Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Comprehensive procedure for injecting Evusheld® for hematological diseases in a single institute.

Tixagevimab and cilgavimab (EVA, Evusheld®), monoclonal antibody combination treatments, consisted of two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). EVA showed prophylactic and therapeutic effects against coronavirus disease 2019. The Japanese Society of Hematology recommended EVA for such patients with active treatment, but each institution decided on comprehensive administration. We develop a systematic procedure for comprehensive EVA injection prophylactically in patients with hematological malignancies without any over/under-indication. We listed all patients with the required indications from November 2022 to March 2023. We included 178 cases, 84 females and 94 males, with a median age of 70 (range: 19-90) years. Underlying diseases are myeloid neoplasms in 36 (20%), lymphoid neoplasms in 75 (73%), and others. Indications were intensively hematological malignancy treatment, rituximab treatment within 12 months, burton kinase inhibitor treatment, after chimeric antigen receptor T cell immunotherapy, and after stem cell transplantation in 74 (41%), 73 (41%), 3 (2%), 5 (3%), and 23 (13%) cases, respectively. Of the 178 cases, 22 (12.4%) refused EVA injection. Further, 42 and 136 cases were administered outpatient and inpatient, respectively. Over 95% of the listed cases received EVA injection within 3 months. No severe toxicities were observed among them (N = 156), and 8 (5.2%) cases had breakthrough SARS-CoV-2 infection, which was significantly lower (P = 0.02) than those without EVA (4 [18.2%] of 22 cases). Both groups showed no moderate or severe infection cases. This single-center experience showed that comprehensive EVA injection management effectively generated safer completion with preferable clinical impact.

An observational study of once-weekly carfilzomib in patients with multiple myeloma in Japan (Weekly-CAR study).

Background: The ARROW study demonstrated that once-weekly carfilzomib and dexamethasone (wKd) therapy significantly prolonged progression-free survival compared with twice-weekly carfilzomib and dexamethasone therapy in relapsed or refractory multiple myeloma patients. Aim: To describe the treatment patterns, effectiveness and safety of wKd therapy in real-world settings in Japan. Methods: We investigated data from the medical records of 126 Japanese patients with relapsed or refractory multiple myeloma. Results: The overall response rate was 66.3%. The median progression-free survival was 9.5 months. The incidence of treatment-emergent adverse events of any grade and grade ≥3 were 45.8 and 20.8%, respectively. Conclusion: There were no new or unexpected safety signals in this study. This study demonstrated the effectiveness and safety profiles of wKd therapy in Japan.

Carfilzomib became available for daily clinical practice as a drug for cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous drug (relapsed or refractory). This drug was approved in the USA in 2012, and in Japan in 2016. In this study, we looked at how once-weekly carfilzomib works and how safe it is in real-life situations in Japan. We screened 126 patients with relapsed or refractory multiple myeloma in Japan. The median age of the patients was 70 years, with 25% being over 75 years. This study also included some patients who were not in the best overall health, had a history of many treatments or had heart complications. In 66.3% of patients, the cancer had disappeared or the extent of the cancer had reduced after treatment. Side effects and serious side effects occurred in 45.8 and 14.2% of patients, respectively. The most common side effects were low levels of blood platelets (9.2%), high blood pressure (5.8%), loose or watery stools (5.0%), fever (5.0%), and low levels of red blood cells (4.2%). Heart disorders occurred in five patients. But all patients recovered or improved with treatment such as blood pressure lowering drugs and diuretics. These results showed that once-weekly carfilzomib works well and is safe in real-world settings in Japan. This information can help us think about how to pick the right patients and handle heart disease risks when using carfilzomib treatment.

Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: The L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. METHODS: To search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors' institutions. RESULTS: Median sL-index(30) was 11 712 (range, 4419-18 511) and median ALC(30) was 404 (range, 0-3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00-1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00-1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89-1.00, P = 0.04 for every increase of 100/µL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88-1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3-4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00-1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99-1.01, P = 0.63). ALC(30) was not associated with rates of grade 3-4 acute GVHD (HR, 1.02, 95% CI, 0.88-1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98-1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. CONCLUSIONS: sL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

Immunological disease activity parameters at conception are risk factors for preterm birth and low birth weight in patients with systemic lupus erythematosus.

OBJECTIVE: This study aimed to identify which disease activity parameters may be risk factors for preterm birth (PB) and low birth weight (LBW) in patients with systemic lupus erythematosus (SLE). We also analyzed the extent to which these parameters affected PB and LBW. METHODS: We collected the SLE Disease Activity Index (SLEDAI), the rate of lupus low disease activity state (LLDAS) attainment, complement levels, and the titer of anti-double stranded DNA (dsDNA) antibody as disease activity parameters. We retrospectively analyzed the associations of these parameters with PB and LBW. RESULTS: Sixty pregnancies were included in this study. C3 levels and anti-dsDNA antibody titers at conception were strongly associated with PB (p = 0.03 and p = 0.01, respectively), whereas C3 and CH50 levels were associated with LBW (p = 0.02 and p = 0.03, respectively). A logistic regression analysis showed that the cutoff values of C3 and anti-dsDNA antibody for PB were 62.0 mg/dl and 5.4 IU/ml, respectively. The cutoff values of C3 and CH50 for LBW were 87.0 mg/dl and 41.8 U/ml, respectively. The risk of PB or LBW was increased when divided by the cutoff value, and the combination of these cutoff values showed a significantly higher risk of PB and LBW (p = 0.01 and p < 0.01, respectively). CONCLUSIONS: PB and LBW are strongly associated with disease activity parameters in patients with SLE. Therefore, strictly monitoring and controlling these disease activity parameters, with or without clinical manifestation, is important for women who want to become mothers.

Repeated spontaneous remission of acute myeloid leukemia in response to various infections: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is a progressive hematological malignancy that can be fatal when left untreated. However, spontaneous remission is rarely observed in the presence of infectious diseases. CASE PRESENTATION: We treated an 80-year-old woman with AML who spontaneously underwent remission after infections. Spontaneous remission was observed after each of three independent clinical infections caused by different pathogens-nontuberculous Mycobacterium infection, pulmonary aspergillosis, and Escherichia coli bacteremia. All infections were treated promptly with antimicrobials. Mycobacterium avium infection was treated with azithromycin, rifampin, and ethambutol. Pulmonary aspergillosis was treated with itraconazole followed by voriconazole. E. coli infection was treated with meropenem. During each infectious episode, leukemic cells disappeared from the patient's peripheral blood and pancytopenia improved without routine blood transfusion. These clinical effects lasted for several months. The patient has survived for > 2 years beyond the median survival time of end-stage AML. Thus, this case represents an immunological antileukemic effect of systemic infections. CONCLUSIONS: We have discussed a common mechanism of spontaneous remission of AML without chemotherapy, clinically exhibited by infection immunology. We believe that infections exert a limited immunological effect against AML, which may prolong survival among elderly individuals with AML.

Efficacy and safety of apremilast and its impact on serum cytokine levels in patients with Behçet's disease.

To evaluate the long-term clinical efficacy of apremilast in Behçet's disease (BD) and its effect on serum cytokine levels. This study included 15 BD patients who were treated with apremilast. The rates of change in oral and genital ulcers, skin lesions, arthritis, and arthralgia were evaluated every 3 months for 12 months. The efficacy of apremilast was compared between patients with and without oral ulcer remission. Changes in the serum levels of interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-10, IL-17A, IL-6, IL-8, and IL-23 between baseline and 3 months after apremilast initiation were compared. After 3 months, oral and genital ulcers disappeared in most cases. The skin and joint lesions tended to improve for up to 6 months; however, recurrence was observed after 9 months. The improvement of genital ulcers was earlier in the oral ulcer remission group than the oral ulcer non-remission group, with the genital ulcers disappearing within the first 3 months. The baseline levels of serum cytokines, analyzed in seven patients, did not exhibit significant associations with specific organ lesions. After administration of apremilast, the TNF-α and IL-23 levels significantly decreased; however, the IFN-γ, IL-6, IL-8, and IL-10 levels did not show significant changes. The rates of decrease in the serum IL-6, IFN-γ, and IL-10 levels were greater in patients with improved oral ulcers. Modulation of serum cytokine levels with apremilast might underlie the efficacy of apremilast in oral ulcers in BD patients.

Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies.

Oncolytic herpes simplex virus type 1 (HSV-1) has been investigated to expand its application to various malignancies. Because hematopoietic cells are resistant to HSV-1, its application to hematological malignancies has been rare. Here, we show that the third generation oncolytic HSV-1, T-01, infected and killed 18 of 26 human cell lines and 8 of 15 primary cells derived from various lineages of hematological malignancies. T-01 replicated at low levels in the cell lines. Viral entry and the oncolytic effect were positively correlated with the expression level of nectin-1 and to a lesser extent 3-O-sulfated heparan sulfate, receptors for glycoprotein D of HSV-1, on tumor cells. Transfection of nectin-1 into nectin-1-negative tumor cells made them susceptible to T-01. The oncolytic effects did not appear to correlate with the expression or phosphorylation of antiviral molecules in the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) and PKR-eIF2α pathways. In an immunocompetent mouse model, intratumoral injection of T-01 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infiltration of antigen-specific CD8+ T cells. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Nectin-1 expression may be the most useful biomarker for optimal efficacy.

Improving patient outcomes by promoting antimicrobial stewardship for patients with positive blood cultures: Investigation of patients with gram negative bacterium.

WHAT IS KNOWN AND OBJECTIVE: In this study, changes in patient outcomes were analysed to evaluate the effects of prospective audit and feedback (PAF), which was promoted under a new system of antimicrobial stewardship (AS), in patients with gram-negative rod (GNR)-positive blood cultures. METHODS: This study included patients with positive blood cultures treated at Kagawa University Hospital between 2019 and 2020. The effects of PAF, as promoted in 2020 and performed within a few days of treatment initiation, were examined in terms of patient prognosis and estimated cost of extra hospital stay associated with GNR infection. RESULTS AND DISCUSSION: As AS activities under the new system, proposals were made for targeted therapy based on susceptibility results and for the duration of antimicrobial therapy, escalation and dose increases, and imaging evaluation. Between 2019 and 2020, there was no difference in the rate of de-escalation in the form of switching to a narrower-spectrum intravenous antimicrobial, the rate of image inspection, but the rate of switching to oral therapy after receiving culture results increased from 19.7% to 31.3%, the rate of sensitivity-based treatment increased from 76.4% to 92.2%. Regarding patient outcomes, the 90-day mortality rate and the duration of hospital stay were similar between the groups. The rate of recurrent bloodstream infections decreased from 8.7% to 0.9%. WHAT IS NEW AND CONCLUSION: Most of the changes in the indicators related to patient outcomes analysed in this study suggest that the increased use of PAF in AS activities improved patient outcomes.

Programmed cell death 1-expressing CD56-negative natural killer (NK) cell expansion is a hallmark of chronic NK cell activation during dasatinib treatment.

Dasatinib treatment markedly increases the number of large granular lymphocytes including natural killer (NK) cells in a proportion of Ph+ leukemia patients, which associates with a better prognosis. In-depth immune profiling of NK cells can predict therapeutic response in these patients. In the present study, we showed that CD56-negative (CD56neg ) NK cells increased exclusively in cytomegalovirus-seropositive (CMV+ ) patients treated with dasatinib. The increase longitudinally paralleled with progressive differentiation of CD56dim NK cells during dasatinib therapy driven by CMV reactivation as shown by principal component analysis on 19 NK cell markers. The CD56neg NK cells showed downregulation of NK-activating receptors, upregulation of PD-1, and lower cytotoxicity and cytokine production, indicating that these cells are anergic and dysfunctional as seen in chronic infections with HIV-1 or hepatitis C virus. Moreover, cytolytic activity of CD56dim and CD56neg NK cells against leukemia cells was partially restored by nivolumab in proportion to the frequency of PD-1+ NK cells. The proportion of patients who achieved deep molecular responses at 2 years was significantly higher in dasatinib-treated patients with ≥3% CD56neg NK cells than in those with fewer CD56neg NK cells (54.5% vs 15.8%, P = .0419). These findings suggest that CD56neg NK cells may be an exhausted population induced by chronic activation through CMV reactivation during dasatinib therapy. Expansion of CD56neg NK cells is a hallmark of chronic NK cell activation in patients treated with dasatinib and may predict a better clinical outcome. Furthermore, PD-1 blockade may enhance anti-leukemia responses of such NK cells.

Oncolytic herpes simplex virus type 1 (HSV-1) in combination with lenalidomide for plasma cell neoplasms.

Oncolytic viruses exert an anti-tumour effect through two mechanisms: direct oncolytic and indirect immune-mediated mechanisms. Although oncolytic herpes simplex virus type 1 (HSV-1) has been approved for melanoma treatment and is being examined for its applicability to a broad spectrum of malignancies, it is not known whether it has an anti-myeloma effect. In the present study, we show that the third-generation oncolytic HSV-1, T-01, had a direct oncolytic effect on five of six human myeloma cell lines in vitro. The anti-tumour effect was enhanced in the presence of peripheral blood mononuclear cells (PBMCs) from healthy individuals and, to a lesser extent, from patients with myeloma. The enhancing effect of PBMCs was abrogated by blocking type I interferons (IFNs) or by depleting plasmacytoid dendritic cells (pDCs) or natural killer (NK) cells, suggesting that pDC-derived type I IFNs and NK cells dominated the anti-tumour effect. Furthermore, the combination of T-01 and lenalidomide exhibited enhanced cytotoxicity, and the triple combination of T-01, lenalidomide and IFN-α had a maximal effect. These data indicate that oncolytic HSV-1 represents a viable therapy for plasma cell neoplasms through direct oncolysis and immune activation governed by pDCs and NK cells. Lenalidomide is likely to augment the anti-myeloma effect of HSV-1.

c-D-index is a risk factor for prolonged febrile neutropenia during chemotherapy in patients with acute myeloid leukemia.

BACKGROUND: D-index is a recently established clinical tool for assessing neutropenia severity. This study examined whether the D-index can predict the onset of various infections in patients with febrile neutropenia (FN). METHODS: We retrospectively investigated FN events in consecutive patients aged < 65 years who were treated for newly diagnosed acute myeloid leukemia at our institution. We collected data on all FN events during chemotherapy and evaluated the association of FN severity with infectious events. RESULTS: This study included 35 patients (18 women and 17 men; median age, 51 years [range 18-65 years]) with 122 FN events. The response rate to induction chemotherapy was 60% (21/35), and all but one patient survived the treatment. The D-index did not predict FN onset. However, in multivariate analysis, high-dose cytarabine and total D-index were statistically significant explanatory factors for microbiological-proven infections. In addition, multivariate analysis showed that diabetes mellitus is the only risk factor for FN onset. Furthermore, older age, consolidation therapy, and cumulative D-index (c-D-index) were risk factors for prolonged FN. The FN period was the longest in patients with respiratory infections. CONCLUSION: The D-index did not predict the onset of infection. However, FN duration might be prolonged during consolidation therapy in elderly patients with diabetes mellitus, and it is important to manage respiratory infections. These findings indicate the c-D-index is a useful tool to predict prolonged FN.

Graft failure after reduced-intensity stem cell transplantation for congenital sideroblastic anemia.

Congenital sideroblastic anemia (CSA) is a rare hereditary disease causing disorders of hemoglobin synthesis. Severe, progressive congenital sideroblastic anemia becomes transfusion dependent and results in iron overload. In such cases, patients must undergo stem cell transplantation (SCT) before critical organ dysfunction occurs. However, there has been no consensus on the criteria for SCT for congenital sideroblastic anemia. A 17-year-old Japanese boy was newly diagnosed with congenital sideroblastic anemia manifesting dyspnea on effort. His gene analysis revealed ALAS2 R170L. He gradually become dependent on RBC transfusion. Vitamin B6 (pyridoxal, 30 mg/day) therapy and high-dose alpha-linoleic acid supplementation (150 mg/day) had not been effective. We treated the patient with reduced-intensity SCT from a human leukocyte antigen (HLA) alle 8/8-identical unrelated female donor. The preparation regimen applied consisted of cyclophosphamide, fludarabine, total body irradiation (2 Gy), and anti-thymocyte globulin. We experienced secondary graft failure, nevertheless we used enough immunosuppression. Here we discuss the optimal transplantation regimen for an adult-onset congenital sideroblastic anemia patient with transfusion dependency and mild hemosiderosis. We consider a positive indication for SCT in younger (< 20-year-old) patients with congenital sideroblastic anemia with transfusion dependency. Each case should be individually considered for their suitability for SCT depending on the feasibility and the clinical condition of the patient.

Amelioration of NK cell function driven by Vα24+ invariant NKT cell activation in multiple myeloma.

NK cells represent a first line of immune defense, but are progressively dysregulated in multiple myeloma (MM) patients. To restore and facilitate their antitumor effect, NK cells are required in sufficient quantities and must be stimulated. We initially assessed the proportions of NKT and NK cells in 34 MM patients. The frequencies of both in PBMC populations correlated with those in BMMNCs irrespective of low BMMNC numbers. We then assessed the adjunctive effect of stimulating NKT cells with CD1d and α-GalCer complexes on the NK cells. The expression of NKG2D on CD56dimCD16+ NK cells and DNAM-1 on CD56brightCD16- NK cells increased after NKT cell activation. Apparently, NK cell-mediated anti-tumor effects were dependent on NKG2D and DNAM-1 ligands on myeloma cells. Thus, NK cell function in patients could be ameliorated, beyond the effect of immunosuppression, by NKT cell activation. This NKT-driven NK cell therapy could represent a potential new treatment modality.

The usefulness of pleural fluid presepsin, C-reactive protein, and procalcitonin in distinguishing different causes of pleural effusions.

BACKGROUND: We aimed to determine the presepsin concentration in pleural fluid from patients with pleural effusions of different aetiologies and to compare its diagnostic value with that of pleural fluid C-reactive protein (CRP) and procalcitonin (PCT). METHODS: We enrolled 132 patients with pleural effusion who underwent diagnostic evaluation, and we classified them into six categories: empyema, parapneumonic effusion, tuberculous effusion, malignant effusion, paramalignant effusion, and transudate effusion. Additionally, all pleural effusions were categorised as infectious or non-infectious effusions. RESULTS: Receiver operating characteristic analysis was used to evaluate diagnostic performance. When diagnosing empyema, the marker with the highest sensitivity was pleural fluid presepsin (cut-off: 754 pg/mL; sensitivity: 90.9%, specificity: 74.4%) and that with the highest specificity was pleural fluid CRP (cut-off: 4.91 mg/dL; sensitivity: 63.6%, specificity: 89.3%). Pleural fluid PCT tended to be lower in patients with empyema than in those with parapneumonic effusion, but this was not useful for the diagnosis of empyema. When diagnosing infectious pleural effusion, a combination of pleural fluid CRP (cut-off: 2.59 mg/dL) and presepsin (cut-off: 680 pg/mL) produced the highest diagnostic accuracy (83.3%). CONCLUSIONS: Pleural fluid presepsin was found at high levels in patients with empyema and parapneumonic effusion. This pattern closely resembles the previously reported pattern of pleural fluid CRP. Some combinations of pleural fluid inflammatory markers may be more clinically useful than these markers in isolation.

[Cancer therapy using bispecific antibodies].

Bispecific antibodies comprise two antigen-binding sites that recognize different antigens or epitopes. Blinatumomab, a bispecific T-cell engager (BiTE) that lacks the Fc portion, recognizes CD19 on B tumor cells and CD3 on T cells and induces the T cell-mediated killing of the B tumor cells. The Food and Drug Administration has approved the use of blinatumomab for the treatment of precursor B-cell acute lymphoblastic leukemia (ALL) with minimal residual disease and relapsed/refractory ALL. Various bispecific antibodies have been developed, including BiTEs that target surface molecules on myeloma cells or intracellular antigens presented on the major histocompatibility complex and Fc portion-containing bispecific antibodies that have a potent T cell-activating capacity and a long half-life. These efforts could lead to the development of potent, off-the-shelf bispecific antibodies for the treatment of a broad array of hematological malignancies.

T memory stem cells are the hierarchical apex of adult T-cell leukemia.

Adult T-cell leukemia (ATL) is a peripheral CD4(+) T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). Despite several investigations using human specimens and mice models, the exact origin of ATL cells remains unclear. Here we provide a new insight into the hierarchical architecture of ATL cells. HTLV-1-infected cells and dominant ATL clones are successfully traced back to CD45RA(+) T memory stem (TSCM) cells, which were recently identified as a unique population with stemlike properties, despite the fact that the majority of ATL cells are CD45RA(-)CD45RO(+) conventional memory T cells. TSCM cells from ATL patients are capable of both sustaining themselves in less proliferative mode and differentiating into other memory T-cell populations in the rapidly propagating phase. In a xenograft model, a low number of TSCM cells efficiently repopulate identical ATL clones and replenish downstream CD45RO(+) memory T cells, whereas other populations have no such capacities. Taken together, these findings demonstrate the phenotypic and functional heterogeneity and the hierarchy of ATL cells. TSCM cells are identified as the hierarchical apex capable of reconstituting identical ATL clones. Thus, this is the first report to demonstrate the association of a T-cell malignancy with TSCM cells.

Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression.

BACKGROUND: The influence of lung fibroblasts on lung cancer progression is not fully understood. METHODS: Lung fibroblasts (HFL1, MRC5, and IMR90 cells) and non-small cell lung cancer (NSCLC)-derived cell lines (A549, EBC1, and HI1017) were cultured under serum-free conditions, and the resulting culture media were designated "cell-conditioned media". Cell survival (viability) was assessed by WST-1 assay. Concentrations of hepatocyte growth factor (HGF) were measured by ELISA. The BALB/c-nu mouse strain was used for the xenograft model. RESULTS: Lung fibroblast-conditioned media enhanced the survival of the three NSCLC cell lines tested. HGF was produced to a greater extent by lung fibroblasts than NSCLC cells. Exogenous HGF enhanced the survival of NSCLC cells. Either an anti-HGF neutralizing antibody or the Met inhibitor PHA-665752 inhibited the fibroblast-conditioned media-enhanced survival of NSCLC cells. The co-inoculation of mice with NSCLC cells and fibroblasts enhanced tumorigenicity and tumor progression in a mouse xenograft model. PHA-665752 significantly inhibited tumor progression that occurred after the co-inoculation of NSCLC cells and fibroblasts. In addition, HGF production by fibroblasts was stimulated by NSCLC cells. CONCLUSIONS: The current study provides evidence for an interaction between fibroblasts and NSCLC cells via the HGF/Met signaling pathway, which affects NSCLC cell survival and tumor progression. These findings may contribute to the development of anti-cancer-associated fibroblast therapeutic strategies. TRIAL REGISTRATION: No trial registration is required because this study is not a clinical trial. This study does not include any participants or patients.