Oxford University Press (OUP) Acta Medica Okayama 1465-3621 55 5 2025 Multicenter, open-label, randomized, controlled study to test the utility of electronic patient-reported outcome monitoring in patients with unresectable advanced cancers or metastatic/recurrent solid tumors 547 555 EN Naruto Taira Department of Breast and Thyroid Surgery, Kawasaki Medical School Naomi Kiyota Department of Medical Oncology and Hematology, Cancer Center, Kobe University Hospital Yuichiro Kikawa Department of Breast Surgery, Kansai Medical University Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Kyoko Kato Department of Medical Oncology, National Hospital Organization Nagoya Medical Center Kaoru Kubota Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School Ryosuke Tateishi Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo Akinobu Nakata Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine Keiichiro Nakamura Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukiya Narita Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Hiroji Iwata Department of Advanced Clinical Research and Development, Nagoya City University Akihiko Gemma Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School Kojiro Shimozuma Department of Biomed Sciences, College of Life Sciences, Ritsumeikan University Kei Muro Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine Tetsuya Iwamoto Center for Outcomes Research and Economic Evaluation for Health, National Institute of Public Health Yuki Takumoto Center for Outcomes Research and Economic Evaluation for Health, National Institute of Public Health Takeru Shiroiwa Center for Outcomes Research and Economic Evaluation for Health, National Institute of Public Health Takashi Fukuda Center for Outcomes Research and Economic Evaluation for Health, National Institute of Public Health Takuhiro Yamaguchi Division of Biostatistics, Tohoku University Graduate School of Medicine Yasuhiro Hagiwara Department of Biostatistics, Division of Health Sciences and Nursing, The University of Tokyo Graduate School of Medicine Hironobu Minami Division of Medical Oncology and Hematology, Department of Medicine, Kobe University Graduate School of Medicine Electronic patient-reported outcome (ePRO) monitoring for patients undergoing cancer chemotherapy may provide qualified and early detection of adverse events or disease-related symptoms, leading to improved patient care. The aim of this study is to examine whether addition of ePRO monitoring to routine medical care contributes to improved overall survival and quality of life of cancer patients undergoing chemotherapy. Patients with unresectable advanced cancers or metastatic/recurrent solid tumors receiving systemic chemotherapy will be randomized to an ePRO monitoring group and a usual care group. The ePRO group will conduct weekly symptom monitoring using an electronic device after study enrollment until the end of the study. Monitoring results will be returned to medical personnel and used as information for patient care. The primary endpoints are overall survival and health related quality of life. The initial target sample size for the study was 1500 patients. However, due to delays in enrollment, the target was readjusted to 500 patients. Enrollment has been completed, and the study is now in the follow-up phase. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 64 23 2025 Remarkable Efficacy of Capmatinib in a Patient with Cancer of Unknown Primary with MET Amplification 3460 3464 EN Takaaki Tanaka Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Ryohei Sumii Department of General Internal Medicine, NHO Fukuyama Medical Center Rika Omote Department of Pathology, NHO Fukuyama Medical Center Yayoi Ando Clinical Research Support Office, National Cancer Center Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital This case report describes a 70-year-old female with cancer of unknown primary origin (CUP) who exhibited multiple distant lymph node metastases. Despite conventional chemotherapy (carboplatin and paclitaxel) and immunotherapy (nivolumab), disease progression was noted. Genomic profiling revealed MET amplification, leading to the administration of capmatinib, a selective MET tyrosine kinase inhibitor. The patient experienced substantial tumor reduction with dose adjustments due to adverse effects, indicating the potential efficacy of capmatinib in treating CUP with MET amplification. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 64 23 2025 A Prompt Diagnosis of Ascites and Dramatic Effect of Alectinib for Advanced Lung Adenocarcinoma Harboring EML4-ALK Fusion 3413 3418 EN Takahiro Baba Department of Respiratory Medicine, Okayama University Hospital Hirofumi Inoue Department of Medical Support, Okayama University Hospital Hiromi Matsuoka Department of Medical Support, Okayama University Hospital Mio Kyakuno Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Yusuke Yoshinaga Department of Respiratory Medicine, Okayama University Hospital Tetsuya Takeguchi Department of Respiratory Medicine, Okayama University Hospital Miho Fujiwara Department of Respiratory Medicine, Okayama University Hospital Kotaro Yamada Department of Respiratory Medicine, Okayama University Hospital Eri Nakamura Department of Respiratory Medicine, Okayama University Hospital Ayako Morita Department of Respiratory Medicine, Okayama University Hospital Naofumi Hara Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Hisao Higo Department of Respiratory Medicine, Okayama University Hospital Masanori Fujii Department of Geriatric Medicine, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Kammei Rai Center for Innovative Clinical Medicine, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yosuke Togashi Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital A 75-year-old never-smoker woman presented with dyspnea and loss of appetite. A mass was identified in the left upper lobe of the lung, and the patient was referred to our hospital. Despite the diagnosis of lung adenocarcinoma via bronchoscopy, anaplastic lymphoma kinase (ALK) immunostaining was negative. Rapid weight gain and abdominal distension caused by ascites prompted fluid testing using the AmoyDx® Pan Lung Cancer PCR Panel. EML4-ALK fusion was confirmed, and alectinib therapy was initiated immediately. The tumor size had decreased significantly, and the patient was discharged on day 34. This case highlights the necessity of multiplex genetic testing even when ALK immunostaining is negative. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1556-0864 20 5 2025 Amivantamab Plus Lazertinib in Patients With EGFR-Mutant NSCLC After Progression on Osimertinib and Platinum-Based Chemotherapy: Results From CHRYSALIS-2 Cohort A 651 664 EN Benjamin Besse Paris-Saclay University, Institut Gustave Roussy Koichi Goto National Cancer Center Hospital East Yongsheng Wang Institute of Clinical Trial Center and Cancer Center, West China Hospital, Sichuan University Se-Hoon Lee Samsung Medical Center, Sungkyunkwan University School of Medicine Melina E. Marmarelis University of Pennsylvania, Perelman School of Medicine Yuichiro Ohe National Cancer Center Hospital Reyes Bernabe Caro Hospital Universitario Virgen Del Rocio Dong-Wan Kim Seoul National University College of Medicine and Seoul National University Hospital Jong-Seok Lee Seoul National University College of Medicine and Seoul National University Hospital Sophie Cousin Institut Bergonié Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Yongsheng Li Chongqing University Cancer Hospital Luis Paz-Ares Hospital Universitario 12 de Octubre Akira Ono Shizuoka Cancer Center Rachel E. Sanborn Earle A. Chiles Research Institute, Providence Cancer Institute Naohiro Watanabe Department of Thoracic Oncology, Aichi Cancer Center Hospital Maria Jose de Miguel START Madrid-CIOCC, Hospital HM Sanchinarro Carole Helissey Clinical Research unit, Military Hospital Begin Catherine A. Shu Columbia University Medical Center Alexander I. Spira Virginia Cancer Specialists Pascale Tomasini Aix Marseille University - CNRS, INSERM, CRCM; CEPCM - AP-HM Hopital de La Timone James Chih-Hsin Yang National Taiwan University Cancer Center Yiping Zhang Zhejiang Cancer Hospital Enriqueta Felip Medical Oncology Service, Vall dfHebron Institute of Oncology (VHIO), Vall dfHebron University Hospital Campus, Universitat Autonoma de Barcelona Frank Griesinger Pius-Hospital, University Medicine of Oldenburg Saiama N. Waqar Division of Oncology, Washington University School of Medicine Antonio Calles Hospital General Universitario Gregorio Marañón Joel W. Neal Stanford University Medical Center Christina S. Baik University of Washington, Fred Hutchinson Cancer Center Pasi A. Jänne Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute S. Martin Shreeve Johnson & Johnson Joshua C. Curtin Johnson & Johnson Bharvin Patel Johnson & Johnson Michael Gormley Johnson & Johnson Xuesong Lyu Johnson & Johnson Jun Chen Johnson & Johnson Pei-Ling Chu Johnson & Johnson Janine Mahoney Johnson & Johnson Leonardo Trani Johnson & Johnson Joshua M. Bauml Johnson & Johnson Meena Thayu Johnson & Johnson Roland E. Knoblauch Johnson & Johnson Byoung Chul Cho Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine Introduction: Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited.<br> Methods: CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib.<br> Results: In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22–36). The blinded independent central review–assessed ORR was 35% (95% CI: 27–42), with a median duration of response of 8.3 months (95% CI: 6.7–10.9) and a clinical benefit rate of 58% (95% CI: 50–66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1–5.8); median overall survival was 14.8 months (95% CI: 12.2–18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).<br> Conclusions: For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 4 2025 A Rare Presentation of Pneumonic-Type Adenocarcinoma Hidden behind Empyema 305 309 EN Satoru Senoo Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Eito Niman Department of General Thoracic Surgery, National Hospital Organization Fukuyama Medical Center Ryoko Tsuji Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Kohei Takata Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Shunsuke Matsumori Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Fumika Murano Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Yuka Sugisaki Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Hiroki Omori Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Akihiko Taniguchi Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Rika Omote Department of Diagnostic Pathology, National Hospital Organization Fukuyama Medical Center Eiki Ichihara Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Kenji Takahashi Department of General Thoracic Surgery, National Hospital Organization Fukuyama Medical Center Toshiaki Okada Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center Case Report 10.18926/AMO/69158 Pneumonic-type adenocarcinoma (P-ADC) can closely mimic pneumonia. We report a P-ADC initially diagnosed as pneumonia which developed into a pulmonary abscess and empyema. A 50-year-old Japanese male diagnosed with pneumonia, pulmonary abscess, and empyema was administered antibiotics and a chest tube for drainage, which improved his symptoms and blood test results. However, chest computed tomography showed an enlarged infiltrative shadow. The patient underwent bronchoscopy and was diagnosed with an adenocarcinoma. This case highlights the importance of considering P-ADC in differential diagnoses when a pneumonia-like shadow enlarges post-empyema treatment. Diagnostic and clinical tests, e.g., bronchoscopy, should be performed in such cases. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0941-4355 33 4 2025 Cancer-related alopecia and wig acquisition: how age, sex, and treatment affect patient choices 283 EN Hideki Katayama Department of Palliative and Supportive Care, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Ayako Morita Department of Allergy and Respiratory Medicine , Okayama University Hospital Go Makimoto Department of Allergy and Respiratory Medicine , Okayama University Hospital Shunsuke Kagawa Center for Clinical Oncology, Okayama University Hospital Ayano Ishii Integrated Support Center for Patients and Self-Learning , Okayama University Hospital Masahiro Tabata Department of Palliative and Supportive Care, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Purpose This study aimed to explore the prevalence and cost of wig purchases among patients with cancer in Okayama Prefecture, Japan, and examine the relationship between wig purchases and various demographic, social, and clinical factors. The findings aim to provide insights into appearance care and support systems for patients with cancer, particularly wig subsidies.<br> Methods A survey was conducted between July and August 2023 among 3000 patients with cancer at 13 designated cancer care hospitals in Okayama Prefecture. Data on demographics, cancer treatment status, and wig purchase details were collected. Statistical analyses, including the Mann–Whitney U test, chi-square test, and logistic regression, were performed to identify factors significantly associated with wig purchases.<br> Results Among the 863 respondents, 31.4% (271 patients) reported purchasing wigs. Factors significantly associated with wig purchase included young age (odds ratio [OR] = 1.04), female sex (OR = 1.61), and current cancer treatment (OR = 1.16). No significant correlation was found between wig purchase and household income, although higher-income patients tended to purchase more expensive wigs.<br> Conclusion The findings suggest that younger female patients with cancer and those undergoing treatment were more likely to purchase wigs, highlighting the importance of appearance care and the need for enhanced financial support for low-income patients. No potential conflict of interest relevant to this article was reported.

Nature Portfolio Acta Medica Okayama 2045-2322 15 1 2025 Plasma S100A8/A9 level predicts response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer 2577 EN Tadahiro Kuribayashi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rie Kinoshita Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kiichiro Ninomiya Department of Allergy and Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Toshio Kubo Department of Allergy and Respiratory Medicine, Okayama University Hospital Kammei Rai Department of Allergy and Respiratory Medicine, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Katsuyuki Hotta Department of Allergy and Respiratory Medicine, Okayama University Hospital Masahiro Tabata Department of Allergy and Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Blood-based predictive markers for the efficacy of immune checkpoint inhibitors (ICIs) have not yet been established. We investigated the association of the plasma level of S100A8/A9 with the efficacy of immunotherapy. We evaluated patients with unresectable stage III/IV or recurrent non-small cell lung cancer (NSCLC) who were treated with ICIs at Okayama University Hospital. The pre-treatment plasma levels of S100A8/A9 were analyzed. Eighty-one eligible patients were included (median age, 69 years). Sixty-two patients were men, 54 had adenocarcinoma, 74 had performance status (PS) 0–1, and 47 received ICIs as first-line treatment. The median time to treatment failure (TTF) for ICIs was 5.7 months, and the median overall survival (OS) was 19.6 months. The TTF and OS were worse in patients with high plasma S100A8/A9 levels (≥ 2.475 µg/mL) (median TTF: 4.3 vs. 8.5 months, p = 0.009; median OS: 15.4 vs. 38.0 months, p = 0.001). Multivariate analysis revealed that PS ≥ 2, liver metastasis, and high plasma S100A8/A9 levels were significantly associated with short TTF and OS. In conclusion, plasma S100A8/A9 level may have a limited effect on ICI therapy for NSCLC. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2072-6694 16 23 2024 Frequency and Significance of Body Weight Loss During Immunochemotherapy in Patients with Advanced Non-Small Cell Lung Cancer 4089 EN Masataka Taoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Toshihide Yokoyama Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital Koji Inoue Department of Respiratory Medicine, Ehime Prefectural Central Hospital Tomoki Tamura Department of Respiratory Medicine, NHO Iwakuni Clinical Center Akiko Sato Department of Internal Medicine, National Hospital Organization Okayama Medical Center Naohiro Oda Department of Respiratory Medicine, Fukuyama City Hospital Hirohisa Kano Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital Kayo Nakamura Department of Respiratory Medicine, Japanese Red Cross Himeji Hospital Haruyuki Kawai Department of Internal Medicine, Okayama Saiseikai General Hospital Masaaki Inoue Department of Chest Surgery, Shimonoseki City Hospital Nobuaki Ochi Department of General Internal Medicine 4 , Kawasaki Medical School Nobukazu Fujimoto Department of Respiratory Medicine, Okayama Rosai Hospital Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Chihiro Ando Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital Isao Oze Division of Cancer Information and Control, Aichi Cancer Center Research Institute Katsuyuki Kiura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Background: Limited data are available on the frequency and significance of body weight loss during cancer therapy. This study investigated the frequency of patients who experienced body weight loss during immune checkpoint inhibitor (ICI) plus chemotherapy for advanced non-small cell lung cancer (NSCLC) and the impact of weight loss on treatment outcomes. Methods: Using the clinical data of 370 patients with NSCLC who received a combination of ICI and chemotherapy at 13 institutions, this study investigated the frequency of body weight loss > 5% during treatment and determined the impact of body weight loss on patient outcomes. Results: Of the 370 included patients, 141 (38.1%) lost more than 5% of their body weight during ICI plus chemotherapy (WL group). The 2-month landmark analysis showed that patients who experienced body weight loss of >5% during treatment had worse overall survival (OS) and progression-free survival (PFS) than those who did not (OS 14.0 and 31.1 months in the WL non-WL groups, respectively, p < 0.001; PFS 6.8 and 10.9 months in the WL non-WL groups, respectively, p = 0.002). Furthermore, a negative impact of body weight loss on survival was observed even in those who had obesity (body mass index [BMI] >= 25.0) at the start of therapy (OS 12.8 and 25.4 months in the WL non-WL groups, respectively, p < 0.001; PFS 5.7 and 10.7 months in the WL non-WL groups, respectively, p = 0.038). Conclusions: In conclusion, weight loss of >5% during ICI plus chemotherapy negatively influenced patient outcomes. Further and broader studies should investigate the role of nutritional status, specifically weight change and nutritional support, in responsiveness to ICI plus chemotherapy. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 63 19 2024 A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing 2655 2660 EN Hiroaki Matsuura Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Naohiro Oda Department of Respiratory Medicine, Fukuyama City Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Hisao Higo Department of Respiratory Medicine, Okayama University Hospital Masanori Fujii Department of Respiratory Medicine, Okayama University Hospital Kammei Rai Center for Innovative Clinical Medicine, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Nuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor. No potential conflict of interest relevant to this article was reported.

American Society of Clinical Oncology (ASCO) Acta Medica Okayama 2473-4284 8 2024 Response to Imatinib in a Patient With Gastric Adenocarcinoma With KIT Q556_K558 In-Frame Deletion: A Case Report e2400228 EN Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Kunio Okamoto Department of Medical Oncology, Kagawa Prefectural Central Hospital Midori Ando Department of Pathology, Kagawa Prefectural Central Hospital, Satoko Nakamura Department of Pathology, Kagawa Prefectural Central Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Yoshiyuki Ayada Department of Pathology, Okayama University Hospital Go Makimoto Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Natsuko Okita Research Management Division, Clinical Research Support Office, National Cancer Center Hospital Shinichi Toyooka Center for Comprehensive Genomic Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2213-0071 51 2024 Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy 102104 EN Masahiro Yamashita Department of Allergy and Respiratory Medicine, Okayama University Hospital Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Chiaki Matsumoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Masanori Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Kammei Rai Center for Innovative Clinical Medicine, Okayama University Hospital Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuaki Miyahara Department of Allergy and Respiratory Medicine, Okayama University Hospital A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1661-6596 25 15 2024 Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients 8370 EN Mitsuru Tsuge Department of Pediatrics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Kou Hasegawa Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kenichiro Kudo Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Yasushi Tanimoto Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Kazuhiro Nouso Department of Gastroenterology, Okayama City Hospital Naohiro Oda Department of Internal Medicine, Fukuyama City Hospital Sho Mitsumune Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Goro Kimura Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Haruto Yamada Department of Infectious Disease, Okayama City Hospital Ichiro Takata Department of Internal Medicine, Fukuyama City Hospital Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Akihiko Taniguchi Department of Allergy and Respiratory Medicine, Okayama University Hospital Kohei Tsukahara Department of Emergency, Critical Care and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiyuki Aokage Department of Emergency, Critical Care and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hideharu Hagiya Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrine Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hirokazu Tsukahara Department of Pediatrics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University This study investigated the correlation between oxidative stress and blood amino acids associated with nitric oxide metabolism in adult patients with coronavirus disease (COVID-19) pneumonia. Clinical data and serum samples were prospectively collected from 100 adult patients hospitalized for COVID-19 between July 2020 and August 2021. Patients with COVID-19 were categorized into three groups for analysis based on lung infiltrates, oxygen inhalation upon admission, and the initiation of oxygen therapy after admission. Blood data, oxidative stress-related biomarkers, and serum amino acid levels upon admission were compared in these groups. Patients with lung infiltrations requiring oxygen therapy upon admission or starting oxygen post-admission exhibited higher serum levels of hydroperoxides and lower levels of citrulline compared to the control group. No remarkable differences were observed in nitrite/nitrate, asymmetric dimethylarginine, and arginine levels. Serum citrulline levels correlated significantly with serum lactate dehydrogenase and C-reactive protein levels. A significant negative correlation was found between serum levels of citrulline and hydroperoxides. Levels of hydroperoxides decreased, and citrulline levels increased during the recovery period compared to admission. Patients with COVID-19 with extensive pneumonia or poor oxygenation showed increased oxidative stress and reduced citrulline levels in the blood compared to those with fewer pulmonary complications. These findings suggest that combined oxidative stress and abnormal citrulline metabolism may play a role in the pathogenesis of COVID-19 pneumonia. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 63 9 2024 Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer 1261 1267 EN Takaaki Tanaka Department of Respiratory Medicine, Okayama University Hospital Masataka Taoka Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Hisao Higo Department of Respiratory Medicine, Okayama University Hospital Masanori Fujii Department of Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1759-7706 15 17 2024 Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report 1390 1394 EN Hiroaki Matsuura Department of Respiratory Medicine, Okayama University Hospital Hisao Higo Department of Respiratory Medicine, Okayama University Hospital Tadahiro Kuribayashi Department of Respiratory Medicine, Okayama University Hospital Akihiko Tamaoki Okayama Health Foundation Hospital, Okayama Health Foundation Takamasa Nakasuka Department of Respiratory Medicine, Okayama University Hospital Mari Uno Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Respiratory Medicine, Okayama University Hospital Masanori Fujii Department of Respiratory Medicine, Okayama University Hospital Kammei Rai Department of Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Department of Respiratory Medicine, Okayama University Hospital Nobuaki Miyahara Department of Respiratory Medicine, Okayama University Hospital Masahiro Tabata Department of Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis. No potential conflict of interest relevant to this article was reported.

AME Publishing Company Acta Medica Okayama 2218-6751 12 10 2023 CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer EN Naofumi Hara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Hirohisa Kano Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital Chihiro Ando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ayako Morita Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tatsuya Nishi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsuko Hirabae Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masaya Abe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Kiichiro Ninomiya Center for Comprehensive Genomic Medicine, Okayama University Hospital Go Makimoto Center for Clinical Oncology, Okayama University Hospital Masanori Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Toshio Kubo Department of Allergy and Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Background: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance.<br> Methods: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC.<br> Results: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation.<br> Conclusions: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC. No potential conflict of interest relevant to this article was reported.

Public Library of Science Acta Medica Okayama 1932-6203 18 10 2023 A randomized controlled trial of teprenone in terms of preventing worsening of COVID-19 infection e0287501 EN Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Kou Hasegawa Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kenichiro Kudo Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Yasushi Tanimoto Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Kazuhiro Nouso Department of Gastroenterology, Okayama City Hospital Naohiro Oda Department of Internal Medicine, Fukuyama City Hospital Sho Mitsumune Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Haruto Yamada Department of Infectious Disease, Okayama City Hospital Ichiro Takata Department of Internal Medicine, Fukuyama City Hospital Hideharu Hagiya Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Akihiko Taniguchi Department of Allergy and Respiratory Medicine, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kohei Tsukahara Department of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyuki Aokage Department of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hirokazu Tsukahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Background<br> Some COVID-19 patients develop life-threatening disease accompanied by severe pneumonitis. Teprenone induces expression of heat-shock proteins (HSPs) that protect against interstitial pneumonia in preclinical models. We explored whether teprenone prevented worsening of COVID-19 infections. <br> Methods<br> This open-label, randomized, pilot phase 2 clinical trial was conducted at five institutions in Japan. We randomized patients hospitalized for COVID-19 with fever to teprenone or noteprenone groups in a 1:1 ratio. We stratified patients by sex, age < and >= 70 years and the existence (or not) of complications (hypertension, diabetes, ischemic heart disease, chronic pulmonary disease and active cancer). No limitation was imposed on other COVID-19 treatments. The primary endpoint was the intubation rate. <br> Results<br> One hundred patients were included, 51 in the teprenone and 49 in the no- teprenone groups. The intubation rate did not differ significantly between the two groups: 9.8% (5/51) vs. 2.0% (1/49) (sub-hazard ratio [SHR] 4.99, 95% confidence interval [CI]: 0.59-42.1; p = 0.140). The rates of intra-hospital mortality and intensive care unit (ICU) admission did not differ significantly between the two groups: intra-hospital mortality 3.9% (2/51) vs. 4.1% (2/ 49) (hazard ratio [HR] 0.78, 95%CI: 0.11-5.62; p = 0.809); ICU admission 11.8% (6/51) vs. 6.1% (3/49) (SHR 1.99, 95%CI: 0.51-7.80; p = 0.325). <br> Conclusion<br> Teprenone afforded no clinical benefit. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2213-0071 38 2022 Massive hemoptysis in a post-operative patient with recurrent lung cancer successfully treated by the combination therapy of Endobronchial Watanabe Spigot and bronchial artery embolization 101669 EN Masataka Taoka Department of Allergy and Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Noriyuki Umakoshi Department of Radiology, Okayama University Hospital Kiichiro Ninomiya Department of Allergy and Respiratory Medicine, Okayama University Hospital Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital Yuka Kato Center for Innovative Clinical Medicine, Okayama University Hospital Masanori Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital A 76-year-old woman who was treated with lorlatinib for postoperative recurrent anaplastic lymphoma kinase-positive lung adenocarcinoma visited our hospital with massive hemoptysis. Chest computed tomography showed massive bleeding from the right upper lobe; however, the cause of bleeding was unclear. After bronchial artery embolization (BAE), bronchial occlusion was performed using an Endobronchial Watanabe Spigot (EWS) that was easily placed because BAE had reduced the bleeding volume. Treatment with BAE alone was inadequate; however, additional therapy with EWS after BAE successfully controlled the massive hemoptysis, especially in this patient who underwent lobectomy to prevent respiratory dysfunction. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0020-7136 154 1 2023 Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies 169 179 EN Naoya Kemmotsu Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kiichiro Ninomiya Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kei Kunimasa Department of Thoracic Oncology, Osaka International Cancer Institute Takamasa Ishino Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Joji Nagasaki Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshihiro Otani Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroyuki Michiue Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eiki Ichihara Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kadoaki Ohashi Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takako Inoue Department of Thoracic Oncology, Osaka International Cancer Institute Motohiro Tamiya Department of Thoracic Oncology, Osaka International Cancer Institute Kazuko Sakai Department of Genome Biology, Kindai University Faculty of Medicine Youki Ueda Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiromichi Dansako Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuto Nishio Department of Genome Biology, Kindai University Faculty of Medicine Katsuyuki Kiura Department of Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Isao Date Department of Neurological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yosuke Togashi Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 114 11 2023 Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer 4343 4354 EN Chihiro Ando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Tatsuya Nishi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ayako Morita Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Naofumi Hara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kenji Takada Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiromi Watanabe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hirohisa Kano Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Go Makimoto Center for Clinical Oncology, Okayama University Hospital Takumi Kondo Department of Hematology and Oncology, Okayama University Hospital Kiichiro Ninomiya Department of Allergy and Respiratory Medicine, Okayama University Hospital Masanori Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Toshio Kubo Department of Allergy and Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Ken-Ichi Matsuoka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings. No potential conflict of interest relevant to this article was reported.

American Association for Cancer Research Acta Medica Okayama 2767-9764 2 7 2022 Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration 739 753 EN Takao Morinaga Chiba Cancer Center, Research Institute Takashi Inozume Chiba Cancer Center, Research Institute Masahito Kawazu Chiba Cancer Center, Research Institute Youki Ueda Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Nicolas Sax KOTAI Biotechnologies Inc Kazuo Yamashita KOTAI Biotechnologies Inc Shusuke Kawashima Chiba Cancer Center, Research Institute Joji Nagasaki Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Toshihide Ueno Division of Cellular Signaling, National Cancer Center Research Institute Jason Lin Chiba Cancer Center, Research Institute Yuuki Ohara Department of Pathology, National Cancer Center Hospital East Takeshi Kuwata Department of Genetic Medicineand Services, National Cancer Center Hospital East Hiroki Yukami Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East Akihito Kawazoe Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East Kohei Shitara Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East Akiko Honobe-Tabuchi 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 Yu Kawahara Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Yasuhiro Nakamura Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center Yukiko Kiniwa Department of Dermatology, Shinshu University School of Medicine Ayako Morita Department of Allergy and Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Tomohiro Enokida Department of Head and Neck Medical Oncology, National Cancer Center Hospital East Makoto Tahara Department of Head and Neck Medical Oncology, National Cancer Center Hospital East Yoshinori Hasegawa Department of Applied Genomics, Kazusa DNA Research Institute 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 Yosuke Togashi Department of Tumor Microenvironment, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.<br> Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0169-5002 178 2023 PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer 1 10 EN Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Hirabae Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kenji Takada Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chihiro Ando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromi Watanabe Department of Respiratory Medicine, Okayama University Hospital Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine Masanori Fujii Department of Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Hiromi Kumon Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Objectives: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored.<br> Materials and methods: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined.<br> Results: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity.<br> Conclusion: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2072-6694 14 24 2022 The Effect of Pleural Effusion on Prognosis in Patients with Non-Small Cell Lung Cancer Undergoing Immunochemotherapy: A Retrospective Observational Study 6184 EN Tomoka Nishimura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Toshihide Yokoyama Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital Koji Inoue Department of Respiratory Medicine, Ehime Prefectural Central Hospital Tomoki Tamura Department of Respiratory Medicine, NHO Iwakuni Clinical Center Ken Sato Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Naohiro Oda Department of Internal Medicine, Fukuyama City Hospital Hirohisa Kano Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital Daizo Kishino Department of Respiratory Medicine, Japanese Red Cross Society Himeji Hospital Haruyuki Kawai Department of Internal Medicine, Okayama Saiseikai General Hospital Masaaki Inoue Department of Chest Surgery, Shimonoseki City Hospital Nobuaki Ochi Department of General Internal Medicine 4, Kawasaki Medical School Nobukazu Fujimoto Department of Respiratory Medicine, Okayama Rosai Hospital Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Chihiro Ando Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Simple Summary Minimal data exists on pleural effusion (PE) for non-small cell lung cancer (NSCLC) patients undergoing combined ICI and chemotherapy. We retrospectively investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival and overall survival than those without PE. In addition, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. In conclusion, PE was associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy. Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group-Immune Chemotherapy Database (OLCSG-ICD) between December 2018 and December 2020; the OLCSG-ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient's programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy. No potential conflict of interest relevant to this article was reported.

Karger Acta Medica Okayama 1662-6575 15 2 2022 Successful and Prompt Treatment with Tepotinib for Lung Adenocarcinoma Harboring MET Exon 14 Skipping Mutation Combined with Lung Abscess Formation: A Case Report 494 498 EN Go Makimoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Atsushi Shimonishi Department of Allergy and Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Allergy and Respiratory Medicine, Okayama University Hospital Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital Yuka Kato Center for Innovative Clinical Medicine, Okayama University Hospital Masanori Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Tepotinib, the novel MET-tyrosine kinase inhibitor, shows an antitumor effect for patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. In January 2022, the AmoyDx (R) Pan Lung Cancer polymerase chain reaction Panel (AmoyDx (R) panel), which had a shorter turnaround time than the conventional test, was launched in Japan as a tepotinib companion test. We report a patient with an advanced MET-mutant NSCLC promptly diagnosed using the AmoyDx (R) panel and successfully treated with tepotinib. Although the patient's performance status (PS) worsened due to the rapid tumor progression and lung abscess formation, the tumor shrank immediately after tepotinib treatment with marked PS improvement. No potential conflict of interest relevant to this article was reported.

JAPAN SOC INTERNAL MEDICINE Acta Medica Okayama 0918-2918 61 3 2022 Pulmonary Aspergilloma and Allergic Bronchopulmonary Aspergillosis Following the 2018 Heavy Rain Event in Western Japan 379 383 EN Eri Ando Center for Graduate Medical Education, Okayama University Hospital Takamasa Nakasuka Allergy and Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Akihiko Taniguchi Allergy and Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Kato Allergy and Respiratory Medicine, Okayama University Hospital Eiki Ichihara Allergy and Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Allergy and Respiratory Medicine, Okayama University Hospital Kammei Rai Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Allergy and Respiratory Medicine, Okayama University Hospital Masaomi Yamane Departments of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuaki Miyahara Allergy and Respiratory Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Allergy and Respiratory Medicine, Okayama University Hospital A 16-year-old boy with asthma participated in recovery volunteer work following the 2018 heavy rains in Japan. One month later, he experienced chest pain and dyspnea. Chest computed tomography revealed a cavity with a fungal ball, and Aspergillus fumigatus was detected in his bronchoalveolar lavage fluid. He was treated with voriconazole, but new consolidations appeared rapidly. He also experienced allergic bronchopulmonary aspergillosis. After prednisolone prescription, the consolidations improved; however, his asthma worsened. He underwent partial lung resection to avoid allergens, and his symptoms improved. We must recognize cases of infection after a disaster, especially in patients with chronic respiratory diseases. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1465-993X 23 1 2022 Identification of targetable kinases in idiopathic pulmonary fibrosis 20 EN Hisao Higo Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Hiromasa Yamamoto Department of Thoracic Surgery, Okayama University Hospital Seiichiro Sugimoto Organ Transplant Center, Okayama University Hospital Satoru Senoo Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Go Makimoto Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Akihiko Taniguchi Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Nobuaki Miyahara Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Background Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). Methods Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). Results Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. Conclusions We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF. No potential conflict of interest relevant to this article was reported.

The Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 60 17 2021 Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease 2831 2837 EN Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kammei Rai Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuharu Fujii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Kato Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiko Taniguchi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshio Kubo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eiki Ichihara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuaki Miyahara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Hotta Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masahiro Tabata Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy. No potential conflict of interest relevant to this article was reported.

Spandidos Publications Acta Medica Okayama 1792-1074 22 3 2021 Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1ƒΏ/TGF‑ƒΏ expression 639 EN Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Hiromi Watanabe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Go Makimoto Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisao Higo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kiichiro Ninomiya Department of Respiratory Medicine, Okayama University Hospital Yuka Kato Center for Innovative Clinical Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Kammei Rai Department of Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression‑free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia‑inducible factor‑1ƒΏ (HIF‑1ƒΏ) and transforming growth factor‑ƒΏ (TGF‑ƒΏ) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF‑ƒΏ attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF‑1ƒΏ/TGF‑ƒΏ. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2021 VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers EN Hiromi Watanabe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Hiroe Kayatani Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Go Makimoto Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hisao Higo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Chihiro Ando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Sachi Okawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takamasa Nakasuka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hirohisa Kano Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Naofumi Hara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsuko Hirabae Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuka Kato Center for Innovative Clinical Medicine, Okayama University Hospital Takashi Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Kammei Rai Department of Allergy and Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC. No potential conflict of interest relevant to this article was reported.

“ϊ–{“ΰ‰ΘŠw‰ο Acta Medica Okayama 0918-2918 59 2 2020 Managing Lung Cancer with Comorbid Interstitial Pneumonia 163 167 EN Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Nobuaki Miyahara Department of Medical Technology, Okayama University Graduate School of Health Sciences Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Systemic therapy for advanced non-small cell lung cancer (NSCLC) has dramatically changed in the latest 15 years. Molecular-targeted therapy has brought about an era of precision medicine, and immune checkpoint inhibitors have brought hope for a cure for advanced NSCLC. In the wake of this remarkable advancement, lung cancer with comorbid interstitial pneumonia (IP) has been completely left behind, as most clinical trials exclude patients with comorbid IP. IP, especially idiopathic pulmonary fibrosis (IPF), is often accompanied by lung cancer, and acute exacerbation can develop during various cancer therapies, including surgery, radiotherapy and pharmacotherapy. In this review, we focus on the clinical questions concerning pharmacotherapy in cases of advanced lung cancer with comorbid IP and discuss what we can do with the currently available data. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 Rapid Disease Progression of Advanced Non-small Cell Lung Cancer Five Months after Cessation of Pembrolizumab 423 425 EN Atsuko Hirabae Department of Allergy and Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Ryota Sunami Department of Allergy and Respiratory Medicine, Okayama University Hospital Moeko Ota Department of Allergy and Respiratory Medicine, Okayama University Hospital Yoshitaka Iwamoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Case Report 10.18926/AMO/60802 We report a case of late-onset hyperprogressive disease after cessation of a PD-1 inhibitor. A male was diagnosed with metastatic lung adenocarcinoma with little progression for 2 months before treatment. He received pembrolizumab as a second-line treatment and was subsequently prescribed docetaxel for 3 months until a slight increase in pleural effusion. At the time of progression to docetaxel, he commenced prednisolone because of immune-system-related diarrhea. After that, his general condition rapidly worsened with severe fatigue and hypoxia. Computed tomography revealed a massive increase of pleural effusion and replacement of almost the entire liver with cancer over a period of 5 weeks. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 111 10 2020 Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status 3739 3746 EN Hirohisa Kano Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Daijiro Harada Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center Koji Inoue Department of Respiratory Medicine, Ehime Prefectural Central Hospital Hiroe Kayatani Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Shinobu Hosokawa Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital Daizo Kishino Department of Respiratory Medicine, Himeji Red Cross Hospital Kazuhiko Watanabe Department of Internal Medicine, Okayama Saiseikai General Hospital Nobuaki Ochi Department of General Internal Medicine 4, Kawasaki Medical School Naohiro Oda Department of Internal Medicine, Fukuyama City Hospital Naofumi Hara Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kiichiro Ninomiya Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months;P < .001 and median OS, 17.4 vs 4.0 months;P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1471-2369 21 2020 Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report 113 EN Natsumi Matsuoka Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kenji Tsuji Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eiki Ichihara Department of Hematology, Oncology, Allergy and Respiratory Medicine,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takayuki Hara Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuhiko Fukushima Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kishio Toma Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinji Kitamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kenichi Inagaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hitoshi Sugiyama Department of Human Resource Development of Dialysis Therapy for Kidney Disease, 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 Background</br> The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism.</br> Case presentation</br> A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism.</br> Conclusion</br> All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 2 2020 Association between Histological Types and Enhancement of Dynamic CT for Primary Lung Cancer 129 135 EN Shogo Fukuma Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayoshi Shinya Department of Radiology, Okayama University Hospital Junichi Soh Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryuichiro Fukuhara Department of Pediatric Radiology, Okayama University Hospital Nanako Ogawa Department of Radiology, Okayama University Hospital Fumiyo Higaki Department of Radiology, Okayama City General Medical Center Takehiro Tanaka Department of Pathology, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Takao Hiraki Department of Radiology, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Kanazawa Department of Radiology, Okayama University Hospital Original Article 10.18926/AMO/58271 The aim of this study was to explore enhancement patterns of different types of primary lung cancers on 2-phase dynamic computed tomography (CT). This study included 217 primary lung cancer patients (141 adenocarcinomas [ADs], 48 squamous cell carcinomas [SCCs], 20 small cell lung carcinomas [SCLCs], and 8 others) who were examined using a 2-phase dynamic scan. Regions of interest were identified and mean enhancement values were calculated. After excluding the 20 SCLCs because these lesions had different clinical stages from the other cancer types, the mean attenuation values and subtractions between phases were compared between types of non-small cell lung carcinomas (NSCLCs) using the Kruskal–Wallis test. Late phase attenuation and attenuation of the late minus unenhanced phase (LMU) of SCCs were significantly higher than those of ADs (p<0.05). To differentiate SCC and AD in the late phase, a threshold of 80.21 Hounsfield units (HU) gave 52.9% accuracy. In LMU, a threshold of 52.16 HU gave 59.3% accuracy. Dynamic lung CT has the potential to aid in differentiating among NSCLC types. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 15560864 14 11 2019 Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden 2009 2018 EN Go Makimoto Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Okayama University Hospital Biobank, Okayama University Hospital Kazuya Nishii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Matsubara Okayama University Hospital Biobank, Okayama University Hospital Hiroe Kayatani Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisao Higo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akiko Sato Department of Respiratory Medicine, Okayama University Hospital Hiromi Watanabe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hirohisa Kano Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Ninomiya Department of Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Kammei Rai Department of Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center of Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Shinichi Toyooka Okayama University Hospital Biobank, Okayama University Hospital Minoru Takata Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Graduate School of Biostudies, Radiation Biology Center, Kyoto University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Introduction<br/> The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. <br/> Methods<br/> Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. <br/>Results<br/> ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. <br/>Conclusions<br/> High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 71 5 2017 Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease 453 457 EN Akihiko Taniguchi Department of Allergy and Respiratory Medicine, Okayama University Hospital Nobuaki Miyahara Department of Allergy and Respiratory Medicine, Okayama University Hospital Naohiro Oda Department of Allergy and Respiratory Medicine, Okayama University Hospital Daisuke Morichika Department of Allergy and Respiratory Medicine, Okayama University Hospital Eiki Ichihara Department of Allergy and Respiratory Medicine, Okayama University Hospital Isao Oze Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute Yasushi Tanimoto National Hospital Organization Minami-Okayama Medical Center Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Utako Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Mitsune Tanimoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Arihiko Kanehiro Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Clinical Study Protocol 10.18926/AMO/55446 Although recent retrospective studies suggested that the use of ƒΐ-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of ƒΐ-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective ƒΐ-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 4 2016 Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation 243 253 EN Masahiro Osawa Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshio Kubo Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eiki Ichihara Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Saburo Takata Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nagio Takigawa Department of General Internal Medicine 4, Kawasaki Medical School Minoru Takata Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University Mitsune Tanimoto Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/54499 Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, pƒ0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1347-9032 103 10 2012 JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation 1795 1802 EN Daijiro Harada Nagio Takigawa Nobuaki Ochi Takashi Ninomiya Masayuki Yasugi Toshio Kubo Hiromasa Takeda Eiki Ichihara Kadoaki Ohashi Saburo Takata Mitsune Tanimoto Katsuyuki Kiura Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 612 similar to months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 312 similar to h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.(Cancer Sci, doi: 10.1111/j.1349-7006.2012.02363.x, 2012) No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1347-9032 104 1 2013 Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy 78 84 EN Toshio Kubo Nagio Takigawa Masahiro Osawa Daijiro Harada Takashi Ninomiya Nobuaki Ochi Eiki Ichihara Hiromichi Yamane Mitsune Tanimoto Katsuyuki Kiura Tumors are presumed to contain a small population of cancer stem cells (CSCs) that initiate tumor growth and promote tumor spreading. Multidrug resistance in CSCs is thought to allow the tumor to evade conventional therapy. This study focused on expression of CD133 and CD87 because CD133 is a putative marker of CSCs in some cancers including lung, and CD87 is associated with a stem-cell-like property in small-cell lung cancer (SCLC). Six SCLC cell lines were used. The expression levels of CD133 and CD87 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry. CD133+/- and CD87+/- cells were isolated by flow cytometry. The drug sensitivities were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Non-obese diabetic/severe combined immunodeficiency mice were used for the tumor formation assay. SBC-7 cells showed the highest expression levels of both CD133 and CD87 among the cell lines. CD133-/CD87-, CD133+/CD87-, and CD133-/CD87+ cells were isolated from SBC-7 cells; however, CD133+/CD87+ cells could not be obtained. Both CD133+/CD87- and CD133-/CD87+ subpopulations showed a higher resistance to etoposide and paclitaxel and greater re-populating ability than the CD133-/CD87- subpopulation. CD133+/CD87- cells contained more G0 quiescent cells than CD133-/CD87- cells. By contrast, CD133-/CD87- cells showed the highest tumorigenic potential. In conclusion, both CD133 and CD87 proved to be inadequate markers for CSCs; however, they might be beneficial for predicting resistance to chemotherapy. (Cancer Sci 2013; 104: 7884) No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1535-7163 10 9 2011 Liposomal Delivery of MicroRNA-7-Expressing Plasmid Overcomes Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistance in Lung Cancer Cells 1720 1727 EN Kammei Rai Nagio Takigawa Sachio Ito Hiromi Kashihara Eiki Ichihara Tatsuji Yasuda Kenji Shimizu Mitsune Tanimoto Katsuyuki Kiura Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR-7), targeting multiple sites in the 30-untranslated region of EGFR mRNA. Two EGFR-TKI-sensitive cell lines (PC-9 and H3255) and two EGFR-TKI-resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7-expressing plasmid. After transfection of the miR-7-expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR-7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC-9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7-expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7-expressing plasmids against EGFR oncogene-addicted lung cancers including T790M resistance by liposomal delivery. Mol Cancer Ther; 10(9); 1720-7. No potential conflict of interest relevant to this article was reported.

‰ͺŽRˆγŠw‰ο Acta Medica Okayama 0030-1558 124 3 2012 EGFRƒ`ƒƒVƒ“ƒLƒi[ƒ[‘jŠQ–ς‘ϐ«”xŠΰΧ–E‚Ι‘Ξ‚·‚ιmicroRNA-7”­Œ»ƒvƒ‰ƒXƒ~ƒh‚ΜƒŠƒ|ƒ\[ƒ€‚π—p‚’‚½“±“ό‚Ι‚ζ‚ιŽ•ž‚ΜŒŸ“’ 207 210 EN Kammei Rai Nagio Takigawa Sachio Ito Hiromi Kashihara Eiki Ichihara Tatsuji Yasuda Kenji Shimizu Mitsune Tanimoto Katsuyuki Kiura No potential conflict of interest relevant to this article was reported.