Publications by authors named "Shunsuke Ono"

56 Publications

Evaluation of Stopping Power Ratio Calculation Using Dual-energy Computed Tomography With Fast Kilovoltage Switching for Treatment Planning of Particle Therapy.

In Vivo 2022 Jan-Feb;36(1):103-110

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: This study evaluated the calculation accuracy of the stopping power ratio (SPR) using dual-energy computed tomography with fast kilovoltage switching (FKSCT) for particle therapy.

Materials And Methods: A tissue characterization phantom with various reference materials was scanned to obtain single-energy computed tomography (SECT) images and generate virtual monochromatic images at 77 keV (VMI) and 140 keV (VMI), water density (WD) images, and effective Z (Z) images. For SECT, VMI and VMI lookup tables were generated to convert the measured Hounsfield value into the theoretical SPR for a normal phantom size. Subsequently, the reference materials were scanned in small and large phantoms. The SPR was calculated using the lookup tables of SECT (SPR) images, VMI (SPR), and VMI (SPR), and it was derived from the WD and Z (SPR).

Results: In the normal-sized phantom, the overall mean difference between SPR and theoretical SPR was -0.3%, and remained below 2% for most reference materials. For the large phantom, the overall mean absolute difference for SPR (3.0%, p=0.006) and SPR (3.2%, p=0.002) for the reference materials was significantly lower than that for SPR (5.9%). For the small phantom, a significant reduction in the mean difference in the SPR calculation was observed in SPR (1.0%, p=0.001) and SPR (1.1%, p=0.013) compared with SPR (2.2%).

Conclusion: VMI generated using FKSCT significantly improves the estimation accuracy of SPR compared with SECT. Thus, FKSCT may be used to improve the dose calculation accuracy for treatment planning of particle therapy.
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http://dx.doi.org/10.21873/invivo.12681DOI Listing
January 2022

Artifact removal in the contour areas of SAXS-CT images by Tikhonov-L1 minimization.

J Appl Crystallogr 2021 Dec 30;54(Pt 6):1784-1792. Epub 2021 Nov 30.

Institute for Chemical Research, Kyoto University, Gokasho, Uji, 6110011, Japan.

Small-angle X-ray scattering (SAXS) coupled with computed tomography (CT), denoted SAXS-CT, has enabled the spatial distribution of the characteristic parameters ( size, shape, surface, length) of nanoscale structures inside samples to be visualized. In this work, a new scheme with Tikhonov regularization was developed to remove the effects of artifacts caused by streak scattering originating from the reflection of the incident beam in the contour regions of the sample. The noise due to streak scattering was successfully removed from the sinogram image and hence the CT image could be reconstructed free from artifacts in the contour regions.
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http://dx.doi.org/10.1107/S1600576721011523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662970PMC
December 2021

Machine log file-based dose verification using novel iterative CBCT reconstruction algorithm in commercial software during volumetric modulated arc therapy for prostate cancer patients.

Phys Med 2021 Nov 24;92:24-31. Epub 2021 Nov 24.

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Purpose: To evaluate the utility of the use of iterative cone-beam computed tomography (CBCT) for machine log file-based dose verification during volumetric modulated arc therapy (VMAT) for prostate cancer patients.

Methods: All CBCT acquisition data were used to reconstruct images with the Feldkamp-Davis-Kress algorithm (FDK-CBCT) and the novel iterative algorithm (iCBCT). The Hounsfield unit (HU)-electron density curves for CBCT images were created using the Advanced Electron Density Phantom. The I'mRT and anthropomorphic phantoms were irradiated with VMAT after CBCT registration. Subsequently, fourteen prostate cancer patients received VMAT after CBCT registration. Machine log files and both CBCT images were exported to the PerFRACTION software, and a 3D patient dose was reconstructed. Mean dose for planning target volume (PTV), the bladder, and rectum and the 3D gamma analysis were evaluated.

Results: For the phantom studies, the variation of HU values was observed at the central position surrounding the bones in FDK-CBCT. There were almost no changes in the difference of doses at the isocenter between measurement and reconstructed dose for planning CT (pCT), FDK-CBCT, and iCBCT. Mean dose differences of PTV, rectum, and bladder between iCBCT and pCT were approximately 2% lower than those between FDK-CBCT and pCT. For the clinical study, average gamma analysis for 2%/2 mm was 98.22% ± 1.07 and 98.81% ± 1.25% in FDK-CBCT and iCBCT, respectively.

Conclusions: A similar machine log file-based dose verification accuracy is obtained for FDK-CBCT and iCBCT during VMAT for prostate cancer patients.
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http://dx.doi.org/10.1016/j.ejmp.2021.11.004DOI Listing
November 2021

Focal surface occlusion.

Opt Express 2021 Oct;29(22):36581-36597

This paper proposes focal surface occlusion to provide focal cues of occlusion masks for multiple virtual objects at continuous depths in an occlusion-capable optical see-through head-mounted display. A phase-only spatial light modulator (PSLM) that acts as a dynamic free-form lens is used to conform the focal surface of an occlusion mask to the geometry of the virtual scene. To reproduce multiple and continuous focal blurs while reducing the distortion of the see-through view, an optical design based on afocal optics and edge-based optimization to exploit a property of the occlusion mask is established. The prototype with the PSLM and transmissive liquid crystal display can reproduce the focus blur of occluded objects at multiple and continuous depths with a field of view of 14.6°.
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http://dx.doi.org/10.1364/OE.440024DOI Listing
October 2021

Patient Preferences for Attributes of Chemotherapy for Lung Cancer: Discrete Choice Experiment Study in Japan.

Front Pharmacol 2021 20;12:697711. Epub 2021 Jul 20.

Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Our study objective was to determine lung cancer chemotherapy attributes that are important to patients in Japan. A discrete choice experiment survey in an anonymous web-based questionnaire format with a reward was completed by 200 lung cancer patients in Japan from November 25, 2019, to November 27, 2019. The relative importance of patient preferences for each attribute was estimated using a conditional logit model. A hierarchical Bayesian logit model was also used to estimate the impact of each demographic characteristic on the relative importance of each attribute. Of the 200 respondents, 191 with consistent responses were included in the analysis. In their preference, overall survival was the most important, followed by diarrhea, nausea, rash, bone marrow suppression (BMS), progression-free survival, fatigue, interstitial lung disease, frequency of administration, and duration of administration. The preferences were influenced by demographic characteristics (e.g., gender and age) and disease background (e.g., cancer type and stage). Interestingly, the experience of cancer drug therapies and adverse events had a substantial impact on the hypothetical drug preferences. For the Japanese lung cancer patients, improved survival was the most important attribute that influenced their preference for chemotherapy, followed by adverse events, including diarrhea, nausea, rash, and BMS. The preferences varied depending on the patient's demographic and experience. As drug attributes can affect patient preferences, pharmaceutical companies should be aware of the patient preferences and develop drugs that respond to segmented market needs.
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http://dx.doi.org/10.3389/fphar.2021.697711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329447PMC
July 2021

Evaluation of two-dimensional electronic portal imaging device using integrated images during volumetric modulated arc therapy for prostate cancer.

Rep Pract Oncol Radiother 2021 14;26(2):281-290. Epub 2021 Apr 14.

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: The aim of the study was to evaluate analysis criteria for the identification of the presence of rectal gas during volumetric modulated arc therapy (VMAT) for prostate cancer patients by using electronic portal imaging device (EPID)-based dosimetry (IVD).

Materials And Methods: All measurements were performed by determining the cumulative EPID images in an integrated acquisition mode and analyzed using PerFRACTION commercial software. Systematic setup errors were simulated by moving the anthropomorphic phantom in each translational and rotational direction. The inhomogeneity regions were also simulated by the I'mRT phantom attached to the Quasar phantom. The presence of small and large air cavities (12 and 48 cm) was controlled by moving the Quasar phantom in several timings during VMAT. Sixteen prostate cancer patients received EPID-based IVD during VMAT.

Results: In the phantom study, no systematic setup error was detected in the range that can happen in clinical (< 5-mm and < 3 degree). The pass rate of 2% dose difference (DD2%) in small and large air cavities was 98.74% and 79.05%, respectively, in the appearance of the air cavity after irradiation three quarter times. In the clinical study, some fractions caused a sharp decline in the DD2% pass rate. The proportion for DD2% < 90% was 13.4% of all fractions. Rectal gas was confirmed in 11.0% of fractions by acquiring kilo-voltage X-ray images after the treatment.

Conclusions: Our results suggest that analysis criteria of 2% dose difference in EPID-based IVD was a suitable method for identification of rectal gas during VMAT for prostate cancer patients.
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http://dx.doi.org/10.5603/RPOR.a2021.0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241304PMC
April 2021

Financial Literacy and Gambling Behavior in the United States.

J Gambl Stud 2021 May 4. Epub 2021 May 4.

School of Economics, Hirsohima University, Hiroshima, Japan.

Problem gambling is becoming a growing concern in the United States because of the proliferation of, and state support for, gambling opportunities. The economic cost along with the physical and mental health problems associated with problem gambling make it necessary to study how problem gambling can be reduced. Our study examines whether financial literacy could be a means to reducing gambling frequency in the United States. We use data from the Preference Parameter Study of Osaka University, Japan, and apply instrumental variable probit regression models. The results show that, generally, financial literacy does not have a relationship with gambling frequency, but the relationship is significant in the states where electronic gambling machines (EGMs) are available. The results imply that gamblers are irrational and fail to assess the risks of gambling as well as the probabilities that maximize expected payoffs. It appears that gamblers' psychological gain from gambling outweighs the negative expected utility when there is easy access to gambling. Thus, rationality with regard to gambling decisions does not work unless the easy access to EGMs is controlled. Our results further show that males, older people, people with higher household income, and people who have easy access to gambling are likely to be frequent gamblers.
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http://dx.doi.org/10.1007/s10899-021-10030-5DOI Listing
May 2021

Comparison of Successful and Unsuccessful Cases of New Drug Approvals Based on the International Council on Harmonization E5 Guidelines in Japan.

Clin Pharmacol Drug Dev 2021 05 30;10(5):434-439. Epub 2021 Mar 30.

Department of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan.

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http://dx.doi.org/10.1002/cpdd.942DOI Listing
May 2021

Financial Literacy, Financial Education, and Smoking Behavior: Evidence From Japan.

Front Public Health 2020 15;8:612976. Epub 2021 Jan 15.

School of Economics, Hiroshima University, Hiroshima, Japan.

In this study, we examine the relationship between financial literacy, financial education, and smoking behavior among the Japanese population. We hypothesize that financially literate and financially educated people, who have the ability to make more rational decisions, are less likely to smoke. Using the Preference Parameters Study of Osaka University, conducted in 2010 ( = 3,706), the probit regression results show that both financial literacy (with an emphasis on knowledge of investments) and financial education (with an emphasis on savings behavior) have a significant negative impact on smoking behavior. In addition, gender, age, education, marital status, household income and assets, risky behaviors, a myopic view of the future, risk preference, and level of happiness also significantly predict the likelihood of a person being a current smoker. This study provides empirical evidence that enhancing the rational decision-making ability of individuals through financial literacy and financial education may curtail smoking behavior.
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http://dx.doi.org/10.3389/fpubh.2020.612976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844398PMC
May 2021

Detectability of fiducials' positions for real-time target tracking system equipping with a standard linac for multiple fiducial markers.

J Appl Clin Med Phys 2020 Nov 15;21(11):153-162. Epub 2020 Oct 15.

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Purpose: To investigate the detectability of fiducial markers' positions for real-time target tracking system equipping with a standard linac. The hypothesis is that the detectability depends on the type of fiducial marker and the gantry angle of acquired triggered images.

Methods: Three types of ball fiducials and four slim fiducials with lengths of 3 and 5 mm were prepared for this study. Triggered images with three similar fiducials were acquired at every 10° during the conformal arc irradiation to detect the target position. Although only one type of arrangement was prepared for the ball fiducials, a three-type arrangement was prepared for the slim fiducials, such as parallel, orthogonal, and oblique with 45° to the gantry-couch direction. To measure the detectability of the real-time target tracking system for each fiducial and arrangement, detected marker positions were compared with expected marker positions at every angle of acquired triggered images.

Results: For the ball-type fiducial, the maximum difference between the detected marker positions and expected marker positions was 0.3 mm in all directions. For the slim fiducial arranged parallel and oblique with 45°, the maximum difference was 0.4 mm in all directions. When each slim fiducial was arranged orthogonal to the gantry-couch direction, the maximum difference was 1.5 mm for the length of 3 mm, and 3.2 mm for the length of 5 mm.

Conclusions: The detectability of fiducial markers' positions for the real-time target tracking system equipping with a standard linac depends on the form and insertion angles of the fiducials.
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http://dx.doi.org/10.1002/acm2.13050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700931PMC
November 2020

Exploratory Analysis of the Factors Associated With Success Rates of Confirmatory Randomized Controlled Trials in Cancer Drug Development.

Authors:
Can Wu Shunsuke Ono

Clin Transl Sci 2021 01 21;14(1):260-267. Epub 2020 Aug 21.

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

This study examined the outcomes of recent confirmatory randomized controlled trials (RCTs) in phase III that were initiated between 2005 and 2017 for oncologic drugs in the United States and identified several factors that were associated with the success of RCTs. Our regression analysis showed that studies with progression-free survival or response rate as primary end point were more likely to succeed than studies with overall survival (odds ratio (OR) = 2.94 and 6.23, respectively). The status of development was also linked with success rates. Studies for non-lead indication tended to have lower success rates than studies for lead indication (OR = 0.68). Studies for first-line therapy were observed to have low success rates compared with studies for post second-line therapies (OR = 0.37). Studies for which strong prior evidence was not listed in their publication tended to be more successful than studies that followed rigorous RCTs or single arm studies for the indication. These results suggest that historical success rates may reflect not only the important features of trials, which can be observed directly from study design and results, but also the background status of trials in clinical development pathways.
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http://dx.doi.org/10.1111/cts.12852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877835PMC
January 2021

Quantitative Preferences for Lung Cancer Treatment from the Patients' Perspective: A Systematic Review.

Patient 2020 10;13(5):521-536

Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Background: Regulatory agencies as well as private organizations pursue programs that advocate patient centricity and emphasize the importance of dialog with patients. Various methods are applied to elicit the preferences of patients regarding the aspects of treatment they lend more importance to. Decisions on treatment choices are critical to patients with lung cancer because of their poor prognosis and the serious trade-off between safety and efficacy in traditional cytotoxic chemotherapy.

Methods: We conducted a systematic literature review of quantitative patient preference studies of patients with lung cancer. Our exhaustive search of MEDLINE, CINAHL, EMBASE, PLOS, and SpringerLink identified 15 relevant studies published from January 2000 to April 2020 that enabled us to assess the relative importance of treatment attributes according to lung cancer patients' perspective.

Results: The literature review revealed that patients with lung cancer tend to place a higher weight on efficacy and quality of life (QoL) attributes than on other attributes. Overall survival was found to be the most important among the efficacy attributes. The consequences of adverse events seemed less important than the possible efficacy from therapies. The clinical utility of treatment, such as the route of administration, was generally not considered important. It remains inconclusive whether sociodemographic factors and/or medical history affect the relative importance of a patient's preference.

Conclusion: Our systematic review clarified that patients generally prefer a better efficacy profile to a better safety profile, which underscores the importance of improved benefits in anti-lung cancer drug development.
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http://dx.doi.org/10.1007/s40271-020-00434-7DOI Listing
October 2020

Dosimetric impact of baseline drift in volumetric modulated arc therapy with breath holding.

Rep Pract Oncol Radiother 2020 Sep-Oct;25(5):703-708. Epub 2020 Jun 8.

Department of Radiation Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuou-ku, Osaka, 537-8567, Japan.

Background: We investigated the change of dose distributions in volumetric modulated arc therapy (VMAT) under baseline drift (BD) during breath holding.

Materials And Methods: Ten VMAT plans recalculated to a static field at a gantry angle of 0° were prepared for measurement with a 2D array device and five original VMAT plans were prepared for measurement with gafchromic films. These measurement approaches were driven by a waveform reproducing breath holding with BD. We considered breath holding times of 15 and 10 s, and BD at four speeds; specifically, BD0 (0 mm/s), BD0.2 (0.2 mm/s), BD0.3 (0.3 mm/s), and BD0.4 (0.4 mm/s). The BD was periodically reproduced from the isocenter along the craniocaudal direction and the shift during breath holding (Shift) ranged 0-6 mm.The dose distribution of BD0.2, BD0.3 and BD0.4 were compared to that of BD0 using gamma analysis with the criterion of 2%/2 mm.

Results: The mean pass rates of each Shift were 99.8% and 98.9% at 0 mm, 96.8% and 99.4% at 2 mm, 94.9% and 98.6% at 3 mm, 91.5% and 98.4% at 4 mm, 70.8% and 94.1% at 4.5 mm, and 55.0% and 83.6% at 6 mm for the array and film measurements, respectively.

Conclusion: We found significant differences in Shift above 4 mm ( < 0.05). Hence, it is recommended that breath holding time should be shortened for patients to preserve the reproducibility of dose distributions.
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http://dx.doi.org/10.1016/j.rpor.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358624PMC
June 2020

Improving grazing-incidence small-angle X-ray scattering-computed tomography images by total variation minimization.

J Appl Crystallogr 2020 Feb 1;53(Pt 1):140-147. Epub 2020 Feb 1.

Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.

Grazing-incidence small-angle X-ray scattering (GISAXS) coupled with computed tomography (CT) has enabled the visualization of the spatial distribution of nanostructures in thin films. 2D GISAXS images are obtained by scanning along the direction perpendicular to the X-ray beam at each rotation angle. Because the intensities at the positions contain nanostructural information, the reconstructed CT images individually represent the spatial distributions of this information ( size, shape, surface, characteristic length). These images are reconstructed from the intensities acquired at angular intervals over 180°, but the total measurement time is prolonged. This increase in the radiation dosage can cause damage to the sample. One way to reduce the overall measurement time is to perform a scanning GISAXS measurement along the direction perpendicular to the X-ray beam with a limited interval angle. Using filtered back-projection (FBP), CT images are reconstructed from sinograms with limited interval angles from 3 to 48° (FBP-CT images). However, these images are blurred and have a low image quality. In this study, to optimize the CT image quality, total variation (TV) regularization is introduced to minimize sinogram image noise and artifacts. It is proposed that the TV method can be applied to downsampling of sinograms in order to improve the CT images in comparison with the FBP-CT images.
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http://dx.doi.org/10.1107/S1600576719016558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998772PMC
February 2020

Amino-acid selective isotope labeling enables simultaneous overlapping signal decomposition and information extraction from NMR spectra.

J Biomol NMR 2020 Mar 30;74(2-3):125-137. Epub 2020 Jan 30.

Laboratory for Cellular Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan.

Signal overlapping is a major bottleneck for protein NMR analysis. We propose a new method, stable-isotope-assisted parameter extraction (SiPex), to resolve overlapping signals by a combination of amino-acid selective isotope labeling (AASIL) and tensor decomposition. The basic idea of Sipex is that overlapping signals can be decomposed with the help of intensity patterns derived from quantitative fractional AASIL, which also provides amino-acid information. In SiPex, spectra for protein characterization, such as N relaxation measurements, are assembled with those for amino-acid information to form a four-order tensor, where the intensity patterns from AASIL contribute to high decomposition performance even if the signals share similar chemical shift values or characterization profiles, such as relaxation curves. The loading vectors of each decomposed component, corresponding to an amide group, represent both the amino-acid and relaxation information. This information link provides an alternative protein analysis method that does not require "assignments" in a general sense; i.e., chemical shift determinations, since the amino-acid information for some of the residues allows unambiguous assignment according to the dual selective labeling. SiPex can also decompose signals in time-domain raw data without Fourier transform, even in non-uniformly sampled data without spectral reconstruction. These features of SiPex should expand biological NMR applications by overcoming their overlapping and assignment problems.
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http://dx.doi.org/10.1007/s10858-019-00295-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080692PMC
March 2020

Stereotactic body radiation therapy planning for liver tumors using functional images from dual-energy computed tomography.

Radiother Oncol 2020 04 7;145:56-62. Epub 2020 Jan 7.

Department of Radiation Oncology, Osaka International Cancer Institute, Japan.

Purpose: This study aimed to generate a functional image of the liver using dual-energy computed tomography (DECT) and a functional-image-based stereotactic body radiation therapy plan to minimize the dose to the volume of the functional liver (V).

Material And Methods: A normalized iodine density (NID) map was generated for fifteen patients with liver tumors. The volume of liver with an NID < 0.46 was defined as V, and the ratio between V and the total volume of the liver (FLR) was calculated. The relationship between the FLR and Fibrosis-4 (FIB-4) was assessed. For patients with 15% < FLR < 85%, functional volumetric modulated-arc therapy plans (F-VMAT) were retrospectively generated to preserve V, and compared to the clinical plans (C-VMAT).

Results: FLR showed a significantly strong correlation with FIB-4 (r = -0.71, p < 0.01). For ten generated F-VMAT plans, the dosimetric parameters of D, D, D and the conformity index were comparable to those of the C-VMAT (p > 0.05). For V, F-VMAT plans achieved lower V (122.4 ± 31.7 vs 181.1 ± 57.3 cc), V (44.4 ± 22.2 vs 98.2 ± 33.3 cc), V (22.6 ± 20.3 vs 49.8 ± 33.7 cc), V (11.6 ± 14.1 vs 24.9 ± 25.1 cc), and D (3.9 ± 2.3 vs 5.8 ± 3.0 Gy) values than the C-VMAT plans (p < 0.01).

Conclusions: The functional image derived from DECT was successfully used, allowing for a reduction in the dose to the V without compromising target coverage.
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http://dx.doi.org/10.1016/j.radonc.2019.12.002DOI Listing
April 2020

Assessment of factors associated with completeness of spontaneous adverse event reporting in the United States: A comparison between consumer reports and healthcare professional reports.

J Clin Pharm Ther 2020 Jun 25;45(3):462-469. Epub 2019 Nov 25.

Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

What Is Known And Objective: The objectives of this study were to explore completeness of direct adverse event (AE) reports from consumers and healthcare professionals (HCPs), and to discuss the reasons completeness varied among reporters with different occupations.

Methods: We used a total of 5475 direct AE reports to the United States (US) Food and Drug Administration (FDA) from the first and second quarters of 2016 and assessed completeness of basic information (eg, patient sex, age, weight) and information relevant to AEs (eg, suspect and concomitant drugs). Logistic regression analysis was conducted to evaluate the associations between report completeness and reporting backgrounds.

Results And Discussion: The completeness of AE reports from consumers was generally greater than that of reports from HCPs. Completeness of specific items varied among different occupations, which may reflect accessibility to, and/or availability of, relevant information for each type of reporter. There was a clear association between the proportion of 'known' ADRs in a report and completeness, suggesting that consumers and HCPs are likely to consult labelling information when reporting AEs.

What Is New And Conclusion: The quality of AE reports seemed to depend on information costs accrued to potential reporters. Researchers should consider the impact of database heterogeneity and possible sample selection bias when using spontaneous AE reports as a sample of events in the United States.
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http://dx.doi.org/10.1111/jcpt.13086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317542PMC
June 2020

Survey of Japanese Orphan Drug Program: Factors Related to Successful Marketing Approval.

J Clin Pharmacol 2020 01 31;60(1):117-124. Epub 2019 Jul 31.

The University of Tokyo Graduate School of Pharmaceutical Sciences Faculty of Pharmaceutical Sciences, Laboratory of Pharmaceutical Regulatory Science, Tokyo, Japan.

The basic components of regulatory and supporting policies for orphan drug development appear similar between the United States and Japan, but drugs designated as orphan drugs have been different between the 2 countries. The probabilities of development success (ie, marketing approval) in designated orphan drugs have also been significantly different. In this study, we analyzed recent outcomes of development for orphan drugs designated from 1993 to 2017 in Japan, considering their development and approval status in the United States. Our analysis showed that success for orphan drug development in Japan was apparently associated with prior approval status in the United States. Company size, orphan development experience, and patient enrichment were also positively associated with successful marketing approval. Although similar designations and priority review systems for orphan drugs have been enacted, economic incentives and regulatory conditions provided by the systems seem to be different between the 2 countries, which may lead to varied performance in orphan designation and approval. We need to pay close attention to the impact of industrial global development strategies when comparing the outcomes and performance of different orphan drug promotion systems.
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http://dx.doi.org/10.1002/jcph.1501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972571PMC
January 2020

Analysis of Global Drug Development Pathways and Postmarketing Safety in Japan: Local Studies May Reduce Drug-Related Deaths.

Clin Transl Sci 2019 07 23;12(4):408-415. Epub 2019 Apr 23.

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Recent International Conference on Harmonization (ICH) guidelines provide pharmaceutical companies with regulatory justifications to pursue various global drug-development pathways, in some of which "local" dose-ranging and/or pivotal phase III studies are skipped. We examined the association between the clinical development pathway and postmarketing safety in Japan for 177 new molecular entities approved between 2004 and 2013 focusing on dose setting histories for each drug. The risk of drug-related deaths was higher when companies did not conduct local (i.e., Japanese) dose-ranging studies and/or pivotal studies. Even when local dose-ranging studies were conducted, the risk remained higher in some drugs for which the approved dose in Japan was set equal to that in the United States. Drugs developed under a bridging strategy tended to show lower risks. These results suggested that local clinical studies may play a substantial role in achieving optimization of postmarketing drug use in each local target population.
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http://dx.doi.org/10.1111/cts.12631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662395PMC
July 2019

Exploratory analysis of comparative clinical trials used for marketing approval in patients with type 2 diabetes in Japan.

SAGE Open Med 2019 8;7:2050312118823407. Epub 2019 Jan 8.

Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Background/objectives: The results of phase 2 and 3 clinical trials, which justify decisions regarding marketing approval for new drugs, are used for comparison of drugs in the post-marketing phase. A number of meta-analyses of approved antidiabetics have been performed, but the heterogeneity of trials has not been fully examined. The aim of this study was to explore factors that may influence baseline HbA1c in trial samples and treatment outcomes (i.e. HbA1c reductions and effect sizes), with the goal of providing unbiased and fair retrospective comparisons between different antidiabetics.

Method: We conducted three meta-regression analyses using 78 randomized or non-randomized comparative phase 2 or 3 trials of 24 approved antidiabetics in Japan, conducted from 1987 to 2012.

Results: Baseline HbA1c of each arm was higher in phase 2 trials, trials with a greater number of subjects, trials with a lower proportion of male subjects, trials of combination therapy, or trials with longer subject disease duration. Entry criteria were different among drug classes and caused variations in baseline HbA1c. HbA1c reductions were larger in non-randomized trials, trials with a shorter treatment period, or trials with a lower proportion of male subjects. Effect sizes were larger in phase 2 trials, or trials of combination therapy. Larger effect sizes were observed in drugs with later market entry for alpha-glucosidase inhibitors and glinides.

Conclusion: Baseline HbA1c, an important characteristic of subjects enrolled in trials of antidiabetics, differed significantly across trials. Differences in features of study subjects were caused by explicit stipulations in eligibility criteria of HbA1c and also by other conditions (e.g. trial design, regulatory guidance, treatment guideline) and/or interventions of investigators and pharmaceutical companies that were specific to drugs and trials. Healthcare professionals should carefully consider these heterogeneities in trials used for marketing approval review when making a retrospective comparison to select the best treatment option for patients.
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http://dx.doi.org/10.1177/2050312118823407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329034PMC
January 2019

The Current Status of Drug Discovery and Development as Originated in United States Academia: The Influence of Industrial and Academic Collaboration on Drug Discovery and Development.

Clin Transl Sci 2018 11 30;11(6):597-606. Epub 2018 Jul 30.

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Academic drug discovery is a vital component to current drug discovery and development environments. In this study, we investigated 798 drug discovery projects that took place between 1991 and 2015 at 36 academic institutions in the United States. The observed success rates of academic drug discovery and development were 75% at phase I, 50% at phase II, 59% at phase III, and 88% at the new drug application/biologics license application (NDA/BLA) phase. These results were similar to the corresponding success rates of the pharmaceutical industry. Collaboration between academic institutions and the pharmaceutical industry seemed more important at later stages than earlier ones; all projects that succeeded at phase III or the NDA/BLA stage involved academic-industrial collaboration. Many academic research projects involved neoplasms and infectious diseases, and were focused on small molecules and biologics. The success rates and possible effects of academic-industrial collaboration seemed to vary depending on disease domains and drug modalities.
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http://dx.doi.org/10.1111/cts.12577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226120PMC
November 2018

Spontaneous Reporting on Adverse Events by Consumers in the United States: An Analysis of the Food and Drug Administration Adverse Event Reporting System Database.

Drugs Real World Outcomes 2018 Jun;5(2):117-128

Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: Voluntary reports on adverse events (AEs) submitted by consumers have been facilitated through the MedWatch program in the United States (US), but few studies have described the characteristics of voluntary reports.

Objective: The aim of this study was to reveal the characteristics of current voluntary reports on AEs reported by consumers and healthcare professionals.

Methods: We performed analysis on voluntary reports of AEs in the US Food and Drug Administration AE Reporting System (FAERS) database submitted in 2016. We compared reports by consumers with those by healthcare professionals.

Results: The number of voluntary reports by consumers has increased since 2013 in the US. Reports by consumers were different from ones by health professionals in several important aspects such as demographics and outcomes of patients, AEs, and suspect drugs. The proportion of reports on female patients and on disability as a patient outcome were higher in reports by consumers than in those by healthcare professionals. Consumers more frequently reported concomitant drugs compared with healthcare professionals. Time to report varied among the occupations and depending on seriousness of outcomes.

Conclusions: Our analysis of voluntary AE reports in the US FAERS database has shown that voluntary reports tended to include AEs related to subjective symptoms, as in some previous studies on patient reporting in the EU. Voluntary reports by consumers seemed to be different from ones by healthcare professionals in important aspects including demographics and reporting behaviors. These findings suggest that the heterogeneities should be addressed appropriately in using spontaneous reports.
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http://dx.doi.org/10.1007/s40801-018-0134-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984610PMC
June 2018

Heterogeneity of Clinical Trials for Antihypertensive Drugs in Japan: Exploratory Analysis of Confirmatory Phase III Trials Used for Marketing Approval.

Clin Pharmacol Ther 2018 07 20;104(1):120-129. Epub 2017 Nov 20.

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

The results of pivotal trials, which provide a rationale for marketing approval decisions for new drugs, are considered for various comparative purposes in postmarketing analyses. Using meta-regression analysis of 91 randomized controlled trials of 61 approved antihypertensive drugs in Japan, we show that mean baseline blood pressure (BP) of each arm was associated with predetermined entry criteria (EC), age, and trial start year (TSY). BP changes following treatment were associated with EC, subject characteristics (e.g., age, complications, baseline BP), study design (e.g., concomitant drug use), and TSY. Effect sizes were generally larger in trials for the first and second drugs in the same class than in trials for follow-on drugs. Results of pivotal trials may vary depending on many factors, suggesting possible challenges associated with the comparison of these results indirectly. Due to the heterogeneity in pivotal trials, caution should be exercised when comparing approved drugs and conducting meta-analyses retrospectively.
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http://dx.doi.org/10.1002/cpt.922DOI Listing
July 2018

Analysis of Safety-Related Regulatory Actions for New Drugs in Japan by Nature of Identified Risks.

Pharmaceut Med 2017 13;31(5):317-327. Epub 2017 Jul 13.

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan.

Background: Mechanisms underlying safety events may be heterogeneous and depend on conditions of development and marketing, including the populations studied in clinical trials and the amount of data required for approval, especially under pathways for accelerated access.

Objective: This study was conducted to investigate possible factors affecting the first post-marketing safety-related regulatory actions (SRRAs) after launch of new drugs in Japan.

Methods: We studied 338 new molecular entities (NMEs) approved in Japan between 2004 and 2014. We focused on three different types of SRRAs: (1) all-SRRAs (i.e. SRRAs from domestic cases and other countries), (2) domestic-SRRAs (i.e. SRRAs from domestic cases) and (3) domestic unknown-SRRAs (i.e. SRRAs of unknown risks from domestic cases). Occurrences of the three types of SRRAs were analyzed using Kaplan-Meier analysis and Cox-regression.

Results: SRRAs tended to occur sooner for NMEs launched in recent years versus those launched towards the beginning of the study period. Risk of SRRA was high for antineoplastics. Drugs for cardiovascular diseases, central nervous system, and diabetes had positive associations with all-SRRAs, but the associations were weaker with domestic-SRRAs. Domestic-SRRAs were more likely for drugs with relatively novel modes of action (MOAs). Longer lag to Japanese launch after first global launch significantly lowered SRRA risks. While most of the variables showed similar associations across the three types of SRRAs, adoption of bridging strategies showed higher risks only for domestic-SRRAs, not for all-SRRAs. FDA safety labeling changes and non-orphan priority review drugs presented higher domestic-SRRA risks. The number of adverse drug reactions (ADRs) from spontaneous reports had positive correlations with the three types of SRRAs, whereas the number from company-led surveillance showed no association.

Conclusions: Our results indicated that global clinical development pathways and marketing status should be considered more seriously in implementing locally optimized pharmacovigilance activities. Caution may be needed not only for drugs with novel MOAs, but also for drugs for which local dose-finding studies have been skipped, expedited review status has been given, timing of launch is close to those in the USA and the EU, and spontaneous reports rather than company-lead surveillance suggest possible safety risks.
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http://dx.doi.org/10.1007/s40290-017-0198-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629242PMC
July 2017

Regulatory Review of New Therapeutic Agents.

N Engl J Med 2017 06;376(26):2598

University of Tokyo Graduate School of Pharmaceutical Sciences, Tokyo, Japan

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http://dx.doi.org/10.1056/NEJMc1705868DOI Listing
June 2017

$L_{0}$ Gradient Projection.

Authors:
Shunsuke Ono

IEEE Trans Image Process 2017 Apr 11;26(4):1554-1564. Epub 2017 Jan 11.

Minimizing L gradient, the number of the non-zero gradients of an image, together with a quadratic data-fidelity to an input image has been recognized as a powerful edge-preserving filtering method. However, the L gradient minimization has an inherent difficulty: a user-given parameter controlling the degree of flatness does not have a physical meaning since the parameter just balances the relative importance of the L gradient term to the quadratic data-fidelity term. As a result, the setting of the parameter is a troublesome work in the L gradient minimization. To circumvent the difficulty, we propose a new edge-preserving filtering method with a novel use of the L gradient. Our method is formulated as the minimization of the quadratic data-fidelity subject to the hard constraint that the L gradient is less than a user-given parameter α . This strategy is much more intuitive than the L gradient minimization because the parameter α has a clear meaning: the L gradient value of the output image itself, so that one can directly impose a desired degree of flatness by α . We also provide an efficient algorithm based on the so-called alternating direction method of multipliers for computing an approximate solution of the nonconvex problem, where we decompose it into two subproblems and derive closed-form solutions to them. The advantages of our method are demonstrated through extensive experiments.
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http://dx.doi.org/10.1109/TIP.2017.2651392DOI Listing
April 2017

Safety Profile Based on Concordance of Nonclinical Toxicity and Clinical Adverse Drug Reactions for Blood Cancer Drugs Approved in Japan.

Drugs R D 2017 Mar;17(1):133-143

Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555, Japan.

Background: In drug development, animal toxicology data are very important for the evaluation of clinical safety. We quantitatively assessed the safety profiles of blood cancer drugs approved in Japan from category I (high) to V (low). We examined the ratios of drug exposure in animals at the no observed adverse effect level to those in humans at the expected therapeutic dose. In addition, qualitative analysis of the relationship between toxicological findings and adverse drug reactions (ADRs) is one of the primary approaches for determining the risk-benefit profile of a pharmaceutical. This study thus aimed to evaluate the potential of nonclinical safety assessments for predicting ADRs in humans.

Methods: We examined toxicological findings at the lowest observed adverse effect level and ADRs in pivotal clinical studies. We calculated concordance rates as the ratio of the number of concordant ADRs to all ADRs.

Results: Twenty-seven drugs were eligible for analysis. Concordance rates ranged from 0 to 84.8%. No significant differences were observed in concordance rates between antibodies (median 14.3%) and small molecules (median 18.5%). There was a significant correlation between concordance rates and quantitative safety profiles (p = 0.047), suggesting that some drugs with low safety profiles (categories III, IV, or V) have high concordance rates.

Conclusion: The results suggested that ADRs in clinical trials could be predicted based on toxicity data obtained in animal tests, especially for some drugs with a low quantitative safety profile.
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http://dx.doi.org/10.1007/s40268-016-0160-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318328PMC
March 2017

Differences between the United States and Japan in labels of oncological drugs.

Pharmacoepidemiol Drug Saf 2017 02 26;26(2):143-151. Epub 2016 Sep 26.

Laboratory of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Purpose: Our study addresses how the information in the labels differed between United States (US) and Japan, what factors were associated with the decision to place the boxed warning on the label, and the relation of both countries in terms of drug label policy.

Methods: We investigated adverse drug reactions (ADRs) in boxed warnings for 44 oncological drug labels approved from 2004 to 2014 in both Japan and the US. We applied conditional logistic regression to examine how likely it was for each ADR to be included in a boxed warning.

Results: There were substantial differences in all sections of the labels. The concordance rate between US and Japanese labels was 44.1% for serious adverse reactions and 30.5% for boxed warnings. Our regression analysis indicated that deaths and/or terminations related to specific ADRs reported in clinical trials were significantly associated with inclusion of the ADR in boxed warnings in Japan, but not in the US. The boxed warnings of similar drugs seemed to affect those of follow-on drugs in both countries. US drug labels were likely to influence Japanese labels, but not vice versa.

Conclusion: This study suggests that the observed differences are not solely due to differences in clinical outcomes between the two countries, but rather due to differences in regulatory considerations and historical factors in both local and global contexts. Further research is needed to examine the impact of these differences on public health and to determine how and to what extent we should intervene with this status quo. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pds.4111DOI Listing
February 2017

Evaluation of Safety Profiles of Blood Cancer Drugs Approved in Japan.

Ther Innov Regul Sci 2016 Mar;50(2):228-235

1 Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, Josai International University, Chiba, Japan.

Background: In drug development, the safety of a test drug for human use is first assessed in animal toxicology studies; therefore, the no-observed-adverse-effect-level (NOAEL) and toxicokinetic data are very important for the evaluation of clinical safety. The ratio of drug exposure in animals at the NOAEL to that of humans at the expected therapeutic dose is one of the primary measures for determining the risk-benefit profile of a pharmaceutical. The objective of this study was to evaluate the safety profiles of drugs for blood cancer approved in Japan by examining safety indices (SIs).

Methods: SIs were calculated as animal-to-human ratios in doses and exposure using NOAEL, severely toxic dose 10% of the animals, highest nonseverely toxic dose, maximum approved dose, and exposure levels (C and area under the curve [AUC]) at the NOAEL and maximum approved dose. If the SI of a certain drug is <1.0, either the maximum therapeutic dose exceeds the NOAEL, or the exposure level at the maximum therapeutic dose exceeds the exposure level at the NOAEL.

Results: A total of 8 of 17 SIs by dose were <1.0; 6 of 8 SIs by C were <1.0, and 6 of 9 SIs by AUC were <1.0.

Conclusions: In cases where the SI is <1.0, no drug safety margin can be assured based on animal data. When extrapolating data from animal studies to safety assessment in clinical studies, safety profile would be one of aspects to be carefully considered in drug development, including postmarketing surveillance.
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http://dx.doi.org/10.1177/2168479015619658DOI Listing
March 2016

[Regulatory science].

Authors:
Shunsuke Ono

Nihon Yakurigaku Zasshi 2015 Oct;146(4):236-8

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http://dx.doi.org/10.1254/fpj.146.236DOI Listing
October 2015
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