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  • 1.
    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.

  • 2.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gill, Anthony J.
    Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW 2065, Australia.;Univ Sydney, Sydney, NSW 2006, Australia..
    Sidhu, Stan
    Univ Sydney, Sydney, NSW 2006, Australia.;Royal N Shore Hosp, Dept Surg, St Leonards, NSW 2065, Australia..
    Norlen, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Sydney, Sydney, NSW 2006, Australia.;Royal N Shore Hosp, Dept Surg, St Leonards, NSW 2065, Australia..
    Dina, Roberto
    Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Histopathol, London, England..
    Palazzo, F. Fausto
    Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Endocrine Surg, London, England..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma2016In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, article id 31Article in journal (Refereed)
    Abstract [en]

    Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.

  • 3.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prabhawa, Surendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Uppsala Univ Hosp, Rudbeck Lab, Uppsala, Sweden..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    A Role of TETs and 5-Hydroxymethylcytosine in SI-NETs2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 18-18Article in journal (Other academic)
  • 4.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prabhawa, Surendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors.2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, no 1, article id 764Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs.

    METHODS: The analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines.

    RESULTS: Variable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor).

    CONCLUSIONS: SI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.

  • 5.
    Botling, Johan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lamarca, Angela
    Bajic, Dragan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lönngren, Vincent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kjaer, Josefin
    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.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rindi, Guido
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    High-grade progression confers poor survival in pancreatic neuroendocrine tumors.2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Little is known about how Pancreatic Neuroendocrine Tumors (PanNETs) evolve over time and if changes towards a more aggressive biology correlates with prognosis. The purpose of this study was to characterize changes PanNET differentiation and proliferation over time, and to correlate findings to overall survival (OS).

    PATIENTS AND METHODS: In this retrospective cohort study we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were re-evaluated with regard to tumor histopathology and Ki-67 index.

    RESULTS: Forty-six patients with 106 tumor samples (56 available for pathology re-evaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n=8, grade 2 n=36, and grade 3 n=2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n=24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (HR 3.89, 95% CI 1.91-7.94, P<0.001).

    CONCLUSIONS: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

  • 6.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Metastases from Neuroendocrine Tumors to the Breast Are More Common than Previously Thought. A Diagnostic Pitfall?2013In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 37, no 7, p. 1701-1706Article in journal (Refereed)
    Abstract [en]

    Metastases from neuroendocrine tumors (NETs) to the breast have been described as a rare phenomenon. Presentation, imaging results, and cytopathologic findings of these tumours may closely mimic those of a mammary carcinoma. This study was a retrospective review of 661 patients with metastatic NETs, of whom 280 were females, treated at Uppsala University Hospital, Uppsala, Sweden. Patients with pathological breast lesions were identified. Histopathological slides from available NET breast lesions were analyzed for mammary carcinoma and neuroendocrine markers. We have identified 20 female patients with NET metastases to the breast, 11/235 with small intestinal NETs, 8/55 with lung NETs, and 1/6 with thymic NETs. There were no male patients with NET metastatic to the breast. Four patients had their breast lesion initially diagnosed as mammary carcinoma. Retrospectively, these lesions showed negative staining for mammary carcinoma markers. Metastases to the breast from neuroendocrine tumors may be more common than previously thought. Patients with a lesion to the breast and symptoms typical for NET may benefit from additional histopathological investigation, because NET metastases and mammary carcinoma have different immunohistochemical profiles.

  • 7.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gustavsson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Edfeldt, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors2015In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 22, p. 1428-1435Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene.

    METHODS: This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors.

    RESULTS: Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found.

    CONCLUSION: This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.

  • 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.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Edfeldt, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Midkine Is a New Novel Serum Biomarker in Small Intestinal Neuroendocrine Tumors (SI-NETs)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 45-45Article in journal (Refereed)
  • 11.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hessman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stuart, Heather C.
    Division of Surgical Oncology, University of Miami, Florida, USA.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.2018In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 4, no 2, p. 183-189Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

    Exposure: PUSCO vs DSANCO.

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

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

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

     

  • 12.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Clinical signs of fibrosis in small intestinal neuroendocrine tumours2017In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no 1, p. 69-75Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In patients with small intestinal neuroendocrine tumours (SI-NETs), serotonin and other cytokines released from tumour cells may induce fibrosis, leading to carcinoid heart disease and abdominal fibrotic reactions. The aim of this study was to assess the prevalence, clinical complications and management of this reaction in the abdomen.

    METHODS: This was a retrospective cohort study of patients with SI-NETs diagnosed between 1985 and 2015. Clinical data, outcomes, radiological findings, and surgical and radiological interventions were reviewed.

    RESULTS: A total of 824 patients were diagnosed with SI-NETs in the study interval. Clinically significant abdominal signs and symptoms of fibrosis occurred in 36 patients. Of these, 20 had critically symptomatic central mesenteric fibrosis causing obstruction of mesenteric vessels, and 16 had retroperitoneal fibrosis causing obstructive uropathy with hydronephrosis. Extensive fibrosis causing mesenteric vessel obstruction and/or obstructive uropathy was more often associated with symptomatic and advanced disease encompassing lymph node metastases in the mesenteric root, para-aortic lymph node metastases, as well as liver metastases and peritoneal carcinomatosis. Palliative intervention in terms of superior mesenteric vein stenting or resection of central mesenteric metastases and/or percutaneous nephrostomy and J stent treatment was beneficial in the majority of the patients.

    CONCLUSION: Extensive abdominal fibrosis associated with clinically significant symptoms of intestinal ischaemia and/or obstructive uropathy was linked to advanced disease in patients with SI-NETs. Prompt recognition and minimally invasive intervention was effective in disease palliation.

  • 13.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ Hosp, Dept Surg Sci, Endocrine Surg Unit, S-75185 Uppsala, Sweden.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Applying the use of novel biomarkers for neuroendocrine tumors in the clinic: where are we now?2019In: INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY, ISSN 2045-0869, Vol. 6, no 1, article id IJE14Article in journal (Other academic)
  • 14.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ex vivo activity of cytotoxic drugs and targeted agents in Small Intestinal NETsManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Small Intestinal Neuroendocrine Tumours (SI-NET) are considered to be generally resistant to systemic treatment. To date predictive markers for drug activity are lacking.

    Patients and Methods: Tumour samples from 27 patients with SI-NET were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer, and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinico-pathological variables and pre-treatment biomarkers.

    Results: For standard cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinums, gemcitabine and doxorubicin compared with CRC. For targeted kinase inhibitors, SI-NET was among the most sensitive diagnoses. CLL and ovarian cancer were generally the most sensitive diagnoses to both cytotoxic drugs and protein kinase inhibitors. The mTOR inhibitor sirolimus exhibited modest cytotoxic activity.

    Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors.

    Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo.

    Conclusions: SI-NETs exhibit variable but generally intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinico-pathological factors and currently used biomarkers were not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NETs. The great variability in drug sensitivity calls for individualized selection of therapy.

  • 15.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ex Vivo Activity of Cytotoxic Drugs and Targeted Agents in Small Intestinal Neuroendocrine Tumors2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 189-189Article in journal (Other academic)
  • 16.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ex vivo activity of cytotoxic drugs and targeted agents in small intestinal neuroendocrine tumors2018In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 4, p. 471-480Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo. SI-NETs exhibit intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy.

  • 17.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Daskalakis, Kosmas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 2, p. 170-181Article in journal (Refereed)
    Abstract [en]

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

  • 18.
    Eriksson, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ögren, Mats
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ihre-Lundgren, Catharina
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Primary small intestinal tumours are highly prevalent and often multiple before metastatic disease developsIn: Article in journal (Refereed)
  • 19.
    Fraser, Sheila
    et al.
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Bender, Kyle
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Davidson, Joanne
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Bajenov, Sonya
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Fahey, David
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Li, Shawn
    Royal North Shore Hosp, Dept Anaesthesia, Sydney, NSW, Australia.
    Sidhu, Stan
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Sywak, Mark
    Univ Sydney, Endocrine Surg Unit, Sydney, NSW, Australia.
    Randomized trial of low versus high carbon dioxide insufflation pressures in posterior retroperitoneoscopic adrenalectomy2018In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 163, no 5, p. 1128-1133Article in journal (Refereed)
    Abstract [en]

    Background: Posterior retroperitoneoscopic adrenalectomy has gained widespread acceptance for the removal of benign adrenal tumors. Higher insufflation pressures using carbon dioxide (CO2) are required, although the ideal starting pressure is unclear. This prospective, randomized, single-blinded, study aims to compare physiologic differences with 2 different CO2 insufflation pressures during posterior retroperitoneoscopic adrenalectomy.

    Methods: Participants were randomly assigned to a starting insufflation pressure of 20 mm Hg (low pressure) or 25 mm Hg (high pressure). The primary outcome measure was partial pressure of arterial CO2 at 60 minutes. Secondary outcomes included end-tidal CO2, arterial pH, blood pressure, and peak airway pressure. Breaches of protocol to change insufflation pressure were permitted if required and were recorded.

    Results: A prospective randomized trial including 31 patients (low pressure: n = 16; high pressure: n = 15) was undertaken. At 60 minutes, the high pressure group had greater mean partial pressure of arterial CO2 (64 vs 50 mm Hg, P = .003) and end-tidal CO2 (54 vs 45 mm Hg, P = .008) and a lesser pH (7.21 vs 7.29, P = .0005). There were no significant differences in base excess, peak airway pressure, operative time, or duration of hospital stay. Clinically indicated protocol breaches were more common in the low pressure than the high pressure group (8 vs 3, P = .03).

    Conclusion: In posterior retroperitoneoscopic adrenalectomy, greater insufflation pressures are associated with greater partial pressure of arterial CO2 and end-tidal CO2 and lesser pH at 60 minutes, be significant. Commencing with lesser CO2 insufflation pressures decreases intraoperative acidosis.

  • 20.
    Fyrsten, Ellen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hessman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism?2016In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 40, no 3, p. 615-621Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) is surgically treated with either a subtotal parathyroidectomy removing 3 or 3,5 glands (SPX), less than 3 glands (LSPX), or a total parathyroidectomy with autotransplantation (TPX). Previous studies with shorter follow-up have shown that LSPX and SPX are associated with recurrent HPT, and TPX with hypocalcemia and substitution therapy. We examined the situation after long-term follow-up (median 20,6 years).

    METHODS: Sixty-nine patients with MEN1 HPT underwent 110 operations, the first operation being 31 LSPX, 30 SPX, and 8 TPX. Thirty patients underwent reoperative surgery in median 120 months later, as completion to TPX (n = 12), completion of LSPX to SPX (n = 9), extirpation of single glands (n = 3) still resulting in LSPX, and resection of forearm grafts (n = 3). Nine patients underwent a second, and 2 a third reoperation. In 24 patients genetic testing confirmed MEN1, and in the remaining heredity and phenotype led to the diagnosis.

    RESULTS: TPX had higher risk for hypoparathyroidism necessitating substitution therapy, at latest follow-up 50 %, compared to SPX (16 % after 3-6 months; none at latest follow-up). Recurrent HPT was common after LSPX, leading to 24 reoperations in 17 patients. No need for substitution therapy after SPX indicated forthcoming recurrent disease. Not having hypocalcemia in the postoperative period and less radical surgery than TPX were significantly associated to risk for recurrence. Further, mutation in exon 3 in the MEN1 gene may eventually be linked to risk of recurrence.

    CONCLUSION: LSPX is highly associated with recurrence and TPX with continuous hypoparathyroidism, also after long-term follow-up. SPX should be the chosen method in the majority of patients with MEN1 HPT.

  • 21. Glover, Anthony R
    et al.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gundara, Justin S
    Morris, Michael
    Sidhu, Stan B
    Use of the Nerve Integrity Monitor during Thyroid Surgery Aids Identification of the External Branch of the Superior Laryngeal Nerve.2015In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 22, no 6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The external branch of the superior laryngeal nerve (EBSLN) is at risk during thyroid surgery. Despite meticulous dissection and visualization, the EBSLN can be mistaken for other structures. The nerve integrity monitor (NIM) allows EBSLN confirmation with cricothyroid twitch on stimulation.

    AIMS: The aim of this study was to assess any difference in identification of EBSLN and its anatomical sub-types by dissection alone compared to NIM-aided dissection.

    METHODS: Routine intra-operative nerve monitoring (IONM) was used, when available, for 228 consecutive thyroid operations (129 total thyroidectomies, 99 hemi-thyroidectomies) over a 10-month period. EBSLN identification by dissection alone (with NIM confirmation of cricothyroid twitch) and by NIM-assisted dissection was recorded prospectively. Anatomical sub-types were defined by the Cernea classification.

    RESULTS: Of 357 nerves at risk, 97.2 % EBSLNs (95 % confidence interval [CI], 95.5-98.9) were identified by visualization and NIM-aided dissection compared to 85.7 % (95 % CI, 82.1-89.3) identified by dissection alone (<0.001). EBSLN frequency was 34 % for type 1, 55 % for type 2a, and 11 % for type 2b. All identified EBSLNs were stimulated to confirm a cricothyroid twitch after superior thyroid vessel ligation.

    CONCLUSION: Using the NIM and meticulous dissection of the upper thyroid pole improves EBSLN identification. As the EBSLN is at risk during thyroidectomy and can lead to voice morbidity, the NIM can aid identification of the EBSLN and provide a functional assessment of the EBSLN after thyroid resection.

  • 22. Langusch, Catherine C
    et al.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Titmuss, Angela
    Donoghue, Kim
    Holland, Andrew J A
    Shun, Albert
    Delbridge, Leigh
    Focused image-guided parathyroidectomy in the current management of primary hyperparathyroidism.2015In: Archives of Disease in Childhood, ISSN 0003-9888, E-ISSN 1468-2044, Vol. 100, no 10Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Primary hyperparathyroidism (PHPT) in childhood and adolescence has been considered a different disease to that seen in adults, with predominantly familial aetiology mandating open exploration to exclude parathyroid hyperplasia in contrast to the adoption of focused image-guided parathyroidectomy (FP) in adults.

    STUDY DESIGN: A retrospective cohort study in a tertiary referral hospital setting of all children and adolescents (<18 years) undergoing parathyroid surgery for PHPT. Data were obtained from a dedicated endocrine surgery database and hospital medical records.

    RESULTS: Over the 35-year study period (1980-2014), there were 31 patients who underwent parathyroidectomy for PHPT. 3 patients were from known multiple endocrine neoplasia type 1 syndrome (MEN1) families, 3 had an isolated family history of PHPT and 25 were sporadic. In the sporadic group, 24 (96%) presented with symptomatic hypercalcaemia, affecting the gastrointestinal, musculoskeletal, genitourinary or neuropsychiatric systems. In the 25 patients with sporadic PHPT, nine (36%) had FP with a single adenoma removed with a 100% initial cure rate. Sixteen patients (64%) in the sporadic group had an open exploration: 14 had single gland disease while 2 patients required a second procedure to achieve a final cure rate of 100%. Of the three patients with MEN1, one was cured, one has persistent hyperparathyroidism after FP and the third has permanent hypoparathyroidism after open exploration.

    CONCLUSIONS: The majority of children and adolescents with PHPT have symptomatic disease due to a single adenoma. They can therefore be managed in a similar fashion to their adult counterparts with preoperative localisation studies aiming to permit FP in a day case setting.

  • 23.
    Mansson, Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gallstone Ileus Post-cholecystectomy2015In: Acta Chirurgica Belgica, ISSN 0001-5458, Vol. 115, no 2, p. 159-161Article in journal (Refereed)
    Abstract [en]

    Gallstone ileus is a rather rare condition and in most cases it involves a cholecysto-enteric fistula, through which a gallstone passes into the bowel. If the gallstone is large enough it may obstruct the bowel and a gallstone ileus emerges. In the presented case, the patient was subjected to a cholecystectomy over 40 years ago, but despite this, he developed a gallstone ileus. A gallstone that obstructed the small bowel was suspected with computed tomography and confirmed with exploratory laparotomy. Although a few cases of gallstone ileus after cholecystectomy are described in the literature, our case describes a unique pathogenic mechanism.

  • 24.
    Norlen, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stalberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Zedenius, J.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Outcome after resection and radiofrequency ablation of liver metastases from small intestinal neuroendocrine tumours2013In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 100, no 11, p. 1505-U1514Article in journal (Refereed)
    Abstract [en]

    Background: In patients with small intestinal neuroendocrine tumour (SI-NET), liver resection or radiofrequency ablation (RFA) of liver metastases is performed for palliation of carcinoid syndrome, and in an effort to improve survival. Data are generally reported from case series, and no randomized trials have studied these treatments. The aim was to compare outcome after liver resection and/or RFA with that of non-surgical treatment in patients with liver metastases from SI-NET. Methods: The study included patients with liver metastases from SI-NET who underwent liver RFA/resection or were treated non-surgically. A propensity score match was performed to reduce bias between groups, using baseline variables such as the Charlson co-morbidity index, age, symptoms, carcinoid heart disease, extent of metastases and proliferation index. Results: Some 103 patients who had RFA and/or liver resection were compared with 273 controls. Propensity score matching resulted in two matched groups, each of 72 patients, with no significant differences in baseline variables. The matched resection/RFA and control groups showed no difference in overall survival (both 74 per cent at 5 years; P = 0.869) or disease-specific survival (74 versus 78 per cent respectively at 5 years; P = 1.000). However, urinary 5-hydroxyindoleacetic acid levels were lower (median 77 versus 120 mu mol per 24 h; P = 0.005) and the proportion of patients with progressive disease within the liver was smaller (2 of 18 versus 8 of 18; P < 0.001) in the resection/RFA group after 5 years. Conclusion: These data do not support the use of liver resection and/or RFA in an effort to prolong survival in patients with liver metastases from SI-NET.

  • 25.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Small Intestinal Neuroendocrine Tumor: A Rare Malignancy with Favorable Outcome2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with computed tomography for easier interpretation, as RFA areas are not clearly distinguishable with 11C-5HTP-PET alone. Paper V studied gallstone complications after somatostatin analog treatment in SI-NET patients, and concluded that there was a rather high risk to be subjected to a cholecystectomy due to biliary colic, cholecystitis, cholangitis or pancreatitis after primary surgery in somatostatin analog treated patients.

    List of papers
    1. Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center
    Open this publication in new window or tab >>Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center
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    2012 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 6, p. 1419-1431Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Small intestinal neuroendocrine tumors (SI-NETs) are uncommon, with an annual incidence of about 1 per 100,000 individuals. The primary tumor (PT) is generally small, but nevertheless the majority of patients have mesenteric lymph node metastases and liver metastases at diagnosis. Our aim was to identify prognostic factors for survival and to evaluate outcome after surgery in SI-NET patients.

    MATERIAL AND METHODS:

    We included 603 consecutive patients (325 men; age at diagnosis 63 ± 11 years [mean ± SD]) with histopathologically verified SI-NET, who were diagnosed between 1985 and 2010. Hospital charts were reviewed and were scrutinized for carcinoid heart disease (CHD), flush and/or diarrhea, proliferation by Ki-67 index, mesenteric lymph node metastases (m.lgllm), distant abdominal lymph node metastases (da.lgllm), liver tumor load (LTL), extra-abdominal metastases (EAM), locoregional resective surgery, as well as debulking of LTL, and adverse events after surgery.

    RESULTS:

    Median overall survival (OS) was 8.4 years; 5-year OS was 67%, and 5-year relative survival was 74%. Independent prognostic factors by univariate and multivariate analysis were age at diagnosis, CHD, m.lgllm, da.lgllm, LTL, EAM, peritoneal carcinomatosis (PC), and proliferation. Locoregional resective surgery was associated with increased survival on crude and multivariate analysis. The 30-day mortality in our institution after initial locoregional resective surgery was 0.5% (1/205).

    CONCLUSIONS:

    For the first time, m.lgllm and da.lgllm, LTL, PC, and EAM are demonstrated to be independent prognostic factors by multivariate analysis. Locoregional removal of the PT/m.lgllm. was a positive prognostic factor by crude and adjusted analysis and may influence survival.

    National Category
    Cancer and Oncology Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-163767 (URN)10.1007/s00268-011-1296-z (DOI)000304096800031 ()21984144 (PubMedID)
    Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2017-12-08Bibliographically approved
    2. Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling
    Open this publication in new window or tab >>Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling
    Show others...
    2014 (English)In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 156, no 6, p. 1512-1522Article in journal (Refereed) Published
    Abstract [en]

    Background. One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. Methods. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Results. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). Conclusion. SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-185070 (URN)10.1016/j.surg.2014.08.090 (DOI)000345255700031 ()25456945 (PubMedID)
    Available from: 2012-11-19 Created: 2012-11-19 Last updated: 2017-12-07
    3. Outcome after surgery and radiofrequency ablation of liver metastases in small intestinal neuroendocrine tumors: A propensity score matched treatment-control study
    Open this publication in new window or tab >>Outcome after surgery and radiofrequency ablation of liver metastases in small intestinal neuroendocrine tumors: A propensity score matched treatment-control study
    (English)Manuscript (preprint) (Other academic)
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-185069 (URN)
    Available from: 2012-11-19 Created: 2012-11-19 Last updated: 2013-11-06
    4. 11C-5-hydroxytryptophan positron emission tomography after radiofrequency ablation of neuroendocrine tumor liver metastases
    Open this publication in new window or tab >>11C-5-hydroxytryptophan positron emission tomography after radiofrequency ablation of neuroendocrine tumor liver metastases
    Show others...
    2012 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 6, p. 883-890Article in journal (Refereed) Published
    Abstract [en]

    Aim: The aim was to assess the feasibility of C-11-5-hydroxy-tryptophan positron emission tomography ( C-11-5-HTP-PET) in the follow-up after radiofrequency ablation (RFA) of liver metastases from neuroendocrine tumors (NETS). Background: Contrast-enhanced computed tomography (CECT) and contrast-enhanced ultrasound (CEUS) are commonly used to evaluate the liver after RFA of NETs. In general, C-11-5-HTP-PET is more sensitive in the visualization of NETs, but no studies have investigated its role after RFA.

    Methods: Six consecutive patients with liver metastases from NETs were subjected to RFA treatment. All patients underwent baseline imaging before RFA and on two occasions (1-2 and 6-11 months) after RFA. The imaging consisted of C-11-5-HTP-PET, CEUS and CECT on all three occasions.

    Results: Thirty RFA areas were evaluated, and residual tumors (RTs) were depicted in eight areas (22%). C-11-5-HTP-PET depicted RTs after RFA with maximum sensitivity (100%) and specificity (100%), using radiological follow-up as the gold standard. C-11-5-HTP-PET detected five out of eight RTs earlier than CECT or CEUS. In general, the sensitivity of C-11-5-HTP-PET exceeded that of CECT and CEUS for early visualization of NET liver metastases.

    Conclusion: C-11-5-HTP-PET can be used in the follow-up after RFA for the purpose of detecting RT, and it provides additional information to CEUS and CECT by detecting new lesions.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-181929 (URN)10.1016/j.nucmedbio.2011.12.013 (DOI)000307041000018 ()
    Available from: 2012-10-02 Created: 2012-10-02 Last updated: 2017-12-07Bibliographically approved
    5. Prophylactic Cholecystectomy in Midgut Carcinoid Patients
    Open this publication in new window or tab >>Prophylactic Cholecystectomy in Midgut Carcinoid Patients
    Show others...
    2010 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 34, no 6, p. 1361-1367Article in journal (Refereed) Published
    Abstract [en]

    Patients with midgut carcinoid (MGC) tumors are commonly treated with somatostatin analogs. Adverse effects of these drugs include impairment of gallbladder function, formation of gallstones, and cholecystitis. Prophylactic cholecystectomy has been advocated, but data to support this recommendation are sparse. We have analyzed a cohort of 235 patients with MGC focusing on the risk for gallstone formation and complications thereof. Forty-eight of the 235 patients had been cholecystectomized before surgery for MGC. Of the remaining 187 patients, 144 were treated with somatostatin analogs. Eighteen of the 187 patients had their gall bladder removed during the primary carcinoid surgery. Twenty-two of the 144 somatostatin-analog-treated patients developed complications, such as gallbladder empyema (n = 1), cholangitis (n = 2), acute cholecystitis (n = 6), acute pancreatitis (n = 1) or acute pancreatitis and cholecystitis (n = 1), or biliary colic (n = 11). Ninety-two of the 144 were examined during surgery, by computed tomography, or by ultrasound, most for reasons other than gallbladder-related indications, and 63% (58/92) of these examinations revealed gallstones. Of the 43 patients not treated with somatostatin analogs, only 3 patients suffered from biliary colic and underwent cholecystectomy. In our study the incidence of gallstone-related complications seems to be higher than in the general population. We recommend that prophylactic cholecystectomy is liberally performed during laparotomy for MGC if patients are planned to undergo treatment with somatostatin analogs.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-136429 (URN)10.1007/s00268-010-0428-1 (DOI)000277714300031 ()20130865 (PubMedID)
    Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
  • 26.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Charlton, Amanda
    Childrens Westmead Hosp, Dept Histopathol, Westmead, NSW, Australia..
    Sarkis, Leba M.
    Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW, Australia.;Univ Sydney, St Leonards, NSW 2065, Australia..
    Henwood, Tony
    Childrens Westmead Hosp, Dept Histopathol, Westmead, NSW, Australia..
    Shun, Albert
    Childrens Westmead Hosp, Dept Surg, Westmead, NSW, Australia..
    Gill, Anthony J.
    Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW, Australia.;Univ Sydney, St Leonards, NSW 2065, Australia..
    Delbridge, Leigh
    Univ Sydney, Endocrine Surg Unit, Royal N Shore Hosp, St Leonards, NSW 2065, Australia..
    Risk of malignancy for each Bethesda class in pediatric thyroid nodules2015In: Journal of Pediatric Surgery, ISSN 0022-3468, E-ISSN 1531-5037, Vol. 50, no 7, p. 1147-1149Article in journal (Refereed)
    Abstract [en]

    Purpose: The Bethesda classification for cytology is used to classify thyroid nodules into one of six categories, and for each category there is an implied cancer risk and also recommendation for management. Despite lack of data in children, the American thyroid association promotes the use of the same management guidelines as in adults. Our aim was to study the risk of malignancy for each Bethesda class in children with thyroid nodules. Methodology: We included all patients <= 18 years of age that had underwent a thyroid fine needle aspiration (FNA) at one of two centers between January 1998 and July 2013. FNA results were reclassified according to the Bethesda criteria. Histological, repeat cytological, radiological and clinical follow-up were recorded. Results: Fifty-six patients (66 nodules) underwent FNB. Mean age was 13.6 years. Numbers of nodules reported as BI-BVI were 7, 38, 11, 4, 3 and 3, respectively. Follow-up was achieved for 55 (83%) nodules. Twelve (18%) nodules were malignant by histology and revealed papillary (n=7), follicular (n=3) or insular thyroid cancer (n=2), The proportion of nodules with malignancy for BI-BVI was: 0%, 0%, 18%, 100%, 100% and 100%. Conclusion: The rate of malignancy in thyroid nodules in children seems to be higher than reported in adults. The Bethesda criteria seem to accurately identify benign nodules, but other categories have a very high rate of malignancy and BIII nodules pose a particular challenge.

  • 27.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Daskalakis, Kosmas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Indication for Liver Transplantation in Young Patients with Small Intestinal NETs Is Rare?2014In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 38, no 3, p. 742-747Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    A majority of patients with small intestinal neuroendocrine tumors (SI-NETs) present with or develop liver metastases (LM). A number of treatments for LM are used clinically, including liver transplantation (LTx). Indications for LTx are under debate; young age (<65 years), absence of extrahepatic disease, resected primary tumor and limited extent of LM have been suggested as inclusion criteria for LTx with the aim to optimize outcome.

    MATERIALS AND METHODS:

    From our series of 672 patients with SI-NET treated at the University Hospital in Uppsala between 1985 and 2012, we identified 78 patients according to the following criteria: <65 years of age, locoregional surgery (LRS) of the primary tumor and mesenteric metastases successfully performed, LM present but no extrahepatic disease. Baseline was chosen as the first date the following points were met: First visit to our center, LRS performed, LM present. The patients underwent treatment according to the standard clinical protocols at our center, and during this time period we did not perform or refer any SI-NET patients for LTx. Kaplan-Meier survival analyses were performed in three different groups based on hypothetical criteria for LTx.

    RESULTS:

    Five-year overall survival rates for patients <65 years (n = 78) and <55 years (n = 36) of age were 84 ± 8 and 92 ± 9 %, respectively. For patients fulfilling the Milan criteria (n = 33) the 5-year survival was 97 ± 6 %.

    CONCLUSIONS:

    Most young patients (<65 years) with SI-NET and LM have a favorable survival with standardized multimodality treatment. Indeed, most survival figures reported after LTx of NET do not surpass these figures.

  • 28.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Edfeldt, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling2014In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 156, no 6, p. 1512-1522Article in journal (Refereed)
    Abstract [en]

    Background. One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. Methods. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Results. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). Conclusion. SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC.

  • 29.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Glover, Anthony
    Zaidi, Nisar
    Aniss, Adam
    Sywak, Mark
    Sidhu, Stan
    Delbridge, Leigh
    The Weight of the Resected Gland Predicts Rate of Success After Image-Guided Focused Parathyroidectomy2015In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 39, no 8, p. 1922-1927Article in journal (Refereed)
    Abstract [en]

    A recent study of focused minimally invasive parathyroidectomy (FPTX) in sporadic primary hyperparathyroidism (pHPT) using intraoperative parathyroid hormone (ioPTH) measurements shows that inadequate ioPTH drop and multiglandular disease are more commonly found when a first gland < 200 mg is resected. Our aim was to study if a resected gland that weighed < 200 mg was associated with an increased persistence rate after FPTX. This is a cohort study of FPTX for pHPT performed in the period 1998-2013. FPTX was performed in patients with pHPT where Sestamibi and Ultrasound imaging localized single-gland disease, only one gland was excised and the weight recorded. IoPTH was not used routinely. Two groups were composed according to the weight of the resected gland: Group A < 200 mg and Group B a parts per thousand yen200 mg. Persistent or recurrent disease was defined if it occurred within, or after 6 months. The primary outcome measure was the rate of persisting pHPT. A total of 3,511 parathyroidectomies were performed, and a total 1,745 FPTX (1,347 female) met inclusion criteria. There were 245 and 1,500 patients in groups A and B, respectively. The rate of persistent pHPT was higher in Group A, 6.1 versus 2.0 % (p < 0.001). Findings at re-operative surgery showed that the ipsilateral gland was diseased in 47 % (7/15) of persistent cases in group A. The risk of persistent disease after MIP was higher if the resected gland weighed a parts per thousand currency sign200 mg, and this corroborates the findings of a recent study. A heightened awareness of the possibility of multigland disease should be raised, and ioPTH monitoring, identification of the ipsilateral gland or bilateral exploration may be advisable in such cases.

  • 30.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hessman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Prophylactic Cholecystectomy in Midgut Carcinoid Patients2010In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 34, no 6, p. 1361-1367Article in journal (Refereed)
    Abstract [en]

    Patients with midgut carcinoid (MGC) tumors are commonly treated with somatostatin analogs. Adverse effects of these drugs include impairment of gallbladder function, formation of gallstones, and cholecystitis. Prophylactic cholecystectomy has been advocated, but data to support this recommendation are sparse. We have analyzed a cohort of 235 patients with MGC focusing on the risk for gallstone formation and complications thereof. Forty-eight of the 235 patients had been cholecystectomized before surgery for MGC. Of the remaining 187 patients, 144 were treated with somatostatin analogs. Eighteen of the 187 patients had their gall bladder removed during the primary carcinoid surgery. Twenty-two of the 144 somatostatin-analog-treated patients developed complications, such as gallbladder empyema (n = 1), cholangitis (n = 2), acute cholecystitis (n = 6), acute pancreatitis (n = 1) or acute pancreatitis and cholecystitis (n = 1), or biliary colic (n = 11). Ninety-two of the 144 were examined during surgery, by computed tomography, or by ultrasound, most for reasons other than gallbladder-related indications, and 63% (58/92) of these examinations revealed gallstones. Of the 43 patients not treated with somatostatin analogs, only 3 patients suffered from biliary colic and underwent cholecystectomy. In our study the incidence of gallstone-related complications seems to be higher than in the general population. We recommend that prophylactic cholecystectomy is liberally performed during laparotomy for MGC if patients are planned to undergo treatment with somatostatin analogs.

  • 31.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Montan, Harald
    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.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Preoperative Ga-68-DOTA-Somatostatin Analog-PET/CT Hybrid Imaging Increases Detection Rate of Intra-abdominal Small Intestinal Neuroendocrine Tumor Lesions2018In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 42, no 2, p. 498-505Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Small intestinal neuroendocrine tumors (SI-NETs) are the most common form of neoplasm in the small bowel. Radiological identification of primary tumors (PT), which may be multiple, is difficult, and therefore palpation of the entire small bowel is routinely performed during laparotomy. The aim was to determine detection rates of PT and peritoneal carcinomatosis (PC) with 68Ga-DOTATOC/TATE-PET/CT in comparison with i.v. contrast-enhanced computed tomography (CE-CT) and thus to clarify whether modern functional imaging can mitigate the need for palpation of bowel during surgery enabling oncologically adequate laparoscopic resection.

    METHODS:

    A total of 28 patients with SI-NET who preoperatively underwent both 68Ga-DOTATOC/TATE-PET/CT and CE-CT were included. The detection rates of PT and PC for PET/CT and CE-CT were compared to the findings in the surgical and histopathological reports. Appropriate statistical tests were used, and significance was set to p < 0.05.

    RESULTS:

    Out of 82 PT, 43 PT were not detected by any imaging modality. More PT lesions were detected with PET/CT (n = 39 [47.5%]) than with CE-CT (n = 10 [12.2%], p < 0.001). Also, PET/CT identified significantly more PC lesions than CE-CT (78 and 38%, p = 0.004, respectively).

    CONCLUSION:

    PET/CT detected more PT and PC lesions than CE-CT. Some PTs and PC lesions were only detected by one of the modalities, and CT performed in conjunction with PET/CT should therefore be performed as a fully diagnostic CE-CT for optimal results. Palpation of the small bowel remains crucial during surgery in these patients because several PTs escaped detection by both PET/CT and CE-CT.

  • 32.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nilsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Krause, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    11C-5-hydroxytryptophan positron emission tomography after radiofrequency ablation of neuroendocrine tumor liver metastases2012In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 6, p. 883-890Article in journal (Refereed)
    Abstract [en]

    Aim: The aim was to assess the feasibility of C-11-5-hydroxy-tryptophan positron emission tomography ( C-11-5-HTP-PET) in the follow-up after radiofrequency ablation (RFA) of liver metastases from neuroendocrine tumors (NETS). Background: Contrast-enhanced computed tomography (CECT) and contrast-enhanced ultrasound (CEUS) are commonly used to evaluate the liver after RFA of NETs. In general, C-11-5-HTP-PET is more sensitive in the visualization of NETs, but no studies have investigated its role after RFA.

    Methods: Six consecutive patients with liver metastases from NETs were subjected to RFA treatment. All patients underwent baseline imaging before RFA and on two occasions (1-2 and 6-11 months) after RFA. The imaging consisted of C-11-5-HTP-PET, CEUS and CECT on all three occasions.

    Results: Thirty RFA areas were evaluated, and residual tumors (RTs) were depicted in eight areas (22%). C-11-5-HTP-PET depicted RTs after RFA with maximum sensitivity (100%) and specificity (100%), using radiological follow-up as the gold standard. C-11-5-HTP-PET detected five out of eight RTs earlier than CECT or CEUS. In general, the sensitivity of C-11-5-HTP-PET exceeded that of CECT and CEUS for early visualization of NET liver metastases.

    Conclusion: C-11-5-HTP-PET can be used in the follow-up after RFA for the purpose of detecting RT, and it provides additional information to CEUS and CECT by detecting new lesions.

  • 33.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Popadich, Aleksandra
    Kruijff, Schelto
    Gill, Anthony J.
    Sarkis, Leba M.
    Delbridge, Leigh
    Sywak, Mark
    Sidhu, Stan
    Bethesda III Thyroid Nodules: The Role of Ultrasound in Clinical Decision Making2014In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 21, no 11, p. 3528-3533Article in journal (Refereed)
    Abstract [en]

    Assessment for thyroid nodules includes ultrasound (US) and cytology according to the Bethesda classification. There is no firm consensus regarding clinical management for nodules classified as Bethesda III. Our aim was investigate the value of US to predict malignancy in these nodules. Patients with Bethesda III nodules who underwent thyroid surgery from July 2011 to July 2013 were included. Inclusion criteria mandated that US were available for review by two observers blinded to each other's results and histological outcome. The nodules were scrutinized with six US criteria: hypoechoic attenuation (HA), irregular margins (IM), taller than wide, microcalcifications (MC), loss of halo, and increased central vascularity. Disagreements between observers were solved by consensus. There were 141 patients (121 women) with a mean age of 55 years. Mean nodule size was 25 mm. The malignancy rate was 13 %. Interobserver ratios were moderate to very strong for all six predictors (kappa = 0.60-0.94). However, only HA, IM, and MC were predictors of malignancy by univariate analysis (all p < 0.002). Logistic regression revealed an odds ratio of malignancy versus no malignancy for HA 4.8, IM 3.3, and MC 4.0 (all p < 0.05). The positive and negative predictive value for malignancy when having one or more of these three criteria was 22 % and 98 %, respectively. HA, IM, and MC were predictors of malignancy in Bethesda III nodules. In addition, the negative predictive value for any of these three criteria was high; a nodule that lacks all of these three criteria is thus unlikely to be malignant.

  • 34.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sidhu, S.
    Sywak, M.
    Delbridge, L.
    Long-term outcome after parathyroidectomy for lithium-induced hyperparathyroidism2014In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 101, no 10, p. 1252-1256Article in journal (Refereed)
    Abstract [en]

    Background: The accepted management of lithium-associated hyperparathyroidism (LiHPT) is open four-gland parathyroid exploration (OPTX). This approach has recently been the subject of controversy. A recent study has shown very high long-term recurrence rates after OPTX, whereas some have promoted unilateral focused parathyroidectomy as appropriate management. The aim was to evaluate long-term outcomes after surgery for LiHPT and to assess the accuracy of preoperative imaging. Methods: This was a retrospective cohort study that comprised all patients undergoing initial surgery for LiHPT between 1990 and 2013. The cumulative recurrence rate was calculated by the Kaplan-Meier method. The sensitivity and specificity of sestamibi scintigraphy and ultrasound imaging for identification of single-gland versus multigland disease was investigated using intraoperative assessment as reference. Results: Of 48 patients, 45 had OPTX and three underwent focused parathyroidectomy. Multiglandular disease was documented in 27 patients and 21 had a single adenoma. The median follow-up was 5.9 (range 0.3-22) years and 16 patients died during follow-up. The 10-year cumulative recurrence rate was 16 (95 per cent confidence interval 2 to 29) per cent. No permanent complications occurred after primary surgery for LiHPT. Twenty-four patients had at least one preoperative ultrasound or sestamibi scan. For concordant sestamibi scintigraphy and ultrasound imaging, the sensitivity and specificity for identifying single-gland versus multigland disease was five of nine and five of eight respectively. Conclusion: Surgery provided a safe and effective management option for patients with LiHPT in this series, with a long-term cure rate of well over 80 per cent.

  • 35.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Therapy for Locoregional Disease: Ileum2017In: Neuroendocrine Tumors in Real Life / [ed] A Colao, A Faggiano, W de Herder, Springer, 2017, p. 255-263Chapter in book (Refereed)
  • 36.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hedberg, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Hessman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center2012In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 6, p. 1419-1431Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Small intestinal neuroendocrine tumors (SI-NETs) are uncommon, with an annual incidence of about 1 per 100,000 individuals. The primary tumor (PT) is generally small, but nevertheless the majority of patients have mesenteric lymph node metastases and liver metastases at diagnosis. Our aim was to identify prognostic factors for survival and to evaluate outcome after surgery in SI-NET patients.

    MATERIAL AND METHODS:

    We included 603 consecutive patients (325 men; age at diagnosis 63 ± 11 years [mean ± SD]) with histopathologically verified SI-NET, who were diagnosed between 1985 and 2010. Hospital charts were reviewed and were scrutinized for carcinoid heart disease (CHD), flush and/or diarrhea, proliferation by Ki-67 index, mesenteric lymph node metastases (m.lgllm), distant abdominal lymph node metastases (da.lgllm), liver tumor load (LTL), extra-abdominal metastases (EAM), locoregional resective surgery, as well as debulking of LTL, and adverse events after surgery.

    RESULTS:

    Median overall survival (OS) was 8.4 years; 5-year OS was 67%, and 5-year relative survival was 74%. Independent prognostic factors by univariate and multivariate analysis were age at diagnosis, CHD, m.lgllm, da.lgllm, LTL, EAM, peritoneal carcinomatosis (PC), and proliferation. Locoregional resective surgery was associated with increased survival on crude and multivariate analysis. The 30-day mortality in our institution after initial locoregional resective surgery was 0.5% (1/205).

    CONCLUSIONS:

    For the first time, m.lgllm and da.lgllm, LTL, PC, and EAM are demonstrated to be independent prognostic factors by multivariate analysis. Locoregional removal of the PT/m.lgllm. was a positive prognostic factor by crude and adjusted analysis and may influence survival.

  • 37.
    Norlén, Olov
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wang, Kuan Chi
    Tay, Yeng Kwang
    Johnson, William R
    Grodski, Simon
    Yeung, Meei
    Serpell, Jonathan
    Sidhu, Stan
    Sywak, Mark
    Delbridge, Leigh
    No need to abandon focused parathyroidectomy: a multicenter study of long-term outcome after surgery for primary hyperparathyroidism.2015In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 261, no 5Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate long-term outcomes after focused parathyroidectomy (FPTX) and open 4-gland parathyroid exploration (OPTX) for primary hyperparathyroidism (pHPT).

    BACKGROUND: Concerns about increased long-term recurrence rates after FPTX in conjunction with decreased operative times for OPTX have led some groups to abandon FPTX in favor of routine 4-gland exploration.

    METHODS: This is a multicenter retrospective cohort study of patients undergoing parathyroidectomy for pHPT from 1990 to 2013. The patient cohort was divided into 2 groups, FPTX and OPTX, based on intention-to-treat analysis. The primary outcome measure was the persistence of pHPT. Secondary outcome measures were differences in the long-term recurrence rate of persisting pHPT and surgical complications.

    RESULTS: A total of 4569 patients (3585 females) were included. The overall persistence and recurrence rates were 2.2% and 0.9%, respectively, after a median follow-up of 6.5 years. There were 2531 FPTX cases and 2038 OPTX cases. The initial persistence rate was higher for FPTX than for OPTX (2.7% vs 1.7%, P = 0.036); however, the long-term recurrence rate was not different (5-year 0.6% vs 0.4%, log-rank P = 0.08). Complications were more common in OPTX than in FPTX (7.6% vs 3.6%, P < 0.001).

    CONCLUSIONS: FPTX was associated with fewer operative complications and an equivalent rate of long-term recurrence than with OPTX. Although initial persistence rates were higher after FPTX than after OPTX, most were readily resolved with subsequent early reoperation. FPTX should not be abandoned in patients with positive preoperative localization.

  • 38.
    Sarkis, Leba M
    et al.
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, Sydney, NSW, Australia.
    Zaidi, Nisar
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, Sydney, NSW, Australia.
    Norlén, Olov
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, Sydney, NSW, Australia.
    Delbridge, Leigh W
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, Sydney, NSW, Australia.
    Sywak, Mark S
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, Sydney, NSW, Australia.
    Sidhu, Stan B
    Univ Sydney, Royal North Shore Hosp, Endocrine Surg Unit, Sydney, NSW, Australia.
    Bilateral recurrent laryngeal nerve injury in a specialized thyroid surgery unit: would routine intraoperative neuromonitoring alter outcomes?2017In: ANZ journal of surgery, ISSN 1445-1433, E-ISSN 1445-2197, Vol. 87, no 5, p. 364-367Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bilateral recurrent laryngeal nerve (RLN) palsy following total thyroidectomy is a rare complication, however, poses significant morbidity to the patient when it does occur. The purpose of this paper was to determine the incidence of bilateral RLN palsy in a specialized thyroid unit and determine whether the routine use of intraoperative nerve monitoring (IONM) would alter the outcome.

    METHODS: This is a retrospective review of prospectively gathered data. A total of 7406 patients underwent total thyroidectomy at the University of Sydney Endocrine Surgical Unit between January 1990 and February 2014. IONM was utilized on a selective basis and we sought to assess whether IONM would have altered outcome in those patients who developed bilateral RLN palsy.

    RESULTS: Of the 7406 patients who underwent total thyroidectomy, seven patients (0.09%) developed bilateral RLN palsy during the study period. There was one permanent RLN palsy (0.01%) and routine IONM may have prevented one death and altered the outcome in two of the seven patients.

    CONCLUSION: Bilateral RLN palsy is a rare entity occurring in one out of 1000 cases in a specialized thyroid unit. IONM may facilitate the decision to pursue delayed surgery where the signal is lost on the first surgical side and has the potential to avoid bilateral RLN palsy following total thyroidectomy.

  • 39.
    Stephenson, Carlos
    et al.
    University of Sydney, Sydney, New South Wales, Australia.
    Norlén, Olov
    University of Sydney, Sydney, New South Wales, Australia.
    Shun, Albert
    Department of Surgery, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
    Karpelowsky, Jonathon
    Department of Surgery, Children's Hospital at Westmead, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia.
    Robinson, Bruce
    Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, New South Wales, Australia.
    Delbridge, Leigh
    University of Sydney, Sydney, New South Wales, Australia.
    Papillary thyroid cancer in childhood: is parental screening helpful?2017In: ANZ journal of surgery, ISSN 1445-1433, E-ISSN 1445-2197, Vol. 87, no 7/8, p. 615-618Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Familial non-medullary thyroid cancer (FNMTC) mandates family screening with ultrasound; however, the need for screening paediatric thyroid cancer with no family history has not been addressed.

    METHODS: This study conducted a retrospective cohort study in a tertiary hospital. The study group is composed of patients ≤18 years undergoing surgery for papillary thyroid cancer (PTC) from 2008 to 2014.

    RESULTS: During the study period, 15 paediatric patients had PTC. Only one patient had a prior family history of PTC involving two second-degree relatives. Of the 30 parents, four were lost to follow-up, with the remaining 26 undergoing screening thyroid ultrasound. Nodular thyroid disease was documented in eight ultrasounds performed. Subsequently, one has not undergone fine-needle biopsy, five were benign and two underwent surgical resection: one having a benign follicular adenoma and the other a papillary microcarcinoma with nodal micrometastasis.

    CONCLUSIONS: Routine ultrasound screening of parents of children presenting with PTC and no family history do not demonstrate an increased incidence of FNMTC. Screening of affected families is likely to demonstrate the expected background incidence of nodular thyroid disease and incidental papillary microcarcinoma. As such, it is unlikely to be useful.

  • 40.
    Vyakaranam, Achyut Ram
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Crona, Joakim
    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.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Garske-Román, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Sahlgrens Univ Hosp, Dept Nucl Med, 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.
    Thiis-Evensen, Espen
    Oslo Univ Hosp, Rikshosp, Dept Gastroenterol, Oslo, Norway.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.2019In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 909Article in journal (Refereed)
    Abstract [en]

    Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

  • 41.
    Vyakaranam, Achyut Ram
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Crona, Joakim
    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.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma2019In: Cancers, ISSN 2072-6694, Vol. 11, no 6, article id 847Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing C-11-hydroxy-ephedrine (C-11-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. C-11-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of C-11-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor C-11-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R-2 = 0.22, p = 0.016). C-11-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor C-11-HED uptake were not helpful for tumor characterization.

1 - 41 of 41
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