Artifact-free coronary magnetic resonance angiography and coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent.

BACKGROUND: Coronary in-stent restenosis cannot be directly assessed by magnetic resonance angiography (MRA) because of the local signal void of currently used stainless steel stents. The aim of this study was to investigate the potential of a new, dedicated, coronary MR imaging (MRI) stent for artifact-free, coronary MRA and in-stent lumen and vessel wall visualization. METHODS AND RESULTS: Fifteen prototype stents were deployed in coronary arteries of 15 healthy swine and investigated with a double-oblique, navigator-gated, free-breathing, T2-prepared, 3D cartesian gradient-echo sequence; a T2-prepared, 3D spiral gradient-echo sequence; and a T2-prepared, 3D steady-state, free-precession coronary MRA sequence. Furthermore, black-blood vessel wall imaging by a dual-inversion-recovery, turbo spin-echo sequence was performed. Artifacts of the stented vessel segment and signal intensities of the coronary vessel lumen inside and outside the stent were assessed. With all investigated sequences, the vessel lumen and wall could be visualized without artifacts, including the stented vessel segment. No signal intensity alterations inside the stent when compared with the vessel lumen outside the stent were found. CONCLUSIONS: The new, coronary MRI stent allows for completely artifact-free coronary MRA and vessel wall imaging.

Nilotinib compassionate use in advanced GIST : a retrospective analysis

Introduction: Tyrosine kinase inhibitors (TKI) have considerably improved outcome of patients with advanced GIST and extended overall survival to more than 5 years. Yet, the median progression-free survival is approximately 2 years with first-line imatinib and 24 weeks with second-line sunitinib, which calls for treatment alternatives. Nilotinib is a second-generation TKI with at least similar inhibitory activity as imatinib. A Phase I study has shown that nilotinib monotherapy has clinical activity in GIST. Methods: After failure of all available therapeutic options patients had access to nilotinib on a compassionate use (CU) programm. Nilotinib was started at a dose of 400 mg bid, with dose reduction to 400mg qd allowed in the case of toxicity. 94 pts were approved for nilotinib CU in 10 European countries. We herein present retrospective data of 42 pts from 5 European countries treated in 11 centers. Results: Median age at nilotinib treatment start was 59 years (median; range 24-79 y). 30 of 42 patients were male. Most pts had metastatic disease of gastric origin at initial diagnosis. KIT exon 11 mutations were most frequent. The median number of surgical resections was 1 (range 0-8). All pts had failed both imatinib and sunitinib before nilotinib, and few had also received additional investigational treatments. Nilotinib was well tolerated, and discontinued due to toxicity in 15% only. Median follow-up is 176 days (range 15-876 d). Nilotinib treatment duration is 75 days (median; range 3-727 d). Partial remission with nilotinib treatment was seen in 11% of pts. Median OS was 263 days (Kaplan-Meier). Conclusion: This is the largest series reported assessing efficacy of nilotinib for imatinib- and sunitinib-refractory GIST reported yet. Nilotinib displays significant clinical activity in this heavily pretreated group of pts. These results warrant further investigation of nilotinib in GIST, including its use in first or second-line treatment. Patient and data collection is ongoing, updated results will be presented.

Group mentoring for women starting a PhD: a "duty free zone" to build professional identity

Despite increasing numbers of women attaining higher level academic degrees, gender disparities remain among higher education and among university faculties. Some have posited that this may stem from inadequate academic identity development of women at the doctoral level. While existing gender differences may stem from multiple and variable origins, mentoring has been proposed as a viable means to promote academic identity development and address these gender gaps. This study used a qualitative, narrative case study design to evaluate "StartingDoc" a structured mentoring program launched among Swiss Universities aimed at promoting networking and academic identity development among female doctoral students. Herein we describe the 9 emergent themes which arose from the small-group mentoring program and suggest that such an approach is both feasible and beneficial for young female academics. Further work is needed to elucidate the most effective strategies for developing and retaining women in academia.

Interpolation-free Coregistration and Phase-Correction of Airborne SAR Interferograms

This letter discusses the detection and correction ofresidual motion errors that appear in airborne synthetic apertureradar (SAR) interferograms due to the lack of precision in the navigationsystem. As it is shown, the effect of this lack of precision istwofold: azimuth registration errors and phase azimuth undulations.Up to now, the correction of the former was carried out byestimating the registration error and interpolating, while the latterwas based on the estimation of the phase azimuth undulations tocompensate the phase of the computed interferogram. In this letter,a new correction method is proposed, which avoids the interpolationstep and corrects at the same time the azimuth phase undulations.Additionally, the spectral diversity technique, used to estimateregistration errors, is critically analyzed. Airborne L-bandrepeat-pass interferometric data of the German Aerospace Center(DLR) experimental airborne SAR is used to validate the method

PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers.

BACKGROUND: Renal calcium stones and hypercalciuria are associated with a reduced bone mineral density (BMD). Therefore, the effect of changes in calcium homeostasis is of interest for both stones and bones. We hypothesized that the response of calciuria, parathyroid hormone (PTH) and 1.25 vitamin D to changes in dietary calcium might be related to BMD. METHODS: A single-centre prospective interventional study of 94 hyper- and non-hypercalciuric calcium stone formers consecutively retrieved from our stone clinic. The patients were investigated on a free-choice diet, a low-calcium diet, while fasting and after an oral calcium load. Patient groups were defined according to lumbar BMD (z-score) obtained by dual X-ray absorptiometry (group 1: z-score <-0.5, n = 30; group 2: z-score -0.5-0.5, n = 36; group 3: z-score >0.5, n = 28). The effect of the dietary interventions on calciuria, 1.25 vitamin D and PTH in relation to BMD was measured. RESULTS: An inverse relationship between BMD and calciuria was observed on all four calcium intakes (P = 0.009). On a free-choice diet, 1.25 vitamin D and PTH levels were identical in the three patient groups. However, the relative responses of 1.25 vitamin D and PTH to the low-calcium diet were opposite in the three groups with the highest increase of 1.25 vitamin D in group 1 and the lowest in group 3, whereas PTH increase was most pronounced in group 3 and least in group 1. CONCLUSION: Calcium stone formers with a low lumbar BMD exhibit a blunted response of PTH release and an apparently overshooting production of 1.25 vitamin D following a low-calcium diet.

Medical treatments and risk factors for resection surgery in Crohn's disease: results from the Swiss IBD Cohort Study

Background: Surgery has been previously reported to be necessary in up to 80% of Crohn's disease (CD) patients, and up to 65% of patients needed reoperation after 10 years. Prevention of surgery is therefore a particularly important issue for these patients. Treatment options are controversial and data on them are scarce. This study reports medical treatments and main clinical risk factors in CD patients having undergone one or several surgeries. Risks for being free from surgery were also assessed. Methods: Retrospective cohort study, using data from patients included in the Swiss IBD cohort study from November 2006 to July 2011. History of resective surgeries, clinical characteristics and drug regimens were collected through detailed medical records. Univariate and multivariate analyses for clinical and therapeutic factors were performed. Cox regression was made to estimate free-of-surgery risks for different phenotypes and drugs. Results: Out of 1138 CD patients in the cohort, 721 (63.4%) were free of surgery at inclusion; 203 (17.8%) had 1 surgery and 214 (18.8%) >1 surgery. Main risk factors for surgery were disease duration 5-10 years (OR=2.92; p<0.001) and >10 years (OR=10.45; p<0.001), as well as stricturing (OR=8.33; p<0.001) or fistulizing disease (OR=7.34; p<0.001). Risk factors for repeated surgery was disease duration >10 years (OR=2.55; p=0.006) or fistulizing disease (OR=3.79; p<0.001). At inclusion, 107 patients (25.7%) had at least one anti-TNF alpha, 168 (40.3%) at least one immunosuppressive agent, and 41 (9.8%) at least 5-ASA or antibiotics. 64 (15.3%) were not exposed to any medical treatment. Kaplan-Meier curves showed that the risk of being free of surgery was 65% after 10 years, 42% after 20 years and 23% after 40 years. Surgical risks were four resp. five time higher for fistulizing and stricturing phenotypes (Hazard ratio (HR) =4.2; p<0.001; resp. HR=4.7; p<0.001) compared to inflammatory phenotype. Surgical risk was 4 times lower (HR=0.27; p=0.063) in CD patients under anti-TNF alpha compared to those under other or no drugs. Conclusion: The risk of having resective surgery was confirmed to be very high for CD in our cohort. Duration of disease, fistulizing and stricturing disease pattern enhance the risk of surgery. Anti-TNF alpha tends to lower this risk.

Free-breathing black-blood coronary MR angiography: initial results

The authors developed a free-breathing black-blood coronary magnetic resonance (MR) angiographic technique with a potential for exclusive visualization of the coronary blood pool. Results with the MR angiographic technique were evaluated in eight healthy subjects and four patients with coronary disease identified at conventional angiography. This MR angiographic technique accurately depicted luminal disease in the patients and permitted visualization of extensive continuous segments of the native coronary tree in both the healthy subjects and the patients. Black-blood coronary MR angiography provides an alternative source of contrast enhancement.

Improved coronary artery definition with T2-weighted, free-breathing, three-dimensional coronary MRA.

BACKGROUND: Three-dimensional (3D) navigator-gated and prospectively corrected free-breathing coronary magnetic resonance angiography (MRA) allows for submillimeter image resolution but suffers from poor contrast between coronary blood and myocardium. Data collected over >100 ms/heart beat are also susceptible to bulk cardiac and respiratory motion. To address these problems, we examined the effect of a T2 preparation prepulse (T2prep) for myocardial suppression and a shortened acquisition window on coronary definition. METHODS AND RESULTS: Eight healthy adult subjects and 5 patients with confirmed coronary artery disease (CAD) underwent free-breathing 3D MRA with and without T2prep and with 120- and 60-ms data-acquisition windows. The T2prep resulted in a 123% (P<0. 001) increase in contrast-to-noise ratio (CNR). Coronary edge definition was improved by 33% (P<0.001). Acquisition window shortening from 120 to 60 ms resulted in better vessel definition (11%; P<0.001). Among patients with CAD, there was a good correspondence with disease. CONCLUSIONS: Free-breathing, T2prep, 3D coronary MRA with a shorter acquisition window resulted in improved CNR and better coronary artery definition, allowing the assessment of coronary disease. This approach offers the potential for free-breathing, noninvasive assessment of the major coronary arteries.

Bortezomib(Velcade (R))-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation.

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35.

Relationship between motion of coronary arteries and diaphragm during free breathing: lessons from real-time MR imaging.

OBJECTIVE: Diaphragmatic navigators are frequently used in free-breathing coronary MR angiography, either to gate or prospectively correct slice position or both. For such approaches, a constant relationship between coronary and diaphragmatic displacement throughout the respiratory cycle is assumed. The purpose of this study was to evaluate the relationship between diaphragmatic and coronary artery motion during free breathing. SUBJECTS AND METHODS: A real-time echoplanar MR imaging sequence was used in 12 healthy volunteers to obtain 30 successive images each (one per cardiac cycle) that included the left main coronary artery and the domes of both hemidiaphragms. The coronary artery and diaphragm positions (relative to isocenter) were determined and analyzed for effective diaphragmatic gating windows of 3, 5, and 7 mm (diaphragmatic excursions of 0-3, 0-5, and 0-7 mm from the end-expiratory position, respectively). RESULTS: Although the mean slope correlating the displacement of the right diaphragm and the left main coronary artery was approximately 0.6 for all diaphragmatic gating windows, we also found great variability among individual volunteers. Linear regression slopes varied from 0.17 to 0.93, and r2 values varied from .04 to .87. CONCLUSION: Wide individual variability exists in the relationship between coronary and diaphragmatic respiratory motion during free breathing. Accordingly, coronary MR angiographic approaches that use diaphragmatic navigator position for prospective slice correction may benefit from patient-specific correction factors. Alternatively, coronary MR angiography may benefit from a more direct assessment of the respiratory displacement of the heart and coronary arteries, using left ventricular navigators.

ET-1 and NOS III gene expression regulation by plaque-free and plaque-prone hemodynamic conditions

Résumé: Les environnements hémodynamiques, favorisant ou protégeant contre la formation de la plaque, induisent tout deux une augmentation de la production d'anion superoxide dans les cellules endothéliales (ECs). Par ailleurs, une régulation différente de l'expression des gènes a été décrite dans les cellules exposées à ces différentes conditions. Dans le but d'investiguer le rôle de l'augmentation du stress oxydatif dans l'expression des gènes régulée par le flux, nous avons d'abord exposé les EC à un flux unidirectionnel, non pulsé. Dans ces conditions, l'état oxydatif des cellules endothéliales est augmenté de façon transitoire. L'expression du gène de l'endothéline 1 (ET-1) est aussi induite de façon transitoire par un tel flux, alors que l'expression du gène de la nitiric oxyde synthase endothéliale (NOS III) est stimulé de façon durable. Au contraire, un flux unidirectionnel pulsé, qui induit une augmentation durable de la production d'anion superoxide, augmente aussi de façon durable l'expression des gènes de ET-1 comme de NOS III. Un flux oscillatoire (favorisant la plaque), qui lui aussi ,a des effets à long terme sur la production d'anion superoxide, a uniquement augmenté l'expression de ET-1. De plus, l'utilisation d'un antioxydant, a seulement partiellement inhibé la stimulation de l'expression du gène NOS III par le flux unidirectionnel pulsé, alors qu'il a complètement abrogé la stimulation de l'expression du gène ET-1 par le flux unidirectionnel pulsé et oscillatoire. Ceci suggère que les forces mécaniques régulent l'expression des gènes dans les EC par un double mécanisme dépendant et indépendant du stress oxidatif des cellules. Par ailleurs, ces résultats supportent ultérieurement l'hypothèse que la balance entre la réponse oxidative et anti-oxidante dans les cellules endothéliales exposées à un environnement hémodynamique est une des clés de la prédisposition à un dysfonctionnement endothélial observé dans des régions exposées à des flux perturbés. Abstract: Both plaque-free and plaque-prone hemodynamic environments induce an increase in the oxidative state of endothelial cells (ECs), whereas differential gene expression regulation was described in cells exposed to these conditions. In order to investigate the role of the increased oxidative state in flow-regulation of gene expression, we first exposed EC to non-pulsed unidirectional shear stress. These conditions only slightly increases ECs oxidative state and endothelin-1 (ET-1) mRNA expression, whereas endothelial nitric oxide synthase (NOS III) mRNA level were significantly up-regulated. On the contrary, both ET-1 and NOS III gene expression were significantly induced in EC exposed to pulsed-unidirectional flow (plaque-free). Only ET-1 gene expression was up-regulated by oscillatory flow (plaque-prone). Moreover, use of an antioxidant only partially inhibited NOS III gene up-regulation by unidirectional flow, whereas it completely abrogated ET-1 gene up-regulation by unidirectional and oscillatory flows. Thus suggesting that mechanical forces regulate gene expression in ECs both via oxidative stress-dependent and -independent mechanisms.