Thermal assessment of 40-MHz ultrasound at soft tissue-bone interfaces

Tissue exposure to diagnostic ultrasound (US) can cause significant temperature rises. However, little has been reported on thermal effects of high-frequency US, and guidelines for the use of US do not necessarily apply to higher frequencies. Temperature rise induced by US biomicroscopy (UBM) was measured in phantoms containing mouse skulls and in anesthetized mice and mice post mortem, with a 50-microm K-type thermocouple. The operating frequency was 40 MHz with a free field I(SPTA) of 2.6 mW/cm(2) (B-mode) and 11.9 W/cm(2) (Doppler). Peak negative pressures were 5.22 MPa (B mode) and 7.32 MPa (Doppler), resulting in a mechanical index (MI) of 0.83 (B-mode) and 1.05 (Doppler mode). In Doppler mode, mean temperature rises of 1.80 degrees C and 1.73 degrees C were measured for proximal and distal skull phantom surfaces after a 3-min insonation. In vivo, the proximal mouse skull surface showed a mean temperature rise of 2.1 degrees C, with no statistically significant differences post mortem. Our results indicate temperature rise from insonation of bone interfaces using similar exposure parameters should not cause adverse bioeffects.     

Biological effects of high-frequency ultrasound exposure during mouse organogenesis

Little has been reported on bioeffects of high-frequency ultrasound (US) and guidelines for US use do not necessarily apply to high frequencies. Pregnant CD-1 mice were exposed to Doppler or B-mode US biomicroscopy (UBM) on embryonic day (E) 8.5 or E10.5, during organogenesis. Operating frequency was 40 MHz with a free field I(SPTA) of 11.9 W/cm(2) (Doppler) and 2.6 mW/cm(2) (B-mode), peak negative pressures of 6.61 MPa and MI of 1.05 (B-mode). Offspring were assessed weekly from 1 day postnatally to euthanasia at 6 weeks, with no significant difference in pup weight, body length or crown-rump length observed. E8.5 Doppler-exposed mice showed a small reduction in weight and length at 3 weeks and in weight at 6 weeks. E10.5 Doppler-exposed animals exhibited slight growth reduction in weeks 2 to 4, but were not significantly different at 6 weeks. Our results indicate similar exposures of mice should not cause significant adverse bioeffects.     

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.     

In vivo imaging of embryonic development in the mouse eye by ultrasound biomicroscopy

PURPOSE: New imaging tools now provide an unprecedented opportunity to visualize anatomic and functional development of the mouse eye. In this study, normal embryonic development of the mouse eye was studied by ultrasound biomicroscopy (UBM), with a focus on the formation of the retina, lens, and cornea. METHODS: The growth of 65 embryonic eyes from timed-pregnant CD-1 mice was examined at various stages of development between embryonic day (E)11.5 and E18.5, using 40-MHz UBM. RESULTS: The morphogenesis of ocular tissues including the lens, retina, and orbit were revealed from the earliest stages of development. The major axis of the CD-1 lens grows at a rate of 68 micro m/d, whereas that of the globe grows at a rate of 122 microm/d, with a concomitant exponential increase in volume. CONCLUSIONS: UBM allows noninvasive assessment of ocular morphogenesis in vivo and can be used to calculate relative growth rates of ocular structures.     

In vivo assessment of postnatal murine ocular development by ultrasound biomicroscopy

PURPOSE: Ultrasound biomicroscopy (UBM) can noninvasively provide anatomical information about mouse ocular structures. We present the quantitation of postnatal murine eye development using UBM. MATERIALS AND METHODS: The eyes from CD-1 mice were examined at 1, 2, 4, 6, and 8 weeks of postnatal development using 40 MHz UBM. Patterns of ocular tissue growth including the lens, globe, and anterior chamber were calculated. RESULTS: Postnatal CD-1 lens and globe volumes are consistent with an exponential decay of growth during the first 8 postnatal weeks. Anterior chamber depth increases most sharply in the first 2 postnatal weeks but continues to increase up to the 8th postnatal week. Anterior segment angle was observed to increase from 1 to 4 weeks. CONCLUSIONS: UBM can be used to obtain in vivo quantitative measurements of postnatal murine ocular structures. Our ability to obtain ocular anatomical information will facilitate future assessments of mouse models of human disease.     

Quantitation of hemodynamic function during developmental vascular regression in the mouse eye

PURPOSE: Ultrasound biomicroscopy (UBM) utilizes frequencies higher than conventional diagnostic ultrasound and can noninvasively provide anatomic and functional information about mouse ocular structures in vivo at high resolution. Vascular development can also be assessed with high-frequency Doppler imaging, which permits detection and characterization of ocular blood flow not detectable at lower, conventional Doppler frequencies. METHODS: The eyes of CD-1 mice were examined daily from the day of birth to postnatal day (P)16. Hyaloid vascular system anatomy was imaged with UBM and microcomputed tomography (microCT). Blood flow velocity was also measured with Doppler UBM imaging in the hyaloid artery, vasa hyaloidea propria, tunica vasculosa lentis, and retina. RESULTS: In the mouse, the hyaloid vasculature degenerated from a well-defined structure at birth by progressive loss of branches. Hyaloid regression coincided with a progressive decrease in blood velocity detected in the hyaloid vascular structures, which is thought to be one of the major triggering factors of the regression in these vessels. At P13, no further blood flow was detected in the CD-1 mouse hyaloid vasculature. An inverse relationship was also shown between peak blood velocity in the lens and retina. CONCLUSIONS: UBM imaging provides a valuable means of rapidly and noninvasively characterizing ocular development in vivo. MicroCT scans have also provided intralumenal images of hyaloid vascular structure. This is the first study of vascular structure and function during the dynamic process of hyaloid vascular regression during mouse neonatal eye development and the first three-dimensional images of the complex hyaloid vascular structure.