Japanese Society of Internal MedicineActa Medica Okayama0918-291863132024Activated 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 Therapy18631872ENWataruKitamuraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalShuntaroIkegawaDepartment of Hematology and Oncology, Okayama University Hospital, JapanHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalChihiroKamoiDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalKeikoFujiiDivision of Clinical Laboratory, Okayama University HospitalNobuharuFujiiDivision of Blood Transfusion, Okayama University HospitalKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalObjective 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 LLCActa Medica Okayama0925-571012122024Outcomes of allogeneic SCT versus tisagenlecleucel in patients with R/R LBCL and poor prognostic factors232243ENKentaHayashinoDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityToshikiTeraoDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityWataruKitamuraDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityHirokiKobayashiDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityChihiroKamoiDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityKeisukeSeikeDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityNoboruAsadaDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityKeikoFujiiDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityNobuharuFujiiDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Hospital, Okayama UniversityThis 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.ElsevierActa Medica Okayama0006-497114582025Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease881896ENYuiKambaraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Medical SchoolHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalAkiraYamamotoDepartment of Hematology and Oncology, Okayama University HospitalKazuyoshiGotohDepartment of Medical Laboratory Science, Okayama University Graduate School of Health SciencesShumaTsujiDepartment of Microbiology and Genetics, Okayama University Graduate School of Health SciencesMariKunihiroDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiOyamaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesToshikiTeraoDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAyameSatoDivision of Hospital Dentistry, Okayama University HospitalTakehiroTanakaDepartment of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDanielPeltierDivision 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 MedicineKeisukeSeikeDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University HospitalKeikoFujiiDepartment of Clinical Laboratory, Okayama University HospitalNobuharuFujiiDivision of Blood Transfusion, Okayama University HospitalKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalYoshihikoSogaDivision of Hospital Dentistry, Okayama University HospitalPavanReddyDan L Duncan Comprehensive Cancer Center, Baylor College of MedicineMaedaYoshinobuDepartment of Hematology and Oncology, Okayama University HospitalThe 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.WileyActa Medica Okayama2688-6146542024Combination 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 transplantation810814ENToshikiTeraoDepartment of Hematology and Oncology, Okayama University HospitalTakumiKondoDepartment of Hematology and Oncology, Okayama University HospitalMakotoNakamuraDepartment of Hematology and Oncology, Okayama University HospitalHirokiTakasukaDepartment of Hematology and Oncology, Okayama University HospitalHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalKeikoFujiiDepartment of Hematology and Oncology, Okayama University HospitalNobuharuFujiiDepartment of Hematology and Oncology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalKen-IchiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalWe 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.Okayama University Medical SchoolActa Medica Okayama0386-300X7822024Sigle Agent of Posttransplant Cyclophosphamide Without Calcineurin Inhibitor Controls Severity of Experimental Chronic GVHD123134ENKyosukeSaekiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalKeisukeSeikeDepartment of Hematology and Oncology, Okayama University HospitalTaigaKuroiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalTakehiroTanakaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuharuFujiiDivision of Transfusion, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOriginal Article10.18926/AMO/66915Chronic 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 HematologyActa Medica Okayama2473-95297242023Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study74597470ENTomohiroUrataDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeNaoiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAixiangJiangBritish Columbia Cancer, Centre for Lymphoid CancerMerrillBoyleBritish Columbia Cancer, Centre for Lymphoid CancerKazutakaSunamiDepartment of Hematology, NHO Okayama Medical CenterToshiImaiDepartment of Hematology and Blood Transfusion, Kochi Health Sciences CenterYuichiroNawaDivision of Hematology, Ehime Prefectural Central HospitalYasushiHiramatsuDepartment of Hematology and Oncology, Japanese Red Cross Society Himeji HospitalKazuhikoYamamotoDepartment of Hematology and Oncology, Okayama City HospitalSoichiroFujiiDepartment of Hematology, Japanese Red Cross Okayama HospitalIsaoYoshidaDepartment of Hematologic Oncology, NHO Shikoku Cancer CenterTomofumiYanoDepartment of Internal Medicine, Okayama Rosai HospitalRyotaChijimatsuCenter for Comprehensive Genomic Medicine, Okayama University HospitalHiroyukiMurakamiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuhiroIkeuchiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirokiKobayashiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsumaTaniDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHidekiUjiieCenter for Comprehensive Genomic Medicine, Okayama University HospitalHirofumiInoueClinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceShutaTomidaCenter for Comprehensive Genomic Medicine, Okayama University HospitalAkiraYamamotoDepartment of Hematology and Oncology, Okayama University HospitalTakumiKondoDepartment of Hematology and Oncology, Okayama University HospitalHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalKeikoFujiiDepartment of Hematology and Oncology, Okayama University HospitalNobuharuFujiiDepartment of Hematology and Oncology, Okayama University HospitalKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalKeisukeSawadaDepartment of Pathology, Saitama Medical Center, Saitama Medical UniversityShujiMomoseDepartment of Pathology, Saitama Medical Center, Saitama Medical UniversityJun-ichiTamaruDepartment of Pathology, Saitama Medical Center, Saitama Medical UniversityAsamiNishikoriDepartment of Molecular Hematopathology, Okayama University Graduate School of Health SciencesYasuharuSatoDepartment of Molecular Hematopathology, Okayama University Graduate School of Health SciencesTadashiYoshinoDepartment of Pathology, Okayama UniversityYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDavid W.ScottBritish Columbia Cancer, Centre for Lymphoid CancerDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University HospitalThe 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.WileyActa Medica Okayama0041-11326372023Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch13441353ENTakumiKondoDivision of Transfusion, Okayama University HospitalKeikoFujiiDivision of Clinical Laboratory, Okayama University HospitalNobuharuFujiiDivision of Transfusion, Okayama University HospitalYuichiSumiiDivision of Transfusion, Okayama University HospitalTomohiroUrataDivision of Transfusion, Okayama University HospitalMaikoKimuraDivision of Transfusion, Okayama University HospitalMasayukiMatsudaDivision of Transfusion, Okayama University HospitalShuntaroIkegawaDivision of Transfusion, Okayama University HospitalKanaWashioDepartment of Pediatrics/Pediatric Hematology and Oncology, Okayama University HospitalHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalKen‐ichiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalFumioOtsukaDivision of Clinical Laboratory, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalBackground: 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.Okayama University Medical SchoolActa Medica Okayama0386-300X7712023A Case of Radiation-Induced Osteosarcoma with RB1 Gene Alteration Treated by Skull Base Surgery and Craniofacial Reconstruction8590ENYukiMatsudaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshihiroOtaniDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakaoYasuharaDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMizuoAndoDepartment of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakayaHigakiDepartment of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakumaMakinoDepartment of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroshiMatsumotoDepartment of Plastic and Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiOyamaDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalIsaoDateDepartment of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCase Report10.18926/AMO/64367A 35-year-old female presented with headache, photophobia and developed sudden loss of vision after having undergone right-side ophthalmectomy and radiochemotherapy for retinoblastoma in infancy. A neoplastic lesion was found in the left middle cranial fossa and was surgically removed. The diagnosis was radiation-induced osteosarcoma with RB1 gene alteration. Although she received chemotherapy for the residual tumor, it progressed 17 months later. Maximal surgical resection with craniofacial reconstruction was required. We utilized two three-dimensional models for surgical planning. She was discharged without neurological deficits other than loss of light perception subsequent to left ophthalmectomy. In cases where retinoblastoma is treated with radiotherapy, long-term follow-up is necessary to monitor for radiation-induced tumor development.No potential conflict of interest relevant to this article was reported.KargerActa Medica Okayama1662-65751532022Sequential Combination of FLAM and Venetoclax plus Azacitidine to Bridge to Cord Blood Transplantation in a Patient with Primary Induction Failure Acute Myeloid Leukemia974979ENHiroyukiMurakamiDepartment of Hematology and Oncology, Okayama University HospitalKen-IchiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalTakeruAsanoDepartment of Hematology and Oncology, Japanese Red Cross Society Himeji HospitalTakashiMoriyamaDepartment of Hematology and Oncology, Okayama University HospitalAkifumiMatsumuraDepartment of Hematology and Oncology, Okayama University HospitalHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalKeikoFujiiDepartment of Hematology and Oncology, Okayama University HospitalNobuharuFujiiDepartment of Hematology and Oncology, Okayama University HospitalTomohiroTojiDepartment of Pathology, Okayama University HospitalTadashiYoshinoDepartment of Pathology, Okayama University HospitalYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalVenetoclax (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 ScienceActa Medica Okayama1932-62031792022Prevention of non-infectious pulmonary complications after intra-bone marrow stem cell transplantation in micee0273749ENYoshikoYamasuji-MaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeisukeSeikeDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAkiraYamamotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTaigaKuroiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKyosukeSaekiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHarukoFujinagaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSachiyoOkamotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKen-IchiMatsuokaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuharuFujiiDepartment of Transfusion Medicine, Okayama University HospitalTakehiroTanakaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahiroFujiiDepartment of Animal Resources, Advanced Science Research Center, Okayama UniversityKatsumiMominokiDepartment of Animal Resources, Advanced Science Research Center, Okayama UniversityTakuroKanekuraDepartment of Dermatology, Kagoshima University Graduate School of Medical and Dental SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNon-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.The Japanese Society for Lymphoreticular Tissue ResearchActa Medica Okayama1346-42806212022Transformed diffuse large B-cell lymphoma from marginal zone lymphoma in the anterior mediastinum: A case report and review of the literature3540ENWataruKitamuraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalTetsuyaTabataDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesReiShibataDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTatsuyaNishiDepartment of Respiratory and Allergy, Okayama University HospitalYukaKatoCenter for Innovative Clinical Medicine, Okayama University HospitalHirokiTakasukaDepartment of Hematology and Oncology, Okayama University HospitalHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalNobuharuFujiiDepartment of Transfusion Medicine, Okayama University HospitalKen-IchiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalKatsuyukiKiuraDepartment of Respiratory and Allergy, Okayama University HospitalTadashiYoshinoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalMarginal 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.The Japanese Society of Internal MedicineActa Medica Okayama0918-291860192021Nodal Peripheral T-cell Lymphoma with T Follicular Helper Phenotype Presenting as Chorea During Treatment: A Case Report and Literature Review31553160ENWataruKitamuraDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiCenter for Comprehensive Genomic Medicine, Okayama University HospitalRyoyaYukawaDepartment of Hematology and Oncology, Okayama University HospitalRyoSasakiDepartment of Neurology, Okayama University HospitalChikamasaYoshidaDepartment of Hematology, Okayama City HospitalHirokiTakasukaDepartment of Hematology and Oncology, Okayama University HospitalHideakiFujiwaraDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalKeikoFujiiDivision of Clinical Laboratory, Okayama University HospitalNobuharuFujiiDivision of Blood Transfusion, Okayama University HospitalKen-IchiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalKojiAbeDepartment of Neurology, Okayama University HospitalTadashiYoshinoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalA 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.Okayama University Medical SchoolActa Medica Okayama0386-300X7522021Successful Treatment of Acute Promyelocytic Leukemia Complicated with Endometrial Cancer by Arsenic Trioxide219224ENHiroyukiSugiuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHirofumiMatsuokaDepartment of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeiichiroNakamuraDepartment of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeikoFujiiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuharu FujiiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKen-ichi MatsuokaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesCase Report10.18926/AMO/61904Acute 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.Massachusetts Medical SocietyActa Medica Okayama0028-47933842021Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria10281037ENPeterHillmenthe Department of Haematology, St. James’s University HospitalJeffSzerthe Department of Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne HospitalIleneWeitzJane Anne Nohl Division of Hematology, Keck School of Medicine of USCAlexanderRöththe Department of Hematology, West German Cancer Center University Hospital Essen, University of Duisburg-EssenBrittaHöchsmannthe Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service and University Hospital UlmJensPansethe Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH AachenKensukeUsuki the Department of Hematology, NTT Medical Center TokyoMoragGriffinthe Department of Haematology, St. James’s University HospitalJean-JacquesKiladjianCentre d’Investigations Cliniques, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Université de ParisCarlosde Castrothe Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke UniversityHisakazuNishimorithe Department of Hematology and Oncology, Okayama University HospitalLisaTanLisa Tan Pharma ConsultingMohamedHamdaniApellis PharmaceuticalsPascalDeschateletsApellis PharmaceuticalsCedricFrancoisApellis PharmaceuticalsFedericoGrossiApellis PharmaceuticalsTemitayoAjayiApellis PharmaceuticalsAntonioRisitanothe Hematology and BMT Unit, AORN San Giuseppe MoscatiRégisPeffault de la Tourthe French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Université de ParisBackground</br>
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis.</br>
Methods</br>
We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed.</br>
Results</br>
Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy–Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group.</br>
Conclusions</br>
Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549. opens in new tab.)No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0918-291859162020Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case20232028ENHiroyukiSugiuraDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisakazuNishimoriDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKazuyaNishiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTomohiroTojiDepartment of Pathology, Okayama University HospitalKeikoFujiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuharuFujiiDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKen-ichiMatsuokaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKohNakataDepartment of Bioscience Medical Research Center, Niigata University Medical & Dental HospitalKatsuyukiKiuraDepartment of Allergy and Respiratory Medicine, Okayama University HospitalYoshinobuMaedaDepartment of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPulmonary 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.日本内科学会Acta Medica Okayama0918-291859212020Adult T-cell Leukemia-lymphoma with Primary Breast Involvement: A Case Report and Literature Review27572761ENHirokiKobayashiDepartment of Hematology and Oncology, Okayama University HospitalNoboruAsadaDepartment of Hematology and Oncology, Okayama University HospitalTakuroIgawaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasayaAbeDepartment of Hematology and Oncology, Okayama University HospitalYusukeMeguriDepartment of Hematology and Oncology, Okayama University HospitalDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalNobuharuFujiiDepartment of Transfusion Medicine, Okayama University HospitalKen-ichiMatsuokaDepartment of Hematology and Oncology, Okayama University HospitalTadashiYoshinoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalBreast 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.Nature ResearchActa Medica Okayama2045-232210120205-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy17237ENYasuhisaSandoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKen-IchiMatsuokaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYuichiSumiiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakumiKondoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShuntaroIkegawaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiSugiuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMakotoNakamuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMikiIwamotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYusukeMeguriDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNoboruAsadaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDaisukeEnnishiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeikoFujiiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNobuharuFujiiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAtaeUtsunomiyaDepartment of Hematology, Imamura General HospitalTakashiOkaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesPhotodynamic 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.American Society of HematologyActa Medica Okayama2473-95292152018Outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplantation19011903ENYoshihiroInamoto National Cancer Center HospitalTomohiroMatsuda National Cancer Center HospitalKenTabuchi Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome HospitalSaikoKurosawa National Cancer Center HospitalHidekiNakasoneSaitama Medical Center, Jichi Medical UniversityHisakazuNishimoriOkayama University HospitalSatoshiYamasakiNational Hospital Organization Kyushu Medical CenterNorikoDoki Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome HospitalKojiIwatoHiroshima Red Cross Hospital & Atomic-bomb Survivors HospitalTakehikoMori Keio University School of MedicineSatoshiTakahashi The Institute of Medical Science, The University of TokyoHiromasaYabeTokai University Hospital,AkioKohnoJA Aichi Konan Kosei HospitalHirohisaNakamae Osaka City UniversityToruSakuraSaiseikai Maebashi HospitalHisakoHashimoto Kobe City Medical Center General HospitalJunichiSugitaHokkaido University HospitalHiroatsuAgoShimane Prefectural Central HospitalTakahiroFukuda National Cancer Center HospitalTatsuoIchinohe Research Institute for Radiation Biology and Medicine, Hiroshima UniversityYoshikoAtsutaJapanese Data Center for Hematopoietic Cell TransplantationTakuyaYamashita St. Luke's International HospitalJapan Society for Hematopoietic Cell Transplantation Late Effects and Quality of Life Working GroupTo characterize the outcomes of patients who developed a particular subsequent solid cancer after hematopoietic cell transplantation (HCT), age at cancer diagnosis, survival, and causes of death were compared with the respective primary cancer in the general population, using data from the national HCT registry and population-based cancer registries in Japan. Among 31 867 patients who underwent a first HCT between 1990 and 2013 and had progression-free survival at 1 year, 713 patients developed subsequent solid cancer. The median age at subsequent solid cancer diagnosis was 55 years, which was significantly younger than the 67 years for primary cancer patients in the general population (P < .001). The overall survival probability was 60% at 3 years after diagnosis of subsequent solid cancer and differed according to cancer type. Development of most solid cancers was associated with an increased risk of subsequent mortality after HCT. Subsequent solid cancers accounted for 76% of causes of death. Overall survival probabilities adjusted for age, sex, and year of diagnosis were lower in the HCT population than in the general population for colon, bone/soft tissue, and central nervous system cancers and did not differ statistically for other cancers. In conclusion, most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages. Subsequent solid cancers showed similar or worse survival compared with primary cancers. Biological and genetic differences between primary and subsequent solid cancers remain to be determined.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama11912012Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.285295ENHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakanoriTeshimaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHarukoSugiyamaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKoichiroKobayashiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshikoYamasujiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSachiyoKadohisaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHidetakaUryuDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKengoTakeuchiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakehiroTanakaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTadashiYoshinoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoichiroIwakuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.No potential conflict of interest relevant to this article was reported.Elsevier ScienceActa Medica Okayama0925-571010562017Predictors of vasovagal reactions during preoperative autologous blood donation: a single-institution analysis812818ENHisakazuNishimoriDepartment of Transfusion Medicine, Okayama University HospitalNobuharuFujii Department of Transfusion Medicine, Okayama University HospitalKeikoFujii Department of Transfusion Medicine, Okayama University HospitalTohruIkeda Department of Transfusion Medicine, Okayama University HospitalNaomiAsano Department of Transfusion Medicine, Okayama University HospitalHiroakiOgo Department of Transfusion Medicine, Okayama University HospitalMiwaYamakawaDepartment of Nursing, Okayama University HospitalNaoeTakagiDepartment of Nursing, Okayama University HospitalFumioOtsukaDepartment of Transfusion Medicine, Okayama University HospitalKazumaIkedaDepartment of Transfusion Medicine, Okayama University Hospital Studies examining risk factors associated with vasovagal reactions (VVRs) during autologous blood donations, especially in younger subjects, have been limited. The aim of the present study was to define risk factors for VVRs during preoperative autologous blood donation in patients, including those younger than 18 years old. We retrospectively analyzed 4192 autologous, preoperative blood donations between 2007 and 2015 at Okayama University Hospital. Eighty-seven (2.08%) of the patients experienced VVRs. VVRs occurred approximately three times as often in patients 0-17 years old (16/320, 5.0%) than in patients 18 years and older (71/3872, 1.8%). In particular, VVRs occurred more frequently in those 10-13 years old, and decreased with older age (P = 0.006). In a univariate analysis, younger age, lower body mass index, lower systolic blood pressure, lower body weight, lower total blood volume, female gender, first-time collection, and higher heart rate were associated with a higher incidence of VVRs. In a multivariate analysis, lower systolic blood pressure (P < 0.001), higher heart rate (P = 0.007), and first-time collection (P = 0.015), remained independent predictors of VVRs. These results emphasize the need for careful attention during blood collection.No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama1471-24071712017Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study314322ENT.YokotaDivision of Gastrointestinal Oncology, Shizuoka Cancer CenterT.OgawaDepartment of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of MedicineS.TakahashiDepartment of Medical Oncology, The Cancer Institute Hospital of JFCRK.OkamiDepartment of Otolaryngology, Center of Head and Neck Surgery, Tokai UniversityT.FujiiDepartment of Otolaryngology, Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular DiseasesK.TanakaDepartment of Medical Oncology, Kindai University Faculty of MedicineS.IwaeDepartment of Head and Neck Cancer, Hyogo Cancer CenterI.OtaDepartment of Otolaryngology-Head and Neck Surgery, Nara Medical UniversityT.UedaDepartment of Otorhinolaryngology-Head and Neck Surgery, Hiroshima University HospitalN.MondenDepartment of Head and Neck Surgery, Shikoku Cancer CenterK.MatsuuraDepartment of Head and Neck Surgery, Miyagi Cancer CenterH.KojimaDepartment of Otorhinolaryngology, Jikei University School of MedicineS.Ueda Medical Oncology, Nara Hospital, Kindai University School of MedicineK.SasakiHead and Neck, Chiba Cancer CenterY.FujimotoDepartment of Otorhinolaryngology, Nagoya University, Graduate School of MedicineY.HasegawaDepartment of Head and Neck Surgery, Aichi Cancer Center Hospital and Research InstituteT.BeppuDivision of Head and Neck Surgery, Saitama Cancer CenterHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalS.HiranoDepartment of Otolaryngology-Head and Neck Surgery, Kyoto University HospitalY.Naka Headquarters of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd.Y.Matsushima Headquarters of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd.M.FujiiDepartment of Otolaryngology, Eiju General HospitalM.TaharaDepartment of Head and Neck Medical Oncology, National Cancer Center Hospital EastBACKGROUND:
Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC).
METHODS:
Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee.
RESULTS:
From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups.
CONCLUSIONS:
The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide.
TRIAL REGISTRATION:
ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7052016An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease409412ENYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalYoshihiroInamotoDepartment of Hematopoietic Stem Cell Transplantation, National Cancer Center HospitalHirohisaNakamaeDepartment of Hematology, Osaka City University HospitalMasashiSawaDepartment of Hematology and Oncology, Anjo Kosei HospitalYasuoMoriDepartment of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical SciencesKazuteruOhashiHematology Division, Tokyo Metropolitan Cancer and Infectious Diseases CenterShin-ichiroFujiwaraDivision of Hematology, Department of Medicine, Jichi Medical UniversityMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University HospitalClinical Study Protocols10.18926/AMO/54603Chronic 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.岡山医学会Acta Medica Okayama0030-155812722015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133137ENHisakazuNishimoriYoshinobuMaedaNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1083-87912022014Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease183191ENHarukoSugiyamaYoshinobuMaedaHisakazuNishimoriYoshikoYamasujiKen-ichiMatsuokaNobuharuFujiiEiseiKondoKatsujiShinagawaTakehiroTanakaKengoTakeuchiTakanoriTeshimaMitsuneTanimotoChronic 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.Biomed Central LtdActa Medica Okayama1465-993X142013IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in miceENEtsukoKurimotoNobuakiMiyaharaArihikoKanehiroKoichiWasedaAkihikoTaniguchiGenyoIkedaHikariKogaHisakazuNishimoriYasushiTanimotoMikioKataokaYoichiroIwakuraErwin W.GelfandMitsuneTanimotoBackground: Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it's role in the inflammatory response of elastase-induced emphysema remains unclear.
Methods: In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid.
Results: Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment.
Conclusions: These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812612014糖尿病の腎臓においてcholecystokininはマクロファージに対する抗炎症作用を介した新規の保護効果を発揮する16ENSatoshiMiyamotoKenichiShikataKyokoMiyasakaShinichiOkadaMotofumiSasakiRyoKoderaDaishoHirotaNobuoKajitaniTetsuharuTakatsukaHitomiKataoka UsuiShingoNishishitaChikageHoriguchi SatoAkihiroFunakoshiHisakazuNishimoriHaruhito AdamUchidaDaisukeOgawaHirofumiMakinoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6712013Chronic Graft-versus-Host Disease: Disease Biology and Novel Therapeutic Strategies18ENHisakazuNishimoriYoshinobuMaedaMitsuneTanimotoReview10.18926/AMO/49251Graft-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.岡山医学会Acta Medica Okayama0030-155812432012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197201ENHisakazuNishimoriYoshinobuMaedaMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.