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Three monoclonal antibodies (MAbs) c74.33, c74.180 and c74.22, exhibit high degrees of specificity for Listeria monocytogenes serotype 4b. Antibody c74.22 fails to recognizes few epidemic-associated strains, while other two recognize all the serotype 4b strains. Heat treatment nullifies the activity of c74.22 but not of the c74.33 MAb. c74.22 recognizes a surface antigen that has the capacity of bacteria to enter cultured mammalian cells.

Background: Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases., Methods: The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output., Results: In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea., Conclusions: PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for B cell malignancies. A certain fraction of patients, however, experience post-CAR-T relapse, and due to the difficulty of precise relapse prediction, biomarkers that can predict the strength and duration of CAR-T efficacy are needed before CAR-T infusion. Therefore, we performed a single-center cohort study including 91 diffuse large B cell lymphoma (DLBCL) patients treated with CAR-T in order to identify such a new prognostic biomarker. After confirming that each of the already reported prognostic parameters (disease status at leukapheresis, primary refractoriness, number of treatment lines, CD3 + cell counts at leukapheresis) has only limited predictive performance, we established a new composite parameter by integrating these four variables, and found that it predicts progression-free survival (PFS) after CAR-T infusion with statistical significance. Moreover, after comprehensive correlation analyses of this new composite parameter with all individual laboratory variables, we determined that the standard deviation of red blood cell distribution width (RDW-SD) at leukapheresis shows significant correlation with the composite parameter and may be a prognostic biomarker (R 2  = 0.76, p = 0.02). Validation analysis indicated that a higher RDW-SD is significantly associated with poorer PFS after CAR-T cell therapy (HR, 3.46, P = 0.03). Thus, this study suggests that a single parameter, RDW-SD at leukapheresis, is a novel, useful biomarker that can be obtained early to predict therapeutic effects of CAR-T cell therapy. Post-CAR-T maintenance or re-induction therapies should be adopted for higher risk patients, who may relapse after CAR-T therapy., (© 2024. The Author(s).)

Prolonged hematotoxicity is the most common long-term adverse event in chimeric antigen receptor T cell therapy (CAR-T). To evaluate the impact on prolonged cytopenia of inflammatory status after CAR T infusion, we performed a single-center retrospective study and analyzed patients with B cell lymphomas after CAR-T. Among 90 patients analyzed at 90 days after infusion, the cumulative incidence was 57.5% for prolonged neutropenia, 36.7% for anemia, and 49.8% for thrombocytopenia. Patients who experienced cytokine release syndrome (CRS) had significantly higher incidence and longer duration of prolonged cytopenia. In addition, we found that among patients with grade 1 CRS, those with a longer duration of CRS-related symptoms (>5 days; grade 1b in modified CRS grading [m-CRS]) had a significantly higher incidence and longer duration of prolonged cytopenia than those whose CRS-related symptoms resolved within 5 days (grade 1a m-CRS). Multivariate analysis revealed that a higher m-CRS grade (grade 1b or 2; hazard ratio [HR], 2.42), higher peak CRP (≥10 mg/dL; HR, 1.66), longer duration of elevated CRP (≥10 days; HR, 1.83), and a decrease in serum inorganic phosphorus concentration (≥30% from baseline; HR, 1.95) were associated with significantly higher cumulative incidence of prolonged neutropenia, as well as anemia and thrombocytopenia. Using these factors, we developed a new predictive scoring model for prolonged hematotoxicity, the KyoTox a-score, which can successfully stratify the incidence and duration of cytopenia independent of the existing model, CAR-HEMATOTOX, which is based on laboratory data at lymphodepletion. Thus, this newly developed post-CAR-T inflammation-dependent score is accurate and useful for predicting prolonged hematotoxicity., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has a poor prognosis. Nelarabine has recently shown relatively good results in patients with relapsed or refractory T-ALL/LBL, but requires careful monitoring for neurological complications. A 50-year-old man with early recurrence of T-LBL after allogenic peripheral blood stem cell transplantation received nelarabine monotherapy and achieved complete remission after 1 cycle. He then received umbilical cord blood transplantation, and experienced sustained disturbance of consciousness. He later died of multiple organ failure, and autopsy suggested that nelarabine-induced leukoencephalopathy had caused the disturbance of consciousness. This case suggests that physicians should carefully monitor patients for neurological complications and consider imaging follow-up and consultation with a neurologist.

Acute kidney injury (AKI) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of multiple antimicrobials is one of the major causes of post-transplantation AKI, owing to the potential nephrotoxicity of each agent and of drug-drug interactions (DDIs). No satisfactory reports on DDIs the field of allo-HSCT have been published. We performed a retrospective analysis to compare the incidence of AKI within 100 days post-transplantation. A total of 465 allo-HSCTs in 416 patients were analyzed, and the cumulative incidence of AKI was 40.0%. AKI was associated with significantly reduced overall survival (hazard ratio [HR], 2.66; 95% confidence interval [CI] 1.95 to 3.55; P < .01) and increased transplantation-related mortality (HR, 4.77, 95% CI, 2.90 to 7.88; P < .01). A higher incidence of AKI was significantly associated with the use of ciprofloxacin, cefepime, tazobactam/piperacillin, meropenem, vancomycin, liposomal amphotericin B, ganciclovir, and foscarnet. Among these drugs, combinations of vancomycin plus tazobactam/piperacillin (HR, 2.23; P = .09 for interaction), ganciclovir plus cefepime (HR, 5.93; P = .04), and ganciclovir plus meropenem (HR, 2.63; P = .12) synergistically increased the risk of AKI, whereas combinations involving teicoplanin did not. This is the first report dealing with DDIs after allo-HSCT, indicating that such combinations should be avoided to preserve renal function and reduce AKI-related morbidity and mortality., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Optimized management of citrate-induced hypocalcemia is required to provide safe leukapheresis. We prospectively analyzed subjects who underwent leukapheresis for cytotherapy, and evaluated serum ionized (iCa) concentrations before, at the end of, and 1 h after leukapheresis. During leukapheresis, calcium gluconate solution was continuously supplemented intravenously with hourly measurement of iCa. 76 patients including 49 lymphapheresis for chimeric antigen receptor T-cell therapy and 27 stem cell collections were enrolled. Median processing blood volume was 10 L (range, 6-15 L). Fluctuating hypercalcemia, in which the iCa concentration rose above its upper limit 1 h after leukapheresis, was observed in 58 subjects (76.3%). Multivariate analysis revealed that higher ratios of processing blood volume to body weight, more rapid calcium supplementation, and lower iCa concentration at the end of leukapheresis significantly increased elevation of serum iCa concentration by 1 h after leukapheresis. Based on multivariate analyses, we developed a formula and a diagram that accurately estimates serum iCa concentration 1 h post-leukapheresis. This suggests optimal targets for iCa concentration and calcium supplementation rates. In cases with high ratios of processing blood volume to body weight, slowing the rate of blood processing, rather than increasing calcium supplementation should safely alleviate hypocalcemia during leukapheresis without inducing hypercalcemia thereafter., (© 2023. Springer Nature Limited.)

Autoimmune neutropenia (AIN) is an exceptionally rare condition that occurs after liver transplantation. Here, we report an adult case of refractory AIN 3.5 years after liver transplantation. A 59-year-old man who underwent brain-dead donor liver transplantation in August 2018 developed rapid neutropenia (0.07 × 10 9 /L) in December 2021. The patient was diagnosed with AIN based on positivity for anti-human neutrophil antigen-1a antibody. There was no response to granulocyte colony-stimulating factor (G-CSF), prednisolone, or rituximab, and intravenous immunoglobulin (IVIg) therapy induced only a temporary recovery in neutrophil count. The patient continued to have a low neutrophil count for several months. However, the response to IVIg and G-CSF improved after the post-transplant immunosuppressant was changed from tacrolimus to cyclosporine. Post-transplant AIN has many unknown aspects. Tacrolimus-induced immunomodulation and graft-associated alloimmunity may be involved in its pathogenesis. Further studies are needed to elucidate the underlying mechanisms and explore new treatment options., (© 2023. Japanese Society of Hematology.)

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by UBA1 somatic mutations and is characterized by late-onset systemic autoimmune inflammation and blood abnormalities such as cytopenia, vacuolation of myeloid/erythroblastic cells, and myelodysplastic syndrome (MDS). It is often resistant to immunosuppressive therapy, and no treatment strategy has been established. A 65-year-old man presented with palpable erythema, fever, macrocytic anemia, and arthralgia. He was subsequently diagnosed with MDS complicated by Sweet's disease. Treatment with azacitidine was initiated due to suspected skin invasion by MDS cells and resistance of the skin rash to steroid therapy. Next-generation sequencing of bone marrow samples prior to treatment initiation revealed the presence of UBA1 p.M41L (VAF 0.38) and DNMT3A p.L605fs mutations (VAF 0.184). Based on the findings of systemic inflammation, a diagnosis of VEXAS syndrome was made. The fever and skin rash improved with azacitidine therapy. In conclusion, somatic mutations in UBA1 should be explored in patients with MDS exhibiting systemic autoimmune inflammation. Furthermore, azacitidine may be a good treatment option for systemic autoinflammation in MDS associated with VEXAS syndrome., (© 2023. Japanese Society of Hematology.)

The combination of calcineurin inhibitors and short-term methotrexate has been used as a standard graft-versus-host-disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation. Mini-dose methotrexate (mini-MTX), consisting of 5 mg/m 2 /d on days 1, 3, 6, and 11, is occasionally selected as an alternative considering toxicity. The significance of day 11 administration remains unclear. We performed a retrospective study of 135 cases of unrelated bone marrow transplantation at our institute between 2006 and 2019 and compared the outcomes between day 11 MTX dose omitted (n = 72) and full-doses of mini-MTX (n = 63). In total cohort, the 4-year overall survival (OS) was 58.7 %, and the omitted group showed poor GVHD/relapse-free-survival (P = .01) with comparable OS (P = .11) and relapse-free survival (P = .11). Human leukocyte antigen (HLA) mismatch is a major risk factor for severe GVHD. We analyzed the impact of omitting day 11 MTX in 2 cohorts from HLA matched or mismatched donors. In both cohorts, the omitted group had a higher risk of severe acute and chronic GVHD. In conclusion, the omission of day 11 MTX was associated with a higher risk of severe GVHD. Therefore the omission of the day 11 dose is not recommended., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Prediction of responses to chimeric antigen receptor (CAR)-T cell therapies is essential to maximize their therapeutic efficacy for diffuse large B-cell lymphoma (DLBCL). While several tumor-intrinsic risk factors of resistance and/or early relapse have been identified, clinically useful markers that determine potential activity of CAR-T cells have not been fully investigated. T-cell property at the time of leukapheresis may serve as such a marker. Therefore, we evaluated the clinical impact of CD3 + cell count in peripheral blood at leukapheresis on clinical outcomes of CAR-T cell therapy. In total, 44 patients with relapsed or refractory (r/r) DLBCL who received tisagenlecleucel at Kyoto University Hospital were included. According to CD3 + cell counts, patients were categorized into CD3 LOW and CD3 HIGH groups with a threshold of 553/μL, based on receiver operating characteristic curve analysis. 1-year progression-free survival was significantly higher in the CD3 HIGH group than the CD3 LOW group (68.3% vs. 17.3%; adjusted hazard ratio [aHR], 0.37; p = 0.042). Overall survival was also superior in the CD3 HIGH group (aHR, 0.24; p = 0.043). Moreover, higher CD3 + cell counts at leukapheresis were associated with significantly higher lymphocyte counts in peripheral blood at day 7 after CAR-T cell infusion (median 860 vs. 420/μL, P = 0.021), suggesting more extensive expansion of infused CAR-T cells in vivo. In conclusion, we demonstrated that the CD3 + cell count at leukapheresis predicts both expansion of CAR-T cells after infusion and outcomes of CAR-T cell therapy, and are useful for building comprehensive therapeutic strategies at the time of leukapheresis., (© 2022. The Author(s).)

Anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy has facilitated progress in treatment of refractory/relapsed diffuse large B-cell lymphoma (DLBCL). A well-known adverse event after CAR-T therapy is cytokine release syndrome(CRS). However, the etiology and pathophysiology of CRS-related coagulopathy remain unknown. Therefore, we conducted a prospective cohort study to comprehensively analyze coagulation/ fibrinolysis parameters present in peripheral blood of adult DLBCL patients treated with tisagenlecleucel in a single institution. Samples were collected from 25 patients at 3 time points: before lymphocyte-depletion chemotherapy and on days 3 and 13 after CAR-T infusion. After infusion, all patients except 1 experienced CRS, and 13 required the administration of tocilizumab. A significant elevation in the plasma level of total plasminogen activator inhibitor 1 (PAI-1), which promotes the initial step of coagulopathy (mean, 22.5 ng/mL before lymphocyte-depletion and 41.0 on day 3, P = .02), was observed at the onset of CRS. Moreover, this suppressed fibrinolysis-induced relatively hypercoagulable state was gradually resolved after CRS remission with normalization of total PAI-1 to preinfusion levels without any organ damage (mean values of soluble fibrin: 3.16 µg/mL at baseline, 8.04 on day 3, and 9.16 on day 13, P < .01; and mean PAI-1: 25.1 ng/mL on day 13). In conclusion, a hypofibrinolytic and relatively hypercoagulable state concomitant with significant total PAI-1 elevation was observed at the onset of CRS even in DLBCL patients with mild CRS. Our results will facilitate understanding of CRS-related coagulopathy, and they emphasize the importance of monitoring sequential coagulation/fibrinolysis parameters during CAR-T therapy., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Essential thrombocythemia gradually developed into secondary myelofibrosis and progressed to leukemia eight months later in a 53-year-old man. After remission induction therapy, he achieved remission by undergoing allogeneic hematopoietic stem cell transplantation from unrelated patients in non-remission. However, peripheral blood WT-1 mRNA gradually increased, and the disease relapsed three years and six months after transplantation. He was taking prednisolone (7.5 mg) and tacrolimus (5 mg) for chronic pulmonary graft-versus-host disease (GVHD) and was reluctant to reduce or discontinue immunosuppressive drugs; therefore, donor lymphocyte infusion (DLI) was performed for a total of five times. Four months after the fifth DLI, cutaneous GVHD appeared, a slow decrease in WT-1 mRNA was observed, and blasts in the peripheral blood disappeared. One year and three months after the last DLI, he achieved complete remission. Although DLI for post-transplant relapse in patients with secondary myelofibrosis or leukemia is rare, it can be beneficial for post-relapse therapy.

Background: BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase., Methods: DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period., Findings: Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed., Interpretation: Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population., Funding: Bristol-Myers Squibb., Competing Interests: Declaration of interests KM has received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, Celgene, Eisai, Sanofi, Janssen, and Otsuka Pharmaceuticals. TKu received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals. HT received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals. KN received grants from Kyowa-Kirin, and honoraria from Alexion. CY received honoraria from Bristol-Myers Squibb, Novartis KK, Pfizer Japan, Otsuka Pharmaceutical, AbbVie GK, Janssen Pharmaceutical KK, Nippon Shinyaku, and Chugai Pharmaceutical. NU received honoraria from Eisai and Janssen Pharmaceutical. KU received grants from Astellas Pharma, AbbVie, Apellis, SymBio, Daiichi-Sankyo, Novartis, Janssen, Otsuka, Astellas Amgen Biopharma, Takeda, Nippon-Shinyaku, Bristol-Myers Squibb, Amgen, Alexion, Incyte, Ono, Kyowa-Kirin, Celgene, Sumitomo-Dainippon, Chugai, Pfizer, Mundi, Yakult, MSD, Gilead, and Nippon-Boehringer-Ingelheim and honoraria from Novartis, Bristol-Myers-Squibb, Sanofi, Pfizer, Abbvie, Takeda, Ono, Kyowa-Kirin, Astellas, Alexion, Eisai, MSD, Otsuka, Celgene, Daiichi-Sankyo, Nippon-Shinyaku, PharmaEssentia, Yakult, SymBio, Alexion, and Chugai. JK received grants from Bristol-Myers Squibb, Sysmex, Celgene, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Kyowa Kirin, Sanofi, Chugai Pharmaceutical, Eisai, Dainippon Sumitomo Pharma, Nippon Shinyaku, Takeda, Shionogi, Asahi Kasei, Daiichi Sankyo, MSD, Taiho Pharmaceutical, and Abbvie; has received honoraria from Bristol–Myers Squibb, Janssen Pharmaceutical KK, Celgene Corporation, Ono Pharmaceutical, Takeda, Sanofi, Kyowa Kirin, Chugai Pharmaceutical, Eisai, Astellas Pharma, Nippon Shinyaku, Dainippon Sumitomo Pharma, Symbio, Daiichi Sankyo, Fujimoto Pharmaceutical, Abbvie, and Otsuka Pharmaceutical; and consulting fees from Janssen Pharmaceutical KK, Bristol-Myers Squibb, Sanofi, and Abbvie. TO received grants from Celgene, Kyowa Hakko Kirin, Chugai Pharmaceutical, TAIHO Phamaceutical; and honoraria from Celgene, Kyowa Hakko Kirin, Chugai Pharmaceutical, Novartis, Bristol-Myers Squibb, Pfizer, Otsuka Pharmaceutical, ONO Pharmaceutical, Takeda Pharmaceutical, Astellas Pharma, Eisai Pharmaceuticals, Janssen Pharm, Daiichi Sankyo, and Mundipharma. KF received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals. HS received honoraria from Takeda, Ono, Novartis, Janssen, Chugai, Eizai, Nippon Shinyaku, Sanofi, AstraZeneca, Bristol-Myers Squibb, Otsuka, Mundi Pharma and Kyowa Kirin; and research funding from Janssen, Ono, Celgene, Novartis, Sanofi, AstraZeneca, AbbVie, and Chugai. TKo received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, Otsuka Pharmaceuticals, and Abbvie; and has served in an advisory role for Astellas Pharma and Otsuka Pharmaceutical. YMi received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Astellas; and research funding from Ono and CMIC Holdings. ShK has received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals; and research funding from Bristol-Myers Squibb, Pfizer, Otsuka Pharmaceuticals, and Ohara Pharmaceuticals. All other authors declare no competing interests, (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Among non-tuberculous mycobacteria (NTM), the Mycobacterium simiae complex is one of the largest groups, consisting of 18 species of slow-growing mycobacteria. In 2009, a case of NTM-associated infectious skin disease was reported in Shiga Prefecture, Japan. The patient presented with scattered nodules on the chest, back and extremities, and an M. simiae-like organism was isolated from skin biopsy specimens obtained from one of these lesions. Based on several assessments, including multiple-gene analyses, biochemical characterization and drug susceptibility testing, we concluded that this isolate represented a novel species of NTM, and proposed the name 'Mycobacterium shigaense'. Since 2009, five more cases of NTM-associated infectious disease in which there was a suspected involvement of 'M. shigaense' have been reported. Interestingly, four of these six cases occurred in Shiga Prefecture. Here we performed multiple-gene phylogenetic analyses, physiological and biochemical characterization tests, drug susceptibility tests, and profiling of proteins, fatty acids and mycolic acids of eight clinical isolates from the six suspected 'M. shigaense' cases. The results confirmed that all of the clinical isolates were 'M. shigaense', a slow-growing, scotochromogenic species. Here M. shigaense is validly proposed as a new member of the M. simiae complex, with the type strain being UN-152 T (=JCM 32072 T =DSM 46748 T ).

IgG4-related disease (IgG4RD) is a multi-organ disorder characterized by an elevated serum IgG4 level and IgG4-positive plasma cell infiltration of the affected organs, accompanied by tissue fibrosis and sclerosis. Although it can affect any organ, to our knowledge, no cases involving concurrent autoimmune neutropenia and thrombocytopenia have been reported. A 62-year-old man visited our hospital and was diagnosed with IgG4RD accompanied by interstitial pneumonitis, lymphadenopathy, and interstitial nephritis. During his clinical course, he developed autoimmune neutropenia and idiopathic thrombocytopenic purpura. Our case, invoving multiple hematological abnormalities, might help deepen our understanding of the pathophysiology of IgG4RD.

A 44-year-old woman in the first remission phase of mixed-phenotype acute leukemia (T-lymphoid and myeloid lineages) suddenly exhibited thrombocytopenia (1.1×10 4 /µl) with generalized petechiae approximately 150 days after bone marrow transplantation (BMT) from a one-locus (HLA-B) mismatched unrelated donor. Until then, the donor bone marrow had smoothly engrafted, and the platelet count had promptly normalized. Despite extensively searching for the triggering agent such as GVHD, graft failure, relapsed leukemia, or adverse drug effects, it could not be determined. Suspecting immune thrombocytopenia secondary to BMT, prednisolone (1 mg/kg/2 days) therapy was initiated, but its effects were unsatisfactory. Next, eltrombopag, a thrombopoietin receptor agonist (TPO-RA), was administered, which exhibited a marked effect on thrombocytopenia, resulting in the withdrawal of prednisolone. Even though the efficacy of eltrombopag against immune thrombocytopenia is well established, limited studies have reported the efficacy and safety of eltrombopag against immune thrombocytopenia after allogeneic stem cell transplantation. Herein we report a case in which thrombocytopenia occurred late after transplantation but was successfully treated with a TPO-RA. In addition, we discuss suspected causative mechanisms and review the literature.

Iron overload is considered a risk factor for mortality in patients with hematopoietic malignancies. Hepcidin is a key regulator of systemic iron balance. We previously reported dynamic changes of serum hepcidin-25 levels in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we retrospectively analyzed the association of pretransplant hepcidin-25 levels with overall survival (OS), engraftment, and other clinical outcomes of allo-HSCT in patients with hematologic malignancies. A total of 166 patients were divided into two groups depending on their pretransplant serum hepcidin-25 levels; their median age was 49.5 years, and the median follow-up time was 46.8 months. At 3 years, the patients in the high-hepcidin group had a significantly lower OS than those in the low-hepcidin group (49.2 vs. 69.0%, respectively; P = 0.006). Multivariate analysis revealed that pretransplant serum hepcidin-25 level, sex, and disease status were independently associated with OS. The incidence of platelet engraftment was significantly lower in the high-hepcidin group than in the low-hepcidin group, whereas no significant differences were observed in neutrophil and reticulocyte engraftments between these groups. Hence, pretransplant serum hepcidin levels can be a marker for predicting delayed platelet recovery after allo-HSCT., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Ferritin is an iron-storage protein composed of different ratios of 24 light (L) and heavy (H) subunits. The serum level of ferritin is a clinical marker of the body's iron level. Transferrin receptor (TFR)1 is the receptor not only for transferrin but also for H-ferritin, but how it binds two different ligands and the blood cell types that preferentially incorporate H-ferritin remain unknown. To address these questions, we investigated hematopoietic cell-specific ferritin uptake by flow cytometry. Alexa Fluor 488-labeled H-ferritin was preferentially incorporated by erythroid cells among various hematopoietic cell lines examined, and was almost exclusively incorporated by bone marrow erythroblasts among human primary hematopoietic cells of various lineages. H-ferritin uptake by erythroid cells was strongly inhibited by unlabeled H-ferritin but was only partially inhibited by a large excess of holo-transferrin. On the other hand, internalization of labeled holo-transferrin by these cells was not inhibited by H-ferritin. Chinese hamster ovary cells lacking functional endogenous TFR1 but expressing human TFR1 with a mutated RGD sequence, which is required for transferrin binding, efficiently incorporated H-ferritin, indicating that TFR1 has distinct binding sites for H-ferritin and holo-transferrin. H-ferritin uptake by these cells required a threshold level of cell surface TFR1 expression, whereas there was no threshold for holo-transferrin uptake. The requirement for a threshold level of TFR1 expression can explain why among primary human hematopoietic cells, only erythroblasts efficiently take up H-ferritin.

Background: Lipocalin 2 (LCN2 or neutrophil gelatinase-associated lipocalin) is a secretory protein discovered from neutrophils, which accumulates in the blood and urine during acute kidney injury (AKI) and in the blood by bacterial infection. Little is known about the tissue source and molecular forms of this protein under normal and pathophysiologic conditions., Methods: By sandwich ELISA, serum and urinary LCN2 levels were measured in 36 patients with hematologic malignancies who transiently became neutropenic by stem cell transplantation (SCT). To evaluate contribution of neutrophil-derived LCN2 in the physiologic blood LCN2 concentrations, we examined CCAAT/enhancer-binding protein ε (C/EBPε) knockout mice, which lack mature neutrophils., Results: In patients without AKI and bacterial infection, at 1 week after SCT, the median blood neutrophil counts became zero and serum LCN2 levels were decreased by 76 ± 6 % (p < 0.01), but urinary LCN2 levels were not altered. During neutropenic conditions, bacterial infection caused only a modest rise of serum LCN2 but AKI produced a marked rise of serum and urinary LCN2 levels. Serum LCN2 concentrations in C/EBPε knockout mice were reduced by 66 ± 11 % compared to wild-type mice (p < 0.05). Blood LCN2 existed predominantly in high molecular weight forms (>100 kDa), while urinary LCN2 was mainly in low molecular weight forms., Conclusion: Our findings suggest that neutrophils are the major source of circulating LCN2 in normal and infected conditions, whereas blood and urinary LCN2 mainly derive from the kidney during AKI, and that the molecular forms and regulation of blood and urinary LCN2 are clearly distinct.

Studies have suggested an association between pretransplant serum levels of ferritin and C-reactive protein (CRP) and complications of allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the prognostic impact of these biomarkers on the development of acute and chronic graft-versus-host disease (GVHD), we retrospectively studied 211 patients who underwent allogeneic HSCT for hematologic diseases at our institution. The cumulative incidence rate of chronic GVHD at 3 years was 40.7 %. In the multivariate analysis, elevated CRP levels (≥2 mg/L) were significantly associated with a high incidence of chronic GVHD, whereas high ferritin levels (≥880 ng/mL) showed a tendency, though not statistically significant, to association with a low incidence of chronic GVHD. No significant association was observed between the pretransplant serum ferritin or CRP levels and the incidence of acute GVHD. Multivariate analysis indicated that high pretransplant serum ferritin levels were significantly associated with increases in treatment-related mortality and relapse rates. Overall, an elevated pretransplant serum ferritin level, but not an elevated serum CRP level, is a strong risk factor for overall mortality (hazard ratio, 2.16; P = 0.002). Our results also indicate that pretransplant serum CRP levels may be a useful biomarker for predicting the risk of chronic GVHD.

Hepcidin is the central regulator of body iron homeostasis, and dysregulation of hepcidin expression causes various clinical disorders, such as anemia and hemochromatosis. Various stimuli, including iron load and interleukin-6, are involved in the regulation of hepcidin expression. We previously reported that serum hepcidin levels were high in patients with end-stage renal disease, compared with healthy subjects. Since metabolic acidosis is commonly observed in these patients, we hypothesized that acidic milieu might augment hepcidin expression. In this study, we investigated the effect of changes in the pH of the microenvironment on hepcidin expression in human hepatoma and leukemia cell lines. We found that hepcidin expression in these cells was augmented by the acidic milieu created with lactic acid, hydrochloric acid and excess carbon dioxide. Acidic milieu did not clearly enhance hepcidin promoter activity, but rather stabilized hepcidin transcript in the hepatoma cells. We speculate that metabolic acidosis may contribute in part to the elevation of serum hepcidin levels in patients with end-stage chronic kidney disease. Further studies are needed to elucidate the association between acidosis and hepcidin expression in various clinical settings.

We report a 75-year-old man who was initially suggested to have acute leukemia. The hemoglobin level was 3.8 g/dL, white cell count was 7,700/µL with an absence of mature neutrophils and 69.0% leukemic cells, and platelet was 0.4 × 10(4)/µL. Coombs' antiglobulin test was positive. Leukemic cells were CD5(-), CD10(+), CD20(+), CD23(-), and IgG/λ(dim+). The bone marrow consisted of normal hematopoietic precursors, whereas fluorescence in situ hybridization detected the BCL2/IgH fusion gene. He was treated with rituximab-containing chemotherapy, resulting in the resolution of pancytopenia. The underlying disease was a leukemic B-cell tumor with t(14;18)(q32;q21), and the pancytopenia was mainly caused by autoimmune mechanisms.

Background: Although subcutaneous implantable ports have been indicated as venous access for chemotherapy, these devices have not been used routinely for hematological tumors., Methods: Between May 2006 and April 2009, 39 ports were implanted in 37 patients with hematological tumors and 16 ports were implanted in 14 patients with nonhematological tumors. The patients were treated with standard/first-line and/or salvage/second-line or greater chemotherapy, and were prospectively followed until port removal, death, or the end of the study., Results: Thirty-five (96%) patients with hematological tumors developed grade 4 hematological toxicity, while 1 (7%) patient with nonhematological tumors showed grade 4 neutropenia. The actual duration of the port in situ ranged from 14 to 719 days (mean, 271.4 days) in the hematology group, and from 50 to 955 days (mean, 419.5 days) in the nonhematology group (P = 0.039). The Kaplan-Meier-estimated median duration of port in situ in the hematology group was 364 days, which was significantly shorter than that in the nonhematology group (P = 0.009). When patient death and port removal for the end of treatment were censored, the rate of port functioning at 1 year was estimated to be 83% in the hematology group. Bloodstream infection (BSI) occurred in 7 patients with hematological tumors and in 1 patient with metastatic colorectal cancer; however, microbiological confirmation that the implantable port was the source of the BSI was inconclusive., Conclusion: The duration of port functioning in patients with hematological tumors was comparable to that in patients with nonhematological tumors. The higher rate of BSI in the hematology group was primarily attributable to profound neutropenia.

The association of iron overload with complications of allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested in previous studies. Because hepcidin plays a central role in the regulation of iron homeostasis, we analyzed the association between pretransplant serum hepcidin-25 levels and early infectious complications after allogeneic HSCT. We studied 55 consecutive adult patients with a median age of 47 years (range: 20-64 years) who underwent allogeneic HSCT for hematologic malignancies at our institution. Thirty-two patients had myelogenous malignancies; the remaining 23 had lymphogenous malignancies. The median pretransplant serum hepcidin level of patients in the study was 21.6 ng/mL (range: 1.4-371 ng/mL), which was comparable to that of healthy volunteers (median: 19.1 ng/mL [range: 2.3-37 ng/mL]; n = 17). When cumulative incidences of documented bacterial and cytomegalovirus (CMV) infections at day 100 were compared according to pretransplant hepcidin-25 levels, the incidence of bacterial, but not CMV, infection, was significantly higher in the high-hepcidin group (> or = 50 ng/mL; n = 17) than in the low-hepcidin group (<50 ng/mL; n = 38) (65% [95% confidence interval, 38%-82%] versus 11% [3%-23%]; P < .001). This finding was confirmed by multivariate Cox analysis adjusted for confounders, including pretransplant ferritin and C-reactive protein (CRP) levels. No fungal infection was documented in either group. These results suggest that the pretransplant serum hepcidin-25 level may be a useful marker for predicting the risk of early bacterial complications after allogeneic HSCT. Larger prospective studies are, however, warranted to confirm our findings.

Thymic mucosa-associated lymphoid tissue (MALT) lymphoma shows distinct immunological characteristics, such as the expression of the IgA isotype, the frequent presence of immunoglobulin abnormalities, and a strong association with autoimmune disease, especially Sjögren's syndrome (SjS). We report a case of thymic MALT lymphoma, who exhibited biphasic changes in her clinical characteristics during the 4-year observation period after thymectomy. A 71-year-old woman was admitted because of suspected SjS. A diagnosis of primary thymic MALT lymphoma was made, and SjS was confirmed. Serological abnormalities such as polyclonal hypergammaglobulinemia, IgA M protein, and elevated levels of rheumatoid factor were noted. These abnormalities improved rapidly after the thymectomy, but did not completely disappear. Interestingly, the remaining abnormalities, which can be ascribed to the proliferation of B cells throughout the body under the influence of SjS, have been improving slowly but steadily during the 4-year observation period. It is suspected that the removal of the tumor by thymectomy has more or less normalized the immunological environment and alleviated the SjS disease activity.

We evaluated the efficacy of a post-grafting immunosuppressive regimen consisting of tacrolimus, methotrexate, and mycophenolate mofetil (MMF) in 21 adults (median age, 55 years) with poor-risk hematologic malignancy who underwent unrelated bone marrow transplantation after fludarabine-based reduced-intensity conditioning (RIC). In combination with intravenous tacrolimus and minidose methotrexate (5 mg/m2 on days 1, 3, and 6), MMF was orally administered at 30 mg/kg daily in three divided doses between days 7 and 27. All patients achieved neutrophil recovery with donor-type chimerism at a median of 19 days (range, 13-35). Cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 33% (95% CI, 15-53%) and 5% (95% CI, 0.3-20%), respectively. Five of 20 evaluable patients developed extensive chronic GVHD. Toxicities associated with the use of MMF were acceptable, although one patient experienced intractable GVHD immediately after the cessation of MMF. With a median follow-up of 24 months, overall survival at 3 years was 38% (95% CI, 14-63%). No late graft failure was observed. In conclusion, post-transplant MMF combined with tacrolimus and methotrexate was well tolerated and conferred stable donor cell engraftment, low risk of severe acute GVHD, and encouraging overall survival in unrelated donor marrow transplantation after RIC regimens.

Background: The clinical epidemiology of group A streptococcal (GAS) infections in Hawaii seems different from that in the continental United States with frequent skin infections and endemically high rates of acute rheumatic fever (ARF)., Methods: GAS emm types in Hawaii were determined to identify any possible association between the emm types and specific clinical manifestations. A convenience sample of 1482 Hawaii GAS isolates collected between February 2000 and December 2005 was used. All isolates were characterized by emm sequence typing. The distribution of emm types in Hawaii was compared with the published continental US data for pharyngeal and invasive GAS strains, the CDC database from similar time periods, as well as with emm types present in a candidate GAS vaccine., Results: Ninety-three distinct emm types were recognized among the 1482 GAS isolates. The most frequently identified emm types in order of decreasing frequency were 12, 1, 28, 4, 22, 77, 81, 58, 65/69, 49, 74, 85, 92, 75, 101 and 2. Of this study sample, 27 of the 50 invasive GAS isolates belonged to uncommon continental US emm types (54% in Hawaii cultures vs. 10% reported from the continental US). Of the 1179 pharyngeal isolates, 509 belonged uncommon continental US emm types (43% in Hawaii cultures vs. 27% reported from the continental US)., Conclusions: The prevalent emm types in Hawaii differ from those in the continental US. The prevalence of these unusual emm types might limit the effectiveness of any proposed multivalent type-specific GAS vaccine in Hawaii.