膜乳化デバイスによるエマルションを用いたウサギVX2肝腫瘍モデノレへの肝動脈化学塞栓術における抗腫瘍効果、薬物動態の検討

Purpose: To evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits. Materials and methods: Epirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n = 24) and a 3-way-stopcock group (n = 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100-300-μm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope. Results: The area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 μg min/mL and 0.13 ± 0.06 μg/mL, respectively, in the device group and 0.71 ± 0.45 μg min/mL and 0.22 ± 0.17 μg/mL, respectively, in the 3-way-stopcock group (P = .013 and P = .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 μg/g tissue, respectively (P = .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P = .039). Conclusions: Conventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.博士（医学）・乙第1443号・令和元年12月5日Copyright © 2019 SIR. Published by Elsevier Inc. All rights reserved

ラット肝腫瘍モデルにおける化学療法の早期効果判定に有用なダイナミック造影超音波のパラメータについて

Objectives: The objective of the study is to determine a parameter on the time-intensity curve (TIC) of dynamic contrast-enhanced ultrasonography (DCE-US) that best correlates with tumor growth and to evaluate whether the parameter could correlate with the early response to irinotecan in a rat liver tumor model. Material and Methods: Twenty rats with tumors were evaluated (control: Saline, n = 6; treatment: Irinotecan, n = 14) regarding four parameters from TIC: Peak intensity (PI), k value, slope (PI × k), and time to peak (TTP). Relative changes in maximum tumor diameter between day 0 and 10, and parameters in the first 3 days were evaluated. The Mann-Whitney U-test was used to compare differences in tumor size and other parameters. Pearson’s correlation coefficients (r) between tumor size and parameters in the control group were calculated. In the treatment group, relative changes of parameters in the first 3 days were compared between responder and non-responder (<20% and ≥20% increase in size on day 10, respectively). Results: PI, k value, PI × k, and TTP significantly correlated with tumor growth (r = 0.513, 0.911, 0.665, and 0.741, respectively). The mean RC in k value among responders (n = 6) was significantly lower than non-responders (n = 8) (mean k value, 4.96 vs. 72.5; P = 0.003). Conclusion: Parameters of DCE-US could be a useful parameter for identifying early response to irinotecan.博士（医学）・甲第879号・令和5年3月15

ラット凍結肩モデルを用いた経カテーテル的動脈塞栓術の効果に関する検討

Purpose: To assess the angiographic findings and the effects of transcatheter arterial embolization on physical activity and histopathology using a frozen shoulder rat model. Materials and methods: First, the angiographic and histopathologic findings of rats in which the shoulder was immobilized with molding plaster for 6 weeks (n = 4) were compared to control rats with normal non-immobilized shoulders (n = 4). Next, a total of 16 frozen shoulder rats were divided into 2 groups. In the transcatheter arterial embolization group (n = 8), imipenem/cilastatin was injected into the left thoracoacromial artery. The changes of physical activity before and after procedures were evaluated and compared with a saline-injected control group (n = 8). Histopathologic findings were also compared between the 2 groups. Results: Angiography revealed abnormal shoulder staining in all of the rats with a frozen shoulder. On histopathology, the numbers of microvessels and mononuclear inflammatory cells in the synovial membrane of the joint capsule were significantly higher compared with the control rats (both P = .03). In the transcatheter arterial embolization group, the running distance and speed were improved (P = .03 and P = .01, respectively), whereas there were no significant differences in the control group. The number of microvessels and mononuclear inflammatory cells in the transcatheter arterial embolization group were significantly lower than the control group (P = .002 and P = .001, respectively). Conclusions: The rat frozen shoulder model revealed the development of neovascularization. Transcatheter arterial embolization decreased the number of blood vessels and inflammatory changes in the frozen shoulder and increased the moving distance and speed of the rats.博士（医学）・甲第789号・令和3年3月15日Copyright © 2020 SIR(Society of Interventional Radiology). Published by Elsevier Inc. All rights reserved

ミスマッチ修復遺伝子発現欠損を伴う子宮体癌のMRI所見と臨床像

Purpose: The purpose of this study was to identify the magnetic resonance imaging (MRI) features of uterine endometrial carcinoma (EC) with DNA mismatch repair (MMR) deficiency. Materials and methods: This was a retrospective study approved by our institutional review board. The study included 118 patients pathologically diagnosed as having EC in our institution from April 2014 to December 2016. Of 118 patients, 8 were excluded because of insufficient data. Immunohistochemical analysis of MMR was performed retrospectively to observe the expressions of MLH1, MSH2, MSH6, and PMS2. A tumor with MMR deficiency was detected in 17 of 110 cases (15%). Clinical background characteristics and MRI findings were reviewed. These findings were compared between MMR deficiency group and the other group as a control group. Statistical significance was determined using the Fisher's exact test and the Mann-Whitney U test, as appropriate. Results: The clinical background characteristics of patients with EC with MMR deficiency were not significantly different from those of other patients. On MRI, the tumor was significantly more often located in the lower uterine site (MMR(-) vs. MMR(+): 29.4 vs. 8.9% [p = 0.0366]). Conclusion: EC with MMR deficiency tends to be located lower in the uterus, though most other findings were not significantly different from those of EC without MMR deficiency.博士（医学）・甲第749号・令和2年6月30日© Japan Radiological Society 2018© 2018 Springer Nature Switzerland AG. Part of Springer Nature.This is a post-peer-review, pre-copyedit version of an article published in Japanese journal of radiology. The final authenticated version is available online at: http://doi.org/10.1007/s11604-018-0741-4

Direct exploration of the role of the ventral anterior temporal lobe in semantic memory:Cortical stimulation and local field potential evidence from subdural grid electrodes

Semantic memory is a crucial higher cortical function that codes the meaning of objects and words, and when impaired after neurological damage, patients are left with significant disability. Investigations of semantic dementia have implicated the anterior temporal lobe (ATL) region, in general, as crucial for multimodal semantic memory. The potentially crucial role of the ventral ATL subregion has been emphasized by recent functional neuroimaging studies, but the necessity of this precise area has not been selectively tested. The implantation of subdural electrode grids over this subregion, for the presurgical assessment of patients with partial epilepsy or brain tumor, offers the dual yet rare opportunities to record cortical local field potentials while participants complete semantic tasks and to stimulate the functionally identified regions in the same participants to evaluate the necessity of these areas in semantic processing. Across 6 patients, and utilizing a variety of semantic assessments, we evaluated and confirmed that the anterior fusiform/inferior temporal gyrus is crucial in multimodal, receptive, and expressive, semantic processing

発症早期ALS患者に対する超高用量メチルコバラミンの有効性・安全性について : ランダム化比較試験

Importance: Post hoc analysis in a phase 2/3 trial indicated ultra-high dose methylcobalamin slowed decline of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 16 as well as at week 182, without increase of adverse events, in patients with amyotrophic lateral sclerosis (ALS) who were enrolled within 1 year from onset. Objective: To validate the efficacy and safety of ultra-high dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design: A multicenter, placebo-controlled, double-blind, randomized phase 3 trial with 12-week observation and 16-week randomized period, conducted from October 2017 to September 2019. Setting: Twenty-five neurology centers in Japan. Participants: Patients with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in ALSFRS-R total score, a percent forced vital capacity over 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulant. The target number was 64 in both methylcobalamin and placebo groups. Of 203 patients enrolled in the observation, 130 patients (age, 61.0 ± 11.7 years; female, 56) met the criteria and were randomly assigned through an electronic web-response system to methylcobalamin or placebo (65 for each). Of these, 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Interventions: Intramuscular injection of methylcobalamin 50 mg or placebo twice weekly for 16 weeks. Main outcomes and measures: The primary endpoint was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: The least-squares mean difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 versus −4.63; 95% CI, 0.44–3.50; P = 0.012). The incidence of adverse events was similar between the two groups. Conclusions and relevance: Ultra-high dose methylcobalamin was efficacious in slowing functional decline and safe in the 16-week treatment period in ALS patients in the early stage and with moderate progression rate. Trial registration: UMIN-CTR Identifier: UMIN000029588 (umin.ac.jp/ctr); ClinicalTrials.gov Identifier: NCT03548311 (clinicaltrials.gov

超音波加温による動脈塞栓後の肝腫瘍内部のリピオドール集積検出能に関する生体内での検討

Computed tomography (CT) is the standard method to evaluate Lipiodol deposition after transarterial embolization (TAE) for a long period. However, iodine but not Lipiodol can be observed on CT. A minimally invasive other method to detect Lipiodol has been needed to evaluate accurate evaluation after procedure. The purpose of this study was to evaluate the efficacy of using the rate of change in sound velocity caused by ultrasonic heating to reflect Lipiodol accumulation after TAE in a rat liver tumor model. We analyzed the association of this developed technique with CT images and histological findings. Eight rats bearing N1S1 cells were prepared. After confirmation of tumor development in a rat liver, Lipiodol was injected via the hepatic artery. Seven days after TAE, CT scan and sound velocity changes caused by ultrasonic heating were measured, and then the rats were sacrificed. An ultrasonic pulse-echo method was used to measure the sound velocity. The temperature coefficient of the sound velocity in each treated tumor was evaluated and compared with the mean CT value and the histological Lipiodol accumulation ratio. Pearson's correlation coefficients were calculated to assess the correlation between the measured values. The correlation coefficient (r) of the mean CT value and histological Lipiodol accumulation ratio was 0.835 (p = 0.010), which was considered statistically significant. Also, those of the temperature coefficient of the sound velocity and the histological Lipiodol accumulation ratio were statistically significant (r = 0.804; p = 0.016). To our knowledge, this is the first study that reported the efficacy of ultrasonic heating to detect Lipiodol accumulation in rat liver tumors after TAE. Our results suggest that the rate of change in sound velocity caused by ultrasonic heating can be used to evaluate Lipiodol accumulation in liver tumors after TAE, and thus could represent an alternative to CT in this application. This new innovative technique is easy to treat and less invasive in terms of avoiding radiation compared with CT.博士（医学）・甲第836号・令和4年3月15日© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)

Development of liposomal contrast agent with high iodine concentration and minimal effect on renal function

Purpose: The use of contrast media is essential to achieve high accuracy in diagnostic imaging. Iodine contrast media, one of these contrast media, has nephrotoxicity as a side effect. Therefore, the development of iodine contrast media that can reduce nephrotoxicity is expected. Since liposomes are generally adjustable in size (100–300 nm) and are not filtered by the renal glomerulus, we hypothesized that iodine contrast media could be encapsulated in liposomes and administered to avoid the nephrotoxicity of iodine contrast media. The aim of this study is to develop an iomeprol-containing liposome (IPL) agent with high iodine concentration and to investigate the effect of intravenous administration of IPL on renal function in a rat model with chronic kidney injury. Materials and methods: IPLs were prepared by encapsulating an iomeprol (400mgI/mL) solution in liposomes by a kneading method using a rotation–revolution mixer. Radiodensities of iomeprol and IPL were measured. IPL or iopamidol at normal dose (0.74 g I/kg) or high dose (3.7 g I/kg) was administered to healthy and 5/6-nephrectomized rats (n = 3–6). Serum creatinine (sCr) and histopathological change of tubular epithelial cells were evaluated after injection. Results: The iodine concentration of IPL was 220.7 mgI/mL, equivalent to 55.2% of the iodine concentration of iomeprol. The CT values of IPL was 4731.6 ± 53.2 HU, 59.04% that of iomeprol. The ratios of change in sCr in 5/6-nephrectomized rats that received high-dose iopamidol were 0.73, which were significantly higher than that in 5/6-nephrectomized rats that received high-dose IPL (−0.03) (p = 0.006). Change in foamy degeneration of tubular epithelial cells was confirmed in 5/6-nephrectomized rats that received high-dose iopamidol than that in the sham control group and healthy rats that received normal dose iopamiron (p = 0.016, p = 0.032, respectively). Foamy degeneration of tubular epitherial cells was rarely observed in the IPL injection group. Conclusions: We developed new liposomal contrast agents that have high iodine concentration and minimal effect on renal function

Effects of menopause on brain structural changes in schizophrenia.

AIM:The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI).METHODS:Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5.RESULTS:Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group.CONCLUSION:Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia