by (68)Ga-DOTATOC/DOTATATE PET/CT scanning which provide higher sensitivity and specificity and is also more convenient for the patient because it is a one-stop-procedure. Both (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE are important new therapies for malignant metastatic NETs. However, the precise role in the treatment algorithm has to be determined in forthcoming randomized trials.
    Preview · Article · May 2012 · Theranostics
  • Kjell Oberg
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    ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) constitute a diverse group of neoplasms arising from the diffuse neuroendocrine cell system. During the last 2 years a new classification system, the WHO 2010, has come into clinical practice together with Tumor Nodes Metastases (TNM) staging and grading systems, developed by the European Neuroendocrine Tumor Society/American Joint Cancer Committee. At the same time new targeted agents have been developed for treatment of GEP-NETs and it is important discuss these new agents in relation to the classification and staging system. The current article is reviewing the most important clinical trials of targeting agents within the field of neuroendocrine tumors. Tyrosine kinase inhibitors as well as PI3 kinase mTOR inhibitors have been applied in the treatment of neuroendocrine tumors. Sunitinib and everolimus have recently been registered for treatment of pancreatic neuroendocrine tumors worldwide. The role of these new targeted agents in the treatment algorithm of neuroendocrine tumors will be discussed. A large number of phase I and phase II trials have been performed in GEP-NETs with rather limited results and no significant impact on the clinical management of patients with GEP-NETs. However, there are two phase III trials that have completely changed the treatment landscape for pancreatic neuroendocrine tumors, e.g., sunitinib and everolimus demonstrating an increased progression free survival of 11 vs. 5 months for the placebo group.
    No preview · Article · Apr 2012 · Current opinion in oncology
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    Full-text · Article · Oct 2011 · Human Gene Therapy
  • K E Oberg
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    ABSTRACT: Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumour progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show that octreotide LAR 30mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs.
    No preview · Article · Sep 2011 · Clinical Oncology
  • M Essand · J Leja · V Giandomenico · K E Oberg
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    ABSTRACT: Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.
    No preview · Article · May 2011 · Hormone and Metabolic Research
  • Eric H Liu · Kjell Oberg
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    ABSTRACT: Fundamental medical principles, such as hormone action, distant physiologic regulation, and ductless secretion were once mysteries. They now form the basis of basic medical diagnostics and therapeutics. This article discusses and reviews the rich history that served as the foundation of modern medicine, from the early descriptions of tumors, to the discovery of hormones and assays, and how they resulted in the treatments available today.
    No preview · Article · Dec 2010 · Endocrinology and metabolism clinics of North America
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    K Oberg · P Hellman · D Kwekkeboom · S Jelic

    Preview · Article · May 2010 · Annals of Oncology
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    K Oberg · G Akerström · G Rindi · S Jelic

    Full-text · Article · May 2010 · Annals of Oncology
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    ABSTRACT: Twenty-five patients with endocrine tumours (13 with endocrine pancreatic tumours and 12 with carcinoids) were examined with angiography, computed tomography, magnetic resonance imaging and ultrasonography. Seventeen patients had liver metastases and were followed between 3 and 66 months with serial examinations during treatment with chemotherapeutic agents and interferon. The efficiency of the various techniques to detect metastases was investigated. Analysis of changes in tumour size during treatment was made to see if treatment effects could be monitored with radiologic examinations. Ultrasonography was the best non-invasive method for detection of metastases and is recommended as standard method for imaging in this group of patients. Angiography was even better showing extremely small metastases, less than 5 mm, and is recommended in selected cases. With one exception, no significant change in tumour size was noted in spite of clear laboratory and clinical signs of therapy effect indicating that tumour size determination is not useful for therapy monitoring in this type of disease.
    No preview · Article · Jan 2010 · Acta Radiologica
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    K Oberg · S Jelic

    Preview · Article · May 2009 · Annals of Oncology

Publication Stats

14k Citations
1,375.70 Total Impact Points


  • 1988-2013
    • Uppsala University
      • • Department of Medical Sciences
      • • Division of Scientific Computing
      • • Department of Public Health and Caring Sciences
      Uppsala, Uppsala, Sweden
  • 1979-2013
    • Uppsala University Hospital
      • • Department of Endocrine Oncology
      • • Department of Radiology
      • • Department of Internal Medicine
      Uppsala, Uppsala, Sweden
  • 2004
    • Charité Universitätsmedizin Berlin
      • Medical Department, Division of Hepatology and Gastroenterology
      Berlín, Berlin, Germany
  • 2001
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1999
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 1998
    • National Veterinary Institute, Sweden
      Uppsala, Uppsala, Sweden
  • 1988-1998
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 1994
    • Lund University
      • Department of Pediatric Surgery
      Lund, Skåne, Sweden
  • 1987-1994
    • Ludwig Institute for Cancer Research Sweden
      Uppsala, Uppsala, Sweden
    • Universitätsmedizin Göttingen
      Göttingen, Lower Saxony, Germany
  • 1987-1992
    • Karolinska University Hospital
      • Department of Clinical Genetics
      Stockholm, Stockholm, Sweden
  • 1989
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1982
    • Utrecht University
      • Department of Chemistry
      Utrecht, Utrecht, Netherlands