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  • 1.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, no 3, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

  • 2.
    Ali, Abir A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Hjortland, G. O.
    Univ Oslo, Dept Oncol, Oslo, Norway.
    Grønbæk, H.
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Ladekarl, M.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark.
    Langer, S. W.
    Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, L. W.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Österlund, P.
    Tampere Helsinki Univ Hosp, Dept Oncol, Tampere, Finland.;Tampere Helsinki Univ, Tampere, Finland.
    Knigge, U.
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark; Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.
    Sørbye, H.
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway; Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Intravenous versus Oral Etoposide: Efficacy and Correlation to Clinical Outcome in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 184-184Article in journal (Other academic)
  • 3.
    Ali, Abir Salwa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3: Biological and Clinical Aspects2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to investigate biological and clinical aspects of G3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs).

    In our first study, the expression of the tumor suppressor p53 was investigated. In a cohort of G3 GEP-NENs we found the expression of p53 protein to be present in 39% of 124 cases. Expression of p53 correlated to poorer progression-free survival (PFS) and overall survival (OS) for patients with G3 GEP-NENs originating from colon or rectum. In the next study, we aimed to demonstrate the prevalence of PD-L1 expression in G3 GEP-NENs and its possible clinical importance. Ten per cent of 136 tumor specimens were immunoreactive for PD-L1 in either tumor cells or immune cells. In contrast to p53 expression that could be correlated to PFS and OS in a subgroup of patients the expression of PD-L1 did not correlate to any clinicopathological variables and conclusively, PD-L1 may not have a vital role for the pathogenesis of G3 GEP-NENs. In a further study, we sought to identify new potential biomarkers and a panel of immuno-oncological proteins were measured in serum collected from pancreatic G3 NENs and healthy controls. Out of 87 proteins, 62% were significantly lower in serum concentration in healthy controls compared to patients. One protein, FasL, was present in significantly higher levels in healthy controls compared to patients. FasL may have a protective role in its ability to activate T cells in the immune system. Other proteins of interest were chemokine (c-c motif) ligand and interleukin 8 that both correlated to poorer prognosis in G3 pancreatic NEN patients. More studies are needed for further understanding of the roles and clinical relevance of immuno-oncological proteins in G3 pancreatic NENs.

    Finally, we evaluated whether intravenous or oral administration of etoposide differed with regards to PFS and OS in patients with G3 GEP-NENs. There was no significant difference in PFS nor OS between patients receiving oral compared to intravenous etoposide; demonstrating that an oral option of etoposide is not inferior in its efficacy as compared to the more used intravenous formulation. These results suggest that considering oral options of etoposide is important since they are more often preferred by patients, increase the quality of life for the patients and reduce hospital costs.

    This thesis has contributed to an understanding of the distribution and clinical relevance of p53 and PD-L1 in GEP-NENs. A potential role of FasL, chemokine and interleukin 8 as prognostic and/or diagnostic factors in pancreatic G3 NENs has been identified and should be further investigated. The thesis also gave some insight into the role of oral etoposide as an alternative option to intravenous formulation with regards to efficacy. Oral formulations are preferred by many patients and improve quality of life while decreasing hospital-related costs. Further studies are needed to compare the tolerability of oral formulation compared to the intravenous formulation. 

     

     

     

    List of papers
    1. Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
    Open this publication in new window or tab >>Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
    Show others...
    2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed) Published
    Abstract [en]

    Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-341933 (URN)10.1371/journal.pone.0187667 (DOI)000414572100031 ()29112960 (PubMedID)
    Funder
    Swedish Cancer Society, CAN558/2014
    Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2019-04-21Bibliographically approved
    2. PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine Neoplasms
    Open this publication in new window or tab >>PD-L1 expression in G3 Gastroenteropancreatic Neuroendocrine Neoplasms
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    G3 Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare but highly aggressive tumors and traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers making them escape the immune system and hence progress making them excellent targets for treatment. Our aim was investigate the immunohistochemical expression of PD-L1 protein in G3 GEP-NEN (Ki67 >20%) and to evaluate the frequency and location of expression and its correlation to clinical parameters.

       In a cohort of 136 patients, 14 tumor samples (10%) had PD-L1 immunoreactive cells; in four (3%) patient’s expression was seen in the tumor cells and in 10 (7%) expression was seen in immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival.    We conclude that PD-L1 expression is present only in a subset of G3 GEP-NENs. Further studies are needed to fully understand the role of PD-L1 in patients with G3 GEP-NEN, and to assess the potential treatment with immune checkpoint inhibitors.

    Keywords
    PD-L1, immune check inhibitors, G3 GEP-NEN, immunohistochemistry
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-382058 (URN)
    Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-21
    3. Serum biomarkers in Pancreatic G3 Neuroendocrine Neoplasms
    Open this publication in new window or tab >>Serum biomarkers in Pancreatic G3 Neuroendocrine Neoplasms
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Pancreatic G3 neuroendocrine neoplasms (NENs) are rare, aggressive and poorly understood tumors that compose 1-2% of all pancreatic tumors. Generally treated with chemotherapy with poor progression free survival according to their WHO 2010 classification, these tumors are heterogeneous and new diagnostic and prognostic biomarkers are needed to fully understand their biology, sub-categorize them and effectively treat them.

    Materials and methods: Serum from 42 patients and 42 healthy controls were screened for the presence of 96 different proteins with an immune-oncology panel using the proximity extension assay provided by Olink Biosciences. Immunohistochemical staining was performed on 16 patient tumor specimens with a commercial antibody versus FasL.

    Results: Fifty-four out of 87 evaluable proteins differed significantly in concentration between serum from patients and serum from healthy controls. FasL concentration in serum was significantly lower in patients compared to controls. Furthermore, chemokine (c-c motif) ligand 4 (CCL4) and interleukin 8 (IL8) were present in significantly higher serum concentration in patients who had progressive disease.  Five of 15 evaluable specimens showed FasL immunoreactivity in the tumor cells and 10 showed immunoreactivity in immune cells.

    Conclusion: FasL concentration in serum was significantly lower in patients with pancreatic G3 NENs compared to controls, and the expression in tumor tissue was variable. CCL4 and IL8 correlated to worse prognosis. However, further studies in larger cohorts are needed for evaluation of the true clinical value of these proteins for patients with pancreatic G3 NENs.

    Keywords
    PEA, FasL, CCL4, IL8, pancreatic neuroendocrine neoplasm, immunohistochemistry
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-382060 (URN)
    Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-21
    4. Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)
    Open this publication in new window or tab >>Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)
    Show others...
    2018 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, no 4, article id 47Article in journal (Refereed) Published
    Abstract [en]

    High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter-and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan-Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy.

    Place, publisher, year, edition, pages
    Springer, 2018
    Keywords
    Chemotherapy, Intravenous, Oral, Etoposide, Neuroendocrine neoplasms, WHO G3
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-351690 (URN)10.1007/s12032-018-1103-x (DOI)000428784500004 ()29511910 (PubMedID)
    Funder
    Swedish Cancer Society, CAN558/2014
    Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2019-04-21Bibliographically approved
  • 4.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Federspiel, Birgitte
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Scoazec, Jean-Yves
    Inst Gustave Roussy, Villejuif, France.
    Hjortland, Geir Olav
    Univ Oslo, Oslo, Norway.
    Gronbaek, Henning
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ladekarl, Morten
    Aarhus Univ Hosp, Aarhus, Denmark.
    Langer, Seppo W.
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, Lene Weber
    Odense Univ Hosp, Odense, Denmark.
    Arola, Johanna
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland.
    Osterlund, Pia
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland; Tampere Univ Hosp, Tampere, Finland.
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Bergen, Norway; Univ Bergen, 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, Endocrin Oncology. Uppsala Univ, Sect Endocrine Oncol, Dept Med Sci, Uppsala, Sweden..
    Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed)
    Abstract [en]

    Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

  • 5.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Langer, Seppo W.
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark.;Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark..
    Ladekarl, Morten
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    Hjortland, Geir Olav
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Vestermark, Lene Weber
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Österlund, Pia
    Tampere Univ Hosp, Dept Oncol, Tampere, Finland.;Tampere Univ, Tampere, Finland.;Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Gronbaek, Henning
    Aarhus Univ Hosp, Dept Hepatol, Aarhus, Denmark.;Aarhus Univ Hosp, Dept Gastroenterol, Aarhus, Denmark..
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark.;Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.;Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)2018In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 35, no 4, article id 47Article in journal (Refereed)
    Abstract [en]

    High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter-and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan-Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy.

  • 6.
    Almquist, M.
    et al.
    Skane Univ Hosp, Dept Surg, Lund, Sweden..
    Myrenfors, P.
    IPSEN, Stockholm, Sweden..
    Strom, T.
    IPSEN, Stockholm, Sweden..
    Kozlovacki, Gordana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    STREET - Somatostatin Treatment Experience Trial2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 191-191Article in journal (Other academic)
  • 7.
    Anthony, L.
    et al.
    Univ Kentucky, Lexington, KY USA..
    Kulke, M. H.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Hoersch, D.
    Zent Klin Bad Berka, Bad Berka, Germany..
    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, Endocrin Oncology.
    Lombard-Bohas, C.
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, P.
    Stanford Univ, Palo Alto, CA 94304 USA..
    Valle, J. W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England..
    Kassler-Taub, K.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Fleming, R.
    Charite, Berlin, Germany..
    Pavel, M.
    Charite, Berlin, Germany..
    Impact of Concomitant Medication on Efficacy of Telotristat Ethyl - A Post Hoc Subgroup Analysis of the Phase 3 TELESTAR Study in Carcinoid Syndrome2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 212-212Article in journal (Other academic)
  • 8.
    Antonodimitrakis, Pantelis Clewemar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study2017In: International Journal of Endocrine Oncology, Vol. 4, no 1, p. 9-22Article in journal (Refereed)
    Abstract [en]

    Aim: Vasoactive intestinal polypeptide producing neuroendocrine tumors are rare and cause severe hormonal symptoms. Patients/methods: Eighteen patients with vasoactive intestinal polypeptide producing neuroendocrine tumors were analyzed with reviews of medical records, radiology and tumor tissue specimens. Results: Twelve patients (67%) had liver metastases at diagnosis. Chemotherapy, somatostatin analogs and interferon were given as medical therapies. Streptozocin/5-fluorouracil produced an objective response in 40% of the evaluable patients. Somatostatin analogs gave a clinical/biochemical response in eight out of nine patients. Transarterial embolization of the liver and peptide receptor radionuclide therapy was given to refractory cases. Sixteen patients died during the observation period. The median overall survival from diagnosis was 102 months. Conclusion: Systemic chemotherapy and somatostatin analogs should be given in cases of advanced disease or for hormonal symptoms.

  • 9.
    Antonodimitrakis, Pantelis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Streptozocin and 5-FU for the treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, no 3-4, p. 345-353Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumors (pNETs) over the past few decades. The objective of the current study was to assess the efficacy, prognostic factors and safety of the combination of STZ and 5-FU.

    PATIENTS AND METHODS: Medical records and radiological reports of 133 patients with pNETs who received the combination of STZ and 5-FU during the period 1981-2014 were retrospectively evaluated.

    RESULTS: Median survival from start of treatment was 51.9 months in the whole group. In the radiologically evaluable patients (n = 100) progression-free survival was 23 months. Complete response was reached in 3 patients (3%), partial response in 25 patients (25%), 64 patients (64%) had stable disease and 8 patients (8%) had progressive disease. In a multivariate analysis, surgery of the primary tumor and having a G3 tumor were significant positive and negative prognostic factors of survival from start of treatment, respectively. Having either a G3 tumor or stage IV tumor were significant prognostic factors for shorter progression-free survival. Chemotherapy had to be discontinued in 29 patients due to side-effects, of which kidney toxicity (mainly grade 1-2) was the most frequent.

    CONCLUSION: As shown in recent reports, the combination of STZ and 5-FU is effective in the treatment of pNETs in terms of survival and radiological response, and has an acceptable toxicity profile.

  • 10.
    Baudin, Eric
    et al.
    Inst Gustave Roussy, Oncol Endocrinienne & Med Nucl, Villejuif, France.
    Hayes, Aimee R.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Scoazec, Jean-Yves
    Univ Lyon, Dept Pathol, Lyon, France.
    Filosso, Pier Luigi
    Univ Torino, Dept Thorac Surg, Turin, Italy.
    Lim, Eric
    Royal Brompton Hosp, Dept Thorac Surg, London, England.
    Kaltsas, Gregory
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol, Athens, Greece.
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England.
    Chen, Jie
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China.
    Kos-Kudła, Beata
    Slaska Akad Med, Klin Endokrynol, Zabrze, Poland.
    Gorbunova, Vera
    Russian Acad Med Sci, FSBI NN Blokhin Russian Canc Res Ctr, Moscow, Russia.
    Wiedenmann, Bertram
    Charite Univ Med Berlin, Campus Charite Mitte, Dept Gastroenterol & Hepatol, Berlin, Germany; Charite Univ Med Berlin, Campus Virchow Klinikum, Berlin, Germany.
    Nieveen van Dijkum, Els
    Acad Med Ctr, Dept Surg, Amsterdam, Netherlands.
    Ćwikła, Jaroslaw B
    Univ Warmia & Mazury, Fac Med Sci, Dept Radiol, Olsztyn, Poland.
    Falkerby, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Valle, Juan W.
    Univ Manchester, Inst Canc Sci, Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England.
    Kulke, Matthew H
    Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA.
    Caplin, Martyn E
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Sundin, Anders (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tiensuu Janson, Eva (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Welin, Staffan (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no 1, p. 7-17Article in journal (Refereed)
    Abstract [en]

    Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.

  • 11.
    Bjorstad, A.
    et al.
    Nord Hlth Econ, Gothenburg, Sweden..
    Marlow, T.
    Nord Hlth Econ, Gothenburg, Sweden..
    Lesen, E.
    Nord Hlth Econ, Gothenburg, Sweden..
    Bollano, E.
    Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Marteau, F.
    Ipsen Pharma, Boulogne, France..
    Gabriel, S.
    Ipsen Pharma, Boulogne, France..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Fcuilly, M.
    Ipsen Pharma, Boulogne, France..
    Real-World Resource Use And Costs Of Carcinoid Heart Disease In Patients With Neuroendocrine Tumors: A Retrospective Swedish Study2017In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 9, p. A552-A552Article in journal (Other academic)
  • 12.
    Borjesson, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of 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, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics. 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 Medical Sciences, Endocrin Oncology.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Arving, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nurses’ experiences of taxane-induced pain in people treated for breast cancerIn: Article in journal (Other academic)
  • 13.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    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 Medical Sciences, Endocrin Oncology.
    Rissanen, Ritva
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    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.
    Colored body images reveal the perceived intensity anddistribution of pain in women with breast cancer treated with adjuvant taxanes:: a prospective multi-method study of pain experience2018In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, p. 581-591Article, review/survey (Refereed)
    Abstract [en]

    Background and aims:

    Breast cancer is the most prevalent adult cancer worldwide. A broader use of screening for early detection and adjuvant systemic therapy with chemotherapy has resulted in improved survival rates. Taxane-containing chemotherapy is one of the cornerstones of the treatment. However, taxane-containing chemotherapy may result in acute chemotherapy-induced nociceptive and neuropathic pain. Since this pain may be an additional burden for the patient both during and after taxane chemotherapy, it is important to rapidly discover and treat it. There is yet no gold standard for assessing taxane-induced pain. In the clinic, applying multiple methods for collecting information on pain may better describe the patients’ pain experiences. The aim was to document the pain during and after taxane through the contribution of different methods for collecting information on taxane-induced pain. Fifty-three women scheduled for adjuvant sequential chemotherapy at doses of ≥75 mg/m2 of docetaxel and epirubicin were enrolled in the study.

    Methods:

    Prospective pain assessments were done on a visual analog scale (VAS) before and during each cycle of treatment for about 5 months, and using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire’s (EORTC-QLQ-C30) two pain questions at baseline, 3 months, and 12 months. Participants scoring pain on the VAS >30 and undergoing an interview also colored their pain on a body image during treatment and at 12 months.

    Results:

    Surprisingly widespread, intense pain was detected using a multi-method approach. The colored body image showed pain being perceived on 51% of the body surface area during treatment, and on 18% 12 months after inclusion. In general, the pain started and peaked in intensity after the first cycle of taxane. After Cycle 3, most women reported an increase in pain on the VAS. Some women continued to report some pain even during the epirubicin cycles. The VAS scores dropped after the last chemotherapy cycle, but not to the baseline level. At baseline, 3 months and 12 months after inclusion, the women who estimated VAS >30 reported higher levels of pain on the pain questions of the EORTC-QLQ-C30.

    Conclusions:

    This study contributes information on how different pain assessment tools offer different information in the assessment of pain. The colored body image brings another dimension to pain diagnostics, providing additional information on the involved body areas and the pain intensities as experienced by the women. A multi-method approach to assessing pain offers many advantages. The timing of the assessment is important to properly assess pain.

    Implications:

    Pain relief needs to be included in the chemotherapy treatment, with individual assessment and treatment of pain, in the same way as is done in chemotherapy-triggered nausea. There is a time window whereby the risk of pain development is at its highest within 24–48 h after receiving taxane chemotherapy. Proper attention to pain evaluation and treatment should be in focus during this time window.

  • 14.
    Capdevila, Jaume
    et al.
    Vall Hebron Univ Hosp, VHIO, Barcelona, Spain.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, New York, NY USA.
    Davies, Philippa
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Gorbounova, Vera
    Inst Russian Acad Med Sci, Dept Oncol, Moscow, Russia.
    Jensen, Robert T.
    NIH, Bethesda, MD USA.
    Knigge, Ulrich P.
    Univ Copenhagen, Dept Surg, Copenhagen, Denmark.
    Krejs, Guenter J.
    Med Univ Graz, Graz, Austria.
    Krenning, Eric
    Erasmus MC, Cyclotron Rotterdam BV, Rotterdam, Netherlands.
    O'Connor, Juan Manuel
    Alexander Fleming Inst, Caba, Argentina.
    Peeters, Marc
    Antwerp Univ Hosp, Dept Oncol, Antwerp, Belgium.
    Rindi, Guido
    Univ Cattolica Sacro Cuore, Fdn Policlin Univ A Gemelli IRCCS Roma, Rome, Italy.
    Salazar, Ramon
    Catalan Inst Oncol, Oncobell Program, IDIBELL, Cerca,Ciberonc, Barcelona, Spain.
    Vullierme, Marie-Pierre
    Beaujon Hop Assistance Publ, Radiol Dept, Paris, France.
    Pavel, Marianne E.
    Friedrich Alexander Univ Erlangen Nurnberg, Univ Klinikum Erlangen, Erlangen, Germany.
    Sundin, Anders (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tiensuu Janson, Eva (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Welin, Staffan (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Unmet Medical Needs in Metastatic Lung and Digestive Neuroendocrine Neoplasms2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Unmet medical needs are not infrequent in oncology, and these needs are usually of higher magnitude in rare cancers. The field of neuroendocrine neoplasms (NENs) has evolved rapidly during the last decade, and, currently, a new WHO classification is being implemented and several treatment options are available in the metastatic setting after the results of prospective phase III clinical trials. However, several questions are still unanswered, and decisions in our daily clinical practice should be made with limited evidence. In the 2016 meeting of the advisory board of the European Neuroendocrine Tumor Society (ENETS), the main unmet medical needs in the metastatic NENs setting were deeply discussed, and several proposals to try to solve them are presented in this article, including biomarkers, imaging, and therapy.

  • 15.
    Carlsen, Esben Andreas
    et al.
    Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Cluster Mol Imaging, Copenhagen, Denmark.
    Fazio, Nicola
    European Inst Oncol IRCCS, Div Gastrointestinal Med Oncol & Neuroendocrine T, IEO, Milan, Italy.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Dept Endocrinol & Metab, Neuroendocrine Tumor Unit, Med Ctr, Jerusalem, Israel.
    Ahmadzadehfar, Hojjat
    Univ Hosp Bonn, Dept Nucl Med, Bonn, Germany.
    Grana, Chiara Maria
    European Inst Oncol IRCCS, Div Nucl Med, IEO, Milan, Italy.
    Zandee, Wouter T.
    Erasmus MC, Rotterdam, Netherlands.
    Cwikla, Jaroslaw
    Univ Warmia & Mazury, Med Sch, Olsztyn, Poland.
    Walter, Martin A.
    Univ Hosp Geneva, Dept Nucl Med, Geneva, Switzerland.
    Oturai, Peter Sandor
    Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark.
    Rinke, Anja
    Univ Hosp Giess & Marburg, Dept Gastroenterol, Marburg, Germany.
    Weaver, Andrew
    Churchill Hosp, Dept Oncol, Oxford, England.
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England.
    Gritti, Sara
    European Inst Oncol IRCCS, Div Gastrointestinal Med Oncol & Neuroendocrine T, IEO, Milan, Italy.
    Arveschoug, Anne Kirstine
    Aarhus Univ Hosp, Dept Nucl Med & PET, Aarhus, Denmark.
    Meirovitz, Amichay
    Hadassah Hebrew Univ, Med Ctr, Dept Oncol, Jerusalem, Israel;Hadassah Hebrew Univ, Med Ctr, Radiat Therapy Unit, Jerusalem, Israel.
    Knigge, Ulrich
    Univ Copenhagen, Dept Biomed Sci, Cluster Mol Imaging, Copenhagen, Denmark;Rigshosp, Dept Surg Gastroenterol, Copenhagen, Denmark;Rigshosp, Dept Clin Endocrinol, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study2019In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 2, p. 227-239Article in journal (Refereed)
    Abstract [en]

    Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 >= 55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

  • 16.
    Casar Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Stigare, Jerker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Boldt, Henning Bünsow
    Kristensen, Bjarne Winther
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Trouillas, Jacqueline
    Serotonin, ATRX, and DAXX Expression in Pituitary Adenomas: Markers in the Differential Diagnosis of Neuroendocrine Tumors of the Sellar Region.2017In: American Journal of Surgical Pathology, ISSN 0147-5185, E-ISSN 1532-0979, Vol. 41, no 9, p. 1238-1246Article in journal (Refereed)
    Abstract [en]

    Differential diagnosis based on morphology and immunohistochemistry between a clinically nonfunctioning pituitary neuroendocrine tumor (NET)/pituitary adenoma and a primary or secondary NET of nonpituitary origin in the sellar region may be difficult. Serotonin, a frequently expressed marker in the NETs, has not been systematically evaluated in pituitary NETs. Although mutations in ATRX or DAXX have been reported in a significant proportion of pancreatic NETs, the mutational status of ATRX and DAXX and their possible pathogenetic role in pituitary NETs are unknown. Facing a difficult diagnostic case of an invasive serotonin and adrenocorticotroph hormone immunoreactive NET in the sellar region, we explored the immunohistochemical expression of serotonin, ATRX, and DAXX in a large series of pituitary endocrine tumors of different types from 246 patients and in 2 corticotroph carcinomas. None of the pituitary tumors expressed serotonin, suggesting that serotonin immunoreactive sellar tumors represent primary or secondary NETs of nonpituitary origin. Normal expression of ATRX and DAXX in pituitary tumors suggests that ATRX and DAXX do not play a role in the pathogenesis of pituitary endocrine tumors that remain localized to the sellar and perisellar region. A lack of ATRX or DAXX in a sellar NET suggests a nonpituitary NET, probably of pancreatic origin. One of the 2 examined corticotroph carcinomas, however, demonstrated negative ATRX immunolabeling due to an ATRX gene mutation. Further studies on a larger cohort of pituitary carcinomas are needed to clarify whether ATRX mutations may contribute to the metastatic potential in a subset of pituitary NETs.

  • 17.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10,Room 1E-3140, Bethesda, MD 20892 USA.
    Backman, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Taieb, David
    Aix Marseille Univ, Dept Nucl Med, La Timone Univ Hosp, European Ctr Res Med Imaging, F-13385 Marseille, France.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Pacak, Karel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10,Room 1E-3140, Bethesda, MD 20892 USA.
    RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective2018In: Cancers, ISSN 2072-6694, Vol. 10, no 12, article id 518Article in journal (Refereed)
    Abstract [en]

    Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features.

  • 18.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA.
    Lamarca, Angela
    Christie NHS Fdn Trust, Dept Med Oncol, ENETS Ctr Excellence, Manchester, Lancs, England.
    Ghosal, Suman
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Pacak, Karel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA.
    Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis2019In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 5, p. 539-550Article, review/survey (Refereed)
    Abstract [en]

    Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients according to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 (95% CI 1.79-18.06)) as well as norepinephrine (OR 3.01 (95% CI 1.02-8.79)) and dopa mine (OR 6.39 (95% CI 1.62-25.24)) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 (95% CI 1.02-1.06)) and metastases (HR 6.13 (95% CI 2.86-13.13)) but neither paraganglioma nor SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL.

  • 19.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    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, Endocrin 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 Tumor Biology.
    Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumors2017In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 3, p. 441-441Article in journal (Other academic)
  • 20.
    Dam, G.
    et al.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Grønbæk, H.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Sørbye, H.
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Thiis-Evensen, E.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Transplantat Med, Neuroendocrine Tumor Ctr Excellence, Oslo, Norway.
    Paulsson, B.
    Novartis Sverige AB, Täby, Sweden.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jensen, C.
    Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Radiol, Copenhagen, Denmark.
    Ebbesen, D.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Radiol, Aarhus, Denmark.
    Knigge, U.
    Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Endocrinol, Copenhagen, Denmark.;Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Surg Gastroenterol, Copenhagen, Denmark.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    A Prospective Nordic Study on the Use of Chromogranin A for the Prediction of Progression in Patients with Pancreatic and Small Intestinal Neuroendocrine Tumors2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 152-152Article in journal (Other academic)
  • 21.
    Daskalakis, Kosmas
    et al.
    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.
    Hessman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stuart, Heather C.
    Division of Surgical Oncology, University of Miami, Florida, USA.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Hellman, Per
    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.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.2018In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 4, no 2, p. 183-189Article in journal (Refereed)
    Abstract [en]

    Importance: Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV Small Intestinal Neuroendocrine Tumors (SI-NETs) is controversial.

    Objective:  To determine whether locoregional surgery performed at diagnosis in asymptomatic SI-NETs patients with distant metastases affects overall survival (OS), morbidity and mortality, length of hospital stay (LOS) and re-operation rates.

    Design: This investigation was a cohort study of asymptomatic patients with stage IV SI-NET, diagnosed between 1985 and 2015, using the prospective Uppsala database of SI-NETs and the Swedish National Patient Register. Patients included were followed until May 2016 and divided to a first group, which underwent Prophylactic Upfront Surgery within six months from diagnosis Combined with Oncological treatment (PUSCO group) and a second group, which was either treated non-surgically or operated later (Delayed Surgery As Needed Combined with Oncological treatment [DSANCO group]).

    Setting: A tertiary referral center with follow-up data from the Swedish National Patient Register.

    Participants: We included 363 stage IV SI-NET patients without any abdominal symptoms within 6 months from diagnosis, treated either with PUSCO (n=161) or DSANCO (n=202).

    Exposure: PUSCO vs DSANCO.

    Main Outcomes and Measures: Overall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality and re-operation rates measured from baseline. Propensity score match was performed between the two groups.

    Results: Two isonumerical groups (n=91) occurred after propensity score matching. There was no difference between groups in OS (PUSCO median 7.9 vs DSANCO 7.6 years; [hazard ratio] HR, 0.98; [95% CI, 0.70-1.37]; log-rank P=.93) and cancer-specific survival (median 7.7 vs 7.6 years, HR, 0.99; [95%CI, 0.71-1.40]; log-rank P=.99). There was no difference in 30-day mortality (0% in both matched groups) or postoperative morbidity (2% vs 1%; P>.99), LOS (median 73 vs 76 days; P=.64), LOS due to local tumor-related symptoms (median 7 vs 11.5 days; P=.81) or incisional hernia repairs (4% in both groups; P>.99).  Patients from the PUSCO group underwent more re-operative procedures (14%) compared to the DSANCO group (3%) due to intestinal obstruction (P< .001).

    Conclusion: Prophylactic upfront locoregional surgery confers no survival advantage in asymptomatic stage IV SI-NET patients. Delayed surgery as needed seems to be comparable in all examined outcomes, whilst offering the advantage of less re-operations for intestinal obstruction.  The value of a priori locoregional surgery in the presence of distant metastases is challenged and needs to be elucidated in a randomized controlled study.

     

  • 22.
    Dillon, J.
    et al.
    Univ Iowa, Iowa City, IA USA.
    Kulke, M.
    Dana Farber Canc Inst, Boston, MA USA.
    Warner, R.
    Icahn Sch Med Mt Sinai, New York, NY USA.
    Bergsland, E.
    Univ Calif San Francisco, San Francisco, CA USA.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    O'Dorisio, T.
    Univ Iowa, Iowa City, IA USA.
    Mckee, C.
    Lexicon Pharmaceut, The Woodlands, TX USA.
    Lapuerta, P.
    Lexicon Pharmaceut, The Woodlands, TX USA.
    Pavel, M.
    Friedrich Alexander Univ, Erlangen, Germany.
    Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Two Phase 3 Studies in Carcinoid Syndrome2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 224-224Article in journal (Other academic)
  • 23.
    Dillon, Joseph S.
    et al.
    Univ Iowa, Iowa City, IA USA.
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA USA.
    Pavel, Marianne
    Charite, Berlin, Germany; Friedrich Alexander Univ, Nurnberg, Germany.
    Horsch, Dieter
    Zent Klin Bad Berka, Bad Berka, Germany.
    Anthony, Lowell B.
    Univ Kentucky, Lexington, KY USA.
    Warner, Richard R. P.
    Icahn Sch Med Mt Sinai, New York, NY USA.
    Bergsland, Emily
    Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    O'Dorisio, Thomas M.
    Univ Iowa, Iowa City, IA USA.
    Patel, Nilay
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, The Woodlands, TX USA.
    Time to Sustained Improvement in Bowel Movement Frequency With Telotristat Ethyl: Analysis of the Phase 3 TELESTAR Study2018In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 337-338Article in journal (Other academic)
  • 24.
    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.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    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.

  • 25.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Daskalakis, Kosmas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Norlén, Olov
    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.
    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.
    DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 2, p. 170-181Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.

  • 26.
    Fust, K.
    et al.
    Optum, Boston, MA USA..
    Maschio, M.
    Optum, Burlington, ON, Canada..
    Pastor, M.
    Optum, Burlington, ON, Canada..
    Kohli, M.
    Optum, Burlington, ON, Canada..
    Weinstein, M. C.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    Singh, S.
    Sunnybrook Res Inst, Toronto, ON, Canada..
    Pritchard, M.
    Univ Liverpool, Liverpool, Merseyside, England..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Marteau, R.
    Ipsen Pharma, Boulogne, France..
    Gabriel, S.
    Ipsen Pharma, Boulogne, France..
    Feuilly, M.
    Ipsen Pharma, Boulogne, France..
    A Budget Impact Model Of The Addition Of Telotristat Ethyl Treatment In Patients With Uncontrolled Carcinoid Syndrome2017In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 9, p. A548-A549Article in journal (Other academic)
  • 27.
    Galleberg, R. B.
    et al.
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Knigge, U.
    Univ Copenhagen, Rigshosp, Dept Surg & Endocrinol PE C, Copenhagen, Denmark..
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, L. W.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Haugvik, S. P.
    Oslo Univ Hosp, Rikshosp, Dept Hepatopancreatobiliary Surg 5, Oslo, Norway..
    Ladekarl, M.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Univ Copenhagen, Rigshosp, Dept Oncol 7, Copenhagen, Denmark..
    Gronbaek, H.
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol 8, Aarhus, Denmark..
    Osterlund, P.
    Univ Helsinki, Cent Hosp, Dept Oncol 9, Helsinki, Finland..
    Hjortland, G.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Assmus, J.
    Haukeland Hosp, Ctr Clin Res 11, Bergen, Norway..
    Tang, L.
    MSKCC, Dept Pathol, New York, NY USA..
    Perren, A.
    Univ Bern, Dept Pathol, Bern, Switzerland..
    Sorbye, H.
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Resection of Liver Metastases in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Carcinomas: A Nordic Multicenter Study2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 264-264Article in journal (Other academic)
  • 28.
    Galleberg, R. B.
    et al.
    Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway..
    Knigge, U.
    Univ Copenhagen, Dept Surg C, Rigshosp, Copenhagen, Denmark.;Univ Copenhagen, Dept Endocrinol PE, Rigshosp, Copenhagen, Denmark..
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, L. W.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Haugvik, S. -P
    Ladekarl, M.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Univ Copenhagen, Dept Oncol, Rigshosp, Copenhagen, Denmark..
    Gronbaek, H.
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol, Aarhus, Denmark..
    Osterlund, P.
    Univ Helsinki, Dept Oncol, Cent Hosp, Helsinki, Finland..
    Hjortland, G. O.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Assmus, J.
    Haukeland Hosp, Ctr Clin Res, Bergen, Norway..
    Tang, L.
    MSKCC, Dept Pathol, New York, NY USA..
    Perren, A.
    Univ Bern, Dept Pathol, Bern, Switzerland..
    Sorbye, H.
    Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas2017In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 43, no 9, p. 1682-1689Article in journal (Refereed)
    Abstract [en]

    Background: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce. The aim of this study was to evaluate the results of curatively intended resection/radiofrequency ablation (RFA) of liver metastases in patients with metastatic GEP-NEC. Methods: 32 patients with a diagnosis of high-grade gastroenteropancreatic neuroendocrine neoplasm (Ki-67 > 20%) and with intended curative resection/RFA of liver metastases, were identified among 840 patients from two Nordic GEP-NEC registries. Tumor morphology (well vs poor differentiation) was reassessed. Overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan Meier analyses for the entire cohort and for subgroups. Results: Median OS after resection/RFA of liver metastases was 35.9 months (95% -CI: 20.6-51.3) with a five-year OS of 43%. The median PFS was 8.4 months (95% -CI: 3.9-13). Four patients (13%) were disease -free after 5 years. Two patients had well -differentiated morphology (NET G3) and 20 patients (63%) had Ki-67 >= 55%. A Ki-67 < 55% and receiving adjuvant chemotherapy were statistically significant factors of improved OS after liver resection/RFA. Conclusion: This study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

  • 29.
    Garske, Ulrike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fröss-Baron, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lundin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Khan, Tanweera Shaheena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no 6, p. 970-988Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

    METHODS: Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%).

    RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

    CONCLUSIONS: Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

  • 30.
    Georgantzi, Kleopatra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology. University Children's Hospital, Uppsala, Sweden.
    Sköldenberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery. University Children's Hospital, Uppsala, Sweden.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology. University Hospital, Uppsala, Sweden.
    Kogner, Per
    Department of Women´s and Children´s Health, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Jakobson, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology. University Children's Hospital, Uppsala, Sweden.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Christofferson, Rolf. H.B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery. University Children's Hospital, Uppsala, Sweden.
    Chromogranin A and neuron-specific enolase in neuroblastoma: Correlation to stage and prognostic factors.2018In: Pediatric Hematology & Oncology, ISSN 0888-0018, E-ISSN 1521-0669, Vol. 35, no 2, p. 156-165Article in journal (Refereed)
    Abstract [en]

    Chromogranin A (CgA) and neuron specific enolase (NSE) are important markers in adult neuroendocrine tumors (NET). Neuroblastoma (NB) has certain neuroendocrine properties. The aim of this study was to correlate blood concentrations of CgA, chromogranin B (CgB), and NSE to prognostic factors and outcome in children with NB. Blood samples from 92 patients with NB, 12 patients with benign ganglioneuroma (GN), 21 patients with non-NB solid tumors, 10 patients with acute leukemias, and 69 healthy children, were analyzed. CgA concentrations were higher in neonates vs. children older than one month in the control group (p < 0.0001), and in neonates with NB vs. the control group (p < 0.01). CgA and NSE concentrations were higher in patients with stages 3 and 4 disease (p < 0.05 and p < 0.05), in patients having tumors with amplification of MYCN (p < 0.05 and p < 0.001), or chromosome 1 p deletion (p < 0.05 and p < 0.05). NSE correlated to the tumor size at diagnosis (p < 0.001) and to tumor related death (p < 0.01) in NB. CgA and NSE concentrations were elevated in patients with NB and especially in those with advanced disease. Both CgA and NSE correlated to genetic markers, while only NSE correlated to primary tumor size and outcome in NB. We found that CgA and NSE are clinically valuable tumor markers in NB and they merit prospective clinical evaluations as such.

  • 31.
    Georgantzi, Kleopatra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Sköldenberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Jakobson, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Christofferson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Diagnostic Ultrasound-Guided Cutting Needle Biopsies in Neuroblastoma: a safe and efficient procedure2019In: Journal of Pediatric Surgery, ISSN 0022-3468, E-ISSN 1531-5037, Vol. 54, no 6, p. 1253-1256Article in journal (Refereed)
    Abstract [en]

    Background

    Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and accounts for 15% of deaths in pediatric oncology. Apart from the clinical stage at diagnosis, molecular factors are important for the characterization of the tumor and for decision on adequate treatment. Pretreatment diagnosis and molecular profiling are based on analysis of a tumor sample, obtained either by fine needle aspiration cytology (FNAC), cutting needle biopsy or open surgical biopsy. The method used depends on local tradition and routines. Ultrasound-guided cutting needle biopsy (UCNB) has been used at the Uppsala University Hospital since 1988 for diagnosis of pediatric solid tumors.

    Procedures

    Medical records of 29 patients with NB who underwent pretreatment, diagnostic, ultrasound-guided needle biopsy were reviewed. Information extracted from the patients’ records included: age at diagnosis, gender, tumor site, clinical stage, molecular profiling made on biopsies (e.g. MYCN status, ploidy and chromosomal aberrations), and UCNB complications (i.e. bleeding, pain, or anesthesiologic complications).

    Results

    A total of 34 UCNBs were performed in the 29 patients. Repeated biopsies were done in three patients. UCNB was diagnostic in 90% (26/29). A complete molecular profiling was obtained in all UCNBs after 2008. Two patients (7%) developed a significant bleeding and two (7%) needed analgesics following UCNB. Neither infection nor tumor growth in the needle tract was observed. There were no anesthesiologic complications.

    Conclusions

    UCNB is reasonably safe in patients with NB and usually gives a sufficient amount of tumor tissue for a histological diagnosis, molecular profiling, and biobank storage.

  • 32.
    Grönberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ahlin, Cecilia
    Orebro Univ, Fac Med & Hlth, Dept Oncol, Orebro, Sweden..
    Naeser, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, London, England..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176059Article in journal (Refereed)
    Abstract [en]

    Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer with tumor size <= 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy, 190 women were identified who died from breast cancer and randomly selected 190 women alive at the corresponding time as controls. Tumor tissues were immunostained with antibodies versus the peptides. Ghrelin expression was associated with better breast cancer specific survival in univariate analyses (OR 0.55, 95% CI 0.36-0.84) and in multivariate models, adjusted for endocrine treatment and age (OR 0.57, 95% CI 0.36-0.89). Obestatin expression was non-informative (OR 1.2, 95% CI 0.60-2.46). Ghrelin expression is independent prognostic factor for breast cancer death in node negative patients-halving the risk for dying of breast cancer. Our data implies that ghrelin could be a potential therapeutic target in breast cancer treatment.

  • 33.
    Grönberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Nilsson, Cecilia
    Vastmanland Cty Hosp, Ctr Clin Res, Vasteras, Sweden.
    Markholm, Ida
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden;Lund Univ, CREATE Hlth Strateg Ctr Translat Canc Res, Lund, Sweden.
    Hedenfalk, Ingrid
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden;Lund Univ, CREATE Hlth Strateg Ctr Translat Canc Res, Lund, Sweden.
    Blomqvist, Carl
    Univ Helsinki, Dept Oncol, Helsinki, Finland;Orebro Univ Hosp, Dept Oncol, Orebro, Sweden.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, London, England.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ghrelin expression is associated with a favorable outcome in male breast cancer2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 13586Article in journal (Refereed)
    Abstract [en]

    Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18-0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17-0.87). HR for obestatin was 0.38 (95% CI 0.11-1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.

  • 34.
    Hicks, Rodney J.
    et al.
    Peter MacCallum Canc Ctr, Canc Imaging & Neuroendocrine Serv, 305 Grattan St.
    Kwekkeboom, Dik J.
    Erasmus MC, ENETS Ctr Excellence Rotterdam, Div Nucl Med, Dept Internal Med.
    Krenning, Eric
    Erasmus MC, Cyclotron Rotterdam BV.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Med Ctr, Neuroendocrine Tumor Unit, Endocrinol & Metab Serv,Dept Med.
    Arnold, Rudolf
    Munich, Germany.
    Borbath, Ivan
    Clin Univ St Luc, Serv Gastroenterol.
    Cwikla, Jaroslaw
    Univ Warmia & Mazury, Dept Radiol, Fac Med Sci.
    Toumpanakis, Christos
    Royal Free Hosp, Neuroendocrine Tumour Unit.
    Kaltsas, Greg
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol.
    Davies, Philippa
    Royal Free Hosp, Neuroendocrine Tumour Unit.
    Hoersch, Dieter
    Gastroenterol & Endocrinol Ctr Neuroendocrine Tum.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ramage, John
    Hampshire Hosp NHS Trust, Gastroenterol Dept, Basingstoke.
    ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Peptide Receptor Radionuclide Therapy with Radiolabelled Somatostatin Analogues2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, p. 295-309Article in journal (Refereed)
    Abstract [en]

    The purpose of these guidelines is to assist physicians caring for patients with neuroendocrine neoplasia in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT) and in defining the minimum requirements for PRRT. It is not these guidelines' aim to give recommendations on the use of specific radiolabelled somatostatin analogues for PRRT as different analogues are being used, and their availability is governed by varying international regulations. However, a recent randomized controlled trial, NETTER-1, has provided evidence that may establish Lu-177-DOTA-octreotate (LutaThera (R)) as the first widely approved agent. It also makes recommendations on what minimal patient, tumour, and treatment outcome characteristics should be reported for PRRT to facilitate robust comparisons between studies.

  • 35.
    Humphries, Matthew P.