超声联合微泡在肿瘤化疗增敏的基础研究与临床应用进展

恶性肿瘤是一类死亡率很高的疾病，化疗是其重要的治疗方法之一。应用微泡的声孔效应提高细胞对化疗药物的摄取以增加肿瘤组织局部药物浓度达到增敏化疗的目的，是目前肿瘤治疗研究的新方向之一。超声联合微泡可增加肿瘤组织局部药物浓度、增强细胞毒作用，促进肿瘤细胞凋亡，缩小肿瘤体积，改善肿瘤对化疗药物的耐药性，具有良好的临床应用价值及前景。本文拟从超声联合微泡增敏肿瘤化疗的基础研究及临床运用方面进行综述。     

Using Speed of Sound Imaging to Characterize Breast Density

A population of 165 women with negative mammographic screens also received an ultrasound tomography (UST) examination at the Karmanos Cancer Institute in Detroit, MI. Standard statistical techniques were employed to measure the associations between the various mammographic- and UST-related density measures and various participant characteristics such as age, weight and height. The mammographic percent density (MPD) was found to have similar strength associations with UST mean sound speed (Spearman coefficient, r_s = 0.722, p < 0.001) and UST median sound speed (r_s = 0.737, p < 0.001). Both were stronger than the associations between MPD with two separate measures of UST percent density, a k-means (r_s = 0.568, p < 0.001) or a threshold (r_s = 0.715, p < 0.001) measure. Segmentation of the UST sound speed images into dense and non-dense volumes showed weak to moderate associations with the mammographically equivalent measures. Relationships were found to be inversely and weakly associated between age and the UST mean sound speed (r_s = ?0.239, p = 0.002), UST median sound speed (r_s = ?0.226, p = 0.004) and MPD (r_s = ?0.204, p = 0.008). Relationships were found to be inversely and moderately associated between body mass index (BMI) and the UST mean sound speed (r_s = ?0.429, p < 0.001), UST median sound speed (r_s = ?0.447, p < 0.001) and MPD (r_s = ?0.489, p < 0.001). The results confirm and strengthen findings presented in previous work indicating that UST sound speed imaging yields viable markers of breast density in a manner consistent with mammography, the current clinical standard. These results lay the groundwork for further studies to assess the role of sound speed imaging in risk prediction.     

Impact of Filling Gas on Subharmonic Emissions of Phospholipid Ultrasound Contrast Agents

Subharmonic signals backscattered from gas-filled lipid-shelled microbubbles have generated significant research interest because they can improve the detection and sensitivity of contrast-enhanced ultrasound imaging. However, the emission of subharmonic signals is strongly characterized by a temporal dependence, the origins of which have not been sufficiently elucidated. The features that influence subharmonic emissions need to be identified not only to better develop next-generation microbubble contrast agents, but also to develop more efficient subharmonic imaging (SHI) modes and therapeutic strategies. We examined the effect of microbubble filling gas on subharmonic emissions. Phospholipid shelled-microbubbles with different gaseous compositions such as sulfur hexafluoride (SF₆), octafluoropropane (C₃F₈) or decafluorobutane (C₄F₁₀), nitrogen (N₂)/C₄F₁₀ or air were insonated using a driving frequency of 10 MHz and peak negative pressure of 450 kPa, and their acoustic responses were tracked by monitoring both second harmonic and subharmonic emissions. Microbubbles were first acoustically characterized with their original gas and then re-characterized after substitution of the original gas with air, SF₆ or C₄F₁₀. A measureable change in intensity of the subharmonic emissions with a 20- to 40-min delayed onset and increasing subharmonic emissions of the order 12–18 dB was recorded for microbubbles filled with C₄F₁₀. Substitution of C₄F₁₀ with air eliminated the earlier observed delay in subharmonic emissions. Significantly, substitution of SF₆ for C₄F₁₀ successfully triggered a delay in the subharmonic emissions of the resultant agents, whereas substitution of C₄F₁₀ for SF₆ eliminated the earlier observed suppression of subharmonic emissions, clearly suggesting that the type of filling gas contained in the microbubble agent influences subharmonic emissions in a time-dependent manner. Because our agents were dispersed in air-stabilized phosphate-buffered saline, these results suggest that the diffusivity of the gas from the agent to the surrounding medium is correlated with the time-dependent evolution of subharmonic emissions.     

Articular Ultrasound in Asymptomatic Volunteers: Identification of the Worst Measures of Synovial Hypertrophy,Synovial Blood Flow and Joint Damage Among Small-, Medium- and Large-Sized Joints

Articular ultrasound of 6500 joint recesses was performed for the purpose of identifying which joint had the highest measurements among small-sized (SSJ), medium-sized (MSJ) and large-sized (LSJ) joints. Quantitative measurements of synovial hypertrophy (QSR) and semiquantitative measurements of synovial hypertrophy (SSH), power Doppler (SPD) and bone erosion (SBE) (score: 0–3) were made. Higher measurements (p < 0.01) of QSR were obtained in the second metatarsophalangeal joint (MTP), talonavicular joint, and hip. The highest SSH scores (2/3) were obtained in the second MTP, talonavicular joint, hip and knee; the highest SPD scores (1/2/3) in the first MTP, second MTP, dorsal second metacarpophalangeal (MCP) and radiocarpal recesses; and the highest SBE scores (2/3) in the radiocarpal, ulnocarpal and posterior recesses of the glenohumeral joint. In conclusion, higher measurements of synovial hypertrophy were found in the first and second MTPs (SSJ), talonavicular recess (MSJ) and hip (LSJ). Synovial blood flow was frequent in the first MTP and radiocarpal recess. Bone erosion stood out only in the glenohumeral joint.     

Monodisperse Versus Polydisperse Ultrasound Contrast Agents: Non-Linear Response,Sensitivity, and Deep Tissue Imaging Potential

It has been proposed that monodisperse microbubble ultrasound contrast agents further increase the signal-to-noise ratio of contrast-enhanced ultrasound imaging. Here, the sensitivity of a polydisperse pre-clinical agent was compared experimentally with that of its size- and acoustically sorted derivatives by using narrowband pressure- and frequency-dependent scattering and attenuation measurements. The sorted monodisperse agents had up to a two-orders-of-magnitude increase in sensitivity, that is, in the average scattering cross section per bubble. Moreover, we found, for the first time, that the highly non-linear response of acoustically sorted microbubbles can be exploited to confine scattering and attenuation to the focal region of ultrasound fields used in clinical imaging. This property is a result of minimal pre-focal scattering and attenuation and can be used to minimize shadowing effects in deep tissue imaging. Moreover, it potentially allows for more localized therapy using microbubbles through the spatial control of resonant microbubble oscillations.     

Inactivation behaviors of foodborne microorganisms in multi-frequency power ultrasound-treated orange juice

This study established the inactivation kinetic parameters of some pathogenic bacteria including Escherichia coli O157:H7, Salmonella enterica serotypes, and Listeria monocytogenes; and spoilage yeasts namely, Debaryomyces hansenii, Clavispora lusitaniae, Torulaspora delbrueckii, Pichia fermentans, and Saccharomyces cerevisiae in orange juice subjected to multi-frequency Dynashock power ultrasound treatment. All test organisms exhibited a biphasic inactivation behavior with a sigmoidal inactivation curve consisted of an initial inactivation lag, followed by logarithmic linear inactivation. Injury accumulation in the inactivation lag phase was established in acid-adapted bacteria. The time necessary to reduce initial inoculated populations by 5 log cycles (99.999%), T_5D values, significantly increased with acid adaptation. The T_5D of E. coli, S. enterica, and L. monocytogenes increased from 37.64, 36.87, and 34.59 respectively; to 54.72, 40.38, and 37.83 min respectively after acid exposure. Temperature increase due to sensible heat propagation during ultrasound treatment decreased the resistance of the test bacteria. The cocktail of E. coli O157:H7 had significantly greater resistance towards ultrasound treatment (T_5D = 54.72 min) than any of the individual strain (T_5D = 41.48–47.48 min) in the mix. Similar results were found in the composited (T_5D = 60.02 min) and individual species (T_5D = 20.31–59.04 min). The results established in this work provide baseline information on microbial behavior in multi-frequency ultrasound-treated orange juice for establishment of pasteurization process schedules.     

Effect of ultrasound irradiation on some freezing parameters of ultrasound-assisted immersion freezing of strawberries

In this study, the effect of ultrasound irradiation temperature and ultrasound intensity on the freezing and nucleation in strawberry samples was studied. The application of ultrasound irradiation at different temperatures was able to induce nucleation at lower degree of supercooling compared to the control samples. The achieved degree of supercooling in the ultrasound irradiated strawberries was linearly correlated to the ultrasound irradiation temperature. At the ultrasound irradiation temperature of −1.6 °C, the characteristic freezing time (CFT) was significantly shorter than that in the control sample (p < 0.05). The application of ultrasound at higher intensities was found to effectively shorten the CFT. The degree of supercooling in ultrasound irradiated samples was not linearly correlated to ultrasound intensity. In conclusion, the combination of ultrasound irradiation temperature and intensity can be effective in controlling nucleation and freezing processes of perishable fruits such as strawberry.     

Small Breast Lesion Classification Performance Using the Normalized Axial-Shear Strain Area Feature

Breast cancers that are found and confirmed because they are causing symptoms tend to be larger and are more likely to have already spread to the lymph nodes and beyond. Thus, early detection and confirmation are of paramount importance. The normalized axial–shear strain area (NASSA) feature from the axial-shear strain elastogram (ASSE) has been shown to be a feature that can identify the boundary-bonding conditions that are indicative of the presence of cancer. Recently, we investigated and reported on the potential of the NASSA feature for breast lesion classification into fibroadenomas and cancers. In this article, we investigate the size distribution of the lesions that were part of the previous study and analyze classification performance specifically on small lesions (<10 mm diameter). A total of 33 biopsy-proven malignant tumors and 30 fibroadenomas were part of the study that involved three observers blinded to the Breast Imaging Reporting and Data System (BIRADS) ultrasound scores. The observers outlined the lesions on the sonograms and the lesion size (maximum circle-equivalent diameter in millimeters) was computed from this outline. The ASSE was automatically segmented and color-overlaid on the sonogram, and the NASSA feature from ASSE was computed semi-automatically. Receiver operating characteristic curves were then generated for the subset of cases involving small lesions. Box plots were produced for the two different lesion size groups, small and large, from a logistic regression classifier that was built previously. The results of our study show that approximately 38% and 22% of the fibroadenomas and cancers, respectively, were small. Furthermore, it was found that the NASSA feature resulted in a perfect classification of the small lesions, both in the training data and in the cross-validation. For lesions <10 mm the difference in fibroadenoma and cancer mean scores was 0.73 ± 0.13 (p < 0.001), whereas lesions >10 mm had a difference of 0.52 ± 0.24 (p < 0.001). The results also showed that the small lesions actually had better classification than the larger lesions (>10 mm). These results suggest that the ASSE feature can work equally well, even on small lesions, to improve the standard ultrasound BIRADS–based breast lesion classification of fibroadenoma and malignant tumors.