American Association for Cancer Research (AACR) Acta Medica Okayama 1078-0432 2026 Incidence of B-cell Malignancies in Patients with Lung Cancer Receiving PD-1 Blockade Therapy EN Toshifumi Ninomiya Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Caiyang Fang Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hirofumi Hamano Department of Pharmacy, Okayama University Hospital, Okayama University Teruya Morinaga Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Wenhao Zhou Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshihiro Koyama Department of Pharmaceutical Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Sakura Miki Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Li Zhu Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yusuke Naoi Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Ennishi Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoya Katsuta Department of Respiratory Medicine, Ehime Prefectural Central Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital, Okayama University Shin Morizane Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoka Ohki-Ikeda Department of Pathology, Okayama University Hospital, Okayama University Tatsuya Nishi Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Youki Ueda Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takamasa Ishino Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Isamu Okamoto Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University Yoshito Zamami Department of Pharmacy, Okayama University Hospital, Okayama University Joji Nagasaki Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yosuke Togashi Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Purpose: Many patients with various cancer types have received immune checkpoint inhibitors (ICI) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B-cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematologic malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies.<br> Experimental Design: We performed IHC staining on the clinical samples from patients with B-cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments.<br> Results: A higher incidence of B-cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). The identified lymphomas had a large amount of CD4+ T follicular helper (TFH) cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL4/IL4R, IL21/IL21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL4R, IL21R, and CD40.<br> Conclusions: Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings in which ICIs are used. No potential conflict of interest relevant to this article was reported.

Japanese Society for Medical and Biological Engineering Acta Medica Okayama 2187-5219 15 2026 Automatic Detection of Turning Over in Bed with Protection of Privacy Using Four Low-resolution Thermal Sensors to Support Nursing Care 265 271 EN Jyun-Jhe Chou Department of Computer Science and Information Engineering, National Taiwan University Kammei Rai 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 Mizuki Morita Department of Biomedical Informatics, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chi-Sheng Shih Graduate Institute of Networking and Multimedia, National Taiwan University Turning over in bed, especially turning over at night, is a vital human unconscious behavior. Clinically, this movement disperses pressure between the body and bed, thus preventing bedsores. Several devices, such as acceleration and pressure sensors, can count turning overs automatically; however, they often require installation on the patients or in the bed. The simplest and noninvasive method to count turning overs is to record and count on video images, but this method cannot protect privacy. Images obtained using thermal sensors have been used to protect privacy; however, there are no reports of counting turning overs automatically using low-resolution sensors. We developed a novel device equipped with four low-resolution thermal sensors, with each sensor recording only an 8×8-pixel thermal image. The original data can protect patient privacy because the resolution is only ~28.8×28.8 cm per body, which is the lowest resolution compared to previous reports using thermal images. Using four sensors simultaneously enables us to collect sufficient data for automatic identification. We first used the bilinear interpolation method employed in a previous report to count turning overs; however, the results were unsatisfactory because turning overs produced extremely subtle changes in the original data compared with postural changes such as falls. After several attempts, we finally developed a unique identification program that interleaved all data from four sensors and then identified turning overs using residual neural network-18. Using the new system, the accuracy, recall, and precision of counting turning overs in bed improved to approximately 90% with an acceptable computation load in an experiment conducted on volunteers. This study demonstrated the feasibility of our device to count turning overs in clinical settings by the new identification program using four 8×8-pixel thermal images per frame, which have sufficiently low resolution to protect patient privacy. No potential conflict of interest relevant to this article was reported.

American Association for Cancer Research (AACR) Acta Medica Okayama 2767-9764 6 2 2026 Clinical Characteristics and Spatial Transcriptome Analysis of Non–Small Cell Lung Cancers Exhibiting Early Alectinib Resistance: A Retrospective OLCSG Study 284 293 EN Tadahiro Kuribayashi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Go Makimoto Department of Respiratory Medicine, Okayama University Hospital Kadoaki Ohashi Department of Respiratory Medicine, Okayama University Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Hirofumi Inoue Center for Comprehensive Genomic Medicine, Okayama University Hospital Toshihide Yokoyama Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital Shoichi Kuyama Department of Respiratory Medicine, NHO Iwakuni Clinical Center Yuka Kato Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center Kenichiro Kudo Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Naokatsu Horita Department of Respiratory Medicine, Kure Kyosai Hospital Hiroe Kayatani Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital Masaaki Inoue Department of Chest Surgery, Shimonoseki City Hospital Keisuke Sugimoto Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital Kiichiro Ninomiya 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 Yosuke Togashi Department of Respiratory Medicine, Okayama University Hospital Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Some anaplastic lymphoma kinase (ALK) gene rearrangement–positive lung cancers show early resistance, within 3 months, to alectinib. This study investigated the clinical and molecular characteristics of these patients. We analyzed patients with unresectable stage III/IV disease without indications for radical radiotherapy and recurrent ALK-positive lung cancer who received alectinib as the primary ALK tyrosine kinase inhibitor between 2013 and 2021 at nine hospitals. In total, 103 patients were included. The median age was 65 years; 44 were male and 22 had brain metastases. The median progression-free survival and overall survival (OS) were 28.7 and 80.6 months. Nineteen patients treated for ≤3 months and 84 treated for >3 months were categorized into the early resistance and responder groups, respectively. The early resistance group had significantly shorter OS (8.4 months vs. not estimable, P < 0.001) and was significantly more likely to have brain metastases (42% vs. 17%, P = 0.027). They also showed elevated inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR). Univariate analysis identified brain metastases and high NLR as significant predictors of early resistance. Spatial transcriptome analysis and immunohistochemical staining revealed upregulation of annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein involved in inflammation and cancer progression, in the early resistance group. Interleukin 6 stimulation, prompted by elevated inflammatory markers, increased ANXA1 expression and reduced alectinib sensitivity. Knockdown of ANXA1 improved alectinib sensitivity in alectinib-resistant cells. In conclusion, brain metastases and high NLR are associated with early resistance. ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0041-1132 2026 Pediatric autologous peripheral blood stem cell collection without heparin using a highly concentrated sodium citrate anticoagulant: A retrospective comparison with standard ACD-A EN Keiko Fujii Department of Hematology, Okayama University Hospital Wataru Kitamura Department of Hematology, Okayama University Hospital Kana Washio Department of Pediatrics, Okayama University Hospital Kazuhiro Ikeuchi Department of Hematology, Okayama University Hospital Joji Shimono Department of Hematology, Okayama University Hospital Hiroyuki Murakami Department of Hematology, Okayama University Hospital Fumio Otsuka Division of Clinical Laboratory, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Okayama University Hospital Nobuharu Fujii Department of Hematology, Okayama University Hospital Background: Heparin combined with sodium citrate has been used in leukocytapheresis for pediatric patients. Since 2022, we have performed leukocytapheresis using a highly concentrated sodium citrate solution (HSC, 5.32%) instead of acid citrate dextrose solution A (ACD-A). We conducted this study to determine whether HSC use reduces run time and the total amount of anticoagulant solution in children.<br> Study Design and Methods: We retrospectively analyzed data from consecutive autologous peripheral blood stem cell harvests (auto-PBSCHs) between June 2012 and May 2025, including patient characteristics, mobilization methods, protocol used, anticoagulant type, run time, total anticoagulant solution volume, and collection efficiency.<br> Results: Auto-PBSCH was performed using the mononuclear cell collection (MNC) protocol in 28 procedures and the continuous MNC protocol in 20 procedures. ACD-A was used in 35 procedures and HSC in 13. The run time was significantly shorter (204 [range, 117–302] vs. 157 min [range, 103–227], p = .02) in the HSC group and also confirmed in multivariable regression analysis (coefficient, −55.6; 95% confidence interval, −106.2 to −5.04; p = .03). In a subgroup analysis of cMNC procedures, CD34+ collection efficiency showed a strong negative correlation with the proportion of run time devoted to establishing the initial interface (r = −.73, p = .0003).<br> Conclusion: Delays in establishing the initial interface can reduce the duration of the effective MNC collection phase and may negatively affect collection efficiency. Careful attention to the initial interface phase is therefore warranted when using HSC. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2772-5723 5 2 2026 Feasibility and Diagnostic Utility of Mucosal T-Cell Flow Cytometry for Intestinal Graft-Versus-Host Disease 100820 EN Masaya Iwamuro Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takumi Kondo Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Daisuke Ennishi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Nobuharu Fujii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Mai Hiramatsu Division of Medical Support, Okayama University Hospital Araki Hirabata Division of Medical Support, Okayama University Hospital Takahide Takahashi Division of Medical Support, Okayama University Hospital Takehiro Tanaka Department of Pathology, 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 Motoyuki Otsuka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Background and Aims: Timely diagnosis of intestinal complications after hematopoietic stem cell transplantation (HSCT), including graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy, and cytomegalovirus infection, is essential for appropriate management. This study evaluated whether mucosal T-cell profiling from endoscopic biopsies could support the diagnosis of these post-transplant conditions.<br> Methods: We prospectively analyzed 58 intestinal biopsy specimens from 21 post-HSCT patients. Paired samples were obtained from the stomach and duodenum during upper endoscopy and from the ileum and large intestine during colonoscopy. Lymphocytes were isolated from each specimen and analyzed using flow cytometry. These data were integrated with those of a previously collected cohort (35 patients, 51 samples) for comparative immunophenotypic analysis across histologically defined groups.<br> Results: Duodenal biopsies yielded more lymphocytes than did gastric biopsies (mean ± standard deviation: 532 ± 823 vs 233 ± 392 cells; P = .070), with comparable yields between the ileum and colon. Among 41 evaluable cases, the CD56+:CD3+ ratio was significantly lower in patients with GVHD (5.5 ± 2.2%) than in those with nonspecific or no inflammation (28.4 ± 16.3%; P = .006). A cutoff value of <11% provided 85.7% sensitivity and 83.3% specificity for diagnosing GVHD (area under the curve = 0.91).<br> Conclusion: Mucosal T-cell profiling using endoscopic biopsies is feasible and may aid in the diagnosis of GVHD after HSCT. A decreased CD56+:CD3+ ratio is a promising marker for distinguishing GVHD from other post-transplant intestinal conditions. No potential conflict of interest relevant to this article was reported.

Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 63 13 2024 Activated CD4+ T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy 1863 1872 EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Shuntaro Ikegawa Department of Hematology and Oncology, Okayama University Hospital, Japan Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Chihiro Kamoi Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Division of Clinical Laboratory, Okayama University Hospital Nobuharu Fujii Division of Blood Transfusion, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion.<br> Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022.<br> Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included.<br> Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4+CD25+CD127+ T cells (hereafter referred to as "activated CD4+ T cells" ) among the total CD4+ T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4+ T cells among the total CD4+ T cells <0.73 (p=0.01, and p<0.01, respectively).<br> Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 6 2025 Recurrence of FVIII Inhibitor during Surgery in a Patient with Severe Hemophilia A Receiving Emicizumab Prophylaxis 451 455 EN Moe Hagihara Department of Hematology and Oncology, Okayama University Hospital Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital Kenta Hayashino Department of Hematology and Oncology, Okayama University Hospital Takao Yasuhara Department of Neurological Surgery, Okayama University Hospital Kyohei Kin Department of Neurological Surgery, Okayama University Hospital Yuichi Hirata Department of Neurological Surgery, Okayama University Hospital Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Hospital Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Division of Transfusion and Cell Therapy, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Case Report 10.18926/AMO/69848 Emicizumab, a bispecific monoclonal antibody, benefits patients with severe hemophilia A. It alters laboratory assessments of coagulation activity, requiring anti-idiotype monoclonal antibodies for accurate monitoring. A 64-year-old man, receiving emicizumab regularly, was admitted for laminoplasty. We planned to use FVIII replacement during the perioperative period after confirming the disappearance of inhibitors, monitoring coagulation activity with anti-idiotype monoclonal antibodies. Activated partial thromboplastin time was prolonged on postoperative day 2, prompting an immediate switch to eptacog alfa. The patient recovered without bleeding. This case underscores the necessity of anti-idiotype monoclonal antibodies for accurate monitoring. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1473-0502 64 4 2025 Factors affecting the development of hypokalemia during apheresis in healthy donors 104195 EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Hospital Masaya Abe Department of Hematology and Oncology, Okayama University Hospital Takuya Fukumi Department of Hematology and Oncology, Okayama University Hospital Kazuhiro Ikeuchi Department of Hematology and Oncology, Okayama University Hospital Fumio Otsuka Division of Clinical Laboratory, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Despite being generally safe, apheresis for peripheral blood stem cell collection potentially disrupts electrolyte balance owing to the use of citric acid as an anticoagulant. As prior research has primarily studied hypocalcemia, information on the kinetics of potassium levels during apheresis in healthy donors is scarce. We investigated the fluctuation in potassium levels during apheresis and the risk factors for hypokalemia. This subanalysis used data from an open-label, randomized controlled trial of “oral calcium supplementation versus placebo in mitigating citrate toxicity” conducted between January 2021 and July 2022, at Okayama University Hospital. Potassium levels were significantly reduced after 5-day granulocyte colony-stimulating factor (G-CSF) administration (p < 0.0001), with seven patients (16.7 %) given oral potassium administration before apheresis because the treating physician deemed potassium levels potentially unsafe and three (7.1 %) presenting with hypokalemia at apheresis. Potassium levels after apheresis were significantly lower than those before apheresis (baseline; p < 0.0001), and 28 of 42 donors (66.7 %) experienced biochemical, clinically unapparent hypokalemia immediately after the completion of apheresis. A > 15 % reduction in potassium levels from baseline was associated with age and the acid citrate dextrose solution A (ACD-A) volume in univariate analysis. In the multivariable analysis, both factors were associated (hazard ratio [HR], 11.60; 95 % confidence interval [CI], 1.60–83.70; p = 0.02 and HR, 17.50; 95 % CI, 1.07–136.00; p = 0.04). In conclusion, G-CSF administration and apheresis ultimately induced hypokalemia in two-thirds of the donors. Older age and higher ACD-A volume may affect potassium levels during apheresis in healthy donors. 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 1473-0502 64 6 2025 Novel leukocytapheresis method using highly concentrated sodium citrate solution for the manufacturing of tisagenlecleucel 104265 EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Masaya Abe Department of Hematology and Oncology, Okayama University Hospital Kazuhiro Ikeuchi Department of Hematology and Oncology, Okayama University Hospital Kana Washio Department of Pediatrics, Okayama University Hospital Fumio Otsuka Division of Clinical Laboratory, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital For the manufacturing of tisagenlecleucel (tisa-cel) requires the non-mobilized mononuclear cell collection (MNC). CD3+ cell collection is performed using the same protocol as autologous peripheral blood stem cell harvest (auto-PBSCH), but this procedure necessitates the same target CD3+ cell yields regardless of age or body weight, which may take several days especially in pediatric and small female patients with low white blood cell counts. We previously demonstrated a novel method using highly concentration sodium citrate (HSC), which reduced the need for an anticoagulant (AC) solution and shortened the procedure time in auto-PBSCH. This novel method was expected to offer advantages for smaller patients, prompting us to investigate its application in leukocytapheresis for the manufacturing of tisa-cel. We retrospectively analyzed consecutive leukocytapheresis data obtained using Spectra Optia continuous MNC mode between November 2022 and June 2024 at our institution (n = 9). In six of nine patients, pre-leukocytapheresis CD3+ cell counts were less than 500 /μL, but all could obtain the target CD3+ cell yields in one day upon processing blood volume adjustment. When we compared patients who had received CD3+ cell collection using normal-concentration sodium citrate (NSC) as our previously reported using propensity score-matched pair analysis, the total AC solution volume was significantly lower (1168 vs. 316 mL, p < 0.001) and procedure time was significantly shorter (254 vs. 228 min, p = 0.04) in the HSC group compared to the NSC group. In conclusion, this procedure was also useful for non-mobilized MNC. Our findings warrant validation in a larger patient cohort. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0041-1132 65 9 2025 Novel method for autologous peripheral blood stem cell harvest using highly concentrated sodium citrate solution replacing acid citrate dextrose solution A 1662 1672 EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Masaya Abe Department of Hematology and Oncology, Okayama University Hospital Kazuhiro Ikeuchi Department of Hematology and Oncology, Okayama University Hospital Joji Shimono Department of Hematology and Oncology, Okayama University Hospital Kana Washio Department of Pediatrics, Okayama University Hospital Fumio Otsuka Division of Clinical Laboratory, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Background: As the processed blood volume increases, a larger amount of anticoagulant (AC) is required, which leads to a serious issue of fluid dilution in large-volume leukocytapheresis (defined as ≥3-fold total blood volume). We previously reported a novel method for allogeneic peripheral blood stem cell harvest (PBSCH) using highly concentrated sodium citrate (HSC; 5.32%), which shortened the procedure time and reduced the need for an AC solution without heparin. In this study, we extended this novel method to autologous PBSCH (auto-PBSCH) and compared it with patients who received auto-PBSCH using normal concentrated sodium citrate (NSC; 2.2%).<br> Study Design and Methods: We retrospectively analyzed consecutive auto-PBSCH data obtained using the Spectra Optia continuous mononuclear cell collection mode between May 2017 and May 2025 at our institution.<br> Results: Leukocytapheresis was performed using NSC in 36 patients and HSC in 22. In the HSC group, patients tended to be younger, had significantly lower body weight, and had significantly fewer hematopoietic tumors as primary diseases compared to the NSC group. After propensity score-matched cohort adjusted for patient background, the total amount of AC solution was significantly lower (694 [range, 77–1648] vs. 298 mL [range, 64–797], p = .02), and procedure time was significantly shorter (224 [range, 117–395] vs. 181 min [range, 103–309], p = .048) in the HSC group. Furthermore, the loss rates of magnesium and potassium were lower in the HSC group.<br> Conclusion: This novel leukocytapheresis method demonstrated the efficacy and safety in auto-PBSCH, while minimizing the patient burden. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0925-5710 122 5 2025 Cytomegalovirus reactivation in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy 689 699 EN Kenta Hayashino Department of Hematology and Oncology, Okayama University Keisuke Seike Department of Hematology and Oncology, Okayama University Taro Masunari Department of Hematology, Chugoku Central Hospital Risa Hashida Division of Hematology, Ehime Prefectural Central Hospital Satoshi Oka Department of Hematology and Blood Transfusion, Kochi Health Science Center Yuki Fujiwara Department of Hematology and Oncology, Japanese Red Cross Society Himeji Hospital Toshiki Terao Department of Hematology and Oncology, Okayama University Wataru Kitamura Department of Hematology and Oncology, Okayama University Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Chihiro Kamoi Department of Hematology and Oncology, Okayama University Takumi Kondo Department of Hematology and Oncology, Okayama University Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Noboru Asada Department of Hematology and Oncology, Okayama University Daisuke Ennishi Department of Hematology and Oncology, Okayama University Keiko Fujii Department of Hematology and Oncology, Okayama University Nobuharu Fujii Department of Hematology and Oncology, Okayama University Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes of relapsed and/or refractory large B-cell lymphoma (r/r LBCL). However, its off-tumor effects result in severe prolonged humoral immune deficiency. Cytomegalovirus (CMV) is a latent virus that can be life-threatening in immunosuppressed patients. In the setting of CAR T-cell therapy, Asian race is a risk factor for clinically significant CMV infection. However, the effect of CAR T-cell therapy on CMV reactivation in Japanese patients remains unclear. Previous reports used polymerase chain reaction (PCR), but we used the pp65 antigenemia assay to retrospectively investigate long-term effects in patients with r/r LBCL. The study included 46 patients. Nine (19.6%) developed CMV reactivation, with a median onset of 13 days. Six of these patients received preemptive therapy, and none developed CMV end-organ disease. Primary refractory disease, grade 2–4 cytokine release syndrome, and high-dose corticosteroids were risk factors for CMV reactivation. Long-term follow-up showed that CMV reactivation rarely occurred later than 28 days post-infusion. Our study using the pp65 antigenemia assay showed a similar incidence of CMV reactivation, onset, and risk factors to those in the previous reports using PCR. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2688-6146 6 5 2025 Late‐Onset Invasive Aspergillosis With Pituitary Involvement and Dysfunction Following CD19 Chimeric Antigen Receptor T‐Cell Therapy e70138 EN Daisuke Ikeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomohiro Nawada The Center for Graduate Medical Education, Okayama University Hospital Takumi Kondo Department of Hematology and Oncology, Okayama University Hospital Takayuki Shinohara Department of Fungal Infection, National Institute of Infectious Diseases Tomohiro Nagano Department of Hematology and Oncology, Okayama University Hospital Saya Kubota Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryuichiro Hiyama Department of Hematology and Oncology, Okayama University Hospital Masaya Ueno Department of Hematology and Oncology, Okayama University Hospital Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Hospital Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Masanori Makita Department of Hematology, Chugoku Central Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Introduction: Invasive fungal infection (IFI) after chimeric antigen receptor (CAR) T-cell therapy is less common than bacterial and viral infections, but can be fatal once it develops. As most cases occur within 30 days after CAR T-cell infusion, late-onset IFI―particularly mould infection―appears to be under-recognised.<br> Discussion: We report an illustrative case of pituitary aspergillosis developing as late as one year after CD19 CAR T-cell therapy, highlighting a persistent risk in certain patients with delayed immune reconstitution.<br> Conclusion: This case underscores the need for continued vigilance and individualised antifungal strategies to prevent IFI beyond the early post-infusion period.<br> Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 64 4 2024 Computed tomography findings of idiopathic multicentric Castleman disease subtypes 292 296 EN Toshihiro Iguchi Department of Radiological Technology, Faculty of Health Sciences, Okayama University Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Noriko Iwaki Department of Hematology, National Cancer Center Hospital Katsuhide Kojima Department of Radiology, Okayama University Hospital Takashi Asahara Department of Radiological Technology, Faculty of Health Sciences, Okayama University Fumio Otsuka Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takao Hiraki Department of Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University This study retrospectively evaluated the computed tomography (CT) findings of idiopathic multicentric Castleman disease (iMCD) at a single center and compared the CT findings of iMCD-TAFRO with those of iMCD-non-TAFRO. CT images obtained within 30 days before diagnostic confirmation were reviewed for 20 patients with iMCD (8 men and 12 women, mean age 52.8 ± 12.3 years, range 25–74 years). Twelve patients were diagnosed with iMCD-TAFRO, five with iMCD-idiopathic plasmacytic lymphadenopathy, and three with iMCD-not otherwise specified. CT images revealed anasarca and lymphadenopathy in all 20 patients. The iMCD-TAFRO group showed significantly higher frequencies of ascites (100% vs. 37.5%, P = 0.004), gallbladder wall edema (75.0% vs. 12.5%, P = 0.020), periportal collar (91.7% vs. 25.0%, P = 0.004), and anterior mediastinal lesions (non-mass-forming infiltrative lesions) (66.7% vs. 12.5%, P = 0.028). Para-aortic edema tended to be more frequent in patients with the iMCD-TAFRO group (83.3% vs. 37.5%, P = 0.062), while the absence of anterior mediastinal lesions tended to be more frequent in the iMCD-non-TAFRO group (16.7% vs. 62.5%, P = 0.062). These CT findings may have clinical implications for improving the accuracy and speed of iMCD diagnosis and differentiating iMCD-TAFRO from other subtypes. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0925-5710 121 2 2024 Outcomes of allogeneic SCT versus tisagenlecleucel in patients with R/R LBCL and poor prognostic factors 232 243 EN Kenta Hayashino Department of Hematology and Oncology, Okayama University Hospital, Okayama University Toshiki Terao Department of Hematology and Oncology, Okayama University Hospital, Okayama University Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital, Okayama University Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital, Okayama University Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Hospital, Okayama University Chihiro Kamoi Department of Hematology and Oncology, Okayama University Hospital, Okayama University Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital, Okayama University Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital, Okayama University Noboru Asada Department of Hematology and Oncology, Okayama University Hospital, Okayama University Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital, Okayama University Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital, Okayama University Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital, Okayama University Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital, Okayama University Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital, Okayama University This study investigated the efficacy of tisagenlecleucel (tisa-cel) and allogeneic hematopoietic stem cell transplantation (allo-SCT) for patients with relapsed and/or refractory (r/r) large B-cell lymphoma (LBCL) with poor prognostic factors, defined as performance status (PS) ≥ 2, multiple extranodal lesions (EN), chemorefractory disease, or higher lactate dehydrogenase (LDH). Overall, the allo-SCT group demonstrated worse progression-free survival (PFS), higher non-relapse mortality, and a similar relapse/progression rate. Notably, the tisa-cel group showed better PFS than the allo-SCT group among patients with chemorefractory disease (3.2 vs. 2.0 months, p = 0.092) or higher LDH (4.0 vs. 2.0 months, p = 0.018), whereas PFS in the two cellular therapy groups was similar among those with PS ≥ 2 or multiple EN. Survival time after relapse post-cellular therapy in patients with poor prognostic factors was 1.6 with allo-SCT and 4.6 months with tisa-cel. These findings were confirmed in a propensity score matching cohort. In conclusion, tisa-cel resulted in better survival than allo-SCT in patients with poor prognostic factors. However, patients who relapsed post-cellular therapy had dismal outcomes regardless of therapy. Further strategies are warranted to improve outcomes in these patients. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0041-1132 2025 Novel method of leukocytapheresis using a highly concentrated sodium citrate solution alternative to acid citrate dextrose solution A EN Masaya Abe Division of Transfusion and Cell Therapy, Okayama University Hospital Keiko Fujii Division of Clinical Laboratory, Okayama University Hospital Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Wataru Kitamura Division of Transfusion and Cell Therapy, Okayama University Hospital Kazuhiro Ikeuchi Division of Transfusion and Cell Therapy, Okayama University Hospital Takuya Fukumi Division of Transfusion and Cell Therapy, Okayama University Hospital Kana Washio Department of Pediatric Hematology and Oncology, Okayama University Hospital Fumio Otsuka Division of Clinical Laboratory, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Division of Transfusion and Cell Therapy, Okayama University Hospital Background: Large-volume leukocytapheresis is time consuming. The upper limit of the inlet flow rate is determined by the inlet: anticoagulant (AC) ratio and can be changed by combining the AC with heparin. Here, we devised a protocol to increase the AC ratio using a highly concentrated sodium citrate solution without heparin.<br> Study Design and Methods: We collected data from 40 consecutive apheresis procedures performed using the Spectra Optia system on 40 donors for allogeneic peripheral blood stem cells between June 2022 and June 2023. We used AC containing 2.2% sodium citrate (normal concentrated sodium citrate [NSC]) and 5.32% sodium citrate (highly concentrated sodium citrate [HSC]). The AC ratios were set to 12:1 and 24:1 for the NSC and HSC, respectively.<br> Results: The processed volume was not different; the maximum inlet flow rate increased, the total processing time was reduced, the AC solution used was reduced, and the product volume was reduced in the HSC group, compared to the NSC group. Although the CD34+ cell CE2 was reduced in the HSC group, no difference was observed in the number of collected CD34+ cells. The incidences of citrate-related reactions were similar.<br> Discussion: We propose a novel leukocytapheresis method using HSC that shortens the procedure time and reduces the amount of AC solution used compared to the conventional method No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 116 5 2025 High Antigenicity for Treg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in Treg Cells 1214 1226 EN Hiroaki Matsuura Department of Tumor Microenvironment, Okayama University Takamasa Ishino Department of Tumor Microenvironment, Okayama University Toshifumi Ninomiya Department of Tumor Microenvironment, Okayama University Kiichiro Ninomiya Department of Hematology, Oncology and Respiratory Medicine,Okayama University Kota Tachibana Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Akiko Honobe-Tabuchi Department of Dermatology, University of Yamanashi Yoshinori Muto Department of Dermatology, University of Yamanashi Takashi Inozume Department of Dermatology, University of Yamanashi Youki Ueda Department of Tumor Microenvironment, Okayama University Kadoaki Ohashi Department of Hematology, Oncology and Respiratory Medicine,Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine,Okayama University Joji Nagasaki Department of Tumor Microenvironment, Okayama University Yosuke Togashi Department of Tumor Microenvironment, Okayama University Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in Treg cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that Treg cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for Treg cells were resistant to PD-1 blockade in vivo due to PD-1+ Treg-cell infiltration. Because such PD-1+ Treg cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high Treg cell infiltration. We propose that the high antigenicity of Treg cells confers resistance to PD-1 blockade therapy via high PD-1 expression in Treg cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb. 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.

Springer Science and Business Media LLC Acta Medica Okayama 0941-4355 33 4 2025 Characteristics of oral mucositis in patients undergoing haploidentical stem cell transplantation with posttransplant cyclophosphamide: marked difference between busulfan and melphalan regimens 252 EN Saki Ogura Division of Dental Hygienist, Okayama University Hospital Yoshihiko Soga Division of Hospital Dentistry, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Rumi Miura Division of Dental Hygienist, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology, Oncology and Respiratory Medicine, 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 Takuo Kuboki Division of Dental Hygienist, Okayama University Hospital Purpose This study was performed to examine the effects of conditioning regimens on oral mucositis in haploidentical (haplo) donor hematopoietic stem cell transplantation (HSCT) with posttransplant cyclophosphamide (PTCy).<br> Methods Thirty consecutive patients (male, 23; female, 7; 18–68 years, median, 59 years) undergoing haplo-HSCT with PTCy using one of three conditioning regimens―reduced intensity conditioning (RIC)-melphalan (Mel); RIC-Busulfan (Bu); and myeloablative conditioning (MAC)-Bu―were enrolled in this study. Data on the WHO grade of oral mucositis (day − 7 to + 20) were collected retrospectively. The incidences of ulcerative and severe mucositis (Grade 2–4 and Grade 3–4, respectively) were compared between the three groups.<br> Results Ulcerative mucositis occurred in 0% (0/10) of patients in the RIC-Mel group, 57.1% (4/7) in the RIC-Bu group, and 100% (13/13) in the MAC-Bu group. The differences between the RIC-Mel and RIC-Bu groups and between the RIC-Bu and MAC-Bu groups were significant (all P < 0.05). Severe mucositis occurred in 57.1% (4/7) of patients in the RIC-Bu group and 100% (13/13) of patients in the MAC-Bu group, and the difference was significant (P < 0.05). The rates of ulcerative mucositis (≥ grade 2) and of severe mucositis (≥ grade 3) were significantly higher in the MAC-Bu group than the RIC-Bu group on days 10, 13, 15, and 16 and on days 10, 14, 15, and 16, respectively (all P < 0.05).<br> Conclusion The risk of oral mucositis in patients undergoing haplo-HSCT with PTCy is highest with the MAC-Bu conditioning regimen, followed by RIC-Bu, and lowest with RIC-Mel. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0939-5555 2025 A randomized controlled trial of conventional GVHD prophylaxis with or without teprenone for the prevention of severe acute GVHD EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Mitsuru Tsuge Department of Pediatric Acute Diseases, Okayama University Academic Field of Medicine Dentistry, and Pharmaceutical Sciences Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Hospital Chihiro Kamoi Department of Hematology and Oncology, Okayama University Hospital Akira Yamamoto Department of Hematology and Oncology, Okayama University Hospital Takumi Kondo Department of Hematology and Oncology, Okayama University Hospital Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Therapies that effectively suppress graft-versus-host disease (GVHD) without compromising graft-versus-leukemia/lymphoma (GVL) effects is important in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic malignancies. Geranylgeranylacetone (GGA) is a main component of teprenone, a gastric mucosal protectant commonly used in clinical practice. In preclinical models, GGA suppresses proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), which are associated with GVHD as well as induces thioredoxin-1 (Trx-1), which suppresses GVHD while maintaining GVL effects. Here, we investigated whether the addition of teprenone to standard GVHD prophylaxis could reduce the cumulative incidence of severe acute GVHD (aGVHD) without attenuating GVL effects. This open-label, randomized clinical trial enrolled 40 patients (21 control and 19 teprenone group) who received allo-HSCT between May 2022 and February 2023 in our institution. Patients in the teprenone group received 50 mg of teprenone orally thrice daily for 21 days from the initiation of the conditioning regimen. The cumulative incidence of severe aGVHD by day 100 after allo-HSCT was not significantly different in the two groups (27.9 vs. 16.1%, p = 0.25). The exploratory studies revealed no obvious changes in Trx-1 levels, but the alternations from baseline in IL-1β and TNF-α levels at day 28 after allo-HSCT tended to be lower in the teprenone group. In conclusion, we could not demonstrate that teprenone significantly prevented the development of severe aGVHD. Discrepancy with preclinical model suggests that appropriate dose of teprenone may be necessary to induce the expression of antioxidant enzymes that suppress severe aGVHD. Clinical Trial Registration number:jRCTs 061210072. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0361-8609 96 10 2021 Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease 1241 1252 EN Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences David C. Fajgenbaum Center for Cytokine Storm Treatment & Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Sheila K. Pierson Center for Cytokine Storm Treatment & Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Noriko Iwaki Hematology/Respiratory Medicine, Kanazawa University Graduate School of Medical Science Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Mitsuhiro Kawano Department of Rheumatology, Kanazawa University Graduate School of Medical Science Naoya Nakamura Department of Pathology, Tokai University School of Medicine Koji Izutsu Department of Hematology, National Cancer Center Hospital Kengo Takeuchi Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research Midori Filiz Nishimura Department of Pathology, 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 Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuyuki Yoshizaki Department of Organic Fine Chemicals, Institute of Scientific and Industrial Research, Osaka University Eric Oksenhendler Department of Clinical Immunology, Hôpital Saint-Louis Frits van Rhee Myeloma Center, University of Arkansas for Medical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword “TAFRO” to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO. 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.

Springer Science and Business Media LLC Acta Medica Okayama 2192-3183 14 1 2024 Successful immunotherapy with ipilimumab and nivolumab in a patient with pulmonary sclerosing pneumocytoma 60 63 EN Yumi Inukai-Motokura Department of Allergy and Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Allergy and Respiratory Medicine, Okayama University Hospital Takahiro Baba Department of Allergy and Respiratory Medicine, Okayama University Hospital Hiroki Omori Department of Allergy and Respiratory Medicine, Okayama University Hospital Tetsuya Takeguchi Department of Allergy and Respiratory Medicine, Okayama University Hospital Mari Uno Department of Allergy and Respiratory Medicine, Okayama University Hospital Yoshiyuki Ayada Department of Pathology, Okayama University Hospital Takehiro Tanaka Department of Pathology and Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Pulmonary sclerosing pneumocytoma (PSP) is a rare form of lung cancer that occasionally presents with lymph node and extrapulmonary metastases, and multiple lesions. The treatment of metastatic PSP remains undefined. This study reports the case of a 48-year-old female patient diagnosed with PSP following surgical intervention for a solitary nodule in the left lower lobe. Four years later, recurrence occurred in the left hilar and mediastinal lymph nodes, necessitating an additional resection. Concurrently, sacral metastases developed and required palliative radiotherapy. Genetic analysis identified an AKT1 E17K mutation, characteristic of PSP, and absence of programmed cell death ligand 1 (PD-L1) expression in the tumor. Two years post-recurrence, the tumor recurred in the left mammary gland and mediastinal lymph nodes. Combination immunotherapy with ipilimumab and nivolumab yielded a significantly positive response in this metastatic PSP case. This is the first reported case of successful treatment of multiple distant metastatic PSP with ipilimumab and nivolumab, following the failure of various local treatments. Further case series are warranted to validate the efficacy of immunotherapy in metastatic PSP. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2077-0383 13 22 2024 The Clinical Significance of Interstitial Pneumonia with Autoimmune Features in Cryptogenic Organizing Pneumonia: A Prospective Multicenter Observational Study 6870 EN Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Yukako Arakawa Department of Respiratory Medicine, KKR Takamatsu Hospital Yoshihiro Mori Department of Respiratory Medicine, KKR Takamatsu Hospital Tomoki Tamura Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center Shoichi Kuyama Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center Chiaki Matsumoto Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital Keisuke Sugimoto Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital Noboru Hamada Department of Respiratory Medicine, Okayama City Hospital Toshimitsu Suwaki Department of Respiratory Medicine, Okayama City Hospital Junko Itano Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Yasushi Tanimoto Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Satoru Senoo Department of Respiratory Medicine, Fukuyama Medical Center Akihiko Taniguchi Department of Respiratory Medicine, Fukuyama Medical Center Yumi Inukai Department of Allergy and Respiratory Medicine, Okayama University Hospital Machiko Arita Department of Respiratory Medicine, Kurashiki Central Hospital Satoko Makimoto Department of Radiology, Okayama University Hospital Katsuhide Kojima Department of Radiology, Okayama University Hospital Takashi Matsushita Department of Dermatology, Kanazawa University Graduate School of Medical Science 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 Background: There are cases of idiopathic interstitial pneumonias (IIPs) that do not meet the diagnostic criteria for connective tissue disease but have clinical features suggestive of autoimmune process. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept for these patients. Although several prospective studies on IPAF have been conducted, its clinical significance in cryptogenic organizing pneumonia (COP) remains unclear. Methods: Patients aged >= 20 years with suspected COP were prospectively enrolled between June 2018 and December 2022. Among the enrolled patients, those diagnosed with COP based on computed tomography (CT) and bronchoalveolar lavage (BAL) findings were compared between the IPAF and non-IPAF groups. Results: A total of 56 patients were enrolled in this study. Of these, 30 were diagnosed with COP and included in the analysis. Clinical and serological features were positive in two and six patients, respectively. Each feature was exclusive, and eight patients (26.7%) were diagnosed with IPAF. There were no differences between the IPAF and non-IPAF groups in terms of clinical features, including BAL findings, laboratory data, CT findings, and clinical course. During the one-year follow-up period, the frequency of COP exacerbation did not differ between the IPAF and non-IPAF groups, and no cases of systemic autoimmune disease or death occurred in either group. Conclusions: The COP characteristics of the IPAF and non-IPAF groups are similar in all aspects, and distinguishing between the two groups may be of little significance. 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.

JMIR Publications Acta Medica Okayama 2369-3762 10 2024 Enhancing Medical Interview Skills Through AI-Simulated PatientInteractions:Nonrandomized Controlled Trial e58753 EN Akira Yamamoto Department of Hematology and Oncology, Okayama University Hospital Masahide Koda Co-learning Community Healthcare Re-innovation Office, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroko Ogawa Department of Primary Care and Medical Education, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Tomoko Miyoshi Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideo Ino Center for Education in Medicine and Health Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background: Medical interviewing is a critical skill in clinical practice, yet opportunities for practical training are limited in Japanese medical schools, necessitating urgent measures. Given advancements in artificial intelligence (AI) technology, its application in the medical field is expanding. However, reports on its application in medical interviews in medical education are scarce. <br> Objective: This study aimed to investigate whether medical students' interview skills could be improved by engaging with Al-simulated patients using large language models, including the provision of feedback. <br> Methods: This nonrandomized controlled trial was conducted with fourth-year medical students in Japan. A simulation program using large language models was provided to 35 students in the intervention group in 2023, while 110 students from 2022 who did not participate in the intervention were selected as the control group. The primary outcome was the score on the Pre-Clinical Clerkship Objective Structured Clinical Examination (pre-CC OSCE), a national standardized clinical skills examination, in medical interviewing. Secondary outcomes included surveys such as the Simulation-Based Training Quality Assurance Tool (SBT-QA10), administered at the start and end of the study. <br> Results: The Al intervention group showed significantly higher scores on medical interviews than the control group (Al group vs control group: mean 28.1, SD 1.6 vs 27.1, SD 2.2; P=.01). There was a trend of inverse correlation between the SBT-QA10 and pre-CC OSCE scores (regression coefficient-2.0 to-2.1). No significant safety concerns were observed. <br> Conclusions: Education through medical interviews using Al-simulated patients has demonstrated safety and a certain level of educational effectiveness. However, at present, the educational effects of this platform on nonverbal communication skills are limited, suggesting that it should be used as a supplementary tool to traditional simulation education. 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.

Elsevier BV Acta Medica Okayama 2212-5345 62 5 2024 A randomized, open-label phase II study on the preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: The OLCSG2101 study protocol 897 900 EN Naoki Nakamura Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Go Makimoto Department of Allergy and Respiratory Medicine, Okayama University Hospital Takaaki Tanaka Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Kato Center of Innovative Clinical Medicine, Okayama University Hospital Isao Oze Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute Toshiyuki Kozuki Department of Respiratory Medicine, Shikoku Cancer Center Toshihide Yokoyama Department of Respiratory Medicine, Kurashiki Central Hospital Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Shoichi Kuyama Department of Respiratory Medicine, Iwakuni Clinical Center Naofumi Hara Department of Respiratory Medicine, Okayama Rosai Hospital Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Hotta Center of Innovative Clinical Medicine, Okayama University Hospital Background: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX.<br> Methods: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled.<br> Discussion: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL.<br> Ethics and dissemination: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences.<br> Trial registration: Japan Registry of Clinical Trials (registration number jRCTs061210047). 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.

Wiley Acta Medica Okayama 2688-6146 5 4 2024 Combination of reduced post-transplant cyclophosphamide and early tacrolimus initiation increases the incidence of chronic graft-versus-host disease in human leukocyte antigen-haploidentical peripheral blood stem-cell transplantation 810 814 EN Toshiki Terao Department of Hematology and Oncology, Okayama University Hospital Takumi Kondo Department of Hematology and Oncology, Okayama University Hospital Makoto Nakamura Department of Hematology and Oncology, Okayama University Hospital Hiroki Takasuka Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital We evaluated the clinical impacts of the concurrent modification of post-transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)-initiation timing in 61 patients with human leukocyte antigen-haploidentical transplantation. Reduced-dose PTCy (80 mg/kg) was associated with a higher incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) than standard-dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early-initiation Tac (day -1) increased moderate-to-severe chronic GVHD than standard-initiation Tac (day 5) in the reduced-dose PTCy group (p = 0.032), whereas Tac-initiation timing did not impact chronic GVHD in the standard-dose PTCy group. These data indicate that the combination of reduced-dose PTCy and early-initiation Tac can amplify chronic GVHD. 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.

Springer Science and Business Media LLC Acta Medica Okayama 0925-5710 120 1 2024 Spontaneous regression of multiple solitary plasmacytoma harboring Epstein–Barr virus: a case report and literature review 128 134 EN Wataru Kitamura Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Hiroki Kobayashi Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Minori Noda Department of Otorhinolaryngology, National Hospital Organization Iwakuni Clinical Center Akiko Iseki Department of Pathology, National Hospital Organization Iwakuni Clinical Center Yumi Sato Department of Pathology, National Hospital Organization Iwakuni Clinical Center Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Shoichi Kuyama Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center We report a rare case of spontaneous regression (SR) in an elderly untreated patient with multiple solitary plasmacytoma (MSP). Diagnosis of MSP was confirmed through surgical resection of the left nasal cavity mass and subsequent biopsy of the right humerus. The patient was considered ineligible for chemotherapy due to poor performance status. At 3-month post-diagnosis, the patient’s condition worsened with deteriorating bone lesions and emergence of a new serum monoclonal protein. However, these clinical findings completely disappeared at 6 months, and positron emission tomography–computed tomography at 1 year confirmed complete metabolic remission. Notably, peripheral blood lymphocyte counts were inversely correlated with tumor progression and remission. Pathological re-evaluation of the initial biopsy specimens revealed programmed cell death protein 1 (PD-1) expression in tumor-infiltrating CD8+ T cells. In addition, tumor cells were infected with Epstein–Barr virus (EBV) but were negative for programmed cell death ligand 1 (PD-L1) expression, which is the most potent immune escape mechanism in tumor cells. While the mechanism underlying SR remains unclear, our findings suggest that host immune response as well as EBV infection may contribute to SR. Further studies are needed to elucidate the clinicopathologic mechanisms of tumor regression in plasma cell neoplasms. 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.

Okayama University Medical School Acta Medica Okayama 0386-300X 78 2 2024 Sigle Agent of Posttransplant Cyclophosphamide Without Calcineurin Inhibitor Controls Severity of Experimental Chronic GVHD 123 134 EN Kyosuke Saeki Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital Taiga Kuroi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuharu Fujii Division of Transfusion, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/66915 Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis remains unclear. Recently, haplo-identical HCT with post-transplant cyclophosphamide (Haplo-HCT with PTCY) was found to achieve a low incidence rate of acute GVHD and chronic GVHD. However, while the pathogenesis of acute GVHD following Haplo-HCT with PTCY has been well investigated, that of chronic GVHD remains to be elucidated, especially in HLA-matched HCT with PTCY. Based on its safety profile, PTCY is currently applied for the human leucocyte antigen (HLA)-matched HCT setting. Here, we investigated the mechanisms of chronic GVHD following HLA-matched HCT with PTCY using a well-defined mouse chronic GVHD model. PTCY attenuated clinical and pathological chronic GVHD by suppressing effector T-cells and preserving regulatory T-cells compared with a control group. Additionally, we demonstrated that cyclosporine A (CsA) did not show any additional positive effects on attenuation of GVHD in PTCY-treated recipients. These results suggest that monotherapy with PTCY without CsA could be a promising strategy for the prevention of chronic GVHD following HLA-matched HCT. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 78 2 2024 The Roles of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response 95 106 EN Junko Itano 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 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 Review 10.18926/AMO/66912 The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 115 4 2024 Antitumor activity of α-pinene in T-cell tumors 1317 1332 EN 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 Maiko Kimura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chie Fukui Division of Hematology, Department of Medicine, Kobe University Hospital Daisuke Yamada Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ziyi Wang Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masayuki Miyake Division of Medical Support, Okayama University Hospital Takeshi Takarada Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mitsuaki Ono Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michinori Aoe Division of Medical Support, Okayama University Hospital Wataru Kitamura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masayuki Matsuda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Moriyama Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akifumi Matsumura 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 T-cell acute leukemia and lymphoma have a poor prognosis. Although new therapeu-tic agents have been developed, their therapeutic effects are suboptimal. α- Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic ma-lignancies. This report provides a comprehensive analysis of the potential benefits of using α- pinene as an antitumor agent for the treatment of T-cell tumors. We found that α- pinene inhibited the proliferation of hematologic malignancies, especially in T- cell tumor cell lines EL-4 and Molt-4, induced mitochondrial dysfunction and re-active oxygen species accumulation, and inhibited NF-κB p65 translocation into the nucleus, leading to robust apoptosis in EL-4 cells. Collectively, these findings suggest that α- pinene has potential as a therapeutic agent for T-cell malignancies, and further investigation is warranted. No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 63 4 2023 Sutimlimab suppresses SARS-CoV-2 mRNA vaccine-induced hemolytic crisis in a patient with cold agglutinin disease 246 250 EN Hiroki Kobayashi Department of Internal Medicine, Tsuyama Chuo Hospital Tomoki Ouchi Department of Internal Medicine, Tsuyama Chuo Hospital Wataru Kitamura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shoji Asakura Department of Internal Medicine, Okayama Rosai Hospital Tomofumi Yano Department of Internal Medicine, Okayama Rosai Hospital Hiromasa Takeda Department of Internal Medicine, Tsuyama Chuo Hospital Yoshiyuki Tokuda Department of Internal Medicine, Tsuyama Chuo Hospital Tadashi Yoshino Department of Pathology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations. No potential conflict of interest relevant to this article was reported.

American Society of Hematology Acta Medica Okayama 2473-9529 7 24 2023 Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study 7459 7470 EN Tomohiro Urata Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Naoi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Aixiang Jiang British Columbia Cancer, Centre for Lymphoid Cancer Merrill Boyle British Columbia Cancer, Centre for Lymphoid Cancer Kazutaka Sunami Department of Hematology, NHO Okayama Medical Center Toshi Imai Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Yuichiro Nawa Division of Hematology, Ehime Prefectural Central Hospital Yasushi Hiramatsu Department of Hematology and Oncology, Japanese Red Cross Society Himeji Hospital Kazuhiko Yamamoto Department of Hematology and Oncology, Okayama City Hospital Soichiro Fujii Department of Hematology, Japanese Red Cross Okayama Hospital Isao Yoshida Department of Hematologic Oncology, NHO Shikoku Cancer Center Tomofumi Yano Department of Internal Medicine, Okayama Rosai Hospital Ryota Chijimatsu Center for Comprehensive Genomic Medicine, Okayama University Hospital Hiroyuki Murakami Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Ikeuchi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroki Kobayashi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuma Tani Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideki Ujiie Center for Comprehensive Genomic Medicine, Okayama University Hospital Hirofumi Inoue Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Akira Yamamoto Department of Hematology and Oncology, Okayama University Hospital Takumi Kondo Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Keisuke Sawada Department of Pathology, Saitama Medical Center, Saitama Medical University Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Jun-ichi Tamaru Department of Pathology, Saitama Medical Center, Saitama Medical University Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences David W. Scott British Columbia Cancer, Centre for Lymphoid Cancer Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell–like (GCB) DLBCL, activated B-cell–like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas. 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 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.

MDPI Acta Medica Okayama 2077-0383 12 16 2023 Switching to Dupilumab from Other Biologics without a Treatment Interval in Patients with Severe Asthma: A Multi-Center Retrospective Study 5174 EN Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Yukako Arakawa Department of Respiratory Medicine, KKR Takamatsu Hospital Yoshihiro Mori Department of Respiratory Medicine, KKR Takamatsu Hospital Junko Itano Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Akihiko Taniguchi Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Satoru Senoo Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Goro Kimura Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Yasushi Tanimoto Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Kohei Miyake Department of Respiratory Medicine, National Hospital Organization Himeji Medical Center Tomoya Katsuta Department of Respiratory Medicine, Ehime Prefectural Central Hospital Mikio Kataoka Department of Respiratory Medicine, Onomichi Municipal 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 Nobuaki Miyahara Department of Allergy and Respiratory Medicine, Okayama University Hospital Okayama Respiratory Disease Study Group (ORDSG) Background: Dupilumab is a fully humanized monoclonal antibody that blocks interleukin4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics. Methods: This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded. Results: The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/ mu L), but all were asymptomatic and able to continue dupilumab therapy. Conclusions: Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 4 2023 Feasibility of Flow Cytometry Analysis of Gastrointestinal Tract-Residing Lymphocytes in Hematopoietic Stem Cell Transplant Recipients 347 357 EN Masaya Iwamuro Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takumi Kondo Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Ennishi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuharu Fujii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takahide Takahashi Division of Medical Support, Okayama University Hospital Araki Hirabata Division of Medical Support, Okayama University Hospital Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, 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 Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/65740 The feasibility of lymphocyte isolation and flow cytometry using a single endoscopic biopsy specimen from the gastrointestinal tract of patients who have undergone hematopoietic stem cell transplantation has not been investigated. We acquired 51 endoscopic biopsy specimens from the gastrointestinal tract of 35 patients. We divided the flow cytometry samples into two groups: group A, successful lymphocyte isolation (n=24), and group B, incomplete isolation (n=27). We compared the backgrounds of the samples between the groups to reveal crucial elements in the successful isolation of lymphocytes residing in the gastrointestinal tract. Comparison between the groups revealed lymphocyte isolation success rates differed between biopsy sites. Isolation was most successful in samples from the duodenum (8/9, 88.9%), followed by the ileum (4/8, 50.0%), large intestine (4/11, 36.4%), and stomach (8/23, 34.8%). Tacrolimus was used more frequently in group B (92.6%) than in group A (62.5%) (p=0.015). Logistic regression analysis revealed that isolation from the duodenum or ileum was a significant factor for successful isolation, while tacrolimus use was not statistically significant. In conclusion, the duodenum and ileum are more suitable sites than the stomach and colorectum for acquiring samples for flow cytometry. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2213-0071 45 2023 Mycobacterium shinjukuense infection successfully treated with clarithromycin, rifampicin, and ethambutol 101894 EN Kayo Nakamura Department of Medicine, Japanese Red Cross Society Himeji Hospital Etsuko Murakami Department of Medicine, Japanese Red Cross Society Himeji Hospital Daizo Kishino Department of Medicine, Japanese Red Cross Society Himeji Hospital Shuko Mashimo Department of Medicine, Japanese Red Cross Society Himeji Hospital Yusuke Kurioka Department of Medicine, Japanese Red Cross Society Himeji Hospital Yusaku Shibata Department of Medicine, Japanese Red Cross Society Himeji Hospital Arihiko Taniguchi Department of Allergy and Respiratory Medicine, Okayama University Hospital Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital Yasushi Hiramatsu Department of Medicine, Japanese Red Cross Society Himeji Hospital Yoshinobu Maeda Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuaki Miyahara Department of Allergy and Respiratory Medicine, Okayama University Hospital We present the case of a 59-year-old woman diagnosed with Mycobacterium shinjukuense infection using mass spectrometry of bronchioalveolar lavage fluid. We initiated treatment with clarithromycin, rifampicin, and ethambutol based on the results of drug susceptibility testing, which improved lung opacities. Most previous cases were treated with the standard regimen for Mycobacterium tuberculosis. However, our regimen may provide a therapeutic option for this rare nontuberculous Mycobacterium infection. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0041-1132 63 7 2023 Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch 1344 1353 EN Takumi Kondo Division of Transfusion, Okayama University Hospital Keiko Fujii Division of Clinical Laboratory, Okayama University Hospital Nobuharu Fujii Division of Transfusion, Okayama University Hospital Yuichi Sumii Division of Transfusion, Okayama University Hospital Tomohiro Urata Division of Transfusion, Okayama University Hospital Maiko Kimura Division of Transfusion, Okayama University Hospital Masayuki Matsuda Division of Transfusion, Okayama University Hospital Shuntaro Ikegawa Division of Transfusion, Okayama University Hospital Kana Washio Department of Pediatrics/Pediatric Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Ken‐ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Fumio Otsuka Division of Clinical Laboratory, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Background: Granulocyte transfusion therapy is a rational therapeutic option for patients with prolonged, severe neutropenia. Although high molecular weight hydroxyethyl starch (hHES) facilitates the separation of red blood cells during granulocyte collection, renal dysfunction has been noted as a potential side effect. HES130/0.4 (Voluven®) is a medium molecular weight HES (mHES) with superior safety profiles compared to hHES. Although HES130/0.4 is reportedly effective in the collection of granulocytes, we lack studies comparing the efficiency of granulocyte collection using HES130/0.4 and hHES.<br> Study Design and Methods: We retrospectively collected the data from 60 consecutive apheresis procedures performed on 40 healthy donors at the Okayama University Hospital between July 2013 and December 2021. All procedures were performed using the Spectra Optia system. Based on the HES130/0.4 concentration in the separation chamber, granulocyte collection methods using HES130/0.4 were classified into m0.46, m0.44, m0.37, and m0.8 groups. We used HES130/0.4 and hHES groups to compare the various sample collection methods.<br> Results: The median granulocyte collection efficiency (CE) was approximately 24.0% and 28.1% in the m0.8 and hHES groups, respectively, which were significantly higher than those in the m0.46, m0.44, and m0.37 groups. One month following granulocyte collection with HES130/0.4, no significant changes were observed in serum creatinine levels compared to those before the donation.<br> Conclusion: Therefore, we propose a granulocyte collection approach employing HES130/0.4, which is comparable to the use of hHES in terms of the granulocyte CE. A high concentration of HES130/0.4 in the separation chamber was considered crucial for granulocyte collection. No potential conflict of interest relevant to this article was reported.

nature portfolio Acta Medica Okayama 2045-2322 12 1 2022 Early-stage antibody kinetics after the third dose of BNT162b2 mRNA COVID-19 vaccination measured by a point-of-care fingertip whole blood testing 20628 EN Hideharu Hagiya Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuhiro Nakano Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masanori Furukawa Clinical Laboratory, Okayama University Hospital Naruhiko Sunada Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toru Hasegawa Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasue Sakurada Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kou Hasegawa Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koichiro Yamamoto Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroko Ogawa Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takafumi Obara Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kouhei Ageta Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naomi Matsumoto Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rumi Matsuo Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoka Kadowaki Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihito Higashikage Clinical Laboratory, Okayama University Hospital Takao Hikita Office of Innovative Medicine, Organization for Research Strategy and Development, Okayama University Takashi Yorifuji Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Departments of General Thoracic Surgery and Breast and Endocrinological Surgery, 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 Yoshinori Yokokura Yokokura Hospital Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masanori Nakayama Office of Innovative Medicine, Organization for Research Strategy and Development, Okayama University Amid the Coronavirus Disease 2019 pandemic, we aimed to demonstrate the accuracy of the fingertip whole blood sampling test (FWT) in measuring the antibody titer and uncovering its dynamics shortly after booster vaccination. Mokobio SARS-CoV-2 IgM & IgG Quantum Dot immunoassay (Mokobio Biotechnology R&D Center Inc., MD, USA) was used as a point-of-care FWT in 226 health care workers (HCWs) who had received two doses of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) at least 8 months prior. Each participant tested their antibody titers before and after the third-dose booster up to 14-days. The effect of the booster was observed as early as the fourth day after vaccination, which exceeded the detection limit (>30,000 U/mL) by 2.3% on the fifth day, 12.2% on the sixth day, and 22.5% after the seventh day. Significant positive correlations were observed between the pre- and post-vaccination (the seventh and eighth days) antibody titers (correlation coefficient, 0.405; p<0.001). FWT is useful for examining antibody titers as a point-of-care test. Rapid response of antibody titer started as early as the fourth day post-vaccination, while the presence of weak responders to BNT162b2 vaccine was indicated. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2513-0390 6 7 2023 Particle and Heavy Ion Transport Code System‐Based Microdosimetry for the Development of Boron Agents for Boron Neutron Capture Therapy 2300163 EN Takafumi Shigehira Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Hanafusa Neutron Therapy Research Center, Okayama University Kazuyo Igawa Neutron Therapy Research Center, Okayama University Tomonari Kasai Neutron Therapy Research Center, Okayama University Shuichi Furuya Research Laboratory of Accelerator-Based BNCT system, Graduate School of Engineering Nagoya University Hisakazu Nishimori Department of Hematology and Oncology Okayama University Hospital Okayama Okayama 700–8558 Japan Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Hiroyuki Michiue Neutron Therapy Research Center, Okayama University Atsushi Fujimura Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Boron neutron capture therapy (BNCT) is a radiation therapy that selectively kills cancer cells at the cellular level using the boron neutron capture reaction (BNCR) (10B(n.α)7Li). The amount of boron 10B delivers in boronophenylalanine (BPA)-BNCT to achieve anti-tumor effects is ≈15–40 ppm. The same is true for all boron drugs; however, whether the same amount of 10B is required for other boron drugs with different accumulation characteristics has not been intensively investigated. Therefore, herein, a virtual cell model with intracellular organelles is prepared, and the BPA equivalent dose concentration to the cell nucleus is analyzed using particle and heavy ion transport code system-based microdosimetry. Additionally, the intranuclear minimal region (IMR) is set as a reference for the concept of the intranuclear domain in the microdosimetric kinetic model, and the BPA equivalent dose concentration to the IMR is estimated. The required boron delivery dose greatly varies depending on the dose assessment based on the accumulation characteristics of boron agents in intracellular organelles. Evaluation of the BNCR effect according to the accumulation characteristics without being influenced by the specified value of 15–40 ppm is recommended. No potential conflict of interest relevant to this article was reported.

The Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 62 9 2023 Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy 1319 1322 EN Tomoka Nishimura Department of Allergy and Respiratory Medicine, Okayama University Hospital Kiichiro Ninomiya Department of Allergy and Respiratory Medicine, Okayama University Hospital Mitsutaka Nakashima Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Akagi Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiro Kuribayashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Hisao Higo Department of Allergy and Respiratory Medicine, Okayama University Hospital 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 Hiroshi Ito Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus che-motherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fa-tigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulmi-nant myocarditis as an irAE, and the further exploration of viable treatment strategies is required. No potential conflict of interest relevant to this article was reported.

American Society for Clinical Investigation Acta Medica Okayama 2379-3708 8 8 2023 Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide e162180 EN Yuichi Sumii Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takumi Kondo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuntaro Ikegawa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuya Fukumi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Miki Iwamoto Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Sugiura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuhisa Sando Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Makoto Nakamura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Meguri Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takashi Matsushita Department of Dermatology, Faculty of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University Naoki Tanimine Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University Maiko Kimura 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 Daisuke Ennishi 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 Ken-Ichi Matsuoka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft -versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 134 2 2022 吉備中央町が本邦初の革新的事業連携型国家戦略特区指定を受けて―デジタル田園健康特区と規制改革の実現に向けた大学の役割― 115 118 EN Yasutomo Nasu Executive Director for Research, Okayama University Jota Maki Department of Obstetrics and Gynecology, Okayama University Hospital Jun Sakurai Center for Innovative Clinical Medicine, Okayama University Hospital Hisashi Masuyama Department of Obstetrics and Gynecology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Executive Director for Hospital, Okayama University No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 63 1 2023 Benefit of prednisolone alone in nodal peripheral T-cell lymphoma with T follicular helper phenotype 37 42 EN Wataru Kitamura Department of Hematology, National Hospital Organization Iwakuni Clinical Center Hiroki Kobayashi Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Medical School Tomohiro Urata Department of Hematology, National Hospital Organization Iwakuni Clinical Center Yumiko Sato Department of Pathology, National Hospital Organization Iwakuni Clinical Center Yusuke Naoi Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Medical School Shoichi Kuyama Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center A 71-year-old Japanese man presented with severe thrombocytopenia. A whole-body CT at presentation showed small cervical, axillary, and para-aortic lymphadenopathy, leading to suspicion of immune thrombocytopenia due to lymphoma. Biopsy was difficult to perform because of severe thrombocytopenia. Thus, he received prednisolone (PSL) therapy and his platelet count gradually recovered. Two and a half years after PSL therapy initiation, his cervical lymphadenopathy slightly progressed without other clinical symptoms. Hence, a biopsy from the left cervical lymph node was performed, and he was diagnosed with nodal peripheral T-cell lymphoma (PTCL) with T follicular helper (TFH) phenotype. Due to various complications, we continued treatment with prednisolone alone after the diagnosis of lymphoma; however, there was no further increase in lymph node enlargement and no other lymphoma-related symptoms for one and a half years after diagnosis. Although immunosuppressive therapy has been reported to produce a response in some patients with angioimmunoblastic T-cell lymphoma, our experience suggests that a similar subset may exist in patients with nodal PTCL with TFH phenotype, which has the same cellular origin. Immunosuppressive therapies may constitute an alternative treatment option even in the era of novel molecular-targeted therapies, especially for elderly patients who are ineligible for chemotherapy. 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.

Spandidos Publications Acta Medica Okayama 2049-9450 18 2 2022 Bladder tuberculosis with ureteral strictures after bacillus Calmette‑Guérin therapy for urinary bladder cancer: A case report 7 EN Yusuke Tominaga Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masanori Fujii Department of Allergy and Respiratory Medicine, Okayama University Hospital Takuya Sadahira Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Katayama Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Iwata Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shingo Nishimura Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kensuke Bekku Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Edamura Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Kobayashi Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuyuki Kobayashi Department of Urology, 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 Allergy and Respiratory Medicine, Okayama University Hospital Koichiro Wada Department of Urology, Shimane University Faculty of Medicine Motoo Araki Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Intravesical immunotherapy using bacillus Calmette‑Guérin (BCG) is recommended for patients with intermediate‑ to high‑risk non‑muscle invasive bladder cancer. Bladder tuberculosis (TB) is a rare complication of BCG therapy. The present study describes the case of a 73‑year‑old man who underwent intravesical BCG therapy for urothelial carcinoma in situ of the bladder. Red patches around the resection scar were first detected 1 year and 5 months after BCG treatment; these findings gradually spread to encompass more of the bladder wall. Transurethral biopsy revealed a benign lesion, but the patient developed bilateral hydronephrosis and mild voiding dysfunction. The patient was eventually diagnosed with bladder TB by mycobacterial urine culture and TB‑specific polymerase chain reaction (PCR). The patient was given multidrug therapy (isoniazid, rifampicin and ethambutol) and their bladder TB was completely cured; however, their voiding dysfunction and bilateral hydronephrosis did not fully improve. Bladder TB can occur long after intravesical BCG administration and cystoscopy findings consistent with inflammation can be the key to suspecting this condition. Acid‑fast examination and PCR testing of a urine sample are necessary for early diagnosis. No potential conflict of interest relevant to this article was reported.

Karger Acta Medica Okayama 1662-6575 15 3 2022 Sequential Combination of FLAM and Venetoclax plus Azacitidine to Bridge to Cord Blood Transplantation in a Patient with Primary Induction Failure Acute Myeloid Leukemia 974 979 EN Hiroyuki Murakami Department of Hematology and Oncology, Okayama University Hospital Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Takeru Asano Department of Hematology and Oncology, Japanese Red Cross Society Himeji Hospital Takashi Moriyama Department of Hematology and Oncology, Okayama University Hospital Akifumi Matsumura Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Tomohiro Toji Department of Pathology, Okayama University Hospital Tadashi Yoshino Department of Pathology, Okayama University Hospital Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Venetoclax (VEN) is an oral B-cell lymphoma-2 (BCL-2) inhibitor that has been widely used to treat various hematological disorders. Recent studies have demonstrated that VEN in combination with fludarabine-enhanced high-dose cytarabine (FLA) is effective for treating relapsed or refractory acute myeloid leukemia (AML). In the combination therapy, salvage chemotherapy and VEN are basically concurrently administrated; however, further optimization may enable the treatment to apply to larger numbers of patients with various clinical backgrounds. Here, we describe a case of refractory AML treated with a sequential combination of the intensive chemotherapy (fludarabine, cytarabine, and mitoxantrone; FLAM) and VEN/AZA to bridge to an unrelated cord blood transplantation (uCBT). By continuously adding VEN/AZA after FLAM, the patient achieved morphologic leukemia free state with only minor toxicities. Blood cell counts did not recover until the time of transplantation because of the deep myelosuppression caused by the treatment sequence, but the infection risk was safely managed during this period. After engraftment, maintenance therapy with VEN/AZA was performed, and the patient has survived without disease recurrence for over 9 months after transplantation. Our case suggests that bridging therapy with VEN and AZA from the time of the last chemotherapy to allogeneic transplantation may provide an effective and tolerable treatment strategy for refractory AML. Further studies of larger numbers of cases are needed to validate the effectiveness of this treatment. No potential conflict of interest relevant to this article was reported.

Public Library Science Acta Medica Okayama 1932-6203 17 9 2022 Prevention of non-infectious pulmonary complications after intra-bone marrow stem cell transplantation in mice e0273749 EN Yoshiko Yamasuji-Maeda Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keisuke Seike Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Yamamoto Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Taiga Kuroi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kyosuke Saeki Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruko Fujinaga Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sachiyo Okamoto Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuharu Fujii Department of Transfusion Medicine, Okayama University Hospital Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masahiro Fujii Department of Animal Resources, Advanced Science Research Center, Okayama University Katsumi Mominoki Department of Animal Resources, Advanced Science Research Center, Okayama University Takuro Kanekura Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Non-infectious pulmonary complications including idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans syndrome (BOS), which are clinical and diagnostic manifestations of lung chronic graft-versus-host disease (GVHD), cause significant mortality after allogeneic stem cell transplantation (SCT). Increasing evidence suggests that alloantigen reactions in lung tissue play a central role in the pathogenesis of IPS and BOS; however, the mechanism is not fully understood. Several clinical and experimental studies have reported that intrabone marrow (IBM)-SCT provides high rates of engraftment and is associated with a low incidence of acute GVHD. In the present study, allogeneic SCT was conducted in mouse models of IPS and BOS, to compare intravenous (IV)-SCT with IBM-SCT. Allogeneic IBM-SCT improved the clinical and pathological outcomes of pulmonary complications compared to those of IV-SCT. The mechanisms underlying the reductions in pulmonary complications in IBM-SCT mice were explored. The infiltrating lung cells were mainly CD11b+ myeloid and CD3+ T cells, in the same proportions as in transplanted donor cells. In an in vivo bioluminescence imaging, a higher proportion of injected donor cells was detected in the lung during the early phase (1 h after IV-SCT) than after IBM-SCT (16.7 +/- 1.1 vs. 3.1 +/- 0.7 x 10(5) photons/s/animal, IV-SCT vs. IBM-SCT, P = 1.90 x 10(-10)). In the late phase (5 days) after SCT, there were also significantly more donor cells in the lung after IV-SCT than after IBM-SCT or allogeneic-SCT (508.5 +/- 66.1 vs. 160.1 +/- 61.9 x 10(6) photons/s/animal, IV-SCT vs. IBM-SCT, P = 0.001), suggesting that the allogeneic reaction induces sustained donor cell infiltration in the lung during the late phase. These results demonstrated that IBM-SCT is capable of reducing injected donor cells in the lung; IBM-SCT decreases donor cell infiltration. IBM-SCT therefore represents a promising transplantation strategy for reducing pulmonary complications, by suppressing the first step in the pathophysiology of chronic GVHD. 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.

American Thoracic Society Acta Medica Okayama 1044-1549 67 6 2022 Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis through IL-1β Inhibition 654 665 EN Junko Itano Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Akihiko Taniguchi Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Satoru Senoo Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Yuka Gion Department of Medical Technology, Okayama University Graduate School of Health Sciences Yuria Egusa Department of Medical Technology, Okayama University Graduate School of Health Sciences Lili Guo Department of Medical Technology, Okayama University Graduate School of Health Sciences Naohiro Oda Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kota Araki Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Medical Technology, Okayama University Graduate School of Health Sciences Shinichi Toyooka Department of General Thoracic Surgery, Breast and Endocrinological Surgery, 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, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Nobuaki Miyahara Department of Allergy and Respiratory Medicine, Okayama University Hospital Neuropeptide Y (NPY), a 36 amino acid residue polypeptide distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1 beta concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1 beta concentrations in the lungs. Moreover, IL-1 beta neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1 beta release, and Y1 receptor antagonists inhibited IL-1 beta release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1 beta concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays a protective role against pulmonary fibrosis by suppressing IL-1 beta release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression. 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.

Frontiers Media Acta Medica Okayama 1664-3224 13 2022 Responses of regulatory and effector T-cells to low-dose interleukin-2 differ depending on the immune environment after allogeneic stem cell transplantation 891925 EN Yusuke Meguri Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takeru Asano Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takanori Yoshioka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Miki Iwamoto Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuntaro Ikegawa Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Sugiura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Kishi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Makoto Nakamura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuhisa Sando Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takumi Kondo Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuichi Sumii 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 Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences CD4(+)Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs promptly respond to low concentrations of IL-2 through the constitutive expression of high-affinity IL-2 receptors. It has been reported that low-dose IL-2 therapy increased circulating Tregs and improved clinical symptoms of chronic GVHD. Clinical studies of IL-2 therapy so far have mainly targeted patients in the chronic phase of transplantation when acute immune responses has subsided. However, the biological and clinical effects of exogenous IL-2 in an acute immune environment have not been well investigated. In the current study, we investigated the impact of exogenous IL-2 therapy on the post-transplant homeostasis of T cell subsets which influence the balance between GVHD and GVL in the acute phase, by setting the various immune environments early after HSCT in murine model. We initially found that 5,000 IU of IL-2 was enough to induce the active proliferation of Treg without influencing other conventional T cells (Tcons) when administered to normal mice. However, activated Tcons showed the response to the same dose of IL-2 in recipients after allogeneic HSCT. In a mild inflammatory environment within a threshold, exogenous IL-2 could effectively modulate Treg homeostasis with just limited influence to activated T cells, which resulted in an efficient GVHD suppression. In contrast, in a severely inflammatory environment, exogenous IL-2 enhanced activated T cells rather than Tregs, which resulted in the exacerbation of GVHD. Of interest, in an immune-tolerant state after transplant, exogenous IL-2 triggered effector T-cells to exert an anti-tumor effect with maintaining GVHD suppression. These data suggested that the responses of Tregs and effector T cells to exogenous IL-2 differ depending on the immune environment in the host, and the mutual balance of the response to IL-2 between T-cell subsets modulates GVHD and GVL after HSCT. Our findings may provide useful information in the optimization of IL-2 therapy, which may be personalized for each patient having different immune status. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2213-0071 37 2022 Dasatinib-induced massive left chylothorax in a patient with chronic myeloid leukemia 101662 EN Go Makimoto Department of Allergy and Respiratory Medicine, Okayama University Hospita Mahito Misawa Department of Hematology, Ako Central 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 Hospita Dasatinib, an effective second-generation tyrosine kinase inhibitor, is used to treat breakpoint cluster region-Ableson-positive chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphocytic leukemia. One common adverse event associated with dasatinib use is fluid retention, including pleural effusion. Chylothorax, however, is a rare adverse event. Although the precise mechanism of dasatinib-induced chylothorax is unclear, almost all cases involve right or bilateral chylothorax, and mostly occur within 5 years of dasatinib initiation. Here, we report a rare case of a patient with dasatinib-induced massive left chylothorax 10 years after dasatinib initiation, which improved after dasatinib termination and a switch to bosutinib. No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 62 1 2022 Transformed diffuse large B-cell lymphoma from marginal zone lymphoma in the anterior mediastinum: A case report and review of the literature 35 40 EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Tetsuya Tabata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Rei Shibata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tatsuya Nishi Department of Respiratory and Allergy, Okayama University Hospital Yuka Kato Center for Innovative Clinical Medicine, Okayama University Hospital Hiroki Takasuka Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Transfusion Medicine, Okayama University Hospital Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Katsuyuki Kiura Department of Respiratory and Allergy, Okayama University Hospital Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Marginal zone lymphoma (MZL) arising from the anterior mediastinum is rare. In the majority of reported cases, the tumor was incidentally discovered, reflecting its indolent clinical features. We present a 38-year-old woman who had no medical history, and presented with a bulky anterior mediastinal tumor complicated by life-threatening compression of the vasculature and bronchi. Biopsy specimens of the neoplasm suggested transformed diffuse large B-cell lymphoma (DLBCL) from MZL. To our best knowledge, this is the first case report of anterior mediastinum MZL associated with an aggressive clinical course and life-threatening complications likely due to transformation to DLBCL. 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 19 2021 Nodal Peripheral T-cell Lymphoma with T Follicular Helper Phenotype Presenting as Chorea During Treatment: A Case Report and Literature Review 3155 3160 EN Wataru Kitamura Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Ryoya Yukawa Department of Hematology and Oncology, Okayama University Hospital Ryo Sasaki Department of Neurology, Okayama University Hospital Chikamasa Yoshida Department of Hematology, Okayama City Hospital Hiroki Takasuka Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Division of Clinical Laboratory, Okayama University Hospital Nobuharu Fujii Division of Blood Transfusion, Okayama University Hospital Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Koji Abe Department of Neurology, Okayama University Hospital Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital A 72-year-old man presented with chorea while undergoing treatment for recurrence of nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. An examination by brain N-isopropyl-p-iodoamphetamine (I-123-IMP)-single photon emission computed tomography (SPECT) revealed no abnormalities other than a decreased cerebral blood flow (CBF) in the left striatum. After four courses of salvage chemotherapy, his clinical symptoms and asymmetric cerebral perfusion improved, suggesting that the decreased CBF had caused chorea. The significance of brain SPECT has not been fully clarified in patients with chorea-associated malignant lymphoma, warranting further investigations. Brain SPECT is an alternative approach to identify abnormalities in such patients. No potential conflict of interest relevant to this article was reported.

The Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 60 18 2021 Dramatic Response to Carboplatin Plus Paclitaxel in Pancreatic Mucinous Cystadenocarcinoma with Liver Metastasis 2967 2971 EN Naohiro Oda Department of Allergy and Respiratory Medicine, Okayama University Hospital Masahiro Tabata Center for Clinical Oncology, Okayama University Hospital Masatoshi Uno Department of Internal Medicine, Kaneda Hospital Yuzo Umeda Department of Hepato-Biliary-Pancreatic Surgery, Okayama University Hospital Hironari Kato Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Satoru Senoo Department of Allergy and Respiratory Medicine, Okayama University Hospital Takahito Yagi Department of Hepato-Biliary-Pancreatic Surgery, Okayama University Hospital Toshiyoshi Fujiwara Department of Gastroenterological Surgery, 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 Allergy and Respiratory Medicine, Okayama University Hospital Mucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA+PTX). CBDCA+PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma. 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‑1α/TGF‑α 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‑1α (HIF‑1α) and transforming growth factor‑α (TGF‑α) 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‑α 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‑1α/TGF‑α. No potential conflict of interest relevant to this article was reported.

Nature Research Acta Medica Okayama 2045-2322 11 1 2021 Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis 11882 EN Kuniaki Katsui Department of Proton Beam Therapy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takeshi Ogata Department of Radiology, Iwakuni Clinical Center Soichi Sugiyama Department of Radiology, Okayama University Hospital Kotaro Yoshio Department of Radiology, Okayama University Hospital Masahiro Kuroda Department of Radiological Technology, Graduate School of Health Sciences, Okayama University Takao Hiraki Department of Radiology, 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 Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Kanazawa Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (>= 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28-6.64 for PS, and 2.36 and 1.15-4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients. No potential conflict of interest relevant to this article was reported.

Nature Research Acta Medica Okayama 2045-2322 11 1 2021 Reduced dose of PTCy followed by adjuvant alpha-galactosylceramide enhances GVL effect without sacrificing GVHD suppression 13125 EN Makoto Nakamura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Meguri Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuntaro Ikegawa Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takumi Kondo Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuichi Sumii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuya Fukumi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Miki Iwamoto Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuhisa Sando Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Sugiura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Emi Fukuda-Kawaguchi REGiMMUNE Corporation Yasuyuki Ishii REGiMMUNE Corporation Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by alpha -galactosylceramide (alpha -GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of alpha -GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4(+)Foxp3(+) regulatory T cells. These studies indicate that alpha -GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0015-5632 63 5 2018 Unusual oral mucosal microbiota after hematopoietic cell transplantation with glycopeptide antibiotics: potential association with pathophysiology of oral mucositis 587 597 EN Misato Muro Division of Hospital Dentistry, Okayama University Hospital Yoshihiko Soga Division of Hospital Dentistry, Okayama University Hospital Tomoko Higuchi Division of Hospital Dentistry, Okayama University Hospital Kota Kataoka Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Ekuni Department of Preventive Dentistry, 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 Manabu Morita Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Severe oral mucositis occurs frequently in patients receiving hematopoietic stem cell transplantation (HCT). Oral mucosal bacteria can be associated with progression of oral mucositis, and systemic infection may occur via ulcerative oral mucositis. However, little information is available regarding the oral microbiota after HCT. Here, PCR-denaturing gradient gel electrophoresis (DGGE) was performed to characterize the oral mucosal microbiota, which can be affected by antibiotics, before and after HCT. Sixty reduced-intensity HCT patients were enrolled. Three patients with the least antibiotic use (quinolone prophylaxis and/or β-lactam monotherapy group) and three patients with the most antibiotic use (β-lactam-glycopeptide combination therapy group) were selected. Bacterial DNA samples obtained from the oral mucosa before and after HCT were subjected to PCR-DGGE. The trajectory of oral mucositis was evaluated. The oral mucosal microbiota in the β-lactam-glycopeptide combination therapy group was different from that in the quinolone prophylaxis and/or β-lactam monotherapy group, and Staphylococcus spp. and Enterococcus spp. were identified. Lautropia mirabilis was dominant in one patient. Ulcerative oral mucositis was observed only in the β-lactam-glycopeptide combination therapy group. In conclusion, especially with the use of strong antibiotics, such as glycopeptides, the oral mucosal microbiota differed completely from that under normal conditions, and consisted of Staphylococcus spp., Enterococcus spp., and unexpectedly L. mirabilis. The normal oral microbiota consists not only of bacteria, but these unexpected bacteria could be involved in the pathophysiology as well as systemic infection via oral mucositis. Our results can be used as the basis for future studies in larger patient populations. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 2 2021 Successful Treatment of Acute Promyelocytic Leukemia Complicated with Endometrial Cancer by Arsenic Trioxide 219 224 EN Hiroyuki Sugiura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hirofumi Matsuoka Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiichiro Nakamura Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiko Fujii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuharu Fujii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-ichi Matsuoka 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 Case Report 10.18926/AMO/61904 Acute promyelocytic leukemia (APL) is a hematological emergency that requires urgent intervention because of the high incidence of early hemorrhagic death. When patients with APL experience a synchronous solid organ tumor, the tumor’s treatment must also be done properly. Differentiation-inducing therapy using arsenic trioxide (ATO) has less hematological toxicity compared to cytotoxic chemotherapy and might be preferable for untreated APL patients with a synchronous solid organ tumor. Here we describe the first successful case of untreated APL and synchronous endometrial cancer (in an adult Japanese woman) treated with ATO consolidation therapy and the subsequent surgery and chemotherapy for endometrial cancer. 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.

BMC Acta Medica Okayama 1748-717X 16 1 2021 Lung stereotactic body radiation therapy for elderly patients aged >= 80 years with pathologically proven early-stage non-small cell lung cancer: a retrospective cohort study 39 EN Kenta Watanabe Department of Radiology, Okayama University Hospital Kuniaki Katsui Department of Proton Beam Therapy, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Soichiro Sugiyama Department of Radiology, Okayama University Hospital Kotaro Yoshio Department of Radiology, Okayama University Hospital Masahiro Kuroda Department of Radiological Technology, Graduate School of Health Sciences, Okayama University Takao Hiraki Department of Radiology, 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 Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Susumu Kanazawa Department of Radiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Background</br> Stereotactic body radiation therapy (SBRT) is an established therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). Many elderly patients are medically inoperable owing to comorbidities. Therefore, SBRT may be a useful therapy for elderly patients. However, the application of SBRT for patients aged ≥ 80 years has not been completely elucidated. Therefore, this study aimed to assess the clinical utility of SBRT for elderly patients aged ≥ 80 years with pathologically proven early-stage NSCLC.</br> Methods</br> We retrospectively evaluated the data of patients aged ≥ 80 years with pathologically proven primary NSCLC who underwent SBRT at our institution between January 2009 and March 2020. Treatment outcomes and toxicities were analyzed. We used the Kaplan–Meier method to estimate survival curves and the log-rank test to compare the survival curves. We performed univariate and multivariate Cox regression analyses. p-values < 0.05 were regarded significant.</br> Results</br> Sixty-four patients (65 lesions) were included, and the median follow-up period was 38.7 (range 3.5–95.7) months. The median age was 82.9 (range 80.0–94.8) years. Sixteen patients were medically operable, and 48 patients were medically inoperable. The prescribed dose of SBRT was either 48 Gy in four fractions or 60 Gy in 10 fractions. The median survival time was 60.0 months (95% confidence interval, 43.5–71.1). The 1-, 3-, and 5-year local control, cancer-specific survival, progression-free survival, and overall survival rates were 98.4%, 98.4%, 81.0%, and 88.9%; 90.1%, 93.7%, 58.9%, and 68.3%; and 87.4%, 83.5%, 38.2%, and 47.5%, respectively. Multivariate analysis revealed that inoperability and solid nodules were the predictors of poor overall survival after SBRT in elderly patients. Two patients (3.1%) had grade 3 radiation pneumonitis, and one patient (1.6%) had grade 5 radiation pneumonitis.</br> Conclusions</br> SBRT was feasible in patients aged ≥ 80 years with NSCLC. It achieved good local control with minimal toxicity. SBRT may be beneficial in elderly patients with early-stage NSCLC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 75 1 2021 Volumetric PET Parameters Predict Prognosis after Definitive Chemoradiotherapy with Cisplatin/Docetaxel for Stage III Non-Small Cell Lung Cancer 15 23 EN Kuniaki Katsui Department of Proton Beam Therapy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takeshi Ogata Department of Radiology, Iwakuni Clinical Center Akihiro Tada Department of Radiology, Okayama Diagnostic Imaging Center Soichi Sugiyama Department of Radiology, Okayama University Hospital Kotaro Yoshio Department of Radiology, Okayama University Hospital Masahiro Kuroda Department of Radiological Technology, Graduate School of Health Sciences, Okayama University Katsuyuki Kiura Allergy and Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takao Hiraki Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Kanazawa Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/61429 The aim of this study was to investigate whether volumetric positron emission tomography (PET) parameters are prognostic predictors in stage III non-small cell lung cancer patients receiving definitive concurrent chemo-radiotherapy (CCRT) with cisplatin/docetaxel. Cases involving definitive CCRT were reviewed retrospectively, and the maximum standardized uptake value, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. The relationships between these PET parameters and prognosis were analyzed. MTV and TLG were significant predictors of distant metastasis-free survival (DMFS) (p = 0.0003 and 0.0005, respectively) and progression-free survival (PFS) (p = 0.001 and 0.0007, respectively). The three-year DMFS rates in patients with low and high MTV were 13.3% and 64.6%, respectively, and the corresponding values in those with low and high TLG were 13.3% and 65.2%, respectively. The three-year PFS rates in patients with low and high MTV were 13.3% and 57.8%, respectively, and the corresponding values in patients with low and high TLG were 13.3% and 57.8%, respectively. However, MTV and TLG were not predictors of local control or overall sur-vival. We demonstrated that volumetric PET parameters were predictors of patients receiving definitive CCRT. Our findings contradict the findings of previous reports and warrant further research to validate them. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0918-2918 59 16 2020 Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case 2023 2028 EN Hiroyuki Sugiura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisakazu Nishimori 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 Tomohiro Toji Department of Pathology, Okayama University Hospital Keiko Fujii 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 Ken-ichi Matsuoka Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koh Nakata Department of Bioscience Medical Research Center, Niigata University Medical & Dental Hospital 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 Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence. No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 0941-4355 29 2020 Demand for weekend outpatient chemotherapy among patients with cancer in Japan 1287 1297 EN Hideki Katayama Department of Palliative and Supportive Care, Okayama University Hospital Masahiro Tabata Department of Palliative and Supportive Care, Okayama University Hospital Toshio Kubo Department of Allergy and Respiratory Medicine, Okayama University Hospital Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Junji Matsuoka Department of Palliative and Supportive Care, Okayama University Hospital Yoshinobu Maeda Department of Palliative and Supportive Care, Okayama University Hospital Background</br> Advanced cancer therapeutics have improved patient survival, leading to an increase in the number of patients who require long-term outpatient chemotherapy. However, the available schedule options for chemotherapy are generally limited to traditional business hours.</br> Method</br> In 2017, we surveyed 721 patients with cancer in Okayama, Japan, regarding their preferences for evening and weekend (Friday evening, Saturday, and Sunday) chemotherapy appointments.</br> Results</br> A preference for evening and weekend appointment options was indicated by 37% of the respondents. Patients who requested weekend chemotherapy were younger, female, with no spouse or partner, living alone, employed, and currently receiving treatment. Among these factors, age and employment status were significantly associated with a preference for weekend chemotherapy, according to multivariate analysis.</br> Conclusion</br> Our findings reveal a demand for evening and weekend outpatient chemotherapy, especially among young, employed patients. No potential conflict of interest relevant to this article was reported.

日本内科学会 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.

日本内科学会 Acta Medica Okayama 0918-2918 59 21 2020 Adult T-cell Leukemia-lymphoma with Primary Breast Involvement: A Case Report and Literature Review 2757 2761 EN Hiroki Kobayashi Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Takuro Igawa Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masaya Abe Department of Hematology and Oncology, Okayama University Hospital Yusuke Meguri Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Transfusion Medicine, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Breast involvement of Adult T-cell leukemia-lymphoma (ATLL) is extremely rare, and the data on the characteristics are limited. We herein describe a 49-year-old woman who presented with skin involvement of ATLL. Positron emission tomography/computed tomography showed bilateral breast lesions. Although the patient once achieved a complete metabolic response, a relapse of her ATLL occurred. The patient received subsequent allogeneic hematopoietic stem cell transplantation (HSCT). To our knowledge, only four cases of ATLL with breast involvement have previously been reported, and the prognoses have generally been poor. Breast lesions of ATLL have aggressive features, and intensive systemic chemotherapy and HSCT are required to improve survival. No potential conflict of interest relevant to this article was reported.

Spandidos Publications Acta Medica Okayama 1792-1074 20 6 2020 Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction 393 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 Tomoki Tamura 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 Takehiro Matsubara Okayama University Hospital Biobank Satoru Senoo 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 Hiromi Watanabe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naohiro Oda 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 Hisao Higo 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 Respiratory Medicine, Okayama University Hospital Toshio Kubo Center for Clinical Oncology, Okayama University Hospital Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Okayama University Hospital Biobank Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Masahiro Tabata Center for Innovative Clinical 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 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 The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non‑small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC‑ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54‑81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post‑operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC‑ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC‑ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC‑ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult. No potential conflict of interest relevant to this article was reported.

Nature Research Acta Medica Okayama 2045-2322 10 1 2020 5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy 17237 EN Yasuhisa Sando Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuichi Sumii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takumi Kondo Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuntaro Ikegawa Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Sugiura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Makoto Nakamura Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Miki Iwamoto Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Meguri Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Noboru Asada Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Ennishi Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiko Fujii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuharu Fujii Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atae Utsunomiya Department of Hematology, Imamura General Hospital Takashi Oka 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 Photodynamic therapy (PDT) is an emerging treatment for various solid cancers. We recently reported that tumor cell lines and patient specimens from adult T cell leukemia/lymphoma (ATL) are susceptible to specific cell death by visible light exposure after a short-term culture with 5-aminolevulinic acid, indicating that extracorporeal photopheresis could eradicate hematological tumor cells circulating in peripheral blood. As a bridge from basic research to clinical trial of PDT for hematological malignancies, we here examined the efficacy of ALA-PDT on various lymphoid malignancies with circulating tumor cells in peripheral blood. We also examined the effects of ALA-PDT on tumor cells before and after conventional chemotherapy. With 16 primary blood samples from 13 patients, we demonstrated that PDT efficiently killed tumor cells without influencing normal lymphocytes in aggressive diseases such as acute ATL. Importantly, PDT could eradicate acute ATL cells remaining after standard chemotherapy or anti-CCR4 antibody, suggesting that PDT could work together with other conventional therapies in a complementary manner. The responses of PDT on indolent tumor cells were various but were clearly depending on accumulation of protoporphyrin IX, which indicates the possibility of biomarker-guided application of PDT. These findings provide important information for developing novel therapeutic strategy for hematological malignancies. 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.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 Anaplastic Lymphoma Kinase Fusion: A Review of Therapeutic Drugs and Treatment Strategies 371 379 EN Go Makimoto Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center 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 Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital Review 10.18926/AMO/60796 The prognosis of advanced non-small cell lung cancer (NSCLC) patients has improved in recent decades, especially for patients with an oncogenic driver mutation. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are effective for patients with the echinoderm microtubule-associated protein-like 4-ALK fusion gene. Several ALK-TKIs have been established: the first-generation ALK-TKI, crizotinib; second-generation ALK-TKIs, alectinib and ceritinib; and third-generation ALK-TKI, lorlatinib. Some ALK-TKIs are effective for tumors that are resistant to other ALK-TKIs; however, as is known in epidermal growth factor receptormutant lung cancer, tumor resistance is inevitable. ALK-positive NSCLCs acquire resistance via various mechanisms, making it a heterogeneous disease. Therefore, it is necessary to develop next-generation treatment strategies, such as the use of next-generation ALK-TKIs for secondary mutations, or combination therapies with ALK-TKIs and other TKIs. In this review, we summarize the development and use of ALK-TKIs, prior pivotal clinical trials, and resistance mechanisms. No potential conflict of interest relevant to this article was reported.

Public Library of Science Acta Medica Okayama 1932-6203 15 8 2020 Nintedanib can be used safely and effectively for idiopathic pulmonary fibrosis with predicted forced vital capacity <= 50%: A multi-center retrospective analysis e0236935 EN Satoru Senoo Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuaki Miyahara Department of Medical Technology, Okayama University Graduate School of Health Sciences Akihiko Taniguchi Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naohiro Oda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junko Itano 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 Naofumi Hara 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 Toshimitsu Suwaki Department of Respiratory Medicine, Okayama City Hospital Yasuko Fuchimoto Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety Okayama Rosai Hospita Kazuhiro Kajimoto Department of Respiratory Medicine, Japanese Red Cross Kobe Hospita Hirohisa Ichikawa Department of Respiratory Medicine, KKR Takamatsu Hospital Kenichiro Kudo Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Takuo Shibayama Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center Yasushi Tanimoto Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center Shoichi Kuyama Department of Respiratory Medicine, National Hospital Organization Iwakuni Clinical Center Arihiko Kanehiro Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety Okayama Rosai Hospital 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 Okayama Respiratory Disease Study Group (ORDSG) Background</br> Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%.</br> Methods</br> This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months.</br> Results</br> 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib.</br> Conclusions</br> Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment. 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.

Wiley Acta Medica Okayama 2045-7634 2020 Radiation pneumonitis after definitive concurrent chemoradiotherapy with cisplatin/docetaxel for non-small cell lung cancer: Analysis of dose-volume parameters EN Kuniaki Katsui Department of Proton Beam Therapy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Takeshi Ogata Department of Radiology, Iwakuni Clinical Center Kenta Watanabe Department of Radiology, Okayama University Hospital Norihisa Katayama Department of Radiology, Okayama University Hospital Masahiro Kuroda Department of Radiological Technology, Graduate School of Health Sciences, Okayama University Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Takao Hiraki Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Shinichi Toyooka Departments of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Susumu Kanazawa Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Background: Radiation pneumonitis (RP) is a major pulmonary adverse event of chest radiotherapy. The PACIFIC trial that identified durvalumab as an effective subsequent-line therapy after concurrent chemoradiotherapy (CCRT) found that patients with grade 2 or higher RP may have to be excluded from treatment under certain criteria. The purpose of this study was to investigate the relationship between grade ≥2 RP and the parameters of dose-volume histograms after CCRT with cisplatin/docetaxel for stage III non-small cell lung cancer and conduct a subset analysis of severe RP that can lead to the permanent discontinuation of treatment per the PACIFIC trial criteria to help determine treatment strategy. <br/> Methods: We calculated the percentage of the lung volume received at least 5 Gy (V5) and 20 Gy (V20), the mean lung dose (MLD), and the lung volume spared from a 5 Gy dose (VS5) to the total lung volume. Factors affecting the incidence of grade ≥2 RP were identified; severe RP was defined as grade ≥3 as well as grade 2 RP that required ≥10 mg prednisolone for at least 12 weeks. <br/> Results: This study included 45 patients. On univariate analysis, all parameters and total lung volume were found to be significant predictors of grade ≥2 RP (P = .001, .003, .03, .004, and .02, respectively). On multivariate analysis, V20 was a significant predictive factor of grade ≥2 RP (P = .007). Severe RP developed in 6 of 37 patients (16.2%) whose V20 values were 35% or lower. On univariate analysis, only V20 was a significant predictor of severe RP in these patients (P = .01). <br/> Conclusions: The best approach to reduce the rate of grade ≥2 RP is to maintain the V5, V20, MLD, and VS5 as low as possible during radiotherapy planning in patients receiving definitive CCRT with cisplatin/docetaxel. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 22125345 58 3 2020 Deterioration of high-resolution computed tomography findings predicts disease progression after initial decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone 185 189 EN Hisao Higo Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Nobuaki Miyahara Okayama University Hospital Akihiko Taniguchi Okayama University Hospital Satoru Senoo Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Junko Itano Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiromi Watanabe Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Naohiro Oda Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroe Kayatani National Hospital Organization Okayama Medical Center Hirohisa Ichikawa KKR Takamatsu Hospita Takuo Shibayama National Hospital Organization Okayama Medical Center Kazuhiro Kajimoto Kobe Red Cross Hospital Yasushi Tanimoto National Hospital Organization Minami-Okayama Medical Center Arihiko Kanehiro Okayama Rosai Hospital Yoshinobu Maeda Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Katsuyuki Kiura Okayama University Hospital OKAYAMA respiratory disease study group (ORDSG) Background</br> Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline.</br> Methods</br> This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled.</br> Results</br> We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009).</br> Conclusions</br> We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone. No potential conflict of interest relevant to this article was reported.

The Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 59 6 2020 Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review 823 828 EN Junko Itano Department of Respiratory Medicine, Okayama University Hospital Hisao Higo 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 Go Makimoto 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 Katsuyuki Hotta Department of Respiratory Medicine, Okayama University Hospital Nobuaki Miyahara 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 Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2213-0071 28 2019 Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review 100938 EN Go Makimoto Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kadoaki Ohashi Department of Allergy and Respiratory Medicine, Okayama University Hospital Kohei Taniguchi Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiko Taniguchi Department of Allergy and Respiratory Medicine, Okayama University Hospital Nobuaki Miyahara Department of Medical Technology, Okayama University Graduate School of Health Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, 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 Allergy and Respiratory Medicine, Okayama University Hospital Pleural effusion is a relatively rare feature of IgG4-related disease (IgG4-RD). Here, we report a case of a 72-year-old woman who presented with pleural effusion. Although the pleural adenosine deaminase level was increased, surgical biopsy of the pleura and left inguinal lymph node indicated that the effusion was due to IgG4-RD. Active surveillance was initiated because serum IgG4 and pleural effusion naturally decreased and then completely disappeared. The patient has shown no recurrence for >4 years. This case suggests that pleural biopsy can be used to distinguish IgG4-RD from tuberculosis; moreover, some cases with pleural effusion could improve without treatment. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2213-0071 28 2019 A case of axillary lymphadenitis caused by Mycobacterium intracellulare in an immunocompetent patient 100947 EN Junko Itano 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 Satoru Senoo Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naohiro Oda 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 Akihiko Taniguchi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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 Respiratory Medicine, Okayama University Hospital Axillary lymphadenitis caused by non-tuberculous mycobacteria is rare and has been reported in immunocompromised hosts. Herein, we report the case of a 67-year-old man without immunodeficiency who developed right axillary lymphadenitis caused by Mycobacterium intracellulare and showed a small nodular shadow in the left pulmonary apex. Biopsy of the right axillary lymph node revealed several epithelioid granulomas, and the culture of the lymph node aspirate yielded Mycobacterium intracellulare. The lymph node lesion and left lung apex shadow resolved spontaneously after careful outpatient monitoring. This case suggests that axillary lymphadenitis could be caused by Mycobacterium intracellulare in an immunocompetent patient. 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 70 5 2016 An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease 409 412 EN Yoshinobu Maeda Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Yoshihiro Inamoto Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital Hirohisa Nakamae Department of Hematology, Osaka City University Hospital Masashi Sawa Department of Hematology and Oncology, Anjo Kosei Hospital Yasuo Mori Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences Kazuteru Ohashi Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Shin-ichiro Fujiwara Division of Hematology, Department of Medicine, Jichi Medical University Mitsune Tanimoto Department of Hematology and Oncology, Okayama University Hospital Clinical Study Protocols 10.18926/AMO/54603 Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD. No potential conflict of interest relevant to this article was reported.

Springer-Verlag Acta Medica Okayama 0941-4355 21 2 2013 Antibiotic sensitivity of bacteria on the oral mucosa after hematopoietic cell transplantation 367 368 EN Yoshihiko Soga Yoshinobu Maeda Mitsune Tanimoto Takayuki Ebinuma Hiroshi Maeda Shogo Takashiba No potential conflict of interest relevant to this article was reported.

Springer Berlin Heidelberg Acta Medica Okayama 0941-4355 22 6 2014 Distribution of oral mucosal bacteria with mecA in patients undergoing hematopoietic cell transplantation 1679 1683 EN Takayuki Ebinuma Yoshihiko Soga Takamaro Sato Kazuyuki Matsunaga Chieko Kudo Hiroshi Maeda Yoshinobu Maeda Mitsune Tanimoto Shogo Takashiba [Purpose] We recently reported frequent detection of antibiotic-resistant bacteria on the oral mucosa during the period of hematopoietic cell transplantation (HCT) and suggested an association between oral mucositis and antibiotic-resistant bacterial infection. Methicillin-resistant Staphylococcus spp. were frequently detected, and the oral cavity may be a reservoir of the gene mediating methicillin resistance, mecA. Here, we examined the frequency of mecA carriers in patients undergoing HCT. [Methods] Fifty-nine patients (male (M) = 37, female (F) = 22, 47.3 ± 11.0 years) receiving HCT were enrolled in this study. Buccal swab samples were obtained four times from day −7 to day +20 (once/week), and mecA was detected by PCR. Fifty-two subjects without systemic disease, who completed dental treatment, especially periodontal treatment (M = 21, F = 31, 55.4 ± 14.2 years), were also enrolled as controls and checked for mecA on the oral mucosa. [Results] Seventy-six percent (45/59) of the HCT patients carried mecA at least once in the study period (days −7 to +20), while no control subjects had mecA. The frequency of mecA carriers was 19.2 % from days −7 to −1, while it was significantly increased on days +7 to +13 and +14 to +20, with frequencies of 60.9 and 63.2 %, respectively (P < 0.01, ANOVA). [Conclusions] mecA was detected in oral mucosa of patients undergoing HCT. The high detection frequency of staphylococci resistant to penicillin and beta-lactams in our recent report was supported. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 2 2015 慢性移植片対宿主病に対するタミバロテン（AM80G）の医師主導臨床第�U相試験 133 137 EN Hisakazu Nishimori Yoshinobu Maeda No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0046-8177 45 7 2014 Low-grade B-cell lymphoma presenting primarily in the bone marrow 1379 1387 EN Kayoko Iwatani Katsuyoshi Takata Yasuharu Sato Tomoko Miyata-Takata Noriko Iwaki Wei Cui Seiko Sawada-Kitamura Hiroshi Sonobe Maiko Tamura Katsuhiko Saito Katsuya Miyatani Rie Yamasaki Ichiro Yamadori Nobuharu Fujii Yasushi Terasaki Yoshinobu Maeda Mitsune Tanimoto Naoya Nakamura Tadashi Yoshino Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1083-8791 20 2 2014 Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease 183 191 EN Haruko Sugiyama Yoshinobu Maeda Hisakazu Nishimori Yoshiko Yamasuji Ken-ichi Matsuoka Nobuharu Fujii Eisei Kondo Katsuji Shinagawa Takehiro Tanaka Kengo Takeuchi Takanori Teshima Mitsune Tanimoto Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into OH model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with GSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1618-1247 100 2 2012 Histological and immunohistochemical features of gingival enlargement in a patient with AML 254 257 EN Norihiro Sonoi Yoshihiko Soga Hiroshi Maeda Koichi Ichimura Tadashi Yoshino Kazutoshi Aoyama Nobuharu Fujii Yoshinobu Maeda Mitsune Tanimoto Richard Logan Judith Raber-Durlacher Shogo Takashiba Here, we discuss the pathophysiology of leukemia-associated gingival enlargement based on a case of acute myelomonocytic leukemia (AML-M4) with typical gingival enlargement. Uniquely, this patient was well enough to allow full periodontal examination and incisional gingival biopsy to be performed both before and after chemotherapy. The patient was a 39-year-old Japanese woman with AML-M4 showing gingival enlargement. Histological and immunohistochemical features of gingiva and bacterial counts in the periodontal pockets were examined before and after chemotherapy. The results were as follows: (1) infiltration of myelomonocytic blasts in enlarged gingiva; (2) resolution of gingival enlargement with complete remission of AML by anticancer chemotherapy; and (3) the numbers of bacteria in the periodontal pockets were not high and were not altered before or after chemotherapy. In patients with AML-M4, remarkable mucosal enlargement is not generally observed in the body except in the gingiva. We hypothesized that antigens derived from periodontal bacteria, even if they are not present in large numbers, could act as chemoattractants for myelomonocytic leukemic cells. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 2 2014 リンパ腫・骨髄腫 143 150 EN Kyosuke Saeki Yoshinobu Maeda Mitsune Tanimoto No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 1 2014 白血病および白血病類縁疾患における分子標的治療 49 54 EN Yoshinobu Maeda Mitsune Tanimoto No potential conflict of interest relevant to this article was reported.

電通サドラー・アンド・ヘネシー株式会社 Acta Medica Okayama 20 2010 移植後合併症の看護ポイント─GVHD�B 口腔GVHD 2 3 EN No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0046-8177 44 9 2013 Distinct morphologic, phenotypic, and clinical-course characteristics of indolent peripheral T-cell lymphoma 1927 1936 EN Eiko Hayashi Katsuyoshi Takata Yasuharu Sato Yukie Tashiro Yoshiro Tachiyama Seiko Sawada-Kitamura Yasushi Hiramatsu Shun Sugiguchi Soichiro Nose Mitsuyoshi Hirokawa Midori Ando Lamia Abd Mader Yoshinobu Maeda Mitsune Tanimoto Tadashi Yoshino Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) consists of a heterogeneous group of lymphomas. Patients. generally show an aggressive clinical course and very poor outcome. Although the 2008 World Health Organization classification of PTCL-NOS includes 3 variants, low-grade lymphoma is not Included. Of 277 PTCL-NOS cases recorded in our consultation files, we examined the clinicopathologic characteristics of 10 patients with T-cell lymphomas composed of small-sized cells with slight nuclear atypia. Eight patients showed extranodal involvement (5 patients, spleen; 3 patients, thyroid), and 5 patients were at clinical stage I or II. Histologically, all samples presented diffuse infiltrate of small lymphoid cells, with few mitotic figures. Immunohistologically, all samples were positive for CD3, and CD:20 Was detected in 5 samples. All samples showed a low Ki-67 labeling index (mean, 1.05%), and 7 samples were positive for central memory T-cell markers. Clonal T-cell receptor gamma chain and/or alpha-beta chain gene rearrangements were detected in all 10 patients. Five patients received chemotherapy, whereas for 3 patients, treatment consisted only of observation following surgical resection of the spleen or thyroid. Nine patients were alive at a median follow-up time of 19.5 months, whereas 1 patient died of an unrelated disease. The present study strongly indicates that T-cell lymphoma with small-sized lymphoma cells and a low Ki-67 labeling index is a distinct variant. Recognition of this novel lymphoma subtype, which should not be defined merely as PTCL-NOS, should be seriously considered. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 67 5 2013 Preparation of Enteric-coated Capsules of Beclomethasone Dipropionate for Patients with Intestinal Graft-versus-Host Disease and a Case Study 319 324 EN Kiminaka Murakawa Tomoaki Sato Yoshinobu Maeda Yoshihisa Kitamura Mitsune Tanimoto Toshiaki Sendo Case Report 10.18926/AMO/51868 Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP-EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 2 2013 十二指腸濾胞性リンパ腫はAIDの発現を欠くがBACH2の発現を有しmemoryB細胞としての性質を有する 103 107 EN Katsuyoshi Takata Yasuharu Sato Naoya Nakamura Mami Tokunaka Yukari Miki Yara Yukie Kikuti Kazuhiko Igarashi Etsuro Ito Hideo Harigae Seiichi Kato Eiko Hayashi Takashi Oka Yoshinobu Hoshii Akira Tari Hiroyuki Okada ABD Alkader Lamia Mohamado Yoshinobu Maeda Mitsune Tanimoto Tomohiro Kinoshita Tadashi Yoshino No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 67 1 2013 Chronic Graft-versus-Host Disease: Disease Biology and Novel Therapeutic Strategies 1 8 EN Hisakazu Nishimori Yoshinobu Maeda Mitsune Tanimoto Review 10.18926/AMO/49251 Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Chronic GVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases. Standard treatment is 1-2mg/kg/day of prednisone or an equivalent dose of methylprednisolone, with continued administration of a calcineurin inhibitor for steroid sparing. However, the prognosis of steroid-refractory chronic GVHD remains poor. Classically, chronic GVHD was said to involve predominantly Th2 responses. We are now faced with a more complex picture, involving possible roles for thymic dysfunction, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), B cells and autoantibodies, and Th1/Th2/Th17 cytokines, as well as regulatory T cells (Tregs), in chronic GVHD. More detailed research on the pathophysiology of chronic GVHD may facilitate the establishment of novel strategies for its prevention and treatment. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0941-4355 19 7 2011 Bacterial substitution of coagulase-negative staphylococci for streptococci on the oral mucosa after hematopoietic cell transplantation 995 1000 EN Yoshihiko Soga Yoshinobu Maeda Fumihiko Ishimaru Mitsune Tanimoto Hiroshi Maeda Fusanori Nishimura Shogo Takashiba Coagulase-negative staphylococci (CoNS) are frequently isolated from blood cultures of hematopoietic cell transplantation (HCT) patients. Generally, the use of central venous catheters is recognized as a significant risk factor for CoNS infection, while the impact of CoNS infection from oral ulcerative mucositis, which occurs frequently in HCT, may be underestimated. Here, we examined the bacteria on the buccal mucosa after HCT. Sixty-one patients were examined for bacteria on the buccal mucosa routinely once a week from 1 week before to 3 weeks after allogeneic HCT. Subjects were divided into groups with short and long periods of antibiotic use, and differences in bacterial substitution were evaluated. The relationships between type of HCT (conventional HCT or RIST) and bacterial substitution were also evaluated. The changes in detection frequencies of CoNS and alpha-streptococci from before to 3 weeks after HCT were significant (P < 0.05, chi (2) test): 14.5-53.3% and 92.7-53.1%, respectively. Significant bacterial substitution of CoNS for streptococci was observed in the long-term antibiotic use group (P < 0.05, chi (2) test), but also occurred in cases with short-term or no antibiotic use. No relationships between type of HCT (conventional HCT or RIST) were observed. Bacterial substitution of CoNS for streptococci occurred frequently on the buccal mucosa after HCT. In addition to antibiotic use, environmental factors may be involved in bacterial substitution. It is important to consider the presence of oral mucositis in CoNS infection after HCT. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0941-4355 18 1 2010 Oral mucositis in patients receiving reduced-intensity regimens for allogeneic hematopoietic cell transplantation: comparison with conventional regimen 115 119 EN Kanayo Takahashi Yoshihiko Soga Yumeno Murayama Mika Udagawa Hitomi Nishimoto Yuko Sugiura Yoshinobu Maeda Mitsune Tanimoto Shogo Takashiba Severe oral mucositis induced by allogeneic hematopoietic cell transplantation (HCT) is associated with intolerable pain and risk of systemic bacteremia infection. Differences between conventional HCT and reduced-intensity regimens for allogeneic HCT (RIST) may influence the occurrence and severity of oral mucositis. Here, we evaluated oral mucositis in patients undergoing RIST and compared the results with those in conventional allogeneic HCT patients to facilitate predictive measures for mucositis. A total of 127 consecutive patients undergoing HCT (conventional, 63; RIST, 64) were included in this study. Severity of oral mucositis during HCT period was evaluated daily. Differences in severity of mucositis among HCT types were analyzed. Use of morphine to control pain due to oral mucositis was evaluated in each HCT method. The severity of oral mucositis was reduced in patients undergoing RIST. Worsening of oral mucositis was delayed in patients receiving RIST. Use of morphine to control pain due to oral mucositis was significantly decreased in patients undergoing RIST compared with those receiving conventional allogeneic HCT. The severity of oral mucositis was reduced and the peak day of oral mucositis was delayed in RIST patients compared with those receiving conventional HCT. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0941-4355 17 5 2009 Febrile neutropenia and periodontitis: lessons from a case periodontal treatment in the intervals between chemotherapy cycles for leukemia reduced febrile neutropenia 581 587 EN Yoshihiko Soga Yoshiko Yamasuji Chieko Kudo Kaori Matsuura-Yoshimoto Kokoro Yamabe Yuko Sugiura Yoshinobu Maeda Fumihiko Ishimaru Mitsune Tanimoto Fusanori Nishimura Shogo Takashiba Oral and systemic infections arising from the oral cavity are significant problems in clinical management of patients undergoing leukemia treatment. However, there is significant disparity in the reported incidences of development of periodontal infections. Evidence is limited to those showing the systemic influence of periodontal infection in neutropenic patients. This study indicated an association between febrile neutropenia (FN) and periodontitis in a case in which periodontal treatment in the intervals between chemotherapy cycles reduced FN in subsequent courses of chemotherapy and hematopoietic transplantation (HCT). Periodontal treatment was performed in a 61-year-old man with advanced periodontitis, who received HCT following three cycles of chemotherapy. After recovery from neutropenia induced by initial chemotherapy, periodontal treatment was performed in each chemotherapy interval period. Following extraction of teeth with severe advanced periodontitis, all teeth were subjected to periodontal pocket curettage and root planning, which are common periodontal treatments to reduce periodontal pockets harboring anaerobic periodontal bacteria, before HCT. Periodontal treatment successfully reduced periodontal pockets from 4.1 +/- 1.5 mm to 3.0 +/- 0.6 mm, which was almost within the healthy range (< 3.0 mm), before HCT. The frequency of FN decreased significantly with increasing cycles of chemotherapy, and decreases in FN corresponded to progress of periodontal treatment. Blood cultures obtained a total of 12 times throughout leukemia treatment were all negative. The observations reported here indicate the importance of periodontal treatment in clinical management of patients undergoing leukemia treatment to prevent FN, although all blood cultures were negative. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0941-4355 19 2 2011 Progress of oral care and reduction of oral mucositis-a pilot study in a hematopoietic stem cell transplantation ward 303 307 EN Yoshihiko Soga Yuko Sugiura Kanayo Takahashi Hitomi Nishimoto Yoshinobu Maeda Mitsune Tanimoto Shogo Takashiba Oral mucositis is a common symptomatic complication associated with hematopoietic stem cell transplantation (HCT). We use simple strategies aimed to reduce oral mucositis by keeping the oral cavity clean and moist. Here, we report on the progress of oral care and the changes in the degree of oral mucositis. The purpose of this pilot study is to evaluate the effects of our strategies on the prevalence and the severity of oral mucositis. Fifty-three consecutive patients from 2003 to 2006 administered with conventional allogeneic HCT were enrolled in this study. The degree of oral mucositis was evaluated daily in all patients. Our oral care program was divided into two periods: "examination and trial period (2003 and 2004)" and "intensive oral care period (2005 and 2006)." In the latter, an oral care regimen was carried out systematically by a multidisciplinary team. Using our oral care strategies, the prevalence of ulcerative oral mucositis was decreased significantly. The rate was reduced from 76% (10 of 13) of patients with ulcerative oral mucositis in 2003 to only 20% (3 of 15) in 2006. Our pilot study suggests that oral mucositis in HCT patients can be alleviated by simple strategies aimed at keeping the oral cavity clean and moist. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 124 3 2012 合成レチノイドAm80はTh1とTh17を抑制することにより慢性移植片対宿主病を改善する 197 201 EN Hisakazu Nishimori Yoshinobu Maeda Mitsune Tanimoto No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 124 1 2012 同種抗原による移植片対白血病効果減弱のメカニズム 5 8 EN Shoji Asakura Daigo Hashimoto Shuichiro Takashima Haruko Sugiyama Yoshinobu Maeda Koichi Akashi Mitsune Tanimoto Takanori Teshima No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 6 2011 Successful Extracorporeal Life Support for Life-threatening Hypercapnia with Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplantation 403 406 EN Koichi Waseda Yasushi Tanimoto Shingo Ichiba Nobuaki Miyahara Toshi Murakami Nobuaki Ochi Michihisa Terado Osamu Nagano Yoshinobu Maeda Arihiko Kanehiro Yoshihito Ujike Mitsune Tanimoto Case Report 10.18926/AMO/47266 Bronchiolitis obliterans (BO) is a disease with a poor prognosis, and a key factor that limits long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). We here report a case of a 31-year woman with acute lymphatic leukemia, which was treated by chemotherapy and HSCT, and consequently developed BO 2 years after HSCT. A non-tuberculous mycobacterial infection occurred and showed gradual exacerbation. She started taking anti-mycobacterial drugs, but lost appetite, felt tired and finally lost consciousness one month after beginning medication. Arterial blood gas revealed marked hypercapnia. Using extracorporeal life support (ECLS), the carbon dioxide concentration was reduced and her consciousness recovered. To our knowledge, this is the first case in which ECLS was successfully used for hypercapnia in a patient with BO. No potential conflict of interest relevant to this article was reported.

IEEE SMC Hiroshima Chapter Acta Medica Okayama 1883-3977 2009 1 2009 Evaluation of an economic model composed of producer agents 122 126 EN In recent years, the existence of a "social divide", comprising factors such as income and professional status, has been noted as one significant type of social issue. It has been stated that, among the disparate groups, a member belonging to one group cannot move to any other groups. Such a rigidity in terms of social status results in non-activation of the economy. In this study, we have suggested a dynamic economic model described by a multi-agent system, and have evaluated its dynamics in order to try to understand the mechanisms by which how the social divide emerges within the model. We used Gini's coefficient to evaluate the social divide and its economic efficiency. As a result, it is suggested that economies under conditions of low competitiveness, being a state composed of relatively more consumer agents than producer agents, display a higher negative relationship between Gini's coefficient and economic efficiency than those under conditions of high competitiveness. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1999 Monitoring of human herpesviruses after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation EN No potential conflict of interest relevant to this article was reported.