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.

Springer Science and Business Media LLC Acta Medica Okayama 2168-8184 17 6 2025 Whole-Eye Radiation for the Local Control of Choroidal Lymphoma in Primary Central Nervous System Lymphoma: A 14-Year Case Study e85680 EN Toshihiko Matsuo Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Tomofumi Yano Department of Internal Medicine, Okayama Rosai Hospital Kotaro Yoshio Department of Radiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Takehiro Tanaka Department of Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Hirotake Nishimura Department of Pathology, Kawasaki Medical School Ken-ichi Matsuoka Department of Hematology and Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Involved-site radiation therapy is effective for curative and palliative treatments of cancers, including lymphoma. This case study describes the use of whole-eye radiation for primary intraocular lymphoma occurring during primary central nervous system lymphoma. The patient, a 68-year-old man, developed personality changes and apathy two weeks after cataract surgery combined with vitrectomy for vitreous opacity in the left eye. Magnetic resonance imaging revealed a mass lesion in the left frontal lobe, and biopsy by craniotomy confirmed diffuse large B-cell lymphoma. He underwent chemotherapy using rituximab combined with high-dose methotrexate and high-dose cytarabine in association with intrathecal methotrexate and cytarabine injections, leading to complete remission. At age 75, he noticed forgetfulness, and fluorodeoxyglucose positron emission tomography and magnetic resonance imaging revealed a relapse of lymphoma in the splenium of the corpus callosum. He underwent chemotherapy using rituximab combined with high-dose methotrexate, followed by monthly rituximab monotherapy for one year and then rituximab monotherapy every two months for one year. He maintained complete remission with no treatment until age 78, when he developed subretinal choroidal lesions in the left eye and underwent whole-eye radiation at 40 Gy. One year later, he developed subretinal choroidal lesions in the right eye and underwent whole-eye radiation at 40 Gy. At age 81, he had lower limb weakness with disorientation. Magnetic resonance imaging showed a relapse of lymphoma in the right frontal to temporal lobe. The brain lesions showed a marked response to four weeks of oral tirabrutinib as a salvage therapy, but the lesions regrew, and the patient died seven months later. Throughout the treatment, he maintained a visual acuity of 0.7 (decimal scale) in both eyes. In conclusion, whole-eye radiation should be considered as a treatment option for the local control of active intraocular lymphoma, especially choroidal lesions, for patients with primary central nervous system lymphoma with no active brain lesions and without systemic treatment. 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.

Springer Science and Business Media LLC Acta Medica Okayama 2168-8184 17 3 2025 A Natural Course From Primary Intraocular Lymphoma to Brain Lymphoma in Four Years According to Patient's Choice e81476 EN Toshihiko Matsuo Department of Ophthalmology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Takehiro Tanaka Department of Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Joji Ishida Department of Neurological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Shotaro Kondo Department of Internal Medicine, Kurashiki Municipal Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Primary intraocular lymphoma or vitreoretinal lymphoma is a rare entity of diffuse large B-cell lymphoma that presents vitreous opacity and retinal and choroidal infiltration. Primary central nervous system lymphoma would occur previously, later, or concurrently with respect to primary intraocular lymphoma. This study reported a 72-year-old patient with a pathological diagnosis of primary intraocular lymphoma who developed central nervous system lymphoma four years later in the course of no treatment. She presented with a four-year history of blurred vision in both eyes after cataract surgeries. Three weeks previously, she underwent a vitrectomy in the left eye at a clinic, and measurements of the vitreous fluid showed a high level of interleukin-10 at 5739 pg/mL, in contrast with interleukin-6 at 142 pg/mL. Cytology of the vitreous fluid was class III on the Papanicolaou classification. Head magnetic resonance imaging detected nothing abnormal. She underwent vitrectomy in the right eye as a diagnostic procedure to show large cells in the vitreous which were positive for CD20 and Ki-67 and negative for CD3, leading to a pathological diagnosis of large B-cell lymphoma. Prophylactic chemotherapy with high-dose methotrexate was recommended as a therapeutic option, but she chose observation since she did not have any eye or systemic symptoms. In the follow-up every three months by an oncologist and an ophthalmologist, she did not have any symptoms, and serum levels of soluble interleukin-2 receptor were in the normal range at each visit. She was well for four years until the age of 76 years when she fell and hit her head, and an emergency head computed tomography scan showed a mass in the left occipital lobe. Magnetic resonance imaging demonstrated a well-defined circular mass in the left occipital lobe with a hyperintense signal in the T2-weighted fluid-attenuated inversion recovery (FLAIR) image and diffusion-weighted image. Fluorodeoxyglucose positron emission tomography showed no abnormal uptake systemically, except for the left occipital lesion. She underwent a brain biopsy by craniotomy to pathologically prove diffuse large B-cell lymphoma. She was recommended to receive first-line chemotherapy as the standard treatment but chose observation with no treatment and died of brain lymphoma nine months later. This case happened to illustrate a natural course of primary intraocular lymphoma which proceeded to central nervous system lymphoma four years later. 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.

Elsevier Acta Medica Okayama 0006-4971 145 8 2025 Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease 881 896 EN Yui Kambara Department of Hematology, Oncology and Respiratory Medicine, Okayama University Medical School Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Akira Yamamoto Department of Hematology and Oncology, Okayama University Hospital Kazuyoshi Gotoh Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences Shuma Tsuji Department of Microbiology and Genetics, Okayama University Graduate School of Health Sciences Mari Kunihiro Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Oyama Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiki Terao Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ayame Sato Division of Hospital Dentistry, Okayama University Hospital Takehiro Tanaka Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daniel Peltier Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Simon Cancer Center, Indiana University School of Medicine Keisuke Seike Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Keiko Fujii Department 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 Yoshihiko Soga Division of Hospital Dentistry, Okayama University Hospital Pavan Reddy Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine Maeda Yoshinobu Department of Hematology and Oncology, Okayama University Hospital The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD. 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.

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.

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.

Frontiers Media SA Acta Medica Okayama 1664-3224 12 2021 Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives 713358 EN Shuntaro Ikegawa Department of Hematology and Oncology, Okayama University Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.</p> 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.

The Japanese Society of Internal Medicine Acta Medica Okayama 0918-2918 59 23 2020 Four Cases of Desquamative Esophagitis Occurring after Hematopoietic Stem Cell Transplantation 3015 3022 EN Masaya Iwamuro Department of Gastroenterology and Hepatology, 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 Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Hospital Shotaro Okanoue Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuka Obayashi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroyuki Sakae Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshiro Kawahara Department of Practical Gastrointestinal Endoscopy, Okayama University Hospital Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences We herein report four patients with desquamative esophagitis that developed one to nine days after peripheral blood stem cell transplantation (PBSCT). Three patients underwent allogeneic PBSCT for leukemia, and the other underwent autologous PBSCT for pineoblastoma. Esophagogastroduodenoscopy revealed mucosal sloughing and fresh blood in the esophagus. Fasting and intravenous proton pump inhibitor therapy in addition to blood transfusion improved the esophageal lesions within five to seven days in three patients. These cases indicate that desquamative esophagitis can occur in patients who receive hematopoietic stem cell transplantation. Although blood transfusions may be required, it can be resolved within seven days. 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.

MDPI Acta Medica Okayama 2072-6694 12 2 2020 Sensitive Photodynamic Detection of Adult T-cell Leukemia/Lymphoma and Specific Leukemic Cell Death Induced by Photodynamic Therapy: Current Status in Hematopoietic Malignancies 335 EN Takashi Oka Department of Hematology, Oncology & Respiratory Med., Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ken-Ichi Matsuoka Department of Hematology, Oncology & Respiratory Med., Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Atae Utsunomiya Department of Hematology, Imamura General Hospital Adult T-cell leukemia/lymphoma (ATL), an aggressive type of T-cell malignancy, is caused by the human T-cell leukemia virus type I (HTLV-1) infections. The outcomes, following therapeutic interventions for ATL, have not been satisfactory. Photodynamic therapy (PDT) exerts selective cytotoxic activity against malignant cells, as it is considered a minimally invasive therapeutic procedure. In PDT, photosensitizing agent administration is followed by irradiation at an absorbance wavelength of the sensitizer in the presence of oxygen, with ultimate direct tumor cell death, microvasculature injury, and induced local inflammatory reaction. This review provides an overview of the present status and state-of-the-art ATL treatments. It also focuses on the photodynamic detection (PDD) of hematopoietic malignancies and the recent progress of 5-Aminolevulinic acid (ALA)-PDT/PDD, which can efficiently induce ATL leukemic cell-specific death with minor influence on normal lymphocytes. Further consideration of the ALA-PDT/PDD system along with the circulatory system regarding the clinical application in ATL and others will be discussed. ALA-PDT/PDD can be promising as a novel treatment modality that overcomes unmet medical needs with the optimization of PDT parameters to increase the effectiveness of the tumor-killing activity and enhance the innate and adaptive anti-tumor immune responses by the optimized immunogenic cell death. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 5 2016 Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease 429 433 EN Takeru Asano Department of Hematology and Oncology, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Satoshi Iyama Department of Medical Oncology and Hematology, Sapporo Medical University Hospital Kazuteru Ohashi Hematology division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital Yoshihiro Inamoto Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital Chikako Ohwada Department of Hematology, Chiba University Hospital Makoto Murata Department of Hematology and Oncology, Nagoya University Graduate School of Medicine Atsushi Satake First Department of Internal Medicine, Kansai Medical University Chikamasa Yoshida Division of Hematology, National Hospital Organization Minami-Okayama Medical Center Koichi Nakase Division of Hematology, Ehime Prefectural Central Hospital Yasuo Mori Department of Hematology and Oncology, Kyushu University Hospital Mitsune Tanimoto Department of Hematology and Oncology, Okayama University Hospital Clinical Study Protocols 10.18926/AMO/54608 Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT. 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.