Dabigatran versus vitamin k antagonist: an observational across-cohort comparison in acute coronary syndrome patients with atrial fibrillation.

Essentials Acute coronary syndrome (ACS) with atrial fibrillation (AF) is a therapeutic challenge. Dual and triple antithrombotic therapy showed a similar thrombotic risk in ACS patients with AF. The omission of aspirin during the first month did not increase the rate of ischemic events. Replacement of vitamin K antagonist by dabigatran leads to an increased thrombotic risk. SUMMARY: Background Dual antithrombotic therapy comprising a vitamin K antagonist (VKA) plus clopidogrel reduces the incidence of major bleeding compared with triple therapy (VKA + clopidogrel + aspirin) in acute coronary syndrome (ACS) patients with atrial fibrillation (AF), with a similar thrombotic risk. The oral thrombin inhibitor dabigatran (150 mg twice a day) showed superiority over VKA in non-valvular AF, but data supporting its use in AF patients presenting with ACS are limited. Objective We sought to evaluate the efficacy of dabigatran vs. VKA in the management of AF patients undergoing percutaneous coronary intervention for an ACS. Methods In this open-label study, 133 consecutive patients received dabigatran plus clopidogrel. Another cohort of 133 patients treated with VKA plus clopidogrel was used as the control group. Results After propensity score adjustment, the cumulative incidence of major adverse cardiovascular events over 24 months was higher with dabigatran vs. VKA (adjusted hazard ratio, 2.28; 95% confidence interval, 1.46-3.56). Similar rates of major bleeding were found (adjusted hazard ratio, 1.17; 95% confidence interval, 0.46-2.96). Conclusions In AF patients presenting with ACS, replacement of VKA by dabigatran concurrently with clopidogrel is associated with an increased thrombotic risk, without a reduction in major bleeding.

[Management of NSTEMI in a hospital without interventional cardiology and without use of GRACE score: Does the clinician appreciation match the GRACE score calculated retrospectively for the coronarography delay?] / Prise en charge des syndromes coronaires aigus sans sus décalage du ST dans un hôpital sans cardiologie interventionnelle : l'appréciation du clinicien rejoint-elle le score de GRACE dans le délai de réalisation de la coronarographie ?

PURPOSE: The management of non-ST segment elevation acute coronary syndromes (NSTEACS) remains an issue for mobidity, mortality, and an economic stake. The first aim of the study was to evaluate the additional value of the GRACE score for the compliance with the recommended times to coronary angiography in an hospital without interventional cardiology. We also analysed the in-hospital and 6-month mortality and the predictive factors of compliance for the coronarography delays. METHODS: Retrospective monocenter cross-sectional study including consecutive patients with chest pain suggestive of a NSTEACS during 1 year. Data of the delay to coronarography were collected and GRACE score was calculated a posteriori. RESULTS: The time to perform coronary angiography was non-compliant in 49% of cases (27 patients out of 55). The calculation of the GRACE score would have allowed correcting the delay for two patients of our cohort. Clinical appreciation, troponin elevation, ECG modifications were associated with the delay compliance. Age <75 years predisposed to recommended delays. Renal failure and history of coronaropathy were significantly associated with non compliant delays. A non-compliant delay was significantly associated with higher mortality. CONCLUSION: In our experience, the knowledge of the GRACE score had little impact on the timing of coronary angiography. However, as a predictor of mid and long term mortality, GRACE score remains SCA ST+ useful to intensify surveillance of high-risk patients.

Treatment of drug-eluting stents in-stent restenosis with paclitaxel-coated balloon angioplasty: Insights from the French "real-world" prospective GARO Registry.

BACKGROUND: Data about paclitaxel-eluting balloon (PCB) angioplasty to treat drug-eluting stents (DES) in-stent restenosis (ISR) were mainly collected in selected patient populations in the setting of randomized trials. The main goal of this prospective registry was to confirm the positive findings of these studies in an unselected population in clinical practice. METHODS: Consecutive patients with DES-ISR treated by PCB angioplasty were recruited in this prospective real-world registry. The primary endpoint was clinically driven target-lesion revascularization (TLR) at 9 months. Secondary endpoints included acute technical success, in-hospital outcomes, 9-month major adverse cardiac events (MACE) a composite of death, myocardial infarction (MI) and TLR and the occurrence of target vessel revascularization. RESULTS: A total of 206 patients (67.7 ± 10.2 years, 80.6% male, 41.3% diabetics) with 210 lesions were recruited. Unstable coronary artery disease was present in 55.3% of patients. The time from DES implantation to DES-ISR was 3.0 ± 2.4 years. Quantitative analyses revealed that patterns of treated DES-ISR were focal in 55.7% and diffuse in 44.3%. The reference diameter was 2.76 ± 0.64 mm. The 9-month follow-up rate was 90.8% (187/206). At 9 months, the TLR rate was 7.0% (13/187) whereas the rates for MACE, MI and cardiac death were 10.7% (20/187), 4.8% (9/187) and 2.1% (4/187) respectively. Results were consistent in patients with paclitaxel and non-paclitaxel-eluting stents (PES) ISR. CONCLUSION: This large prospective registry demonstrated acceptable rates of TLR and MACE at 9 months after treatment of DES-ISR by PCB angioplasty. PCB angioplasty was equally effective in patients with PES-ISR and non PES-ISR.

The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1.

In non-small cell lung cancer (NSCLC), receptor tyrosine kinases (RTKs) stand out among causal dominant oncogenes, and the ablation of RTK signaling has emerged as a novel tailored therapeutic strategy. Nonetheless, long-term RTK inhibition leads invariably to acquired resistance, tumor recurrence and metastatic dissemination. In ALK+ cell lines, inhibition of ALK signaling was associated with coactivation of several RTKs, whose pharmacological suppression reverted the partial resistance to ALK blockade. Remarkably, ERBB2 signaling synergized with ALK and contributed to the neoplastic phenotype. Moreover, the engagement of wild-type epidermal growth factor receptor or MET receptors could sustain cell viability through early growth response 1 (EGR1) and/or Erk1/2; Akt activation and EGR1 overexpression prevented cell death induced by combined ALK/RTK inhibition. Membrane expression of ERBB2 in a subset of primary naive ALK+ NSCLC could be relevant in the clinical arena. Our data demonstrate that the neoplastic phenotype of ALK-driven NSCLC relays 'ab initio' on the concomitant activation of multiple RTK signals via autocrine/paracrine regulatory loops. These findings suggest that molecular and functional signatures are required in de novo lung cancer patients for the design of efficacious and multi-targeted 'patient-specific' therapies.

Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel.

BACKGROUND: Post-treatment platelet reactivity (PR) is associated with ischemic and bleeding events in patients receiving P2Y12 receptor antagonists. OBJECTIVES: We aimed to study the relationship between post-treatment PR after a 60-mg loading dose (LD) of prasugrel and 1-year thrombotic and bleeding events. METHOD: Patients were prospectively included in this multicenter study if they had a successful percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and received prasugrel. The platelet reactivity index (PRI) was measured using the Vasodilator-Stimulated Phosphoprotein index (VASP) after a prasugrel LD. Endpoints included the rate of thrombotic events and bleeding events at 1 year. RESULTS: Among the 301 patients enrolled, 9 (3%) were lost to follow-up at 1 year. The rates of thrombotic and bleeding events at 1 year were of 7.5% and 6.8%, respectively. Receiver-operating curve (ROC) analysis demonstrated an optimal cut-off value of 53.5% of PRI to predict thrombotic events at 1 year. Using this cut-off value we observed that patients exhibiting high on-treatment platelet reactivity (HTPR) had a higher rate of thrombotic events (22.4% vs. 2.9%; P < 0.001). In parallel the optimal cut-off value of PRI to predict bleeding was 16%. Patients with a PRI ≤ 16% had a higher rate of bleeding events compared with those with a PRI > 16% (15.6% vs. 3.3%; P < 0.001). In multivariate analysis, the PRI predicted both thrombotic and bleeding events (OR: 1.44, 95% confidence interval [CI]: 1.2-1.72; P < 0.001 and OR: 0.75, 95% CI: 0.59-0.96; P = 0.024 [respectively, per 10% increase]). CONCLUSION: Platelet reactivity measurement after a prasugrel LD predicts both ischemic and bleeding events at 1 year follow-up for ACS patients undergoing PCI.

EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations.

PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.

Mobilization of CD34+ KDR+ endothelial progenitor cells predicts target lesion revascularization.

BACKGROUND: Endothelial lesion and regeneration are critical events in the process leading to in-stent restenosis (ISR) after bare metal stent (BMS) percutaneous coronary intervention (PCI). OBJECTIVES: To prospectively investigate the relationship between biomarkers reflecting endothelial turnover and the occurrence of ISR. METHODS: We performed a multicenter prospective observational study that included 156 patients undergoing elective PCI with BMS. Endothelial lesion was assessed by the enumeration of circulating endothelial cells (CECs). Endothelial regeneration was evaluated by enumeration of circulating CD34+ progenitor cells (CD34+ PCs) and CD34+ KDR+ endothelial progenitor cells (EPCs). Measurements were performed before PCI, and 6 and 24 h after PCI. Dynamic changes were evaluated by calculating the delta value of each marker. The primary and secondary endpoints of the study were clinical target lesion revascularizations (TLRs) and major adverse cardiovascular events (MACEs) after 6 months of follow-up. RESULTS: During follow-up, 28 MACEs were recorded, including 27 TLRs. PCI induced a significant rise in the numbers of CECs, CD34+ PCs, and CD34+ KDR+ EPCs. Baseline, 6-h and 24-h levels of these markers did not differ between patients with and without TLR. The delta percentage of CD34+ KDR+ EPCs was significantly reduced in patients with TLR as compared with patients without TLR (- 0.56 ± 8.1 vs. 2.91 ± 6.2; P = 0.015). In multivariate analysis, the delta percentage of CD34+ KDR+ EPCs independently predicted the occurrence of TLR and MACEs (P = 0.02 and P = 0.014, respectively). CONCLUSION: The endothelial regenerative response to injury induced by PCI, assessed by CD34+ KDR+ EPCs mobilized among progenitor cells, determines the risk of TLR and MACEs in stable coronary artery disease patients.

Solitary fibrous tumours: unusual aspects of a rare disease.

BACKGROUND: In literature there are only a few descriptions of the typical presentation of solitary fibrous tumours (SFT) and only a few case reports showing its unusual clinical and radiological features. METHODS: We retrospectively evaluated the computed tomography scans of 36 patients presenting with a histological diagnosis of SFT between 1998 and 2008. RESULTS: We present five cases of SFT with an atypical clinical presentation and radiological features. CONCLUSIONS: SFT can occasionally present with unusual radiological features making a differential diagnosis difficult. Even thought imaging plays a fundamental role in the initial diagnostic approach, final diagnosis in only confirmed by biopsy and histology.

[Role of angioplasty in the treatment of renal artery stenosis]. / Place de l'angioplastie des artères rénales.

Atherosclerotic renal artery stenosis is frequent and is associated with a high incidence of morbidity and mortality, with a strong correlation with coronary artery disease, (Kalra et al., 2005; Cheung et al., 2002; Guo et al., 2007 [1-3]). The atherosclerotic renal artery stenosis is an independent predictive factor of death (Conlon et al., 1998 [4]). The treatment of this lesion does not have strong evidence. A lot of studies in this area suggest the angioplasty is superior in a big majority between surgery, and angioplasty with stent is superior between balloon angioplasty, but some studies fail to prove the superiority of angioplasty versus medical treatment. These studies have sadly a lot of mistakes and nowadays we don't know what is the treatment for our patients in a lot of cases. The angioplasty is indicated when there is a failure of antihypertensive medications for control of blood pressure, when it is associated with a renal insufficiency quickly progressive or when there is a lesion on each renal artery. Other studies must be organized for prove the superiority of angioplasty when there is a real stenosis, maybe with the use of fractional flow reserve.

Unveiling the mysteries of clopidogrel metabolism and efficacy.

Clopidogrel is an important antiplatelet agent, but a considerable variability in the biological effect of the drug has been observed. Additionally, patients with insufficient platelet reactivity inhibition following a loading dose (LD) of clopidogrel have a poor outcome. The mechanisms of variability are dependent on genetic polymorphisms of enzymes involved in clopidogrel metabolism. Paraoxonase 1 has been identified as the main determinant of the biological and clinical efficacy of clopidogrel. This finding could enable the use of pharmacogenomics to tailor antiplatelet agents.

Breast MR with special focus on DW-MRI and DCE-MRI.

The use of magnetic resonance imaging (MRI) for the assessment of breast lesions was first described in the 1970s; however, its wide application in clinical routine is relatively recent. The basic principles for diagnosis of a breast lesion rely on the evaluation of signal intensity in T2-weighted sequences, on morphologic assessment and on the evaluation of contrast enhancement behaviour. The quantification of dynamic contrast behaviour by dynamic contrast-enhanced (DCE) MRI and evaluation of the diffusivity of water molecules by means of diffusion-weighted MRI (DW-MRI) have shown promise in the work-up of breast lesions. Therefore, breast MRI has gained a role for all indications that could benefit from its high sensitivity, such as detection of multifocal lesions, detection of contralateral carcinoma and in patients with familial disposition. Breast MRI has been shown to have a role in monitoring of neoadjuvant chemotherapy, for the evaluation of therapeutic results during the course of therapy. Breast MRI can improve the determination of the remaining tumour size at the end of therapy in patients with a minor response. DCE-MRI and DW-MRI have shown potential for improving the early assessment of tumour response to therapy and the assessment of residual tumour after the end of therapy. Breast MRI is important in the postoperative work-up of breast cancers. High sensitivity and specificity have been reported for the diagnosis of recurrence; however, pitfalls such as liponecrosis and changes after radiation therapy have to be carefully considered.

Breast ductal carcinoma and metastatic lymphoma to the contralateral breast in patient with cutaneous non-Hodgkin lymphoma.

Breast lymphoma is a rare condition, both as a primary and a metastatic manifestation. The primary form has an incidence ranging from 0.04% to 0.5% of all breast neoplasms, whereas the metastatic form has an incidence of 0.07%. We hereby report a clinical case of a patient who presented with cutaneous non-Hodgkin lymphoma (NHL) in the left scapulohumeral region treated with surgery followed by radiotherapy (40 Gy total). Three years following radiotherapy, the patient was diagnosed with a left breast infiltrating ductal carcinoma, treated with conservative surgery and adjuvant therapy. The following year, i.e. four years after the initial diagnosis of NHL, two lymphoproliferative relapses occurred: in the left cutaneous scapulohumeral region at the original site of disease, and in the right breast. The aim of this paper is to highlight an uncommon oncologic disorder such as breast lymphoma, highlighting its clinical and radiological manifestations. Some studies reported a possible aetiological role of radiotherapy in the development of breast cancer following treatment of NHL, and in the development of breast cancer following treatment of Hodgkin lymphoma, which could potentially explain our findings.

Intraobserver and interobserver variability in the calculation of apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (DW-MRI) of breast tumours.

PURPOSE: This study evaluated intraobserver and interobserver variability in the measurement of apparent diffusion coefficient (ADC) values in breast carcinomas. MATERIALS AND METHODS: Twenty-eight patients with solid breast lesions >10 mm underwent conventional contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted MRI (DW-MRI). Two observers (expert and trainee) segmented the lesion from the surrounding breast tissue on DW images with high b-value (1,000 s/mm(2)). This analysis was repeated by the expert reader after 6 months. Volumes were analysed to obtain mean, median and standard deviation (SD) of the ADC values. Interobserver and intraobserver variation was analysed using the Bland-Altman graph. RESULTS: All lesions were breast carcinomas, with a mean ADC value of 1.07 × 10(-3) mm(2)/s. The mean of the differences was 0.012 × 10(-3) mm(2)/s, corresponding to an intraobserver variability of 1.1% (limits of agreement: -5%/+8%). The mean interobserver difference was 0.022 × 10(-3) mm(2)/s, corresponding to an interobserver variability of 2% (limits of agreement: -9%/+14%). CONCLUSIONS: We found a low intraobserver and interobserver variability in calculating ADC in breast carcinomas, which supports its potential use in routine clinical practice.

CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells.

Homing of chronic lymphocytic leukemia (CLL) cells to sites favoring growth, a critical step in disease progression, is principally coordinated by the CXCL12/CXCR4 axis. A cohort of 62 CLL patients was divided into migrating and nonmigrating subsets according to chemotaxis toward CXCL12. Migrating patients phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) proteins more than nonmigrating patients (P<0.0002). CD38 expression was the parameter most strongly associated with heightened CXCL12 signaling (P<0.0001), confirmed by independent statistical approaches. Consistent with this observation, CD38(-) CLL cells in samples with bimodal CD38 expression responded less to CXCL12 than the intact clone (P=0.003). Furthermore, lentivirus-induced de novo expression of CD38 was paralleled by increased responses to CXCL12, as compared with cells infected with a control virus. CD38 ligation with agonistic monoclonal antibodies (mAbs) enhanced CXCL12 signaling, whereas blocking anti-CD38 mAbs inhibited chemokine effects in vitro. This is attributed to physical proximity on the membrane between CD38 and CXCR4 (the CXCL12 receptor), as shown by (i) coimmunoprecipitation and (ii) confocal microscopy experiments. Blocking anti-CD38 mAbs significantly compromised homing of CLL cells from blood to lymphoid organs in a mouse model. These results indicate that CD38 synergizes with the CXCR4 pathway and support the working hypothesis that migration is a central step in disease progression.

Perfusion CT in solid body-tumours. Part II: Clinical applications and future development.

Perfusion computed tomography (CTP) has shown great potential in diagnosing tumours and evaluating and predicting treatment response and has been the subject of numerous experimental and clinical studies. Its increasing availability and simplicity allow it to be performed alongside morphological imaging to complete the evaluation of neoplastic lesions. The aim of this paper is to describe our personal experience and review the literature on the applications of CTP in tumours of different body regions, with particular regard to fields of development for new research. Increased clinical application is desirable, especially in relation to a wider use of antiangiogenic drugs. Additional and ideally multicentre studies are necessary to define the role of this technique.

Role of operator experience in ultrasound-guided fine-needle aspiration biopsy of the thyroid.

PURPOSE: Thyroid nodules are commonly encountered in clinical practice, and ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the gold standard in diagnosing the pathological nature of undetermined thyroid nodules. The aim of this study was to evaluate whether operator experience influences the diagnostic accuracy of US-guided FNAB. MATERIALS AND METHODS: A total of 700 consecutive US-guided FNAB done by a single radiologist between 2000 and 2007 were retrospectively analysed. The same freehand technique and capillary-action technique with 22- or 25-gauge needles was used for all nodules, All specimens were prepared and fixed without the cytologist on site and were subsequently analysed by two expert cytologists. The procedures were chronologically divided into seven groups and classified as diagnostic or nondiagnostic. RESULTS: The rate of nondiagnostic procedures for each group was 32% in group 1, 13% in group 2, 17% in group 3, 11% in group 4, 10% in group 5, 5% in group 6 and 8% in group 7. No major complications were recorded. CONCLUSIONS: The rate of nondiagnostic US-guided FNAB is heavily dependent on the operator's experience. We estimated that at least 200 procedures need to be performed in order to achieve the levels of diagnostic accuracy reported in the literature. We therefore suggest specific training before operators routinely perform this procedure in clinical practice.