Ultrasound Visualization and Recording of Transient Myocardial Vibrations.

OBJECTIVE: A new visualization and recording method used to assess and quantitate autogenic high-velocity motions in myocardial walls to provide a new description of cardiac function is described. METHODS: The regional motion display (RMD) is based on high-speed difference ultrasound B-mode images and spatiotemporal processing to record propagating events (PEs). Sixteen normal participants and one patient with cardiac amyloidosis were imaged at rates of 500-1000/s using the Duke Phased Array Scanner, T5. RMDs were generated using difference images and spatially integrating these to display velocity as function of time along a cardiac wall. RESULTS: In normal participants, RMDs revealed four discrete PEs with average onset timing with respect to the QRS complex of -31.7, +46, +365 and +536 ms. The late diastolic PE propagated apex to base in all participants at an average velocity of 3.4 m/s by the RMD. The RMD of the amyloidosis patient revealed significant changes in the appearance of PEs compared with normal participants. The late diastolic PE propagated at 5.3 m/s from apex to base. All four PEs lagged the average timing of normal participants. CONCLUSION: The RMD method reliably reveals PEs as discrete events and successfully allows reproducible measurement of PE timing and the velocity of at least one PE. The RMD method is applicable to live, clinical high-speed studies and may offer a new approach to characterization of cardiac function.

Contractile Fronts In The Interventricular Septum: A Case For High Frame Rate Echocardiographic Imaging.

The real time high frame rate (HFR) 2-dimensional ultrasound system, T5, at Duke University is capable of imaging at up to 1000 images per second for adult cardiac imaging. A method for detecting and visualizing the mechanical contraction fronts using HFR echocardioagraphy-derived Strain Rate Image (SRI) was described in 26 patients. The Tissue Shortening Onset front durations for echocardiographic normal patients were significantly shorter than conduction disorder patients with left bundle branch block (LBBB) with intrinsic conduction and conduction disorder patients without LBBB (non-LBBB) with simulated LBBB (sLBBB). Echocardiographic normal patients had significantly higher correlation coefficients between their SRIs and spatially inverted versions of themselves compared to non-LBBB patients with intrinsic conduction and sLBBB. In conclusion, SRIs could spatially resolve contractile event fronts in patients.

Quantitative Parameters of High-Frame-Rate Strain in Patients with Echocardiographically Normal Function.

Recently, we developed a high-frame-rate echocardiographic imaging system capable of acquiring images at rates up to 2500 per second. High imaging rates were used to quantify longitudinal strain parameters in patients with echocardiographically normal function. These data can serve as a baseline for comparing strain parameters in disease states. The derived timing data also reveal the propagation of mechanical events in the left ventricle throughout the cardiac cycle. High-frame-rate echocardiographic images were acquired from 17 patients in the apical four-chamber view using Duke University's phased array ultrasound system, T5. B-Mode images were acquired at 500-1000 images per second by employing 16:1 or 32:1 parallel processing in receive, a scan depth ≤14 cm and an 80° field of view with a 3.5-MegaHertZ (MHz), 96-element linear array. The images were analyzed using a speckle tracking algorithm tailored for high-frame-rate echocardiographic images developed at Aalborg and Duke University. Four specific mechanical events were defined using strain curves from six regions along the myocardial contour of the left ventricle. The strain curves measure the local deformation events of the myocardium and are independent of the overall cardiac motion. We observed statistically significant differences in the temporal sequence among different myocardial segments for the first mechanical event described, myocardial tissue shortening onset (p < 0.01). We found that the spatial origin of tissue shortening was located near the middle of the interventricular septum in patients with echocardiographically normal function. The quantitative parameters defined here, based on high-speed strain measurements in patients with echocardiographically normal function, can serve as a means of assessing degree of contractile abnormality in the myocardium and enable the identification of contraction propagation. The relative timing pattern among specific events with respect to the Q wave may become an important new metric in assessing cardiac function and may, in turn, improve diagnosis and prognosis.

High-Frame-Rate Deformation Imaging in Two Dimensions Using Continuous Speckle-Feature Tracking.

The study describes a novel algorithm for deriving myocardial strain from an entire cardiac cycle using high-frame-rate ultrasound images. Validation of the tracking algorithm was conducted in vitro prior to the application to patient images. High-frame-rate ultrasound images were acquired in vivo from 10 patients, and strain curves were derived in six myocardial regions around the left ventricle from the apical four-chamber view. Strain curves derived from high-frame-rate images had a higher frequency content than those derived using conventional methods, reflecting improved temporal sampling.

Live high-frame-rate echocardiography.

We describe an advanced real-time high-speed echocardiographic system with live display while scanning. Images are acquired at rates up to 1000 per second for adult cardiac applications and are stored in computer memory. Images may be played back in slow motion or frame by frame to analyze cardiac motion at the millisecond time scale. Images are acquired using the T5 Duke University Phased Array Scanner that allows 32:1 hardware parallel processing in receive and uses a defocused transmit beam. Clinical scans of 70 patients at rates of 240 to 1000 fps showed adequate image quality for diagnostic purpose. We anticipate that high temporal resolution cardiac images will enable the realization of more accurate and new quantitative descriptors of cardiac function in disease and health.

Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer.

PURPOSE: MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704. PATIENTS AND METHODS: Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed. RESULTS: Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2). CONCLUSION: Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.

Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma.

BACKGROUND: Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP-associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion. METHODS: From June 1, 1998 through September 28, 2000, 42 patients with AIPC were registered to receive docetaxel (70 mg/m2 intravenously over 1 hour) and EMP (280 mg orally every 6 hours x 5 doses) every 21 days, up to a maximum of 6 cycles. Dexamethasone was administered prior to docetaxel and coumadin 2 mg orally every day was taken during the study treatment period. Patient characteristics included a median age of 68 years, a median Eastern Cooperative Oncology Group performance status of 1, a median prostate specific antigen (PSA) level at study entry of 110.5 ng/mL, and a median of 2 prior hormonal manipulations. Ten patients (25%) had received prior chemotherapy, and 14 patients (33%) had received prior palliative radiation therapy. RESULTS: Forty patients were evaluable for response and toxicity. Eighteen patients (45%; 95% confidence interval, 29-62%) had a decline > 50% in PSA level that lasted > 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 4.0 months. Four of 20 patients (20%) had partial soft tissue responses. Ten of 17 symptomatic patients (59%) had improvement in pain. The median survival for all patients was 13.5 months. The most prominent Grade 3 and 4 toxicities were reversible myelosuppression and fatigue. Nausea, emesis, diarrhea, and peripheral edema were minimal. No thromboembolic or hepatic complications were seen. CONCLUSIONS: Docetaxel plus 1 multidose day of oral EMP was active in patients with AIPC and was associated with an acceptable toxicity profile. Overall, the therapeutic index of this regimen compared favorably with regimens that employed a longer administration of EMP.