Publications by authors named "Hideaki Shiraishi"

92 Publications

Pseudocirrhosis due to liver metastasis from lung adenocarcinoma.

Thorac Cancer 2021 Jul 17. Epub 2021 Jul 17.

Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Pseudocirrhosis is a radiological diagnosis of cirrhosis without histological evidence and occurs as a complication of liver metastases from solid tumors. A 50-year-old man without any previous history of liver disease was diagnosed with adenocarcinoma of the left upper lung lobe and liver metastasis. After chemotherapy, the liver metastases shrank; however, over time, the liver shrank and showed cirrhosis-like morphological changes. His performance status deteriorated due to ascites and leg edema, and chemotherapy was terminated. Physicians treating lung adenocarcinoma with liver metastases should be aware that pseudocirrhosis is a rare but important complication that can worsen performance status (PS) and hinder treatment continuation.
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http://dx.doi.org/10.1111/1759-7714.14084DOI Listing
July 2021

Current medico-psycho-social conditions of patients with West syndrome in Japan.

Epileptic Disord 2021 Jul 13. Epub 2021 Jul 13.

Department of Pediatrics, School of Medicine, Shinshu University, Matsumoto, Japan.

Objective: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan.

Methods: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset.

Results: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%.

Significance: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.
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http://dx.doi.org/10.1684/epd.2021.1301DOI Listing
July 2021

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Kurume Med J 2021 Jun 15. Epub 2021 Jun 15.

Department of Pediatrics, Showa University School of Medicine.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.
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http://dx.doi.org/10.2739/kurumemedj.MS662007DOI Listing
June 2021

Development of a reading difficulty questionnaire for adolescents in Japanese.

Brain Dev 2021 May 26. Epub 2021 May 26.

Department of Child and Adolescent Psychiatry, Hokkaido University Hospital, Sapporo, Hokkaido, Japan.

Background: Dyslexia is a neurodevelopmental disorder which occurs in childhood but continues to influence academic and occupational function in adulthood. Recently, a Japanese dyslexia questionnaire and diagnostic procedure was established for primary school children. However, there is currently no procedure for the diagnosis or screening of dyslexia in individuals at or above junior high school age; accordingly, we aimed to develop a questionnaire to screen for reading difficulties in those individuals.

Methods: A questionnaire with various candidate items was developed from two English questionnaires, one Japanese questionnaire, and newly devised items focusing on the Japanese writing system and the most appropriate 28 items were selected. In total, 462 adults and 127 junior high to high school students were enrolled. Of those, 191 participants also took part in reading tests. After the exploratory factor analysis, reliability and validity were evaluated using the above control participants and 12 adolescents with dyslexia.

Results: The questionnaire included three factors, i.e., silent reading sub-scale (four items), writing sub-scale (four items), and aloud reading sub-scale (three items). Five were newly devised items focusing on the Japanese writing system. Cronbach's alphas of the three factors were 0.706, 0.638, and 0.568, respectively, and the interclass correlation coefficients (2,1) were 0.743, 0.609, and 0.695, respectively. The silent reading and aloud reading sub-scales were positively correlated with word, non-word, and passage reading time.

Discussion: The newly developed questionnaire correlated well with actual reading performance and may be used to screen reading difficulty in Japanese individuals at or above junior high school age.
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http://dx.doi.org/10.1016/j.braindev.2021.05.007DOI Listing
May 2021

Selective Eating in Autism Spectrum Disorder Leading to Hair Color Change.

Pediatr Neurol 2021 Jul 2;120:1-2. Epub 2021 Apr 2.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2021.03.001DOI Listing
July 2021

Appraisal of definition of baseline length for somatosensory evoked magnetic fields.

J Neurosci Methods 2021 07 2;359:109213. Epub 2021 May 2.

Department of Systems Neuroscience, School of Medicine, Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan. Electronic address:

Background: The baseline (BL) segment in the prestimulus period is generally assigned as a reference of evoked activities. However, an experimenter empirically defines its length in each condition. So far, the criterion for the length of a BL segment has not been established.

New Method: We evaluated the effect of the length of the BL segment by recording somatosensory evoked magnetic fields (SEFs) under fixed stimulus onset asynchrony (SOA). For the evaluation of the length of the BL segment in the prestimulus period, five proportions in relation to SOA were used as the BL segment. In addition, we adopted other two types of BL segment which were the single data point measured from the value of stimulus onset (BL0) and the mean value of the whole raw data throughout the recording (DC mean). We investigated the influence of the BL segments on SEFs by utilizing two indicators: normalized N20 m amplitudes and estimated locations of corresponding equivalent current dipoles (ECDs).

Results: Both indicators did not show any significant differences, based on the factor of BL segments, in any SOA conditions.

Comparison With Existing Method: The BL0 had by far the largest variation in the ECD locations.Therefore, utilizing stimulus onset as the BL segment should be avoided. In addition, considering that other BL segments provided comparable values by the two indicators, the DC mean can reasonably be adopted.

Conclusions: We suggest that utilizing the DC mean could be employed as the BL segment.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109213DOI Listing
July 2021

The use of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide-based colorimetric assay in the viability analysis of the filamentous cyanobacterium Arthrospira platensis.

Biosci Biotechnol Biochem 2021 Feb;85(3):739-742

Graduate School of Biostudies, Kyoto University, Kyoto, Japan.

The applicability of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to an industrially valuable filamentous cyanobacterium Arthrospira platensis was examined. When it was applied to A. platensis NIES-39, as few as 10 viable trichomes were quantitatively detected. However, depending on the experimental conditions, it also generated artifactual viability signals. The results should help clarify the scope and limits of the MTT assay in viability analysis.
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http://dx.doi.org/10.1093/bbb/zbaa050DOI Listing
February 2021

Selective Eating in Autism Spectrum Disorder Leading to Kwashiorkor and Brain Edema.

Pediatr Neurol 2021 03 26;116:55-56. Epub 2020 Dec 26.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.12.007DOI Listing
March 2021

Variance in the pathophysiological impact of the hemizygosity of gamma-aminobutyric acid type A receptor subunit genes between Prader-Willi syndrome and Angelman syndrome.

Brain Dev 2021 Apr 5;43(4):521-527. Epub 2021 Jan 5.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Electronic address:

Introduction: Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders caused by loss of function of maternally expressed UBE3A and paternally expressed contiguous genes on chromosome 15q11-13, respectively. A majority of these syndromes suffer from a large deletion of the relevant chromosome (AS Del or PWS Del), which includes biallelically expressed gamma-aminobutyric acid type A receptor subunit (GABAaR) genes, while remaining individuals present without the deletion (AS non-Del or PWS non-Del). We previously reported that AS Del, but not AS non-Del individuals, show aberrantly desynchronized somatosensory-evoked magnetic fields (SEFs) and speculated that it might reflect GABAergic dysfunction due to the hemizygosity of GABAaR genes. To verify its pathophysiological impact on PWS and AS, we analyzed the SEFs of PWS individuals.

Method: SEFs were recorded from eight PWS Del and two PWS non-Del individuals. The latency and strength of the first peak (N1m) were compared with those of AS Del/non-Del individuals and controls, most of which were obtained earlier.

Results: In contrast to AS, both PWS Del and PWS non-Del showed normal SEF waveforms. Desynchronized response with delayed N1m peak latency was exclusively indicated in AS Del. N1m strength was statistically higher in AS Del and AS non-Del, but not in PWS Del and PWS non-Del.

Conclusions: Our results indicate that the pathophysiological impact of the hemizygosity of GABAaR genes is lower in PWS than AS. UBE3A deficiency and the hemizygosity of GABAaR genes could synergistically deteriorate neuronal function, resulting in aberrant SEFs in AS Del.
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http://dx.doi.org/10.1016/j.braindev.2020.12.014DOI Listing
April 2021

Flurothyl-induced seizure paradigm revealed higher seizure susceptibility in middle-aged Angelman syndrome mouse model.

Brain Dev 2021 Apr 4;43(4):515-520. Epub 2021 Jan 4.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Electronic address:

Introduction: Epilepsy is one of the main clinical problems in Angelman syndrome (AS). Seizures typically start in early childhood then decrease or are often alleviated by young adulthood. Several studies using AS model mice showed comparable seizure susceptibility during young adulthood. In contrast, the course of epilepsy post young adulthood differs from persistently relieved to rerising among reports. To elucidate this, we evaluated the seizure susceptibility of AS model mice of two different ages.

Methods: Mice lacking maternal Ube3a gene (Ube3a) of C57BL/6 background or their littermate wild type (WT) were divided into two groups by age, 2 to 3 months (2-3 M) and 6 to 12 months (6-12 M), corresponding to adolescent to young adult aged and middle aged humans, respectively. Seizure susceptibility was evaluated by flurothyl inhalation or intraperitoneal injection of pentylenetetrazole (PTZ IP)-induced acute seizure protocol.

Results: In the flurothyl-induced seizure paradigm, the latency to seizure occurrence had a significant interaction with genotype and age. Post-hoc analysis revealed that the latency was significantly shorter at 6-12 M than at 2-3 M in Ube3a mice, and in Ube3a mice than in WT mice at 6-12 M. No significant interaction or difference was observed by PTZ IP.

Conclusion: The flurothyl-induced seizure paradigm revealed that seizure susceptibility of Ube3a mice increased with age, similar to clinical studies reporting the reappearance of epilepsy in older age. The flurothyl-induced seizure paradigm applied to middle-aged Ube3a mice could be a suitable protocol for screening drugs against seizures in AS.
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http://dx.doi.org/10.1016/j.braindev.2020.12.011DOI Listing
April 2021

Reinterpretation of magnetic resonance imaging findings with magnetoencephalography can improve the accuracy of detecting epileptogenic cortical lesions.

Epilepsy Behav 2021 01 13;114(Pt A):107516. Epub 2020 Dec 13.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. Electronic address:

Objective: This study examined whether the application of magnetoencephalography (MEG) to interpret magnetic resonance imaging (MRI) findings can aid the diagnosis of intractable epilepsy caused by organic brain lesions.

Methods: This study included 51 patients with epilepsy who had MEG clusters but whose initial MRI findings were interpreted as being negative for organic lesions. Three board-certified radiologists reinterpreted the MRI findings, utilizing the MEG findings as a guide. The degree to which the reinterpretation of the imaging results identified an organic lesion was rated on a 5-point scale.

Results: Reinterpretation of the MRI data with MEG guidance helped detect an abnormality by at least one radiologist in 18 of the 51 patients (35.2%) with symptomatic localization-related epilepsy. A surgery was performed in 7 of the 51 patients, and histopathological analysis results identified focal cortical dysplasia in 5 patients (Ia: 1, IIa: 2, unknown: 2), hippocampal sclerosis in 1 patient, and dysplastic neurons/gliosis in 1 patient.

Conclusions: The results of this study highlight the potential diagnostic applications of MEG to detect organic epileptogenic lesions, particularly when radiological visualization is difficult with MRI alone.
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http://dx.doi.org/10.1016/j.yebeh.2020.107516DOI Listing
January 2021

Reply to the letter: "Perampanel may be beneficial in leigh syndrome by its anti-oxidative but not anti-epileptic effect".

Brain Dev 2021 02 13;43(2):361-362. Epub 2020 Dec 13.

Department of Pediatrics, Teine Keijinkai Hospital, Japan.

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http://dx.doi.org/10.1016/j.braindev.2020.10.008DOI Listing
February 2021

Short-latency somatosensory-evoked potentials demonstrate cortical dysfunction in patients with Angelman syndrome.

eNeurologicalSci 2021 Mar 1;22:100298. Epub 2020 Dec 1.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan.

Background: Angelman syndrome (AS) is neurodevelopmental disorder, causal gene of which is maternally expressed . A majority of patients results from the large deletion of relevant chromosome which includes GABA receptor subunit genes (GABARs) as well as (AS Del) We previously reported aberrantly desynchronized primary somatosensory response in AS Del by using magnetoencephalography. The purpose of this study is to estimate cortical and subcortical involvement in the deficit of primary somatosensory processing in AS.

Methods: We analyzed short-latency somatosensory-evoked potentials (SSEPs) in 8 patients with AS Del. SSEPs were recorded on a 4-channel system comprising of two cortical electrodes which were placed on the frontal and centro-parietal areas. The peak and onset latency of each component were measured to compare latency and interval times.

Results: The first-cortical peak latency (N20, P20), and N13-N20 peak interval times were significantly prolonged in AS Del compared to healthy controls. In contrast, there was no difference in latencies between subcortical components up to N20 onset or for N11-N20 onset interval times.

Conclusion: Highly desynchronized first-cortical SSEP components and normal latencies of subcortical components indicated cortical dysfunction rather than impairment of afferent pathways in AS Del patients, which might be attributed to GABAergic dysfunction due to loss of function and heterozygosity of GABARs.
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http://dx.doi.org/10.1016/j.ensci.2020.100298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721653PMC
March 2021

Brigatinib and lorlatinib: their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous system metastases.

Jpn J Clin Oncol 2021 Jan;51(1):37-44

Department of Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan.

Major issues in anaplastic lymphoma kinase-positive non-small cell lung carcinoma are acquired resistance against anaplastic lymphoma kinase inhibitors and control of central nervous system metastasis. The development of these inhibitors has changed therapeutic strategy in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Brigatinib and lorlatinib were designed to penetrate the blood-brain barrier and to inhibit resistant mutations against anaplastic lymphoma kinase inhibitors. We review the clinical data supporting treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma with brigatinib and lorlatinib. Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma. Ongoing trials and further studies of these agents' biological and clinical properties would provide insight into the optimal therapeutic strategy for administering them to achieve the best survival benefit.
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http://dx.doi.org/10.1093/jjco/hyaa192DOI Listing
January 2021

Semi-automated brain responses in communication: A magnetoencephalographic hyperscanning study.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:2893-2896

Face to face communication is interactive, and involves continuous feedforward and feedback of information, thoughts, and feelings to the opposite party. To accurately assess the neural processing underlying these interactions, synchronous and simultaneous recording of the brain activity from both parties is needed, a method known as hyperscanning. Here, we investigated the neural processing underlying nonverbal face-to-face communication using a magnetoencephalographic (MEG) hyperscanning system, comprising two fiber optically connected MEGs. Eight pairs of subjects participated. Each individual in each pair viewed a combined 80 randomized 20 s trials of 40 real-time and 40 recorded (hereafter, real and simulated, respectively) videos of the opposite party's face. Non-verbal communication through actions such as gaze, eye blinks, and facial expression was intrinsically only possible during real videos. After each trial, subjects individually subjectively discriminated whether the viewed video was real or simulated. Overall subjective discrimination accuracies were slightly but significantly above chance level. Statistical analysis of brain activity revealed a significant three way interaction between theta-band rhythm amplitude, video type, and subjective discrimination response in the right frontal cortex. Additionally, when subjects responded that videos were simulated, theta activity was significantly lower for real videos compared with simulated videos (p = 0.01). This result not only demonstrates the importance of right frontal theta activity during non-verbal communication, but also indicates the existence of unconscious, semi-automated neural processing during non-verbal communication that underlies one's ability to subjectively discriminate whether or not the opposite party is real.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176538DOI Listing
July 2020

Clinical factors affecting evoked magnetic fields in patients with Parkinson's disease.

PLoS One 2020 17;15(9):e0232808. Epub 2020 Sep 17.

Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

Studies on evoked responses in Parkinson's disease (PD) may be useful for elucidating the etiology and quantitative evaluation of PD. However, in previous studies, the association between evoked responses and detailed motor symptoms or cognitive functions has not been clear. This study investigated the characteristics of the visual (VEF), auditory (AEF), and somatosensory (SEF) evoked magnetic fields in patients with Parkinson's disease (PD), and the correlations between evoked fields and the patient's clinical characteristics, motor symptoms, and cognitive functions. Twenty patients with PD and 10 healthy controls (HCs) were recruited as participants. We recorded VEF, AEF, and SEF, collected clinical characteristics, performed physical examinations, and administered 10 cognitive tests. We investigated differences in the latencies of the evoked fields between patients with PD and HCs. We also evaluated the correlation of the latencies with motor symptoms and cognitive functioning. There were significant differences between the two groups in 6 of the cognitive tests, all of which suggested mild cognitive impairment in patients with PD. The latencies of the VEF N75m, P100m, N145m, AEF P50m, P100m, and SEF P60m components were greater in the patients with PD than in the HCs. The latencies mainly correlated with medication and motor symptoms, less so with cognitive tests, with some elements of the correlations remaining significant after Bonferroni correction. In conclusion, the latencies of the VEF, AEF, and SEF were greater in PD patients than in HCs and were mainly correlated with medication and motor symptoms rather than cognitive functioning. Findings from this study suggest that evoked fields may reflect basal ganglia functioning and are candidates for assessing motor symptoms or the therapeutic effects of medication in patients with PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232808PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498017PMC
October 2020

Myocardial T-mapping and Extracellular Volume Quantification in Patients and Putative Carriers of Muscular Dystrophy: Early Experience.

Magn Reson Med Sci 2020 Sep 7. Epub 2020 Sep 7.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University.

To assess myocardial fibrosis associated with muscular dystrophy, T-mapping and extracellular volume fraction (ECV) quantification was prospectively performed using cardiovascular MR (CMR) imaging in 6 male patients with muscular dystrophy and 5 female putative carriers of Duchenne or Becker muscular dystrophy. Five patients and all putative carriers had an elevated ECV (>29.5% for men and >35.2% for women), suggesting that ECV has a potential to detect diffuse fibrotic changes in patients and putative carriers of muscular dystrophy.
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http://dx.doi.org/10.2463/mrms.bc.2020-0069DOI Listing
September 2020

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency.

Brain Dev 2021 Feb 11;43(2):214-219. Epub 2020 Aug 11.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, Research and Development Division, Japan.

Background: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks.

Patients And Methods: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions.

Results: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment.

Conclusion: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
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http://dx.doi.org/10.1016/j.braindev.2020.07.019DOI Listing
February 2021

Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report.

Brain Dev 2021 Jan 29;43(1):157-159. Epub 2020 Jul 29.

Department of Pediatrics, Nikko Memorial Hospital, Japan.

Background: Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug.

Case Presentation: A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved.

Conclusion And Discussion: Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.
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http://dx.doi.org/10.1016/j.braindev.2020.07.008DOI Listing
January 2021

Correlation between the expression of folate receptor alpha (FRα) and clinicopathological features in patients with lung adenocarcinoma.

Lung Cancer 2020 07 11;145:152-157. Epub 2020 May 11.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Objectives: Folate receptor alpha (FRα) is expressed on the cell surface, mediates its intracellular transport via receptor-mediated endocytosis, and is involved in cell division. Whether FRα could be a potential therapeutic target in FRα-expressing cancers remains unknown. Here, we retrospectively investigated the correlations between tumor FRα expression in lung adenocarcinoma (LADC) and clinicopathological features.

Materials And Methods: FRα expression was evaluated using a tissue microarray (TMA) constructed from surgical specimens of LADC and compared with clinicopathological features including the EGFR mutation status and the expressions of PD-L1, PD-L2, PD-1, CD4, CD8, CD204, and αSMA. If the proportion of positively stained tumor cells was greater than or equal to 5%, the tumor was considered to show FRα expression; if the H-score was more than or equal to 60, the tumor was considered to show high FRα expression.

Results: Overall, 466 TMA cores created from 233 LADC patients were evaluated: FRα-positive expression (FRα-pos)/negative (FRα-neg), 222/11; FRα high expression (FRα-HE)/low (FRα-LE), 190/43. AnEGFR mutation was present in 53.2 % of the patients. The median H-score of FRα expression, FRα-pos rate, and FRα-HE rate for EGFR mutation/wild type were 159/104 (p = 0.0002), 97.6/92.7 % (p = 0.0773), and 88.7/73.4 % (p = 0.0026), respectively. The H-scores for FRα had mild correlations with the proportion of tumor cells with positive staining for PD-L1 (r=-0.2557, p < 0.0001), the number of CD8-positive cells per square millimeter (r=-0.1767, p = 0.0069), and the area with positive staining for αSMA (r = 0.2049, p = 0.0017). No correlations were seen between FRα expression and other cancer-immunity markers.

Conclusion: Tumor FRα expression was significantly higher in LADCs withEGFR mutation than in those with wild-type EGFR. This study suggested that FRα expression was related to cancer and microenvironment-immunity markers such as PD-L1 expression, CD8 cells, and αSMA.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.002DOI Listing
July 2020

Perampanel for nonepileptic myoclonus in Angelman syndrome.

Brain Dev 2020 May 10;42(5):389-392. Epub 2020 Mar 10.

Department of Pediatrics, Hokkaido University Hospital, Japan. Electronic address:

Background: Angelman syndrome (AS) is a neurodegenerative disorder caused by functional loss of the maternal ubiquitin-protein ligase 3A gene. Nonepileptic myoclonus, also described as tremulous movement, often occurs during puberty and increases in adulthood. The involuntary movement in AS has not been defined patho-physiologically and the drugs used such as levetiracetam and piracetam are not always effective. Recently, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, perampanel (PER), was used to alleviate myoclonus in progressive myoclonus epilepsy. Herein, we tested the efficacy of PER for nonepileptic myoclonus.

Methods And Results: Four patients with AS, aged from 20 to 40 years at the beginning of treatment, were enrolled in our study. All patients reported disruption to their daily lives from the myoclonus movement. They experienced mild to moderate improvement with the starting dose of 2 mg. The dose was increased to 4 mg in one patient to achieve sufficient efficacy, while two had their dose reduced to 1 mg due to dizziness or possible exacerbation of myoclonus. The last patient continued to take the starting dose. Follow-up over 16-20 months revealed a significant reduction in the severity of nonepileptic myoclonus in all patients.

Conclusion: Our study suggests that PER could be one of the promising drugs for nonepileptic myoclonus in AS.
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http://dx.doi.org/10.1016/j.braindev.2020.02.007DOI Listing
May 2020

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey.

Mol Genet Metab Rep 2019 Sep 25;20:100496. Epub 2019 Jul 25.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, North 14, West 5, Kita-ku, Sapporo 060-8648, Japan.

Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate.

Materials And Methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9 years; range, 5.8-26.4 years). The bezafibrate administration was continued for a further 102-174 weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health.

Results: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20 years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases.

Conclusion: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661278PMC
September 2019

Difference in central nerve system metastasis during gefitinib or erlotinib therapy in patients with -mutated non-small cell lung cancer: a retrospective study.

J Thorac Dis 2019 Apr;11(4):1347-1354

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

Background: Central nervous system (CNS) metastasis is a poor prognostic factor in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation EGFR-mutant NSCLC and is associated with a deteriorated quality of life (QOL). Some clinical studies have suggested a possible difference in the incidence of CNS metastasis between EGFR-mutant NSCLC patients treated with gefitinib and erlotinib, both of which are classified as first-generation EGFR tyrosine kinase inhibitors (TKIs). However, the difference in the incidence of CNS metastasis between patients receiving these two drugs has not yet been sufficiently well investigated. We analyzed the frequency of occurrence/progression of CNS metastasis in EGFR-mutant NSCLC patients treated with erlotinib and gefitinib as the first-line treatment.

Methods: We analyzed the incidence of CNS metastasis, frequency of progression of CNS metastasis and the treatment outcomes in EGFR-mutant patients who received gefitinib or erlotinib as the first-line EGFR-TKI treatment. CNS progressive disease (PD) was defined as progression of CNS metastasis during EGFR-TKI treatment. We also evaluated the progression-free survival (PFS), CNS-PFS, and overall survival (OS) of the patients who received each of the two drugs.

Results: A total of 170 patients were enrolled in the study, of which 144 had received gefitinib, and 26 had received erlotinib. The frequency of CNS PD in the erlotinib group tended to be lower than that in the gefitinib group (11.5% 29.9%, P=0.06). In patients with no existing CNS metastasis at the start of the EGFR-TKI treatments, the incidence of CNS PD was significantly lower in the erlotinib group than that in the gefitinib group (4.8% 24.5%, P=0.04). A re-biopsy after failure of EGFR-TKI treatment was performed in 48 patients. The incidence of T790M tended to be higher among patients with CNS PD than in those without CNS PD, although the difference was not statistically significant (66.7% 40.4%; P=0.23).

Conclusions: The incidence of progression of CNS metastasis during erlotinib treatment was lower than that during gefitinib treatment. In addition, the difference in the incidence in patients without existing CNS metastasis at the time of start of EGFR-TKI treatment was significantly lower in the patients treated with erlotinib than in those treated with gefitinib.
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http://dx.doi.org/10.21037/jtd.2019.03.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531700PMC
April 2019

Advanced dynamic statistical parametric mapping with MEG in localizing epileptogenicity of the bottom of sulcus dysplasia.

Clin Neurophysiol 2018 06 30;129(6):1182-1191. Epub 2018 Mar 30.

Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:

Objective: To investigate whether advanced dynamic statistical parametric mapping (AdSPM) using magnetoencephalography (MEG) can better localize focal cortical dysplasia at bottom of sulcus (FCDB).

Methods: We analyzed 15 children with diagnosis of FCDB in surgical specimen and 3 T MRI by using MEG. Using AdSPM, we analyzed a ±50 ms epoch relative to each single moving dipole (SMD) and applied summation technique to estimate the source activity. The most active area in AdSPM was defined as the location of AdSPM spike source. We compared spatial congruence between MRI-visible FCDB and (1) dipole cluster in SMD method; and (2) AdSPM spike source.

Results: AdSPM localized FCDB in 12 (80%) of 15 children whereas dipole cluster localized six (40%). AdSPM spike source was concordant within seizure onset zone in nine (82%) of 11 children with intracranial video EEG. Eleven children with resective surgery achieved seizure freedom with follow-up period of 1.9 ± 1.5 years. Ten (91%) of them had an AdSPM spike source in the resection area.

Conclusion: AdSPM can noninvasively and neurophysiologically localize epileptogenic FCDB, whether it overlaps with the dipole cluster or not.

Significance: This is the first study to localize epileptogenic FCDB using MEG.
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http://dx.doi.org/10.1016/j.clinph.2018.03.007DOI Listing
June 2018

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan.

Mol Genet Metab Rep 2018 Jun 22;15:55-63. Epub 2018 Feb 22.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan.

Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the FAO capacity has been reported, the efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs.

Materials And Methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires).

Results: The frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed.

Conclusion: In this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations.
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http://dx.doi.org/10.1016/j.ymgmr.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852296PMC
June 2018

Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene.

Brain Dev 2018 Mar;40(3):226-228

Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan.

Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30 s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis. Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient's younger years.
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http://dx.doi.org/10.1016/j.braindev.2017.11.007DOI Listing
March 2018

[Clinical Applications of Positron Emission Tomography for Neurosurgery(3)PET for Patients with Intractable Epilepsy].

No Shinkei Geka 2017 Oct;45(10):933-942

Department of Pediatrics, Hokkaido University Hospital.

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http://dx.doi.org/10.11477/mf.1436203620DOI Listing
October 2017

The Involvement of Sensory-motor Networks in Reflex Seizure.

NMC Case Rep J 2017 Oct 11;4(4):127-130. Epub 2017 Sep 11.

Department of Neurosurgery, Sapporo Medical University, School of Medicine, Sapporo, Hokkaido, Japan.

Reflex seizures are epileptic events triggered by specific external stimuli, or less commonly, internal mental stimuli. Understanding the characteristics of reflex seizures is important to elucidate the mechanisms underlying network abnormalities in epileptic conditions. This report details a patient with medically intractable reflex seizures provoked by sensory stimuli to the patient's right foot. Single-photon emission computed tomography (SPECT) during the seizure induced by sensory stimulation showed hyperperfusion in broad sensory-motor networks (dorsal column-medial lemniscus pathway, left thalamus, bilateral postcentral gyri and posterior parietal cortices, left supplementary motor area (SMA), and left paracentral lobule) and left caudateputamen. The irritative zones and ictal onset zone were localized to the left medial frontoparietal (SMA, anterior and middle cingulate gyrus, and paracentral lobule) and lateral posterior parietal cortices, as evidenced by amelioration of reflex seizures following intracranial electroencephalography and surgical resection of these areas. The neuroradiological and electrophysiological findings in our case study illustrate that the mechanism of reflex seizures may be associated with hyperexcitability of the broad sensory-motor networks, including the basal ganglia. Disconnection of these networks is necessary to treat reflex seizures.
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http://dx.doi.org/10.2176/nmccrj.cr.2017-0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629358PMC
October 2017

Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).

Epilepsy Behav Case Rep 2017 26;8:44-46. Epub 2017 May 26.

Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

We administered perampanel (PER) to a bedridden 13-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA). The DRPLA diagnosis was based on the presence of a CAG trinucleotide repeat in the gene. The patient experienced continuous myoclonic seizures and weekly generalized tonic-clonic seizures (GTCs). PER stopped the patient's myoclonic seizures and reduced the GTCs to fragmented clonic seizures. The patient recovered his intellectual abilities and began to walk again with assistance. We suggest that PER be considered as one of the key drugs used to treat patients with DRPLA.
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http://dx.doi.org/10.1016/j.ebcr.2017.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565628PMC
May 2017

Actinin-4 protein overexpression as a predictive biomarker in adjuvant chemotherapy for resected lung adenocarcinoma.

Biomark Med 2017 09 29;11(9):721-731. Epub 2017 Jun 29.

Division of Chemotherapy & Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.

Aim: Although several clinical trials demonstrated the benefits of platinum-combination adjuvant chemotherapy for stage II-IIIA lung adenocarcinoma, predictive biomarkers for the efficacy of such therapy have not yet been identified. We evaluated protein overexpression of actinin-4 as a predictive biomarker of the efficacy of adjuvant chemotherapy in resected lung adenocarcinoma.

Materials & Methods: We measured actinin-4 protein levels in patients with completely resected stage II-IIIA lung adenocarcinoma using immunohistochemistry and then retrospectively compared survival between adjuvant chemotherapy and observation groups.

Results: A total of 148 eligible patients were classified into actinin-4 positive or negative cases by immunohistochemistry. In the former, patients with adjuvant chemotherapy survived significantly longer than those with observation (hazard ratio [HR]: 0.307; p = 0.028). But, no significant survival benefit was noted with adjuvant chemotherapy (HR: 0.926; p = 0.876) in the latter.

Conclusion: This marker could predict the efficacy of adjuvant chemotherapy for resected lung adenocarcinoma patients.
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http://dx.doi.org/10.2217/bmm-2017-0150DOI Listing
September 2017