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  • 51.
    Granberg, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Prognostic markers in patients with typical bronchial carcinoid tumors2000In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 85, no 9, p. 3425-3430Article in journal (Refereed)
    Abstract [en]

    Typical bronchial carcinoids are usually considered fairly benign tumors. Metastases do however occur, and up to 10% of the patients ultimately die from their disease. To identify prognostic markers, we immunostained 43 typical bronchial carcinoids with antibodies against 8 possibly relevant hormones, oncogenes, tumor suppressor genes, adhesion molecules, and proliferation markers. Altogether 12 patients (28%) had metastatic disease, of whom 10 had regional lymph node metastases at diagnosis. Distant metastases have occurred in 5 patients (12%); all of these have died from their disease. Patients with high expression of Ki-67 had shorter survival time (P < 0.01). None of the immunostained hormones correlated to distant metastases or shorter survival time, but gastrin-releasing peptide correlated to metastatic disease (P < 0.05). All patients who died had CD44-negative tumors (P < 0.001). Nuclear nm23 staining correlated to decreased risk for metastatic disease and distant metastases per se (P < 0.01). Bcl-2 and p53 were associated with increased risk for distant metastases (P < 0.05 and P < 0.01, respectively). We conclude that some patients with typical bronchial carcinoids die from their disease and that gastrin-releasing peptide, Bcl-2, and p53 may be of importance for the malignant transformation of the tumor. Moreover, CD44, nm23, and Ki-67 may give valuable prognostic information and help identify the patients at risk of disease-related death.

  • 52.
    Halin Lejonklou, Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Térèse
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Ekeblad, Sara
    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.
    Notch signaling factors in the transforming Men1 mouse pancreasManuscript (preprint) (Other academic)
  • 53. Hellman, P
    et al.
    Hennings, J
    Åkerström, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, B
    Department of Medical Sciences. endokrin tumörbiologi.
    Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1.2005In: Br J Surg, ISSN 0007-1323, Vol. 92, no 12, p. 1508-12Article in journal (Refereed)
  • 54.
    Hellman, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Lundstrom, T
    Ohrvall, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, B
    Department of Medical Sciences.
    Skogseid, B
    Department of Medical Sciences.
    Oberg, K
    Department of Medical Sciences.
    Tiensuu Janson, E
    Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases.2002In: World J Surg, Vol. 26, p. 991-Article in journal (Refereed)
  • 55.
    Hellman, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Andersson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karacagil, Sadettin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Surgical strategy for large or malignant endocrine pancreatic tumors2000In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 24, no 11, p. 1353-1360Article in journal (Refereed)
    Abstract [en]

    Endocrine pancreatic tumors (EPTs) are rare but have a remarkably better prognosis than adenocarcinoma of the pancreas. Patients with EPTs benefit from surgical and medical therapy, which may alleviate symptoms due to hormonal excess and increase survival. Patients with large or malignant EPTs with infiltrative disease may suffer from local complications, including gastrointestinal bleeding and obstruction and involvement of the superior mesenteric (SMV) and portal (PV) veins. Among 31 patients with operable and large or malignant EPTs, 7 had hormone-producing syndromes (insulin, glucagon), and 24 had clinically nonfunctioning EPTs. Surgery in these patients included vascular reconstruction of the SMV/PV (n = 4), resection of infiltrated adjacent organs (n = 5; stomach, transverse colon), or resection of concomitant liver metastases (n = 3). Four patients with conspicuously large insulinomas, and three with glucagonoma were successfully operated on with alleviation of hormonal symptoms. Among the 24 nonfunctioning EPTs, 5 patients had been explored earlier and their tumors judged inoperable due to locally invasive disease or misdiagnosis as pancreatic adenocarcinoma. The operations were performed with no mortality and low morbidity. We conclude that large and malignant EPTs with limited spread of disease may benefit from a combination of medical and surgical therapy.

  • 56.
    Hellman, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ladjevardi, Sam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Elvin, A
    Radiofrequency tissue ablation using colled tip for liver metastases of endocrine tumors2002In: World J Surg, Vol. 26, p. 1052-Article in journal (Refereed)
  • 57.
    Hellman, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lundström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öhrvall, Ulf
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases2002In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 26, no 8, p. 991-997Article in journal (Refereed)
    Abstract [en]

    We have evaluated survival and tumor-related symptoms in the presence of mesenteric lymph node and liver metastases in relation to surgical procedures in 314 patients (148 women, mean age at diagnosis 61 years; 249 with liver metastases) treated for midgut carcinoid tumors. Of the operated patients, 46% presented with severe abdominal pain and intestinal obstruction and were operated on before the diagnosis. Medical treatment (somatostatin analogs, interferon-a) was initiated in 67% and 86%, respectively. Surgical attempts included small intestine or ileocecal/right-sided colon resection with excision of mesenteric lymph node metastases. Most of the patients (n = 286) had mesenteric lymph node metastases; 33% of them had unresectable mesenteric lymph node metastases and underwent surgery without mesenteric dissection. Patients who underwent resection for the primary tumor had a longer survival than those with no resection (median survival 7.4 vs. 4.0 years; p <0.01). Patients who underwent successful excision of mesenteric metastases had a significantly longer survival than those with remaining lymph node metastases. Patients operated on for a primary tumor but with remaining lymph nodes but no liver metastases and who subsequently received interferon and somatostatin analog treatment had a median survival of 7.4 years. Resection of the primary tumor and the mesenteric lymph node metastases led to a significant reduction in tumor-related symptoms. Surgery to remove the primary intestinal tumor including mesenteric lymph node metastases is supported by the present results, even in the presence of liver metastases. Liver metastases and significant preoperative weight loss are identified as major negative prognostic factors for survival.

  • 58.
    Hellman, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Postoperative recurrence and hypoparathyroidism in hyperparathyroidism of multiple endocrine neoplasia type 11998In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 124, no 6, p. 993-999Article in journal (Refereed)
    Abstract [en]

    Background.

    Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence.

    Methods.

    Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism.

    Results.

    Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11 C-labeled methionine positron emission tomography.

    Conclusion.

    MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.

  • 59.
    Hellman, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Juhlin, Claes
    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.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type 11998In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 124, no 6, p. 993-999Article in journal (Refereed)
    Abstract [en]

    Background.

    Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence.

    Methods.

    Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism.

    Results.

    Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11 C-labeled methionine positron emission tomography.

    Conclusion.

    MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.

  • 60.
    Hessman, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lindberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Carling, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    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.
    Mutation of the Multiple Endocrine Neoplasia Type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas1998In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 58, no 3, p. 377-379Article in journal (Refereed)
    Abstract [en]

    Endocrine pancreatic tumors are rare neoplasms that occur sporadically or as part of a multiple endocrine neoplasia type 1 (MEN1) syndrome. Germ-line mutations of the MEN1 gene, located at 11q13, have been demonstrated in MEN1 kindreds, and loss of heterozygosity (LOH) on 11q13 together with somatic MEN1 mutations have been detected in 20% of nonfamilial parathyroid tumors. Here, we examine 11 non-MEN1 malignant tumors of the endocrine pancreas, 9 nonfunctioning tumors, and 2 glucagonomas. LOH of at least one informative locus on 11q13 was found in 70% of the tumors. Three tumors displayed somatic mutations of the MEN1 gene together with LOH on 11q13, whereas the corresponding germ-line DNA was normal. These findings support the hypothesis that MEN1 gene mutations contribute to the tumorigenesis of nonfamilial, malignant endocrine pancreatic tumors.

  • 61.
    Hessman, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Westin, Gunnar
    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.
    Multiple allelic deletions and intratumoral genetic heterogeneity in MEN1 pancreatic tumors2001In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 86, no 3, p. 1355-1361Article in journal (Refereed)
    Abstract [en]

    Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome with multiple tumors of the endocrine pancreas, the parathyroid, the pituitary, and other tissues. The MEN1 gene at 11q13 is homozygously mutated in the majority of MEN1 tumors. Here we present a genome-wide loss of heterozygosity (LOH) screening of 23 pancreatic lesions, one duodenal tumor, and one thymic carcinoid from 13 MEN1 patients. Multiple allelic deletions were found. Fractional allelic loss varied from 6-75%, mean 31%. All pancreatic tumors displayed LOH on chromosome 11, whereas the frequency of losses for chromosomes 3, 6, 8, 10, 18, and 21 was over 30%. Different lesions from individual patients had discrepant patterns of LOH. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells, whereas other chromosomal loci were deleted in portions of the analyzed tumor. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. Fractional allelic loss did not correlate to malignancy or to tumor size. Our findings indicate that MEN1 pancreatic tumors fail to maintain DNA integrity and demonstrate signs of chromosomal instability.

  • 62.
    Johansson, T
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekeblad, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lack of Nuclear Expression of Hairy and Enhancer of Split-1 (HES1) in Pancreatic Endocrine Tumors2008In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 40, no 5, p. 354-359Article in journal (Refereed)
    Abstract [en]

    The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.

  • 63.
    Johansson, Terese
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of Achaete-scute complex-like 1 (ASCL1) target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours.2009In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 9, article id 321Article in journal (Refereed)
  • 64.
    Johansson, Térèse A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of Achaete-scute complex-like 1 (ASCL1) target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours2009In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 9, p. 321-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    ASCL1 role in pancreatic endocrine tumourigenesis has not been established. Recently it was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist DKK1. Notch signalling regulates expression of TPH1, the rate limiting enzyme in the biosynthesis of serotonin. Understanding the development and proliferation of pancreatic endocrine tumours (PETs) is essential for the development of new therapies.

    METHODS:

    ASCL1 target genes in the pancreatic endocrine tumour cell line BON1 were identified by RNA interference and microarray expression analysis. Protein expressions of selected target genes in PETs were evaluated by immunohistochemistry.

    RESULTS:

    158 annotated ASCL1 target genes were identified in BON1 cells, among them DKK1 and TPH1 that were negatively regulated by ASCL1. An inverse relation of ASCL1 to DKK1 protein expression was observed for 15 out of 22 tumours (68%). Nine tumours displayed low ASCL1/high DKK1 and six tumours high ASCL1/low DKK1 expression. Remaining PETs showed high ASCL1/high DKK1 (n = 4) or low ASCL1/low DKK1 (n = 3) expression. Nine of twelve analysed PETs (75%) showed TPH1 expression with no relation to ASCL1.

    CONCLUSION:

    A number of genes with potential importance for PET tumourigenesis have been identified. ASCL1 negatively regulated the Wnt signalling antagonist DKK1, and TPH1 expression in BON1 cells. In concordance with these findings DKK1 showed an inverse relation to ASCL1 expression in a subset of PETs, which may affect growth control by the Wnt signalling pathway.

  • 65. Jonkers, Y. M. H.
    et al.
    Claessen, S. M. H.
    Perren, A.
    Schmitt, A. M.
    Hofland, L. J.
    de Herder, W.
    de Krijger, R. R.
    Verhofstad, A. A. J.
    Hermus, A .R.
    Kummer, J .A.
    Skogseid, Britt M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Volante, M.
    Voogd, A. C.
    Ramaekers, F. C. S.
    Speel, E. J. M.
    DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients2007In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 14, no 3, p. 769-779Article in journal (Refereed)
    Abstract [en]

    The clinical behavior of endocrine pancreatic tumors (EPTs) is difficult to predict in the absence of metastases or invasion to adjacent organs. Several markers have been indicated as potential predictors of metastatic disease, such as tumor size 2 cm, Ki67 proliferative index 2%, cytokeratin (CK) 19 status, and recently in insulinomas, chromosomal instability (CIN). The goal of this study was to evaluate the value of these markers, and in particular of the CIN, to predict tumor recurrence or progression and tumor-specific death, using a series of 47 insulinomas and 24 non-insulinoma EPTs. From these EPT cases, a genomic profile has been generated and follow-up data have been obtained. The proliferative index has been determined in 68 tumors and a CK19 expression pattern in 50 tumors. Results are statistically analyzed using Kaplan–Meier plots and the log-rank statistic. General CIN, as well as specific chromosomal alterations such as 3p and 6q loss and 12q gain, turned out to be the most powerful indicators for poor tumor-free survival (P0.0004) and tumor-specific death (P0.0113) in insulinomas. The CIN, chromosome 7q gain, and a proliferative index 2% were reliable in predicting a poor tumor-free survival in non-insulinoma EPTs (P0.0181, whereas CK19 expression was the most optimal predictor of tumor-specific death in these tumors. In conclusion, DNA copy number status is the most sensitive and efficient marker of adverse clinical outcome in insulinomas and of potential interest in non-insulinoma EPTs. As a consequence, this marker should be considered as a prognosticator to improve clinical diagnosis, most practically as a simple multi-target test.

     

  • 66. Jonkers, Y. M. H.
    et al.
    Claessen, S. M. H.
    Veltman, J. A.
    Geurts van Kessel, A.
    Dinjens, W. N. M.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ramaekers, F. C. S.
    Speel, E-J. M.
    Molecular parameters associated with insulinoma progression: chromosomal instability versus p53 and CK19 status2006In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 115, no 3-4, p. 289-297Article in journal (Refereed)
    Abstract [en]

    Insulinomas represent the predominant syndromic subtype of endocrine pancreatic tumors (EPTs). Their metastatic potential cannot be predicted reliably using histopathological criteria. In the past few years, several attempts have been made to identify prognostic markers, among them TP53 mutations and immunostaining of p53 and recently cytokeratin 19 (CK19). In a previous study using conventional comparative genomic hybridization (CGH) we have shown that chromosomal instability (CIN) is associated with metastatic disease in insulinomas. It was our aim to evaluate these potential parameters in a single study. For the determination of CIN, we applied CGH to microarrays because it allows a high-resolution detection of DNA copy number changes in comparison with conventional CGH as well as the analysis of chromosomal regions close to the centromeres and telomeres, and at 1pter -> p32, 16p, 19 and 22. These regions are usually excluded from conventional CGH analysis, because they may show DNA gains in negative control hybridizations. Array CGH analysis of 30 insulinomas (15 tumors of benign, eight tumors of uncertain and seven tumors of malignant behavior) revealed that >= 20 chromosomal alterations and >= 6 telomeric losses were the best predictors of malignant progression. A subset of 22 insulinomas was further investigated for TP53 exon 5-8 gene mutations, and p53 and CK19 expression. Only one malignant tumor was shown to harbor an arginine 273 serine mutation and immunopositivity for p53. CK19 immunopositivity was detected in three malignant tumors and one tumor with uncertain behavior. In conclusion, our results indicate that CIN as well as telomeric loss are very powerful indicators for malignant progression in sporadic insulinomas. Our data do not support a critical role for p53 and CK19 as molecular parameters for this purpose.

  • 67.
    Karlsson, Britt-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Andersson Forsman, Catarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindgren, Per-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Jacobson, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Efficiency of percutaneous core biopsy in pancreatic tumor diagnosis1996In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 120, no 1, p. 75-79Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Radiologic diagnosis of pancreatic tumors exhibits limited precision. The aim of this study was to investigate the outcome and complications of pancreatic core biopsy in patients with suspected pancreatic neoplasms.

    METHODS:

    One hundred patients underwent ultrasonography-guided core biopsy of 1.2 mm external diameter. Medical charts were examined for biochemical and clinical signs of complications. Final diagnosis was settled by operation, autopsy, and clinical signs of the disease including survival with at least 2.3 years of follow-up.

    RESULTS:

    Histopathologic biopsy evaluation showed correct discrimination between exocrine and endocrine tumors and nonneoplastic conditions in 89 patients. No false-positive cancer diagnosis was found, and guidance on nature of primary tumors was obtained for eight of eight metastases. The sensitivity was 91% for exocrine and 87% for endocrine pancreatic tumors, and negative predictive values of these diagnoses were 83% and 97%, respectively. No clinically significant complications were noted.

    CONCLUSIONS:

    Core biopsy is an attractive alternative to diagnostic laparotomy in unresectable pancreatic cancer and efficiently provides diagnosis of endocrine tumors and pancreatic metastases in conjunction with rare complications. Benign biopsy findings cannot be used to exclude presence of primary or metastatic pancreatic neoplasms.

  • 68. Kerkhofs, Tm
    et al.
    Baudin, E
    Terzolo, M
    Allolio, B
    Chadarevian, R
    Mueller, Hh
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Leboulleux, S
    Mantero, F
    Haak, Hr
    Fassnacht, M
    Comparison of Two Mitotane Starting dose Regimens in Patients with Advanced Adrenocortical Carcinoma2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 12, p. 2281-Article in journal (Refereed)
    Abstract [en]

    Context:

    Mitotane is the only approved drug for treatment of adrenocortical carcinoma(ACC). Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head-to-head.

    Objective:

    To investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens.

    Design/Setting:

    Prospective open-label multicenter trial of a predefined duration of twelve weeks.

    Patients/Interventions:

    Forty mitotane-naïve patients with metastatic ACC were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two could be evaluated in detail.

    Main Outcome Measure:

    Difference in median mitotane plasma levels between both treatment groups.

    Results:

    Despite a difference in mean cumulative dose (440±142g versus 272±121g), median maximum plasma levels were not significantly different between the two groups (high-dose 14.3mg/L (6.3-29.7,n=20) versus 11.3mg/L (5.5-20.0,n=12), p=0.235). Ten out of twenty patients on the high-dose regimen reached plasma concentrations ≥14mg/L after 46 days (18-81 days) compared to four of twelve patients on the low-dose regimen after 55 days (46-74 days,p=0.286). All patients who reached 14mg/L at 12 weeks displayed a level ≥4.1 mg/L on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013±494mg.d/L versus 555±168mg.d/L, p=0.080.

    Conclusions:

    The high-dose starting regimen did neither result in significantly different mitotane levels nor in a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.

  • 69.
    Khan, Tanweera Shaheena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Imam, Hassan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gröndal, Staffan
    Tibblin, Sten
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use2000In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, no 10, p. 1281-1287Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    To evaluate the efficacy of streptozocin and o.p'DDD (SO) in adrenocortical cancer (ACC) patients since other chemotherapeutic regimens have limited effects.

    PATIENTS AND METHODS:

    We performed a phase II study with SO therapy in 40 ACC patients (median age 44 years). Oral o,p'DDD administration (1-4 g/d, every day) was given together with intravenous streptozocin (1 g/d for five days, thereafter 2 g once every three weeks). 5HT3-receptor blocker was used as standard premedication for streptozocin.

    RESULTS:

    The SO therapy was found to have significant effects on disease-free interval (P = 0.02) as well as on survival (P = 0.01) in adjuvantly treated cases (n = 17) in comparison to the patients who did not get any therapy after complete resection (n = 11). Complete or partial response was obtained in 36.4% of patients with measurable disease (n = 22). The overall two-year and five-year survival rates were 70% and 32.5%, respectively. The presence of metastases at diagnosis was identified as a poor prognostic factor (P = 0.02).

    CONCLUSIONS:

    The present study necessitates further randomized clinical study of SO therapy in the treatment of ACC, mainly as adjuvant treatment immediately after curative intended surgery, and could be developed into a regular treatment regimen.

  • 70.
    Kindmark, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gustavsson, Bengt
    Eriksson, Camilla
    Larsson, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kozlowacki, Gordana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Five patients with malignant endocrine tumors treated with imatinib mesylate (Glivec®)2010In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, no 1, p. 100-101Article in journal (Refereed)
  • 71.
    Kindmark, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dunder, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years2007In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 24, no 3, p. 330-337Article in journal (Refereed)
    Abstract [en]

    Background  Glucagon-secreting endocrine pancreatic tumor is a rare disease, hence controlled studies on clinical management are lacking. In an attempt to assess the efficacy of diagnostic and therapeutic measures in patients with glucagonoma, a retrospective study was performed using the archives of a tertiary care center. Patients and methods  Records from 340 patients with endocrine pancreatic tumors were reassessed and 23 patients with malignant endocrine pancreatic tumor and elevated plasma glucagon levels were identified. Results  About 7% of patients with histologically verified tumors fullfilled our criteria for glucagonoma. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma. Seventy eight percent had metastatic disease to the liver at diagnosis. Necrolytic migratory erythema was diagnosed or clinically suspected in 52%. Somatostatin receptor scintigraphy was positive in 95%. Nineteen patients received chemotherapy at some point, in 18 cases streptozotocin and 5 FU. With this treatment, objective radiological responses were seen in 50% of evaluable patients. Other treatment modalities used were interferon, somatostatin analogs, hepatic artery embolization, radio-frequency ablation of liver metastases, and radiolabeled somatostatin analogs. During the study period, 11 patients died at a median of 80 months from diagnosis whereas 11 patients are still alive after a median follow up of 52 months. One patient was lost to follow-up. Conclusions  Glucagonomas represent 7% of our comprehensive referal material of endocrine pancreatic tumors. Necrolytic migratory erythema was a common finding (52%) and diabetes less frequent at presentation than previously reported. Tumors were positive on somatostatin receptor scintigraphy and objective responses were seen to chemotherapy.

  • 72. Lagercrantz, J
    et al.
    Larsson, C
    Grimmond, S
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Friedman, E
    Carson, E
    Phelan, C
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordenskjöld, M
    Candidate genes for multiple endocrine neoplasia type 11995In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 238, no 3, p. 245-248Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to isolate and characterize candidates for the multiple endocrine neoplasia type 1 (MEN1) gene. The development of tumours related to MEN1 is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour-suppressor gene in this region. We have isolated five cDNA candidates located within the 900 kb remaining for the MEN1 gene, determined their sequence, and characterized their expression in normal tissues and several endocrine tumours. One of the candidates, encoding for phospholipase C-beta 3, showed properties consistent with the idea of a tumour-suppressor gene.

  • 73.
    Lejonklou, Margareta H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stålberg, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor2012In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 6, p. 2588-2598Article in journal (Refereed)
    Abstract [en]

    Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. Wild-type littermates were used for comparison. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. 1.74%; P = 0.024). The microarray results demonstrated that several genes were differentially expressed. Some selected genes were studied on the protein level, e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate (Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting (P < 0.001 and P < 0.01, respectively). Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. chromatin maintenance and apoptosis. Lower mRNA was observed for genes involved in growth factor binding. In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor.

  • 74. Lim, Eric
    et al.
    Goldstraw, Peter
    Nicholson, Andrew G.
    Travis, William D.
    Jett, James R.
    Ferolla, Piero
    Bomanji, Jamshed
    Rusch, Valerie W.
    Asamura, Hisao
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Baudin, Eric
    Caplin, Martyn
    Kwekkeboom, Dik
    Brambilla, Elisabeth
    Crowley, John
    Proceedings of the IASLC International Workshop on Advances in Pulmonary Neuroendocrine Tumors 20072008In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 3, no 10, p. 1194-1201Article in journal (Refereed)
    Abstract [en]

    The International Association for the Study of Lung Cancer, (IASLC) International Congress on Advances in Pulmonary Neuroendocrine Tumors was a two-day meeting held at the Royal Brompton Hospital in London, United Kingdom on the thirteenth and forteenth of December 2007. The meeting was led by 14 member international faculty-in the disciplines of pathology, surgery, medicine, oncology, endocrinology, nuclear medicine, diagnostic imaging, and biostatistics. The aims were twofold, as an educational meeting, and to develop the IASLC International Pulmonary Neuroendocrine Tumors Registry. The meeting highlighted the difference in presentation of the tumors, management options for early and advanced stage disease including the use of novel agents and approaches. The need, process, and approach to an International Registry of Pulmonary Neuroendocrine Tumors were emphasized. International collaboration to develop a retrospective registry, prospective data collection, virtual tissue bank, and collaborative clinical trials were universally agreed as the best way to advance our understanding and treatment of these rare tumors.

  • 75.
    Lindhe, Örjan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Mitotane Effects in a H295R Xenograft Model of Adjuvant Treatment of Adrenocortical Cancer2010In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 42, no 10, p. 725-730Article in journal (Refereed)
    Abstract [en]

    Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, o,p′-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. o,p′-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [11C]methionine (MET), [11C] metomidate (MTO), 2-deoxy-2-[18F]fluoro-d-glucose (FDG), and [18F]-l-tyrosine (FLT) in the aggregates were assessed ± drug treatment in vitro. Tumor growth was significantly inhibited when o,p′-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with o,p′-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 μM o,p′-DDD (p<0.01) in vitro. MeSO2-DDE (15 μM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with o,p′-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with o,p′-DDD. Further studies in humans are needed to investigate this.

  • 76.
    Lindhe, Örjan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Skogseid, Britt
    Brandt, Ingvar
    Cytochrome P450-catalysed binding of 3-methylsulfonyl-DDE and o,p´-DDD in human adrenal zona fasciculata/reticularis2002In: Journal of Clinical Endocrinology & Metabolism, Vol. 87, no 3, p. 1319-1326Article in journal (Refereed)
  • 77.
    Lindhe, Örjan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Skogseid, Britt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brandt, Ingvar
    Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis.2002In: J Clin Endocrinol Metab, ISSN 0021-972X, Vol. 87, no 3, p. 1319-26Article in journal (Refereed)
  • 78.
    Lopez, Juan R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Claessen, Sandra M. H.
    Macville, Merryn V. E.
    Albrechts, Jozefa C. M.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Speel, Ernst-Jan M.
    Spectral Karyotypic and Comparative Genomic Analysis of the Endocrine Pancreatic Tumor Cell Line BON-12010In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 91, no 2, p. 131-141Article in journal (Refereed)
    Abstract [en]

    BON-1 is a human serotonin-producing endocrine pancreatic tumor (EPT) cell line, which has been used for various studies of tumorigenesis and treatment. Because its genotype, phenotype and degree of differentiation may underlie events that are instrumental to the development of endocrine tumors and, moreover, may vary between labs and over time, we decided to comprehensively characterize the chromosomal constitution of BON-1 by applying conventional GTG-banding, spectral karyotyping (SKY), comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). BON-1 cells proved to be hyperdiploid containing a modal chromosome number of 57 (range 56–64). SKY identified a stemline containing 6 clonal aberrations including del(1p), t(9;12)del(9p)x2, der(10)t(5;10), der(19)t(8;19), der(14)t(9;14)t(9;10), and a sideline harboring an additional del(12q). CGH and FISH confirmed the SKY results and, in addition, highlighted the chromosomal regions involved in the rearrangements. Moreover, they identified a homozygous deletion of the key tumor suppressor genes CDKN2A and CDKN2B at 9p21.3, in accordance with absence of p16INK4A and p14ARF expression as revealed by immunocytochemistry. Apart from deregulation of the cell cycle and p53 pathway this finding indicates escape from replicative senescence (induced by mutated NRAS) and detachment-induced apoptosis as molecular mechanisms underlying the tumorigenesis of BON-1 cells. Immunostaining results for p53, MDM2 and pRb expression were consistent with previously published data using Western analysis. In conclusion, we provide here a comprehensive cytogenetic profile of BON-1. This cell line harbors both numerical and structural genomic alterations indicative for malignant EPTs.

  • 79.
    Lopez-Egido, Juan R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wang, Yi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grimfjärd, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wang, Shu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differentially regulated genes in MEN1-transfected BON cells using RT-differential display and oligonucleotide microarrays2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 6, p. 1859-1866Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Apart from inactivation of the MEN1 gene, the molecular mechanisms involved in tumorigenesis of the endocrine organs and MEN1-associated non-endocrine lesions remain unknown.

    MATERIALS AND METHODS:

    In order to learn more about down-stream effects upon MEN1 gene inactivation BON1 cells were transfected with a MEN1 gene construct (BON/M1C), and both RT-differential display and oligonucleotide microarrays were performed.

    RESULTS:

    Three genes (SMARCC1, OVCA2 and SRp55) found to be differentially regulated on differential display were corroborated by northern blots on cell line RNA when comparing MEN1 transfected cells with control (empty vector transfection). When comparing two different passages of BON/M1C with two passages of vector control using oligonucleotide microarrays, 25 up-regulated genes and 64 down-regulated genes could be found using a cut-off of >or=1.6 times.

    CONCLUSION:

    These findings might contribute to the understanding of the molecular pathways involved in MEN1 tumorigenesis, and may also provide knowledge of genes involved in sporadic endocrine tumorigenesis.

  • 80.
    Monazzam, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Razmara, Masoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed)
    Abstract [en]

    Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

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  • 81.
    Monazzan, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Chu, Xia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    MicroRNA Expression Profiling in adrenals of Multiple Endocrine Neoplasia type 1 MiceManuscript (preprint) (Other academic)
  • 82.
    Oberg, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Skogseid, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Endokrin tumörbiologi.
    The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1.1998In: J Intern Med, ISSN 0954-6820, Vol. 243, no 6, p. 471-6Article, review/survey (Other (popular scientific, debate etc.))
  • 83. Pasieka, JL
    et al.
    McKinnon, JG
    Kinnear, S
    Yelle, CA
    Numerow, L
    Paterson, A
    Rorstad, O
    DiFrancesco, LM
    McEwan, A
    Skogseid, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Carcinoid syndrome symposium on treatment modalities for gastrointestinalcarcinoid tumours: symposium summary.2001In: Can J Surg, Vol. 44, p. 25-Article in journal (Refereed)
  • 84.
    Rastad, J
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Department of Medical Sciences. Endokrin tumörbiologi.
    Endocrine pancreatic tumors without hormonal symptoms2000In: Endocrinologia: Controversias Medico-Quirurgicas, McGraw-Hill Interamericana , 2000Chapter in book (Refereed)
  • 85.
    Rastad, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Diagnosis measures in MEN 1 families1996In:  Endocrinologia / [ed] Herrera MF, Garber IL, Roidrigo JR, Fernandez MC, México, D.F.: McGraw-Hill Interamericana , 1996Chapter in book (Other academic)
  • 86.
    Razmara, Masoud
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Monazzam, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration2018In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, article id 64Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin.

    METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells.

    RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells.

    CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.

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  • 87.
    Skogeid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Developments in the Life Sciences2012In: Scholars in Action: Past–Present–Future / [ed] Engwall, Lars, Uppsala: Acta Universitatis Upsaliensis, 2012, p. 123-138Chapter in book (Other academic)
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    fulltext
  • 88.
    Skogseid, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Nonsurgical treatment of advanced malignant neuroendocrine pancreatictumors and midgut carcinoids.2001In: World J Surg, Vol. 25, p. 700-Article in journal (Refereed)
  • 89.
    Skogseid, B
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Endokrin tumörbiologi.
    Rastad, J
    Department of Surgical Sciences.
    Oberg, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Onkologisk endokrinologi.
    Multiple endocrine neoplasia type 1. Clinical features and screening.1994In: Endocrinol Metab Clin North Am, ISSN 0889-8529, Vol. 23, no 1, p. 1-18Article in journal (Refereed)
  • 90.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Multiple endocrine neoplasia type 1: Clinical genetics and diagnosis1997In: Endocrine Neoplasms / [ed] Andrew Arnold, Boston: Kluwer Academic Publishers, 1997, p. 383-406Chapter in book (Other academic)
  • 91.
    Skogseid, Britt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Surgical Endocrinology: Pancreatic endocrine tumors in multiple endocrine neoplasia type 12001In: Surgical Endocrinology, Lippincot, Williams and Wilkins Publischers , 2001Chapter in book (Refereed)
  • 92.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Doherty, G M
    Clinical challenges in hereditary pancreatic endocrine tumors: Multiple endocrine neoplasia type 11999In: Recent Advances in the pathophysiology and management of inflammatory bowel diseases and digestive endocrine tumors: postgraduate course 1999, Paris, July 2-3 / [ed] Michel Mignon & Jean-Frédéric Colombel, London: John Libbey Publishing, 1999, p. 241-247Chapter in book (Other academic)
  • 93.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Doherty, G M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Multiple endocrine neoplasia type 1: clinical and genetic features1999In: The Italian Journal of Gastroenterology and Hepatology, ISSN 1125-8055, Vol. 31, no Suppl 2, p. S131-S134Article in journal (Refereed)
    Abstract [en]

    Multiple endocrine neoplasia type 1 has intrigued clinicians since its description because of its rarity and complex presentation of tumours in disparate endocrine organs. Its unpredictable course has made the development of strategies for clinical management difficult. The frequently indolent course in some family members, punctuated by lethal, aggressively malignant disease in others, has been frustrating as we strive to develop low-morbidity schemes for the prevention of the lethal manifestations of the syndrome. The recent description of the genetic abnormality responsible for the disease in many, if not all, families, will be of great assistance, even if it only allows the cessation of diagnostic testing for kindred members who are found to not carry the genetic abnormality. In fact, there is great promise in this discovery, as it may shed light on significant aspects of neuroendocrine oncogenesis. In spite of this, the clinical management strategies for these families will require further focused attention, in order to develop rational, prospective studies to answer the many questions that remain.

  • 94.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Eriksson, Barbro
    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 , Ludwig Institute for Cancer Research.
    Lundqvist, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lörelius, Lars Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wide, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerström, Göran
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Multiple endocrine neoplasia type 1: a ten year prospective screening study in four kindreds1991In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 73, no 2, p. 281-287Article in journal (Refereed)
    Abstract [en]

    A total of 80 individuals in 4 kindreds with multiple endocrine neoplasia type 1 (MEN 1) have been subjected to repeated biochemical screening during a 10-yr period with the principal aim being to analyze characteristics of the developing pancreatic lesion. Age at presentation of the MEN 1 trait averaged 18 yr in 7 previously unaffected individuals, and this effect of the screening procedure represented a lowering by almost 2 decades. Pancreatic endocrine involvement was recognized at a mean age of 25 yr and constituted the presenting lesion in a majority of the patients. A standardized meal test and basal values of serum pancreatic polypeptide, insulin, proinsulin, and gastrin were the most efficient markers for the pancreatic lesion and preceded signs of pancreatic tumors upon radiological examinations by a mean of 3.5 yr. A 75% penetrance of the islet cell disease and 90% for primary hyperparathyroidism within the affected individuals equalled the prevalences reported in autopsy studies. Two of the kindreds showed signs of intrafamilial homogeneity with respect to the profile of peptide excess (P less than 0.05) and considerable discrepancy in the malignant potential of the pancreatic lesions. The results of early detection and surgical intervention of the pancreatic tumors in MEN 1 suggested an impact on morbidity, while any effect on the mortality of these individuals remains to be clarified.

  • 95.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, J
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Screening for multiple endocrine neoplasia type 1 syndrome1993In: Diagnostic oncology, ISSN 1013-8129, Vol. 3, p. 91-95Article in journal (Refereed)
  • 96.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grama, D
    Rastad, J
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindgren, PG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lörelius, L E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Åkerström, Göran
    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.
    Operative tumour yield obviates preoperative pancreatic tumour localization in multiple endocrine neoplasia type 11995In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 238, no 3, p. 281-288Article in journal (Refereed)
    Abstract [en]

    The efficiency of pancreatic tumour localization was prospectively evaluated in 12 consecutive patients with multiple endocrine neoplasia type 1 (MEN1), who were subjected to extirpation of 56 islet cell neoplasms of 0.2-4 cm in diameter (mean 0.8 cm) during pancreatic resection and enucleation. Computed tomography, angiography of the coeliac trunc and superior mesenteric artery, and percutaneous ultrasound correctly localized 7-12% of the tumours and 21-37% of the 19 lesions measuring at least one centimetre in diameter. Transhepatic portal vein sampling correctly located tumour sites in the proximal or distal portions of the pancreas in four out of six patients, but demonstrated unsatisfactory specificity. Intra-operative ultrasound and bidigital palpation of the pancreas had overall sensitivities of 86 and 45%, respectively, and eight lesions below 0.3 cm in diameter remained undetected with intraoperative ultrasound. It is concluded that diagnosis of endocrine pancreatic neoplasms is biochemical in MEN1 and that broad screening of tumour markers efficiently reveals pancreatic involvement decades before the development of a clinically overt disease. Intra-operative ultrasound is a requisite for pancreatic endocrine surgery in MEN1, and it obviates the need for conventional pancreatic imaging unless a pre-operative search for metastatic disease and anatomical aberrations is considered important.

  • 97.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grama, D
    Rastad, Jonas
    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.
    Lindgren, PG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lörelius, Lars-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Åkerström, Göran
    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.
    Operative tumor yield obviates preoperative pancreatic localization in multiple endocrine neoplasia type 11995In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 238, no 3, p. 281-288Article in journal (Refereed)
    Abstract [en]

    The efficiency of pancreatic tumour localization was prospectively evaluated in 12 consecutive patients with multiple endocrine neoplasia type 1 (MEN1), who were subjected to extirpation of 56 islet cell neoplasms of 0.2-4 cm in diameter (mean 0.8 cm) during pancreatic resection and enucleation. Computed tomography, angiography of the coeliac trunc and superior mesenteric artery, and percutaneous ultrasound correctly localized 7-12% of the tumours and 21-37% of the 19 lesions measuring at least one centimetre in diameter. Transhepatic portal vein sampling correctly located tumour sites in the proximal or distal portions of the pancreas in four out of six patients, but demonstrated unsatisfactory specificity. Intra-operative ultrasound and bidigital palpation of the pancreas had overall sensitivities of 86 and 45%, respectively, and eight lesions below 0.3 cm in diameter remained undetected with intraoperative ultrasound. It is concluded that diagnosis of endocrine pancreatic neoplasms is biochemical in MEN1 and that broad screening of tumour markers efficiently reveals pancreatic involvement decades before the development of a clinically overt disease. Intra-operative ultrasound is a requisite for pancreatic endocrine surgery in MEN1, and it obviates the need for conventional pancreatic imaging unless a pre-operative search for metastatic disease and anatomical aberrations is considered important.

  • 98.
    Skogseid, Britt
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Endokrin tumörbiologi.
    Rastad, J
    Department of Surgical Sciences.
    Åkerström, Göran
    Department of Surgical Sciences.
    Pancreatic endocrine tumors in multiple endocrine neoplasia type 12001In: Surgical Endocrinolgy, Lippincot, Williams and Wilkins Publischers , 2001, p. 511-524Chapter in book (Refereed)
  • 99.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Backlin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Adrenal lesions in multiple endocrine neoplasia type 11995In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 118, no 6, p. 1077-1082Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Multiple endocrine neoplasia (MEN) type 1 is accompanied by adrenal involvement, but characteristics and clinical handling of this lesion have been insufficiently explored.

    METHODS:

    Patients with MEN 1 (n = 43) were monitored (mean, 6.3 years) with annual biochemical and radiologic adrenal evaluation. Adrenal specimens were examined by in situ RNA-RNA hybridization for expression of the MEN1 candidate gene phospholipase C beta 3 (PLC beta 3) and immunostaining for insulin-like growth factor-1 receptor.

    RESULTS:

    Altogether 17 patients (40%) displayed adrenal enlargement, which was limited to the adrenal cortex and showed signs of progression, marked atypia, and cancer development in three of them. Only the carcinoma exhibited adrenocortical hormone excess. PLC beta 3 was expressed in the hyperplastic and adenomatous proliferation but not the carcinoma. Pancreatic endocrine tumors with insulin-proinsulin excess were overrepresented in the patients with adrenocortical involvement, but significant insulin-like growth factor-1 receptor immunoreactivity was restricted to the carcinoma.

    CONCLUSIONS:

    The prevalent adrenocortical lesion associated with MEN 1 requires regular attention because of malignant potential. It was unrelated to loss of constitution heterozygosity for the MEN1 locus (11q13) and PLC beta 3 expression, except for the cortical carcinoma exhibiting allelic losses involving also the Wiedemann-Beckwith gene at 11p15. Mechanisms for mitogenic relationships between the pancreatic and adrenal lesions of MEN 1 demand further clarification.

  • 100.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rastad, Jonas
    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.
    Pancreatic endocrine tumors in multipible endocrine neoplasia type 12001In: Surgical Endocrinology / [ed] Gerard M Doherty & Britt Skogseid, Philadelphia: Lippincott Williams & Wilkins, 2001, p. 511-524Chapter in book (Other academic)
123 51 - 100 of 132
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