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  • 801.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shuai, Hongyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose lowers cAMP to inhibit glucagon secretion by a direct effect on alpha cells2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S266-S267Article in journal (Refereed)
  • 802.
    Yuan, Jinna
    et al.
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Derraik, Jose G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Natl Sci Challenge, Auckland, New Zealand.
    Fu, Junfen
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Dong, Guanping
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Natl Sci Challenge, Auckland, New Zealand.
    Wu, Wei
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Huang, Ke
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Jiang, Youjun
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Chen, Xiaochun
    Zhejiang Univ, Childrens Hosp, Endocrinol Dept, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Beta-Cell Function in Chinese Youngsters with Type 1 Diabetes and Assessment of Surrogate Markers of Severe Insulin Deficiency2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, p. 644-644Article in journal (Other academic)
  • 803. Yubero-Serrano, Elena M
    et al.
    Delgado-Lista, Javier
    Tierney, Audrey C
    Perez-Martinez, Pablo
    Garcia-Rios, Antonio
    Alcala-Diaz, Juan F
    Castaño, Justo P
    Tinahones, Francisco J
    Drevon, Christian A
    Defoort, Catherine
    Blaak, Ellen E
    Dembinska-Kieć, Aldona
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lovegrove, Julie A
    Perez-Jimenez, Francisco
    Roche, Helen M
    Lopez-Miranda, Jose
    Insulin resistance determines a differential response to changes in dietary fat modification on metabolic syndrome risk factors: the LIPGENE study2015In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 102, no 6, p. 1509-1517Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous data support the benefits of reducing dietary saturated fatty acids (SFAs) on insulin resistance (IR) and other metabolic risk factors. However, whether the IR status of those suffering from metabolic syndrome (MetS) affects this response is not established.

    OBJECTIVE: Our objective was to determine whether the degree of IR influences the effect of substituting high-saturated fatty acid (HSFA) diets by isoenergetic alterations in the quality and quantity of dietary fat on MetS risk factors.

    DESIGN: In this single-blind, parallel, controlled, dietary intervention study, MetS subjects (n = 472) from 8 European countries classified by different IR levels according to homeostasis model assessment of insulin resistance (HOMA-IR) were randomly assigned to 4 diets: an HSFA diet; a high-monounsaturated fatty acid (HMUFA) diet; a low-fat, high-complex carbohydrate (LFHCC) diet supplemented with long-chain n-3 polyunsaturated fatty acids (1.2 g/d); or an LFHCC diet supplemented with placebo for 12 wk (control). Anthropometric, lipid, inflammatory, and IR markers were determined.

    RESULTS: Insulin-resistant MetS subjects with the highest HOMA-IR improved IR, with reduced insulin and HOMA-IR concentrations after consumption of the HMUFA and LFHCC n-3 diets (P < 0.05). In contrast, subjects with lower HOMA-IR showed reduced body mass index and waist circumference after consumption of the LFHCC control and LFHCC n-3 diets and increased HDL cholesterol concentrations after consumption of the HMUFA and HSFA diets (P < 0.05). MetS subjects with a low to medium HOMA-IR exhibited reduced blood pressure, triglyceride, and LDL cholesterol levels after the LFHCC n-3 diet and increased apolipoprotein A-I concentrations after consumption of the HMUFA and HSFA diets (all P < 0.05).

    CONCLUSIONS: Insulin-resistant MetS subjects with more metabolic complications responded differently to dietary fat modification, being more susceptible to a health effect from the substitution of SFAs in the HMUFA and LFHCC n-3 diets. Conversely, MetS subjects without IR may be more sensitive to the detrimental effects of HSFA intake. The metabolic phenotype of subjects clearly determines response to the quantity and quality of dietary fat on MetS risk factors, which suggests that targeted and personalized dietary therapies may be of value for its different metabolic features. This study was registered at clinicaltrials.gov as NCT00429195.

  • 804.
    Zabihi, Sheller
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wentzel, Parri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Altered Uterine Perfusion is Involved in Fetal Outcome of Diabetic Rats2008In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 29, no 5, p. 413-421Article in journal (Refereed)
    Abstract [en]

    Maternal diabetes affects the development of the offspring by altering the uterine environment. We aimed to investigate the extent to which the blood flow (measured as Tissue Perfusion Units; TPU) to implantation sites and the expression of developmentally important genes in the offspring are affected by maternal diabetes. We measured mRNA levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Bcl-2 associated X protein (Bax), B-cell lymphoma protein (Bcl-2), tumor suppressor protein-53 (p53), paired box protein-3 (Pax-3) and vascular endothelial growth factor-A (Vegf-A). Moreover, we studied the effect on uterine blood flow (TPU) and the expression of the genes exerted by embryonic maldevelopment (malformation or resorption). Streptozotocin induced diabetic (D) and non-diabetic (N) pregnant rats were used in the study. Blood flow (TPU) to implantation sites was measured by a laser Doppler flow meter, and gene expression was analyzed by RT-PCR. Maternal diabetes caused increased blood flow (TPU) to implantation sites compared with normal pregnancy. Furthermore, implantation sites of D rats containing malformed offspring showed impaired growth and decreased blood flow (TPU) compared with their littermates at all gestational days. Resorbed offspring from both N and D rats displayed increased blood flow (TPU) compared with their non-resorbed littermates. Moreover, we found that maternal diabetes causes decreased expression of genes involved in the oxidative stress defense system (CuZnSOD in non-malformed D11 embryos, MnSOD at all gestational time points, ECSOD and Gpx-1 at GD11 -GD15, CAT and Gpx-2 at GD15), decreased expression of Pax-3 at GD11, and increased expression of Vegf-A at all gestational time points. We conclude that both maternal metabolism and embryonic developmental state affect the blood flow (TPU) to the implantation site. Maternal diabetes causes decreased expression of anti-oxidative enzymes and enhanced angiogenesis in the offspring in rats.

  • 805.
    Zaidi, Ghazala
    et al.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Bhatia, Vijayalakshmi
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Sahoo, Saroj K.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Sarangi, Aditya Narayan
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bharti, Niharika
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Zhang, Li
    Barbara Davis Ctr Childhood Diabet, Dept Immunol, Denver, CO USA..
    Yu, Liping
    Barbara Davis Ctr Childhood Diabet, Dept Immunol, Denver, CO USA..
    Eriksson, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden..
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.
    Bharani, Nisha
    Amrita Inst Med Sci, Dept Endocrinol, Kochi, Kerala, India..
    Yachha, Surendra Kumar
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Paediat Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bhansali, Anil
    Postgrad Inst Med Educ & Res, Dept Endocrinol, Chandigarh, India..
    Sachan, Alok
    Sri Venkateshwara Inst Med Sci, Dept Endocrinol, Tirupati, India..
    Jain, Vandana
    All India Inst Med Sci, Dept Paediat, New Delhi, India..
    Shah, Nalini
    King Edward Mem Hosp, Seth GS Med Coll, Dept Endocrinol, Bombay, Maharashtra, India..
    Aggarwal, Rakesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Aggarwal, Amita
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Clin Immunol, Lucknow, Uttar Pradesh, India..
    Srinivasan, Muthuswamy
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Med Sci, Lucknow, Uttar Pradesh, India..
    Agarwal, Sarita
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Med Sci, Lucknow, Uttar Pradesh, India..
    Bhatia, Eesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study2017In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 5, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Objective: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design: Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2-19) years. Methods: Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results: Patients varied widely in their age of presentation [3.5 (0.1-17) years] and number of clinical manifestations [5 (2-11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3-23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-a and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions: Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

  • 806.
    Zanchi, Davide
    et al.
    Univ Basel Hosp, Dept Psychiat, CH-4012 Basel, Switzerland..
    Meyer-Gerspach, Anne Christin
    Univ Hosp, Dept Biomed, CH-4031 Basel, Switzerland..
    Suenderhauf, Claudia
    Univ Basel Hosp, Dept Psychiat, CH-4012 Basel, Switzerland..
    Janach, Katharina
    Univ Hosp, Dept Biomed, CH-4031 Basel, Switzerland..
    le Roux, Carel W.
    Univ Coll Dublin, Conway Inst, Diabet Complicat Res Ctr, Dublin, Ireland..
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland.;Affidea CDRC Ctr Diagnost Radiolog Carouge, Carouge, Switzerland.;Univ Hosp Freiburg, Dept Neuroradiol, Freiburg, Germany.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland..
    Drewe, Jurgen
    St Clara Hosp, Dept Res, Basel, Switzerland..
    Beglinger, Christoph
    St Clara Hosp, Dept Res, Basel, Switzerland..
    Wlnerhanssen, Bettina K.
    Univ Hosp, Dept Biomed, CH-4031 Basel, Switzerland.;St Clara Hosp, Dept Res, Basel, Switzerland..
    Borgwardt, Stefan
    Univ Basel Hosp, Dept Psychiat, CH-4012 Basel, Switzerland..
    Differential effects of L-tryptophan and L-leucine administration on brain resting state functional networks and plasma hormone levels2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 35727Article in journal (Refereed)
    Abstract [en]

    Depending on their protein content, single meals can rapidly influence the uptake of amino acids into the brain and thereby modify brain functions. The current study investigates the effects of two different amino acids on the human gut-brain system, using a multimodal approach, integrating physiological and neuroimaging data. In a randomized, placebo-controlled trial, L-tryptophan, L-leucine, glucose and water were administered directly into the gut of 20 healthy subjects. Functional MRI (fMRI) in a resting state paradigm (RS), combined with the assessment of insulin and glucose blood concentration, was performed before and after treatment. Independent component analysis with dual regression technique was applied to RS-fMRI data. Results were corrected for multiple comparisons. In comparison to glucose and water, L-tryptophan consistently modifies the connectivity of the cingulate cortex in the default mode network, of the insula in the saliency network and of the sensory cortex in the somatosensory network. L-leucine has lesser effects on these functional networks. L-tryptophan and L-leucine also modified plasma insulin concentration. Finally, significant correlations were found between brain modifications after L-tryptophan administration and insulin plasma levels. This study shows that acute L-tryptophan and L-leucine intake directly influence the brain networks underpinning the food-reward system and appetite regulation.

  • 807.
    Zang, Guangxiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Activated pancreatic stellate cells can impair pancreatic islet function in mice2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 169-180Article in journal (Refereed)
    Abstract [en]

    Background. Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets. Methods. Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets. Results. PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets cocultured with PSCs for 24-48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days. Conclusion. Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.

  • 808.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Med Prod Agcy, Uppsala, Sweden..
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Comparison between indexes of insulin resistance for risk prediction of cardiovascular diseases or development of diabetes2015In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 110, no 2, p. 183-192Article in journal (Refereed)
    Abstract [en]

    Aim: The predictive effect of various insulin resistance indexes for risk of cardiovascular diseases (CVD) or type 2 diabetes (T2DM) is still unclear. Methods: One thousand and forty-nine 71-years-old male subjects from the Swedish ULSAM study, mean follow-up 9 years. All subjects performed the euglycemic insulin clamp for M/I [glucose disposal/mean insulin], and 75-g oral glucose tolerance test for Ceder-IR: 1/glucose uptake rate/[mean glucose x log mean insulin]; Matsuda-IR: 1/10,000/square root [glucose0 x insulin0 x glucose120 x insulin120]; Belfiore-IR: 1/([glucose0 + glucose120]/normal mean glucose x [insulin0 + insulin120]/normal mean insulin)+1); and HOMA-IR: [glucose0 x insulin0]/22.5. Results: Bland-Altman plots showed best agreement between M/I versus Belfiore-IR and Ceder-IR with mean difference near zero, -0.21 to -0.46, while -0.68 to -0.77 for the other indexes. ISI-Ceder was the strongest predictor for incident nonfatal/fatal ischemic heart disease (CHD) or CVD at Cox regression in all subjects, and for incident T2DM at logistic regression in 1024 subjects with no baseline T2DM, with significantly higher hazard ratios or odds ratios than with all other indexes, also with best model fit, after adjusting for clinical characteristics and the traditional cardiovascular risk factors, including metabolic syndrome for CVD risk. Conclusion: Ceder-IR performed strongest as independent predictor for incidences of CHD/CVD and T2DM.

  • 809.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eliasson, Björn
    Eeg-Olofsson, Katarina
    Svensson, Ann-Marie
    Gudbjörnsdottir, Soffia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    A new model for 5-year risk of cardiovascular disease in type 2 diabetes, from the Swedish National Diabetes Register (NDR)2011In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 93, no 2, p. 276-284Article in journal (Refereed)
    Abstract [en]

    AIM:

    We assessed the association between risk factors and cardiovascular disease (CVD) in an observational study of type 2 diabetes patients from the Swedish National Diabetes Register.

    METHODS:

    A derivation sample of 24,288 patients, aged 30-74 years, 15.3% with previous CVD, baseline 2002, 2488 CVD events when followed for 5 years until 2007. A separate validation data set of 4906 patients, baseline 2003, 522 CVD events when followed for 4 years.

    RESULTS:

    Adjusted hazard ratios at Cox regression for fatal/nonfatal CVD were: onset-age 1.59, diabetes duration 1.55, total-cholesterol-to-HDL-cholesterol ratio 1.20, HbA1c 1.12, systolic BP 1.09, BMI 1.07 (1 SD increase in natural log continuous variables); males 1.41, smoker 1.35, microalbuminuria 1.27, macroalbuminuria 1.53, atrial fibrillation 1.50, previous CVD 1.98 (all p<0.001 except BMI p=0.0018). All 12 variables were used to elaborate an equation for 5-year CVD risk in the derivation dataset: mean 5-year risk 11.9±8.4%. Calibration in the validation dataset was adequate: ratio predicted 4-year risk/observed rate 0.97. Discrimination was sufficient: C statistic 0.72, sensitivity 51% and specificity 78% for top quartile.

    CONCLUSION:

    This CVD risk model from a large observational study of patients in routine care showed adequate calibration and discrimination, and can be useful for clinical practice.

  • 810.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gudbjornsdottir, S.
    Eliasson, B.
    Eeg-Olofsson, K.
    Svensson, A. -M
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Risk factors for atrial fibrillation in type 2 diabetes: Report from the Swedish National Diabetes Register: NDR2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S137-S138Article in journal (Other academic)
  • 811.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Eliasson, Bjorn
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Eeg-Olofsson, Katarina
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Svensson, Ann-Marie
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Electrical atrial vulnerability and renal complications in type 2 diabetes. Reply to Montaigne D, Coisne A, Sosner P et al [letter]2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 4, p. 863-864Article in journal (Other academic)
  • 812.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Dept Med, Sahlgrenska Univ Hosp, Gothenburg, Sweden..
    Eliasson, Bjorn
    Univ Gothenburg, Dept Med, Sahlgrenska Univ Hosp, Gothenburg, Sweden..
    Eeg-Olofsson, Katarina
    Univ Gothenburg, Dept Med, Sahlgrenska Univ Hosp, Gothenburg, Sweden..
    Svensson, Ann-Marie
    Univ Gothenburg, Dept Med, Sahlgrenska Univ Hosp, Gothenburg, Sweden..
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Risk factors for atrial fibrillation in type 2 diabetes: report from the Swedish National Diabetes Register (NDR)2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 10, p. 2259-2268Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Atrial fibrillation (AF) is more frequent in patients with diabetes than in the general population. However, characteristics contributing to AF risk in diabetes remain speculative. Methods Observational study of 83,162 patients with type 2 diabetes, aged 30-79 years, with no baseline AF, 17% had history of cardiovascular disease (CVD) and 3.3% history of congestive heart failure (CHF), followed up for development of AF during mean 6.8 years from 2005-2007 to 2012. A subgroup of 67,780 patients without history of CVD or CHF was also analysed. Results Using Cox regression, cardiovascular risk factors associated with risk for AF were updated mean BMI (HR 1.31 per 5 kg/m(2)) or obesity (HR 1.51), updated mean systolic BP (SBP; HR 1.13 per 10 mmHg) or hypertension (HR 1.71), and cumulative microalbuminuria (HR 1.21), p < 0.001 for all analyses. Male sex, increasing age and height were also significant predictors. HRs were 1.76 for a history of CHF and 2.56 for in-study CHF, while 1.32 for history of CVD and 1.38 for in-study CHD (p < 0.001). Among patients without history of CVD or CHF, significant predictors were similarly BMI, SBP, and cumulative microalbuminuria and CHF. The risk of AF differed in the subgroups achieving or not achieving a target BP < 140/85 mmHg. The HRs for AF were (per 10 mmHg increase) 0.88 and 1.24, respectively. Conclusions/interpretation The modifiable risk factors high BP, high BMI and albuminuria were strongly associated with AF in type 2 diabetes. CVD, advancing age and height were also associated with AF in type 2 diabetes.

  • 813.
    Zhou, Yunting
    et al.
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Li, Wei
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Zhou, Junming
    Nanjing Univ, Jingling Hosp, Dept Outpatient, Army Engn Univ, Nanjing, Jiangsu, Peoples R China.
    Chen, Juan
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Wang, Xiaohang
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Cai, Min
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Li, Fengfei
    Nanjing Med Univ, Nanjing Hosp 1, Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Xu, Wei
    Kings Coll London, Sch Life Course Sci, Dept Diabet, Guys Campus, London, England.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sun, Zilin
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Lipotoxicity reduces beta cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules2019In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 380, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background: Islet stellate cells (ISCs) activation is mainly associated with islet fibrosis, which contributes to the progression of type 2 diabetes. However, the molecular mechanism underlying this process is not fully understood.

    Methods: In order to investigate this process the current study examined ectopic fat accumulation in rats with high-fat diet (HFD) induced obesity. Levels of lipotoxicity-induced ISC activation and islet function were assessed via intraperitoneal glucose and insulin tolerance tests, and immunohistochemistry. The expression of lipid metabolism- and ISC activation-related markers was evaluated in cultured ISCs treated with palmitic acid (PA) using quantitative PCR and western blotting. We also overexpressed sterol regulatory element-binding protein (SREBP)-1c in ISCs by lentiviral transduction, and assessed the effects on insulin release in co-cultures with isolated rat islets.

    Results: HFD increased body weight and ectopic fat accumulation in pancreatic islets. Lipotoxicity caused progressive glucose intolerance and insulin resistance, upregulated a-smooth muscle actin, and stimulated the secretion of extracellular matrix. Lipotoxicity reduced the expression of lipid metabolism-related molecules in ISCs treated with PA, especially SREBP-1c. Overexpression of SREBP-1c in ISCs improved islet viability and insulin secretion in co-cultures.

    Conclucions: These results indicate that lipotoxicity-induced ISC activation alters islet function via regulation of lipid metabolism, suggesting that therapeutic strategies targeting activated ISC may be an effective treatment for prevention of ISC activation-associated islet dysfunction.

  • 814.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Latva-Rasku, Aino
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Dept Endocrinol, Turku, Finland.
    Johansson, Lars
    Antaros Med AB, Gothenburg, Sweden.
    Lisovskaja, Vera
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Cecilia
    AstraZeneca, Gothenburg, Sweden.
    Oscarsson, Jan
    AstraZeneca, Gothenburg, Sweden.
    Nuutila, Pirjo
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Dept Endocrinol, Turku, Finland.
    Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients - a description of the DAPACARD study2019In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 1, p. 59-64Article in journal (Refereed)
    Abstract [en]

    Background: Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels.

    Methods: DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET).

    Conclusion: The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.

  • 815.
    Åkerfeldt, Torbjörn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lipcsey, Miklos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gunningberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Swenne, Christine, Leo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Serum leptin is decreased thirty days after surgery2014In: Journal of Diabetes and Metabolism, ISSN 2155-6156, Vol. 5, no 12Article in journal (Refereed)
    Abstract [en]

    Background: Leptin plays an important role for the regulation of food intake, energy expenditure and glucose control. The aim of this study was to study the effect of surgery on circulating levels of human leptin in a human elective surgery model. Methods: A prospective observational study was conducted. Blood sampling was carried out prior to surgery and four and thirty days after elective surgery, respectively. Patients undergoing orthopedic surgery (n=29) and coronary bypass patients (n=21) were included in the study. Serum leptin levels were measured using sandwich ELISA. C-reactive protein (CRP) was analyzed by turbidimetry. Results: Leptin values was significantly decreased thirty days after surgery in both orthopedic (p=0.002) and coronary bypass patients (p=0.003) in comparison with presurgical values. Conclusion: Elective surgery is associated with decreased leptin levels in the late postsurgical phase.

  • 816.
    Åkerström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University.
    Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas2016Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Open this publication in new window or tab >>Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41926-Article in journal (Refereed) 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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-183242 (URN)10.1371/journal.pone.0041926 (DOI)000306950200128 ()
    Available from: 2012-10-25 Created: 2012-10-23 Last updated: 2017-12-07Bibliographically approved
    2. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
    Open this publication in new window or tab >>Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
    Show others...
    2015 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 5, p. 735-744Article in journal (Refereed) 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.

    Keywords
    ATP1A1; CACNA1D; KCNJ5; primary aldosteronism; aldosterone-producing adenoma
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-266639 (URN)10.1530/ERC-15-0321 (DOI)000364022400010 ()26285814 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2015-11-10 Created: 2015-11-10 Last updated: 2017-12-01
    3. Activating mutations in CTNNB1 in aldosterone producing adenomas
    Open this publication in new window or tab >>Activating mutations in CTNNB1 in aldosterone producing adenomas
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 19546Article in journal (Refereed) 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.

    National Category
    Endocrinology and Diabetes Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-277306 (URN)10.1038/srep19546 (DOI)000368736400001 ()26815163 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2017-11-30Bibliographically approved
    4. Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing Adenomas
    Open this publication in new window or tab >>Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing Adenomas
    Show others...
    (English)Manuscript (preprint) (Other academic)
    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. 

    National Category
    Clinical Medicine Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-281039 (URN)
    Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2016-04-21
  • 817.
    Åkerström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Genetic Alterations in Aldosterone Producing Adenomas2014Licentiate thesis, comprehensive summary (Other academic)
    List of papers
    1. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Open this publication in new window or tab >>Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41926-Article in journal (Refereed) 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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-183242 (URN)10.1371/journal.pone.0041926 (DOI)000306950200128 ()
    Available from: 2012-10-25 Created: 2012-10-23 Last updated: 2017-12-07Bibliographically approved
    2. Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
    Open this publication in new window or tab >>Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-218662 (URN)
    Available from: 2014-02-13 Created: 2014-02-13 Last updated: 2015-06-26Bibliographically approved
    3. Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing Adenomas
    Open this publication in new window or tab >>Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing Adenomas
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    ATP1A1, ATP2B3, Aldosterone producing adenomas, Mutation, KCNJ5
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-218659 (URN)
    Available from: 2014-02-13 Created: 2014-02-13 Last updated: 2014-03-11
  • 818.
    Åkerström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Azizan, Elena A B
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Brown, Morris J
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Activating Mutations in CTNNB1 in Aldosterone Producing AdenomasManuscript (preprint) (Other academic)
  • 819.
    Åkerström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Gomez-Sanchez, Celso
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Activating mutations in CTNNB1 in aldosterone producing adenomas2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 19546Article in journal (Refereed)
    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.

  • 820.
    Åkerström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Svedlund, Jessica
    Gomez-Sanchez, Celso
    Nilsson, Mats
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Peyman, Björklund
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing AdenomasManuscript (preprint) (Other academic)
    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. 

  • 821.
    Åkerström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Volpe, Cristina D
    Bäckdahl, Martin
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Zedenius, Jan
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Peyman, Björklund
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing AdenomasManuscript (preprint) (Other academic)
  • 822.
    Åkerström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Willenberg, Holger Sven
    Cupisti, Kenko
    Ip, Julian
    Moser, Ana
    Robinson, Bruce
    Iwen, Alexander K
    Dralle, Henning
    Volpe, Cristina D
    Bäckdahl, Martin
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Walz, Martin K.
    Lehnert, Hendrik
    Sidhu, Stan
    Zedenius, Jan
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Peyman, Björklund
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing AdenomasManuscript (preprint) (Other academic)
  • 823.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Management of functional neuroendocrine tumors of the pancreas2018In: Gland surgery, ISSN 2227-684X, E-ISSN 2227-8575, Vol. 7, no 1, p. 20-27Article, review/survey (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine tumors (pNETs) constitute a heterogenous group of malignancies with varying clinical presentation, tumor biology and prognosis. The incidence of pNETs has steadily increased during the last decades with an estimated incidence 2012 of 4.8/100,000. Recent whole genome sequencing of pNETs has demonstrated mutations in the DNA repair genes MUTYH and point mutations and gene fusions in four main pathways from chromatin remodeling, DNA damage repair, activation of mechanistic target of rapamycin (mTOR) signaling and the telomere maintenance. This new information will be the foundation for new therapies in the near future for malignant pNETs. The functioning pNETs constitute about 30-40% of all pNETs displaying nine different clinical syndromes: insulinoma, Zollinger-Ellison, Verner-Morrison, glucagonoma, somatostatinomas, ectopic adrenocorticotropic hormone (ACTH) and parathyroid hormone related peptide (PTH-rP) syndromes. Single patients might also present carcinoid syndrome. The diagnostic work-up include histopathology with the new WHO 2017 Classification, biomarkers (CgA, NSE), radiology and molecular imaging including CT-scan, magnetic resonance imaging (MRI), ultrasound and PET-scan. A cornerstone in the treatment of pNETs is surgery which is rarely curative but can reduce the clinical symptoms by debulking which also include radiofrequency ablation, embolization of liver metastases. Medical treatment includes chemotherapy and the targeted agents such as everolimus, sunitinib and peptide receptor radiotherapy (PRRT). Somatostatin analogs has for the last decades been the main stay for management for clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy. Long-term management of functioning pNETs need a combination of different procedures, surgery, local ablation, targeted agents and somatostatin analogs. Future therapies might be based on the recent advances in molecular genetics and tumor biology.

  • 824.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Management of neuroendocrine tumors: Current and future therapies2011In: Expert Reviews Endocrinology & Metabolism, ISSN 1744-6651, Vol. 6, no 1, p. 49-62Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) are a genetically diverse group of malignancies that sometimes produce peptides that cause characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning); both types frequently synthesize more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumor progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumor growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilize tumor growth in many patients. Results from the placebo-controlled, double-blind, prospective randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID study) demonstrate that octreotide LAR 30 mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. Sunitinib, a tyrosine kinase inhibitor, is active in pancreatic NETs. In the future, pasireotide, the multireceptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumor cell proliferation. Peptide receptor radiotherapy with 90Yttrium-DOTATOC or 177Lutetium-DOTATE is also a new interesting treatment option for NETs.

  • 825.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Neuroendocrine Tumours2010In: Management of Rare Adult Tumours / [ed] Yazid Belkacémi, René-Olivier Mirimanoff, Mahmut Ozsahin, Paris: Springer , 2010, p. 539-550Chapter in book (Other academic)
  • 826.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Receptor Ligands: Somatostatin analogs2009In: Bioactive Peptides / [ed] John Howl & Sarah Jones, Boca Raton: CRC Press, 2009, p. 169-187Chapter in book (Other academic)
  • 827.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    The Genesis of the Neuroendocrine Tumors Concept: From Oberndorfer to 20182018In: Endocrinology and metabolism clinics of North America (Print), ISSN 0889-8529, E-ISSN 1558-4410, Vol. 47, no 3, p. 711-731Article in journal (Refereed)
    Abstract [en]

    The concept of neuroendocrine tumors (NETs) began in the 1900s with Oberndorfer's description of carcinoid tumors, followed by specific cytotoxic agents and the identification of somatostatin. NETs diagnosis was confirmed by World Health Organization classification. Histopathology included immunohistochemistry with specific antibodies. Imaging was refined with molecular imaging. Somatostatin is the leading agent for controlling clinical symptoms related to hormone production. Increasing interest in these tumors, previously thought rare, led to increased incidence and prevalence. Between 1960 and 1970, the true NET concept was established with the development of radioimmunoassays for peptides and hormones and imaging with computerized tomography.

  • 828.
    Öberg, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Couvelard, Anne
    Hospital Beaujon, Department of Pathology.
    Delle Fave, Gianfranco
    Ospedale Sant’Andrea, Department of Digestive and Liver Disease.
    Gross, David
    Hadassah University Hospital, Department of Endocrinology and Metabolism.
    Grossman, Ashley
    University of Oxford, Churchill Hospital, Oxford Centre for Diabetes, Endocrinology and Metabolism.
    Jensen, Robert T.
    National Institutes of Health, Digestive Diseases Branch.
    Pape, Ulrich-Frank
    Charité University of Berlin, Department of Internal Medicine.
    Perren, Aurel
    niversity Hospital Zurich, Department of Pathology.
    Rindi, Guido
    Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Institute of Anatomic Pathology.
    Ruszniewski, Philippe
    Beaujon Hopital, Department of Gastroenterology.
    Scoazec, Jean-Yves
    Gustave Roussy Institute, Department of Biopathology, Faculty of Medicine Paris Sud.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Wiedenmann, Bertram
    Charité University Medicine, Department of Hepatology and Gastroenterology.
    Ferone, Diego
    University of Genova, IRCCS AOU San Martino IST, DiMI, CEBR.
    ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, p. 201-211Article in journal (Refereed)
    Abstract [en]

    Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtypes of NETs were regarded as biomarkers to follow during diagnosis and treatment: serotonin for small intestinal (SI) NETs, and gastrin and insulin for pancreatic NETs. However, it became evident that a large number of NETs were so-called nonfunctioning tumors without secreting substances that caused hormone-related symptoms. Therefore, it was necessary to develop so-called "general tumor markers." The most important ones so far have been chromogranin A and neuron-specific enolase (NSE). Chromogranin A is the most important general biomarker for most NETs with a sensitivity and specificity somewhere between 60 and 90%. NSE has been a relevant biomarker for patients with high-grade tumors, particularly lung and gastrointestinal tract tumors. Serotonin and the breakdown product urinary 5-hydroxyindoleacetic acid (U-5-HIAA) is still an important marker for diagnosing and follow-up of SI NETs. Recently, 5-HIAA in plasma has been analyzed by highperformance liquid chromatography and fluorometric detection and has shown good agreement with U-5-HIAA anal ysis. In the future, we will see new tests including circulating tumor cells, circulating DNA and mRNA. Recently, a NET test has been developed analyzing gene transcripts in circulating blood. Preliminary data indicate high sensitivity and specificity for NETs. However, its precise role has to be validated in prospective randomized controlled trials which are ongoing right now.

  • 829.
    Öberg, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ferone, Diego
    Kaltsas, Gregory
    Knigge, Ulrich-Peter
    Taal, Babs
    Plöckinger, Ursula
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biotherapy2009In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 90, no 2, p. 209-213Article in journal (Refereed)
  • 830.
    Öberg, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Krenning, Eric
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bodei, Lisa
    Kidd, Mark
    Tesselaar, Margot
    Ambrosini, Valentina
    Baum, Richard P
    Kulke, Matthew
    Pavel, Marianne
    Cwikla, Jaroslaw
    Drozdov, Ignat
    Falconi, Massimo
    Fazio, Nicola
    Frilling, Andrea
    Jensen, Robert
    Koopmans, Klaus
    Korse, Tiny
    Kwekkeboom, Dik
    Maecke, Helmut
    Paganelli, Giovanni
    Salazar, Ramon
    Severi, Stefano
    Strosberg, Jonathan
    Prasad, Vikas
    Scarpa, Aldo
    Grossman, Ashley
    Walenkamp, Annemeik
    Cives, Mauro
    Virgolini, Irene
    Kjaer, Andreas
    Modlin, Irvin M
    A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management2016In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 5, no 5, p. 174-187Article in journal (Refereed)
    Abstract [en]

    The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

  • 831.
    Öberg, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Imaging of Neuroendocrine Tumors2016In: Imaging in Endocrine Disorders / [ed] M Buchfelder, F Guaraldi, E Ghigo, F Guaraldi, A Benso, Basel: S. Karger, 2016, p. 142-151Chapter in book (Refereed)
  • 832.
    Öberg, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Imaging of Neuroendocrine Tumors2016In: Imaging in Endocrine Disorders / [ed] Buchfelder M., Guaraldi F., Basel: Karger , 2016, Vol. 45, p. 142-151Chapter in book (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies with a very variable clinical expression and progression. They present unique properties that are important to consider for radiological and nuclear imaging, such as APUD-characteristics (amine precursor uptake and dearboxylation), as well as the expression of somatostatin receptors. The most common localizations are the lungs, gastrointestinal tract and pancreas. The only curative treatment is surgery, but more than 50% present metastatic disease at the time of diagnosis. The systemic treatment includes chemotherapy and targeted agents, as well as peptide receptor radiotherapy. The diagnosis and follow-up of these tumors necessitate a large number of different imaging methods, such as CT, MRI, US, SRS and PET. Ultrasonography offers the possibility to take guided biopsies from different lesions. Somatostatin receptor scintigraphy was developed in the 1990s and nowadays presents the standard of care for NETs in most countries. The procedure offers a total body examination and a better staging of the disease. However, it has been replaced in most centers by PET/CT with 68Ga-DOTA-somatostatin analogues with a superior spatial resolution and faster imaging (one-stop procedure). Another tracer used for PET/CT is 18FDG, particularly for high-grade tumors. Other more specific tracers are 18F-L-DOPA, 11C-L-DOPA and 11C-5-hydroxytryptophan, which have demonstrated excellent imaging results. The new targeted agents present a challenge in the evaluation procedure of treatment and, therefore, new imaging techniques and an improvement of currently available techniques are mandatory.

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