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Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic encephalopathy that occurs in children or adolescents. To date, evidence for the management of the post-acute phase of FIRES is focused on drug-resistant epilepsy that continues from the acute phase. Information on involuntary movements, which are newly developed in the chronic phase, is limited. We report a 13-year-old boy, who had a history of FIRES at nine years of age and experienced worsening seizure control that was accompanied by unremitting involuntary　movements after two years of a fairly controlled period. The involuntary movements resulted in motor deterioration and forced him to be bedridden. Although no neuronal autoantibodies were detected, we hypothesized that the boy's neurological deterioration was triggered by an autoimmune response based on the elevation of serum anti-glutamic acid decarboxylase and serum anti-thyroid peroxidase antibodies and hypermetabolism of bilateral lenticular nuclei on 18-fluorodeoxyglucose positron emission tomography that resembled those reported in patients with other types of autoimmune encephalitis. Serial methylprednisolone pulse therapy and intravenous immunoglobulin therapy ameliorated involuntary movements and improved his activities of daily living. Late-onset involuntary movements, along with seizure exacerbation, may appear in the chronic phase of FIRES. Immunotherapy could be effective in treating these symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ohno et al.)

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear., Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8 + tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis., Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p  = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS., Conclusions: PD-L1 expression on tumor cells, CD8 + T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy., Competing Interests: Dr. Kanemura has received grants or funding from 10.13039/100010795Chugai Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd.; honoraria for lectures from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Daiichi Sankyo Co. Ltd. Dr. Yokoyama has received grants or funding from 10.13039/100009947Merck Sharp & Dohme, 10.13039/100010795Chugai Pharmaceutical Co., Ltd., 10.13039/100002491Bristol-Myers Squibb, 10.13039/100017346Boehringer Ingelheim Japan, Takeda Pharmaceutical Co. Ltd., Delta-Fly Pharma, 10.13039/100020707Janssen Pharmaceutical K.K, AbbVie G.K., 10.13039/501100002973Daiichi-Sankyo, and 10.13039/100016751Parexel International; honoraria for lectures from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Merck Sharp & Dohme, Novartis, and Merck Biopharma Co. Ltd. Dr. Mamesaya has received grants or funding from Boehringer Ingelheim, 10.13039/100012781Merck Sharp & Dohme K.K., Chugai Pharmaceutical Co. Ltd., and Arrivent Biopharma; honoraria for lectures from Chugai Pharmaceutical Co. Ltd., Boehringer Ingelheim, AstraZeneca K.K., Taiho Pharmaceutical Co. Ltd., Merck Sharp & Dohme K.K., Ono Pharmaceutical Co. Ltd., and Novartis Pharma K.K. Dr. T. Okamoto has received grants or funding from 10.13039/100018046Nippon Kayaku and 10.13039/100009954Taiho Pharmaceutical; honoraria for lectures from Nippon Kayaku and Taiho Pharmaceutical. Dr. Okishio has received honoraria for lectures from Bristol-Myers Squibb K.K., Takeda Pharmaceutical Company Limited, AstraZeneca K.K., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Sawai Pharmaceutical Co., Ltd. Nippon Kayaku Co., Ltd. Dr. Oki has received grants or funding from 10.13039/100006483AbbVie Inc., Chugai Pharmaceutical Co., Ltd., 10.13039/100015542GlaxoSmithKline K.K., Merck Sharp & Dohme K.K., 10.13039/100016751Parexel International Corporation., 10.13039/100015990Sanofi K.K., 10.13039/100020869AstraZeneca KK, 10.13039/501100019949Fujifilm Toyama Chemical Co., Ltd., 10.13039/100020707Janssen Pharmaceutical K.K, 10.13039/501100013170Ono Pharmaceutical Co., Ltd., 10.13039/100010793Pfizer Japan Inc., Kaneka Medix Corp., 10.13039/100005564Gilead Sciences, Inc., and 10.13039/501100002973Daiichi Sankyo Co., Ltd.; honoraria for lectures from AMCO Inc., Canon Medical Systems Corp., Fujifilm Corp., Merit Medical Japan K.K., Olympus Marketing, Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Kaneka Medix Corp., Novartis Pharma K.K., Sanofi K.K., Eli Lilly Japan K.K., Merck Sharp & Dohme K.K., Intuitive Surgical G.K., GlaxoSmithKline K.K., Nippon Boehringer Ingelheim Co., Ltd., and Merck Biopharma Co., Ltd. Dr. Sakai has received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yodosha Co., Ltd., Qiagen, Inc., and Nippon Kayaku Co., Ltd. Dr. Nishio has received grants or funding from 10.13039/100017346Nippon Boehringer Ingelheim, West Japan Oncology Group, Clinical Research Support Center Kyushu, Nichirei Biosciences Inc., 10.13039/100014422Eli Lilly Japan, 10.13039/100008238Hitachi, 10.13039/100017981Sysmex, and 10.13039/501100007132Otsuka Pharmaceutical.; consulting fees from Symbio Pharmaceuticals, Eli Lilly Japan, and Otsuka Pharmaceutical; honoraria for lectures from Chugai, Pfizer, Eli Lilly Japan, Merck Sharp & Dohme, Novartis Pharma, AstraZeneca, Amgen, Merck Biopharma, Yakult Honsha, Guardant Health, Takeda Pharmaceuticals, Boehringer Ingelheim Japan, FujireBio, Bristol-Myers Squibb, Janssen Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Invitae Japan, and Nichirei. Dr. Yamamoto has received grants or funding from AstraZeneca, Chugai Pharma, Merck Sharp & Dohme, Taiho Pharmaceutical, Boehringer Ingelheim, 10.13039/100004336Novartis, AbbVie, 10.13039/100002429Amgen, Asahi Kasei, Janssen, Bristol-Myers Squibb Japan, IQVIA, EPS Corporation, 10.13039/100002429Amgen, A2 Healthcare, Mebix, and Ono Pharmaceutical; consulting fees from AstraZeneca, Chugai Pharma, Merck Sharp & Dohme, Lilly Japan, Amgen, Novartis, and Ono Pharmaceutical; honoraria for lectures from AstraZeneca, Chugai Pharma, Merck Sharp & Dohme, Takeda, Accuray, AbbVie, Amgen, Ono Pharmaceutical, Guardant Health, Kyorin, Daiichi Sankyo, Taiho Pharmaceutical, Tsumura & Co., Terumo, Lilly Japan, Boehringer Ingelheim Japan, Novartis, Pfizer, Miyarisan Pharmaceutical, Merck Biopharma, and Janssen. Dr. I. Okamoto has received honoraria for lectures from Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., AstraZeneca plc, Eli Lilly Japan K.K., Takeda Pharmaceutical Co. Ltd., and Novartis Pharma K.K. Dr. Nakagawa has received grants or funding from 10.13039/100002429Amgen Inc., Merck Sharp & Dohme K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., AstraZeneca K.K., 10.13039/100016751Parexel International Corp., PRA Health Sciences, EPS Corporation., 10.13039/100016288Kissei Pharmaceutical Co., Ltd., EPS Corporation., Taiho Pharmaceutical Co., Ltd., PPD-SNBL K.K, 10.13039/501100013172Symbio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., 10.13039/100018046Nippon Kayaku Co., Ltd., EP-CRSU Co., Ltd., Mebix, Inc., 10.13039/100020707Janssen Pharmaceutical K.K., 10.13039/501100004948Astellas Pharma Inc., 10.13039/100015731Bayer Yakuhin, Ltd., 10.13039/501100023368Eisai Co., Ltd., Mochida Pharmaceutical Co., Ltd., Labcorp Development Japan K.K. (Covance Japan Inc.), Japan Clinical Research Operations, Takeda Pharmaceutical Co., Ltd., 10.13039/100015542GlaxoSmithKline K.K., 10.13039/100015990Sanofi K.K., 10.13039/100017981Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical Co., Ltd., SRL, Inc., Pfizer R&D Japan G.K., CMIC Co., Ltd., Eisai Inc., 10.13039/501100005612Shionogi & Co., Ltd., Kobayashi Pharmaceutical Co., Ltd., and Ascent Development Services; consulting fees from Eli Lilly Japan K.K. and Ono Pharmaceutical Co., Ltd.; honoraria for lectures from Ono Pharmaceutical Co., Ltd., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Merck Sharp & Dohme K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., CMIC Shiftzero K.K., Life Technologies Japan Ltd., Neo Communication, Daiichi Sankyo Co., Ltd., Incyte biosciences Japan, Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., 3H Clinical Trial Inc., Care Net, Inc., Medical Review Co., Ltd., Medical Mobile Communications co., Ltd., Yodosha Co., Ltd., Nikkei Business Publications, Inc., Japan Clinical Research Operations, CMIC Co., Ltd., Novartis Pharma K.K., Taiyo Pharma Co., Ltd., Janssen Pharmaceutical K.K., and Bristol-Myers Squibb K.K.; patent planned, issued or pending from Daiichi Sankyo Co., Ltd. Dr. Takeda has received honoraria for lectures from Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Bristol-Myers Squibb Company, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim, and Takeda Pharma Ltd. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Back ground: Children with epilepsy are affected by several factors, including clinical and social variables. Among these variables, cognitive decline and behavioral disturbances, perceptions of stigma, and fatigue can lead to reductions in quality of life (QOL). Epileptic activities, including seizure severity, frequent seizures, and status epilepticus (SE), have been identified as important predictors of QOL. In addition, the frequency of interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) may also be an important predictor of QOL, because IEDs can lead to cognitive decline and behavioral disturbances. Moreover, frequent seizures and/or IEDs may play a role in emotional mediators, such as stigma and fatigue, in childhood epilepsy. Seizure severity and/or IEDs are, therefore, important QOL-related factors in childhood epilepsy. Seizure severity as a QOL-related factor: Frontal lobe dysfunctions, such as cognitive decline and behavioral disturbances, can result in reduced QOL for both the child and their family. Frontal and prefrontal lobe growth disturbances can be present during active-phase epilepsy in some children with neuropsychological impairments. Recovery from prefrontal lobe growth disturbances may depend on the active seizure period. Children with a shorter active seizure period can recover from disturbances in prefrontal lobe growth more rapidly. In contrast, recovery may be delayed in children with a longer active seizure period. Moreover, frequent seizures can lead to seizure-associated headaches, perceptions of self-stigma and parental stigma, and fatigue. Accordingly, severe seizures can lead to neuropsychological impairments in association with prefrontal lobe growth disturbances in children with epilepsy. EEG abnormalities as QOL-related factors: IEDs on EEG, representing persistent pathological neuronal discharges, may be associated with several pathological aspects. Frontal IEDs can be a risk factor for recurrent seizures, cognitive decline, and behavioral disturbances, and they may also play a role as emotional mediators similar to stigma. In addition, behavioral disturbances may result in the presence of secondary bilateral synchrony (SBS) on EEG. Behavioral disturbances can be improved in association with a reduction in IEDs in children with frontal IEDs and SBS. Therefore, EEG abnormalities, such as frontal IEDs and SBS, can also lead to neuropsychological impairments in children with epilepsy. Therapeutic strategies in children with epilepsy: Seizure severity and IEDs on EEG may be associated with neuropsychological impairments, leading to QOL reduction. Therapeutic management may be desirable to reduce seizures and EEG abnormalities, such as frontal IEDs and SBS, as early as possible to improve QOL in children with epilepsy. During antiseizure medication (ASM) selection and adjustment, physicians should strategize the therapeutic approach to controlling seizures and suppressing EEG abnormalities in children with epilepsy. Among various ASMs, novel ASMs, such as levetiracetam and perampanel, may suppress both clinical seizures and IEDs on EEG; thus, these novel ASMs may represent an important addition to the treatments available for epileptic children presenting with frontal IEDs and SBS.

Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types., Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system)., Results: The study subjects comprised patients with head and neck cancer ( n = 50), urothelial cancer ( n = 42), renal cell cancer ( n = 37), gastric cancer ( n = 20), esophageal cancer ( n = 10), malignant pleural mesothelioma ( n = 6), or microsatellite instability-high tumors ( n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients., Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy., Competing Interests: TKu: honoraria from AstraZeneca K.K. KC: grants or contracts from Meiji Seika Pharma Co., Ltd., Meiji Holdings Co., Ltd., Shimazu Corporation, and Menarini Biomarkers Singapore.; payment or honoraria from Cosmo Bio Co., Ltd., Bristol Myers Squibb Japan, Merck KGaA, AstraZeneca K.K., CHUGAI PHARMACEUTICAL CO., LTD., Novartis Pharma K.K, Hitachi, Ltd., Corning Incorporated., Agilent Technologies Japan, Ltd., and SBI Pharmaceuticals Co., Ltd.; patents to WO2017/099034, WO2018/084204, WO2017/115816, WO2020/149026, WO2019/188354, WO2021/095599, and PCT/JP2022/006843; program committee of Japanese Cancer Association.; board member of Japanese Society for Immunology, and Japanese Society of Cancer Immunology. SS: research funds from Nippon Boehringer Ingelheim Co., Ltd. HKan: lecture fees or honoraria from Chugai Pharmaceutical Co.,Ltd., and AstraZeneca K.K.; research funds from Chugai Pharmaceutical Co.,Ltd., and Takeda Pharmaceutical Co.,Ltd. SM: payment or honoraria from Taiho Pharmaceutical Co., and Ono Pharmaceutical Co. Ltd.: participation on a Data Safety Monitoring Board or Advisory Board to Chugai Pharmaceutical Co. Ltd. KT: payment or honoraria from AstraZeneca K.K., Merck Biopharma Co., Ltd., Eisai.Inc., Bristol Myers Squibb Company, ONO Pharmaceutical Co., MSD K.K., Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Novartis Pharma K.K. HKaw: Consulting or advisory fees from Astellas Pharma Inc. and Daiichi-Sankyo Co. Ltd.; honoraria from Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Taiho Pharmaceutical Co. Ltd., and Nippon Kayaku Co. Ltd.; and research funding from Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Kobayashi Pharmaceutical Co. Ltd., and Eisai Co. Ltd. YK: honoraria from Eisai Co., Ltd. TKo: lecture fees or honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., and Bayer Yakuhin, Ltd. KN: honoraria from Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Amgen Inc., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K., 3H Clinical Trial Inc., Chugai Pharmaceutical Co., Ltd., Care Net, Inc., Eli Lilly Japan K.K., Medical Review Co., Ltd., MSD K.K., Medical Mobile Communications co., Ltd, Pfizer Japan Inc., YODOSHA CO., LTD., Nippon Boehringer Ingelheim Co., Ltd., Nikkei Business Publications, Inc., Taiho Pharmaceutical Co.,Ltd., Japan Clinical Research Operations, Bayer Yakuhin, Ltd., CMIC Co., Ltd., CMIC ShiftZero K.K., Novartis Pharma K.K., Life Technologies Japan Ltd., TAIYO Pharma Co., Ltd., Neo Communication, Bristol Myers Squibb Company, Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., and Incyte biosciences Japan; research funding from PAREXEL International Corp., Eisai Co., Ltd., PRA HEALTHSCIENCES, AstraZeneca K.K., EPS Corporation., Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Labcorp Development Japan K.K.(Covance Japan Inc.), EPS International Co.,Ltd., Japan Clinical Research Operations, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Taiho Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., MSD K.K., Sanofi K.K., Ono Pharmaceutical Co.,Ltd., Chugai Pharmaceutical Co.,Ltd., PPD-SNBL K.K, Nippon Boehringer Ingelheim Co.,Ltd., SymBio Pharmaceuticals Limited., Sysmex Corporation, IQVIA Services JAPAN K.K., Medical Research Support, SYNEOS HEALTH CLINICAL K.K., Eli Lilly Japan K.K., Nippon Kayaku Co.,Ltd., Amgen Inc., EP-CRSU Co., Ltd., Novartis Pharma K.K., Mebix, Inc., Otsuka Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., SRL, Inc., Janssen Pharmaceutical K.K., Pfizer R&D Japan G.K., CMIC CO., Ltd., Bayer Yakuhin, Ltd, Shionogi & Co., Ltd., Pfizer Japan Inc, Astellas Pharma Inc., Ascent Development Services, Kobayashi Pharmaceutical Co., Ltd., and Eisai Inc.; Consulting or advisor role to Eli Lilly Japan K.K., and Ono Pharmaceutical Co.,Ltd.; patent royalties from Daiichi Sankyo Co., Ltd. TH: grants or contracts from Meiji Seika Pharma Co., Ltd., Meiji Holdings Co., Ltd., Shimazu Corporation, Menarini Biomarkers Singapore; Royalties or licenses from ONO PHARMACEUTICAL CO., LTD.; patents to WO2017/099034, WO2018/084204, WO2017/115816, WO2020/149026, WO2019/188354, WO2021/095599, and PCT/JP2022/006843; honorary member of Japanese Cancer Association, Japanese Society for Immunology, Japanese Biochemical Society. HH: Grants or contracts IQVIA Services JAPAN K.K., Eisai Co., Ltd., SYNEOS HEALTH CLINICAL K.K., EP-CRSU CO., LTD., EPS Corporation., Shionogi & Co., Ltd., Nippon Kayaku Co.,Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., MSD K.K., Sanofi K.K., Amgen Inc., Chugai Pharmaceutical Co.,Ltd., Taiho Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Bristol Myers Squibb Company, SRL Medisearch Inc., Janssen Pharmaceutical K.K., PRA Health Sciences Inc., CMIC CO., Ltd., Astellas Pharma Inc., Pfizer R&D Japan G.K., Ascent Development Services, Labcorp Development Japan K.K., Eisai Inc., Kobayashi Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd, Pfizer Japan Inc.; payment or honoraria from Ono Pharmaceutical Co.,Ltd., Merck Biopharma Co., Ltd., Daiichi Sankyo Co., Ltd., 3H Clinical Trial Inc., AstraZeneca K.K., Novartis Pharma K.K., Chugai Pharmaceutical Co.,Ltd., Bristol Myers Squibb Company, Eli Lilly Japan K.K., Amgen Inc., MSD K.K., Sysmex Corporation, Pfizer Japan Inc., Takeda Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd. TS, CS and MY are employees of and receive remuneration from Sysmex Corporation. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. This study received funding from Sysmex Corporation. The funder had the following involvement with the study: conception and design, acquisition of data, analysis and interpretation of data, and writing and review of the manuscript., (Copyright © 2023 Kurosaki, Chamoto, Suzuki, Kanemura, Mitani, Tanaka, Kawakami, Kishimoto, Haku, Ito, Sato, Suminaka, Yamaki, Chiba, Yaguchi, Omori, Kobayashi, Nakagawa, Honjo and Hayashi.)

Background: The survival rate of very low birth weight (VLBW) infants has recently improved. However, the occurrence of and factors associated with epilepsy in VLBW infants remain unknown. This study aimed to clarify the incidence, characteristics, and factors associated with epilepsy development in VLBW infants., Methods: All VLBW infants admitted to our hospital between 2012 and 2017 were included in this study. VLBW infants with a follow-up period of <1 year were excluded. Chromosomal abnormalities, brain anomalies, severe intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), and hypoxic ischemic encephalopathy (HIE) were considered to be risk factors., Results: Epilepsy occurred in 21/526 (4.0%) VLBW infants. Chromosomal abnormalities, brain anomalies, severe IVH, cystic PVL, HIE, neonatal seizures, advanced maternal age, maternal diabetes mellitus, no administration of antenatal corticosteroids, and low Apgar scores at 1 and 5 min were associated with a risk of epilepsy. The median time to epilepsy onset was 8 months (range: 0-59 months), and the onset occurred within 2 years in 15/21 patients (71.4%) and within 4 years in 18/21 patients (85.7%). VLBW infants with risk factors developed epilepsy earlier and at a significantly higher rate than those without risk factors. Among infants who had risk factors and who developed epilepsy, 86.7% did so within 2 years of age, compared to 33.3% of those who developed epilepsy but did not have risk factors., Conclusion: These findings regarding factors associated with a risk of development of epilepsy and temporal feature of epilepsy may contribute to the development of monitoring and treatment protocols for epilepsy in VLBW infants., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to determine the efficacy of lacosamide (LCM) on interictal epileptiform discharges (IEDs) and evaluate the relationships between IEDs and seizure outcome in pediatric patients with focal epilepsy., Methods: Patient inclusion criteria included (1) newly diagnosed focal epilepsy with unknown etiology; and (2) electroencephalogram recorded twice (before and after starting LCM) under the same conditions. The difference between the highest number of IEDs over five successive minutes (IEDs/5 min) and the location of IEDs was determined. Seizure outcome was evaluated one year after achieving the maintenance dose of LCM. Responders were identified as showing a ≥50% reduction in the pre-LCM seizure frequency., Results: Of 22 patients, 10 showed an increase in IEDs/5 min after starting LCM. The median IEDs/5 min before and after starting LCM was not significantly different, at 1.5 (interquartile range: 0, 31.75) and 10.5 (0, 80.5), respectively. No relationship was identified between the difference in IEDs/5 min and seizure outcome. Patients with multiple regional or diffuse IEDs had significantly poorer seizure outcome compared with patients without those IEDs (P = 0.036 and P = 0.039, respectively). Of 10 patients with single regional IEDs, a tendency of IEDs to disappear was observed between patients with frontal and non-frontal IEDs., Conclusion: The effects of LCM on the number of IEDs may be unrelated to seizure outcome. LCM may be ineffective at improving seizure outcomes in patients with multiple regional or diffuse IEDs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neoadjuvant docetaxel plus cisplatin and 5-FU (NAC-DCF) and adjuvant nivolumab monotherapy are the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been found in perioperative setting. We investigated how programmed death-ligand 1 (PD-L1) changes before and after NAC-DCF and how it relates to the therapeutic effect of NAC-DCF in resectable ESCC., Methods: PD-L1 expression in paired diagnostic biopsy and surgically resected tissues from ESCC patients who underwent surgical resection after receiving two or three NAC-DCF cycles was evaluated. PD-L1 positivity was defined as a combined positive score (CPS) of 10% ≤ . Gene expression analysis was conducted using samples before NAC-DCF., Results: Sixty-six paired samples from 33 patients were included in PD-L1 expression analysis, and 33 Pre-NAC samples acquired by diagnostic biopsy were included in gene expression analysis. Pretreatment, 3 (9%), 13 (39%), and 17 (52%) patients harbored tumors with CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. After NAC-DCF, 5 (15%), 15 (45%), and 13 (39%) tumors presented CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. The concordance rate between Pre-and Post-NAC-DCF samples was 45%. Patients with PD-L1-negative tumors both before and after NAC-DCF (n = 9) had shorter survival and different gene expression profile characterized by upregulation in WNT signaling or neutrophils., Conclusions: A substantial PD-L1 expression alteration was observed, resulting in low concordance rate before and after NAC-DCF. Tumors persistently lacking PD-L1 had distinct gene expression profile with worse clinical outcomes, raising the need for further investigation., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Only four cases of colorectal adenocarcinoma with a yolk sac tumor (YST) component have been reported in the English literature. No genetic investigation has been performed in these cases. We report a case of colorectal adenocarcinoma in which the recurrent tumor had a YST component. A 49-year-old woman presented with a pelvic tumor three years after endoscopic mucosal resection of sigmoid colon adenocarcinoma. The pelvic tumor consisted of an undifferentiated carcinoma component and a YST component. The serum alpha-fetoprotein level was elevated to 42 ng/mL. Treatment as conventional colorectal carcinoma produced some anticancer effects, but the patient died 14 months after the recurrence and 49 months after the EMR. With the help of the next-generation sequencing results of the recurrent tumor, APC c.835 - 8A > G and TP53 c.524G > A (p.R175H) mutations were identified by direct sequencing in both the primary and the recurrent tumors, confirming the relationship between the two metachronous tumors.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients., Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8 + tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing., Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p  = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load., Conclusions: Expression of programmed death-ligand 1, CD8 + T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC., Clinical Trial Registration: UMIN000041056., (© 2022 The Authors.)

Capmatinib is a MET tyrosine kinase inhibitor (TKI) that has recently been approved for the treatment of advanced non-small cell lung cancer (NSCLC) positive for skipping mutations of MET exon 14 (METex14). Drug-induced interstitial lung disease (ILD) is a relatively rare, but potentially serious, side effect of TKIs administered for lung cancer treatment. Here we report a case of capmatinib-induced ILD in a patient with NSCLC harboring a METex14 skipping mutation. Capmatinib should be immediately discontinued if ILD is suspected, and treatment with corticosteroid should be considered., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Aim: The aim of this study was to assess the usefulness of perampanel (PER), and to identify the relationship between behavioral impairments and electroencephalogram (EEG) findings in epilepsy patients with autism spectrum disorder (ASD)., Methods: Participants were ASD patients with epilepsy recruited between June 1, 2016 and June 30, 2018. Inclusion criteria were: seizures refractory to two appropriate antiseizure medications (ASMs); presence of neuropsychological impairments; and ≥12 months of monitoring. PER was administered once daily, starting at a dose of 2 mg/day, increased to 12 mg/day. Seizure/EEG responders were identified as participants showing a >50 % reduction in seizure/interictal epileptiform discharge (IED) frequency (indicated as complete disappearance and response). Behavioral responders were identified as participants with a ≥50 % reduction in scores of the Japanese manuals for the Aberrant Behavior Checklist (ABC-J)., Results: Eleven (64.7 %) of 17 patients were considered to be both seizure and EEG responders. Five (45.5 %) of these 11 patients with seizure/EEG response were considered as behavioral responders. Mean ABC-J scores were significantly decreased at 12 months after PER administration (p = 0.0002). A correlation between decreased IED frequency and ABC-J score was evident in frontal IEDs, but not in non-frontal IEDs. Participants presenting with frontal IEDs showed a significantly higher correlation between seizures/EEG and behavioral improvements (p = 0.023). Moreover, 2 of 6 patients without seizure/EEG improvement were considered as behavioral responders. No patients discontinued PER., Conclusions: The results from this study suggest the utility of PER treatment in reducing clinical seizures and IEDs for ASD patients with intractable epilepsy, at least in some patients. Moreover, the present results also indicate the usefulness of PER in improving neuropsychiatric impairments, including behavioral disturbances in ASD related to improvement of clinical seizures/frontal IEDs, but also unrelated to seizure/EEG improvement in at least some ASD patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Clinically mild encephalopathy with a reversible splenial lesion (MERS) is the second commonest cause of encephalopathy. Several pathogens have been detected in patients with MERS type 2, such as influenza A and B, but little is known about the proportion of cases of MERS type 2 with this pathogenesis. Human herpesvirus 6 (HHV6) is the second commonest pathogen causing acute encephalopathy. However, HHV6 has not been previously reported in patients with MERS type 2., Patient Description: In this report, we describe a five-year-old boy with MERS type 2 caused by HHV6 infection. The present case was diagnosed with MERS type 2 caused by HHV6 infection based on the characteristic clinical course, the results of the virus testing, and imaging findings., Discussion: This is the first description of MERS type 2 caused by HHV6 infection. Although there is a report of MERS type 1 caused by HHV6 infection, there are no detailed reports in the literature about MERS type 2 associated with HHV6 infection. Thus the clinical findings associated with MERS type 2 caused by HHV6 infection are poorly understood. This report indicates that HHV6 can cause MERS type 2., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine the efficacy of perampanel (PER) on secondary bilateral synchrony (SBS) and behavioral problems in adolescents with epilepsy who showed insufficient response to levetiracetam (LEV)., Methods: The primary criterion for patient selection was the presence of SBS. The criteria such as age between 12 and 18 years, seizures refractory to antiseizure medications including LEV, at least four seizures a month, neuropsychological impairments, and at least 12 months of follow-up also had to be fulfilled. Patients were given PER at an initial dose of 2 mg/day, followed by increments of +2 mg/day every 2 weeks. Concomitant medications remained unchanged during evaluation period. Responders for electroencephalogram (EEG) and seizures were identified as showing a ≥50 % reduction from the baseline SBS on EEG and seizure frequency, respectively. Neuropsychological impairments as per the Japanese manuals for the Aberrant Behavior Checklist (ABC-J) were evaluated before and after PER administration., Results: Eight of 14 patients were considered responders for seizures. Among these 8 responders, 6 patients were considered responders for EEG and behavioral problems. Mean ABC-J scores in both EEG non-responders and responders were decreased significantly at 12 months (p < 0.05 and p < 0.05, respectively). ABC-J scores were significantly lower in EEG responders than in EEG non-responders at 12 months (p < 0.01). Moreover, among patients with decreased ABC-J scores, the degree of decrease was larger in EEG responders than in EEG non-responders (p < 0.01)., Conclusions: PER may be useful in reducing SBS on EEG, seizure frequency, and behavioral problems., Competing Interests: Declaration of Competing Interest Dr. Hideaki Kanemura has received speaker’s fees from Eisai Co., Ltd and Otsuka Pharmaceutical Co., Ltd. None of the other authors have any conflicts of interest to disclose., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Introduction: Thymic epithelial tumors are a rare type of neoplasm. Accordingly, it is difficult to perform phase III trials in patients with thymic epithelial tumors, and thus, no standard treatment has been established for these tumors. In this study, we aimed to investigate the current status of thymic epithelial tumor treatment in Japan., Methods: This retrospective observational study enrolled patients with thymic epithelial tumor whose data were recorded in a nationwide Hospital-based Cancer Registry that was linked with health insurance claims data for the registered patients between 2012 and 2014. The patients' treatment details were obtained from a health insurance claims database., Results: A total of 813 patients with thymoma and 547 with thymic carcinoma were included in the analysis. Overall, 549 (67.5%) thymoma patients underwent surgical resection alone. Among patients with thymic carcinoma, 230 (42.0%) underwent initial surgery, and 124 (53.9%) received subsequent radiotherapy and chemotherapy. Chemotherapy regimens varied across the hospitals; overall, 21 and 22 regimens were used to treat thymoma and thymic carcinoma, respectively. Platinum-based combination regimens were predominantly selected for both diseases., Conclusions: This study revealed the real-world patterns of thymic epithelial tumor treatment in Japan. Although the nature of this study did not enable the determination of optimal treatment strategies, the simultaneous analysis of nationwide registry, insurance, efficacy and prognostic data may contribute to the establishment of a standard treatment strategy for rarely occurring cancers such as thymic epithelial tumor., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Eribulin is a chemotherapeutic agent used for advanced breast cancer, but there are some reports of eribulin-induced lung injuries. Three of our patients experienced eribulin-related lung injuries. Radiology revealed organizing pneumonia in two cases and diffuse ground-glass shadows indicative of hypersensitivity pneumonitis in the third. A retrospective survey of patients treated with eribulin at our hospital identified no other cases of eribulin-induced lung injuries. Overall, drug-related lung injuries occurred in 2.8% of our eribulin-treated patients, which is similar to the rates reported for other anticancer drugs. The findings from these three cases provide guidance for the safe use of eribulin.

Objective: To investigate the effect of guidelines for management of febrile seizures on the clinical practice, we conducted a nationwide survey in Japan., Methods: The Japanese guidelines for management of febrile seizures 2015 (GL2015) was released in 2015. In 2016, a questionnaire was sent to all 512 certified hospitals (3 pediatricians each) of the Japan Pediatric Society and all 47 prefecture Pediatric Associations (10 private pediatricians each) in Japan asking about management policies for febrile seizures (FSs) during 2013-2014 and 2016. The questionnaires were about the following procedures: (1) lumbar punctures, blood examinations, and diazepam suppositories for children after a first simple FS at emergency departments; and (2) prophylactic diazepam during febrile illnesses in children with two or three past simple FSs, with no known predictors of recurrence., Results: A total of 1327 pediatricians (66.2%) answered the questionnaire. Numbers of pediatricians performing lumbar punctures and blood examinations, and giving diazepam suppositories after a first simple FS were less in 2016 than in 2013-2014 (1.2% and 2.0%, 53.1% and 61.3%, and 36.7% and 51.9%, respectively). Pediatricians recommending prophylactic diazepam for children with two and three FSs decreased from 45.7% and 82.4% in 2013-2014 to 31.0% and 65.0% in 2016, respectively., Conclusion: GL2015 had an effect on the clinical practices of pediatricians. On the other hand, 65% recommended prophylactic diazepam to children with three simple FSs even though GL2015 did not recommend use of diazepam based on number of previous FS. Anxiety about frequent seizures may affect pediatricians' clinical practice., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Chest radiography showed a right posterior mass on the mediastinum of an 84-year-old woman. The mass had been growing gradually for four years. Surgical excision was performed, and a pathological examination found the mass to be consistent with primary synovial sarcoma (SS) of the mediastinum. To our knowledge, this is a rare case in which follow-up imaging was able to be performed over a period of four years. This disease is aggressive, and its early diagnosis is key to achieving a cure. It is important to consider primary SS in the differential diagnosis of a primary intra-thoracic tumor, even if the tumor grows slowly.

A 26-year-old healthy patient had a fever and chest pain three days after nasal carbon dioxide (CO 2 ) laser surgery for chronic and allergic rhinitis. In the emergency room, he was diagnosed as a right pneumothorax and managed as outpatients with oral antibiotic therapy and close follow-up. Six days later, in follow-up clinic, his presenting signs and symptoms included right chest pain, tachypnoea and elevated levels of white blood cell count and C reactive protein. He was diagnosed as septic pulmonary embolism (SPE) by the detection of multiple nodules with cavitation on chest CT. Culture of pleural fluids showed Pseudomonas aeruginosa Intravenous antibiotic treatment and drainage of the pleural effusion improved his condition. Since SPE occurred after nasal CO 2 laser surgery in this case, careful attention should be paid to infectious complications of nasal CO 2 laser surgery., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose was to evaluate the efficacy of treatment and the occurrence of aggression-related adverse events among children receiving perampanel (PER) with concomitant levetiracetam (LEV)., Methods: Patients were selected according to the following criteria: 1) between 12 and 18 years old; 2) seizures refractory to at least 2 first-line drugs; 3) at least 4 seizures a month before PER administration; and 4) at least 12 months of follow-up. Patients were subdivided into groups with and without LEV as concomitant treatment. PER was administered at a dose of 2 mg/day, increasing by 2 mg/day every 2 weeks up to 12 mg/day if seizures appeared. In comparison with the baseline seizure frequency, response to PER treatment was classified as follows: complete cessation (100% seizure control); response (≥50% reduction in seizures); and exacerbation (≥50% increase in seizures). Responders were identified as patients showing complete cessation or response., Results: The study group comprised 39 outpatients with a mean age of 13.7 years at enrollment. Responder status was seen in 13 of the 19 patients with LEV and 4 of the 20 patients without LEV. PER appeared significantly more effective in patients with LEV than in those without LEV (p = 0.0076). Seizure-free status was significantly more frequent among patients with LEV (47.4%) than among those without LEV (15.0% (p = 0.0407)). Aggression was present in 2 patients without LEV, but none with LEV., Conclusion: The present study suggests the utility of PER with concomitant LEV for children with drug-resistant epilepsy., (Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Aim: The purpose of this study was to examine the association between seizure-related features and fatigue levels in children with epilepsy., Methods: All children were classified into three subgroups based on the state of their seizure control: well-controlled epilepsy (WCE; seizure-free), intermediate-controlled epilepsy (ICE; seizure frequency < 1×/month) and uncontrolled epilepsy (UCE; seizure frequency > 1×/month). Participants were asked to rate on a 7-point scale, from 1 (strongly disagree) to 7 (strongly agree), how often they felt the ways described by nine items on the Fatigue Severity Scale (FSS). A higher score is suggestive of greater fatigue., Results: The study participants comprised 58 children with epilepsy and 15 children without seizures, who served as the healthy (non-epilepsy) group. The mean FSS scores of the children with epilepsy were significantly higher than those of the healthy (non-epilepsy) group (4.40 vs. 1.55, respectively; P < 0.0001). Multiple linear regression analysis showed that seizure frequency was the only characteristic significantly associated with fatigue (P < 0.0001). In the three epilepsy subgroups, the mean FSS scores for the WCE, intermediate-controlled epilepsy and UCE groups were 2.30, 3.97 and 6.28, respectively. A higher seizure frequency was associated with more severe fatigue. In particular, children in the UCE group had significantly more severe fatigue than those in the WCE group (P < 0.0001)., Conclusions: The results suggest that seizure frequency is also associated with fatigue in children with epilepsy. Improved control of seizures may help reduce fatigue levels and improve the quality of life of children with epilepsy., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)