Impact of the Clinical Trials Act 2018 on clinical trial activity in Japan from 2018 to 2020: a retrospective database study using new and conventional Japanese registries.

OBJECTIVE: To clarify the impact of Japan's Clinical Trials Act (CTA), which was enacted in April 2018, on subsequent clinical trial activity through an analysis of Japanese registry data. DESIGN: Retrospective database study. SETTING: We extracted information on clinical intervention studies registered between 1 April 2018 and 30 September 2020 in the conventional University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) and the new Japan Registry of Clinical Trials (jRCT). We collected and analysed information on registration dates, intervention types, funding, secondary sponsors and use of designated staff in multidisciplinary roles (research planning support, research administration, data management, statistical analysis, monitoring and auditing). The temporal trends in clinical trial activity after CTA enactment were examined. RESULTS: A total of 577 CTA-compliant specified clinical trials (ie, studies funded by pharmaceutical companies or studies evaluating the efficacy and safety of off-label drugs or devices in humans) were registered in the jRCT. During the same period, 5068 clinical trials were registered in the UMIN-CTR. The number of specific clinical trials increased immediately after the implementation of the CTA and stabilised in late 2019, whereas the number of clinical trials registered in the UMIN-CTR generally declined over time. Specified clinical trials that received industry funding and public grants were more likely to use designated staff in multidisciplinary roles. CONCLUSIONS: The implementation of the CTA has not reduced the number of specified clinical trials, but has reduced the total number of intervention trials. The use of designated staff in multidisciplinary roles is associated with funding, secondary sponsors and multicentre studies. It was inferred that funding was needed to establish research infrastructure systems that support high-quality research.

¹³C MRS reveals a small diurnal variation in the glycogen content of human thigh muscle.

There is marked diurnal variation in the glycogen content of skeletal muscles of animals, but few studies have addressed such variations in human muscles. (13)C MRS can be used to noninvasively measure the glycogen content of human skeletal muscle, but no study has explored the diurnal variations in this parameter. This study aimed to investigate whether a diurnal variation in glycogen content occurs in human muscles and, if so, to what extent it can be identified using (13)C MRS. Six male volunteers were instructed to maintain their normal diet and not to perform strenuous exercise for at least 3 days before and during the experiment. Muscle glycogen and blood glucose concentrations were measured six times in 24 h under normal conditions in these subjects. The glycogen content in the thigh muscle was determined noninvasively by natural abundance (13)C MRS using a clinical MR system at 3 T. Nutritional analysis revealed that the subjects' mean carbohydrate intake was 463 ± 137 g, being approximately 6.8 ± 2.4 g/kg body weight. The average sleeping time was 5.9 ± 1.0 h. The glycogen content in the thigh muscle at the starting point was 64.8 ± 20.6 mM. Although absolute and relative individual variations in muscle glycogen content were 7.0 ± 2.1 mM and 11.3 ± 4.6%, respectively, no significant difference in glycogen content was observed among the different time points. This study demonstrates that normal food intake (not fat and/or carbohydrate rich), sleep and other daily activities have a negligible influence on thigh muscle glycogen content, and that the diurnal variation of the glycogen content in human muscles is markedly smaller than that in animal muscles. Moreover, the present results also support the reproducibility and availability of (13)C MRS for the evaluation of the glycogen content in human muscles.

Price difference as a predictor of the selection between brand name and generic statins in Japan.

OBJECTIVES: This study aimed to explore the predictors of the selection between brand name drug (BR) and generic drug (GE) and to clarify the quantitative relationship about selection. METHODS: We identified "incident users" who dispensed statins between April 2008 and June 2011 in commercially databases consisted of dispensing claims databases (DCD) of out-of-hospital pharmacies and hospital claims databases (HCD) of in-house pharmacies in Japan. Predictors of the selection between BR and GE, including price difference (PD), the price of BR, their interaction and percent change of the price of GE relative to BR were explored by logistic regression using DCD and HCD separately. RESULTS: We extracted records of 670 patients who have opportunity for selection both BR and GE. Logistic regression analysis demonstrated that PD, the price of BR, interaction between them, and prescriber affiliation were factors significantly associated with the selection in the DCD; logit (p)=9.735-0.251×PD-0.071×the price of BR+0.002×PD×the price of BR-1.816×affiliation+0.220×gender-0.008×age+0.038×monthly medical fee. PD was inversely proportional to BR choice in DCD and lead to the opposite result in HCD. Numerical simulation of selection revealed that the quantitative relationships heavily depend on situations. CONCLUSIONS: PD and the price of BR are predictors of the selection between BR and GE interactively in out-of-hospital pharmacies, but not in in-house pharmacies of medical facilities. Results may support policies which increase the power of out-of-hospital pharmacies for selection.

[Application of brain diffusion-weighted imaging performed using readout segmentation of long variable echo trains].

We report the preliminary use of the readout segmentation of long variable echo trains(RESOLVE)sequence, a novel magnetic resonance(MR)scanning technique based on a readout segmented echo planar imaging(EPI)strategy. RESOLVE enables high-resolution diffusion-weighted imaging(DWI)by minimizing susceptibility distortions and T2* blurring. The software for this sequence was provided by Siemens AG, Germany. Previously, we determined appropriate sequence parameters to obtain sufficiently high-resolution images through phantom studies. Then, we applied the sequence to some clinical cases with neurological disorders and analyzed the RESOLVE-DWI data with diffusion tensor imaging(DTI)techniques. In this article, we report clinical application of the RESOLVE sequence in two cases, one with cerebellar infarction and one with an intracranial epidermoid cyst. In both cases, RESOLVE-DWI clearly exposed structures that were obscured or severely distorted by artifacts on usual single-shot EPI-DWI. DTI analyses for RESOLVE-DWI data provided detailed information about fiber tracts and cranial nerves.

[Influence of imaging parameters on the measurement of apparent diffusion coefficient].

The apparent diffusion coefficient (ADC) values are calculated by using signal intensity in diffusion-weighted images (DWIs) with two or more different b-value. Therefore, the signal to noise ratio (SNR) of DWI with higher b-value may have a big influence on the measured ADC value. We examined the influence of the imaging parameters on the calculated ADC values. The SNR of DWI increased by using a larger voxel size, by means of a decreased number of matrix, an increased slice thickness, and an increased field of view (FOV). However, when the number of excitations was increased to improve the SNR of DWI, the signal intensity of background noise was observed to be slightly increased. It was suggested that the consistency of measured ADC was not preserved when the signal of the DWIs with higher b-value dropped close to the noise level.

Development of a high-precision image-processing automatic measurement system for MRI visceral fat images acquired using a binomial RF-excitation pulse.

Development of a rapid and accurate method for visceral fat measurement is an important task, given the recent increase in the number of patients with metabolic syndrome. In this study, we optimized the Fast Low Angle Shot (FLASH) sequence using a binominal radiofrequency excitation pulse, in which the acquisition time is short, and measured changes in the amount of visceral fat in subjects after a period of wearing clothes with a fat-reducing effect during walking. We solved the reproducibility problem associated with the number of slices, and developed automatic measurement software for high-precision separation and extraction of abdominal visceral fat images. This software was developed using intensity correction with the coil position, derivation of a threshold by histogram analysis and fat separation by template matching for abdominal images. The cross-sectional area of a single slice varies for every acquisition due to visceral organ movement, but the relative error largely converged for seven slices. The measured amount of abdominal fat tended to be consistent with changes in the body fat and waist circumference of the subjects. The correlation coefficients between automatic extraction using the measurement software and manual extraction were 0.9978 for subcutaneous fat and 0.9972 for visceral fat, showing very strong positive correlations. The consistency rates were 0.9502+/-0.0167 for subcutaneous fat and 0.9395+/-0.0147 for visceral fat, and the shapes of the regions were also extracted very accurately. These results show that the magnetic resonance imaging acquisition method and image processing system developed in this study are beneficial for measurement of abdominal visceral fat. Therefore, this method may have a major role in future diagnosis of metabolic syndrome.

[Distortion in diffusion weighted imaging].

The definitional equation of the distortion of echo planar imaging(EPI)was examined. We compared measured values with calculated values by using the definitional equation of the chemical shift of the EPI method that first composed the diffusion-weighted image, and examined the possibility of applying it to the distortion. The results showed that the chemical shift with the definitional equation and the measurement corresponded, and the correlation between the chemical shift and the distortion was acquired. Next, the distortion of each images that composed DWI with the increase and the sign acceptable method difference of b value. The difference in the distortion between each image has increased with the increase in b value. It was assumed that the influence of the eddy currents was due to the high motion probing gradient.

In vivo structural analysis of articular cartilage using diffusion tensor magnetic resonance imaging.

PURPOSE: The articular cartilage is a small tissue with a matrix structure of three layers between which the orientation of collagen fiber differs. A diffusion-weighted twice-refocused spin-echo echo-planar imaging (SE-EPI) sequence was optimized for the articular cartilage, and the structure of the three layers of human articular cartilage was imaged in vivo from diffusion tensor images. MATERIALS AND METHODS: The subjects imaged were five specimens of swine femur head after removal of the flesh around the knee joint, five specimens of swine articular cartilage with flesh present and the knee cartilage of five adult male volunteers. Based on diffusion-weighted images in six directions, the mean diffusivity (MD) and the fractional anisotropy (FA) values were calculated. RESULTS: Diffusion tensor images of the articular cartilage were obtained by sequence optimization. The MD and FA value of the specimens (each of five examples) under different conditions were estimated. Although the articular cartilage is a small tissue, the matrix structure of each layer in the articular cartilage was obtained by SE-EPI sequence with GRAPPA. The MD and FA values of swine articular cartilage are different between the synovial fluid and saline. In human articular cartilage, the load of the body weight on the knee had an effect on the FA value of the surface layer of the articular cartilage. CONCLUSION: This method can be used to create images of the articular cartilage structure, not only in vitro but also in vivo. Therefore, it is suggested that this method should support the elucidation of the in vivo structure and function of the knee joint and might be applied to clinical practice.

MRI analysis of structural changes in skeletal muscles and surrounding tissues following long-term walking exercise with training equipment.

Muscular recovery after exercise is an important topic in sports medicine, and accurate and quantitative measurements of changes in muscle are required to assess muscular recovery. In the present study, we report a new analytical method to measure muscular changes quantitatively. The technique consists of three independent methods: image processing of two-dimensional MR images, morphological analysis using three-dimensional MR images, and diffusion tensor MRI. Using this method, we investigated changes in the quadriceps and biceps femoris and gluteus maximus muscles and surrounding tissues before and after 1 mo of exercise wearing training equipment. The subjects were 21 healthy adult female volunteers, 14 of whom wore training equipment and 7 who wore normal equipment. The percentage of adipose tissue in muscle after exercise in subjects who wore training equipment was on average 4.4% (P < 0.001) lower than that before exercise, and the peak point of the dorsal hip after exercise with use of the equipment was on average 10.8 mm higher than that before exercise. Further, the fractional anisotropy of water diffusion in muscles increased by an average of 0.039 (P < 0.001) after exercise with use of training equipment. In contrast, there was no significant difference before and after exercise in subjects who wore normal equipment. These results show that walking exercise while wearing training equipment thickens and tightens the muscular fiber tissues. This noninvasive measurement approach may allow quantitation of the athletic ability of the muscles, which is not measured conventionally, and is an effective method for analyzing skeletal muscles.

Observation of contrast enhancement in the cochlear fluid space of healthy subjects using a 3D-FLAIR sequence at 3 Tesla.

In animals, the enhancement of perilymph in the cochlea has been reported using 1.25 mmol/kg of Gd-DTPA, allowing the separate visualisation of perilymph and endolymph for the diagnosis of Meniere's disease. The purpose of this study was three-fold: (1) to determine the optimal timing for detecting cochlear fluid enhancement using 3D-FLAIR (fluid-attenuated inversion recovery) after intravenous administration of 0.1 mmol/kg of Gd-DTPA in healthy human subjects; (2) to examine the reliability of enhancement in multiple healthy subjects; and (3) to investigate whether endolymph and perilymph space can be visually discriminated. In two healthy subjects, 3D-FLAIR images were obtained before, immediately after and 2 h, 4 h and 6 h after the injection. Three more healthy subjects were scanned before and 4 h after the injection. In all four ears of the initial two subjects, cochlear fluid was found to be most intensely enhanced 4 h after the injection. In all of the additional three subjects, the cochlear fluid signal had increased after 4 h from injection. However, visual differentiation of endolymph and perilymph fluid could not be achieved. Using 3D-FLAIR and Gd-DTPA, cochlear fluid enhancement can be observed in healthy human ears, even with a single dose of contrast-medium injection.

Diffusion-weighted images of the liver: comparison of tumor detection before and after contrast enhancement with superparamagnetic iron oxide.

PURPOSE: To study the recognition of malignant lesions of the liver on diffusion-weighted images (DWI) can be improved by the administration of superparamagnetic iron oxide (SPIO). MATERIALS AND METHODS: Pre- and post-SPIO mediated DWI of the liver was compared in six patients with suspected malignant liver lesions at 1.5 Tesla using a parallel imaging technique. RESULTS: Post-SPIO DWI showed improved contrast-to-noise ratio between malignant lesions and liver. Furthermore, the spleen signal was decreased on post-SPIO DWI, thus avoiding the overlap of the spleen and left lobe of the liver on maximum intensity projections (MIP). CONCLUSION: Recognition of malignant lesions of the liver was improved by SPIO on DWI. On MIP images of DWI, SPIO helped to decrease the overlap of spleen signal on the liver in some projection angles.

Differentiation of noncancerous tissue and cancer lesions by apparent diffusion coefficient values in transition and peripheral zones of the prostate.

PURPOSE: To compare the apparent diffusion coefficient (ADC) values of prostate cancer in both the peripheral zone (PZ) and the transition zone (TZ) with those of benign tissue in the same zone using echo-planar diffusion weighted imaging with a parallel imaging technique. MATERIALS AND METHODS: A total of 29 consecutive male patients (mean age 61.3 years, age range 53-88 years) with suspected prostate cancer were referred for MR imaging. All patients underwent transrectal ultrasound (TRUS)-guided biopsy of the prostate after MR imaging at 1.5 T, including ADC. For each patient, seven to 10 specimens were obtained from the prostate, and regions of interest (ROIs) were drawn on the ADC map by referring to the urologist's illustration of TRUS-guided biopsy sites. ADC values of cancerous tissue in both the PZ and TZ were compared to those of noncancerous tissue in the same zone. RESULTS: Out of 29 patients, 23 had cancer tissue. In the 23 patients with cancer, the mean ADC value of all cancer ROIs and that of all noncancer ROIs, respectively, were 1.11 +/- 0.41 x 10(-3) and 1.68 +/- 0.40 x 10(-3) mm(2)/second (values are mean +/- SD) (P < 0.01). The mean ADC value of TZ cancer ROIs and that of TZ noncancer ROIs, respectively, were 1.13 +/- 0.42 x 10(-3) and 1.58 +/- 0.37 x 10(-3) mm(2)/second (P < 0.01). CONCLUSIONS: ADC measurement with a parallel imaging technique showed that ADC values of prostate cancer in both the PZ and TZ were significantly lower than those of benign tissue in the PZ and TZ, respectively.

Apparent diffusion coefficient in cervical cancer of the uterus: comparison with the normal uterine cervix.

A relation between apparent diffusion coefficient (ADC) values and tumor cellular density has been reported. The purpose of this study was to measure the ADC values of cervical cancers in the uterus and compare them with those of normal cervical tissues, and to test whether ADC could differentiate between normal and malignant cervical tissues in the uterus. Twelve consecutive female patients with cervical cancer of the uterus and ten female patients with other pelvic abnormalities were included in this study. ADC was measured at 1.5 T with b-factors of 0, 300 and 600 s/mm2 using single-shot echo-planar diffusion-weighted imaging and a parallel imaging technique. The mean ADC value of cervical cancer lesions was 1.09+/-0.20 x 10(-3) mm2/s, and that of normal cervix tissue was 1.79+/-0.24 x 10(-3) mm2/s (P<0.0001). In nine patients treated by chemotherapy and/or radiation therapy, the mean ADC value of the cervical cancer lesion increased significantly after therapy (P<0.001). The present study showed, with a small number of patients, that ADC measurement has a potential ability to differentiate between normal and cancerous tissue in the uterine cervix. Further study is necessary to determine the accuracy of ADC measurement in monitoring the treatment response.

Serial evaluation of diffusion tensor brain fiber tracking in a patient with severe diffuse axonal injury.

Serial evaluation of diffusion tensor brain fiber tracking was performed in a 27-year-old female patient with diffuse axonal injury after a traffic accident. Although the result of brain fiber tracking was not necessarily parallel to her clinical symptoms, it may have predicted the neurologic prognosis.

Comparison of flow artifacts between 2D-FLAIR and 3D-FLAIR sequences at 3 T.

It has been reported that 3D-FLAIR can reduce the flow artifact resulting from cerebrospinal fluid (CSF) at 1.5 T compared to 2D-FLAIR. Flow-related artifacts tend to be worse at 3 T than at 1.5 T. The purpose of this study was to compare the CSF flow artifacts of 2D-FLAIR and 3D-FLAIR sequences at 3 T in eight healthy volunteers. The grade of CSF-related artifacts were scored through observing the perimedullary cistern, cerebellopontine angle cisterns, fourth ventricule, prepontine cistern, suprasellar cistern, ambient cisterns, sylvian fissures, third ventricle and lateral ventricles. Grading was performed on either axial or sagittal images. The CSF in-flow artifact scores were significantly higher on axial 2D-FLAIR than on axial 3D-FLAIR MPR images in all areas except the bilateral sylvian fissures, and higher on sagittal 2D-FLAIR than on sagittal 3D-FLAIR MPR images in perimedullary, bilateral CP angle and suprasellar cisterns. The CSF-related flow artifacts were significantly reduced by 3D-FLAIR, while structures in the cistern were depicted more clearly, even at 3 T. Further study is necessary to compare the clinical efficacy between 2D-FLAIR and 3D-FLAIR in depicting subtle abnormalities.

Whole-brain vascular reactivity measured by fMRI using hyperventilation and breath-holding tasks: efficacy of 3D prospective acquisition correction (3D-PACE) for head motion.

Functional MR imaging (fMRI) study using hyperventilation and breath-holding task has been reported to be one of the non-invasive methods to examine whole-brain vascular reactivity. The purpose of this study was to evaluate the efficacy of a method for 3D prospective detection and correction of head motion (3D-PACE) in a study of whole-brain vascular reactivity using hyperventilation and breath-holding tasks. Eight healthy volunteers were scanned using an fMRI protocol of hyperventilation and breath-holding task blocks at 3 T in separate runs with and without 3D-PACE. In two subjects, two more runs with and without 3D-PACE were repeated. The mean total number of activated voxels +/- standard deviation was 26,405.3+/-1,822.2 in the run with 3D-PACE and 17,329.9+/-2,766.3 in the run without 3D-PACE ( P<0.05), although there is some intersubject variation regarding the effect of 3D-PACE. In the two subjects whose performed two more runs, the number of activated voxels were smaller in the run without 3D-PACE than even in the run with 3D-PACE performed later. We conclude that 3D-PACE is beneficial for fMRI studies of whole-brain vascular reactivity induced by hyperventilation and breath-holding.

Optimization of diffusion-tensor MR imaging data acquisition parameters for brain fiber tracking using parallel imaging at 3 T.

The purpose of this study was to optimize the parameters of diffusion-tensor magnetic resonance imaging (DT MRI) for brain fiber tracking using a slice thickness of 2 mm, a resolution advantage allowed by the high signal-to-noise ratio at 3 T, combined with an 8-channel phased-array head coil. The b-factor, number of motion probing gradient (MPG) directions, and number of averages were varied, and the results of brain fiber tracking for the pyramidal tract and trigeminal nerve were compared qualitatively and quantitatively. The DT MRI data sufficient for brain fiber tracking in healthy subjects can be obtained in <2 min with a 2-mm slice thickness, 700-s/mm2 b-factor, 6 MPG directions, and no averaging (number of averages=1).

High-speed imaging at 3 Tesla: a technical and clinical review with an emphasis on whole-brain 3D imaging.

Improvements to the inherently high specific-absorption rate (SAR) of high-speed imaging at 3T are necessary in order to render this method clinically feasible. Various efforts have been undertaken to improve the associated hardware and software. In this review, we focus on whole-brain isotropic 3D imaging with a turbo spin-echo sequence with variable flip-angle echo trains (3D-TSE-VFL) and present its technical and clinical features. This sequence can be used to acquire images of various contrasts including T2-weighted, fat-suppressed T2-weighted, fluid-attenuated inversion recovery (FLAIR), fat-suppressed FLAIR, and STIR (short tau inversion recovery). Various aspects of 3D-TSE-VFL are discussed, including CSF (cerebrospinal fluid) and metal artifacts, STIR contrast, small-part visualization other than brain, and the possibility of serial subtraction. Some images from clinical cases are presented.

Measurement of in vivo local shear modulus using MR elastography multiple-phase patchwork offsets.

Magnetic resonance elastography (MRE) is a method that can visualize the propagating and standing shear waves in an object being measured. The quantitative value of a shear modulus can be calculated by estimating the local shear wavelength. Low-frequency mechanical motion must be used for soft, tissue-like objects because a propagating shear wave rapidly attenuates at a higher frequency. Moreover, a propagating shear wave is distorted by reflections from the boundaries of objects. However, the distortions are minimal around the wave front of the propagating shear wave. Therefore, we can avoid the effect of reflection on a region of interest (ROI) by adjusting the duration of mechanical vibrations. Thus, the ROI is often shorter than the propagating shear wavelength. In the MRE sequence, a motion-sensitizing gradient (MSG) is synchronized with mechanical cyclic motion. MRE images with multiple initial phase offsets can be generated with increasing delays between the MSG and mechanical vibrations. This paper proposes a method for measuring the local shear wavelength using MRE multiple initial phase patchwork offsets that can be used when the size of the object being measured is shorter than the local wavelength. To confirm the reliability of the proposed method, computer simulations, a simulated tissue study and in vitro and in vivo studies were performed.

Proton two-dimensional chemical shift imaging for evaluation of prostate cancer: external surface coil vs. endorectal surface coil.

PURPOSE: To compare the diagnostic ability of proton magnetic resonance spectroscopy (MRS) using an external surface coil with that using an endorectal surface coil in patients with prostate cancer. MATERIALS AND METHODS: MR imaging (MRI) and two-dimensional chemical shift imaging (2D CSI) were performed in 5 healthy volunteers and in 35 patients with prostate cancer. The receiver coil was the anterior lower part of a phased-array coil or an endorectal surface coil. RESULTS: Receiver-operating characteristic analysis for diagnosing prostate cancer showed no significant difference (P = 0.784) between the area under the curve of phased-array coil CSI and that of endorectal surface coil CSI. CONCLUSION: The phased-array coil CSI could provide comparable detection accuracy to endorectal surface coil CSI. In patients with rectal diseases or patients who could not tolerate the discomfort with insertion of an endorectal surface coil, we recommend the phased-array coil CSI.