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  • 1.
    Alit, Abir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 43-43Article in journal (Refereed)
  • 2.
    Chu, Xia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Aspects of MEN1 Tumorigenesis in Endocrine Pancreas and Adrenal Glands2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple endocrine neoplasia syndrome type 1 (MEN1) is an autosomal dominantly inherited disease, which is described as an association of tumors mainly in endocrine organs, including pancreas and adrenal glands. Pancreatic neuroendocrine tumors (PNETs) are the most common cause of death in MEN1 patients. More than one third of the MEN1 patients also develop enlargement of the adrenals. MEN1 is caused by a germline mutation of MEN1 gene, a tumor suppressor gene that is located on the human chromosome 11. As noticed, the MEN1 related tumors often develop prior to inactivation of both wild type alleles, indicating MEN1 haploinsufficiency. In this thesis, I utilized a conventional Men1 mouse model that has the phenotype mimicking the human MEN 1 traits, in order to investigate MEN1 tumorigenesis in endocrine pancreas and adrenal glands.  

    The microvascular aberrations contributing to development and maintenance of PNETs were characterized. The increased vascular density of PNETs developed in the Men1 mice was paralleled by an early and extensive redistribution of pericytes within endocrine tissue. These morphological alterations were supported by fine-tuned variations in expression of several angiogenic regulators  (VEGF, FGF and PDGF) and were further potentiated by hypoxia. Vascular reactivity and blood perfusion of tumor arterioles were significantly altered in response to glucose and L-nitro-arginine methyl ester.

    Investigation of adrenals from10-month-old Men1 mice showed 681 proteins in mass spectrometry data sets, in which 52 proteins were commonly found in the Men1+/+ and Men1+/- adrenals, and the differential expression between the genotypes reached significant levels. Prdx3, catalyzing the reduction of oxidative stress to cell survival, is one of the overexpressed proteins. Some proteins belonging to the PPARα pathway, e.g. ACLY were also overexpressed. Subsequent microRNA (miRNA) profiling analysis of adrenals from the same age group revealed 31 miRNAs whose expression was significantly altered in comparison between the genotypes. The tumor suppressor miRNAs, miR-486, miR-330 and miR-214, were significantly downregulated in Men1+/- adrenals. The latter, miR-214, is known to inhibit ACLY expression. This finding was in concordance with the proteomic analysis. The oncogene miRNAs, miR-132 and miR-494, were significantly enhanced in the Men1+/- adrenals. Gene ontology analysis demonstrated overrepresentation of the miRNA-targeted genes that are involved in nucleic acid metabolism, vasculature development, angiogenesis, and transcription. Together, these finding after validation in humans may be exploited to improve MEN1 cancer treatment.  

    List of papers
    1. Multiple Microvascular Alterations in Pancreatic Islets and Neuroendocrine Tumors of a Men1 Mouse Model
    Open this publication in new window or tab >>Multiple Microvascular Alterations in Pancreatic Islets and Neuroendocrine Tumors of a Men1 Mouse Model
    Show others...
    2013 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 182, no 6, p. 2355-2367Article in journal (Refereed) Published
    Abstract [en]

    Vascular therapeutic targeting requires thorough evaluation of the mechanisms activated in the specific context of each particular tumor type. We highlight structural, molecular, and functional microvascular aberrations contributing to development and maintenance of pancreatic neuroendocrine tumors (NETs), with special reference to multiple endocrine neoplasia 1 (MEN1) syndrome, using a Men1 mouse model. Tissue samples were analyzed by immunofluorescence to detect vessel density and pericyte distribution within the endocrine pancreas; expression of angiogenic factors was assessed by immunohistochemistry and quantitative real-time PCR in isolated islets and adenomas cultured under normoxic or hypoxic conditions. The increased vascular density of pancreatic NETs developed in Men1 mice was paralleled by an early and extensive redistribution of pericytes within endocrine tissue. These morphological alterations are supported by, and in some cases preceded by, fine-tuned variations in expression of several angiogenic regulators and are further potentiated by hypoxia. By combining two novel ex vivo and in vivo single-islet and tumor perfusion techniques, we demonstrated that both vascular reactivity and blood perfusion of tumor arterioles are significantly altered in response to glucose and L-nitro-arginine methyl ester. Our findings unravel multiple potential molecular and physiological targets differentially activated in the endocrine pancreas of Men1 mice and highlight the need for in-depth functional studies to fully understand the contribution of each component to development of pancreatic NETs in MEN1 syndrome.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-203534 (URN)10.1016/j.ajpath.2013.02.023 (DOI)000319781800038 ()
    Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
    2. Quantitative Protein Profiling of Adrenal Glands in a Men1 Mouse Model
    Open this publication in new window or tab >>Quantitative Protein Profiling of Adrenal Glands in a Men1 Mouse Model
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-254796 (URN)
    Available from: 2015-06-11 Created: 2015-06-11 Last updated: 2016-01-22Bibliographically approved
    3. MicroRNA Expression Profiling in adrenals of Multiple Endocrine Neoplasia type 1 Mice
    Open this publication in new window or tab >>MicroRNA Expression Profiling in adrenals of Multiple Endocrine Neoplasia type 1 Mice
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-254804 (URN)
    Available from: 2015-06-11 Created: 2015-06-11 Last updated: 2016-01-22Bibliographically approved
  • 3.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Antonodimitrakis, Pantelis
    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.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumours2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 2, p. 445-452Article in journal (Refereed)
    Abstract [en]

    CONTEXT:

    As a group, neuroendocrine tumors (NETs) secrete many different peptide hormones, yet heretofore each NET patient is typically thought to produce at most one hormone that causes a distinct hormonal syndrome. A minority of patients have multiple hormones at diagnosis and may also develop secondary hormone secretion at a later stage.

    OBJECTIVES:

    The objectives of the study were to determine the frequency and to describe the impact of multiple and secondary hormone secretion in sporadic gasteroenteropancreatic NET patients.

    DESIGN, SETTING, AND PARTICIPANTS:

    This was a retrospective analysis of patients (n = 972) with gasteroenteropancreatic NET treated at Uppsala University Hospital, Uppsala, Sweden. Patients with the secretion of multiple hormones at diagnosis and/or those developing secondary hormone secretion during the disease course were identified and studied in further detail.

    RESULTS:

    In pancreatic NETs (PNETs), a total of 19 of 323 patients (6%) had secretion of multiple hormones at diagnosis, and 14 of 323 (4%) had secondary changes during the disease course. These phenomena occurred exclusively in patients with an advanced disease stage, and secondary hormones were detected in a close time span with progressive disease. Patients with secondary insulin hypersecretion had increased morbidity as well as reduced survival (P < .002). In contrast, multiple and secondary hormone secretion was rarely seen in NETs of the small intestine with 0 and 1 of 603 cases, respectively.

    CONCLUSION:

    Diversity of PNET hormone secretion either at diagnosis or during the disease course occurred in a minority of patients (9.3%). These phenomena had a major impact on patient outcome both through increased morbidity and mortality. Our results support that patients with metastatic PNETs should be monitored for clinical symptoms of secondary hormone secretion during the disease course.

  • 4.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Edfeldt, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Midkine Is a New Novel Serum Biomarker in Small Intestinal Neuroendocrine Tumors (SI-NETs)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 45-45Article in journal (Refereed)
  • 5.
    Dumanski, Jan P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rasi, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ali, Abir S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Sorbye, Halfdan
    Grønbæk, Henning
    Cunningham, Janet L
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 8, p. 427-443Article in journal (Refereed)
    Abstract [en]

    The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

  • 6.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Mikael
    Södertörn University, School of Life Sciences, Biology, Huddinge, Sweden.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Magnusson, Patrik K. E.
    Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
    Lindgren, Cecilia M.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
    Morris, Andrew P.
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;Department of Biostatistics, University of Liverpool, Liverpool, UK.
    Cesarini, David
    Center for Experimental Social Science, New York University, New York, NY 10012, USA.
    Johannesson, Magnus
    Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mutagenesis: smoking is associated with mosaic loss of chromosome Y2015In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6217, p. 81-83Article in journal (Refereed)
    Abstract [en]

    Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.

  • 7.
    Hellerstedt-Börjesson, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Holmström, Inger K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Malardalen Univ, Sch Hlth Care & Social Welf, Vasteras, Sweden.
    Arving, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Women Treated for Breast Cancer, Experiences of Chemotherapy-Induced Pain:: Memories, Any Present Pain and Future reflections2016In: Cancer Nursing, ISSN 0162-220X, E-ISSN 1538-9804, Vol. 39, no 6, p. 464-472Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Breast cancer survivors make up a growing population facing treatment that poses long-standing adverse effects including chemotherapy-related body function changes and/or pain. There is limited knowledge of patients' lived experiences of chemotherapy-induced pain (CHIP).

    OBJECTIVE: The aim of this study was to explore CHIP and any long-standing pain experiences in the lifeworld of breast cancer survivors.

    METHODS: Fifteen women participated in a follow-up interview a year after having experienced CHIP. They were interviewed from a lifeworld perspective; the interviews were analyzed through guided phenomenology reflection.

    RESULTS: A past perspective: CHIP is often described in metaphors, leads to changes in a patient's lifeworld, and impacts lived time. The women become entirely dependent on others but at the same time feel isolated and alone. Existential pain was experienced as increased vulnerability. Present perspective: Pain engages same parts of the body, but at a lower intensity than during CHIP. The pain creates time awareness. Expected normality in relationships/daily life has not yet been achieved, and a painful existence emerges in-between health and illness. Future perspective: There are expectations of pain continuing, and there is insecurity regarding whom to turn to in such cases. A painful awareness emerges about one's own and others' fragile existence.

    CONCLUSIONS: Experiencing CHIP can impact the lifeworld of women with a history of breast cancer. After CHIP, there are continued experiences of pain that trigger insecurity about whether one is healthy.

    IMPLICATIONS FOR PRACTICE: Cancer survivors would likely benefit from communication and information about and evaluation of CHIP.

  • 8.
    Hellstrom-Lindahl, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    In vitro binding of [H-3]PIB to human amyloid deposits of different types2014In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Systemic amyloidosis is caused by extracellular deposition of insoluble fibrillar proteins arranged in beta-pleated sheets. [C-11] PIB has been used in PET studies to assess A beta deposition in brain of patients with Alzheimer's disease (AD). The possibility to visualize other types of amyloid deposits with [C-11] PIB would be of potential clinical importance in early diagnosis and for following therapeutic effects. In the present study, we evaluated in vitro binding of [3 H] PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and Ab amyloid. We found significantly higher binding of [H-3] PIB in tissue from systemic amyloidoses than in control tissue, i.e. 4.7 times higher (p<0.05). [H-3] PIB showed the highest affinity to cortex of AD brain (IC50 = 3.84 nM), while IC50 values were much higher for ATTR, AA and AL type of amyloidosis and large variations in affinity were observed even within tissues having the same type of amyloidosis. Extraction with guanidine-HCl, which disrupts the beta-sheet structure, decreased the protein levels and, concomitantly, the binding of [H-3] PIB in all four types of amyloidoses.

  • 9.
    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)
  • 10. James, Paul D.
    et al.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Zhang, Mei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Belletrutti, Paul J.
    Mohamed, Rachid
    Roberts, Derek J.
    Heitman, Steven J.
    Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis2015In: Gastrointestinal Endoscopy, ISSN 0016-5107, E-ISSN 1097-6779, Vol. 81, no 4, p. 848-+Article, review/survey (Refereed)
    Abstract [en]

    Background: Current guidelines recommend CT scan or magnetic resonance imaging as the initial imaging modalities for the work-up of suspected pancreatic neuroendocrine tumors (PNETs). Objective: To determine the incremental benefit of preoperative EUS (IBEUS) for the detection of suspected PNETs after other investigative modalities have been attempted. Design: This systematic review searched MEDLINE, EMBASE, bibliographies of included articles, and conference proceedings for studies reporting original data regarding the preoperative detection of PNETs. Pooled IBEUS was calculated by using random effects models. Heterogeneity was explored by using stratified meta-analysis and meta-regression. Evidence of small-study effects was assessed by using funnel plots and the Begg test. Patients: Patients with suspected PNETs. Interventions: EUS evaluation. Main Outcome Measurements: The pooled IBEUS for the detection of PNETs after CT scan, with or without additional investigative modalities. Results: Among 4505 citations identified, we included 17 cohort studies (612 patients). EUS identified PNETs in 97% of cases. Improved PNET identification with EUS was observed in all of the studies. After adjusting for small-study effects, meta-analysis showed that EUS alone could identify PNETs in approximately 1 in 4 patients (adjusted IBEUS 26%; 95% confidence interval, 17%-37%). The pooled IBEUS varied based on the study design, study size, type of CT scan used, and the number of modalities used prior to EUS. Limitations: The majority of included studies were retrospective. Small-study effects were observed. Conclusion: Preoperative EUS is associated with an increase in PNET detection after other modalities are attempted.

  • 11. 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.

  • 12.
    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. 

  • 13.
    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)
  • 14.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Small Intestinal Neuroendocrine Tumor Analyses: Somatostatin Analog Effects and MicroRNA Profiling2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) originate from serotonin-producing enterochromaffin (EC) cells in the intestinal mucosa. Somatostatin analogs (SSAs) are mainly used to control hormonal secretion and tumor growth. However, the molecular mechanisms leading to the control of SI-NETs are unknown. Although microRNAs (miRNAs) are post transcriptional regulators deeply studied in many cancers, are not well-defined in SI-NETs. We adopted a two-pronged strategy to investigate SSAs and miRNAs: first, to provide novel insights into how SSAs control NET cells, and second, to identify an exclusive SI-NET miRNA expression, and investigate the biological functions of miRNA targets.

    To accomplish the first aim, we treated CNDT2.5 cells with octreotide for 16 months. Affymetrix microarray was performed to study gene variation of CNDT2.5 cells in the presence or absence of octreotide. The study revealed that octreotide induces six genes, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15.

    To accomplish the second aim, SI-NET tissue specimens were used to run genome-wide Affymetrix miRNA arrays. The expression of five miRNAs (miR-96, -182, -183, -196a and -200a) was significantly upregulated in laser capture microdissected (LCM) tumor cells versus LCM normal EC cells, whereas the expression of four miRNAs (miR-31, -129-5p, -133a and -215) was significantly downregulated in LCM tumor cells. We also detected nine tissue miRNAs in serum samples, showing that the expression of five miRNAs is significantly increased in SSA treated patients versus untreated patients. Conversely, SSAs do not change miRNA expression of four low expressed miRNAs. Silencing miR-196a expression was used to investigate functional activities in NET cells. This experimental approach showed that four miR-196a target genes, HOXA9, HOXB7, LRP4 and RSPO2, are significantly upregulated in silenced miR-196a NET cells.

    In conclusion, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15 genes might regulate cell growth and differentiation in NET cells, and play a role in an innovative octreotide signaling pathway. The global SI-NET miRNA profiling revealed that nine selected miRNAs might be involved in tumorigenesis, and play a potential role as novel markers for follow-up. Indeed, silencing miR-196a demonstrated that HOXA9, HOXB7, LRP4 and RSPO2 genes are upregulated at both transcriptional and translational levels.

    List of papers
    1. The Somatostatin Analogue Octreotide Inhibits Growth of Small Intestine Neuroendocrine Tumour Cells
    Open this publication in new window or tab >>The Somatostatin Analogue Octreotide Inhibits Growth of Small Intestine Neuroendocrine Tumour Cells
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e48411-Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-186023 (URN)10.1371/journal.pone.0048411 (DOI)000310600500127 ()
    Available from: 2012-11-29 Created: 2012-11-27 Last updated: 2017-12-07Bibliographically approved
    2. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors.
    Open this publication in new window or tab >>Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors.
    Show others...
    2013 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 5, p. 685-696Article in journal (Refereed) Published
    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.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-194041 (URN)10.1038/modpathol.2012.216 (DOI)000318456200008 ()23328977 (PubMedID)
    Available from: 2013-02-07 Created: 2013-02-07 Last updated: 2017-12-06Bibliographically approved
    3. Circulating microRNA detection in small intestinal neuroendocrine tumor patients treated with somatostatin analogs
    Open this publication in new window or tab >>Circulating microRNA detection in small intestinal neuroendocrine tumor patients treated with somatostatin analogs
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    2014 (English)Article in journal, Meeting abstract (Refereed) Submitted
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-233202 (URN)
    Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-01-11Bibliographically approved
    4. Functional role of miR-196a in neuroendocrine tumor cells
    Open this publication in new window or tab >>Functional role of miR-196a in neuroendocrine tumor cells
    Show others...
    2015 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, no 1-2, p. 87-87Article in journal, Meeting abstract (Refereed) Published
    Place, publisher, year, edition, pages
    S. Karger, 2015
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-233206 (URN)10.1159/000431385 (DOI)000361683500030 ()
    External cooperation:
    Conference
    12th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona, SPAIN, MAR 11-13, 2015
    Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-01-11Bibliographically approved
  • 15.
    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)
  • 16. 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.

  • 17.
    Mörth, Charlott
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Valachis, Antonis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Single-agent versus combination chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer and performance status 2: A literature-based meta-analysis of randomized studies2014In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 84, no 3, p. 209-214Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of this study was to compare the efficacy and tolerability of first-line treatment with combination versus single agent chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) 2.

    METHODS: A systematic literature search was performed to identify randomized trials comparing combination versus single agent chemotherapy in patients with advanced NCSLC. Both trials dedicated to PS 2 patients and trials that performed a subset analysis according to PS were included in the meta-analysis. Standard meta-analytic procedures were used to analyze the study outcomes.

    RESULTS: Twelve trials were considered eligible and were further analyzed. The use of combination chemotherapy resulted in a statistically significant better overall survival compared to single agent chemotherapy (11 trials, 1114 patients; hazard ratio (HR), 0.79, 95% confidence interval (CI): 0.71-0.88). The survival benefit was pronounced when platinum-based combination was used (HR: 0.71, 95% CI: 0.61-0.81) while no survival benefit was observed in non-platinum based combinations (HR: 0.96, 95% CI: 0.80-1.15). Grade 3/4 anemia (OR: 3.12, 95% CI: 1.55-6.27), thrombocytopenia (OR: 12.81, 95% CI: 4.65-33.10), and neutropenia (OR: 7.91, 95% CI: 3.97-15.78) but not febrile neutropenia were significantly more frequent with combination chemotherapy.

    CONCLUSION: This meta-analysis provides evidence supporting the use of combination chemotherapy in patients with NSCLC and PS 2. However, the patients should be informed about the higher risk for toxicity with the combination chemotherapy and the final treatment strategy should be individualized.

  • 18. Selvaraju, Ram Kumar
    et al.
    Bulenga, Thomas N
    Espes, Daniel
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Estrada, Sergio
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Olof
    Dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rodents, pigs, non-human primates and human - repeated scanning in human is possible.2015In: American journal of nuclear medicine and molecular imaging, ISSN 2160-8407, Vol. 5, no 3, p. 259-69Article in journal (Refereed)
    Abstract [en]

    Quantitative PET imaging with [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has potential use in diabetes and cancer. However, the radiation dose to the kidneys has been a concern for the possibility of repeated imaging studies in humans. Therefore, we investigated the dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 based on the biodistribution data in rats, pigs, non-human primates (NHP) and a human.Organ distribution of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rats (Male Lewis; n=12; 30, 60, and 80 min) was measured ex vivo. The dynamic uptake of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in the abdomen was assessed by PET/CT scanning of pigs (male; n = 4, 0-60 min), NHP (Female; cynomolgus; n=3; 0-90 min), and human (female; n=1; 0-40, 100, 120 min).The organ distribution data in each species were extrapolated to those of a human, assuming similar distribution between the species. Residence times were assessed by trapezoidal approximation of the kinetic data. Organ doses (mGy/MBq) and the whole body effective dose (mSv/MBq), was extrapolated by using the OLINDA/EXM 1.1 software. The extrapolated human whole body effective dose was 0.017 ± 0.004 (rats), 0.014 ± 0.004 (pigs), 0.017 ± 0.004 (NHP), and 0.016 (human) mSv/MBq. The absorbed dose to the kidneys was limiting:0.33 ± 0.06 (rats), 0.28±0.05 (pigs), 0.65 ± 0.11 (NHP), and 0.28 (human) mGy/MBq, which corresponded to the maximum yearly administered amounts of 455 (rat), 536 (pig), 231 (NHP), and 536 (human) MBq before reaching the yearly kidney limiting dose of 150 mGy. More than 200 MBq of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 can be administered yearly in a human, allowing for repeated (2-4 times) scanning. This potentially enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma.

  • 19.
    Shi, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Khan, Mohid
    Royal Free Hosp, London NW3 2QG, England.
    Caplin, Martyn
    Royal Free Hosp, London NW3 2QG, England.
    Meyer, Tim
    UCL, Inst Canc, London, England.
    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.
    Functional role of miR-196a in neuroendocrine tumor cells2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, no 1-2, p. 87-87Article in journal (Refereed)
  • 20.
    Söderquist, Fanny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Alit, Abir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Cunningham, Janet L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164354Article in journal (Refereed)
    Abstract [en]

    Background/ Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin's endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function.

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

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

  • 22.
    Tsolakis, Apostolos V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Granerus, Goran
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Falkmer, Sture E.
    Ryhov Cty Hosp, Dept Pathol, SE-55185 Jonkoping, Sweden..
    Janson, Eva T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours2015In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, no 47, p. 13240-13249Article in journal (Refereed)
    Abstract [en]

    AIM:

    To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite.

    METHODS:

    Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients.

    RESULTS:

    In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms.

    CONCLUSION:

    Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

  • 23.
    Wolin, Edward M.
    et al.
    Univ Kentucky, Markey Canc Ctr, Lexington, KY 40536 USA..
    Jarzab, Barbara
    Maria Sklodowska Curie Mem Canc Ctr, Dept Nucl Med & Endocrine Oncol, Gliwice, Poland.;Inst Oncol, Gliwice Branch, Gliwice, Poland..
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Walter, Thomas
    Hop Edouard Herriot, Dept Med Oncol, Lyon, France..
    Toumpanakis, Christos
    Royal Free Hosp, Gastroenterol & Neuroendocrine Tumours, London NW3 2QG, England..
    Morse, Michael A.
    Duke Univ, Med Ctr, Dept Med Oncol, Durham, NC USA..
    Tomassetti, Paola
    Univ Hosp St Orsola, Dept Med & Surg Sci, Bologna, Italy..
    Weber, Matthias M.
    Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, D-55122 Mainz, Germany..
    Fogelman, David R.
    Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA..
    Ramage, John
    North Hampshire Hosp, Gastroenterol Unit, Basingstoke, Hants, England..
    Poon, Donald
    Raffles Hosp, Dept Med Oncol, Singapore, Singapore.;Duke NUS Grad Med Sch, Singapore, Singapore..
    Gadbaw, Brian
    Novartis Pharmaceut, E Hanover, NJ USA..
    Li, Jiang
    Novartis Pharmaceut, E Hanover, NJ USA..
    Pasieka, Janice L.
    Foothills Prov Gen Hosp, Surg & Oncol Fac Med, Calgary, AB T2N 2T9, Canada..
    Mahamat, Abakar
    CHU Nice, Hop Archet, Dept Gastrointestinal Oncol, F-06202 Nice, France..
    Swahn, Fredrik
    Karolinska Univ Sjukhuset, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Newell-Price, John
    Univ Sheffield, Sch Med & Biomed Sci, Dept Human Metab, Sheffield, S Yorkshire, England.;Sheffield Teaching Hosp NHS Fdn Trust, Sheffield, S Yorkshire, England..
    Mansoor, Wasat
    Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues2015In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 9, p. 5075-5086Article in journal (Refereed)
    Abstract [en]

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

  • 24.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Neuroendocrine gastro-enteropancreatic tumors - from eminence based to evidence-based medicine - A Scandinavian view2015In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, no 6, p. 727-739Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) comprise a heterogenous group of neoplasms with variable clinical expression and progression. The primary tumors most frequently occur in the lungs, intestine and the pancreas. The NET incidence is approximately 6.1/100,000 per year with a prevalence higher than 35/100,000 per year. A NET may be functioning with symptoms related to hormone overproduction or non-functioning, not presenting any hormone-related symptoms. From the early 1980s and onwards, Uppsala University Hospital has contributed significantly to diagnosis, just to mention immunohistochemistry, radio-immunoassays for hormones and peptides and molecular imaging. On the therapeutic side, treatments with cytotoxics as well as biologicals such as, somatostatin analogs and interferons have been evaluated. We have furthermore been involved in important phase III trials for registration of so called, new targeted agents such as, RADIANT-3 and RADIANT-2. Our group were also the first to localize the gene for MEN I on chromosome 11 locus q13. Most recent developments have been the establishments of new biomarkers such as, olfactory receptor E51E1 as well as micro-RNAs in carcinoid tumors of the intestine and lung. A new oncolytic virus, Ad-Vince, for treatment of most NETs has been developed and is ready for the clinic. Furthermore, we have been involved in establishing Nordic and international collaborations. Today, NETs is an area with rapid development and recognized by international organizations at conferences, with large attendance. The Nordic countries continue to be significant contributors to the field.

1 - 24 of 24
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