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Oberg K.,Uppsala University Hospital
Seminars in Oncology | Year: 2010

Pancreatic endocrine tumors have been steadily growing in incidence and prevalence during the last two decades, showing an incidence of 45/1,000,000 population. They represent a heterogeneous group with very varying tumor biology and prognosis. About half of the patients present clinical symptoms and syndromes related to substances released from the tumors (Zollinger-Ellison syndrome, insulinoma, glucagonoma, etc) and the other half are so-called nonfunctioning tumors mainly presenting with symptoms such as obstruction, jaundice, bleeding, and abdominal mass. Ten percent to 15% of the pancreatic endocrine tumors are part of an inherited syndrome such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau (VHL), neurofibromatosis, or tuberousclerosis. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, and glucagon. Moreover, the biochemical diagnosis includes measurement of chromogranins A and B or specific hormones such as gastrin, insulin, glucagon, and vasoactive intestinal polypeptide (VIP) in the circulation. In addition to standard localization procedures, radiology (computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasound [US]), somatostatin receptor scintigraphy, and most recently positron emission tomography with specific isotopes such as 11C-5 hydroxytryptamin (11C-5-HTP), fluorodopa and 68Ga-1,4,7, 10-tetra-azacyclododecane-N,N′,N″,N‴-tetra-acetic acid (DOTA)-octreotate are performed. Surgery is still one of the cornerstones in the management of pancreatic endocrine tumors, but curative surgery is rarely obtained in most cases because of metastatic disease. Debulking and other cytoreductive procedures might facilitate systemic treatment. Cytotoxic drugs, biological agents, such as somatostatin analogs, alpha interferons, mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors are routinely used. Tumor-targeted radioactive treatment is available in many centres in Europe and is effective in patients with tumors that express high content of somatostatin receptors type 2 and 5. In the future, treatment will be based on tumor biology and molecular genetics with the aim of so-called personalized medicine. © 2010 Elsevier Inc. All rights reserved.


Oberg K.E.,Uppsala University Hospital
Clinical Oncology | Year: 2012

Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise 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 tumour 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 tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show 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. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs. © 2011 The Royal College of Radiologists.


Background We aimed to investigate whether the benefits of blood pressure-lowering drugs are proportional to baseline cardiovascular risk, to establish whether absolute risk could be used to inform treatment decisions for blood pressure-lowering therapy, as is recommended for lipid-lowering therapy. Methods This meta-analysis included individual participant data from trials that randomly assigned patients to either blood pressure-lowering drugs or placebo, or to more intensive or less intensive blood pressure-lowering regimens. The primary outcome was total major cardiovascular events, consisting of stroke, heart attack, heart failure, or cardiovascular death. Participants were separated into four categories of baseline 5-year major cardiovascular risk using a risk prediction equation developed from the placebo groups of the included trials (<11%, 11-15%, 15-21%, >21%). Findings 11 trials and 26 randomised groups met the inclusion criteria, and included 67 475 individuals, of whom 51 917 had available data for the calculation of the risk equations. 4167 (8%) had a cardiovascular event during a median of 4·0 years (IQR 3·4-4·4) of follow-up. The mean estimated baseline levels of 5-year cardiovascular risk for each of the four risk groups were 6·0% (SD 2·0), 12·1% (1·5), 17·7% (1·7), and 26·8% (5·4). In each consecutive higher risk group, blood pressure-lowering treatment reduced the risk of cardiovascular events relatively by 18% (95% CI 7-27), 15% (4-25), 13% (2-22), and 15% (5-24), respectively (p=0·30 for trend). However, in absolute terms, treating 1000 patients in each group with blood pressure-lowering treatment for 5 years would prevent 14 (95% CI 8-21), 20 (8-31), 24 (8-40), and 38 (16-61) cardiovascular events, respectively (p=0·04 for trend). Interpretation Lowering blood pressure provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions as baseline risk increases. These results support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure-lowering treatment decisions. Funding None. © 2014 Elsevier Ltd.


Hellstrom P.M.,Uppsala University Hospital
Current Opinion in Gastroenterology | Year: 2013

Purpose of review: The obesity epidemic over the world has called to attention different ways to manage this development. As bariatric surgery today is the only manner by which rapid and sustained weight control can be achieved, new ways of treating obesity are under investigation. This review focuses on today's knowledge on satiety signaling as a means to combat obesity. RECENT FINDINGS: The combined knowledge achieved from obesity surgery with gastric bypass and duodenal switch together with the pharmacological treatment of type 2 diabetes have given us some clues of how to manage obesity. The basis for our understanding is the present research focusing on the gut peptide hormones that are released in response to food intake, and the paucity of satiety signaling seems to prevail in obesity. This means that obese patients experience less activation of higher brain centers in association with a meal and therefore compensate with increased meal size or frequent food intake. SUMMARY: Altered satiety signaling primarily emanating from the gastrointestinal tract seems to lead to the development of obesity and type 2 diabetes. Pharmacological tools that enhance the gut hormone signaling are in focus for the upcoming venues of treatment. Copyright © Lippincott Williams & Wilkins.


Friberg L.,Danderyd Hospital | Skeppholm M.,Danderyd Hospital | Terent A.,Uppsala University Hospital
Journal of the American College of Cardiology | Year: 2015

Background Patients with atrial fibrillation (AF) and ≥1 point on the stroke risk scheme CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) are considered at increased risk for future stroke, but the risk associated with a score of 1 differs markedly between studies. Objectives The goal of this study was to assess AF-related stroke risk among patients with a score of 1 on the CHA2DS2-VASc. Methods We conducted this retrospective study of 140,420 patients with AF in Swedish nationwide health registries on the basis of varying definitions of "stroke events." Results Using a wide "stroke" diagnosis (including hospital discharge diagnoses of ischemic stroke as well as unspecified stroke, transient ischemic attack, and pulmonary embolism) yielded a 44% higher annual risk than if only ischemic strokes were counted. Including stroke events in conjunction with the index hospitalization for AF doubled the long-term risk beyond the first 4 weeks. For women, annual stroke rates varied between 0.1% and 0.2% depending on which event definition was used; for men, the corresponding rates were 0.5% and 0.7%. Conclusions The risk of ischemic stroke in patients with AF and a CHA2DS2-VASc score of 1 seems to be lower than previously reported. © 2015 American College of Cardiology Foundation.


Andersen K.,Uppsala University Hospital
Circulation. Heart failure | Year: 2014

BACKGROUND: The nature of the association between levels of physical activity and risk of heart failure is little known. We investigated nonlinear associations of total and leisure time physical activity with risk of heart failure.METHODS AND RESULTS: In 1997, 39 805 persons without heart failure completed a questionnaire of lifestyle factors and medical history. We used Cox regression models to investigate total (adjusting for education and previous myocardial infarction) and direct (multivariable-adjusted) effects of self-reported total and leisure time physical activity on risk of heart failure of any cause and heart failure of nonischemic origin. Heart failure diagnoses were obtained until December 31, 2010. Higher leisure time physical activity was associated with lower risk of heart failure of any cause; hazard ratio of the total effect of leisure time physical activity was for fifth versus first quintile 0.54; 95% confidence interval was 0.44 to 0.66. The direct effect was similar. High total daily physical activity level was associated with lower risk of heart failure, although the effect was less pronounced than for leisure time physical activity (total effect hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; fifth versus first quintile). A similar direct effect observed.CONCLUSIONS: Leisure time physical activity was inversely related to risk of developing heart failure in a dose-response fashion. This was reflected in a similar but less pronounced association of total physical activity with risk of heart failure. Only part of the effects appeared to be mediated by traditional risk factors. © 2014 American Heart Association, Inc.


Waldenstrom A.,Umeå University | Ronquist G.,Uppsala University Hospital
Circulation Research | Year: 2014

Exosomes are nanovesicles released from cells through exocytosis and are known to be mediators of proximal as well as distant cell-to-cell signaling. They are surrounded by a classical bilayered membrane with an exceptionally high cholesterol/phospholipid ratio. Exosomes were first described in 1977, then named prostasomes, and in 1987 the name exosome was coined. Exosomes contain surface proteins, some of which can act as labels in order to find their target cells. Exosomes also contain messages in the form of proteins and nucleic acids (RNA and DNA) that are transferable to target cells. Little is known and written about cardiac exosomes, although Gupta and Knowlton described exosomes containing HSP60 in 2007. It is now known that exosomes from cardiomyocytes can transfect other cells and that the metabolic milieu of the parental cell decides the quality of exosomes released such that they induce differential gene expression in transfected cells. Future clinical use of exosomes in diagnosis, monitoring disease progress, and treatment is promising. © 2014 American Heart Association, Inc.


Oberg K.E.,Uppsala University Hospital
Annals of Oncology | Year: 2010

Gastrointestinal neuroendocrine tumors (GI-NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); 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 GI-NETs is increasing. 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 medical management with the aim of relieving symptoms and suppressing tumor growth and spread. Somatostatin analogues can improve the symptoms of carcinoid syndrome and stabilize tumor growth (PROMID study) in many patients. An antiproliferative effect can also be achieved with the m-TOR inhibitor everolimus, alone or in combination with octreotide LAR. The vascular endothelial growth factor inhibitor sunitinib has demonstrated antitumor effects in pancreatic NETs. Pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome. Peptide receptor radiotherapy with yttrium 90-DOTATOC or lutetium 177-DOTATE are also new interesting treatment options for NETs. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Alm A.,Uppsala University Hospital
Clinical Ophthalmology | Year: 2014

Prostaglandins are approved by the European Glaucoma Society guidelines as first-line treatment for glaucoma. This review focuses on latanoprost, an ester prodrug of prostaglandin (PG) F2α, which was the first of the currently available topical PGF2α analogs to be launched for glaucoma or ocular hypertension and which still accounts for the majority of prescriptions. It is better absorbed than the parent compound through the cornea, and peak concentration of the active drug is in the aqueous humor 1–2 hours after topical dosing (15–30 ng/mL). Metabolism occurs mainly in the liver. Latanoprost (0.005%) has been very well studied in clinical trials and meta-analyses that show it to be generally as effective as the other PG analogs (bimatoprost, travoprost, and tafluprost) and more effective than timolol, dorzolamide, and brimonidine. Latanoprost has good short- and long-term safety and tolerability profiles. In common with other prostaglandins, it lacks systemic effects, but can cause ocular adverse events such as conjunctival hyperemia, pigmentation of the iris, periocular skin or eyelashes, hypertrichosis, and ocular surface effects or irritation. Latanoprost is significantly better tolerated than either bimatoprost or travoprost. Patients treated with latanoprost have better compliance and persist with therapy longer than those that are given other drugs. An improved formulation of latanoprost without the preservative benzalkonium chloride has recently been developed. It is as effective as conventional latanoprost, has a lower incidence of hyperemia, and can be stored at room temperature. In conclusion, latanoprost has the best efficacy–tolerability ratio of the PG analogs available for glaucoma treatment, and has good compliance and persistence. These factors should be improved further by the recent development of preservative-free latanoprost. © 2014 Alm.


Oberg K.,Uppsala University Hospital
Seminars in Oncology | Year: 2013

Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs. © 2013 Elsevier Inc.

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