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  • 1.
    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.

  • 2.
    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.

  • 3.
    Backman, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 2, p. 705-712Article in journal (Refereed)
    Abstract [en]

    Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.

    PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.

    RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.

    CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

  • 4.
    Bergström, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Khan, Tanweera Shaheena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    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 Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Bonasera, T.A.
    Fasth, K.-J.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    PET with [11C]-Metomidate for the Visualization of Adrenocortical Tumors and Discrimination from Other Lesions1999In: Clinical Positron Imaging, ISSN 1095-0397, E-ISSN 1878-5751, Vol. 2, no 6, p. 339-Article in journal (Refereed)
    Abstract [en]

    Purpose:

    The purpose of the study was to evaluate the potential role of PET with the adrenocortical-specific tracer 11C-metomidate in the characterization of incidentally found adrenal cortical lesions and in adrenocortical carcinomas.

    Methods:

    PET with 11C-metomidate was performed in 15 patients with unilateral adrenal mass confirmed by CT (incidentalomas) and in 9 additional patients with adrenocortical cancer. All incidentalomas subsequently underwent surgery, except 2 subjected to biopsy only. These lesions were histopathologically examined and diagnosed as adrenal cortical adenoma (n = 6; 3 nonfunctioning), adrenocortical carcinoma (n = 2) and nodular hyperplasia (n = 1). The remaining were non-cortical lesions including 1 pheochromocytoma, 1 myelolipoma, 2 adrenal cysts, and 2 metastases.

    Results:

    All lesions, except 1, with an adrenocortical origin were easily identified due to exceedingly high uptake of 11C-metomidate, whereas the non-cortical lesions showed very low uptake. The 1 false negative was a cancer that at surgery was found to be extensively necrotic. High uptake was also seen in normal adrenal glands. The tracer uptake kinetics indicated trapping of the tracer in the cortical lesions. For quantitative evaluation of tracer binding in individual lesions, the simple SUV concept was found to be equally accurate as more elaborate kinetic analyses.

    Conclusion:

    The patients presented and altogether over 40 PET investigations have demonstrated 11C-metomidate to be an attractive tracer for the characterization of adrenal masses with the ability to discriminate lesions of adrenal cortical origin from non-cortical lesions. Additionally the method allows the assessment of metastases from adrenocortical cancers, and the very high contrast has allowed partial whole-body examinations.

  • 5.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Caballero-Corbalán, José
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Whole-body MRI including diffusion-weighted MRI compared with 5-HTP PET/CT in the detection of neuroendocrine tumors2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    AIM: We wanted to explore if whole-body magnetic resonance imaging (MRI) including diffusion-weighted (DW) and liver-specific contrast agent-enhanced imaging could be valuable in lesion detection of neuroendocrine tumors (NET). [11C]-5-Hydroxytryptophan positron emission tomography/computed tomography (5-HTP PET/CT) was used for comparison.

    MATERIALS AND METHODS: Twenty-one patients with NET were investigated with whole-body MRI, including DW imaging (DWI) and contrast-enhanced imaging of the liver, and whole-body 5-HTP PET/CT. Seven additional patients underwent upper abdomen MRI including DWI, liver-specific contrast agent-enhanced imaging, and 5-HTP PET/CT.

    RESULTS: There was a patient-based concordance of 61% and a lesion-based concordance of 53% between the modalities. MRI showed good concordance with PET in detecting bone metastases but was less sensitive in detecting metastases in mediastinal lymph nodes. MRI detected more liver metastases than 5-HTP PET/CT.

    CONCLUSION: Whole-body MRI with DWI did not detect all NET lesions found with whole-body 5-HTP PET/CT. Our findings indicate that MRI of the liver including liver-specific contrast agent-enhanced imaging and DWI could be a useful complement to whole-body 5-HTP PET/CT.

  • 6.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Eriksson, Barbro
    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.
    Secondary Hormonal Syndromes in Patients with Sporadic Neuroendocrine Tumors2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 240-240Article in journal (Other academic)
  • 7.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Fanola, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindholm, Daniel P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Antonodimitrakis, Pantelis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Effect of Temozolomide in Patients with Metastatic Bronchial Carcinoids2013In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 98, no 2, p. 151-155Article in journal (Refereed)
    Abstract [en]

    Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with tennozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11(52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxcities grade 3-4 were noted in 4 patients, thrombocytopenia (n =3) and leukopenia (n = 1). Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining tennozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients. Copyright (C) 2013 S. Karger AG, Basel

  • 8.
    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)
  • 9.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Antonodimitrakis, Pantelis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumours2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 2, p. 445-452Article in journal (Refereed)
    Abstract [en]

    CONTEXT:

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

    OBJECTIVES:

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

    DESIGN, SETTING, AND PARTICIPANTS:

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

    RESULTS:

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

    CONCLUSION:

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

  • 10.
    Cunningham, JL
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lopez-Egido, JR
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Tiensuu Janson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Gobl, AE
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Transmembrane protein tyrosine phosphatase IA-2 (ICA512) is expressed inhuman midgut carcinoids but is not detectable in normal enterochromaffincells.2000In: J Endocrinol, Vol. 164, p. 315-Article in journal (Refereed)
  • 11. de Herder, Wouter W.
    et al.
    Niederle, Bruno
    Scoazec, Jean-Yves
    Pauwels, Stanislas
    Kloppel, Gunter
    Falconi, Massimo
    Kwekkeboom, Dik J.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wiedenmann, Bertram
    Rindi, Guido
    O'Toole, Dermot
    Ferone, Diego
    Well-differentiated pancreatic tumor/carcinoma: insulinoma2006In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 84, no 3, p. 183-188Article in journal (Refereed)
  • 12. Demırkan, Binnaz H M
    et al.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Systemic treatment of neuroendocrine tumors with hepatic metastases2012In: The Turkish Journal of Gastroenterology, ISSN 1300-4948, Vol. 23, no 5, p. 427-437Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine tumors, 1-2% of all malignancies, are relatively slow-growing neoplasms. The majority of neuroendocrine tumors belong to the World Health Organization Group 2 with well-differentiated endocrine carcinomas, but some tumors can be aggressive. The most common are gastroenteropancreatic-neuroendocrine tumors, followed by bronchopulmonary neuroendocrine tumors; less frequent locations are the ovaries, testis and hepatobiliary locations. They can be either non-functioning tumors with symptoms related to mass effects and malignant tumor disease or functioning tumors with specific hormones/neuropeptides autonomously secreted to induce specific clinical syndromes. Localized neuroendocrine tumors are less frequent than metastatic ones; in fact, up to 75% of patients with small bowel neuroendocrine tumors and 30-85% of pancreatic neuroendocrine tumors present with liver metastases either at the time of diagnosis or during the course of the disease. The predominant metastatic site is the liver, which is the best prognostic marker of survival regardless of the primary site. If surgical resection or interventional therapies of the hepatic tumor burden are not feasible, or if the metastases are not confined to the liver, systemic treatment remains the only option. None of the systemic therapies is liver-specific, but rather acts on all metastatic sites. The lack of prospective studies comparing different treatment modalities in homogeneous cohorts of patients makes the best treatment strategy poorly defined. Standard systemic therapy options are somatostatin analogues (octreotide and lanreotide), interferon-α and chemotherapy. Somatostatin analogues not only control symptoms related to functioning tumors but tumor growth as well. Because of the studies challenging its efficacy, as well as the potential for side effects, the more widespread acceptance of interferon-α in the treatment of metastatic neuroendocrine tumors has been limited. Well-differentiated neuroendocrine tumors do not show high sensitivity to chemotherapy because of their low mitotic rates, high levels of antiapoptotic protein bcl-2 and increased expression of the multi-drug resistant gene. Traditional chemotherapeutic agents are streptozotocin in combination with 5-fluorouracil or doxorubicin, or to some extent dacarbazine. Temozolomide, capecitabine and oxaliplatin, as monoagents or in combination therapy, show efficacy in phase II trials. Patients with poorly differentiated neuroendocrine tumor, regardless of the primary tumor localization, are candidates for cisplatin and etoposide chemotherapy regimen. Peptide receptor radionuclide therapy is reported to be an effective treatment option for patients with good performance status and high somatostatin-receptor scintigraphy uptake as well as without major liver involvement. Basic fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor alpha and beta, insulin-like growth factor type 1, epidermal growth factor, stem cell factor (c-kit), and corresponding receptors have been shown to be expressed in Neuroendocrine tumors. Current phase II-III clinical trials with molecular-targeted therapies revealed promising agents such as everolimus (RAD001), an oral mTOR inhibitor, and sunitinib malate (SU-11248), an oral multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors, c-kit receptors, glial cell linederived neurotrophic factor, and FMS-like tyrosine kinase-3 (Flt 3), which were approved for the treatment of advanced pancreatic neuroendocrine tumors. Ongoing clinical trials with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, will further define the role of angiogenesis inhibitors in advanced intestinal neuroendocrine tumors. Various further novel strategies of targeted therapy and microRNA-regulated pathways in neuroendocrine tumors are under development.

  • 13.
    Ekeblad, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimfjärd, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Térèse
    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.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    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.
    Co-expression of ghrelin and its receptor in pancreatic endocrine tumours2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 1, p. 115-122Article in journal (Refereed)
    Abstract [en]

    Objective 

    Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index.

    Design 

    Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients.

    Results 

    Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (> 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 ± 569 ng/l) and controls (952 ± 164 ng/l). Mean BMI was 24·3 kg/m2. There was no association between ghrelin or receptor expression and survival.

    Conclusions 

    We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.

  • 14.
    Ekeblad, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dunder, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kozlovacki, Gordana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sigurd, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 10, p. 2986-2991Article in journal (Refereed)
    Abstract [en]

    Purpose: A retrospective analysis of the toxicity and efficacy of temozolomide in advanced neuroendocrine tumors. Experimental Design: Thirty-six patients with advanced stages of neuroendocrine tumor (1 gastric, 7 thymic and 13 bronchial carcinoids, 12 pancreatic endocrine tumors, 1 paraganglioma, 1 neuroendocrine foregut, and 1 neuroendocrine cecal cancer) were treated with temozolomide (200 mg/m2) for 5 days every 4 weeks. Patients had previously received a mean of 2.4 antitumoral medical regimens. Tumor response was evaluated radiologically according to the Response Evaluation Criteria in Solid Tumors every 3 months on an intent-to-treat basis. The circulating tumor marker plasma chromogranin A was also assessed. The expression of 06-methylguanine DNA methyltransferase, an enzyme implicated in chemotherapy resistance, was studied by immunohistochemistry (n = 23) and compared with response to temozolomide. Results: Median overall time to progression was 7 months (95% confidence interval, 3-10). Radiologic response was seen in 14% of patients and stable disease in 53%. Side effects were mainly hematologic; 14% experienced grade 3 or 4 thrombocytopenia (National Cancer Institute toxicity criteria). Ten patients had tumors with 06-methylguanine DNA methyltransferase immunoreactivity in <10% of nuclei, whereas four patients showed radiologic responses. Conclusions: Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses.

  • 15.
    Eriksson, B
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Janson, E T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Skogseid, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Endokrin tumörbiologi.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    [New medical therapy of neuroendocrine gastrointestinal tumors]1990In: Lakartidningen, ISSN 0023-7205, Vol. 87, no 35, p. 2668-72Article in journal (Refereed)
  • 16.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Medical management of islet cell carcinoma2011In: Neuroendocrine Tumors:  , Totowa: Springer Science+Business Media B.V., 2011, p. 137-156Chapter in book (Other academic)
  • 17.
    Eriksson, Barbro
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Bergström, M
    Örlefors, Håkan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Sundin, Anders
    Öberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Långström, B
    PET for clinical diagnosis and research in neuroendocrine tumors2003In: Diagn Nuclear Medicine 4th edition, 2003, p. 747-754Chapter in book (Refereed)
  • 18.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Bergström, Mats
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. onk endo.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    The role of PET in localization of neuroendocrine and adrenocortical tumors2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 970, p. 159-169Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) supplies a range of labeled compounds to be used for the characterization of tumor biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow up, and clinical research. The first routinely used PET tracer in oncology, 18F-labeled deoxyglucose (FDG), was successfully used for diagnosis of cancer, reflecting increased expression of glucose transporter in cancerous tissue. This tracer, however, usually does not show sufficient uptake in well-differentiated tumors such as neuroendocrine tumors. We developed a tracer more specific to neuroendocrine tumors—the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C—and demonstrated increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was so selective and the resolution was so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. To further improve the method, especially to reduce the high renal excretion of the tracer producing streaky artifacts in the area of interest, we introduced premedication by the decarboxylase inhibitor carbidopa, leading to a six-fold decreased renal excretion while the tumor uptake increased three-fold, hence improving the visualization of the tumors.

    11C-labeled l-DOPA was evaluated as an alternative tracer, especially for endocrine pancreatic tumors, which usually do not demonstrate enhanced urinary serotonin metabolites. However, only half of the EPTs, mainly functioning tumors, could be detected with l-DOPA. Instead 5-HTP seems to be a universal tracer for EPT and foregut carcinoids. With new, more sensitive PET cameras, larger field of view and procedures for whole-body coverage, the PET examination with 5-HTP is now routinely performed as reduced whole-body PET examinations with coverage of the thorax and abdomen. With this method we have been able to visualize small neuroendocrine lesions in the pancreas and thorax (e.g., ACTH-producing bronchial carcinoids) not detectable by any other method, including octreotide scintigraphy, MRI, and CT. Another tracer, the 11β-hydroxylase inhibitor, metomidate labeled with 11C, was developed to simplify diagnosis and follow-up of patients with incidentalomas. A large series of patients with incidentally found adrenal masses have been investigated and so far all lesions of adrenocortical origin have been easily identified because of exceedingly high uptake of 11C-metomidate, whereas noncortical lesions showed very low uptake. In addition, adrenocortical cancer shows high uptake, suggesting that this PET tracer can be used for staging purposes.

  • 19.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Endokrin onkologi.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Use of PET in neuroendocrine tumors: In vivo applications and in vitro studies2000In: The Quarterly journal of nuclear medicine, ISSN 1125-0135, Vol. 44, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) performed with various radiolabelled compounds facilitates the study of tumor biochemistry. If the tumor uptake of an administered tracer is greater than that of surrounding normal tissue, it is also possible to localize the tumor. In initial studies, 18F-labeled deoxyglucose (FDG) was attempted to visualize the tumors, since this tracer had been successfully used in oncology, reflecting increased glucose metabolism in cancerous tissue. However, this tracer was not to any significant degree taken up by the neuroendocrine tumors. Instead, the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C was used and showed an increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was selective and the resolution so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. One problem was, however, the high renal excretion of the tracer producing streaky artifacts in the area of interest. Using the decarboxylase inhibitor carbidopa, given as peroral premedication, the renal excretion decreased 6-fold and at the same time the tumor uptake increased 3-fold, hence improving the visualization of the tumors. When patients were followed during treatment with PET using 5-HTP as a tracer, a > 95% correlation between changes in urinary 5-hydroxyindoleacetic acid (U-5-HIAA) and changes in the transport rate constant for 5-HTP was observed. Thus, PET can be used to monitor treatment effects. Elevation of U-5-HIAA is considered to be uncommon in endocrine pancreatic tumors (EPTs). Initially, 11C-labeled L-DOPA was attempted as another amine important in the APUD system. With L-DOPA about half of the EPTs, mainly functioning tumors, could be detected. Recently, 5-HTP was explored as a universal tracer also for EPT and foregut carcinoids, extending the PET-examination to both thorax and abdomen (whole-body PET-examination). With this method we were able to visualize small lesions in the pancreas and thorax (e.g. ACTH-producing bronchial carcinoids) not detectable by any other method including octreotide scintigraphy, MRI and CT. Several other tracers have been investigated, e.g. the monoamineoxidase (MAO-A) inhibitor harmine with promising results in non-functioning EPTs. We are currently exploring a wide range of biochemical systems, including enzymes and receptors, both for neurotransmitters and for peptides and proteins in in vitro assays with the potential to use some of the developed tracers for in vivo visualization and tumor biological studies. In conclusion, PET is a valuable tool in the diagnosis of neuroendocrine tumors. It can detect small lesions in the thorax and abdomen not detected by other methods, which has been of great value preoperatively in several cases. It detects more lesions in the liver and lymph nodes than other methods and furthermore, it can be used to monitor treatment effects.

  • 20.
    Eriksson, Barbro
    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.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Antonodimitrakis, Pantelis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Streptozocin and 5-fluorouracil treatment of pancreatic neuroendocrine tumors: efficacy, toxicity and prognostic factors2014In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 126, no S3, p. S145-S145, article id FP7.1Article in journal (Other academic)
  • 21.
    Eriksson, Barbro
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Tiensuu Janson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Bax, ND
    Mignon, M
    Morant, R
    Opolon, P
    Rougier, P
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Endokrin onkologi.
    The use of new somatostatin analogues, lanreotide and octastatin, inneuroendocrine gastro-intestinal tumours.1996In: Digestion, Vol. 57 Suppl 1, p. 77-Article in journal (Refereed)
  • 22.
    Eriksson, Barbro
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Öberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Neuroendocrine tumors: New perspection in their therapy2000In: Advances in pancreatic disease, Georg Thieme Verlag Stuttgart, New York , 2000, p. 376-96Chapter in book (Refereed)
  • 23.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Långstrom, Bengt
    Bergström, Mats
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Positron emission tomography in neuroendocrine tumours1999In: The Italian Journal of Gastroenterology and Hepatology, ISSN 1125-8055, Vol. Suppl 2, p. S167-S171Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography is an in vivo tracer and imaging technique that utilizes short-lived positron emitting radionuclides (11C, 15O, 13N, 18F) with half-lives ranging between 2 min and 2 hours. These radionuclides are interesting from the labelling viewpoint since they are natural constituents of most biologically active compounds. The short half-life is an advantage with regard to the irradiation dose to the patient but it is also a limitation since it requires the production of these radionuclides in close vicinity to the positron emission tomography camera.

  • 24.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bergström, Mats
    Långström, Bengt
    PET Centre, University Hospital, Uppsala, Sweden.
    Developments in PET for the detection of endocrine tumours2005In: Baillière's Best Practice & Research. Clinical Endocrinology & Metabolism, ISSN 1521-690X, E-ISSN 1532-1908, Vol. 19, no 2, p. 311-324Article in journal (Other academic)
    Abstract [en]

    Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. 18F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [11C]-5-hydroxytryptophan and [11C]-l-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[18F]-fluorodopamine and [11C]-hydroxyephedrine for phaeochromocytomas, and [11C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.

  • 25.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Jansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 10, p. 3428-3437Article in journal (Refereed)
    Abstract [en]

    In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.

  • 26.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin42017In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 11, p. 1039-1045Article in journal (Refereed)
    Abstract [en]

    AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed.

    METHODS: -Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment.

    RESULTS: -Exendin4.

    CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.

  • 27.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Quantitative Imaging of Serotonergic Biosynthesis and Degradation in the Endocrine Pancreas2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 3, p. 460-465Article in journal (Refereed)
    Abstract [en]

    Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer (11)C-5-hydroxy-l-tryptophan ((11)C-5-HTP).

    METHODS: Uptake of (11)C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats).

    RESULTS: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of (11)C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts (11)C-5-HTP to (11)C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes.

    CONCLUSION: The PET tracer (11)C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.

  • 28.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Kandeel, Fouad
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 5, p. 1519-1524Article in journal (Refereed)
    Abstract [en]

    Context:

    Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.

    Objective:

    To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.

    Design:

    Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.

    Setting:

    Uppsala University Hospital, Uppsala, Sweden.

    Patients:

    A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic insulinoma was suspected and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found and a distal pancreatic resection (plus splenectomy) and removal of lymph node was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.

    Interventions:

    The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.

    Main Outcome Measures:

    N/A

    Results:

    The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT which confirmed several small GLP-1R positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.

    Conclusion:

    The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.

  • 29.
    Falconi, M.
    et al.
    Univ Vita & Salute, Hosp San Raffaele, Dept Surg, Milan, Italy..
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Kaltsas, G.
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol, Athens, Greece..
    Bartsch, D. K.
    Univ Marburg, Dept Surg, Marburg, Germany..
    Capdevila, J.
    Vall dHebron Univ Hosp, Inst Oncol VHIO, Barcelona, Spain..
    Caplin, M.
    Royal Free Hosp, Neuroendocrine Tumour Unit, Pond St, London NW3 2QG, England..
    Kos-Kudla, B.
    Med Univ Silesia, Dept Endocrinol, Katowice, Poland..
    Kwekkeboom, D.
    Erasmus MC, Div Nucl Med, Dept Internal Med, Rotterdam, Netherlands..
    Rindi, G.
    Univ Cattolica Sacro Cuore, Policlin A Gemelli, Inst Pathol Anat, Rome, Italy..
    Kloeppel, G.
    Tech Univ Munich, Inst Pathol, D-80290 Munich, Germany..
    Reed, N.
    Gartnavel Royal Hosp, Beatson Oncol Ctr, Glasgow, Lanark, Scotland..
    Kianmanesh, R.
    CHU Robert Debre, Dept Surg, Reims, France..
    Jensen, R. T.
    NIH, Digest Dis Branch, Bldg 10, Bethesda, MD 20892 USA..
    ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, no 2, p. 153-171Article in journal (Refereed)
  • 30. Falconi, Massimo
    et al.
    Bartsch, Detlef Klaus
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Klöppel, Günter
    Lopes, Josém
    O'Connor, Juan M
    Salazar, Ramón
    Taal, Babs G
    Vullierme, Marie Pierre
    O'Toole, Dermot
    ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System: Well-Differentiated Pancreatic Non-Functioning Tumors2012In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 95, no 2, p. 120-134Article in journal (Refereed)
  • 31.
    Fjallskog, ML
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. onk endo.
    Ludvigsen, E
    Stridsberg, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. onk endo.
    Eriksson, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. onk endo.
    Tiensuu Janson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. onk endo.
    Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue andintratumoral vessels in malignant endocrine pancreatic tumors.2003In: Med Oncol, Vol. 20, p. 59-Article in journal (Refereed)
  • 32.
    Fjällskog, M L
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Department of Oncology, Radiology and Clinical Immunology.
    Sundin, A
    Department of Oncology, Radiology and Clinical Immunology.
    Westlin, J E
    Department of Oncology, Radiology and Clinical Immunology.
    Öberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Tiensuu Janson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs.2002In: Med Oncol, ISSN 1357-0560, Vol. 19, no 1, p. 35-42Article in journal (Refereed)
  • 33.
    Fjällskog, Marie-Louise
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Christoffer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Treatment with Cisplatin and Etoposide in Patients with Neuroendocrine Tumors2001In: Cancer, Vol. 92, no 5, p. 1101-1107Article in journal (Refereed)
  • 34.
    Fjällskog, Marie-Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hessman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 6, p. 741-746Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor receptor (PDGFR) beta signaling is involved in autocrine growth stimulation of tumor cells, tumor angiogenesis and regulation of tumor interstitial fluid pressure. Development of PDGFR antagonists has further increased the interest for PDGFR as targets for anticancer treatments. Malignant endocrine pancreatic tumors (EPTs) express PDGFR beta both in stroma and on tumor cells. To investigate the role of PDGFR beta signaling in EPTs we compared PDGFR beta expression in normal endocrine pancreas to malignant EPTs and metastases. PDGFR beta expression was examined by immunohistochemistry using specific polyclonal antibodies in ten tissue samples from normal endocrine pancreas, 21 from primary EPTs and 19 from metastases. In eight patients we compared the expression in normal endocrine pancreas to the corresponding primary tumor and metastases, in two patients normal tissue to the primary tumor and in 11 patients primary tumors to the corresponding metastases. Six of ten tissues containing normal pancreas stained negative for PDGFR beta on endocrine cells, while seven of ten stained positive in the stroma. Eighteen of 21 (86%) primary tumors stained positive for PDGFR beta on tumor cells and all had positive stroma stainings. All 19 metastases stained positive for PDGFR beta on tumor cells and in evaluable stroma (n=16). We have found that PDGFR beta is more frequently expressed in primary EPTs and metastases as compared to normal endocrine pancreatic tissue. This is also true for PDGFR beta expression in the corresponding stroma. We suggest that new therapeutic options to inhibit the growth and spread of EPTs could include targeting of PDGFR beta.

  • 35.
    Fjällskog, Marie-Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Ludvigsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Janson, Eva T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors2003In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 20, no 1, p. 59-67Article in journal (Refereed)
    Abstract [en]

    Somatostatin analogs are well established in the treatment of malignant endocrine pancreatic tumors (EPTs). Our goal is to individualize their treatment using receptor-subtype-specific analogs and, therefore, exploring the receptor expression is highly important. We have examined the expression of somatostatin receptor (sst) subtypes 1–5 on tumor cells and in intratumoral vessels in 28 tumor tissues from malignant EPTs with immunohistochemistry using sst-subtype-specific polyclonal antibodies. We found that sst2 and sst4 stained positive in 90% and sst1 in 70% of the tumor tissues, whereas sst3 and sst5 stained positive in only 50% of the tumor tissues. Sst expression in intratumoral vessels was high for sst2 and sst4 (80%), moderate for sst1 (40%), and low for sst3 and sst5 (10%). The ssts were evenly distributed among the different tumor subtypes. However, tumors belonging to the same subgroup of EPTs showed a variable expression of receptor subtypes. No differences in receptor-subtype expression could be seen between poorly and well-differentiated tumors, nor between primary tumors and metastases. Prior medical treatment did not influence sst expression pattern. In conclusion, sst2 and sst4 were expressed in most tumor tissues and intratumoral vessels from EPTs. However, sst3 and sst5 were lacking in half of the tumor tissues and in most of the intratumoral vessels. These differences indicate the importance of determining each tumor’s subset of receptors before treatment with receptor-subtype-specific analogs is initiated. The importance of sst expression in intratumoral vessels is not yet known.

  • 36.
    Garcia-Carbonero, Rocio
    et al.
    Univ Complutense, CNIO, Hosp Univ Doce Octubre, Med Oncol Dept.
    Rinke, Anja
    Univ Hosp Marburg UKGM, Div Gastroenterol & Endocrinol.
    Valle, Juan W.
    Univ Manchester, Inst Canc Sci, Christie NHS Fdn Trust, Dept Med Oncol, Manchester.
    Fazio, Nicola
    European Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine.
    Caplin, Martyn
    Royal Free Hosp, Neuroendocrine Tumour Unit.
    Gorbounova, Vera
    Inst Russian Acad Med Sci, Dept Oncol.
    O'Connor, Juan
    Inst Alexander Fleming, Dept Clin Oncol, Buenos Aires.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol.
    Kulke, Matthew
    Harvard Med Sch, Dana Farber Canc Inst.
    Chen, Jie
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou.
    Falkerby, Jenny
    Uppsala Univ Hosp, Dept Endocrine Oncol.
    Costa, Frederico
    Hosp Sirio Libanes.
    de Herder, Wouter
    Erasmus MC, ENETS Ctr Excellence Rotterdam, Div Endocrinol, Dept Internal Med.
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Hop Edouard Herriot, Med Oncol Dept.
    Pavel, Marianne
    Charite Univ Med Berlin, Campus Virchow Klinikum, Dept Gastroenterol & Hepatol.
    ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy - Chemotherapy2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, p. 281-294Article in journal (Refereed)
    Abstract [en]

    Systemic chemotherapy is indicated in progressive or bulky advanced pancreatic neuroendocrine tumors (NETs) and in grade 3 (G3) neuroendocrine neoplasms (NENs) as per ENETS guidelines. Chemotherapy may be considered in NETs of other sites (lung, thymus, stomach, colon, and rectum) under certain conditions (e.g., when Ki-67 is at a high level [upper G2 range], in rapidly progressive disease and/or after failure of other therapies, or if somatostatin receptor imaging is negative). An ENETS Consensus Conference was held in Antibes (2015) to elaborate guidelines on the standards of care of different diagnostic procedures and therapeutic interventions in NENs. This article provides guidance on chemotherapy including therapeutic indications, dosing schedules, adverse events (including prevention and management), drug interactions, and evaluation of treatment effect for the chemotherapy agents most commonly used in NENs (streptozocin, dacarbazine, fluoropyrimidines, platinum compounds, etoposide, and irinotecan).

  • 37.
    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.

  • 38.
    Garske, Ulrike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lessons on Tumour Response: Imaging during Therapy with Lu-177-DOTA-octreotate. A Case Report on a Patient with a Large Volume of Poorly Differentiated Neuroendocrine Carcinoma2012In: Theranostics, ISSN 1838-7640, Vol. 2, no 5, p. 459-471Article in journal (Refereed)
    Abstract [en]

    Favourable outcomes of peptide receptor radiotherapy (PRRT) of neuroendocrine tumours have been reported during the last years. Still, there are uncertainties on the radionuclides to be used, the treatment planning, and the indication in patients with a high proliferation rate. This case report describes a patient with a high tumour burden of poorly differentiated neuroendocrine carcinoma of unknown primary with a proliferation rate in liver metastases up to 50%, undergoing fractionated treatment with 7 cycles of Lu-177-DOTA-octreotate (7.4 GBq each) after disease progression on two different chemotherapy regiments. Based on initial staging scintigraphy, somatostatin receptor expression was very high. Longitudinal dosimetry studies during therapy indicated ongoing increases in tumour-to-organ ratios that coincided with an objective response. We conclude that fractionated therapy with Lu-177-DOTA-octreotate should be considered a treatment option also for those patients with large tumours, high proliferation, and high receptor expression.

  • 39.
    Garske, Ulrike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Minor changes in effective half-life during fractionated 177Lu-Octreotate therapy2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 86-96Article in journal (Refereed)
    Abstract [en]

    Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. Patients. Thirty patients, 13 women and 17 men, were included in the study. Methods. During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. Results. The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively. Discussion. The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). Conclusion. With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

  • 40.
    Garske-Roman, Ulrike E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Medical Radiation Sciences.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Fröss-Baron, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Favourable outcome after 177Lu-DOTA-octreotate therapy of patients with neuroendocrine of the rectum -an update2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S211-S211, article id OP235Article in journal (Other academic)
  • 41.
    Giandomenico, V
    et al.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Boccherini, M.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    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. Uppsala Univ Hosp, Uppsala, Sweden..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala Univ Hosp, Uppsala, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Paganelli, G.
    IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, FC, Italy..
    miR-196a Is Specifically Regulated in FDG-PET Positive and Negative Small Intestinal Neuroendocrine Tumor Patients at Late Stage of Disease2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 115-115Article in journal (Refereed)
  • 42.
    Giandomenico, Valeria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Modlin, Irvin M.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Khan, Mohid S.
    Millar, Robert P.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Borlak, Jurgen
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Nielsen, Bengt
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Waterton, John C.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Improving the Diagnosis and Management of Neuroendocrine Tumors: Utilizing New Advances in Biomarker and Molecular Imaging Science2013In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 98, no 1, p. 16-30Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone-secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Oberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions.

  • 43.
    Granberg, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lungcarcinoider: inte så benigna som man trott2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 34, p. 2382-2384Article in journal (Other academic)
  • 44.
    Granberg, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimfjärd, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Experience in treatment of metastatic pulmonary carcinoid tumors2001In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 12, no 10, p. 1383-1391Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The only cure for patients with pulmonary carcinoids is surgery. In the present paper, we report the results of medical treatment of patients with metastatic tumors, their circulating hormone markers, and immunohistochemical profile of the tumors. PATIENTS AND

    METHODS/RESULTS:

    The response to systemic antitumoral treatment was studied in 31 patients with metastatic pulmonary carcinoids. Median survival from treatment start was 25 months. Alpha-interferon treatment has resulted in stable disease in 4 of 27 patients (median duration 15 months), while 23 patients showed progressive disease. Somatostatin analogues given as single drug treatment resulted in progressive disease. Streptozotocin and 5-fluorouracil resulted in progressive disease in seven of seven patients. Stable disease was obtained for 8 and 10 months respectively in two of two patients treated with streptozotocin + doxorubicin. Two of eight patients treated with cisplatinum + etoposide showed a significant decrease in tumor size lasting six and eight months respectively, and one displayed stable disease for seven months. Elevation of plasma chromogranin A was seen in 93%.

    CONCLUSIONS:

    The results of systemic antitumoral treatment of pulmonary carcinoids with distant metastases are generally discouraging. Chemotherapy with cisplatinum + etoposide, or doxorubicin combined with streptozotocin or paclitaxel may be of value. Alpha-interferon and octreotide offer efficient symptomatic relief, but stabilizes tumor growth in merely 15% of the cases. Plasma chromogranin A is the most frequently elevated tumor marker.

  • 45.
    Granberg, Dan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Clinical Chemistry.
    Seensalu, Rein
    Eriksson, Barbro
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Plasma Chromogranin A In Patients with Multiple Endocrine Neoplasia Type 11999In: Journal of Clinical Endocrinology and Metabolism, Vol. 84, no 8, p. 2712-2717Article in journal (Refereed)
  • 46. Grander, D
    et al.
    Oberg, K
    Uppsala University.
    Lundqvist, M L
    Tiensuu Janson, E
    Uppsala University.
    Eriksson, B
    Uppsala University.
    Einhorn, S
    Interferon-induced enhancement of 2',5'-oligoadenylate synthetase in mid-gut carcinoid tumours.1990In: Lancet, ISSN 0140-6736, Vol. 336, no 8711, p. 337-40Article in journal (Refereed)
  • 47.
    Hellman, Per
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Linder, F
    Hennings, Joakim
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Hessman, Ola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Barbro
    Department of Medical Sciences. Department of Medical Sciences.
    Örlefors, Håkan
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Bilateral adrenalectomy for ectopic Cushing syndrome -: discussions on technique and indication2006In: World J Surg, Vol. 30, no 5, p. 909-916Article in journal (Refereed)
  • 48.
    Ilan, Ezgi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Parametric Net Influx Rate Images of 68Ga-DOTATOC and 68Ga-DOTATATE: Quantitative Accuracy and Improved Image Contrast2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no 5, p. 744-749Article in journal (Refereed)
    Abstract [en]

    (68)Ga-DOTATOC and (68)Ga-DOTATATE are radiolabelled somatostatin analogs used for diagnosis of somatostatin receptor expressing neuroendocrine tumors (NETs) and SUV -measurements are suggested for treatment monitoring. However, changes in net-influx rate (Ki) may better reflect treatment effects than those of the SUV, and accordingly there is a need to compute parametric images showing Ki at the voxel level. The aim of this study was to evaluate parametric methods for computation of parametric Ki images by comparison to volume of interest based methods and to assess image contrast in terms of tumor-to-liver ratio.

    METHODS: Ten patients with metastatic NETs underwent a 45-min dynamic PET examination followed by whole-body PET/CT at 1 h post injection of (68)Ga-DOTATOC and (68)Ga-DOTATATE on consecutive days. Parametric Ki images were computed using a basis function method (BFM) implementation of the two tissue irreversible compartment model and the Patlak method using a descending aorta image-derived input function, and mean tumor Ki values were determined for 50% isocontour VOIs and compared to Ki values based on non-linear regression (NLR) of the whole-VOI time-activity curve. A subsample of healthy liver was delineated in the whole-body and Ki images and tumor-to-liver ratios were calculated in order to evaluate image contrast. Correlation and agreement between VOI-based and parametric Ki values were assessed using regression and Bland-Altman analysis.

    RESULTS: Correlation (R2) between NLR-based and parametric image-based (BFM) tumor Ki values was 0.98 (slope 0.81) and 0.97 (slope 0.88) for (68)Ga-DOTATOC and (68)Ga DOTATATE, respectively. For Patlak analysis, correlation between NLR-based and parametric based (Patlak) tumor Ki were 0.95 (slope 0.71) and 0.92 (slope 0.74) for (68)Ga-DOTATOC and (68)Ga-DOTATATE, respectively. There was no bias between NLR and parametric based Ki-values. Tumor-to-liver contrast was 1.6 and 2.0 times higher in the parametric BFM-Ki images, and 2.3 and 3.0 times in the Patlak images, than in the whole-body images for (68)Ga-DOTATOC and (68)Ga-DOTATATE, respectively.

    CONCLUSION: A high correlation and agreement between NLR- and parametric based Ki values was found, showing that parametric net influx rate images are quantitatively accurate. In addition, tumor-to-liver contrast was superior in the parametric Ki images compared to whole-body images both for (68)Ga-DOTATOC and (68)Ga DOTATATE.

  • 49.
    Ilan, Ezgi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. 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 Radiology, Oncology and Radiation Science, Radiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Garske-Román, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Dose Response of Pancreatic Neuroendocrine Tumors Treated with Peptide Receptor Radionuclide Therapy Using 177Lu-DOTATATE2015In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, no 2, p. 177-182Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Peptide receptor radionuclide therapy (PRRT) is a promising treatment for patients with neuroendocrine tumors, giving rise to improved survival. Dosimetric calculations in relation to PRRT have been concentrated to normal organ dosimetry in order to limit side effects. However, the relation between the absorbed dose to the tumor and treatment response has so far not been established. Better knowledge in this respect may improve the understanding of treatment effects, allow for improved selection of those patients who are expected to benefit from PRRT, and avoid unnecessary treatments. The aim of the present work was to evaluate the dose-response relationship for pancreatic neuroendocrine tumors treated with PRRT using (177)Lu-DOTATATE.

    METHODS: Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeated cycles of (177)Lu-DOTATATE at 8-wk intervals. The absorbed dose calculations relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE. The unit density sphere model from OLINDA was used for absorbed dose calculations. The absorbed doses were corrected for partial-volume effect based on phantom measurements. On the basis of these results, only tumors larger than 2.2 cm in diameter at any time during the treatment were included for analysis. To further decrease the effect of partial-volume effect, a subgroup of tumors (>4.0 cm) was analyzed separately. Tumor response was evaluated by CT using Response Evaluation Criteria In Solid Tumors.

    RESULTS: Tumor-absorbed doses until best response ranged approximately from 10 to 340 Gy. A 2-parameter sigmoid fit was fitted to the data, and a significant correlation between the absorbed dose and tumor reduction was found, with a Pearson correlation coefficient (R(2)) of 0.64 for tumors larger than 2.2 cm and 0.91 for the subgroup of tumors larger than 4.0 cm. The largest tumor reduction was 57% after a total absorbed dose of 170 Gy.

    CONCLUSION: The results imply a significant correlation between absorbed dose and tumor reduction. However, further studies are necessary to address the large variations in response for similar absorbed doses.

  • 50.
    Imam, Hassan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lukinius, Agneta
    Tiensuu Janson, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindgren, PG
    Department of Oncology, Radiology and Clinical Immunology.
    Oberg, Kjell
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Induction of apoptosis in neuroendocrine tumors of digestive system during treatment with somatostatin analogs.1997In: Acta Oncol., Vol. 36, p. 60714-Article in journal (Refereed)
12 1 - 50 of 91
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