Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.
Neuroimaging methods have failed to disclose correlation between degree of cerebral atrophy and blood flow in carotid artery stenosis patients. Moreover, intellectual improvement after carotid endarterectomy does not correlate fully with neuroimaging data in such patients. We performed brain electrical activity mapping and psychological testing before and 4 weeks after operation in 28 patients with symptomatic, high-grade, carotid stenosis. Postoperatively, electroencephalographic (EEG) mean frequency and absolute theta power improved significantly (p < 0.01). Mean frequency increased >1 Hz in most areas while power decreased dramatically, mainly because of resolution of high-voltage foci in 8 patients. Differences were conspicuous in both frontal lobes irrespective of the operated side, which suggests changes in perfusion affecting the whole brain. This is a positive effect of endarterectomy. Mini-Mental test and Set Test for verbal fluency had a positive correlation with the qEEG changes. Quantitative EEG as a measure of cerebral function has disclosed discriminative improvement in the early postoperative period. Our results support the thesis of improvement subsequent to endarterectomy.
We studied prospectively 35 elder women aged 65-82 years, with isolated severe symptomatic aortic stenosis, referred for aortic valve surgery. We assessed diastolic function by TEE before and after cardiac surgery, although follow-up data were collected in 26 patients. The examination was performed prior to surgery and 6 months after. The control group consisted of 32 patients referred for TEE. In the preoperative study, the velocities and integrals of the waves in the pulmonary vein flow were similar to the people of their same age, except the A-wave of atrial contraction and the integral of the systolic wave, which were significantly smaller (Control A-wave 26.1 +/- 5.1 vs preoperative A-wave 22.6 +/- 5.6, P = 0.009 and control double product A vel xA dur 2,748 +/- 835 vs preoperative 2,273 +/- 968, P = 0.03; systolic integral 14.6 +/- 3.8 vs 11.3 +/- 4, P = 0.0009). Six months after surgery, the PV flow was similar to the control group except for the wave of atrial contraction, which was significantly smaller but tended to normalization (postoperative A-wave 23.3 +/- 5, P = 0.04 vs control, and postoperative double product A vel x A dur 2460 +/- 893, P = 0.21 vs control). Mitral flow parameters did not change in the preoperative and postoperative period. Left ventricular mass index changed from 166 +/- 54 g/m(2) to 105 +/- 39 g/m(2) (P< 0.0001). The results of this study show that in elderly women with symptomatic severe AS, diastolic function does not change, left ventricular mass reduces, with improvement in symptoms, and the left atrium function, considered by pulmonary vein flow, is preoperative depressed and tends to mild recovery in the postoperative period, suggesting systolic LA failure.
A 75-year-old man had a 2-week history of recurrent, in crescendo episodes of diplopia, dizziness, dysarthria, and right-sided hemiparesis. Transcranial color-coded sonography (TCCS) showed a severe proximal basilar artery (BA) stenosis with an enddiastolic flow velocity of 142 cm/sec (figure, A, arrow) confirmed by angiography. BA angioplasty and stent application was performed in view of persisting crescendo-type symptoms despite combined anticoagulation and antiplatelet therapy. After successful stenting, TCCS showed complete revascularization with flow normalization in the BA ( figure, B), which persisted during 12-month follow-up. Stenting for symptomatic BA stenosis is feasible and may be an alternative in cases refractory to medical therapy.
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