Objectives The aim of this case match study was to compare the outcome of patients with paradoxical low-flow (left ventricular ejection fraction LVEF ≥50% but stroke volume index <35 ml/m2 ), ...low-gradient (mean gradient MG <40 mm Hg), a priori severe (aortic valve area AVA ≤1.0 cm2 ) aortic stenosis (AS) (PLG-SAS group) with that of patients with a severe AS (AVA ≤1.0 cm2 ) and consistent high-gradient (MG ≥40 mm Hg) (HG-SAS group) and with that of patients with a moderate AS (AVA >1.0 cm2 and MG <40 mm Hg) (MAS group). Background In patients with preserved LVEF, a discordance between the AVA (in the severe range) and the gradient (in the moderate range) raises uncertainty with regard to the actual severity of the stenosis and thus the therapeutic management of the patient. Methods In a prospective cohort of AS patients with LVEF ≥50%, we identified 187 patients in the PLG-SAS group. These patients were retrospectively matched: 1) according to the gradient, with 187 patients with MAS; and 2) according to the AVA, with 187 patients with HG-SAS. Results Patients with PLG-SAS had reduced overall survival (1-year: 89 ± 2%; 5-year: 64 ± 4%) compared with patients with HG-SAS (1-year: 96 ± 1%; 5-year: 82 ± 3%) or MAS (1-year: 96 ± 1%; 5-year: 81 ± 3%). After adjustment for other risk factors, patients with PLG-SAS had a 1.71-fold increase in overall mortality and a 2.09-fold increase in cardiovascular mortality compared with the 2 other groups. Aortic valve replacement was significantly associated with improved survival in the HG-SAS group (hazard ratio: 0.18; p = 0.001) and in the PLG-SAS group (hazard ratio: 0.50; p = 0.04) but not in the MAS group. Conclusions Prognosis of patients with paradoxical low-flow, low-gradient severe AS was definitely worse than those with high-gradient severe AS or those with moderate AS. The finding of a low gradient cannot exclude the presence of a severe stenosis in a patient with a small AVA and preserved LVEF and should mandatorily prompt further investigation.
In patients with COPD, cardiovascular diseases are the most common concomitant chronic diseases, a leading cause of hospitalization, and one of the main causes of death. A close connection exists ...between COPD and cardiovascular diseases. Cardiovascular risk scores aim to predict the effect of cardiovascular comorbidities on COPD mortality, but there is a need to better characterize occult and suboccult cardiovascular disease, even in patients with mild to moderate COPD. Among various surrogate markers of cardiovascular risk, arterial stiffness plays a central role and is a strong independent predictor of cardiovascular events beyond classic cardiovascular risk factors. Its measurement is highly suitable, validated, and relatively easy to perform in routine COPD clinical practice. The growing awareness of the increased cardiovascular risk associated with COPD has led to a call for respiratory physicians to measure arterial pulse wave velocity in routine practice. Cross-sectional data establish elevated arterial stiffness as being independently linked to COPD. Candidate mechanisms have been proposed, but surprisingly, only limited data are available regarding the impact of the different COPD treatment modalities on arterial stiffness, although initial studies have suggested a significant positive impact. In this review, we present the various surrogate markers of cardiovascular morbidity in COPD and the central role of arterial stiffness and the underlying mechanisms explaining vascular remodeling in COPD. We also consider the therapeutic impact of COPD medications and exercise training on arterial stiffness and the assessments that should be implemented in COPD care and follow-up.
Summary Background Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain ...stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. Methods We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke–Fahn–Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. Findings The mean Burke–Fahn–Marsden dystonia rating scale movement score improved from 44·2 (SD 21·1) before surgery to 34·7 (21·9) at 1 year post-operatively (p=0·009; mean improvement 24·4 21·1%, 95% CI 11·6–37·1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus GPe). Interpretation Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. Funding National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.
Abstract Background The currently recommended duration of dual antiplatelet therapy (DAPT) in drug-eluting stent (DES) recipients is 12 months to reduce the risk of late stent thrombosis, ...particularly in those with acute coronary syndrome (ACS). Objectives This study hypothesized that antiplatelet treatment with DAPT for 6 months may be noninferior to 24-month DAPT in aspirin-sensitive patients. Methods A multicenter, randomized study assigned patients undergoing implantation of everolimus-eluting stents with confirmed nonresistance to aspirin to receive 6- or 24-month DAPT. The primary endpoint was a composite of death, myocardial infarction, urgent target vessel revascularization, stroke, and major bleeding at 12 months post-stenting. Results A total of 2,031 patients were enrolled in 70 European and Middle Eastern centers. The trial was prematurely terminated due to recruitment problems, leaving 941 patients randomized to 24-month DAPT and 953 to 6-month DAPT. The 2 treatment groups had similar baseline and procedural characteristics. There was no significant difference in the primary endpoint (24-month: 1.5% vs. 6-month: 1.6%; p = 0.85). Noninferiority was demonstrated for 6- versus 24-month DAPT, with an absolute risk difference of 0.11% (95% confidence interval: −1.04% to 1.26%; p for noninferiority = 0.0002). There were no significant differences in stent thrombosis or bleeding complications. In the 792 (44%) high-risk patients with ACS, primary and secondary endpoints did not significantly differ (hazard ratio: 1.7 95% confidence interval: 0.519 to 6.057; p = 0.361). Conclusions Rates of bleeding and thrombotic events were not significantly different according to 6- versus 24-month DAPT after PCI with new-generation DES in good aspirin responders. (Is There A LIfe for DES After Discontinuation of Clopidogrel ITALICplus; NCT01476020 )
Background Long-term antifungal therapy is usually the only treatment option for chronic pulmonary aspergillosis. However, response rates are difficult to compare because the reported clinical, ...mycologic, or radiologic criteria are not standardized. Objective parameters are therefore needed. To define the most relevant CT imaging variables in assessment of response to treatment, we investigated changes over time in CT imaging variables. Methods Changes in CT imaging variables were assessed by systematic analysis of the CT scan findings of 36 patients at diagnosis and 6 months after initiation of treatment. The relevant radiologic variables were determined by selecting those showing significant changes over time. Two experienced thoracic radiologists, blinded for clinical and serologic response, independently performed CT scan analyses. Interreader agreement and concordance between radiologic and clinical response were evaluated. Results Of the 36 patients, seven experienced clinical deterioration while undergoing therapy. Significantly evolving radiologic variables included cavity and pleural wall thickening ( P < .05), which were associated with clinical improvement. There was a strong association between fungus ball disappearance and cavity/pleural wall thickening reduction and clinical improvement ( P = .04). There was poor agreement between size changes of cavities or nodules, and clinical evolution (Cohen’s κ, –0.13 to –0.24). Conclusions Variations in cavity and pleural wall thickness may be the most relevant CT imaging variables for assessing response to treatment. Loss of fungus ball is strongly associated with clinical and radiologic improvement, but cavity size changes are unrelated to chronic pulmonary aspergillosis evolution. All these CT imaging variables may be applied in future clinical trials to assess treatment outcome.
Abstract Background Low flow (LF) can occur with reduced (classic) or preserved (paradoxical) left ventricular ejection fraction (LVEF). Objectives The objective of this study was to compare outcomes ...of patients with low ejection fraction (LEF), paradoxical low flow (PLF), and normal flow (NF) after aortic valve replacement (AVR). Methods We examined 1,154 patients with severe aortic stenosis (AS) who underwent AVR with or without coronary artery bypass grafting. Results Among these patients, 206 (18%) had LEF as defined by LVEF of <50%; 319 (28%) had PLF as defined by LVEF of ≥50% but stroke volume indexed to body surface area (SVi) of ≤35 ml ∙ m−2 ; and 629 (54%) had NF, as defined by LVEF of ≥50% and SVi of >35 ml ∙ m2 . Aortic valve area was lower in low flow/LVEF groups (LEF: 0.71 ± 0.20 cm2 and PLF: 0.65 ± 0.23 cm2 vs. NF: 0.77 ± 0.18 cm2 ; p < 0.001). The 30-day mortality was higher (p < 0.001) in LEF and PLF groups than in the NF group (6.3% and 6.3% vs. 1.8%, respectively). SVi and PLF group were independent predictors of operative mortality (odds ratio OR: 1.18, p < 0.05; and OR: 2.97, p = 0.004; respectively). At 5 years after AVR, overall survival was 72 ± 4% in LEF group, 81 ± 2% in PLF group, and 85 ± 2% in NF group (p < 0.0001). Conclusions Patients with LEF or PLF AS have a higher operative risk, but pre-operative risk score accounted only for LEF and lower LVEF. Patients with LEF had the worst survival outcome, whereas patients with PLF and normal flow had similar survival rates after AVR. As a major predictor of perioperative mortality, SVi should be integrated in AS patients’ pre-operative evaluation.
Objective We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16–related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months. Study Design ...In all, 21 patients with HPV 16–related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy. Results Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up. Conclusion These promising data warrant further development of TG4001 in CIN 2/3 treatment.
Summary Background Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting in patients with HER2-negative metastatic breast cancer improves progression-free survival and the ...proportion of patients achieving pathological complete response. In the BEVERLY-1 (UCBG-0802) trial we aimed to assess the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy in the treatment of patients with HER2-negative inflammatory breast cancer. Methods We did this phase 2, single-arm trial at 20 hospitals in France. We enrolled women aged 18 years or older who had non-metastatic HER2-negative inflammatory breast cancer. Patients underwent 3-week treatment cycles, receiving neoadjuvant intravenous fluorouracil (500 mg/m2 ), epirubicin (100 mg/m2 ), cyclophosphamide (500 mg/m2 ), and bevacizumab (15 mg/kg) during cycles 1–4, then docetaxel (100 mg/m2 ) and bevacizumab during cycles 5–8. 2–4 weeks after surgery, patients received adjuvant radiotherapy, hormone therapy (if they had a hormone receptor-positive tumour), and adjuvant intravenous bevacizumab. The primary endpoint was pathological complete response in breast and axillary lymph nodes after neoadjuvant treatment, determined after centralised review in accordance with Sataloff classification and assessed in the intention-to-treat population. Our analysis of toxic effects included all patients who received at least one dose of bevacizumab. The trial is complete and follow-up is ongoing. This study is registered with ClinicalTrials.gov , number NCT00820547. Findings Between Jan 16, 2009, and Sept 8, 2010, we enrolled 101 patients, one of whom withdrew consent before treatment, leaving 100 patients in the primary endpoint analysis. After neoadjuvant therapy, 19 (19% 95% CI 12–28; p=0·16) of 100 patients achieved a pathological complete response according to centralised review. The most frequent grade 3–4 events during the neoadjuvant phase were neutropenia (89 89% of 100 patients), febrile neutropenia (37 37%), and mucositis (23 23%) and during the adjuvant phase the most frequent grade 3–4 adverse event was proteinuria (5 7% of 75 patients). One (1%) patient died of thrombotic microangiopathy after cycle 1, which was thought to be related to bevacizumab. Two patients (3%) developed transitory heart failure. 48 (48%) patients had serious adverse events, the most frequent of which was febrile neutropenia (28 28%). Interpretation Our results suggest that the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy does not provide clinical benefit to patients with non-metastatic HER2-negative inflammatory breast cancer. Longer follow-up and correlative studies to identify patients who might benefit from bevacizumab are needed. Funding Roche, La Ligue Nationale contre le Cancer, UNICANCER, and Chugai Pharma.
Humoral immune responses during heart transplantation may result in antibody-mediated rejection (AMR), which is now taken into account on endomyocardial biopsy (EMB) specimens and ranked according to ...the pathologic AMR (pAMR) grades of the International Society for Heart and Lung Transplantation classification. This classification might benefit from new immunohistological markers and validation by others biomarkers, namely donor-specific antibodies (DSA).
From the 293 protocol EMBs performed in 113 patients in our institution during a 1-year period for this prospective study, 280 EMB specimens were available with both histology and immunohistochemistry. C4d and labeling of intravascular cells by cluster of differentiation (CD) 68 were performed on paraffin sections. Available sera (n = 150) concomitant of EMB specimens were tested for the presence of DSA. All of the pAMR+ EMB specimens, along with a set of randomized pAMR0 EMB specimens, were immunolabeled for mammalian target of rapamycin (mTOR) effectors, phosphorylated 70 S6-kinase (p70S6K) and phosphorylated S6 ribosomal protein (pS6RP).
AMR was diagnosed in 37 EMB specimens (13.2%): 1 pAMR1(I+), 27 pAMR1(H+), and 9 pAMR2. The proportion of DSA-positive EMB varied according to the pAMR grade, with pAMR0, pAMR1(H+), and pAMR2 EMB presenting 17.6%, 77.3%, and 100% of DSA-positivity, respectively. Among the 30 pAMR+ specimens with available DSA testing and the 30 pAMR0 randomized specimens, mTOR pathway immunohistochemistry showed endothelial cell positivity for p70S6K in 17 pAMR+ EMB specimens (56.7%) and in 1 pAMR0 EMB specimen (3.3%). pS6RP was detected in 8 pAMR+ EMB specimens (26.7%) and in 1 pAMR0 EMB specimen (3.3%).
p70S6K and pS6RP immunohistochemistry afford new markers of AMR on EMB specimens because their expression is correlated with microcirculation inflammation and DSA. The correlation of DSA with pAMR grade suggests that this grading system is valid.
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