983 resultados para Izzo, Jean-Claude
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IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.
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Glucagon-like-peptide-1 (GLP1) analogs may induce thyroid or pancreatic diseases in animals, raising questions about their use in diabetic patients. There is, however, controversy regarding expression of GLP1 receptors (GLP1R) in human normal and diseased thyroid and pancreas. Here, 221 human thyroid and pancreas samples were analyzed for GLP1R immunohistochemistry and compared with quantitative in vitro GLP1R autoradiography. Neither normal nor hyperplastic human thyroids containing parafollicular C cells express GLP1R with either method. Papillary thyroid cancer do not, and medullary thyroid carcinomas rarely express GLP1R. Insulin- and somatostatin-producing cells in the normal pancreas express a high density of GLP1R, whereas acinar cells express them in low amounts. Ductal epithelial cells do not express GLP1R. All benign insulinomas express high densities of GLP1R, whereas malignant insulinomas rarely express them. All ductal pancreatic carcinomas are GLP1R negative, whereas 6/20 PanIN 1/2 and 0/12 PanIN 3 express GLP1R. Therefore, normal thyroid, including normal and hyperplastic C cells, or papillary thyroid cancer are not targets for GLP1 analogs in humans. Conversely, all pancreatic insulin- and somatostatin-producing cells are physiological GLP1 targets, as well as most acini. As normal ductal epithelial cells or PanIN 3 or ductal pancreatic carcinomas do not express GLP1R, it seems unlikely that GLP1R is related to neoplastic transformation in pancreas. GLP1R-positive medullary thyroid carcinomas and all benign insulinomas are candidates for in vivo GLP1R targeting.Modern Pathology advance online publication, 12 September 2014; doi:10.1038/modpathol.2014.113.
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The neodymium (Nd) isotopic composition (Nd) of seawater is a quasi-conservative tracer of water mass mixing and is assumed to hold great potential for paleoceanographic studies. Here we present a comprehensive approach for the simulation of the two neodymium isotopes 143Nd, and 144Nd using the Bern3D model, a low resolution ocean model. The high computational efficiency of the Bern3D model in conjunction with our comprehensive approach allows us to systematically and extensively explore the sensitivity of Nd concentrations and Nd to the parametrisation of sources and sinks. Previous studies have been restricted in doing so either by the chosen approach or by computational costs. Our study thus presents the most comprehensive survey of the marine Nd cycle to date. Our model simulates both Nd concentrations as well as Nd in good agreement with observations. Nd covaries with salinity, thus underlining its potential as a water mass proxy. Results confirm that the continental margins are required as a Nd source to simulate Nd concentrations and Nd consistent with observations. We estimate this source to be slightly smaller than reported in previous studies and find that above a certain magnitude its magnitude affects Nd only to a small extent. On the other hand, the parametrisation of the reversible scavenging considerably affects the ability of the model to simulate both, Nd concentrations and Nd. Furthermore, despite their small contribution, we find dust and rivers to be important components of the Nd cycle. In additional experiments, we systematically varied the diapycnal diffusivity as well as the Atlantic-to-Pacific freshwater flux to explore the sensitivity of Nd concentrations and its isotopic signature to the strength and geometry of the overturning circulation. These experiments reveal that Nd concentrations and Nd are comparatively little affected by variations in diapycnal diffusivity and the Atlantic-to-Pacific freshwater flux. In contrast, an adequate representation of Nd sources and sinks is crucial to simulate Nd concentrations and Nd consistent with observations. The good agreement of our results with observations paves the way for the evaluation of the paleoceanographic potential of Nd in further model studies.
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BACKGROUND Early identification of patients at risk of developing persistent low back pain (LBP) is crucial. OBJECTIVE Aim of this study was to identify in patients with a new episode of LBP the time point at which those at risk of developing persistent LBP can be best identified.METHODS: Prospective cohort study of 315 patients presenting to a health practitioner with a first episode of acute LBP. Primary outcome measure was functional limitation. Patients were assessed at baseline, three, six, twelve weeks and six months looking at factors of maladaptive cognition as potential predictors. Multivariate logistic regression analysis was performed for all time points. RESULTS The best time point to predict the development of persistent LBP at six months was the twelve-week follow-up (sensitivity 78%; overall predictive value 90%). Cognitions assessed at first visit to a health practitioner were not predictive. CONCLUSIONS Maladaptive cognitions at twelve weeks appear to be suitable predictors for a transition from acute to persistent LBP. Already three weeks after patients present to a health practitioner with acute LBP cognitions might influence the development of persistent LBP. Therefore, cognitive-behavioral interventions should be considered as early adjuvant LBP treatment in patients at risk of developing persistent LBP.
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BACKGROUND: There is little knowledge in the literature on the role of time-related variables for the prognosis of acute and subacute low back pain (LBP). OBJECTIVE: The aim of this study was to estimate the relationship between time-related LBP characteristics and prognostic factors for acute/subacute LBP. METHODS: We performed a prospective inception cohort study of 315 patients attending a health practitioner for acute/subacute LBP or recurrent LBP. One-tailed correlations were conducted between patient characteristics and time-related variables. RESULTS: The pattern of correlation between risk factors for and resources against persistent LBP differed between three time-related variables. 'Subacute LBP' and 'delayed presentation' were positively associated with psychological factors. Both indicators were negatively correlated with resources against development of persistent LBP. Moreover, 'delayed presentation' was related positively with occupational stressors. In contrast, 'recurrent LBP' was only related to more impaired health-related factors. CONCLUSIONS: Patients with current LBP waiting longer until seeking help in primary care have a more disadvantageous profile of occupational and psychological risk factors and lower resource levels. A similar but less pronounced pattern occurred in those with subacute LBP compared to those with acute LBP. Consideration of time characteristics of LBP may help to better understand LBP.
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UNLABELLED Gastrin-releasing peptide receptors (GRPrs) are overexpressed on a variety of human cancers, providing the opportunity for peptide receptor targeting via radiolabeled bombesin-based peptides. As part of our ongoing investigations into the development of improved GRPr antagonists, this study aimed at verifying whether and how N-terminal modulations improve the affinity and pharmacokinetics of radiolabeled GRPr antagonists. METHODS The potent GRPr antagonist MJ9, Pip-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) (Pip, 4-amino-1-carboxymethyl-piperidine), was conjugated to 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA), and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and radiolabeled with (68)Ga and (64)Cu. The GRPr affinity of the corresponding metalloconjugates was determined using (125)I-Tyr(4)-BN as a radioligand. The labeling efficiency of (68)Ga(3+) was compared between NODAGA-MJ9 and NOTA-MJ9 in acetate buffer, at room temperature and at 95°C. The (68)Ga and (64)Cu conjugates were further evaluated in vivo in PC3 tumor xenografts by biodistribution and PET imaging studies. RESULTS The half maximum inhibitory concentrations of all the metalloconjugates are in the high picomolar-low nanomolar range, and these are the most affine-radiolabeled GRPr antagonists we have studied so far in our laboratory. NODAGA-MJ9 incorporates (68)Ga(3+) nearly quantitatively (>98%) at room temperature within 10 min and at much lower peptide concentrations (1.4 × 10(-6) M) than NOTA-MJ9, for which the labeling yield was approximately 45% under the same conditions and increased to 75% at 95°C for 5 min. Biodistribution studies showed high and specific tumor uptake, with a maximum of 23.3 ± 2.0 percentage injected activity per gram of tissue (%IA/g) for (68)Ga-NOTA-MJ9 and 16.7 ± 2.0 %IA/g for (68)Ga-NODAGA-MJ9 at 1 h after injection. The acquisition of PET images with the (64)Cu-MJ9 conjugates at later time points clearly showed the efficient clearance of the accumulated activity from the background already at 4 h after injection, whereas tumor uptake still remained high. The high pancreas uptake for all radiotracers at 1 h after injection was rapidly washed out, resulting in an increased tumor-to-pancreas ratio at later time points. CONCLUSION We have developed 2 GRPr antagonistic radioligands, which are improved in terms of binding affinity and overall biodistribution profile. Their promising in vivo pharmacokinetic performance may contribute to the improvement of the diagnostic imaging of tumors overexpressing GRPr.
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Radiolabeled pansomatostatin-like analogues are expected to enhance the diagnostic sensitivity and to expand the clinical indications of currently applied sst2-specific radioligands. In this study, we present the somatostatin mimic [DOTA]LTT-SS28 {[(DOTA)Ser1,Leu8,D-Trp22,Tyr25]SS28} and its 111In radioligand. [DOTA]LTT-SS28 exhibited a pansomatostatin-like profile binding with high affinity to all five hsst1-hsst5 subtypes (IC50 values in the lower nanomolar range). Furthermore, [DOTA]LTT-SS28 behaved as an agonist at hsst2, hsst3, and hsst5, efficiently stimulating internalization of the three receptor subtypes. Radioligand [111In-DOTA]LTT-SS28 showed good stability in the mouse bloodstream. It displayed strong and specific uptake in AR42J tumors 4 h postinjection (9.3±1.6% ID/g vs 0.3±0.0% ID/g during sst2 blockade) in mice. Significant and specific uptake was also observed in HEK293-hsst2-, HEK293-hsst3-, and HEK293-hsst5-expressing tumors (4.43±1.5, 4.88±1.1, and <3% ID/g, respectively, with values of <0.5% ID/g during receptor blockade). In conclusion, the somatostatin mimic [111In-DOTA]LTT-SS28 specifically localizes in sst2-, sst3-, and sst5-expressing xenografts in mice showing promise for multi-sst1-sst5 targeted tumor imaging.
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Preclinical and clinical studies have indicated that somatostatin receptor (sst)-expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In 4 consecutive patients with advanced neuroendocrine tumors, we evaluated whether treatment with (177)Lu-labeled sst antagonists is feasible. METHODS After injection of approximately 1 GBq of (177)Lu-DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2] ((177)Lu-DOTA-JR11) and (177)Lu-DOTATATE, 3-dimensional voxel dosimetry analysis based on SPECT/CT was performed. A higher tumor-to-organ dose ratio for (177)Lu-DOTA-JR11 than for (177)Lu-DOTATATE was the prerequisite for treatment with (177)Lu-DOTA-JR11. RESULTS Reversible minor adverse effects of (177)Lu-DOTA-JR11 were observed. (177)Lu-DOTA-JR11 showed a 1.7-10.6 times higher tumor dose than (177)Lu-DOTATATE. At the same time, the tumor-to-kidney and tumor-to-bone marrow dose ratio was 1.1-7.2 times higher. All 4 patients were treated with (177)Lu-DOTA-JR11, resulting in partial remission in 2 patients, stable disease in 1 patient, and mixed response in the other patient. CONCLUSION Treatment of neuroendocrine tumors with radiolabeled sst antagonists is clinically feasible and may have a significant impact on peptide receptor radionuclide therapy.
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INTRODUCTION The gastrin-releasing peptide receptor (GRPR) was shown to be expressed with high density on several types of cancers. Radiolabeled peptides for imaging and targeted radionuclide therapy have been developed. In this study, we evaluated the potential of statine-based bombesin antagonists, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) through oligoethyleneglycol spacers, labeled with (177)Lu and we determined the effect of polyethyleneglycol (PEG) spacer length on in vitro and in vivo properties. METHODS The bombesin antagonists were synthesized on solid phase using Fmoc chemistry; the spacers Fmoc-dPEGx-OH (x=2, 4, 6 and 12) and the DOTA(tBu)3 were coupled using a standard procedure. The peptides were labeled with (177)Lu and evaluated in vitro (lipophilicity, serum stability, internalization and binding affinity assays). Biodistribution studies were performed in PC-3 tumor-bearing nude mice. RESULTS The solid-phase synthesis was straightforward with an overall yield ranging from 30% to 35% based on the first Fmoc cleavage. The hydrophilicity increased with spacer length (logD: -1.95 vs -2.22 of PEG2 and PEG12 analogs, respectively). There is a tendency of increased serum stability by increasing the spacer length (T1/2=246±4 and 584±20 for PEG2 and PEG6 analogs, respectively) which seems to reverse with the PEG12 analog. The IC50 values are similar with the only significant difference of the PEG12 analog. The (177)Lu-labeled PEG4 and PEG6 conjugates showed similar pharmacokinetic with high tumor uptake and excellent tumor-to-kidney ratios (7.8 and 9.7 at 4h for the PEG4 and PEG6 derivatives, respectively). The pancreas uptake was relatively high at 1h but it shows fast washout (0.46%±0.02% IA/g and 0.29%±0.08% IA/g already at 4h). CONCLUSION Among all the studied analogs the PEG4 and PEG6 showed significantly better properties. The very high tumor-to-non-target organ ratios, in particular tumor-to-kidney ratios, already at early time point will be important in regard to safety concerning kidney toxicity.
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A new family of peptide receptors, the incretin receptor family, overexpressed on many neuroendocrine tumors (NETs) is of great importance because it may enable the in vivo peptide-based receptor targeting of a category of NETs that does not express the somatostatin receptor. Impressive in vivo diagnostic data were published for glucagonlike peptide 1 receptor-targeting radiopeptides. Recently, promising in vitro data have appeared for the second member of the incretin family, the glucose-dependent insulinotropic polypeptide (GIP) receptor. This prompted us to develop and evaluate a new class of radioligands with the potential to be used for the in vivo targeting of GIP receptor-positive tumors. METHODS GIP(1-42) was modified C-terminally, and the truncated peptides [Lys(30)(aminohexanoic acid [Ahx]-DOTA)]GIP(1-30)NH2 (EG1), [Lys(16)(Ahx-DOTA)]GIP(1-30)NH2 (EG2), and [Nle(14), Lys(30)(Ahx-DOTA)]GIP(1-30)NH2 (EG4) were conjugated with Ahx-DOTA via the Lys(16) and Lys(30) side chains. Their inhibitory concentration of 50% (IC50) was determined using [(125)I-Tyr(10)]GIP(1-30) as radioligand and GIP(1-30) as control peptide. The DOTA conjugates were labeled with (111)In and (68)Ga. In vitro evaluation included saturation and internalization studies using the pancreatic endocrine cell line INR1G9 transfected with the human GIP receptor (INR1G9-hGIPr). The in vivo evaluation consisted of biodistribution and PET imaging studies on nude mice bearing INR1G9-hGIPr tumors. RESULTS Binding studies (IC50 and saturation studies) showed high affinity toward GIP receptor for the GIP conjugates. Specific in vitro internalization was found, and almost the entire cell-associated activity was internalized (>90% of the cell-bound activity), supporting the agonist potency of the (111)In-vectors. (111)In-EG4 and (68)Ga-EG4 were shown to specifically target INR1G9-hGIPr xenografts, with tumor uptake of 10.4% ± 2.2% and 17.0% ± 4.4% injected activity/g, 1 h after injection, respectively. Kidneys showed the highest uptake, which could be reduced by approximately 40%-50% with a modified-fluid-gelatin plasma substitute or an inhibitor of the serine protease dipeptidyl peptidase 4. The PET images clearly visualized the tumor. CONCLUSION The evaluation of EG4 as a proof-of-principle radioligand indicated the feasibility of imaging GIP receptor-positive tumors. These results prompt us to continue the development of this family of radioligands for imaging of a broad spectrum of NETs.
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UNLABELLED Ex vivo studies have shown that the gastrin releasing peptide receptor (GRPr) is overexpressed on almost all primary prostate cancers, making it a promising target for prostate cancer imaging and targeted radiotherapy. METHODS Biodistribution, dosimetry and tumor uptake of the GRPr antagonist ⁶⁴Cu-CB-TE2A-AR06 [(⁶⁴Cu-4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)-PEG₄-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-LeuNH₂] were studied by PET/CT in four patients with newly diagnosed prostate cancer (T1c-T2b, Gleason 6-7). RESULTS No adverse events were observed after injection of ⁶⁴Cu-CB-TE2A-AR06. Three of four tumors were visualized with high contrast [tumor-to-prostate ratio > 4 at 4 hours (h) post injection (p.i.)], one small tumor (T1c, < 5% tumor on biopsy specimens) showed moderate contrast (tumor-to-prostate ratio at 4 h: 1.9). Radioactivity was cleared by the kidneys and only the pancreas demonstrated significant accumulation of radioactivity, which rapidly decreased over time. CONCLUSION ⁶⁴Cu-CB-TE2A-AR06 shows very favorable characteristics for imaging prostate cancer. Future studies evaluating ⁶⁴Cu-CB-TE2A-AR06 PET/CT for prostate cancer detection, staging, active surveillance, and radiation treatment planning are necessary.
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BACKGROUND Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy. METHODS [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib (an inhibitor of vascular endothelial growth factor receptors (VEGFR)) or imatinib (a c-kit/PDGFR inhibitor). The control groups included single-agent kinase inhibitor treatments and [Lys40(Ahx-DTPA-natIn)NH2]-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg/kg. Subsequently, [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and treated with vatalanib or imatinib 100 mg/kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified. RESULTS Combination of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and vatalanib was significantly more effective than single treatments (p < 0.05) and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with [Lys40(Ahx-DTPA-111In)NH2]-exendin-4. CONCLUSION The combination of 1.1 MBq of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 with 100 mg/kg vatalanib had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone but without any apparent side effects, such as radiation damage of the kidneys.