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Yuki Kato,1 Yasuhiro Kato,1 Yuji Minegishi,1,2 Takahiro Suzuki,1 Shinji Nakamichi,1 Masaru Matsumoto,1 Akihiko Miyanaga,1 Rintaro Noro,1 Kaoru Kubota,1 Yasuhiro Terasaki,3 Masahiro Seike,1 Akihiko Gemma1 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 2Department of Pulmonary Medicine, Mitsui Memorial Hospital, Tokyo, Japan; 3Department of Analytic Human Pathology, Nippon Medical School, Tokyo, JapanCorrespondence: Yasuhiro KatoDepartment of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi 1-1-5 Bunkyo-ku, Tokyo, 113-8603, JapanEmail y-kato@nms.ac.jpAbstract: Antibody–drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.Keywords: lung cancer, HER2 exon 20 insertion mutation, poor PS, trastuzumab deruxtecan

Positive and negative associations with risk of cognitive decline have been reported for glycated hemoglobin (HbA1c) level and green tea (GT) intake, respectively. This study aimed to assess whether the reduction in the risk of cognitive decline with GT intake depended on HbA1c level. The participants were aged ≥60 years at baseline in the cohort study, wherein examinations were conducted biennially from 2000 to 2012. Subjects (n=1,304) who had no cognitive decline during the first survey and who had participated in the follow-up survey at least once were included. The follow-up end point was the first screening time point for cognitive decline (Mini-Mental State Examination score, This study was also supported in part by JSPS KAKENHI (grant number: 15H02524).

精神遅滞と重度歯周炎を有する上顎前突症患者に，矯正歯科治療を含めた包括歯科治療を行うことで，安定した咬合を得ることができたので報告する． 患者は33歳10か月の女性．重度歯周炎による強い歯の動揺を主訴として来院した．上顎前歯の著しい唇側傾斜と空隙歯列，過蓋咬合を呈し，強い咬唇癖が認められた．歯周基本治療後，矯正歯科治療を開始した． 歯周炎による歯槽骨の低下に配慮し，矯正力は弱く，歯科矯正用アンカースクリューを用いて上下顎前歯の唇側傾斜の改善並びに空隙の閉鎖を行った結果，前歯部の舌側傾斜による挺出と大臼歯の近心移動を防ぐことができた． 動的治療期間は2年6か月であった．保定は補綴物を連結した永久保定とし，保定8年が経過した現在も咬合は安定している．, In this paper we will report a case of maxillary protrusion with severe periodontitis and mental retardation, good results were obtained by comprehensive treatment, including orthodontic treatment. A 33-year-old female with the chief complaints of pathologic teeth mobility was diagnosed as severe generalized chronic periodontitis, maxillary protrusion, the proclined maxillary anterior teeth, spaced arch and deepbite. This patient had finished the initial periodontal therapy before orthodontic treatment. Considering decreased alveolar bone height, the upper and lower dental arches were aligned with light force and using temporary anchorage devices for retraction. The extrusion of the incisors and the mesial movement of the molars were avoided. The orthodontic treatment lasted for 2 years and 6 months. The maxillary teeth were fixed by prosthetic restoration as the permanent retention. 8 years after retension, fine occlusion is obtained.

Adenosine deaminase acting on RNA 1 (ADAR1), an enzyme responsible for adenosine-to-inosine RNA editing, is composed of two isoforms: nuclear p110 and cytoplasmic p150. Deletion of Adar1 or Adar1 p150 genes in mice results in embryonic lethality with overexpression of interferon-stimulating genes (ISGs), caused by the aberrant recognition of unedited endogenous transcripts by melanoma differentiation-associated protein 5 (MDA5). However, among numerous RNA editing sites, how many RNA sites require editing, especially by ADAR1 p150, to avoid MDA5 activation and whether ADAR1 p110 contributes to this function remains elusive. In particular, ADAR1 p110 is abundant in the mouse brain where a subtle amount of ADAR1 p150 is expressed, whereas ADAR1 mutations cause Aicardi–Goutières syndrome, in which the brain is one of the most affected organs accompanied by the elevated expression of ISGs. Therefore, understanding RNA editing–mediated prevention of MDA5 activation in the brain is especially important. Here, we established Adar1 p110–specific knockout mice, in which the upregulated expression of ISGs was not observed. This result suggests that ADAR1 p150–mediated RNA editing is enough to suppress MDA5 activation. Therefore, we further created Adar1 p110/Adar2 double knockout mice to identify ADAR1 p150–mediated editing sites. This analysis demonstrated that although the elevated expression of ISGs was not observed, only less than 2% of editing sites were preserved in the brains of Adar1 p110/Adar2 double knockout mice. Of note, we found that some sites were highly edited, which was comparable to those found in wild-type mice, indicating the presence of ADAR1 p150–specific sites. These data suggest that RNA editing at a very limited sites, which is mediated by a subtle amount of ADAR1 p150, is sufficient to prevents MDA5 activation, at least in the mouse brain., Author summary RNA is subject to various post-transcriptional modifications, which add the information to regulate the fate of each RNA. One such modification is RNA editing, in which certain adenosine in double-stranded RNAs is converted to inosine by deamination reaction that is catalyzed by adenosine deaminases acting on RNA (ADARs). ADAR1 and ADAR2 are active editing enzymes in mammals. In addition, ADAR1 is composed of nuclear p110 and cytoplasmic p150 isoforms. However, the difference in the targets and the function of each ADAR is not fully understood. Previous studies demonstrate that innate immunity is activated in Adar1 p150 knockout mice, which is not observed in Adar2 knockout mice. Here, we established Adar1 p110 knockout mice. These mutant mice showed high levels of mortality during the early post-natal stages, whereas we demonstrated that this is caused by RNA editing–independent function of ADAR1 p110. We further generated Adar1 p110/Adar2 double knockout mice, in which innate immunity is not activated, although more than 98% of all the editing sites are absent in the brain of these double KO mice. Collectively, ADAR1 150–mediated RNA editing at a very limited sites is sufficient to avoid activation of innate immunity, at least in the mouse brain.