Effectiveness of customary use of phytosterol/-stanol enriched margarines on blood cholesterol lowering.

Postlaunch monitoring of functional foods can encompass monitoring of effectiveness under conditions of customary use. To this end, the effectiveness of phytosterol/-stanol enriched margarine consumption in free-living conditions was investigated with data from the Dutch "Doetinchem cohort study". In total, 4,505 subjects (aged 26-70 years) were examined in 1994-1998 and re-examined during 1999-2003. A general and a food frequency questionnaire and non-fasting blood samples for total and HDL cholesterol determination were obtained. Subjects were stratified into phytosterol/-stanol enriched margarine users (n = 84) and non-users (n = 4,421) based on the re-examination data, as these margarines were available on the Dutch market from 1999 onwards. Mean spontaneous daily use (g +/- SD) of phytosterol-containing margarine (n = 71) was 15 +/- 8 and of phytostanol-containing margarine (n = 13) 9+/-6. After five years, total blood cholesterol had increased with 0.26 mmol/l in non-users while it had not significantly changed in users. The difference in total blood cholesterol change in users versus non-users was -0.30 mmol/l (p < 0.001). The beneficial effect of the phytosterol/-stanol enriched margarine, used under customary conditions can be characterized as a stabilization of cholesterol levels. This is the first report finding a modest beneficial effect on blood cholesterol level under customary conditions thereby partly confirming findings from clinical trials

Highlights lecture EANM 2014: “Gimme gimme gimme those nuclear Super Troupers”

The EANM Congress 2014 took place in Gothenburg, Sweden, from 18 to 22 October under the presidency of Prof. Wim Oyen, chair of the EANM Scientific Committee. Prof. Peter Gjertsson chaired the Local Organizing Committee, according to the standardized EANM congress structure. The meeting was a highlight for the multidisciplinary community that forms the heart and soul of nuclear medicine; attendance was exceptionally high. In total almost 5,300 participants came to Gothenburg, and 1,397 colleagues participated via the EANM LIVE sessions (http://eanmlive.eanm.org/index.php). Participants from all continents were presented with an excellent programme consisting of symposia, scientific and featured sessions, CME sessions, and plenary lectures. These lectures were devoted to nuclear medicine therapy, hybrid imaging and molecular life sciences. Two tracks were included in the main programme, clustering multi-committee involvement: the 5th International Symposium on Targeted Radionuclide-therapy and Dosimetry (ISTARD) and the first Molecules to Man (M2M) track, an initiative of the EANM Committees for Translational Molecular Imaging, Radiopharmacy and Drug Development. The industry made a substantial contribution to the success of the congress demonstrating the latest technology and innovations in the field. During the closing Highlights Lecture, a selection of the best-rated abstracts was presented including diverse areas of nuclear medicine: physics and instrumentation, radiopharmacy, preclinical imaging, oncology (with a focus on the clinical application of newly developed tracers) and radionuclide therapy, cardiology and neurosciences. This Highlights Lecture could only be a brief summary of the large amount of data presented and discussed during the meeting, which can be found in much greater detail in the congress proceedings book, published as Volume 41, Supplement 2 of the European Journal of Nuclear Medicine and Molecular Imaging in October 2014

Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues

Prostate Cancer (PC) is a type of cancer that is often diagnosed at very early stages due to improved detection among man in the Western world. Current imaging techniques are not optimal to determine extent of minimal early stage PC even though this is of great clinical importance. Human PC and high-grade PIN have shown high Gastrin-Releasing Peptide Receptor (GRPR) expression, while normal prostate tissue and BPH revealed to be predominantly GRPR-negative. Radiolabelled Gastrin-Releasing Peptide (GRP) or bombesin (BN) analogues targeting the GRPR can be used as non-invasive tools to diagnose, monitor and potentially treat PC. These BN analogues have already proven to be able to image PC in both tumour-bearing mice and clinical patients showing no important side effects. It's desirable that new peptides require fast-track standardised comparative testing in relevant PC models to select the best performing BN analogues for further evaluation in patients. Although knowledge about GRPR expression and development of new BN analogues can be extended, it is time to study performance of BN analogues for peptide receptor based imaging in patients validating results of PC imaging using histopathology as a golden standard

Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts

Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies however on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with 111In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation as compared to slow growing xenografts. Additionally, several other parameters determining the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However liposomal uptake was

Changes in renal tri-iodothyronine and thyroxine handling during fasting

OBJECTIVE: Liver handling of thyroid hormones (TH) has been known to alter significantly during fasting. This study investigates whether renal handling of TH is also changed during fasting. METHODS: We measured urinary excretion rates and clearances of free tri-iodothyronine (T(3)) and free thyroxine (T(4)) in healthy subjects prior to and on the third day of fasting. RESULTS: During fasting, both mean T(3) and T(4) urinary excretion decreased significantly to a mean value of 42% of control. Also, total and free (F) serum T(3) concentrations declined significantly, but serum T(4) did not change. Both FT(3) and FT(4) clearance decreased significantly during fasting (62% and 42% of control). The fasting-induced decrease in uric acid clearance correlated well with the decrease in FT(3) clearance (r=0.94; P<0.001). Serum concentrations of non-esterified fatty acids (NEFA) were significantly elevated during fasting. CONCLUSIONS: The findings cannot be fully explained by the fasting-induced decrease in serum T(3), a

Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in c

Quality of life and voice outcome of patients treated with transoral CO2 laser microsurgery for early glottic carcinoma (T1-T2): a 2-year follow-up study

Purpose Longitudinal studies in laryngeal cancer can provide clinicians information about short-term and long-term functional outcomes, like quality of life (QoL) and voice outco

Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [111In-DOTA]MG11

Background: We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [111In-DOTA]MG11 ([(DOTA)DGlu10]gastrin(10–17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug racecadotril (Race). Besides NEP, angiotensin-converting enzyme (ACE) has also been implicated in the catabolism of gastrin analogs. In the present study, we first compared the effects induced by NEP inhibition (using PA, TO, or Race) and/or by ACE inhibition (using lisinopril, Lis) on the biodistribution profile of [111In-DOTA]MG11 in mice. In addition, we compared the efficacy of PA and TO at different administered doses to enhance tumor uptake. Methods: [111In-DOTA]MG11 was coinjected with (a) vehicle, (b) PA (300 μg), (c) TO (150 μg), (d) Lis (100 μg), (e) PA (300 μg) plus Lis (100 μg), or (f) 30–40 min after intraperitoneal (ip) injection of Race (3 mg) in SCID mice bearing AR42J xenografts. In addition, [111In-DOTA]MG11 was coinjected with vehicle, or with progressively increasing amounts of PA (3, 30, or 300 μg) or TO (1.5, 15, and 150 μg) in SCID mice bearing twin A431-CCK2R(+/−) tumors. In all above cases, biodistribution was conducted at 4 h postinjection (pi). Results: During NEP inhibition, the uptake of [111In-DOTA]MG11 in the AR42J tumors impressively increased from 1.8 ± 1.0 % ID/g (controls) to 15.3 ± 4.7 % ID/g (PA) and 12.3 ± 3.6 % ID/g (TO), while with Race tumor values reached 6.8 ± 2.8 % ID/g. Conversely, Lis had no effect on tumor uptake and no additive effect when coinjected with PA. During the dose dependence study in mice, PA turned out to be more efficacious in enhancing tumor uptake of [111In-DOTA]MG11 in the CCK2R-positive tumors compared to equimolar amounts of TO. In all cases, renal accumulation remained low, resulting in notable increases of tumor-to-kidney ratios. Conclusions: This study has confirmed NEP as the predominant degrading enzyme of [111In-DOTA]MG11 and ruled out the involvement of ACE in the in vivo catabolism of the radiotracer. NEP inhibition with the clinically tested NEP

Influence of tumour size on the efficacy of targeted alpha therapy with 213Bi-[DOTA0,Tyr3]-octreotate

BACKGROUND: Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR(2)), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR(2) in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with (213)Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm(3)) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour). METHODS: Pharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm(3) were euthanized at 10, 30, 60 and 120 min post injection of a single dose of (213)Bi-DOTATATE (1.5–4.8 MBq). To investigate the therapeutic efficacy of (213)Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm(3) were administered daily with a therapeutic dose of (213)Bi-DOTATATE (0.3 nmol, 2–4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq (99m)Tc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to (213)Bi-DOTATATE treatment. RESULTS: Higher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69 tumour-bearing mice, the survival rate was higher. Furthermore, in the small tumour groups, no regrowth of tumour was found in two H69 tumour-bearing mice and in one of the CA20948 tumour-bearing mice. No renal dysfunction was observed in (213)Bi-DOTATATE-treated mice after the doses were applied. CONCLUSIONS: (213)Bi-DOTATATE demonstrated a great therapeutic effect in both small and larger tumour lesions. Higher probability for stable disease was found in animals with small tumours. (213)Bi-DOTATATE was effective in different neuroendocrine (H69 and CA20948) tumour models with overexpression of SSTR(2) in mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-016-0162-2) contains supplementary material, which is available to authorized users