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  • 1.
    Cui, Tao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Cunningham, Janet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olfactory Receptor 51E1 is a Potential Novel Tissue Biomarker for the Diagnosis of Small Intestine Neuroendocrine Tumors2013Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 42, nr 2, s. 373-373Artikkel i tidsskrift (Annet vitenskapelig)
  • 2.
    Cui, Tao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Cunningham, Janet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 is a potential novel tissue biomarker for the diagnosis and prognosis of small intestine neuroendocrine tumors2012Inngår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 177, nr Suppl, s. S18-S18Artikkel i tidsskrift (Annet vitenskapelig)
  • 3.
    Cui, Tao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Cunningham, Janet L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Lind, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas2013Inngår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, nr 2, s. 253-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

  • 4.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Chatzelis, Eleftherios
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece;251 Hellen Air Force & VA Gen Hosp, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Papadopoulou-Marketou, Nektaria
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Linkoping, Sweden.
    Dimitriadis, Georgios K.
    Univ Hosp Coventry & Warwickshire NHS Trust, Arden Net CoE & Human Metab Res Unit HMRU, WISDEM, Coventry CV2 2DX, W Midlands, England.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, CCK, R8 04, Stockholm, Sweden.
    Kaltsas, Gregory
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Endocrine paraneoplastic syndromes in patients with neuroendocrine neoplasms2019Inngår i: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 64, nr 2, s. 384-392Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Our aim was to assess the prevalence of endocrine paraneoplastic syndromes (EPNS) in neuroendocrine neoplasms (NENs) and estimate its impact on patient outcomes.

    Design: This is a retrospective analysis of 834 patients with NENs (611 gastrointestinal, 166 thoracic, 57 of unknown and various other primary origin). We included 719 consecutive NEN patients treated at EKPA-Laiko Hospital, Athens, Greece and 115 patients with lung carcinoid (LC) treated at Uppsala University Hospital, Uppsala, Sweden. EPNS diagnosis was based on standard criteria.

    Methods: Twenty-one patients with EPNS were detected: 16 with ectopic Cushing's syndrome (ECS), one with hypercalcaemia due to parathyroid hormone-related protein (PTHrP) secretion, three with hypercalcitonaemia and one patient with dual secretion of calcitonin and beta-human chorionic gonadotropin (-HCG). All tumours were well-differentiated; 10 patients had Stage IV disease at diagnosis.

    Results: The prevalence of EPNS in the Greek cohort was 1.9%, whereas that of ECS among LC patients in both centres was 6.7%. Median overall survival (OS) for patients with EPNS was 160.7 months (95%CI, 86-235.4) and median event-free survival (EFS) was 25.9 months (95%CI, 0-57.2). Patients presenting with EPNS prior to NEN diagnosis had longer EFS compared to patients with synchronous or metachronous EPNS (log-rank P=0.013). Patients with ECS of extra-thoracic origin demonstrated shorter OS and EFS compared to patients with ECS of lung or thymic origin (log-rank P=0.001 and P<0.001, respectively). LC patients with and without ECS were comparable in 5-year and 10-year OS rates (66.7% and 33.3% versus 89.8% and 60.2%, respectively; 95%CI [189.6-300.4 months], log-rank P=0.94) and in median EFS, 67 versus 183 months, 95%CI [50.5-207.5], log-rank P=0.12).

    Conclusion: EPNS are relatively rare in patients with NENs and mainly concern well-differentiated tumours of the foregut. Among patients with EPNS, LC-related ECS may not adversely affect patient outcomes when diagnosed prior to NEN and effectively been treated.

  • 5.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Kaltsas, Gregory
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden; Karolinska Univ Hosp, Canc Ctr Karolinska, CCK, Stockholm, Sweden.
    Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers2018Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 107, nr 4, s. 355-365Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Aims: Lung carcinoids (LCs) are often diagnosed at an early stage and surgical intervention becomes the next phase of treatment. To date, there is lack of long-term follow-up data after surgery and prognostication based on WHO classification criteria and evolving prognostic markers, particularly the expression of somatostatin receptors (SSR).

    Methods: We included 102 consecutive patients (72 women; age at baseline 51 ± 16 years [mean ± SD]) with LCs, who underwent thoracic surgery (n = 99) and/or laser treatment (n = 8). Hospital charts were reviewed for clinico-pathological parameters. Immunohistochemical (IHC) expression of SSR1–5 and other novel markers were studied with regard to their prognostic value.

    Results: Five- and 10-year overall survival (OS) was 96 and 83% respectively; relative survival (RS) was 101 and 93% respectively; and event-free survival (EFS) was 80 and 67% respectively. Independent prognostic factors for OS, RS and/or EFS were age at diagnosis, histopathological type and the presence of ipsilateral mediastinal subcarinal lymph node metastases. Macro-radicality of resective surgery and its extent were associated with increased OS and EFS. The IHC expression of SSR1–5 and other novel markers was not associated with OS or EFS.

    Conclusion: The long-term outcome of surgically treated patients with LCs is favourable. Age, histopathological type and ipsilateral mediastinal subcarinal lymph node status at baseline were independent prognostic factors for survival and disease recurrence or progression. The extent of surgery and operative macro-radicality also had an impact on prognosis. None of the IHC markers tested appeared to be associated with disease prognosis.

  • 6.
    Diakatou, Evanthia
    et al.
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Alexandraki, Krystallenia I.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kontogeorgos, George
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Chatzellis, Eleftherios
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Leonti, Anastasia
    Alexandra Hosp, Dept Nucl Med, Athens, Greece..
    Kaltsas, Gregory A.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores2015Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, nr 3, s. 420-428Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ContextThe expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. ObjectiveTo investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. DesignProspective two-centre study. Patients and measurementsWe analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n=54) and metastatic (n=27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. ResultsSstr2 was the commonest sstr expressed (654%) and was co-expressed with sstr3 and sstr5 in 321% and 247% of the specimens, respectively. In 67 of 81 specimens (827%), there was concordance of sstr2 immunohistochemistry with SRS findings (P<0001). D2R was expressed in only 8 of 23 (348%) GI-NENs while was co-expressed with sstr2 in all cases. SRS grade, as per Krenning scale, was higher in metastatic foci, large-size (>2cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r=06, P<0001) and D2R (r=05, P<0001) IHC intensity scores than tumour size (r=04, P<0001) and sstr3 (r=04, P<0001) intensity score. ConclusionsSstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours.

  • 7.
    Georgantzi, Kleopatra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, CCK, Stockholm, Sweden.
    Jakobson, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Christofferson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 Are Expressed in Neuroblastoma2019Inngår i: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 30, nr 3, s. 173-179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroblastoma (NB), the most common extracranial cancer in childhood, exhibits neuroendocrine (NE) differentiation. Two well-established NE markers, chromogranin A (CgA) and synaptophysin (syn), are used in the histopathological diagnostics. Our aims were to explore if the NE markers synaptic vesicle protein 2 (SV2) and vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) also are expressed in human NB and if so, evaluate their usefulness in NB histopathological diagnostics. Tumor specimens from 21 NB patients, before and/or after chemotherapy, were immunostained for CgA, syn, SV2, VMAT1, and VMAT2. Clinical data was extracted from patients' records. SV2 was highly expressed in NB, as was CgA while syn was less frequently expressed compared to the other two. Both VMATs were expressed in several NB, VMAT2 in more cases than VMAT1 and its expression was similar to syn. Chemotherapy did not affect the immunoreactivity in an obvious way. SV2 was highly expressed in NB and can thus be useful marker in NB diagnostics. VMAT1 and VMAT2 were also expressed in NB but similar to syn less reliable as tumor markers.

  • 8.
    Georgantzi, Kleopatra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Jakobson, Åke
    Department of Womeńs and Childreńs Health, Astrid Lindgren Childreńs Hospital, Karolinska Institute, Stockholm, Sweden.
    Christofferson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Barnkirurgi.
    Janson, Eva Tiensuu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma2011Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 56, nr 4, s. 584-589Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Neuroblastoma (NB) is a solid tumor of childhood originating from the adrenal medulla or sympathetic nervous system. Somatostatin (SS) is an important regulator of neural and neuroendocrine function, its actions being mediated through five specific membrane receptors. The aim of this study was to investigate the expression of the different somatostatin receptors (SSTRs) in NB tumor cells that may form targets for future therapeutic development.

    PROCEDURE:

    Tumor specimens from 11 children with stage II-IV disease were collected before and/or after chemotherapy. Experimental tumors derived from five human NB cell lines were grown subcutaneously in nude mice. Expression of SSRTs, the neuroendocrine marker chromogranin A (CgA) and SS was detected by immunohistochemistry using specific antibodies.

    RESULTS:

    SSTR2 was detected in 90%, SSTR5 in 79%, SSTR1 in 74%, SSTR3 in 68% whereas SSTR4 was expressed in 21% of the clinical tumors. The experimental tumors expressed SSTRs in a high but variable frequency. All clinical tumors showed immunoreactivity for CgA but not for SS.

    CONCLUSION:

    The frequent expression of SSTRs indicates that treatment with unlabeled or radiolabeled SS analogs should be further explored in NB.

  • 9.
    Giandomenico, Valeria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cui, Tao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pelosi, Giuseppe
    European Institute of Oncology, Milan, Italy; University of Milan School of Medicine, Milan, Italy.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids2013Inngår i: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 51, s. 277-286Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors.

  • 10. Glasberg, S.
    et al.
    Thomas, D.
    Strosberg, J. R.
    Pape, U. F.
    Felder, S.
    Tsolakis, Apostolos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Alexandraki, K.
    Fraenkel, M.
    Saiegh, L.
    Reissman, P.
    Kaltsas, G.
    Gross, D. J.
    Metastatic Type 1 Gastric Carcinoid-A Real Threat or Just a Myth?2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 302-302Artikkel i tidsskrift (Annet vitenskapelig)
  • 11. Grozinsky-Glasberg, Simona
    et al.
    Thomas, Dimitrios
    Strosberg, Jonathan R.
    Pape, Ulrich-Frank
    Felder, Stephan
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Alexandraki, Krystallenia I.
    Fraenkel, Merav
    Saiegh, Leonard
    Reissman, Petachia
    Kaltsas, Gregory
    Gross, David J.
    Metastatic type 1 gastric carcinoid: A real threat or just a myth?2013Inngår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 19, nr 46, s. 8687-8695Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM:

    To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1).

    METHODS:

    Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients' data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria.

    RESULTS:

    We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 +/- 10.83 mm (mean +/- SD). The mean Ki-67 index was 6.8% +/- 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period.

    CONCLUSION:

    Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of >= 1 cm, an elevated Ki-67 index and high serum gastrin levels. (C) 2013 Baishideng Publishing Group Co., Limited. All rights reserved.

  • 12.
    Grönberg, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Tsolakis, Apostolos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Magnusson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Janson, Eva Tiensuu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Saras, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Distribution of obestatin and ghrelin in human tissues: immunoreactive cells in the gastrointestinal tract, pancreas, and mammary glands2008Inngår i: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 56, nr 9, s. 793-801Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obestatin and ghrelin are two peptides derived from the same prohormone. It is well established that ghrelin is produced by endocrine cells in the gastric mucosa. However, the distribution of human obestatin immunoreactive cells is not thoroughly characterized. A polyclonal antibody that specifically recognizes human obestatin was produced. Using this antibody and a commercial antibody vs ghrelin, the distribution of obestatin and ghrelin immunoreactive cells was determined in a panel of human tissues using immunohistochemistry. The two peptides were detected in the mucosa of the gastrointestinal tract, from cardia to ileum, and in the pancreatic islets. Interestingly, epithelial cells in the ducts of mammary glands showed distinct immunoreactivity for both ghrelin and obestatin. By double immunofluorescence microscopy, it was shown that all detected cells were immunoreactive for both peptides. Furthermore, the subcellular localization of obestatin and ghrelin was essentially identical, indicating that obestatin and ghrelin are stored in the same secretory vesicles.

  • 13.
    Grönberg, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Holmbäck, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Janson, Eva T
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Ghrelin and Obestatin in Human Neuroendocrine Tumors: Expression and Effect on Obestatin Levels after Food Intake2013Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 97, nr 4, s. 291-299Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Ghrelin and obestatin are derived from the same peptide hormone precursor and are mainly produced by the gastric mucosa. Ghrelin is involved in many biological processes, whereas the physiological function of obestatin needs further investigation. The aims of the present study were to establish the incidence of ghrelin- and obestatin-immunoreactive cells in a comprehensive panel of human neuroendocrine tumors (NETs) and to investigate if blood obestatin concentrations are influenced during a standardized meal stimulation test in healthy individuals and patients with NETs.

    Materials and Methods:

    The expression of ghrelin and obestatin was investigated in NETs (n = 149) and other endocrine-related disorders (n = 3) using immunohistochemistry with specific polyclonal antibodies. Coexpression of the peptides was evaluated by double immunofluorescence. Concentrations of obestatin in blood were measured during a meal test in 6 healthy individuals and 5 patients with pancreatic NETs.

    Results:

    Ghrelin and obestatin were expressed in 14/152 and 19/152 tumor tissues, respectively, mainly representing NETs of foregut origin and in pancreatic tissue from a nesidioblastosis patient. Double immunofluorescence staining showed colocalization of the peptides. During the meal test, obestatin levels in blood were unchanged in all patients but decreased significantly in the healthy individuals.

    Conclusion:

    Only a minority of NETs express ghrelin and obestatin. However, analysis of patients with tumors originating from tissues that express the peptides in normal conditions could be of importance. The results from the meal test indicate that the hormone levels are affected by food intake in healthy individuals, whereas obestatin levels remained unchanged in pancreatic NET patients.

  • 14. James, Paul D.
    et al.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Zhang, Mei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Belletrutti, Paul J.
    Mohamed, Rachid
    Roberts, Derek J.
    Heitman, Steven J.
    Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis2015Inngår i: Gastrointestinal Endoscopy, ISSN 0016-5107, E-ISSN 1097-6779, Vol. 81, nr 4, s. 848-+Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

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

  • 15.
    Kaltsas, Gregory
    et al.
    Department of Pathophysiology, National University of Athens, Athens 11527, Greece..
    Cunningham, Janet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Falkmer, Sture
    Department of Clinical Pathology and Cytology, the Ryhov County Hospital, Jönköping, Sweden.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Tsolakis, Apostolos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance2011Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 18, nr 1, s. 61-71Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1  cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage.

  • 16. Kaltsas, Gregory
    et al.
    Grozinsky-Glasberg, Simona
    Alexandraki, Krystallenia I.
    Thomas, Dimitrios
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Gross, David
    Grossman, Ashley B.
    Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms2014Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, nr 2, s. 157-168Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The vast majority of gastrin-related gastrointestinal neuroendocrine neoplasms (GI-NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI-NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI-NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long-term follow-up and potential comorbidities of GNEN1s.

  • 17. Kanakis, G. A.
    et al.
    Grimelius, L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kaltsas, G.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Immunohistochemical Expression of Connective Tissue Growth Factor and Insulin-like Growth Factor-1 in Lung Carcinoids2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 289-290Artikkel i tidsskrift (Annet vitenskapelig)
  • 18. Kanakis, G.
    et al.
    Kaltsas, G.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Papaioannou, D.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Unusual Complication of a Pancreatic Neuroendocrine Tumor Presenting with Malignant Hypercalcemia2012Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 4, s. E627-E631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context:

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

    Objective:

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

    Case Illustration:

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

    Discussion:

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

  • 19. Kanakis, George
    et al.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Spathis, Athanasios
    Tringidou, Rodoula
    Rassidakis, George Z.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Kaltsas, Gregory
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role2015Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, nr 3, s. 211-222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 20. Lyros, Ioannis
    et al.
    Fora, Eleni
    Damaskos, Spyridon
    Stanko, Peter
    Tsolakis, Apostolos
    Univ Athens, Dept Orthodont, Athens, Greece.
    An incidental finding on a diagnostic CBCT: a case report2014Inngår i: Australian orthodontic journal, ISSN 0587-3908, Vol. 30, nr 1, s. 67-71Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is known that Cone Beam Computed Tomography (CBCT) provides reliable spatial data and has many clinical applications for dental and particularly orthodontic patients. The present article provides a short review of the literature and reports an unusual CBCT finding in an orthodontic patient referred for the assessment of impacted upper canines. A unilateral lesion in the left maxillary sinus, was an incidental finding. Following a histological examination, which revealed unilateral nasal polyps, surgical removal was performed as the treatment of choice.

  • 21. Nicolaou, Argyro
    et al.
    Thomas, Dimitrios
    Alexandraki, Krystallenia I.
    Sougioultzis, Stavros
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kaltsas, Gregory
    Predictive Value of Gastrin Levels for the Diagnosis of Gastric Enterochromaffin-Like Cell Hyperplasia in Patients with Hashimoto's Thyroiditis2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 2, s. 118-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT. Methods: A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B-12, anti-parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophago-gastroduodenoscopy- obtained biopsies. Results: Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity x specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B-12 levels (96.1% specificity). Conclusion: Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B-12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up. 

  • 22. Nikolaou, A.
    et al.
    Thomas, D.
    Alexandraki, K.
    Sougioultzis, S.
    Tsolakis, Apostolos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kaltsas, G.
    The Predictive Value of Gastrin Levels for the Diagnosis of Gastric Enterochromaffin-like Cells Hyperplasia, in Patients with Hashimoto's Thyroiditis2014Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 256-256Artikkel i tidsskrift (Annet vitenskapelig)
  • 23. Spargias, Konstantinos
    et al.
    Bouboulis, Nikolaos
    Halapas, Antonios
    Chrissoheris, Michael
    Skardoutsos, Spyridon
    Nikolaou, Joulia
    Tsolakis, Apostolos
    Departments of Cardiothoracic Surgery Hygeia Hospital, Athens, Greece.
    Mourmouris, Christos
    Pattakos, Stratis
    Transaortic aortic valve replacement using the Edwards Sapien-XT Valve and the Medtronic CoreValve: initial experience2015Inngår i: Hellenic Journal of Cardiology, ISSN 1109-9666, Vol. 55, nr 4, s. 288-293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Transcatheter aortic valve replacement (TAVR) is now an established treatment for certain patients with severe aortic valve stenosis (AS). However, as the number of patients screened for TAVR increases, many are found to have absolutely no option for peripheral artery access. Transaortic valve replacement (TAoVR) has been proposed as a new alternative route in patients deemed unsuitable for conventional approaches. We present our first series of TAoVR cases using the Edwards Sapien-XT and the Medtronic CoreValve prostheses.

    METHODS: Twenty-five (25) symptomatic patients (mean age 78 ± 8 years, mean logistic EuroSCORE I 25 ± 11%) with severe AS underwent TAoVR using the Sapien-XT valve (10 patients) or the CoreValve (15 patients).

    RESULTS: The mean fluoroscopy time was 15.6 ± 4.2 minutes, the mean time in the intensive care unit was 1.9 ± 1.0 days, and the mean hospital stay was 6.4 ± 1.6 days. The mean effective aortic valve area increased (from 0.68 ± 0.15 cm(2) to 1.82 ± 0.34 cm(2), p<0.001) and the mean transvalvular pressure gradient declined (from 48 ± 15 mmHg to 9 ± 5 mmHg, p<0.05) post implantation. The procedural mortality was 0% and the in-hospital mortality was 4% (one death at day 3 due to cardiogenic shock). The mean NYHA functional class improved from 3.2 ± 0.4 to 1.5 ± 0.9 at 30 days.

    CONCLUSIONS: Our initial experience with the TAoVR approach using both the Edwards Sapien-XT and the Medtronic CoreValve prosthesis demonstrated that it could be performed safely, resulting in substantial acute echocardiographic and early clinical improvement.

  • 24.
    Thomas, Dimitrios
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grozinsky-Glasberg, Simona
    Fraenkel, Merav
    Alexandraki, Krystallenia
    Sougioultzis, Stavros
    Gross, David J.
    Kaltsas, Gregory
    Long-term follow-up of a large series of patients with type 1 gastric carcinoid tumors: Data from a multicenter study2013Inngår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, nr 2, s. 185-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To study the clinical presentation, diagnostic approach, response to treatment and the presence of other pathologies in patients with gastric carcinoid type-1 tumors (GC-1).

    DESIGN AND METHODS:

    Retrospective analysis of 111 patients from 4 institutions and a mean follow-up of 76 months.

    RESULTS:

    The main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter and percentage of cells expressing Κi-67 labeling index were 3.6±3.8, 8±12.1mm and 1.9±2.4%, respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients, respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabelled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention 5 developed tumor progression. Thirty-two patients were treated with long acting somatostatin analogues (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors and CgA immune reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy was initially performed in 20 patients and a complete response was achieved in 13 patients. The most common co-morbidities were vitamin B12 deficiency, thyroiditis and parathyroid adenomas.

    CONCLUSIONS:

    Most GCs-1 are grade 1 (82.72%) tumors presenting with stage I (73.87%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared to conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.

  • 25.
    Tsolakis, Apostolos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    James, P.
    Univ Ottawa, Dept Med, Ottawa, ON, Canada.;Ottawa Hosp Res Inst, Ottawa, ON, Canada..
    Zhang, M.
    Dept Med & Community Hlth Sci, Calgary, AB, Canada..
    Belletrutti, P.
    Dept Med & Community Hlth Sci, Calgary, AB, Canada..
    Mohamed, R.
    Dept Med & Community Hlth Sci, Calgary, AB, Canada..
    Roberts, D.
    Dept Surg & Community Hlth Sci, Calgary, AB, Canada..
    Heitman, S.
    Dept Med & Community Hlth Sci, Calgary, AB, Canada..
    Incremental Benefit of Preoperative Endoscopic Ultrasound for the Detection of Pancreatic Neuroendocrine Tumors: A Meta-Analysis2015Inngår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, nr 1-2, s. 116-116Artikkel i tidsskrift (Annet vitenskapelig)
  • 26.
    Tsolakis, Apostolos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    James, Paul
    Kaplan, Gilaad
    Myers, Robert
    Hubbard, James
    Mohamed, Rachid
    Cole, Martin
    Bass, Sydney
    Love, Jonathan
    Heitman, Steven
    The Need for Repeat Endoscopic Retrograde Cholangiopancreatography in Patients with Biliary Leaks Following Cholecystectomy2013Inngår i: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 108, s. S73-S73Artikkel i tidsskrift (Annet vitenskapelig)
  • 27.
    Tsolakis, Apostolos V.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Granerus, Goran
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Falkmer, Sture E.
    Ryhov Cty Hosp, Dept Pathol, SE-55185 Jonkoping, Sweden..
    Janson, Eva T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours2015Inngår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, nr 47, s. 13240-13249Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

  • 28.
    Tsolakis, Apostolos V
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Islam, Md Shahidul
    Expression of the coiled coil domain containing protein 116 in the pancreatic islets and endocrine pancreatic tumors2012Inngår i: Islets, ISSN 1938-2022, Vol. 4, nr 5, s. 349-353Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Coiled coil domain containing protein 116 (CCDC116) is a product of the gene coiled coil domain containing 116 located on human chromosome 22. Its function has not yet been established. The present study focuses on the expression of this protein in human pancreatic islets and in the endocrine pancreatic tumors (EPTs). Methods and Results: Expression of the protein was evaluated by immunohistochemistry in endocrine pancreas from six patients and in various EPTs from 51 patients. In pancreatic islets, virtually all insulin, approx. 75% of the somatostatin, and approx. 60% of the pancreatic polypeptide (PP) cells were immunoreactive for the CCDC116 protein whereas glucagon, ghrelin and the exocrine cells were not. All insulinomas, gastrinomas, non-functioning sporadic tumors and the hereditary multihormonal EPTs were immunoreactive with variable relative incidence. Two of the three somatostatinomas, and one of the three ACTH-secreting tumors also expressed CCDC116. Conclusions: The CCDC116 protein is expressed in all islet cell types except the glucagon and ghrelin cells. Most of the EPTs also contained CCDC116 protein. These findings suggest that this protein may play some role for the above mentioned endocrine cells and tumors. Its function has to be investigated in future studies.

  • 29.
    Tsolakis, Apostolos V.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Falkmer, Sture E.
    Waldum, Helge L.
    Saras, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Janson, Eva Tiensuu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach2009Inngår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 160, nr 6, s. 941-949Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective:

    Obestatin and ghrelin are derived from the same gene and co-expressed in the same endocrine cells. Vesicular monoamine transporter-2 (VMAT-2), a marker for enterochromaffin-like (ECL) cells, is considered to be expressed in ghrelin cells. The aim was to establish if the two peptides and the transporter are co-expressed, both in normal gastric mucosa and in gastric endocrine tumours.

    Design:

    An immunohistochemical study was performed on gastric biopsy material and on surgical specimens from 63 patients with gastric endocrine tumours and from individuals with normal gastric mucosa. Cells displaying obestatin immunoreactivity were examined regarding co-localization with ghrelin and VMAT-2. Both single- and double-immunostaining techniques were applied. Obestatin concentration in blood was measured in a subgroup of these patients. The results were correlated to various clinico-pathological parameters.

    Results:

    In the normal mucosa, obestatin/ghrelin-immunoreactive cells rarely co-expressed VMAT-2. In most tumour tissue specimens, only a fraction of neoplastic cells displayed immunoreactivity to obestatin, and these cells always co-expressed ghrelin. Neoplastic obestatin-/ ghrelin-IR cells invariably expressed VMAT-2, except for two ghrelinomas. The obestatin concentrations in blood were consistently low and did not correlate to clinico-pathological data.

    Conclusions:

    Obestatin and ghrelin immunoreactivity always occurred in the same endocrine cells in the gastric mucosa but these cells only occasionally co-expressed VMAT-2, opposite to the findings in tumours. These results indicate that endocrine cells expressing obestatin and ghrelin mainly differ from VMAT-2 expressing cells (ECL-cells) and can develop into pure ghrelinomas. Plasma concentrations of obestatin did not correlate to cellular expression.

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