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  • 601.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Surgery on neuroendocrine tumours2007Ingår i: Baillière's Best Practice & Research. Clinical Endocrinology & Metabolism, ISSN 1521-690X, E-ISSN 1532-1908, Vol. 21, nr 1, s. 87-109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuroendocrine tumours of the gastrointestinal tract and pancreas present a major challenge to physicians in their recognition and treatment requirements, and surgical treatment of these tumours has become increasingly important for symptom palliation and survival. For some carcinoid tumours the extent of surgery may depend on tumour size. Midgut carcinoid is the most common cause of the carcinoid syndrome, requiring surgery for primary and mesenteric tumours to minimize the risk for abdominal complications but also for removal of liver metastases to palliate hormonal symptoms. Among endocrine pancreatic tumours, insulinoma and gastrinoma often cause severe symptoms of hormone excess despite their inconspicuous size, but they can be successfully removed with improved pre- and intraoperative localization. Other tumours--glucagonoma, VIPoma, and non-functioning endocrine pancreatic tumours--are often large or metastasizing, but generally require surgical debulking to alleviate hormonal symptoms and have favourable survival.

  • 602.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Surgical aspects of neuroendocrine tumours2009Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 45, nr Suppl 1, s. 237-50Artikel i tidskrift (Refereegranskat)
  • 603.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Parathyroid carcinoma2009Ingår i: Clinical endocrine oncology / [ed] Ian D. Hay & John A.H. Wass, Malden: Blackwell Publishing , 2009, 2, s. 180-184Kapitel i bok, del av antologi (Övrig (populärvetenskap, debatt, mm))
  • 604.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hessman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Gastrointestinal carcinoids2009Ingår i: Endocrine surgery: A companion to specialist surgical practice / [ed] Tom W.J. Lennard, London: Saunders , 2009, s. 163-169Kapitel i bok, del av antologi (Övrig (populärvetenskap, debatt, mm))
  • 605.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Carcinoid: Presentation and diagnosis surgical managment2009Ingår i: Endocrine surgery: Principles and practice / [ed] Johnathan G.H. Hubbard, William B. Inabnet & Chung-Yau Lo, London: Springer , 2009, s. 585-598Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 606.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Surgical Management of MEN-1 and -2: State of the Art2009Ingår i: Surgical Clinics of North America, ISSN 0039-6109, E-ISSN 1558-3171, Vol. 89, nr 5, s. 1047-1068Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Multiple endocrine neoplasia syndrome type 1 (MEN-1) consists of endocrine tumors of the parathyroid, the endocrine pancreas-duodenum, and the pituitary. Surveillance and screening for the endocrinopathies is recommended in gene carriers. Surgery for MEN-1-related hyperparathyroidism is generally performed as radical subtotal parathyroidectomy, because less surgery is likely to result in persistent or recurrent disease. Multiple endocrine neoplasia syndrome type 2 (MEN-2) consists of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Prophylactic thyroidectomy based on DNA testing in the MEN-2 syndrome is considered one of the greater achievements in cancer treatment, because it may be performed before thyroid carcinoma development and provides cure for the patient.

  • 607.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Surgical Management of Multiglandular Parathyroid Disease2013Ingår i: Surgery of the Thyroid and Parathyroid Glands / [ed] Gregory W. Randolph, Philadelphia: Saunders Elsevier, 2013, 2, s. 620-638Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    In 1934, Albright et al.[1] discovered the unusual entity of parathyroid water-clear–cell hyperplasia and thought this resulted from some form of extrinsic glandular stimulation. The more common parathyroid chief-cell hyperplasia was described in 1958 by Cope et al.[2] and was believed to have a similar genesis. However, stimulating agents causing the disease have still not been identified in sporadic parathyroid hyperplasia, in contrast to hyperparathyroidism (HPT) secondary to uremia or long-term lithium therapy (see  Chapter 66, Surgical Management of Secondary and Tertiary Hyperparathyroidism). Despite the fact that they represent a minority among HPT patients, ever since the early days of parathyroid surgery cases of parathyroid hyperplasia have continued to intrigue pathologists and parathyroid surgeons (see  Chapter 70, Surgical Pathology of the Parathyroid Glands). Hyperplasia is easily …

  • 608.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Surgical managment of MEN 1 and MEN 2: State of the art2009Ingår i: Endocrine surgery / [ed] Martha A. Zeiger & Ronald F. Martin, Philadelphia: Saunders , 2009, s. 1047-1068Kapitel i bok, del av antologi (Övrig (populärvetenskap, debatt, mm))
  • 609.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Natural History of untreated primary hyperparathyroidism2016Ingår i: Textbook of Endocrine Surgery: / [ed] Dr. Orlo H Clark MD, Dr. Quan-Yang Duh MD, Dr. Electron Kebebew MD, Dr. Jessica E Gosnell MD and Dr. Wen T Shen MA MD, Jaypee Brothers Medical Publishers , 2016, 3Kapitel i bok, del av antologi (Refereegranskat)
  • 610.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Resection of Small intestinal neuroendocrine tumors2016Ingår i: Atlas of endocrine surgical techniques / [ed] Sally E Carty, Jaypee Brothers Medical Publishers , 2016Kapitel i bok, del av antologi (Refereegranskat)
  • 611.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Surgical management of pancreatico-duodenal tumors in multiple endocrine neoplasia syndrome type 12012Ingår i: Clinics, ISSN 1807-5932, E-ISSN 1980-5322, Vol. 67, nr S 1, s. 173-178Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Pancreatico-duodenal tumors are the second most common endocrinopathy in multiple endocrine neoplasia syndrome type 1, and have a pronounced effect on life expectancy as the principal cause of disease-related death. Previous discussions about surgical management have focused mainly on syndromes of hormone excess and, in particular, the management of multiple endocrine neoplasia syndrome type 1-related Zollinger-Ellison syndrome. Since hormonal syndromes tend to occur late and indicate the presence of metastases, screening with biochemical markers and endoscopic ultrasound is recommended for early detection of pancreatico-duodenal tumors, and with early surgery before metastases have developed. Surgery is recommended in patients with or without hormonal syndromes in the absence of disseminated liver metastases. The suggested operation includes distal 80% subtotal pancreatic resection together with enucleation of tumors in the head of the pancreas, and in cases with Zollinger-Ellison syndrome, excision of duodenal gastrinomas together with clearance of regional lymph node metastases. This strategy, with early and aggressive surgery before metastases have developed, is believed to reduce the risks for tumor recurrence and malignant progression.

  • 612.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hessman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Remedial Parathyroid Surgery2012Ingår i: Surgery of the Thyroid and Parathyroid Glands / [ed] D. Oertli, R. Udelsman, Springer Berlin/Heidelberg, 2012, 2, s. 555-577Kapitel i bok, del av antologi (Refereegranskat)
  • 613.
    Åkerström, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Multiple Endocrine Neoplasia type 22018Ingår i: Textbook of Complex General Surgical Oncology / [ed] Shane Y Morita, Charles M Balch, V. Suzanne Klimberg, Timothy M. Pawlik, Mitchell C. Posner, Kenneth K. Tanabe, McGraw-Hill, 2018Kapitel i bok, del av antologi (Refereegranskat)
  • 614.
    Åkerström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Uppsala University.
    Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Primary Aldosteronism (PA) is caused by autonomous overproduction of aldosterone. Aldosterone is necessary for fluid and ion homeostasis. Aberrant overproduction leads to hypertension and cardiovascular damage. With a prevalence of over 5% in the worlds’ hypertensive community, and with over a billion people worldwide having high blood pressure, PA represents a major contributor to health care costs and morbidity. Importantly, 30% of PA patients have a unilateral dominant secretion, an aldosterone producing adenoma (APA), making it possible to cure a substantial portion of patients with surgery. Unfortunately, there is a large underdiagnosis of PA, leading to delayed diagnosis in many patients, worsening their outcome after surgery. A need for better screening techniques, raised awareness and treatment options for PA is warranted.

    Since 2011, the genetic understanding of APAs has revolutionized. Somatic mutations turning on an autonomous aldosterone production has been observed in up to 80% of tumors. In this thesis we have investigated the genetic landscape and phenotypes of APAs. By international collaborations we have collected one of the largest cohorts of APAs ever sequenced. We have confirmed and extended the understanding of KCNJ5 mutations, its associated phenotype and the specificity for APAs. We have confirmed a high rate of mutations in ATP1A1, ATP2B3 and CACNA1D, and noted distinct clinical and molecular phenotypes in these tumors. We describe a marker of Zona Glomerulosa cells, perhaps important for the normal regulation and function of these cells. We observe somatic mutations in CTNNB1, occurring in a mutually exclusive manner to the other mutations. Using in situ sequencing, we note genetic heterogeneity in APAs with KCNJ5 mutations. Finally, we evaluate intratumoral aldosterone measurement on a large cohort of tumors, validating a high specificity for APAs. Noting also a difference in the level of intratumoral aldosterone between APAs and a possible association with genotype. Remarkably, we also note a robust correlation between the intracellular concentrations and plasma-aldosterone. We hope that with gained knowledge of the genetic background, the understanding of both pathologic and normal states of the adrenals will increase, and hopefully benefit patients in the future.

    Delarbeten
    1. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Öppna denna publikation i ny flik eller fönster >>Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
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    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e41926-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.

    Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

    Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p < 0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p < 0.005).

    Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-183242 (URN)10.1371/journal.pone.0041926 (DOI)000306950200128 ()
    Tillgänglig från: 2012-10-25 Skapad: 2012-10-23 Senast uppdaterad: 2019-10-30Bibliografiskt granskad
    2. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
    Öppna denna publikation i ny flik eller fönster >>Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
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    2015 (Engelska)Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, nr 5, s. 735-744Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aldosterone-producing adenomas (APAs) are found in 1.5-3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca(2) (+) regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca(2) (+) levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

    Nyckelord
    ATP1A1; CACNA1D; KCNJ5; primary aldosteronism; aldosterone-producing adenoma
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-266639 (URN)10.1530/ERC-15-0321 (DOI)000364022400010 ()26285814 (PubMedID)
    Forskningsfinansiär
    CancerfondenVetenskapsrådet
    Tillgänglig från: 2015-11-10 Skapad: 2015-11-10 Senast uppdaterad: 2017-12-01
    3. Activating mutations in CTNNB1 in aldosterone producing adenomas
    Öppna denna publikation i ny flik eller fönster >>Activating mutations in CTNNB1 in aldosterone producing adenomas
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    2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 19546Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalenceof 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitutea large proportion of PA cases and represent a surgically correctable form of the disease. The WNTsignaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling ismutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutationsin a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of thetumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. Allof the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3.The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggestingactivation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and directmeasurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. Thisreport provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occurin APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway maybe important in APA formation.

    Nationell ämneskategori
    Endokrinologi och diabetes Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-277306 (URN)10.1038/srep19546 (DOI)000368736400001 ()26815163 (PubMedID)
    Forskningsfinansiär
    CancerfondenVetenskapsrådet
    Tillgänglig från: 2016-02-19 Skapad: 2016-02-19 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
    4. Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing Adenomas
    Öppna denna publikation i ny flik eller fönster >>Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing Adenomas
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Abstract

    Context

    Primary Aldosteronism is the most common endocrine cause of hypertension. Unilateral disease in the form of Aldosterone producing adenomas (APAs) is found in 1.5-3% of hypertensive. Determining the source of aldosteronism is necessary for correct diagnosis and further molecular analysis.

    Objective

    To evaluate tissue aldosterone as a marker of aldosterone production and correlate it to patient phenotype and tumour mutation status, and to explore molecular heterogeneity in APAs.

    Design

    Forty-six frozen tumour samples from patients diagnosed with APAs were included. Tumours were derived from a single endocrine referral center, and had been stored from 1985 to 2015. Tissue aldosterone concentration was related to clinical characteristics, genotype and molecular phenotype. Genetic heterogeneity was investigated by biopsies and in situ sequencing. Immunohistochemical analysis of Nephronectin, CYP11B1 and CYP11B2 were performed. qRT-PCR and in situ mRNA expression were used to analyze CYP11B2 mRNA expression.

    Results

    Tissue aldosterone content was specific for aldosterone producing tumours and proved stable after long-term storage at -70C. CYP11B2 expression and aldosterone concentrations were higher in tumours with ATP1A1, ATP2B3 and CACNA1D mutations compared to those with KCNJ5 mutations (p<0.0001 and p=0.0018 respectively). The tissue aldosterone content correlated with CYP11B2 protein expression (r2=0.48, p<0.0001), and both CYP11B2 expression and tissue aldosterone content were associated with the plasma level of aldosterone (r2=0.33, p=0.0002 and r2=0.75, p<0.0001 respectively). In four tumours with suspicion of genetic heterogeneity, sampling of DNA revealed a heterogeneous KCNJ5 mutation in one tumour. Using in situ sequencing we confirmed heterogeneous expression of mutated KCNJ5 cDNA in the others. In three tumours classified as APAs, no mutation nor any aldosterone or CYP11B2 were detected, suggesting non-functional tumours.

    Conclusion

    Tissue aldosterone content is specific for aldosterone producing lesions, correlates with plasma levels, and displays variable levels depending on tumour genotype. Genetic heterogeneity is evident in a subgroup of KCNJ5 mutated tumours. The present results show that CYP11B2 expression and tissue aldosterone measurement may be used to clarify the source of aldosterone secretion. 

    Nationell ämneskategori
    Klinisk medicin Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-281039 (URN)
    Tillgänglig från: 2016-03-16 Skapad: 2016-03-16 Senast uppdaterad: 2016-04-21
  • 615.
    Åkerström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Genetic Alterations in Aldosterone Producing Adenomas2014Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Delarbeten
    1. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Öppna denna publikation i ny flik eller fönster >>Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Visa övriga...
    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e41926-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.

    Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

    Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p < 0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p < 0.005).

    Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-183242 (URN)10.1371/journal.pone.0041926 (DOI)000306950200128 ()
    Tillgänglig från: 2012-10-25 Skapad: 2012-10-23 Senast uppdaterad: 2019-10-30Bibliografiskt granskad
    2. Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
    Öppna denna publikation i ny flik eller fönster >>Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-218662 (URN)
    Tillgänglig från: 2014-02-13 Skapad: 2014-02-13 Senast uppdaterad: 2015-06-26Bibliografiskt granskad
    3. Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing Adenomas
    Öppna denna publikation i ny flik eller fönster >>Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing Adenomas
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    ATP1A1, ATP2B3, Aldosterone producing adenomas, Mutation, KCNJ5
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-218659 (URN)
    Tillgänglig från: 2014-02-13 Skapad: 2014-02-13 Senast uppdaterad: 2014-03-11
  • 616.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Azizan, Elena A B
    Maharjan, Rajani
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Brown, Morris J
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Activating Mutations in CTNNB1 in Aldosterone Producing AdenomasManuskript (preprint) (Övrigt vetenskapligt)
  • 617.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Carling, T.
    Endocrine Research Unit, Yale University, New Haven, CT, USA..
    Beuschlein, F.
    Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany..
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Genetics of adrenocortical tumours2016Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, nr 6, s. 540-550Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The recently available genomic sequencing techniques have led to breakthroughs in understanding of the underlying genetic mechanisms in adrenocortical tumours. Disease-causing mutations have been described for aldosterone-producing adenomas, cortisol-producing adenomas and adrenocortical carcinomas. Further, knowledge gained from transcriptome analyses and methylation arrays has provided new insights into the development of these tumours. Elucidation of the genomic landscape of adrenocortical tumours and improved techniques may in the future be useful for early diagnosis through the detection of mutated DNA in the circulation. Moreover, compounds that bind specifically to altered proteins may be used as screening targets or therapeutic agents. Regulation of cortisol release by interaction with an altered subunit in adenylate cyclase may be more complex, but may provide a new option for regulating steroid release. Information about derangements in adrenocortical carcinoma is already helpful for determining patient prognosis. With further knowledge, we may be able to identify novel biomarkers that effectively and noninvasively help in differentiating between benign and malignant disease. It is clear that the next few years will provide much novel information that hopefully will aid in the treatment of patients with adrenocortical tumours.

  • 618.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Verdugo, Alberto Delgado
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Starker, Lee F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Cupisti, Kenko
    Willenberg, Holger S.
    Knoefel, Wolfram T.
    Saeger, Wolfgang
    Feller, Alfred
    Ip, Julian
    Soon, Patsy
    Anlauf, Martin
    Alesina, Pier F.
    Schmid, Kurt W.
    Decaussin, Myriam
    Levillain, Pierre
    Wangberg, Bo
    Peix, Jean-Louis
    Robinson, Bruce
    Zedenius, Jan
    Backdahl, Martin
    Caramuta, Stefano
    Iwen, K. Alexander
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Kraimps, Jean-Louis
    Dralle, Henning
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Sidhu, Stan
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Lehnert, Hendrik
    Walz, Martin K.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Carling, Tobias
    Choi, Murim
    Lifton, Richard P.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e41926-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.

    Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

    Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p < 0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p < 0.005).

    Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

  • 619.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Maharjan, Rajani
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Gomez-Sanchez, Celso
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Activating mutations in CTNNB1 in aldosterone producing adenomas2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 19546Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalenceof 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitutea large proportion of PA cases and represent a surgically correctable form of the disease. The WNTsignaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling ismutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutationsin a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of thetumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. Allof the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3.The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggestingactivation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and directmeasurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. Thisreport provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occurin APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway maybe important in APA formation.

  • 620.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Svedlund, Jessica
    Gomez-Sanchez, Celso
    Nilsson, Mats
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Peyman, Björklund
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing AdenomasManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Abstract

    Context

    Primary Aldosteronism is the most common endocrine cause of hypertension. Unilateral disease in the form of Aldosterone producing adenomas (APAs) is found in 1.5-3% of hypertensive. Determining the source of aldosteronism is necessary for correct diagnosis and further molecular analysis.

    Objective

    To evaluate tissue aldosterone as a marker of aldosterone production and correlate it to patient phenotype and tumour mutation status, and to explore molecular heterogeneity in APAs.

    Design

    Forty-six frozen tumour samples from patients diagnosed with APAs were included. Tumours were derived from a single endocrine referral center, and had been stored from 1985 to 2015. Tissue aldosterone concentration was related to clinical characteristics, genotype and molecular phenotype. Genetic heterogeneity was investigated by biopsies and in situ sequencing. Immunohistochemical analysis of Nephronectin, CYP11B1 and CYP11B2 were performed. qRT-PCR and in situ mRNA expression were used to analyze CYP11B2 mRNA expression.

    Results

    Tissue aldosterone content was specific for aldosterone producing tumours and proved stable after long-term storage at -70C. CYP11B2 expression and aldosterone concentrations were higher in tumours with ATP1A1, ATP2B3 and CACNA1D mutations compared to those with KCNJ5 mutations (p<0.0001 and p=0.0018 respectively). The tissue aldosterone content correlated with CYP11B2 protein expression (r2=0.48, p<0.0001), and both CYP11B2 expression and tissue aldosterone content were associated with the plasma level of aldosterone (r2=0.33, p=0.0002 and r2=0.75, p<0.0001 respectively). In four tumours with suspicion of genetic heterogeneity, sampling of DNA revealed a heterogeneous KCNJ5 mutation in one tumour. Using in situ sequencing we confirmed heterogeneous expression of mutated KCNJ5 cDNA in the others. In three tumours classified as APAs, no mutation nor any aldosterone or CYP11B2 were detected, suggesting non-functional tumours.

    Conclusion

    Tissue aldosterone content is specific for aldosterone producing lesions, correlates with plasma levels, and displays variable levels depending on tumour genotype. Genetic heterogeneity is evident in a subgroup of KCNJ5 mutated tumours. The present results show that CYP11B2 expression and tissue aldosterone measurement may be used to clarify the source of aldosterone secretion. 

  • 621.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Backman, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Moser, Ana
    Maharjan, Rajani
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Robinson, Bruce
    Iwen, K Alexander
    Dralle, Henning
    D Volpe, Cristina
    Bäckdahl, Martin
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Walz, Martin K
    Lehnert, Hendrik
    Sidhu, Stan
    Zedenius, Jan
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.2015Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, nr 5, s. 735-744Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aldosterone-producing adenomas (APAs) are found in 1.5-3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca(2) (+) regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca(2) (+) levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

  • 622.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Volpe, Cristina D
    Bäckdahl, Martin
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Zedenius, Jan
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Peyman, Björklund
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing AdenomasManuskript (preprint) (Övrigt vetenskapligt)
  • 623.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Volpe, Cristina D
    Bäckdahl, Martin
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Zedenius, Jan
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Peyman, Björklund
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing AdenomasManuskript (preprint) (Övrigt vetenskapligt)
  • 624.
    Åström, Lennart
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sandin, Fredrik
    Regional Cancer Center Uppsala-Örebro, Sweden.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Translational Oncology & Urology Research (TOUR), School of Cancer and Pharmaceutical Sciences, King’s College London, UK.
    Good Prognosis following a PSA Bounce after High Dose Rate Brachytherapy and External Radiotherapy in Prostate Cancer2018Ingår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 129, nr 3, s. 561-566Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    PSA kinetics after curative radiotherapy for prostate cancer is an important part of the posttreatment evaluation. We analysed PSA bounce occurrence after combined high dose rate brachytherapy (HDR-BT) and external radiotherapy (ERT).

    Material & methods

    We analysed 623 patients treated from 1995 to 2008. The median age was 66 years (47-79). The median initial PSA was 12 ng/ml (0.1-224). Neoadjuvant endocrine therapy was given to 429 patients. ERT was given with 2 Gy fractions to 50 Gy and HDR-BT in two 10 Gy fractions. The median follow-up was 11 years (range 2-266 months). PSA bounce was defined as a temporary rise in PSA >0.2 ng/ml. PSA failure was defined according to the Phoenix definition.

    Results

    PSA bounce occurred in 159 patients (26%), where 56 patients had a bounce amplitude >2 ng/ml and 31 patients had multiple bounces. Median time to bounce peak was 15 (3-103) months with a median bounce value of 1.5 (0.3-12) ng/ml. Younger age and lower Gleason scores were associated with PSA bounce. In a Cox regression analysis with PSA bounce as a time-dependent covariate and adjusted for other prognostic factors, PSA bounce was associated with a lower risk for PSA failure (HR=0.42; 95% confidence interval 0.26-0.70).

    Conclusion

    PSA bounce after HDR-BT combined with ERT is common and associated with a good prognosis. As the relapse risk after an early bounce is very low, the findings should alert clinicians not to initiate salvage treatment too early. Research in prospective identification of PSA bounce is clinically relevant.

  • 625.
    Öberg, Kjell
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Ferolla, P.
    Papotti, M.
    Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up2012Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, nr suppl. 7, s. vii120-vii123Artikel i tidskrift (Refereegranskat)
  • 626.
    Öberg, Kjell
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Kwekkeboom, D.
    Jelic, S.
    Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up2010Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 21, nr Suppl 5, s. v220-v222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The annual incidence of lung neuroendocrine tumour has been reported to be 1.35/100 000/year and the overall age adjusted incidence for thymic carcinoid 0.02/100 000/year. Of all neuroendocrine tumours, ∼25% are located in the respiratory tract. Both bronchial and thymic carcinoids may be part of multiple endocrine neoplasia type 1 syndrome (MEN-I) (5%–15%). The median age at diagnosis for lung neuroendocrine tumours is 64 years and for thymic tumours 59 years.

  • 627.
    Öberg, Kjell
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Rindi, G.
    Jelic, S.
    Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up2010Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 21, nr Suppl 5, s. v223-v227Artikel i tidskrift (Refereegranskat)
  • 628. Ögmundsdottir Michelsen, Halldora
    et al.
    Sjölin, Ingela
    Schlyter, Mona
    Hagström, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Kiessling, Anna
    Henriksson, Peter
    Held, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hag, Emma
    Nilsson, Lennart
    Bäck, Maria
    Schiopu, Alexandru
    Zaman, M Justin
    Leosdottir, Margret
    Cardiac rehabilitation after acute myocardial infarction in Sweden - evaluation of programme characteristics and adherence to European guidelines: The Perfect Cardiac Rehabilitation (Perfect-CR) study.2020Ingår i: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 27, nr 1, s. 18-27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: While patient performance after participating in cardiac rehabilitation programmes after acute myocardial infarction is regularly reported through registry and survey data, information on cardiac rehabilitation programme characteristics is less well described.

    AIM: The aim of this study was to evaluate Swedish cardiac rehabilitation programme characteristics and adherence to European Guidelines on Cardiovascular Disease Prevention.

    METHOD: Cardiac rehabilitation programme characteristics at all 78 cardiac rehabilitation centres in Sweden in 2016 were surveyed using a web-based questionnaire (100% response rate). The questions were based on core components of cardiac rehabilitation as recommended by European Guidelines.

    RESULTS: There was a wide variation in programme duration (2-14 months). All programmes reported offering an individual post-discharge visit with a nurse, and 90% (n = 70) did so within three weeks from discharge. Most programmes offered centre-based exercise training (n = 76, 97%) and group educational sessions (n = 61, 78%). All programmes reported to the national audit, SWEDEHEART, and 60% (n = 47) reported that performance was regularly assessed using audit data, to improve quality of care. Ninety-six per cent (n = 75) had a core team consisting of a cardiologist, a physiotherapist and a nurse and 76% (n = 59) reported having a medical director. Having other allied healthcare professionals included in the cardiac rehabilitation team varied. Forty per cent (n = 31) reported having regular team meetings where nurses, physiotherapists and cardiologist could discuss patient cases.

    CONCLUSION: The overall quality of cardiac rehabilitation programmes provided in Sweden is high. Still, there are several areas of potential improvement. Monitoring programme characteristics as well as patient outcomes might improve programme quality and patient outcomes both at a local and a national level.

  • 629.
    Örlefors, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    PET-Guided Surgery: High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours2012Ingår i: Cancers, ISSN 2072-6694, Vol. 4, nr 1, s. 100-112Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

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