Publications by authors named "Peter Iversen"

148 Publications

Practical kidney dosimetry in peptide receptor radionuclide therapy using [Lu]Lu-DOTATOC and [Lu]Lu-DOTATATE with focus on uncertainty estimates.

EJNMMI Phys 2021 Nov 13;8(1):78. Epub 2021 Nov 13.

Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, 8200, Aarhus N, Denmark.

Background: Kidney dosimetry after peptide receptor radionuclide therapy using Lu-labelled somatostatin analogues is a procedure with multiple steps. We present the SPECT/CT-based implementation at Aarhus University Hospital and evaluate the uncertainty of the various steps in order to estimate the total uncertainty and to identify the major sources of uncertainty. Absorbed dose data from 115 treatment fractions are reported.

Results: The total absorbed dose with uncertainty is presented for 59 treatments with [Lu]Lu-DOTATOC and 56 treatments with [Lu]Lu-DOTATATE. For [Lu]Lu-DOTATOC the mean and median specific absorbed dose (dose per injected activity) is 0.37 Gy/GBq and 0.38 Gy/GBq, respectively, while for [Lu]Lu-DOTATATE the median and mean are 0.47 Gy/GBq and 0.46 Gy/GBq, respectively. The uncertainty of the procedure is estimated to be about 13% for a single treatment fraction, where the absorbed dose calculation is based on three SPECT/CT scans 1, 4 and 7 days post-injection, while it increases to about 19% if only a single SPECT/CT scan is performed 1 day post-injection.

Conclusions: The specific absorbed dose values obtained with the described procedure are comparable to those from other treatment sites for both [Lu]Lu-DOTATOC and [Lu]Lu-DOTATATE, but towards the lower end of the range of reported values. The estimated uncertainty is also comparable to that from other reports and judged acceptable for clinical and research use, thus proving the kidney dosimetry procedure a useful tool. The greatest reduction in uncertainty can be obtained by improved activity determination, partial volume correction and additional SPECT/CT scans.
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http://dx.doi.org/10.1186/s40658-021-00422-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590641PMC
November 2021

A novel read methodology to evaluate the optimal dose of Ga-satoreotide trizoxetan as a PET imaging agent in patients with gastroenteropancreatic neuroendocrine tumours: a phase II clinical trial.

EJNMMI Res 2021 Sep 6;11(1):84. Epub 2021 Sep 6.

Ipsen Bioscience, Cambridge, MA, USA.

Background: Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist exhibiting higher tumour-to-background ratios and sensitivity compared to Ga-DOTATOC. This randomised, 2 × 3 factorial, phase II study aimed to confirm the optimal peptide mass and radioactivity ranges for Ga-satoreotide trizoxetan, using binary visual reading. To that end, 24 patients with metastatic gastroenteropancreatic neuroendocrine tumours received 5-20 µg of Ga-satoreotide trizoxetan on day 1 of the study and 30-45 µg on day 16-22, with one of three gallium-68  radioactivity ranges (40-80, 100-140, or 160-200 MBq) per visit. Two Ga-satoreotide trizoxetan PET/CT scans were acquired from each patient post-injection, and were scored by experienced independent blinded readers using a binary system (0 for non-optimal image quality and 1 for optimal image quality). For each patient pair of Ga-satoreotide trizoxetan scans, one or both images could score 1.

Results: Total image quality score for Ga-satoreotide trizoxetan PET scans was lower in the 40-80 MBq radioactivity range (56.3%) compared to 100-140 MBq (90.6%) and 160-200 MBq (81.3%). Both qualitative and semi-quantitative analysis showed that peptide mass (5-20 or 30-45 µg) did not influence Ga-satoreotide trizoxetan imaging. There was only one reading where readers diverged on scoring; one reader preferred one image because of higher lesion conspicuity, and the other reader preferred the alternative image because of the ability to identify more lesions.

Conclusions: Binary visual reading, which was associated with a low inter-reader variability, has further supported that the optimal administered radioactivity of Ga-satoreotide trizoxetan was 100-200 MBq with a peptide mass up to 50 µg. Trial registration ClinicalTrials.gov, NCT03220217. Registered 18 July 2017, https://clinicaltrials.gov/ct2/show/NCT03220217.
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http://dx.doi.org/10.1186/s13550-021-00819-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421477PMC
September 2021

C-11 methionine positron emission tomography scans improve the preoperative localization of pathologic parathyroid glands in primary hyperparathyroidism.

Scand J Surg 2021 Aug 16:14574969211036837. Epub 2021 Aug 16.

Department of Otorhinolaryngology, Aarhus university Hospital, Aarhus N, Denmark.

Background And Aims: Preoperative localization of pathologic parathyroid glands is essential in the preparation of a parathyroidectomy. We evaluated the use of a C-11 methionine positron emission tomography/computed tomography scan in a 7-year period in selected patients with primary hyperparathyroidism. The indications to perform a C-11 methionine positron emission tomography/computed tomography were either persistent primary hyperparathyroidism after parathyroidectomy or inconclusive preoperative localization on ultrasound and sestaMIBI.

Materials And Methods: A group of 36 patients was referred for a C-11 methionine positron emission tomography/computed tomography. Biochemical data, pathology, and results of sestaMIBI were collected retrospectively. The primary hyperparathyroidism patients were divided into two groups. In group 1 ( = 17), the C-11 methionine positron emission tomography/computed tomography was performed before parathyroidectomy. In group 2 ( = 19), the C-11 methionine positron emission tomography/computed tomography was performed after unsuccessful parathyroidectomy and before a reoperation.

Results: Overall, in 30 of the 36 patients (83%), C-11 methionine positron emission tomography/computed tomography identified a true-positive pathologic parathyroid gland confirmed by an experienced pathologist, consistent with a positive predictive value of 91%. In group 1, 94% of the patients ( = 16) had pathologic parathyroid tissue identified by C-11 methionine positron emission tomography/computed tomography. This resulted in a clinical benefit in 13 patients (76%). In group 2, the benefit was slightly lower, as 74% of the patients ( = 14) had a true-positive C-11 methionine positron emission tomography/computed tomography scan resulting in a clinical benefit in nine patients (47%).

Conclusion: In two selected groups of patients planned for an initial operation or reoperation of primary hyperparathyroidism and inconclusive conventional imaging, we found C-11 methionine positron emission tomography/computed tomography to give parathyroid surgeons a clinical benefit in the majority of cases, electing the patients for unilateral surgery.
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http://dx.doi.org/10.1177/14574969211036837DOI Listing
August 2021

A randomised, factorial phase II study to determine the optimal dosing regimen for Ga-satoreotide trizoxetan as an imaging agent in patients with gastroenteropancreatic neuroendocrine tumours.

J Nucl Med 2021 Jul 2. Epub 2021 Jul 2.

Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, United States.

Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumour (NET) detection and localisation. However, the optimal peptide mass and radioactivity ranges for Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomised, 2×3 factorial, multicentre, phase II study. Patients received Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on day 16-22, at one of three gallium-68 radioactivity ranges (40-80, 100-140, or 160-200 MBq). Whole-body PET/CT imaging was performed 50-70 minutes after each injection. The primary endpoint was the detection rate of NET lesions imaged by Ga-satoreotide trizoxetan relative to contrast-enhanced CT (CECT) (for each of the six peptide mass/radioactivity range combinations). Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by Ga-satoreotide trizoxetan PET/CT or PET only was at least twice as high as the number of lesions detected by CECT across the six studied peptide mass dose/radioactivity range combinations. There were no differences between the two peptide mass ranges and between the three radioactivity ranges in the number of identified lesions. However, a trend towards a lower relative lesion count was noted in the liver for the 40-80 MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by Ga-satoreotide trizoxetan. Median diagnostic sensitivity of Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. A radioactivity of 100-200 MBq with a peptide mass up to 50 μg were confirmed as the optimal dosing regimen for Ga-satoreotide trizoxetan to be used in future phase III studies.
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http://dx.doi.org/10.2967/jnumed.121.261936DOI Listing
July 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

What is the risk of prostate cancer mortality following negative systematic TRUS-guided biopsies? A systematic review.

BMJ Open 2020 12 18;10(12):e040965. Epub 2020 Dec 18.

Copenhagen Prostate Cancer Center, Urological Department, Rigshospitalet, Copenhagen, Denmark.

Objective: To investigate the risk of prostate cancer-specific mortality (PCSM) following initial negative systematic transrectal ultrasound-guided (TRUS) prostate biopsies.

Design: Systematic review.

Data Sources: PubMed and Embase were searched using a string combination with keywords/Medical Subject Headings terms and free text in the search builder. Date of search was 13 April 2020.

Study Selection: Studies addressing PCSM following initial negative TRUS biopsies. Randomised controlled trials and population-based studies including men with initial negative TRUS biopsies reported in English from 1990 until present were included.

Data Extraction: Data extraction was done using a predefined form by two authors independently and compared with confirm data; risk of bias was assessed using the Newcastle-Ottawa Scale for cohort studies when applicable.

Results: Four eligible studies were identified. Outcomes were reported differently in the studies as both cumulative incidence and Kaplan-Meier estimates have been used. Regardless of the study differences, all studies reported low estimated incidence of PCSM of 1.8%-5.2% in men with negative TRUS biopsies during the following 10-20 years. Main limitation in all studies was limited follow-up.

Conclusion: Only a few studies have investigated the risk of PCSM following initial negative biopsies and all studies included patients before the era of MRI of the prostate. However, the studies point to the fact that the risk of PCSM is low following initial negative TRUS biopsies, and that the level of prostate-specific antigen before biopsies holds prognostic information. This may be considered when advising patients about the need for further diagnostic evaluation.

Prospero Registration Number: CRD42019134548.
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http://dx.doi.org/10.1136/bmjopen-2020-040965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751212PMC
December 2020

Extravasation of [Lu]Lu-DOTATOC: case report and discussion.

EJNMMI Res 2020 Jun 23;10(1):68. Epub 2020 Jun 23.

Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, 8200, Aarhus N, Denmark.

Background: In the case of extravasation of radioactive drugs used in peptide-receptor radionuclide therapy of neuroendocrine tumors, or in radionuclide therapy in general, rapid action is important to reduce or avoid complications. The literature on extravasation of drugs for radionuclide therapy is sparse. Based on the present case, we discuss handling and consequences of extravasation. Further, we demonstrate that dosimetry can aid in judging if the treatment of neuroendocrine tumors is satisfactory even after extravasation.

Case Presentation: A case of extravasation of [Lu]Lu-DOTATOC with a treatment strategy involving exercise and elevation of the affected arm and application of a compression bandage and heating is reported. Redistribution of the drug is verified and quantified by whole-body imaging and quantitative SPECT/CT and measurements of the dose rate at contact with the injection site. [Lu]Lu-DOTATOC was redistributed to tumors and organs within 1 day. The patient did not report any discomfort during or after hospitalization, and no side effects related to extravasation were observed. Quantitative SPECT/CT scans at the subsequent treatment cycle of the same patient were analyzed for a comparison between the treatments. Dosimetry showed the treatments were similar with respect to the kidney and tumor absorbed doses. The radiation dose to the epidermal basal layer near the injection site was estimated and found to be consistent with the lack of side effects.

Conclusions: The treatment of extravasation was successful, and the redistribution of the drug can be easily verified through measurement of the dose rate at contact with the skin. From the results of dosimetry, it was assessed that no change of the treatment course was necessary to compensate for a possibly incomplete treatment as a result of the extravasation.
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http://dx.doi.org/10.1186/s13550-020-00658-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311613PMC
June 2020

68Ga-Prostate-Specific Membrane Antigen Uptake in a Pancreatic Neuroendocrine Tumor.

Clin Nucl Med 2020 May;45(5):379-382

From the Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark.

We present a 60-year-old man with known prostate cancer treated with robot-assisted radical prostatectomy. Prostate-specific antigen levels did not decline accordingly, and a second Ga-PSMA PET/CT demonstrated a new focus with high Ga-PSMA uptake in the pancreatic tail. A subsequent CT scan did not display the lesion as a typical pancreatic tumor, and a spleen scintigraphy was also negative excluding an ectopic intrapancreatic accessory spleen. Ga-DOTATOC PET/CT showed uptake in the same area of the pancreatic tail consistent with a neuroendocrine tumor. This case illustrates that neuroendocrine tumors can be important pitfalls in Ga-PSMA PET/CT performed in prostate cancer patients.
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http://dx.doi.org/10.1097/RLU.0000000000002997DOI Listing
May 2020

Characteristics of finasteride users in comparison with nonusers: A Nordic nationwide study based on individual-level data from Denmark, Finland, and Sweden.

Pharmacoepidemiol Drug Saf 2020 04 11;29(4):453-460. Epub 2020 Feb 11.

National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

Purpose: Published epidemiological studies on the association between finasteride use and the risk of male breast cancer have been inconclusive due to methodological limitations including a few male breast cancer cases included. Determinants of male breast cancer have been studied, but it remains unexplored whether these are also related to finasteride use and thereby constitute potential confounders. This study aimed to assess whether there are differences between finasteride users and nonusers with regard to numerous potential confounders.

Methods: In total, 246 508 finasteride users (≥35 years) were identified in the prescription registries of Denmark (1995-2014), Finland (1997-2013), and Sweden (2005-2014). An equal number of nonusers were sampled. The directed acyclic graph (DAG) methodology was used to identify potential confounders for the association between finasteride and male breast cancer. A logistic regression model compared finasteride users and nonusers with regard to potential confounders that were measurable in registries and population surveys.

Results: Finasteride users had higher odds of testicular abnormalities (odds ratio [OR] 1.40; 95% confidence interval [CI] 1.36-1.44), obesity (1.31; 1.23-1.39), exogenous testosterone (1.61; 1.48-1.74), radiation exposure (1.22; 1.18-1.27), and diabetes (1.07; 1.04-1.10) and lower odds of occupational exposure in perfume industry or in high temperature environments (0.93; 0.87-0.99), living alone (0.89; 0.88-0.91), living in urban/suburban areas (0.97; 0.95-0.99), and physical inactivity (0.70; 0.50-0.99) compared to nonusers.

Conclusions: Systematic differences between finasteride users and nonusers were found emphasizing the importance of confounder adjustment of associations between finasteride and male breast cancer.
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http://dx.doi.org/10.1002/pds.4947DOI Listing
April 2020

Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial.

Eur Urol Oncol 2019 11 3;2(6):677-684. Epub 2018 Dec 3.

OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

Background: In the PREVAIL study, enzalutamide provided significant improvements versus placebo in clinical outcomes in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC). The association of post-treatment prostate-specific antigen (PSA) decline with clinical outcomes may provide important prognostic information.

Objective: To evaluate associations between the magnitude of PSA decline from baseline to month 3 and clinical outcomes among enzalutamide recipients.

Design, Setting, And Participants: This was a post hoc retrospective analysis of PREVAIL, an international, randomized, double-blind, placebo-controlled phase 3 study. Men with mCRPC and no prior chemotherapy from the enzalutamide arm were included (n=872). Patients were grouped by confirmed maximal PSA decline from baseline to month 3 of treatment (n=795 evaluable).

Outcome Measurements And Statistical Analysis: Primary outcomes were overall survival and radiographic progression-free survival. Secondary outcomes included PSA progression-free survival, radiographic response, and degradation of Functional Assessment of Cancer Therapy-Prostate score, which were estimated using the Kaplan-Meier method.

Results And Limitations: Following 3mo of enzalutamide treatment, 88% (701/795), 80% (639/795), and 39% (307/795) of patients had postbaseline confirmed maximal PSA declines of ≥30%, ≥50%, and ≥90%, respectively, whereas 12% (94/795) had no confirmed maximal PSA decline or a decline of <30%. Greater degrees of PSA decline within the first 3mo of enzalutamide treatment were increasingly associated with longer overall survival, time to PSA and radiographic progression, higher objective soft-tissue responses, and longer time to quality-of-life deterioration than no PSA decline or declines of <30% from baseline. PSA flares (rise followed by fall) after enzalutamide treatment were rare (<1%).

Conclusions: The magnitude of PSA decline after 3mo of enzalutamide therapy was strongly associated with better clinical and patient-reported outcomes. This updated prognostic information is of clinical value to this patient population and their health care providers.

Patient Summary: We report that decreases in PSA levels are closely linked to better health and survival after 3mo of enzalutamide treatment in men with metastatic prostate cancer. The PREVAIL trial is registered at clinicaltrials.gov as NCT01212991.
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http://dx.doi.org/10.1016/j.euo.2018.11.005DOI Listing
November 2019

Quantitative estimation of extravascular lung water volume and preload by dynamic 15O-water positron emission tomography.

Eur Heart J Cardiovasc Imaging 2019 Oct;20(10):1120-1128

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus DK, Denmark.

Aims: Left ventricular filling pressure (preload) can be assessed by pulmonary capillary wedge pressure (PCWP) during pulmonary arterial catheterization (PAC). An emerging method [pulse indexed contour cardiac output (PICCO)] can estimate preload by global end-diastolic volume (GEDV) and congestion as extravascular lung water (EVLW) content. However, no reliable quantitative non-invasive methods are available. Hence, in a porcine model of pulmonary congestion, we evaluated EVLW and GEDV by positron emission tomography (PET). The method was applied in 35 heart failure (HF) patients and 9 healthy volunteers.

Methods And Results: Eight pigs were studied. Pulmonary congestion was induced by a combination of beta-blockers, angiotensin-2 agonist and saline infusion. PAC, PICCO, computerized tomography, and 15O-H2O-PET were performed. EVLW increased from 521 ± 76 to 973 ± 325 mL (P < 0.001) and GEDV from 1068 ± 170 to 1254 ± 85 mL (P < 0.001). 15O-H2O-PET measures of EVLW increased from 566 ± 151 to 797 ± 231 mL (P < 0.001) and GEDV from 364 ± 60 to 524 ± 92 mL (P < 0.001). Both EVLW and GEDV measured with PICCO and 15O-H2O-PET correlated (r2 = 0.40, P < 0.001; r2 = 0.40, P < 0.001, respectively). EVLW correlated with Hounsfield units (HU; PICCO: r2 = 0.36, P < 0.001, PET: r2 = 0.46, P < 0.001) and GEDV with PCWP (PICCO: r2 = 0.20, P = 0.01, PET: r2 = 0.29, P = 0.002). In human subjects, measurements were indexed (I) for body surface area. Neither EVLWI nor HU differed between chronic stable HF patients and healthy volunteers (P = 0.11, P = 0.29) whereas GEDVI was increased in HF patients (336 ± 66 mL/m2 vs. 276 ± 44 mL/m2, P = 0.01).

Conclusion: The present study demonstrates that 15O-H2O-PET can assess pulmonary congestion and preload quantitatively. Hence, prognostic information from 15O-H2O-PET examinations should be evaluated in clinical trials.
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http://dx.doi.org/10.1093/ehjci/jez038DOI Listing
October 2019

Finasteride Use and Risk of Male Breast Cancer: A Case-Control Study Using Individual-Level Registry Data from Denmark, Finland, and Sweden.

Cancer Epidemiol Biomarkers Prev 2019 05 6;28(5):980-986. Epub 2019 Mar 6.

National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

Background: In case reports, concerns have been raised as to whether finasteride use increases the risk of male breast cancer. Previous epidemiologic evidence on the potential link is conflicting. This study aimed to assess whether an association between finasteride use and male breast cancer exists after accounting for potential confounders.

Methods: The source population consisted of all men (≥35 years) from Denmark (1995-2014), Finland (1997-2013), and Sweden (2005-2014). Cases with incident male breast cancer were identified in the cancer registries and matched with 50 density-sampled, age, and country-matched male population controls per case. Exposure information on finasteride use was derived from the prescription registries. Potential confounders were identified using the directed acyclic graph methodology and measured by use of information from nation-wide registries.

Results: The study population comprised 1,005 male breast cancer cases and 43,058 controls. Confounder-adjusted odds of finasteride exposure were not statistically significantly increased [OR, 1.09; 95% confidence interval (CI), 0.77-1.54] in breast cancer cases relative to controls. There was no evidence of a dose-response relationship, as the group with greatest exposure to finasteride was associated with lowest OR of male breast cancer [OR, 0.72 (95% CI, 0.40-1.30)]. Sensitivity analyses did not reveal marked changes in results with different exposure definitions or for specific subgroups.

Conclusions: Results from this study provided no evidence that finasteride use was associated with male breast cancer.

Impact: This large confounder-adjusted study supports the view that exposure to finasteride is not associated materially with male breast cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0904DOI Listing
May 2019

Cortical and striatal serotonin transporter binding in a genetic rat model of depression and in response to electroconvulsive stimuli.

Eur Neuropsychopharmacol 2019 04 28;29(4):493-500. Epub 2019 Feb 28.

Translational Neuropsychiatry Unit, Aarhus University, Denmark; Department of Nuclear Medicine and PET Center, Aarhus University, Nørrebrogade 44, Building 10G, 8000 Aarhus C, Denmark. Electronic address:

Depression is a debilitating mental illness and two thirds of patients respond insufficiently to conventional antidepressants. Electroconvulsive therapy (ECT) remains the most effective treatment to alleviate drug-refractory depression, however the neurobiological mechanisms are mostly unknown. The serotonergic system plays an important role in depression and alterations in the serotonin transporter (SERT) are seen both in depression and response to antidepressant pharmacotherapies. The first aim of this study was to investigate SERT density in a genetic rat model of depression, Flinders Sensitive Line (FSL), compared to control Flinders Resistant Line (FRL) and Sprague-Dawley (SD) rats. The second aim was to investigate SERT density in response to electroconvulsive stimuli (ECS), an animal model of ECT. Female rats of each strain were treated with ECS or sham (ear-clip placement with no current) for 10 days before brains were removed, frozen and cut into 20 µm thick sections. SERT density was measured in striatal and cortical regions by quantitative in vitro autoradiography using the SERT-radioligand, [H]-DASB. Higher SERT density was observed in FSL rats compared to SD rats by 36-48% in motor cortex and striatum under sham conditions. In response to ECS, SD rats displayed a significant effect of treatment, whereas no changes were observed in FRL and FSL rats. Increased SERT binding in FSL rats compared to SD supports a dysfunction of the serotonergic system in depression. The increased SERT density after ECS, seen in SD rats but not FSL rats, suggests a different mechanism of action between depressive-like rats and controls.
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http://dx.doi.org/10.1016/j.euroneuro.2019.02.009DOI Listing
April 2019

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2019 02;51(2):363

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0330-6DOI Listing
February 2019

[Prostate cancer surgery].

Ugeskr Laeger 2018 Nov;180(46)

Radical prostatectomy (RP) remains the preferred treatment option for men with localised prostate cancer (PCa). Following the introduction in 1995, approximately 1,100 procedures are performed annually in Denmark. Several studies have demonstrated the Danish standard of RP to be at an international level in terms of both functional and oncological outcomes. In order to reduce the risk of overtreatment, management of localised PCa should be organised in experienced multidisciplinary teams, where a constantly growing armamentarium of diagnostic and therapeutic options can be offered.
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November 2018

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Nat Commun 2018 06 11;9(1):2256. Epub 2018 Jun 11.

Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
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http://dx.doi.org/10.1038/s41467-018-04109-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995836PMC
June 2018

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2018 07 11;50(7):928-936. Epub 2018 Jun 11.

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.
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http://dx.doi.org/10.1038/s41588-018-0142-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568012PMC
July 2018

Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens.

J Urol 2018 11 3;200(5):956-966. Epub 2018 May 3.

Endoceutics, Quebec City, Quebec, Canada.

Purpose: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer.

Materials And Methods: We searched PubMed® for clinical trials with the search terms antiandrogens and prostate cancer combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with prostate cancer.

Results: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, were developed primarily for use in combination with castration to provide combined androgen blockade. Modest clinical benefits were observed with the combination of first generation antiandrogens and castration vs castration alone. With increased knowledge of androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. Apalutamide was recently approved while darolutamide is not yet approved in the United States. These next generation antiandrogens are being actively tested in earlier disease states such as nonmetastatic prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer.

Conclusions: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.
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http://dx.doi.org/10.1016/j.juro.2018.04.083DOI Listing
November 2018

Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer-A population-based analysis of 2 national cohorts.

Cancer 2018 07 3;124(14):2931-2938. Epub 2018 May 3.

Copenhagen Prostate Cancer Center, Department of Urology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life-prolonging treatments have been introduced for patients with advanced PCa. On a populations-based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5-year mortality of men with de novo metastatic PCa.

Methods: Men diagnosed with PCa during the periods 1980 to 2011 and 1995 to 2011 were identified in the US Surveillance, Epidemiology, and End Results (SEER) program and the Danish Prostate Cancer Registry (DaPCaR), respectively, and stratified according to period of diagnosis. Age-standardized incidence rates were calculated. Five-year mortality rates for de novo metastatic PCa were analyzed using competing risk analysis.

Results: Totals of 426,266 and 47,024 men were identified in SEER and DaPCaR, respectively. Of these, 29,555 and 6874 had de novo metastatic PCa. The incidence of de novo metastatic PCa decreased (from 12.0 to 4.4 per 100,000 men) in the SEER cohort (1980-2011), whereas it increased (from 6.7 to 9.9 per 100,000 men) in the DaPCaR cohort (1995-2011). Five-year PCa mortality in the SEER cohort was stable for men diagnosed with de novo metastatic PCa from 1980 to 1994 and increased slightly in the latest periods studied (P < .0001), whereas it decreased by 16.6% (P < .0001) in the DaPCaR cohort.

Conclusions: Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31384DOI Listing
July 2018

The use of transrectal ultrasound-guided biopsy following the introduction of prostate-specific antigen testing in Denmark: a population-based analysis.

Scand J Urol 2018 Jun 8;52(3):169-173. Epub 2018 Mar 8.

a Copenhagen Prostate Cancer Center, Department of Urology , Copenhagen University Hospital, Rigshospitalet, University of Copenhagen , Copenhagen N , Denmark.

Objective: Incidence rates of prostate cancer in Denmark resemble those of countries that endorse prostate-specific antigen (PSA) screening. So far, no studies have described the consequences of PSA testing on diagnostic activity on a population level. The aim of this study was to describe the frequency of systematic transrectal ultrasound-guided biopsy (TRUS-gb) activity, including rebiopsy rates, in Denmark between 1995 and 2011.

Materials And Methods: All men who underwent TRUS-gb during the period were identified in the Danish Prostate Cancer Registry. In total, 83,041 biopsy sets from 64,430 individuals were identified. The diagnostic rate and the frequency of rebiopsy were analyzed. Age, histology and PSA were compared at the time of biopsy.

Results: The number of TRUS-gb per 100,000 men per year increased 4.6-fold. The mean number of TRUS-gb procedures per individual increased from 1.08 in 1995 to 1.46 in 2011 (p = .0001), and the proportion of men with negative initial biopsy sets who underwent rebiopsy increased from 22% in 1995 to 41% in 2004, later decreasing to 31% in 2009.

Conclusions: The diagnostic activity in Denmark and the rebiopsy rates in men with initial negative TRUS-gb have increased substantially, and guidelines for the management of men with a negative initial biopsy are highly warranted.
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http://dx.doi.org/10.1080/21681805.2018.1444672DOI Listing
June 2018

Follicular thyroid cancer avid on C-11 Methionine PET/CT.

Endocrinol Diabetes Metab Case Rep 2018 5;2018. Epub 2018 Jan 5.

Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark.

A case of follicular thyroid cancer with intense focal Methionine uptake on 11C-Methionine PET/CT is reported here. The use of 11C-Methionine PET in differentiated thyroid cancer is currently being investigated as a surrogate tracer compared to the more widely used 18F-FDG PET. This case illustrates the potential incremental value of this modality, not only in the localizing of parathyroid adenoma, but also indicating that 11C-Methionine PET might have a potential of increasing the pretest likelihood of thyroid malignancy in a cold nodule with highly increased Sestamibi uptake.

Learning Points: 11C-Methionine PET/CT and 18F-Fluorocholine PET/CT often visualizes the parathyroid adenoma in case of negative Tc-99m-MIBI SPECT/CT.A cold nodule in Tc-99m Pertechnetat thyroid scintigraphy with a negative Sestamibi scintigraphy has a very low probability of being malignant.However, the pretest likelihood of thyroid cancer in a cold nodule with increased Sestamibi uptake is low.11C-Methionine PET might have a potential incremental value in increasing the pretest likelihood of thyroid malignancy in a cold nodule with highly increased Sestamibi uptake.
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http://dx.doi.org/10.1530/EDM-17-0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763279PMC
January 2018

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

BMJ 2018 01 10;360:j5757. Epub 2018 Jan 10.

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

Objectives: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.

Design: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.

Setting: Multiple institutions that were members of international PRACTICAL consortium.

Participants: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.

Main Outcome Measures: Prediction with hazard score of age of onset of aggressive cancer in validation set.

Results: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score.

Conclusions: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759091PMC
http://dx.doi.org/10.1136/bmj.j5757DOI Listing
January 2018

Finasteride treatment and male breast cancer: a register-based cohort study in four Nordic countries.

Cancer Med 2018 01 13;7(1):254-260. Epub 2017 Dec 13.

National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

A potential link has been suggested between dispensed finasteride and increased risk of male breast cancer (MBC). Due to the rare occurrence of MBC, it remains to be established if such a relationship exists. The purpose of this study was to combine nationwide registers in four countries to assess the potential association between dispensed finasteride and MBC. A cohort of all males with dispensed finasteride in Denmark, Finland, Norway, and Sweden (1,365,088 person years) was followed up for up to 15 years for breast cancer, and compared to a cohort of males unexposed to finasteride. Individual-level register data included country, dates of dispensed finasteride, MBC diagnosis, and death. Incidence rate ratios (IRRs) were estimated using a generalized linear model with a Poisson distribution. An increased risk of MBC was found among finasteride users (IRR = 1.44, 95% confidence interval [95% CI] = 1.11-1.88) compared to nonusers. The IRR increased to 1.60 (95% CI = 1.20-2.13) when users in Norway and Sweden with short follow-up time were excluded. The highest IRR was seen among men with medium duration of dispensed finasteride, medium accumulated consumption of finasteride, and among men with first dispensed finasteride prescription 1-3 years prior to diagnosis. The analyses suggested possible ascertainment bias and did not support a clear relationship between dispensed finasteride and MBC. In conclusion, a significant association between dispensed finasteride and MBC was identified. However, due to limited data for adjustment of potential confounding and surveillance bias in the present study, further research is needed to confirm these results.
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http://dx.doi.org/10.1002/cam4.1273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773955PMC
January 2018

Temporal Trends in Clinical and Pathological Characteristics for Men Undergoing Radical Prostatectomy Between 1995 and 2013 at Rigshospitalet, Copenhagen, Denmark, and Stanford University Hospital, United States.

Clin Genitourin Cancer 2017 Sep 6. Epub 2017 Sep 6.

Department of Urology, Copenhagen Prostate Cancer Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: To analyze how prostate-specific antigen (PSA) screening and practice patterns has affected trends in tumor characteristics in men undergoing radical prostatectomy (RP) in the United States and Denmark. Unlike in the United States, PSA screening has not been recommended in Denmark.

Patients And Methods: We performed an observational register study using pre- and postoperative data on 2168 Danish patients from Rigshospitalet, Copenhagen, Denmark, and 2236 patients from Stanford University Hospital, Stanford, CA, who underwent RP between 1995 and 2013. Patients were stratified according to Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) risk groups and D'Amico risk classification and were clustered into 4 time periods (1995-1999, 2000-2004, 2005-2009, and 2010-2013). Temporal trends in the proportions of patients of a given variable at the 2 institutions were evaluated with Cochran-Armitage test for trends and chi-square testing.

Results: A total of 4404 patients were included. Temporal changes in preoperative PSA, age, grade, and stage was found in both cohorts. Median preoperative PSA declined in both cohorts, while median age increased, with the Danish cohort showing the greatest changes in both PSA and age. In both cohorts, there was a trend for higher-risk preoperative features before RP over time. In 2010-2013, 27.7% and 21.8% of the patients were in the D'Amico high-risk group at Copenhagen and Stanford, respectively.

Conclusion: Despite recommendation against PSA screening in Denmark, Danish men undergoing RP at Rigshospitalet to a considerable extent now resemble American men undergoing RP at Stanford. At both sites, there is continued trend to reduce the number of men undergoing RP for low-risk prostate cancer.
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http://dx.doi.org/10.1016/j.clgc.2017.08.014DOI Listing
September 2017

Active surveillance for localized prostate cancer: update of a prospective single-center cohort.

Scand J Urol 2018 Feb 28;52(1):14-19. Epub 2017 Sep 28.

a Copenhagen Prostate Cancer Center, Department of Urology , Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.

Objective: The purpose of active surveillance (AS) is to reduce overtreatment of men with localized prostate cancer (PCa) without compromising survival. The objective of this study was to update a large Scandinavian single-center AS cohort. Furthermore, the use of curative treatment and subsequent risk of biochemical recurrence were investigated and compared in men with very low-risk, low-risk and intermediate-risk PCa in the cohort.

Materials And Methods: In total, 451 men were followed on AS and monitored with prostate-specific antigen (PSA) tests, digital rectal examinations and rebiopsies. Recommendation of curative treatment was based on protocolled and predefined risk of progression criteria. Biochemical recurrence was defined as PSA ≥0.2 ng/ml after radical prostatectomy and PSA nadir +2 ng/ml after radiotherapy.

Results: Altogether, 34% were defined with very low-risk PCa, 40% with low-risk PCa and 24% with intermediate-risk PCa. The median follow-up was 5.1 years. The estimated 5 year curatively intended treatment-free survival was 60.5% [95% confidence interval (CI) 54.8-66.2%], with no statistically significant difference between men with very low-risk, low-risk or intermediate-risk PCa. The 5 year biochemical recurrence-free survival was 92.3% (95% CI 87.4-97.2), again with no difference between men with very low-risk, low-risk and intermediate-risk PCa.

Conclusion: AS for very low- to low-risk localized PCa is feasible and safe within the short to intermediate time frame. Men with intermediate-risk PCa had the same risk of undergoing curative treatment as men with low-risk PCa, without compromising biochemical recurrence-free survival.
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http://dx.doi.org/10.1080/21681805.2017.1380697DOI Listing
February 2018

Long-Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naïve Prostate Cancer: 3-Year Open Label Followup Results.

J Urol 2018 02 1;199(2):459-464. Epub 2017 Sep 1.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Purpose: A phase 2 study of enzalutamide monotherapy in patients with hormone naïve prostate cancer demonstrated high prostate specific antigen response rates at 25 weeks, 1 year and 2 years with minimal effects on total body bone mineral density and favorable safety. In this followup analysis we evaluated enzalutamide antitumor activity and safety at 3 years.

Materials And Methods: In a single arm analysis 67 patients with hormone naïve prostate cancer and noncastrate testosterone (230 ng/dl or greater) received enzalutamide 160 mg per day orally until disease progression or unacceptable toxicity. The primary end point was the prostate specific antigen response (80% or greater decline from baseline).

Results: No patients discontinued treatment during year 3. Of 42 patients with prostate specific antigen assessments at 3 years 38 (90.5%, 95% CI 77.4-97.3) maintained a prostate specific antigen response. Of 26 patients with metastases at baseline 17 (65.4%) had a complete or partial response as the best overall response during 3 years. In patients who completed the 3-year visit minimal mean changes from baseline were observed in total body bone mineral density or bone mineral density of the femoral neck, trochanter, spine L1-L4 or forearm (range -2.7% to -0.1%). At 3 years total body fat had increased a mean of 16.5%, total lean body mass had decreased a mean of -6.5% and global health status had minimally decreased from baseline. Common adverse events were gynecomastia, fatigue, hot flush and nipple pain.

Conclusions: Enzalutamide antitumor activity was maintained in patients with hormone naïve prostate cancer at 3 years. Overall bone mineral density, global health status and safety results were similar to those at 2 years.
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http://dx.doi.org/10.1016/j.juro.2017.08.103DOI Listing
February 2018

Cytoreductive prostatectomy in metastatic prostate cancer: a systematic review.

Scand J Urol 2018 Feb 18;52(1):1-7. Epub 2017 Aug 18.

a Copenhagen Prostate Cancer Center, Department of Urology , Rigshospitalet, University of Copenhagen , Copenhagen, Denmark.

The impact of cytoreductive radical prostatectomy on oncological outcome in patients with prostate cancer and limited number of bone metastases is unclear. Data from cancer registries, multi-institutional databases and a single institutional case-control study indicate a possible benefit of combined cytoreduction and hormonal therapy compared to hormonal therapy alone. However, the results may be biased by a number of factors. The evidence from studies on cytoreductive prostatectomy is reviewed.
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http://dx.doi.org/10.1080/21681805.2017.1363816DOI Listing
February 2018

Diagnostic characteristics of lethal prostate cancer.

Eur J Cancer 2017 10 2;84:18-26. Epub 2017 Aug 2.

Copenhagen Prostate Cancer Center, Department of Urology, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, Ole maaløes vej 24, Section 7521, DK-2200 Copenhagen, Denmark. Electronic address:

Background: The diagnostic characteristics of men who eventually die from prostate cancer (PCa) and the extent to which early diagnostic strategies have affected these characteristics are unclear. We aimed to investigate trends in survival and clinical presentation at diagnosis in men who eventually died from PCa.

Patients And Methods: Based on the national database, the Danish Prostate Cancer Registry, a nationwide population-based study of all 19,487 men who died from PCa in Denmark between 1995 and 2013 was conducted. Trends in median survival and trends in age, prostate-specific antigen (PSA), clinical stage, and Gleason score (GS) at diagnosis were analysed.

Results: A total of 46.9%, 16.8%, and 36.3% had metastatic (M+), locally advanced/lymph node positive (LaN+), and localised disease, respectively, at diagnosis. Only 0.15% had localised disease, GS ≤ 6 and PSA<10. Over time, the proportion of men with M+ disease at diagnosis decreased from 54.0-38.3% (p < 0.0001), whereas the proportion LaN + disease increased from 8.6-27.3% (p < 0.0001). The proportion of localised disease remained stable at 33.2-41.9%. Median survival increased 2.11 years from 1.88 (95% CI: 1.68-2.08) in 1995 to 3.99 (95% CI: 3.71-4.28) years in 2013, p < 0.0001.

Conclusions: In a large population-based study, the results confirmed concurrent literature that the majority of men who eventually died from PCa had LaN+ or M+ disease at diagnosis. The proportion of men with M+ disease at diagnosis decreased significantly over time, parallelled by an increase in median survival. Taken together, this indicates a lead-time effect on survival, which presently, however, is not substantial enough to result in a reduced PCa-specific mortality.
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http://dx.doi.org/10.1016/j.ejca.2017.07.007DOI Listing
October 2017

Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study.

J Nucl Cardiol 2019 04 2;26(2):585-597. Epub 2017 Aug 2.

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.

Background: The glucagon-like peptide-1 analog liraglutide increases heart rate and may be associated with more cardiac events in chronic heart failure (CHF) patients. We studied whether this could be ascribed to effects on myocardial glucose uptake (MGU), myocardial blood flow (MBF) and MBF reserve (MFR).

Methods And Results: CHF patients with left ventricular ejection fraction ≤45% and without type 2 diabetes were randomized to liraglutide (N = 18) 1.8 mg once daily or placebo (N = 18) for 24 weeks in a double-blinded design. Changes in MGU during an oral glucose tolerance test (OGTT) and changes in MBF and MFR from baseline to follow-up were measured quantitatively by F-FDG and O-HO positron emission tomography. Compared with placebo, liraglutide reduced weight (P = 0.03), HbA1c (P = 0.03) and the 2-hour glucose value during the OGTT (P = 0.004). Despite this, changes in MGU (P = 0.98), MBF (P = 0.76) and MFR (P = 0.89) from baseline to follow-up did not differ between groups. Furthermore, there was no association between the level of insulin resistance at baseline and changes in MGU in patients treated with liraglutide.

Conclusion: Liraglutide did not affect MGU, MBF, or MFR in non-diabetic CHF patients. Any potential increase in cardiac events in these patients seems not to involve changes in MGU, MBF, or MFR.

Trial Registration: Trial registry: http://www.ClinicalTrials.org . Identifier: NCT01472640. Url: https://clinicaltrials.gov/ct2/show/NCT01472640?term=NCT01472640&rank=1.
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http://dx.doi.org/10.1007/s12350-017-1000-2DOI Listing
April 2019
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