Calciprotein Particles Balancing Mineral Homeostasis and Vascular Pathology:Balancing Mineral Homeostasis and Vascular Pathology

Hypercalcemia and hyperphosphatemia associate with an elevated risk of cardiovascular events, yet the pathophysiological basis of this association is unclear. Disturbed mineral homeostasis and the associated hypercalcemia and hyperphosphatemia may result in the formation of circulating calciprotein particles (CPPs) that aggregate the excessive calcium and phosphate ions. If not counteracted, the initially formed harmless amorphous spherical complexes (primary CPPs) may mature into damaging crystalline complexes (secondary CPPs). Secondary CPPs are internalized by vascular cells, causing a massive influx of calcium ions into the cytosol, leading to a proinflammatory response, cellular dysfunction, and cell death. Although the pathophysiological effects induced by CPPs in vascular cells receive increasing attention, a complete picture of how these particles contribute to the development of atherosclerosis and vascular calcification remains elusive. We here discuss existing knowledge on CPP formation and function in atherosclerosis and vascular calcification, techniques for investigating CPPs, and models currently applied to assess CPP-induced cardiovascular pathogenesis. Lastly, we evaluate the potential diagnostic value of serum CPP measurements and the therapeutic potential of anti-CPP therapies currently under development

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

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT

Background: 111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. Methods and Results: ApoE−/− mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of 111In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of 111In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1.7 ± 0.5. In vivo imaging results were validated by ex vivo SPECT/CT imaging, with a TBR up to 11.5 (range 2.6 to 11.5). Plaques, identified by Oil Red O lipid-staining on excised arteries, co-localized with 111In-DANBIRT uptake as determined by ex vivo autoradiography. Subsequent histological processing and in vitro autoradiography confirmed 111In-DANBIRT uptake at plaque areas containing CD68 expressing macrophages and LFA-1 expressing inflammatory cells. Ex vivo incubation of a human carotid endarterectomy specimen with 111In-DANBIRT (~ 950 nmol, ~ 190 MBq) for 2 hours showed heterogeneous plaque uptake on SPECT/CT, after which immunohistochemical analysis demonstrated co-localization of 111In-DANBIRT uptake and CD68 and LFA-1 expressing cells. Conclusions: Our results indicate the potential of radiolabeled DANBIRT as a relevant imaging radioligand for non-invasive evaluation of atherosclerotic inflammation

Pulsed wave tissue Doppler imaging for the quantification of contractile reserve in stunned, hibernating, and scarred myocardium

OBJECTIVES: To assess whether quantification of myocardial systolic velocities by pulsed wave tissue Doppler imaging can differentiate between stunned, hibernating, and scarred myocardium. DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: 70 patients with reduced left ventricular function caused by chronic coronary artery disease. METHODS: Pulsed wave tissue Doppler imaging was done close to the mitral annulus at rest and during low dose dobutamine; systolic ejection velocity (Vs) and the difference in Vs between low dose dobutamine and the resting value (DeltaVs) were assessed using a six segment model. Assessment of perfusion (with Tc-99m-tetrofosmin SPECT) and glucose utilisation (by 18F-fluorodeoxyglucose SPECT) was used to classify dysfunctional regions (by resting cross sectional echocardiography) as stunned, hibernating, or scarred. RESULTS: 253 of 420 regions (60%) were dysfunctional. Of these, 132 (52%) were classified as stunned, 25 (10%) as hibernating, and 96 (38%) as scarred. At rest, Vs in stunned, hibernating, and scar tissue was, respectively, 6.3 (1.8), 6.6 (2.2), and 5.5 (1.5) cm/s (p = 0.001 by ANOVA). There was a gradual decline in Vs during low dose dobutamine infusion between stunned, hibernating, and scar tissue (8.3 (2.6) v 7.8 (1.5) v 6.8 (1.9) cm/s, p < 0.001 by ANOVA). DeltaVs was higher in stunned (2.1 (1.9) cm/s) than in hibernating (1.2 (1.4) cm/s, p < 0.05) or scarred regions (1.3 (1.2) cm/s, p = 0.001). CONCLUSIONS: Quantitative tissue Doppler imaging showed a gradual reduction in regional velocities between stunned, hibernating, and scarred myocardium. Dobutamine induced contractile reserve was higher in stunned regions than in hibernating and scarred myocardium, reflecting different severities of myocardial damag

Ontogeny of iodothyronine deiodinases in human liver

The role of the deiodinases D1, D2, and D3 in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in animals but little is known about the ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently

Pitfalls in neuroendocrine tumor diagnosis

Not available<br /

Imaging inflammation in atherosclerotic plaques, targeting SST2 with [111In]In-DOTA-JR11

Background: Imaging Somatostatin Subtype Receptor 2 (SST2) expressing macrophages by [DOTA,Tyr3]-octreotate (DOTATATE) has proven successful for plaque detection. DOTA-JR11 is a SST2 targeting ligand with a five times higher tumor uptake than DOTATATE, and holds promise to improve plaque imaging. The aim of this study was to evaluate the potential of DOTA-JR11 for plaque detection. Methods and Results: Atherosclerotic ApoE−/− mice (n = 22) fed an atherogenic diet were imaged by SPECT/CT two hours post injection of [111In]In-DOTA-JR11 (~ 200 pmol, ~ 50 MBq). In vivo plaque uptake of [111In]In-DOTA-JR11 was visible in all mice, with a target-to-background-ratio (TBR) of 2.23 ± 0.35. Post-mortem scans after thymectomy and ex vivo scans of the arteries after excision of the arteries confirmed plaque uptake of the radioligand with TBRs of 2.46 ± 0.52 and 3.43 ± 1.45 respectively. Oil red O lipid-staining and ex vivo autoradiography of excised arteries showed [111In]In-DOTA-JR11 uptake at plaque locations. Histological processing showed CD68 (macrophages) and SST2 expressing cells in plaques. SPECT/CT, in vitro autoradiography and immunohistochemistry performed on slices of a human carotid endarterectomy sample showed [111In]In-DOTA-JR11 uptake at plaque locations containing CD68 and SST2 expressing cells. Conclusions: The results of this study indicate DOTA-JR1

Non-puerperal uterine inversion due to submucous myoma in a young woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Inversion of the uterus is an uncommon complication of the puerperium and it is an even rarer complication of the non-puerperal period. A submucous myoma is mostly the cause of the non-puerperal inversion but diagnosis can be difficult. In young women, non-puerperal uterine inversion is likely associated with a malignancy.</p> <p>Case presentation</p> <p>A 19-year-old nulliparous woman presented with abnormal vaginal bleeding, dysmenorrhoea, and a large mass protruding from her cervix. The mass was interpreted as a prolapsed pedunculated submucosal myoma. After extirpation of the mass by clamping and twisting its pedicle, a laparotomy was required under suspicion of a uterine rupture. The diagnosis was confirmed and the patient's uterus could be preserved. Pathological examination revealed a submucous myoma. The uterine inversion happened when the uterus retracted to expel the submucous myoma with fundal attachment. By extirpating the stalk the fundus was also resected, causing a uterine rupture.</p> <p>Conclusion</p> <p>We report a case of non-puerperal uterine inversion associated with a benign submucous myoma. Non-puerperal uterine inversion is very uncommon in women of reproductive age and is usually caused by a malignant tumour. However, uterine-sparing surgery should be attempted in young women until the final pathology is known.</p