Publications by authors named "Hiroki Nakayama"

47 Publications

Neutron flux evaluation model provided in the accelerator-based boron neutron capture therapy system employing a solid-state lithium target.

Sci Rep 2021 Apr 13;11(1):8090. Epub 2021 Apr 13.

Division of Research and Development for Boron Neutron Capture Therapy, National Cancer Center Exploratory Oncology Research & Clinical Trial Center, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.

An accelerator-based boron neutron capture therapy (BNCT) system employing a solid-state Li target can achieve sufficient neutron flux for treatment although the neutron flux is reduced over the lifetime of its target. In this study, the reduction was examined in the five targets, and a model was then established to represent the neutron flux. In each target, a reduction in neutron flux was observed based on the integrated proton charge on the target, and its reduction reached 28% after the integrated proton charge of 2.52 × 10 mC was delivered to the target in the system. The calculated neutron flux acquired by the model was compared to the measured neutron flux based on an integrated proton charge, and the mean discrepancies were less than 0.1% in all the targets investigated. These discrepancies were comparable among the five targets examined. Thus, the reduction of the neutron flux can be represented by the model. Additionally, by adequately revising the model, it may be applicable to other BNCT systems employing a Li target, thus furthering research in this direction. Therefore, the established model will play an important role in the accelerator-based BNCT system with a solid-state Li target in controlling neutron delivery and understanding the neutron output characteristics.
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http://dx.doi.org/10.1038/s41598-021-87627-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044165PMC
April 2021

Polymorphic SERPINA3 prolongs oligomeric state of amyloid beta.

PLoS One 2021 4;16(3):e0248027. Epub 2021 Mar 4.

Department of Life Sciences and Bioengineering, Laboratory of Molecular and Cellular Biology, Faculty of Engineering, University of Toyama, Toyama, Japan.

Molecular chaperon SERPINA3 colocalizes with accumulated amyloid peptide in Alzheimer's disease (AD) patient's brain. From the QTL analysis, we narrowed down Serpina3 with two SNPs in senescence-accelerated mouse prone (SAMP) 8 strain. Our study showed SAMP8 type Serpina3 prolonged retention of oligomeric Aβ 42 for longer duration (72 hr) while observing under transmission electron microscope (TEM). From Western blot results, we confirmed presence of Aβ 42 oligomeric forms (trimers, tetramers) were maintained for longer duration only in the presences of SAMP8 type Serpina3. Using SH-SY5Y neuroblastoma cell line, we observed until 36 hr preincubated Aβ 42 with SAMP8 type Serpina3 caused neuronal cell death compared to 12 hr preincubated Aβ 42 with SAMR1 or JF1 type Serpina3 proteins. Similar results were found by extending this study to analyze the effect of polymorphism of SERPINA3 gene of the Japanese SNP database for geriatric research (JG-SNP). We observed that polymorphic SERPINA3 I308T (rs142398813) prolonged toxic oligomeric Aβ 42 forms till 48 hr in comparison to the presence wild type SERPINA3 protein, resulting neuronal cell death. From this study, we first clarified pathogenic regulatory role of polymorphic SERPINA3 in neurodegeneration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248027PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932536PMC
March 2021

A dosimetric and centeredness comparison of the conventional and novel endobronchial applicators: A preliminary study.

Brachytherapy 2021 Mar-Apr;20(2):467-477. Epub 2021 Jan 19.

Department of Radiation Oncology, National Cancer Center Hospital, Chuo City, Tokyo, Japan.

Purpose: This study compared the applicator position relative to the tracheal wall and dosimetric parameters between conventional and novel applicators among patients receiving endobronchial brachytherapy (EBBT) for intratracheal tumors.

Methods And Materials: Data from 7 patients who received EBBT for intratracheal tumors were retrospectively analyzed; 4 and 3 patients were treated with conventional (2-wing) or novel (5-wing) applicators, respectively. Applicator centrality was evaluated using the distance between the center of the trachea and main bronchus (TMB) lumen and path of source (L). Dosimetric parameters, including plans normalized to D of the TMB = 45 Gy (normalized plan), were compared between the applicators.

Results: The mean and maximum values of L in cases of the 2-wing applicator group were approximately 5.0 mm and 10.0 mm, respectively. In the novel applicator group, the corresponding values were approximately 3.0 and 6.0 mm, respectively. In the normalized plan of the 2-wing applicator group, the ranges of median V of clinical target volume (CTV) and D of the TMB in all cases were 23.0-91.9% and 66.3-153.1 Gy, respectively. In the 5-wing applicator group, the corresponding values were 69.2-83.8% and 60.4-84.5 Gy, respectively.

Conclusions: In the 5-wing applicator group, the range was narrow in all dose-volume parameters except for D of the TMB. Compared to the conventional applicator, the 5-wing applicator can give a stable dose to the CTV and can reduce the maximum dose of the TMB. This suggests that stable EBBT can be given to any patient using the 5-wing applicator.
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http://dx.doi.org/10.1016/j.brachy.2020.11.005DOI Listing
January 2021

Dosimetric effect of the intestinal gas of online adaptive stereotactic body radiotherapy on target and critical organs without online electron density correction for pancreatic cancer.

Br J Radiol 2021 Mar 5;94(1119):20200239. Epub 2021 Feb 5.

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objective: This study aimed to assess the dosimetric effect of intestinal gas of stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) on target and critical organs for pancreatic cancer without online electron density correction (EDC).

Methods: Thirty pancreatic cancer patients who underwent online SMART were selected for this study. The treatment time of each stage and the total treatment time were recorded and analyzed. The concerned dose-volume parameters of target and organs-at-risk (OAR) were compared with and without an intestinal gas EDC using the Wilcoxon-signed rank test. Analysis items with value < 0.05 were considered statistically significant. The relationships between dosimetric differences and intestinal gas volume variations were investigated using the Spearman test.

Results: The average treatment time was 82 min, and the average EDC time was 8 min, which accounted for 10% of the overall treatment time. There were no significant differences in CTV (GTV), PTV, bowel, stomach, duodenum, and skin ( > 0.05) with respect to dose volume parameters. For the of gastrointestinal organs ( = 0.03), the mean dose of the liver ( = 0.002) and kidneys ( = 0.03 and = 0.04 for the left and right kidneys, respectively), there may be a risk of slight overestimation compared with EDC, and for the of the spinal cord ( = 0.02), there may be a risk of slight underestimation compared with EDC. A weak correlation for in the PTV and in the duodenum was observed.

Conclusion: For patients with similar inter-fractional intestinal gas distribution, EDC had little dosimetric effects on the of all GI organs and dose volume parameters of target in most plans.

Advances In Knowledge: By omitting the EDC of intestinal gas, the online SMART treatment time can be shortened.
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http://dx.doi.org/10.1259/bjr.20200239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011255PMC
March 2021

The use of hyperbaric oxygen to treat actinic rectal fistula after SpaceOAR use and radiotherapy for prostate cancer: a case report.

BMC Urol 2020 Dec 14;20(1):196. Epub 2020 Dec 14.

Department of Radiation Therapy, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan.

Background: In definitive radiation therapy for prostate cancer, the SpaceOAR® System, a hydrogel spacer, is widely used to decrease the irradiated dose and toxicity of rectum. On the other hand, periprostatic abscesses formation and rectal perforation are known as rare adverse effects of SpaceOAR. Nevertheless, there is a lack of reports clarifying the association between aggravation of abscesses and radiation therapy, and hyperbaric oxygen therapy (HBOT) is effective for a peri-SpaceOAR abscess and rectal perforation.

Case Presentation: We report a case of a 78-year-old high-risk prostate cancer patient. After SpaceOAR insertion into the correct space, he started to receive external beam radiation therapy (EBRT). He developed a fever, perineal pain and frequent urination after the completion of EBRT, and the magnetic resonance imaging (MRI) revealed a peri-SpaceOAR abscess. Scheduled brachytherapy was postponed, administration of antibiotics and opioid via intravenous drip was commenced, and transperineal drainage was performed. After the alleviation of the abscess, additional EBRT instead of brachytherapy was performed with MRI-guided radiation therapy (MRgRT). On the last day of the MRgRT, perineal pain reoccurred, and MRI and colonoscopy detected the rectal perforation. He received an intravenous antibiotics drip and HBOT, and fully recovered from the rectal perforation.

Conclusions: Our report indicates that EBRT can lead to a severe rectum complication by causing inflammation for patients with a peri-SpaceOAR abscess. Furthermore, HBOT was effective for the peri-SpaceOAR abscess and rectal perforation associated with EBRT.
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http://dx.doi.org/10.1186/s12894-020-00767-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737272PMC
December 2020

Seroepidemiological analysis of anti-pneumococcal surface protein A (PspA) immunoglobulin G by clades in Japanese population.

Vaccine 2020 11 7;38(47):7479-7484. Epub 2020 Oct 7.

Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan; Toyama Institute of Health, Toyama, Japan. Electronic address:

Background: Pneumococcal surface protein A (PspA) is one of the candidates of the novel pneumococcal protein vaccines. The seroepidemiology of naturally acquired anti-PspA immunoglobulin G (IgG) by clades, across a wide range of ages has not been investigated.

Methods: We examined the concentrations of anti-PspA IgG by clades (1, 2, 3, 4, and 5) in 397 sera from persons aged 0-≥70 years by enzyme-linked immunosorbent assay, and determined the geometric mean concentrations (GMCs) by age group. The relationships between concentrations of anti-PspA IgG antibody for each clade for each person were also assessed.

Results: GMC of anti-PspA IgG was lowest, highest, and plateaued in those aged 6-11 months, 5-9-years, and 20-49 years, respectively. It gradually declined in those aged > 70 years. GMCs patterns in different age groups were similar for all clades. Correlations were found especially within the same PspA family (between clades 1 and 2 or clades 4 and 5).

Conclusions: Our data suggested that most people acquired anti-PspA IgG across clades 1, 2, 3, 4, and 5 during childhood. These results would be a fundamental data of clade-specific anti-PspA IgG antibodies.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.068DOI Listing
November 2020

Configuration analysis of the injection position and shape of the gel spacer in gynecologic brachytherapy.

Brachytherapy 2021 Jan-Feb;20(1):95-103. Epub 2020 Oct 1.

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: In this single-institution retrospective study, configuration analysis was performed to determine the optimal location and volume of hyaluronic acid gel spacer injection into the rectovaginal or vesicovaginal septum for effective dose reduction (DR) to the organs at risk (OARs), the rectum and bladder.

Methods And Materials: 70 and 50 intracavitary brachytherapy treatment plans used only vaginal cylinders with gel spacers for the rectal and bladder sides, respectively, whereas 28 did not use spacers. Correlation analysis was performed between the geometrical parameters and injection position of the gel spacers and the 2-cm covering doses of the OARs for each treatment.

Results: A higher DR was predicted for hyaluronic acid gel spacer injection within ±5 mm and ±2.5 mm in the lateral-medial direction from the midpoint on the rectal and bladder sides, and ±10 mm in the cranial-caudal direction from the midpoint on the rectal side. There were correlations between 2-cm covering doses and the gel spacer parameters: the volume on the rectal (p = 0.02) and bladder (p = 0.04) sides; the craniocaudal length on the rectal side (p << 0.05); and ventrodorsad thickness on each OAR (p << 0.05) sides. There was no significant difference in the DR between a volume of ∼10 cm and that of a higher volume (p >> 0.05).

Conclusions: A gel spacer volume of ∼10 cm provides sufficient OAR DR if its gravity point is on the midpoint between the cylinder applicator and OAR, and its craniocaudal length covers the active length of the cylinder applicator.
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http://dx.doi.org/10.1016/j.brachy.2020.08.021DOI Listing
October 2020

Silver-Catalyzed, Chemo- and Enantioselective Intramolecular Dearomatization of Indoles to Access Sterically Congested Azaspiro Frameworks.

J Org Chem 2020 08 31;85(16):10934-10950. Epub 2020 Jul 31.

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.

An asymmetric dearomatization of indoles bearing α-diazoacetamide functionalities was developed for synthesizing high-value spiro scaffolds. A silver phosphate chemoselectively catalyzed the sterically challenging dearomatization, whereas more typically used metal catalysts for carbene transfer reactions, such as a rhodium complex, were not effective and instead resulted in a Büchner ring expansion or cyclopropanation. Mechanistic studies indicated that the spirocyclization occurred through a silver-assisted asynchronous concerted process and not via a silver-carbene intermediate. Analyses based on natural bond orbital population and a distortion/interaction model indicated that the degree of C-Ag mutual interaction is crucial for achieving a high level of enantiocontrol. In addition, an oxidative disconnection of a C(sp)-C(sp) bond in the product provided unconventional access to the corresponding chiral spirooxindole.
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http://dx.doi.org/10.1021/acs.joc.0c01580DOI Listing
August 2020

Safety-Related Regulatory Actions and Risk Factors for Anticancer Drugs in Japan.

Pharmaceut Med 2019 02;33(1):45-52

Global Regulatory Science, Gifu Pharmaceutical University, 1-25-4, Daigakunishi, Gifu, 501-1196, Japan.

Introduction: The approval of anticancer drugs in Japan has increased to meet high medical demand. To maximize the benefits of anticancer drugs, adverse drug reactions (ADRs) must be properly managed. However, in some cases, clinically significant safety issues are detected after launch, and safety-related regulatory actions (SRRAs) are implemented.

Objectives: We aimed to determine the characteristics of SRRAs for anticancer drugs approved in Japan and to identify factors related to the drug development and regulatory approval process associated with the occurrence of an SRRA.

Methods: We defined an SRRA as the issuance of a 'Yellow Letter', 'Blue Letter', or an official notification by the Ministry of Health, Labor and Welfare. Anticancer drugs approved in Japan as new active ingredients from April 2004 to July 2016 were analyzed using publicly available information. The Kaplan-Meier survival curve was plotted to estimate the probability of the occurrence of an SRRA, and the Cox proportional hazards model was used to identify risk factors associated with the occurrence of an SRRA. Independent variables were selected using backward/forward stepwise selection according to Akaike's Information Criterion.

Results: An SRRA was implemented for 38 of 63 anticancer drugs. Approximately 70% of SRRAs occurred within 2 years after approval, and the median time between approval and the occurrence of an SRRA was 1.6 years (interquartile range 0.94-2.4). No Yellow Letter was issued during the follow-up period; however, one Blue Letter was issued for 'acute lung injury and interstitial pneumonia' for sorafenib. According to official notifications, 'clinically significant adverse reactions' was the most revised section of package inserts (62%). The probability of an SRRA at the 1-, 2- and 3-year follow-up was 15.9% (95% confidence interval [CI] 6.4-24.4%), 41.3% (95% CI 27.8-52.3%), and 56.8% (95% CI 41.8-68.0%), respectively. Monoclonal antibodies were associated with a low risk of occurrence of an SRRA (hazard ratio [HR] 0.29, p = 0.019), while the large number of patients in pivotal studies (per 100 patients) was associated with a high risk of occurrence (HR 1.07, p = 0.012).

Conclusions: The high-risk period for the occurrence of an SRRA for anticancer drugs in Japan was within 2 years after approval. Among the factors related to the drug development and regulatory approval process, anticancer drugs in the form of non-monoclonal antibodies, and whose pivotal studies included a large number of patients, were more likely to be associated with an SRRA. Postmarketing follow-up should therefore be carefully performed, especially in the first 2 years after approval and for non-monoclonal antibody anticancer drugs. Moreover, postmarketing follow-up is crucial, even if large-scale pivotal studies for regulatory approval have already been performed.
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http://dx.doi.org/10.1007/s40290-018-0260-8DOI Listing
February 2019

Characterization of the relationship between neutron production and thermal load on a target material in an accelerator-based boron neutron capture therapy system employing a solid-state Li target.

PLoS One 2019 22;14(11):e0225587. Epub 2019 Nov 22.

Department of Medical Physics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

An accelerator-based boron neutron capture therapy (BNCT) system that employs a solid-state Li target can achieve sufficient neutron flux derived from the 7Li(p,n) reaction. However, neutron production is complicated by the large thermal load expected on the target. The relationship between neutron production and thermal load was examined under various conditions. A target structure for neutron production consists of a Li target and a target basement. Four proton beam profiles were examined to vary the local thermal load on the target structure while maintaining a constant total thermal load. The efficiency of neutron production was evaluated with respect to the total number of protons delivered to the target structure. The target structure was also evaluated by observing its surface after certain numbers of protons were delivered. The yield of the sputtering effect was calculated via a Monte Carlo simulation to investigate whether it caused complications in neutron production. The efficiency of neutron production and the amount of damage done depended on the proton profile. A more focused proton profile resulted in greater damage. The efficiency decreased as the total number of protons delivered to the target structure increased, and the rate of decrease depended on the proton profile. The sputtering effect was not sufficiently large to be a main factor in the reduction in neutron production. The proton beam profile on the target structure was found to be important to the stable operation of the system with a solid-state Li target. The main factor in the rate of reduction in neutron production was found to be the local thermal load induced by proton irradiation of the target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225587PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874357PMC
March 2020

Dependence of neutrons generated by Li(p,n) reaction on Li thickness under free-air condition in accelerator-based boron neutron capture therapy system employing solid-state Li target.

Phys Med 2019 Feb 16;58:121-130. Epub 2019 Feb 16.

Department of Medical Physics, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan; Division of Research and Development for Boron Neutron Capture Therapy, National Cancer Center Exploratory Oncology Research & Clinical Trial Center, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan; Department of Radiation Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.

Purpose: An accelerator-based boron neutron capture therapy (BNCT) system with a solid-state Li target is reported to have degradation of the Li target. The degradation reduces the Li thickness, which may change spectra of the generated neutrons corresponding to the Li thickness. This study aims to examine the relationship between the Li thickness and the generated neutrons and to investigate the effects of the Li thickness on the absorbed dose in BNCT.

Method: The neutron energy spectra were calculated via Monte Carlo simulation for Li thicknesses ranging from 20 to 150 μm. Using the system, the saturated radioactivity of gold induced by reactions between Au and the generated neutrons was evaluated with the simulation and the measurement, and those were compared. Additionally, for each Li thickness, the saturated radioactivity was compared with the number of generated neutrons. The absorbed doses delivered by B(n,α)Li, N(n,p)C, H(n, g)H, and (n,n') reactions in water were also calculated for each Li thickness.

Results: The measurement and simulation indicated a reduction in the number of neutrons due to the degradation of the Li target. However, the absorbed doses were comparable for each Li thickness when the requisite number of neutrons for BNCT was delivered. Additionally, the saturated radioactivity of Au could be a surrogate for the number of neutrons even if the Li thickness was varied.

Conclusions: No notable effect to the absorbed dose was observed when required neutron fluence was delivered in the BNCT even if the degradation of the Li was observed.
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http://dx.doi.org/10.1016/j.ejmp.2019.02.010DOI Listing
February 2019

Monte Carlo modeling of a 60Co MRI-guided radiotherapy system on Geant4 and experimental verification of dose calculation under a magnetic field of 0.35 T.

J Radiat Res 2019 Jan;60(1):116-123

Department of Radiation Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.

Our purpose was to establish the commissioning procedure of Monte Carlo modeling on a magnetic resonance imaging-guided radiotherapy system (MRIdian, Viewray Inc.) under a magnetic field of 0.345 T through experimental measurements. To do this, we sought (i) to assess the depth-dose and lateral profiles generated by the Geant4 using either EBT3 film or the BJR-25 data; (ii) to assess the calculation accuracy under a magnetic field of 0.345 T. The radius of the electron trajectory caused by the electron return effect (ERE) in a vacuum was obtained both by the Geant4 and the theoretical methods. The surface dose on the phantom was calculated and compared with that obtained from the film measurements. The dose distribution in a phantom having two air gaps was calculated and measured with EBT 3 film. (i) The difference of depth-dose profile generated by the Geant4 from the BJR-25 data was 0.0 ± 0.8% and 0.3 ± 1.5% for field sizes of 4.5 and 27.3 cm2, respectively. Lateral dose profiles generated by Geant4 agreed well with those generated from the EBT3 film data. (ii) The radius of the electron trajectory generated by Geant4 agreed well with the theoretical values. A maximum of ~50% reduction of the surface dose under a magnetic field of 0.345 T was observed due to elimination of the electron contamination caused by the magnetic field, as determined by both the film measurements and the Geant4. Changes in the dose distributions in the air gaps caused by the ERE were observed on the Geant4 and in the film measurements. Gamma analysis (3%/3 mm) showed a pass rate of 95.1%. Commissioning procedures for the MRI-guided radiotherapy system on the Geant4 were established, and we concluded that the Geant4 had provided high calculation accuracy under a magnetic field of 0.345 T.
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http://dx.doi.org/10.1093/jrr/rry087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373691PMC
January 2019

[Efforts toward Patient Safety: Development of System and Education of Non-Technical Skill].

Igaku Butsuri 2018;38(2):62-67

Department of Radiation Oncology, National Cancer Center Hospital.

Advanced radiotherapy such as intensity-modulated radiotherapy offers many advantages of high accuracy and efficiency of radiotherapy. To date, many technical guidelines with description of quality assurance and quality control have been reported. However, some reports indicated that human factor and environment is major cause of radiotherapy incidents. If radiotherapy systems depend on automation and computer system, individual risk management is degraded and ability of preventing radiotherapy incidents weaken. Recently, the American Association of Physicists in Medicine (AAPM) task group-100 was reported and it has a new concept guideline, which proposed the comprehensive risk management and education of non-technical skills for overall radiotherapy processes. The TG-100 recommends implementation of process map, reporting system, risk assessment such as failure mode and effects analysis (FMEA) and fault tree analysis (FTA) especially for advanced radiotherapy. In this paper, we described effective and efficient procedures to improve the treatment processes and education of non-technical skills using the such management tools proposed by the TG-100 guide-lines.
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http://dx.doi.org/10.11323/jjmp.38.2_62DOI Listing
June 2019

Silver-catalyzed regioselective hydroamination of alkenyl diazoacetates to synthesize γ-amino acid equivalents.

Org Biomol Chem 2018 07 11;16(25):4675-4682. Epub 2018 Jun 11.

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan. and Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.

A simple protocol to directly access γ-amino acid derivatives by intermolecular regioselective hydroamination of trichloroethyl alkenyldiazoacetates with carbamate using a silver tetrafluoroborate catalyst is described. Density functional theory (DFT) calculations to analyze the reaction mechanism revealed that multiple attractive interactions occur in a transition state to promote the vinylogous addition of nitrogen nucleophiles.
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http://dx.doi.org/10.1039/c8ob00894aDOI Listing
July 2018

The drug lag and associated factors for orphan anticancer drugs in Japan compared to the United States.

Invest New Drugs 2019 10 31;37(5):1086-1093. Epub 2018 May 31.

Global Regulatory Science, Gifu Pharmaceutical University, 1-25-4, Daigakunishi, Gifu, 501-1196, Japan.

The approval of orphan anticancer drugs in Japan has increased to meet high social demand. Drug lag, namely the approval lag of new drugs, is recognized as a social issue in Japan. We investigated the approval lag and its components, submission lag and review-time lag, between Japan and the United States (US) to reveal whether an approval lag still exists, and to identify potential factors that may contribute to reducing the approval lag. Anticancer drugs approved in Japan between April 2004 and November 2017 were investigated using publicly available information. Results showed that the median approval lag of orphan anticancer drugs in 2016-2017 was 727.0 days (interquartile range, IQR, 310.0-1054.3). The approval lag was significantly correlated with the submission lag (correlation coefficient = 1.00, P < 0.001) but not with the review-time lag (correlation coefficient = -0.16, P = 0.22). The submission lag was significantly longer for orphan anticancer drugs than non-orphan drugs (median, 712.5 days [IQR, 186.0-1448.3] vs. 387.0 days [92.8-1096.0], P = 0.023). External collaboration in drug development was associated with a longer submission lag (coefficient = 762.1, P = 0.017), while breakthrough therapy designation in the US was associated with a shorter submission lag (coefficient = -832.8, P = 0.035). In conclusion, we revealed that an approval lag for orphan anticancer drugs still existed in 2016-2017. A submission lag for orphan anticancer drugs was the main component affecting the approval lag, and was longer than that for non-orphan drugs. External collaboration in drug development may be a potential factor in reducing the submission lag for orphan anticancer drugs.
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http://dx.doi.org/10.1007/s10637-018-0612-yDOI Listing
October 2019

Unique characteristics of regulatory approval and pivotal studies of orphan anticancer drugs in Japan.

Invest New Drugs 2018 08 17;36(4):702-708. Epub 2018 Apr 17.

Global Regulatory Science, Gifu Pharmaceutical University, 1-25-4, Daigakunishi, Gifu, 501-1196, Japan.

The approval of orphan anticancer drugs has increased, with the number exceeding that of non-orphan drugs in Japan in recent years. Although orphan anticancer drugs may have unique characteristics due to their rarity, these have not been fully characterized. We investigated anticancer drugs approved in Japan between April 2004 and November 2017 to reveal the characteristics of regulatory approval and pivotal studies on orphan anticancer drugs compared to non-orphan drugs. The median regulatory review time and number of patients in pivotal studies on orphan anticancer drugs (281.0 days [interquartile range, 263.3-336.0]; 222.5 patients [66.0-454.3]) were significantly lower than those on non-orphan drugs (353.0 days [277.0-535.5]; 521.0 patients [303.5-814.5], respectively) (P < 0.001). Phase II, non-randomized and non-controlled designs were more frequently used in pivotal studies on orphan anticancer drugs (45.9%, 41.9% and 43.2%) than non-orphan drugs (17.2%, 14.1% and 14.1%, respectively). Response rate was more commonly used as a primary endpoint in pivotal studies on orphan anticancer drugs (48.6%) than non-orphan drugs (17.2%). Indications limited by molecular features, second or later treatment line, and accelerated approval in the United States were associated with the use of response rate in orphan anticancer drug studies. In conclusion, we demonstrated that orphan anticancer drugs in Japan have unique characteristics compared to non-orphan drugs: shorter regulatory review and pivotal studies frequently using phase II, non-randomized, or non-controlled designs and response rate as a primary endpoint, with fewer patients.
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http://dx.doi.org/10.1007/s10637-018-0603-zDOI Listing
August 2018

Chemoselective Asymmetric Intramolecular Dearomatization of Phenols with α-Diazoacetamides Catalyzed by Silver Phosphate.

J Am Chem Soc 2017 08 21;139(30):10188-10191. Epub 2017 Jul 21.

Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.

We report asymmetric dearomatization of phenols using Ag carbenoids from α-diazoacetamides. The Ag catalyst promoted intramolecular dearomatization of phenols, whereas a Rh or Cu catalyst caused C-H insertion and a Büchner reaction. Studies indicated Ag carbenoids have a carbocation-like character, making their behavior and properties unique. Highly enantioselective transformations using Ag carbenoids have not been reported. We achieved a Ag carbenoid-mediated chemo- and highly enantioselective phenol dearomatization with substrate generality for the first time.
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http://dx.doi.org/10.1021/jacs.7b04813DOI Listing
August 2017

Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization.

Sci Rep 2016 Mar 18;6:23372. Epub 2016 Mar 18.

Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.
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http://dx.doi.org/10.1038/srep23372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796892PMC
March 2016

Synthesis of nitrogen-containing fused-polycyclic compounds from tyramine derivatives using phenol dearomatization and cascade cyclization.

Chem Commun (Camb) 2014 Oct;50(84):12775-8

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.

We developed a novel method of synthesizing nitrogen-containing fused-polycyclic compounds using tyramine derivatives as substrates. The method is based on the dearomatization of phenols via an intramolecular ipso-Friedel-Crafts allenylation and sequential bond-forming-cleavage reactions initiated by the construction of an indole skeleton. Structurally diverse fused-heterocycles were produced in reaction sequences requiring only a few steps.
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http://dx.doi.org/10.1039/c4cc04809aDOI Listing
October 2014

A phase II study of paclitaxel and carboplatin with a biweekly schedule in patients with epithelial ovarian cancer: Gynecologic Cancer Network trial.

J Nippon Med Sch 2014 ;81(1):28-34

Department of Obstetrics and Gynecology, Nippon Medical School Hospital.

Aim: The objective of this multicenter phase II study was to evaluate the effects of biweekly paclitaxel and carboplatin combination chemotherapy on response rate and toxicities in patients with epithelial ovarian cancer.

Patients And Methods: Patients with International Federation of Gynecology and Obstetrics stage II to IV ovarian cancer received paclitaxel at a dose of 120 mg/m(2) and carboplatin at an area under the curve of 3 mg/mL per minute every 2 weeks for 8 or more cycles. Inclusion criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2 and no previous chemotherapy. Informed consent was obtained from each patient before the start of treatment.

Results: From March 2003 through July 2009, 42 patients from 5 institutions were eligible to be evaluated for response and toxicity. The median age was 60.5 years (age range, 34-81 years). The International Federation of Gynecology and Obstetrics stage was stage II in 3 patients, stage III in 31 patients, and stage IV in 8 patients. The response rate was 66.7% (95% confidence interval: 50.5%-80.4%). Sixty-nine percent (29 of 42) of patients received 8 or more cycles of chemotherapy. The median progression-free survival was 18.5 months, and overall survival was 59.1 months. The most common grade 3 or 4 hematological toxicity was neutropenia (61.0%). No patients had grade 3 or 4 thrombocytopenia. The most common grade 3 nonhematological toxicities were neuropathy (4.9%) and nausea (2.4%).

Conclusion: Paclitaxel combined with carboplatin using a biweekly schedule is a safe and effective chemotherapy regimen for patients with epithelial ovarian cancer. Our results suggest that a biweekly schedule is well tolerated and is less toxic than a triweekly schedule.
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http://dx.doi.org/10.1272/jnms.81.28DOI Listing
August 2014

Acid-promoted cascade cyclization to produce fused-polycyclic indole derivatives.

Org Lett 2013 Jun 7;15(12):2978-81. Epub 2013 Jun 7.

Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan.

An acid-promoted novel cascade cyclization is described. Using 8 equiv of trifluoroacetic acid or a catalytic amount of Lewis acid as the promoter, structurally diverse polycyclic cyclopenta[b]indoles were obtained in moderate to excellent yield. This cascade process was extremely effective for the synthesis of 8-membered ring-fused cyclopenta[b]indole derivatives.
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http://dx.doi.org/10.1021/ol401128hDOI Listing
June 2013

Diagnosis, clinicopathologic features, treatment, and prognosis of small cell carcinoma of the uterine cervix; Kansai Clinical Oncology Group/Intergroup study in Japan.

Gynecol Oncol 2013 Jun 26;129(3):522-7. Epub 2013 Feb 26.

Division of gynecology, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan.

Objectives: This is a multicenter, collaborative study to accumulate cases of small cell carcinoma of the uterine cervix (SmCC), to clarify its clinical and clinicopathologic features and prognosis, and to obtain findings to establish future individualized treatment.

Methods: At medical centers participating in the Kansai Clinical Oncology Group/Intergroup, patients diagnosed with SmCC between 1997 and 2007 were enrolled. Clinicopathologic features and prognosis were retrospectively evaluated in patients with SmCC diagnosed at a central pathologic review.

Results: A total of 71 patients were registered at 25 medical centers in Japan. Of these, 52 patients (73%) were diagnosed with SmCC based on a pathological review. These 52 patients diagnosed with SmCC were analyzed. The median follow-up period was 57 months. The 4-year progression-free survival (PFS) was: IB1, 59%; IB2, 68%; IIB, 13%; and IIIB, 17%. The 4-year overall survival (OS) was: IB1, 63%; IB2, 67%; IIB, 30%; IIIB, 29%; and IVB, 25%. For postoperative adjuvant therapy, postoperative chemotherapy (a platinum drug in all cases) was compared to non-chemotherapy. The 4-year PFS was 65% and 14%, and the 4-year OS was 65% and 29%. PFS was significantly better (p=0.002), and the OS tended to be better (p=0.073) in the group with postoperative chemotherapy.

Conclusion: Even in patients with early stage SmCC, the prognosis is poor. However, in early stage patients, by adding postoperative chemotherapy, the prognosis may improve. Currently, various treatment protocols are used at each medical center, but in the future, a standardized treatment protocol for SmCC will hopefully be established.
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http://dx.doi.org/10.1016/j.ygyno.2013.02.025DOI Listing
June 2013

[Therapy of the recurrent endometrial cancer].

Authors:
Hiroki Nakayama

Nihon Rinsho 2012 Jun;70 Suppl 4:432-7

Department of Gynecology, Kanagawa Cancer Center.

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June 2012

[Introduction of the operative therapy].

Authors:
Hiroki Nakayama

Nihon Rinsho 2012 Jun;70 Suppl 4:394-9

Department of Gynecology, Kanagawa Cancer Center.

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June 2012

New terminology for intrauterine endometrial samples: a group study by the Japanese Society of Clinical Cytology.

Acta Cytol 2012 26;56(3):233-41. Epub 2012 Apr 26.

Department of Obstetrics and Gynecology, JA Suzuka General Hospital, Suzuka, Japan.

Objective: To evaluate the sensitivity and specificity of endometrial cytology obtained by intrauterine sample using a descriptive reporting format for endometrial cytological diagnosis.

Study Design: 10,152 consecutive endometrial scrapings obtained in 13 different Japanese hospitals were analyzed. Cytological results were classified as 'negative for malignancy', 'atypical endometrial cells' (ATEC), 'endometrial hyperplasia', 'atypical endometrial hyperplasia' or 'malignant tumor'. ATEC was subclassified as 'ATEC, of undetermined significance' (ATEC-US) and 'ATEC, cannot exclude atypical endometrial hyperplasia or more' (ATEC-A). Cytological results were compared with the histological diagnosis as a gold standard. When the cytological result was 'negative for malignancy' and there was no subsequent histological examination, the case was considered a true negative when the endometrium was assessed as normal on transvaginal ultrasonography and there was no abnormal uterine bleeding.

Results: 1,083 cases in which histology was not performed, 557 cases of 'unsatisfactory specimen' and 76 cases of ATEC-US were excluded. In the remaining 8,436 cases, the sensitivity and specificity, positive predictive value and negative predictive value for detecting atypical endometrial hyperplasia or malignant tumors were 79.0 and 99.7, 92.9 and 98.9%, respectively.

Conclusion: The current diagnostic standards for endometrial cytology in Japan were established. Specificity is satisfactory for excluding cancer or precancerous diseases.
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http://dx.doi.org/10.1159/000336258DOI Listing
July 2012

Definitive radiation therapy for invasive carcinoma of the vagina: impact of high-dose rate intracavitary brachytherapy.

Int J Clin Oncol 2013 Apr 7;18(2):314-20. Epub 2012 Feb 7.

Department of Radiation Oncology, Kanagawa Cancer Center, 1-1-2 Nakao Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan.

Background: This study was designed to evaluate the efficacy of definitive radiation therapy (RT) for invasive carcinoma of the vagina.

Methods: Twenty-six patients with invasive carcinoma of the vagina who received RT were studied retrospectively. The median age was 68 years. The pathologic subtype of vaginal carcinoma was squamous cell carcinoma in 24 patients, adenosquamous cell carcinoma in one patient, and adenocarcinoma in one patient. The distribution of clinical stage according to the International Federation of Gynecology and Obstetrics staging system was as follows: stage I, seven patients; stage II, 10 patients, stage III, seven patients; and stage IVA, two patients. Twenty patients received external beam radiation therapy (EBRT) combined with high-dose rate intracavitary brachytherapy (HDR-ICBT), and three received EBRT alone. The remaining three patients with stage I disease were given HDR-ICBT alone. The median dose was 50 Gy for EBRT, and 23 Gy for HDR-ICBT. Systemic chemotherapy was administered concurrently with RT to three patients.

Results: The median follow-up was 90 months. The initial rate of response to RT was 100%, and complete remission was attained in 21 patients (81%). The 5-year overall survival rate (OS) and the median survival time of the 26 patients were 57% and 97 months, respectively. The 5-year OS for the three patients who received HDR-ICBT alone was 100%. Severe toxicity occurred in three patients-grade 3 rectal hemorrhage in one, grade 3 cystitis in one, and grade 4 cystitis in one.

Conclusions: Our results demonstrated that definitive RT with HDR-ICBT is effective for invasive carcinoma of the vagina, with acceptable toxicity.
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http://dx.doi.org/10.1007/s10147-012-0379-7DOI Listing
April 2013

Tandem oxidation/rearrangement of beta-ketoesters to tartronic esters with molecular oxygen catalyzed by calcium iodide under visible light irradiation with fluorescent lamp.

Org Lett 2010 May;12(9):1948-51

Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.

It was found that beta-ketoesters were directly transformed to the corresponding alpha-hydroxymalonic esters, tartronic esters, with molecular oxygen catalyzed by calcium iodide under visible light irradiation from fluorescent lamp. This reaction includes tandem oxidation/rearrangement and has received much attention from the viewpoint of reduction of energy consumption, labor, and solvents.
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http://dx.doi.org/10.1021/ol1003675DOI Listing
May 2010

Inhibition of the expression of the starch synthase II gene leads to lower pasting temperature in sweetpotato starch.

Plant Cell Rep 2010 Jun 20;29(6):535-43. Epub 2010 Mar 20.

National Agricultural Research Center for Kyushu Okinawa Region (KONARC), National Agriculture and Food Research Organization (NARO), 6651-2 Yokoichi, Miyakonojo, Miyazaki, 885-0091, Japan.

The sweetpotato cultivar Quick Sweet (QS) with a lower pasting temperature of starch is a unique breeding material, but the biochemical background of this property has been unknown. To assess the physiological impact of the reduced isoform II activity of starch synthase (SSII) on the starch properties in sweetpotato storage root, transgenic sweetpotato plants with reduced expressions of the SSII gene were generated and evaluated. All of the starches from transgenic plants showed lower pasting temperatures and breakdown measured by a Rapid Visco Analyzer. The pasting temperatures in transgenic plants were approximately 10-15 degrees C lower than in wild-type plants. Distribution of the amylopectin chain length of the transgenic lines showed marked differences compared to that in wild-type plants: more chains with degree of polymerization (DP) 6-11 and fewer chains with DP 13-25. The starch granules from the storage root of transgenic plants showed cracking on the hilum, while those from wild-type plants appeared to be typical sweetpotato starch. In accordance with these observations, the expression of SSII in the storage roots of the sweetpotato cultivar with low pasting temperature starch (QS) was notably lower than in cultivars with normal starch. Moreover, nucleotide sequence analysis suggested that most of the SSII transcripts in the cultivar with low pasting temperature starch were inactive alleles. These results clearly indicate that the activity of SSII in sweetpotato storage roots, like those in other plants, affects the pasting properties of starch through alteration of the amylopectin structure.
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http://dx.doi.org/10.1007/s00299-010-0842-8DOI Listing
June 2010

Analysis of stage IVB endometrial carcinoma patients with distant metastasis: a review of prognoses in 55 patients.

Int J Clin Oncol 2009 Aug 25;14(4):344-50. Epub 2009 Aug 25.

Department of Gynecology, Kanagawa Cancer Center Hospital, Yokohama, Japan.

Background: Adequate treatment for extremely advanced endometrial cancer is unknown. The purpose of this study was to clarify the prognosis of patients with stage IVB endometrial carcinoma and the validity of treatment. Furthermore, we evaluated whether there was a connection between the prognosis and the site of metastasis.

Methods: The prognoses of 55 patients with stage IVB endometrial carcinoma were studied with reference to the initial treatment method and the metastatic site at the time of the initial treatment.

Results: The median survivals of the group of 35 patients who were initially treated with surgery and the group of 10 patients who underwent radiotherapy or chemotherapy as their initial treatment followed by surgery were 11.5 months and 9.5 months, respectively. The residual tumor diameter after surgery was precisely measured in 40 of these 45 patients. The prognosis was significantly better in the patients with a residual tumor diameter of less than 2 cm compared to those with a tumor diameter of 2 cm or greater, and the median survival periods in these two groups were 23.5 months and 11.5 months, respectively (P = 0.027). Furthermore, the prognosis of patients with lung metastasis was significantly better than that of patients with non-lung hematogenous metastasis; the median survival periods of these two groups were 18.5 months and 10.5 months, respectively (P = 0.014).

Conclusion: For operable patients, surgery as an initial treatment and reduction of the residual tumor size to less than 2 cm appeared to contribute to a better prognosis. In addition, conservative initial treatment and the presence of non-lung hematogenous metastasis were poor prognostic factors.
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http://dx.doi.org/10.1007/s10147-009-0878-3DOI Listing
August 2009