Novel image-guided marker aimed at organ-preserving therapies for prostate cancer.

OBJECTIVE: We developed fiducial imaging-guidance markers for the prostate with less imaging artifacts than currently commercially available markers. The aim of this study was to evaluate the imaging artifacts and potential usefulness and safety of these novel fiducial imaging markers in preclinical experiments. METHODS: We selected specific metal materials and a shape that can minimize artifacts in line with a license we obtained for a metal with a gold-platinum (Au-Pt) alloy composition that maximized artifact-free MRI images. Both phantom and canine prostate tests were conducted in order to evaluate the imaging artifacts for three imaging modalities, MRI, CT and ultrasound, and the risk of migration of the markers from the site of insertion to elsewhere, as well as crushing. RESULTS: The newly developed Au-Pt material had less imaging artifacts in the MRI, CT and ultrasound imaging modalities in comparison with current commercially available fiducial markers made from gold materials only. The Au-Pt markers had sufficient strength and durability and were considered to be potentially clinically useful and safe markers. CONCLUSION: The developed Au-Pt markers could be potential tools for accurate lesion-targeted, organ-preserving therapies such as lesion-targeted focal therapy and active surveillance in addition to conventional radiation therapies.

Development of Gold Nanorods Conjugated with Radiolabeled Anti-human Epidermal Growth Factor Receptor 2 (HER2) Monoclonal Antibody as Single-Photon Emission Computed Tomography/Photoacoustic Dual-Imaging Probes Targeting HER2-Positive Tumors.

Surgery remains one of the main treatments of cancer and both precise pre- and intraoperative diagnoses are crucial in order to guide the operation. We consider that using an identical probe for both pre- and intra-operative diagnoses would bridge the gap between surgical planning and image-guided resection. Therefore, in this study, we developed gold nanorods (AuNRs) conjugated with radiolabeled anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and investigated their feasibility as novel HER2-targeted dual-imaging probes for both single photon emission computed tomography (SPECT) (preoperative diagnosis) and photoacoustic (PA) imaging (intraoperative diagnosis). To achieve the purpose, AuNRs conjugated with different amount of trastuzumab (Tra) were prepared, and Tra-AuNRs were labeled with indium-111. After the evaluation of binding affinity to HER2, cell binding assay and biodistribution studies were carried out for optimization. AuNRs with moderate trastuzumab conjugation (Tra2-AuNRs) were proposed as the novel probe and demonstrated significantly higher accumulation in NCI-N87 (HER2 high-expression) tumors than in SUIT2 (low-expression) tumors 96 h post-injection along with good affinity towards HER2. Thereafter, in vitro PA imaging and in vivo SPECT imaging studies were performed. In in vitro PA imaging, Tra2-AuNRs-treated N87 cells exhibited significant PA signal increase than SUIT2 cells. In in vivo SPECT, signal increase in N87 tumors was more notable than that in SUIT2 tumors. Herein, we report that the Tra2-AuNRs enabled HER2-specific imaging, suggesting the potential as a robust HER2-targeted SPECT and PA dual-imaging probe.

Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer.

We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.

Coded excitation using periodic and unipolar M-sequences for photoacoustic imaging and flow measurement.

Photoacoustic imaging is an emerging imaging technology combining optical imaging with ultrasound. Imaging of the optical absorption coefficient and flow measurement provides additional functional information compared to ultrasound. The issue with photoacoustic imaging is its low signal-to-noise ratio (SNR) due to scattering or attenuation; this is especially problematic when high pulse repetition frequency (PRF) lasers are used. In previous research, coded excitation utilizing several pseudorandom sequences has been considered as a solution for the problem. However, previously proposed temporal coding procedures using Golay codes or M-sequences are so complex that it was necessary to send a sequence twice to realize a bipolar sequence. Here, we propose a periodic and unipolar sequence (PUM), which is a periodic sequence derived from an m-sequence. The PUM can enhance signals without causing coding artifacts for single wavelength excitation. In addition, it is possible to increase the temporal resolution since the decoding start point can be set to any code in periodic irradiation, while only the first code of a sequence was available for conventional aperiodic irradiation. The SNR improvement and the increase in temporal resolution were experimentally validated through imaging evaluation and flow measurement.

Artifact reduction in photoacoustic images by generating virtual dense array sensor from hemispheric sparse array sensor using deep learning.

PURPOSE: Vascular distribution is important information for diagnosing diseases and supporting surgery. Photoacoustic imaging is a technology that can image blood vessels noninvasively and with high resolution. In photoacoustic imaging, a hemispherical array sensor is especially suitable for measuring blood vessels running in various directions. However, as a hemispherical array sensor, a sparse array sensor is often used due to technical and cost issues, which causes artifacts in photoacoustic images. Therefore, in this study, we reduce these artifacts using deep learning technology to generate signals of virtual dense array sensors. METHODS: Generating 2D virtual array sensor signals using a 3D convolutional neural network (CNN) requires huge computational costs and is impractical. Therefore, we installed virtual sensors between the real sensors along the spiral pattern in three different directions and used a 2D CNN to generate signals of the virtual sensors in each direction. Then we reconstructed a photoacoustic image using the signals from both the real sensors and the virtual sensors. RESULTS: We evaluated the proposed method using simulation data and human palm measurement data. We found that these artifacts were significantly reduced in the images reconstructed using the proposed method, while the artifacts were strong in the images obtained only from the real sensor signals. CONCLUSION: Using the proposed method, we were able to significantly reduce artifacts, and as a result, it became possible to recognize deep blood vessels. In addition, the processing time of the proposed method was sufficiently applicable to clinical measurement.

Novel image analysis method using ultrasound elastography for noninvasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.

It has been established that the long-term infection of chronic hepatitis C leads to the increased risk of hepatic fibrosis and hepatocellular carcinoma. Currently, histological diagnosis by invasive and painful liver biopsy is the gold standard for evaluating the hepatic fibrosis stage. Because of a side effect or patient inability to cope with the pain, it is difficult to assess the fibrosis stage frequently using liver biopsy. Recently, instead of liver biopsy, many articles have been published showing the usefulness of ultrasound elastography to evaluate the stage of hepatic fibrosis. We also reported the usefulness of real-time tissue elastography (RTE) for liver fibrosis staging in 2007. However, in our previous report, fibrosis classification was performed manually and the number of patients involved was also small. In the current study, the fibrosis staging is performed automatically using software by characterizing the elastography images. We have also increased the number of patients from 64 to 310. Thus, the aim of this study is to increase objectivity by using a newly developed automatic analysis method. We obtain the Liver Fibrosis Index (LFI), which is calculated from image features of RTE images, using multiple regression analysis performed on clinical data of 310 cases as the training data set. The correlation coefficient obtained between the LFI and the stage of hepatic fibrosis was r = 0.68, and significant differences exist between all stages of fibrosis (p < 0.001). Our new method seems promising since it has the ability to diagnose fibrosis even in the presence of inflammation.

JSUM ultrasound elastography practice guidelines: basics and terminology.

Ten years have passed since the first commercial equipment for elastography was released; since then clinical utility has been demonstrated. Nowadays, most manufacturers offer an elastography option. The most widely available commercial elastography methods are based on strain imaging, which uses external tissue compression and generates images of the resulting tissue strain. However, imaging methods differ slightly among manufacturers, which results in different image characteristics, for example, spatial and temporal resolution, and different recommended measurement conditions. In addition, many manufacturers have recently provided a shear wave-based method, providing stiffness images based on shear wave propagation speed. Each method of elastography is designed on the basis of assumptions of measurement conditions and tissue properties. Thus, we need to know the basic principles of elastography methods and the physics of tissue elastic properties to enable appropriate use of each piece of equipment and to obtain more precise diagnostic information from elastography. From this perspective, the basic section of this guideline aims to support practice of ultrasound elastography.

JSUM ultrasound elastography practice guidelines: liver.

In diffuse liver disease, it is extremely important to make an accurate diagnosis of liver fibrosis prior to determining indications for therapy or predicting treatment outcome and malignant potential. Although liver biopsy has long been the gold standard in the diagnosis of liver fibrosis, it is still an invasive method. In addition, the sampling error is an intrinsic problem of liver biopsy. Non-invasive serological methods for the diagnosis of liver fibrosis can be affected by factors unrelated to the liver. Recently, after the introduction of FibroScan, it became possible to measure liver fibrosis directly and non-invasively by elastography, which has attracted attention as a non-invasive imaging diagnostic tool for liver fibrosis. In addition, real-time tissue elastography is currently being used to conduct clinical trials at many institutions. Moreover, virtual touch quantification enables the observation of liver stiffness at any location by simply observing B-mode images. Furthermore, the recently developed ShearWave elastography visualizes liver stiffness on a color map. Elastography is thought to be useful for all types of diffuse liver diseases. Because of its association with portal hypertension and liver carcinogenesis, elastography is expected to function as a novel prognostic tool for liver disease. Although various elastographic devices have been developed by multiple companies, each device has its own measurement principle, method, and outcome, creating confusion in clinical settings. Therefore, it is extremely important to understand the characteristics of each device in advance. The objective of this guideline, which describes the characteristics of each device based on the latest knowledge, is for all users to be able to make the correct diagnosis of hepatic fibrosis by ultrasound elastography.

JSUM ultrasound elastography practice guidelines: breast.

Ten years have passed since the first elastography application: Real-time Tissue Elastography™. Now there are several elastography applications in existence. The Quality Control Research Team of The Japan Association of Breast and Thyroid Sonology (JABTS) and the Breast Elasticity Imaging Terminology and Diagnostic Criteria Subcommittee, Terminology and Diagnostic Criteria Committee of the Japan Society of Ultrasonics in Medicine (JSUM) have advocated breast elastography classifications for exact knowledge and good clinical use. We suggest two types of classifications: the technical classification and the classification for interpretation. The technical classification has been created to use vibration energy and to make images, and also shows how to obtain a good elastic image. The classification for interpretation has been prepared on the basis of interpretation of evidence in this decade. Finally, we describe the character and specificity of each vender equipment. We expect the present guidelines to be useful for many physicians and examiners throughout the world.

A study on the optimal condition of ground truth area for liver tumor detection in ultrasound images using deep learning.

PURPOSE: In recent years, efforts to apply artificial intelligence (AI) to the medical field have been growing. In general, a vast amount of high-quality training data is necessary to make great AI. For tumor detection AI, annotation quality is important. In diagnosis and detection of tumors using ultrasound images, humans use not only the tumor area but also the surrounding information, such as the back echo of the tumor. Therefore, we investigated changes in detection accuracy when changing the size of the region of interest (ROI, ground truth area) relative to liver tumors in the training data for the detection AI. METHODS: We defined D/L as the ratio of the maximum diameter (D) of the liver tumor to the ROI size (L). We created training data by changing the D/L value, and performed learning and testing with YOLOv3. RESULTS: Our results showed that the detection accuracy was highest when the training data were created with a D/L ratio between 0.8 and 1.0. In other words, it was found that the detection accuracy was improved by setting the ground true bounding box for detection AI training to be in contact with the tumor or slightly larger. We also found that when the D/L ratio was distributed in the training data, the wider the distribution, the lower the detection accuracy. CONCLUSIONS: Therefore, we recommend that the detector be trained with the D/L value close to a certain value between 0.8 and 1.0 for liver tumor detection from ultrasound images.

Small calcification indicator in ultrasonography using correlation of echoes with a modified Wiener filter.

PURPOSE: The purpose of this study is to improve the calcification depiction ability in ultrasonography using correlation of echoes with a modified Wiener filter. METHODS: The waveform of an ultrasound pulse changes when it passes through the location of a calcification. Since the change in echo waveform caused by a calcification decreases the correlation of waveforms in adjacent scan lines, we have proposed a calcification depiction method using the decorrelation of echoes. However, the low signal-to-noise ratio of echoes also decreases the correlation of the echoes. In this study, we employ the correlation of echoes with a modified Wiener filter to suppress the effect of noise, as an indicator of a calcification. RESULTS: The proposed calcification indicator depicted copper cylindrical rods 0.2 mm in size at a depth of 2 cm with a sensitivity of 80% and a positive predictive value of 80%, despite being hardly depicted at all on B-mode ultrasound imaging. CONCLUSION: This study suggests the potential of the proposed method to improve the performance of calcification depiction by ultrasound devices.

Shear wave speed measurement bias in a viscoelastic phantom across six ultrasound elastography systems: a comparative study with transient elastography and magnetic resonance elastography.

PURPOSE: To quantify the bias of shear wave speed (SWS) measurements in a viscoelastic phantom across six different ultrasound (US) systems and to compare the SWS with those from transient elastography (TE) and magnetic resonance elastography (MRE). METHODS: A viscoelastic phantom of stiffness representing fibrotic liver or healthy thyroid was measured with nine (linear probe) and 10 (convex probe) modes of six different US-based shear wave elastography (SWE) systems using linear and convex probes. SWS measurements of three regions of interest were repeated thrice at two focal depths, coupling the probe to the phantom using a jig. An MRE system using three motion-encoding gradient frequencies of 60, 90, and 120 Hz and TE were also used to measure the stiffness of the phantom. RESULTS: The SWS from different SWE systems had mean coefficients of variation of 9.0-9.2% and 5.4-5.6% with linear and convex probes, respectively, in viscoelastic phantom measurement. The focal depth was a less significant source of SWS variability than the system. The total average SWS obtained with US-SWE systems was 19.9% higher than that obtained with MRE at 60 Hz, which is commonly used in clinical practice, and 31.5% higher than that obtained with TE using the M probe. CONCLUSIONS: Despite the measurement biases associated with the SWE systems, biases were not necessarily consistent, and they changed with the probes used and depth measured. The SWS of the viscoelastic phantom obtained using different modalities increased according to the shear wave frequency used.

Artificial intelligence (AI) models for the ultrasonographic diagnosis of liver tumors and comparison of diagnostic accuracies between AI and human experts.

BACKGROUND: Ultrasonography (US) is widely used for the diagnosis of liver tumors. However, the accuracy of the diagnosis largely depends on the visual perception of humans. Hence, we aimed to construct artificial intelligence (AI) models for the diagnosis of liver tumors in US. METHODS: We constructed three AI models based on still B-mode images: model-1 using 24,675 images, model-2 using 57,145 images, and model-3 using 70,950 images. A convolutional neural network was used to train the US images. The four-class liver tumor discrimination by AI, namely, cysts, hemangiomas, hepatocellular carcinoma, and metastatic tumors, was examined. The accuracy of the AI diagnosis was evaluated using tenfold cross-validation. The diagnostic performances of the AI models and human experts were also compared using an independent test cohort of video images. RESULTS: The diagnostic accuracies of model-1, model-2, and model-3 in the four tumor types are 86.8%, 91.0%, and 91.1%, whereas those for malignant tumor are 91.3%, 94.3%, and 94.3%, respectively. In the independent comparison of the AIs and physicians, the percentages of correct diagnoses (accuracies) by the AIs are 80.0%, 81.8%, and 89.1% in model-1, model-2, and model-3, respectively. Meanwhile, the median percentages of correct diagnoses are 67.3% (range 63.6%-69.1%) and 47.3% (45.5%-47.3%) by human experts and non-experts, respectively. CONCLUSION: The performance of the AI models surpassed that of human experts in the four-class discrimination and benign and malignant discrimination of liver tumors. Thus, the AI models can help prevent human errors in US diagnosis.

Small calcification depiction in ultrasound B-mode images using decorrelation of echoes caused by forward scattered waves.

PURPOSE: The purpose of this study is to propose a novel method to depict small calcifications in ultrasound B-mode images using decorrelation of forward scattered waves with no decrease in the frame rate. METHODS: Since the waveform of an ultrasound pulse changes when it passes through a calcification location, the echo waveform from regions behind the calcification is quite different from that without a calcification. This indicates that the existence of a calcification is predictable based upon the waveform difference between adjacent scan lines by calculating cross-correlation coefficients. In addition, a high-intensity echo should return from the calcification itself. Therefore, the proposed method depicts the high-intensity echo positions with posterior low correlation coefficient regions. RESULTS: Eleven of 15 wires 0.2-0.4 mm in diameter were depicted using this method, yielding a sensitivity of 73.3% and a specificity of 100%, even though they might go undetected under clinical inspection of ultrasound B-mode images. CONCLUSION: This study suggests that an US device could perform well in terms of calcification detection.

A review of physical and engineering factors potentially affecting shear wave elastography.

It has been recognized that tissue stiffness provides useful diagnostic information, as with palpation as a screening for diseases such as cancer. In recent years, shear wave elastography (SWE), a technique for evaluating and imaging tissue elasticity quantitatively and objectively in diagnostic imaging, has been put into practical use, and the amount of clinical knowledge about SWE has increased. In addition, some guidelines and review papers regarding technology and clinical applications have been published, and the status as a diagnostic technology is in the process of being established. However, there are still unclear points about the interpretation of shear wave speed (SWS) and converted elastic modulus in SWE. To clarify these, it is important to investigate the factors that affect the SWS and elastic modulus. Therefore, physical and engineering factors that potentially affect the SWS and elastic modulus are discussed in this review paper, based on the principles of SWE and a literature review. The physical factors include the propagation properties of shear waves, mechanical properties (viscoelasticity, nonlinearity, and anisotropy), and size and shape of target tissues. The engineering factors include the region of interest depth and signal processing. The aim of this review paper is not to provide an answer to the interpretation of SWS. It is to provide information for readers to formulate and verify the hypothesis for the interpretation. Therefore, methods to verify the hypothesis for the interpretation are also reviewed. Finally, studies on the safety of SWE are discussed.

Non-invasive evaluation of hepatic fibrosis for type C chronic hepatitis.

OBJECTIVE: The aim of this study was to investigate liver fibrosis using non-invasive Real-time Tissue Elastography (RTE) and transient elastography (FibroScan) methods. METHODS: RTE, FibroScan and percutaneous liver biopsy were all performed on patients with chronic liver disease, particularly hepatitis C, to investigate liver fibrosis. RESULTS: FibroScan and RTE were compared for fibrous liver staging (F stage), which was pathologically classified using liver biopsy. In FibroScan, significant differences were observed between F1/F3 and F2/F4, but no such differences were observed between F1/F2, F2/F3 and F3/F4. In RTE, significant differences were observed between F1/F2, F2/F3 and F2/F4. But for F3/F4, no significant differences were observed. CONCLUSION: FibroScan and RTE correlated well with F staging of the liver. In particular RTE was more successful than FibroScan in diagnosing the degree of liver fibrosis.

Calculus detection for ultrasonography using decorrelation of forward scattered wave.

PURPOSE: The purpose of this paper is to propose a novel strategy to detect small calculi efficiently. METHODS: The proposed calculus detection strategy focuses on decorrelation of forward scattered waves caused by the failure of Born's approximation. A calculus causes waveform changes of transmit pulses, resulting in a decrease in the cross-correlation coefficients calculated from IQ signals scattered near the calculus position. Therefore, we can detect calculi from the appearance of dips in correlation coefficients. RESULTS: When a calculus exists in a digital tissue map, sharp and deep dips in cross-correlation coefficients between acoustic IQ signals appear around the calculus. By contrast, no apparent dip exists when a tissue map contains no calculus. A scan line interval of 0.2 mm or less is appropriate for the conditions simulated in this paper, and the proper transmit focal range for the proposed method is at a calculus range. CONCLUSION: These results imply that the proposed strategy can improve the efficiency of US devices for small calculus detection.

Study for quantitative evaluation of photoaging with photoacoustic microscopy.

Skin aging caused by ultraviolet light exposure is one of the serious problems from the viewpoint of beauty and healthcare. This is because ultraviolet light can cause age spot, wrinkles, at the worst case, skin cancer and so on. To evaluate skin aging, various modalities are being used, such as histopathological diagnosis, optical coherence tomography, ultrasound examination (B-mode imaging). However, they have disadvantages in terms of invasiveness, penetration depth and tissue specificity, respectively. To overcome these defects, photoacoustic imaging (PAI), a novel modality was used in this work. This modality can sense differences of tissue characteristics non-invasively. In this experiment, human skin tissues in various generations (i.e. various degrees of photoaging) were measured by using acoustic resolution photoacoustic microscopy (AR-PAM). To verify the feasibility of quantitative skin aging evaluation with PA technique, signals from sectioned human skin (cheek and buttock; female from 28 to 95 years old) were measured with PA microscopy. The effects of photoaging progress on the signal intensity were investigated. The results demonstrated that the PA signal from the dermis significantly increases with aging progress (p < 0.05). These analyses demonstrate the feasibility of quantitative skin aging evaluation with a PAI system.

Intervendor variability of carotid intima-media thickness measurement: validation study using newly developed ultrasound phantom.

PURPOSE: Ultrasonography-derived carotid artery intima-media thickness (IMT) has been established as an early atherosclerotic imaging biomarker. The IMT reference value of a healthy person is approximately 0.1 × (every 10 years of age) + 0.2 (mm); accordingly, it requires an accuracy of at least 0.1 mm. However, one concern of IMT measurement is intervendor variability. In this study, we aimed to verify the intervendor variability using an IMT phantom. METHODS: An improved IMT phantom was developed, and it was possible to analyze the IMT by software for all vendors. RESULTS: With the vendor-specific software, the maximum difference between the devices was 0.08 mm, and the difference in quartile range was 0.06 mm. On the other hand, with the vendor-independent offline software, the maximum difference between the devices was 0.16 mm, and the quartile range of variation was 0.06 mm. CONCLUSION: The intervendor variability assessed using our IMT phantom was less than 0.10 mm, and the on-board vendor-specific software was shown to reduce the difference between the devices significantly compared with the vendor-independent offline software. To further improve the vender difference, adjustment by means of vendor-specific software based on a standardized IMT phantom is warranted.

Correction to: Intervendor variability of carotid intima-media thickness measurement: validation study using newly developed ultrasound phantom.

In the Original publication of the article Table 3 was published incorrectly.