BMJ Acta Medica Okayama 2056-5933 12 1 2026 Dental infection is associated with early relapse in patients with ANCA-associated vasculitis e006392 EN Shoichi Nawachi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshia Miyawaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Moe Sakamoto-Tokunaga Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Natsuki Kubota Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuya Terajima Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuya Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Hirose Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takato Nakadoi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Manami Hirata-Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yu Katayama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Takano-Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shigetomo Tsuji Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Objectives Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease where infections can trigger relapses. Dental infections, being common and associated with systemic inflammation, may play a role in AAV relapse, though their impact remains unclear. We aimed to evaluate the association between severe dental infections and early relapse in patients with AAV. Methods This retrospective cohort study included patients newly diagnosed with AAV between January 2011 and July 2022. Patients with severe dental infections requiring tooth extraction were placed in the dental infection group, while the remaining patients were assigned to the control group. The primary outcome was defined as either vasculitis relapse or all-cause mortality within 1 year of treatment initiation. Adjusted HRs (aHRs) and 95% CIs were estimated using Cox proportional hazards models. Results A total of 93 patients were enrolled with a median age of 74 years. 41 patients (44.1%) had severe dental infections in this cohort. Over the 1-year follow-up period, 13 patients experienced a relapse and two died, resulting in a composite event rate of 20.9 per 100 person-years. Dental infection was independently associated with the composite outcome (aHR, 3.78 (95% CI 1.13 to 12.66); p=0.031). Exploratory analysis indicated that composite outcome rates were similar regardless of tooth extraction among patients with dental infections. Conclusions Severe dental infections were associated with increased risk of early relapse or mortality in AAV. These findings highlight the importance of early dental evaluation in AAV management. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2044-6055 15 12 2025 Effectiveness of education programme to increase competency of health cadres in Indonesia: a cluster non-randomised controlled trial e095428 EN Dewie Sulistyorini Graduate School of Biomedical and Health Sciences, Hiroshima University K A T M Ehsanul Huq Graduate School of Biomedical and Health Sciences, Hiroshima University Abdulfatai Olamilekan Babaita Graduate School of Biomedical and Health Sciences, Hiroshima University Sadia A Aivey Graduate School of Biomedical and Health Sciences, Hiroshima University Gao Huiying Graduate School of Biomedical and Health Sciences, Hiroshima University Kana Kazawa Faculty of Health Sciences, Okayama University Yasuko Fukushima Graduate School of Biomedical and Health Sciences, Hiroshima University Mayumi Kako Graduate School of Biomedical and Health Sciences, Hiroshima University Michiko Moriyama Graduate School of Biomedical and Health Sciences, Hiroshima University Objectives Health cadres, who assist midwives in supporting pregnant women in community settings, need to enhance their competencies in identifying risk factors and referring high-risk pregnant women to midwives for further care. Since the capabilities of these health cadres are influenced by maternal complications, an educational programme was implemented to strengthen their skills. Therefore, this study aimed to evaluate the competency of health cadres by providing a researcher-developed educational programme. Design An open-label, cluster non-randomised controlled trial. Setting and participants Health cadres with at least 1 year of work experience were recruited at six public health centres (PHCs) in Banjarnegara Regency, Indonesia. Interventions Six PHCs were selected and allocated into intervention group (IG=3 PHCs) and control group (CG=3 PHCs) groups. A total of 133 female health cadres were enrolled across the selected PHCs. At each PHC, a systematic random sampling method was used to select the participants. The researchers and health professionals provided a 3-week period of theoretical and scenario-based simulations to the IG, while the CG received no education. Outcome measures Researcher-developed questionnaires and checklists were used to assess the knowledge, skills (health assessment, communication, attitude) and confidence. The primary endpoint was competency, a total score of knowledge and skills. The outcome domains were compared between the two groups, and a linear mixed-effect model was used to account for cluster-level variation. Results A total of 130 (97.7%) completed the study (IG:64, CG:66). The competency score showed significant improvement at endline (CG=49.5 and IG=52.5; p=0.002). The median scores for health assessment skills (CG=12 vs IG=14; p<0.001) and communication skills (CG=7 vs IG=8; p<0.001) were increased in the IG compared with the CG. Mixed-effect model indicated that groups (β (95% CI) 2.49 (0.57 to 4.41), p=0.012), baseline knowledge (β(95% CI) 0.73 (0.54 to 0.92), p<0.001) and midline health assessment skills (β (95% CI) 0.54 (0.25 to 0.82), p<0.001) were significant positive predictors, while age was negatively associated with competency (β (95% CI) －0.20 (－0.30 to －0.10), p<0.001)). Conclusion Education effectively increased the competency of health cadres. A well-structured education programme is necessary for health cadres to improve and maintain their competencies in monitoring high-risk pregnant women. Trial registration number NCT06134518. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 0143-005X 80 2 2025 Exposure-induced mediator–outcome confounders in causal mediation: implications and visualisation 129 130 EN Etsuji Suzuki Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomohiro Shinozaki Interfaculty Initiative in Information Studies, the University of Tokyo Eiji Yamamoto Okayama University of Science No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2044-6055 15 6 2025 Protocol for a multicentre, open-label, dose-escalation phase I/II study evaluating the tolerability, safety, efficacy and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with aggressive natural killer cell leukaemia e098532 EN Noriko Fukuhara Hematology, Tohoku University Graduate School of Medicine Makoto Onizuka Department of Hematology and Oncology, Tokai University School of Medicine Graduate School of Medicine Junya Kanda Department of Hematology, Graduate School of Medicine, Kyoto University Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Koji Kato Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Kiyoshi Ando Department of Hematology, Hiroshima University Introduction Aggressive natural killer cell leukaemia (ANKL) is a rare form of NK cell lymphoma with a very low incidence and poor prognosis. While multi-agent chemotherapy including L-asparaginase has been used to treat ANKL patients, they often cannot receive adequate chemotherapy at diagnosis due to liver dysfunction. PPMX-T003, a fully human monoclonal antibody targeting the transferrin receptor 1, shows promise in treating ANKL by helping patients recover from fulminant clinical conditions, potentially enabling a transition to chemotherapy. This study aimed to evaluate the tolerability, safety, efficacy, and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with ANKL. Methods and analysis This multicentre, open-label, dose-escalation phase I/II study will be conducted at nine hospitals in Japan. Patients diagnosed with ANKL (whether as a primary or recurrent disease) and exhibiting abnormal liver function or hepatomegaly due to the primary disease will be included. The primary endpoint is the tolerability and safety of repeated continuous intravenous administration of PPMX-T003 in the first course, based on adverse events and dose-limiting toxicities. PPMX-T003 will be administered as a continuous intravenous infusion every 24 hours for five consecutive days, followed by a 2-day break. Pretreatment will be provided to minimise the risk of infusion-related reactions. Initial doses of PPMX-T003 will be 0.5, 1.0 or 2.0 mg/kg, with subsequent dose increases determined by the Data and Safety Monitoring Committee. The sample size is set at seven participants, with enrolment increased to up to 12 participants if dose-limiting toxicities occur, based on feasibility due to the rarity of ANKL. Descriptive statistics will summarise data according to initial dose, and pharmacokinetic analysis will be conducted based on administered dose. Ethics and dissemination This study was approved by the institutional review boards at participating hospitals. The results will be disseminated in peer-reviewed journals. Trial registration number jRCT2061230008 (jRCT); NCT05863234 (ClinicalTrials.gov). No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2044-6055 15 8 2025 Neurological outcomes with hypothermia versus normothermia in patients with moderate initial illness severity following resuscitation from out-of-hospital cardiac arrest: protocol for a multicentre randomised controlled trial (R-CAST OHCA) e101809 EN Hiromichi Naito Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Mitsuaki Nishikimi Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University Yohei Okada Department of Preventive Services, School of Public Health, Graduate School of Medicine, Kyoto University Hiroki Maeyama Department of Emergency and Critical Care Medicine, Tsuyama Chuo Hospital Takeyuki Kiguchi Division of Trauma and Surgical Critical Care, Osaka General Medical Center Takashi Yorifuji Department of Epidemiology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Kazuki Nishida Department of Biostatistics, School of Public Health, Graduate School of Medicine, Kyoto University Shigeyuki Matsui Department of Biostatistics, School of Public Health, Graduate School of Medicine, Kyoto University Yasuhiro Kuroda Emergency and Critical Care Center, TMG Asaka Medical Center Kei Nishiyama Division of Emergency and Critical Care Medicine, Niigata University Graduate School of Medical and Dental Science Taku Iwami Department of Preventive Services, School of Public Health, Graduate School of Medicine, Kyoto University Atsunori Nakao Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences JAAM R-CAST OHCA Trial Group Introduction Temperature control is a fundamental intervention for neuroprotection following resuscitation from cardiac arrest. However, evidence regarding the efficacy of hypothermia in post-cardiac arrest syndrome (PCAS) remains unclear. Retrospective studies suggest that the clinical effectiveness of hypothermia may depend on the severity of PCAS. The R-CAST OHCA trial aims to compare the efficacy of hypothermia versus normothermia in improving 30-day neurological outcomes in patients with moderately severe PCAS following out-of-hospital cardiac arrest. Methods and analysis The multicentre, single-blind, parallel-group, superiority, randomised controlled trial (RCT) is conducted with the participation of 35 emergency and critical care centres and/or intensive care units at academic and non-academic hospitals. The study enrols moderately severe PCAS patients, defined as those with a revised post-Cardiac Arrest Syndrome for induced Therapeutic Hypothermia score of 5.5–15.5. A target number of 380 participants will be enrolled. Participants are randomised to undergo either hypothermia or normothermia within 3 hours after return of spontaneous circulation. Patients in the hypothermia group are cooled and maintained at 34°C until 28 hours post-randomisation, followed by rewarming to 37°C at a rate of 0.25°C/hour. Patients in the normothermia group are maintained at normothermia (36.5°C–37.7°C). Total periods of intervention, including the cooling, maintenance and rewarming phases, will occur 40 hours after randomisation. Other treatments for PCAS can be determined by the treating physicians. The primary outcome is a favourable neurological outcome, defined as Cerebral Performance Category 1 or 2 at 30 days after randomisation and compared using an intention-to-treat analysis. Ethics and dissemination This study has been approved by the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, Ethics Committee (approval number: R2201-001). Written informed consent is obtained from all participants or their authorised surrogates. Results will be disseminated via publications and presentations. Trial registration number jRCT1062220035. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2053-3624 12 1 2025 Clinical impact of combined assessment of myocardial inflammation and fibrosis using myocardial biopsy in patients with dilated cardiomyopathy: a multicentre, retrospective cohort study e003250 EN Takafumi Nakayama Department of Cardiology, Nagoya City University Graduate School of Medical Sciences Keiko Ohta Ogo Department of Pathology, National Cerebral and Cardiovascular Center Yasuo Sugano Department of Cardiology, Keiyu Hospital Tetsuro Yokokawa Department of Cardiovascular Medicine, Fukushima Medical University Hiromitsu Kanamori Department of Cardiology, Gifu University Graduate School of Medicine Yoshihiko Ikeda Department of Pathology, National Cerebral and Cardiovascular Center Michiaki Hiroe Department of Cardiology, National Center for Global Health and Medicine Kinta Hatakeyama Department of Pathology, National Cerebral and Cardiovascular Center Hatsue Ishibashi-Ueda Department of Pathology, National Cerebral and Cardiovascular Center Kazufumi Nakamura Center for Advanced Heart Failure, Okayama University Hospital Kaoru Dohi Department of Cardiology and Nephrology, Mie University Graduate School of Medicine Toshihisa Anzai Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine Yoshihiro Seo Department of Cardiology, Nagoya City University Graduate School of Medical Sciences Kyoko Imanaka-Yoshida Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine Background Among patients with dilated cardiomyopathy (DCM), myocardial inflammation and fibrosis are risk factors for poor clinical outcomes. Here, we investigated the combined prognostic value of these two factors, as evaluated using myocardial biopsy samples. Methods This retrospective and multicentre study included patients with DCM―defined as LVEF of ≤45% and left diastolic diameter of >112% of predicted value, without evidence of secondary or ischaemic cardiomyopathy. In myocardial biopsy samples, inflammatory cells were counted using immunohistochemistry, and Masson’s Trichrome staining was performed to quantify the myocardial fibrosis as collagen area fraction (CAF). Higher myocardial inflammation was defined as leucocytes of ≥14/mm², including ≤4 monocytes/mm², with CD3+ T lymphocytes of≥7/mm². Greater myocardial fibrosis was defined as CAF of>5.9% by the Youden’s index. The primary endpoint was cardiac death or left ventricular assist device implantation. Results A total of 255 DCM patients were enrolled (average age, 53.1 years; 78% males). Within this cohort, the mean LVEF was 28.0%, mean CAF was 10.7% and median CD3+ cell count was 8.3/mm2. During the median follow-up period of 2688 days, 46 patients met the primary endpoint. Multivariable Cox proportional hazard analyses revealed that CD3+ cell count and CAF were independent determinants of the primary endpoint. Kaplan–Meier analysis showed that patients with both higher myocardial inflammation and greater fibrosis had the worst prognosis (log-rank p<0.001). When myocardial inflammation was graded as one of three degrees: T lymphocytes of <13/mm² (low); 13 of 13.1–23.9/mm² (moderate); and T lymphocytes of ≥24 /mm² (high), patients with moderate inflammation exhibited a superior survival rate when CAF was ≤5.9%, but a worse survival rate when CAF was >5.9%. Conclusions Having both biopsy-proven higher myocardial inflammation and greater fibrosis predicted the worst clinical prognosis in patients with DCM. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2632-6140 7 1 2025 Reversible cerebral vasoconstriction syndrome in idiopathic multicentric Castleman disease under treatment with tocilizumab e000923 EN Naoya Kamimura Department of Neurology, Yokohama City University Medical Center Naohisa Ueda Department of Neurology, Yokohama City University Medical Center Katsuo Kimura Department of Neurology, Yokohama City University Medical Center Asami Nishikori Yasuharu Sato Hitaru Kishida Department of Neurology, Yokohama City University Medical Center Fumiaki Tanaka Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine Background Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterised by systemic inflammation resulting from overproduction of interleukin 6 (IL-6). While iMCD primarily affects the lymph nodes and related tissues, it can also rarely involve the central nervous system. Case presentation We report the case of a 58-year-old female patient with at least a 3-year history of iMCD, who experienced acute thunderclap headaches due to reversible cerebral vasoconstriction syndrome (RCVS). RCVS occurred 3 months after initiating treatment with tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody, and was accompanied by focal cortical subarachnoid haemorrhage (SAH). Elevated IL-6 levels were found in both serum and cerebrospinal fluid. MR angiography revealed multiple diffuse stenotic lesions in the bilateral middle and posterior cerebral arteries, which, along with bilateral cerebral oedema, resolved within 3 months. The diffuse nature of the cerebral vasospasm and the presence of bilateral brain oedema suggested that cerebral vasospasm was due to RCVS rather than SAH. Conclusions In patients with Castleman disease, RCVS may occur due to IL-6-dependent chronic cerebral vascular inflammation, either as a primary condition or as a complication of tocilizumab treatment. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2053-8790 9 1 2022 Association of one-point glucocorticoid-free status with chronic damage and disease duration in systemic lupus erythematosus: a cross-sectional study e000772 EN Ken-ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Yu Katayama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Yoshia Miyawaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Mariko Takano-Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Ryusuke Yoshimi Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine Yasuhiro Shimojima Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine Shigeru Ohno Center for Rheumatic Diseases, Yokohama City University Medical Center Hiroshi Kajiyama Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University Kunihiro Ichinose Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Shuzo Sato Department of Rheumatology, Fukushima Medical University School of Medicine Michio Fujiwara Department of Rheumatology, Yokohama Rosai Hospital Nobuyuki Yajima Division of Rheumatology, Department of Medicine, Showa University School of Medicine Objective　It is still unclear how glucocorticoids (GCs) affect the long-term clinical course of patients with SLE. The objective of this study is to explore the factors associated with GC-free treatment status. Methods　Using data from the lupus registry of nationwide institutions, GC dose at registration was compared between short, middle and long disease durations of <5, 5–20 and ≥20 years, respectively. After excluding patients who never used GC, we evaluated the relationship between GC-free status and chronic damage using Systemic Lupus International Collaborating Clinics Damage Index. Results　GC doses at enrolment of the 1019 patients were as follows: GC-free in 101 (10%); 0<prednisolone (PSL) ≤5 mg/day in 411 (40%); 5<PSL ≤7.5 in 169 (17%); 7.5<PSL ≤10 in 194 (19%) and PSL≥10 in 144 (14%) patients. Of the patients who were not currently using GCs, patients who never used GC more frequently had short disease duration (66% with short, 23% with middle and 17% with long disease duration, p=0.00029). Univariate analysis of patients who underwent GC treatment showed that patients without GCs exhibited older age, lower disease activity, less immunosuppressant and hydroxychloroquine use and higher C3 levels. Among patients with a disease duration of ≥20 years, GC-free status was more frequent in patients without chronic damage (11% vs 4%, p=0.023). After adjusting for age, sex and disease activity, no chronic damage accrual was associated with GC-free status (OR 3.6, 95% CI 1.1 to 11.3). Conclusion　Even in the patients with long disease duration, one-point GC-free treatment status might be related to no chronic damage accrual. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2051-1426 9 11 2021 TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment e003134 EN Shusuke Kawashima Research Institute, Chiba Cancer Center Takashi Inozume Research Institute, Chiba Cancer Center Masahito Kawazu Research Institute, Chiba Cancer Center Toshihide Ueno Division of Cellular Signaling, National Cancer Center Research Institute Joji Nagasaki Research Institute, Chiba Cancer Center Etsuko Tanji Research Institute, Chiba Cancer Center Akiko Honobe Department of Dermatology, University of Yamanashi Takehiro Ohnuma Department of Dermatology, University of Yamanashi Tatsuyoshi Kawamura Department of Dermatology, University of Yamanashi Yoshiyasu Umeda Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Yasuhiro Nakamura Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Tomonori Kawasaki Department of Pathology, Saitama Medical University International Medical Center Yukiko Kiniwa Department of Dermatology, Shinshu University School of Medicine Osamu Yamasaki Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Fukushima Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University Yuzuru Ikehara Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine Hiroyuki Mano Division of Cellular Signaling, National Cancer Center Research Institute Yutaka Suzuki Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo Hiroyoshi Nishikawa Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Hiroyuki Matsue Department of Dermatology, Chiba University Graduate School of Medicine Yosuke Togashi Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. Methods We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. Results Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. Conclusions The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 1757-790X 14 10 2021 Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome e244861 EN Kazuki Tokumasu Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kanako Ochi Center for Education in Medicine and Health Sciences, Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics. No potential conflict of interest relevant to this article was reported.