Publications by authors named "Takayuki Ikezoe"

141 Publications

deficiency in the intestinal epithelium promotes age-induced obesity via propionate-mediated AKT activation.

Int J Biol Sci 2021 25;17(5):1302-1314. Epub 2021 Mar 25.

The Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Aurora-A kinase, a serine/threonine mitotic kinase involved in mitosis, is overexpressed in several human cancers. A recent study showed that Aurora-A mediates glucose metabolism via SOX8/FOXK1 in ovarian cancer. However, the roles of Aurora-A in metabolic diseases remain unclear. This study found that loss in the intestinal epithelium promoted age-induced obesity and enlargement of lipid droplets in parallel with an increase in infiltrated macrophages in the white adipocyte tissue (WAT) of male mice. Moreover, loss of induced the expression of lipid metabolism regulatory genes, including acetyl-coenzyme A carboxylase 1 (), in association with an increase in the levels of p-AKT in the intestinal epithelium as well as WAT. Blockade of AKT activation reduced the expression of lipid metabolism regulatory genes. In subsequent experiments, we found that the Firmicutes abundance and the levels of short-chain fatty acids (SCFAs) in the gut were dramatically increased in mice compared with mice. Additionally, propionate increased the phosphorylation of AKT . These observations indicated that loss in the intestinal epithelium contributed to gut microbiota dysbiosis and higher levels of SCFAs, especially propionate, leading to AKT activation and lipid metabolism regulatory gene expression, which in turn promoted age-induced obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijbs.56477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040479PMC
March 2021

Targeting HLA-F suppresses the proliferation of glioma cells via a reduction in hexokinase 2-dependent glycolysis.

Int J Biol Sci 2021 25;17(5):1263-1276. Epub 2021 Mar 25.

The Department of Hematology, Fukushima Medical University, Fukushima, Japan.

HLA-F, a nonclassical HLA class I molecule, is required for regulating immune tolerance. In recent years, HLA-F has been found to play a role in a variety of cancers, including glioma (GM). Additionally, high expression of HLA-F predicts the poor overall survival of individuals with GM. However, the functions of HLA-F in GM remain to be further elucidated. In this study, we found that HLA-F expression was elevated in GM tissues. High levels of HLA-F resulted in a high cell proliferation index and predicted GM recurrence. Forced expression of HLA-F promoted the growth of murine C8-D1A cells transplanted in immunodeficient mice. In contrast, silencing HLA-F inhibited cell growth . Furthermore, targeting HLA-F with an anti-HLA-F antibody suppressed the growth of C8-D1A cells stably expressing HLA-F transplanted in immunodeficient mice. In further experiments, we found that forced expression of HLA-F contributed to the aerobic glycolysis phenotype in C8-D1A cells along with an increase in HK2 protein stabilization. Conversely, silencing HK2 by shRNA reduced HLA-F-mediated glycolysis and cell proliferation. Our data indicated that HLA-F promoted cell proliferation via HK2-dependent glycolysis. HLA-F could be a potential therapeutic target for the treatment of GM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijbs.56357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040476PMC
March 2021

Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice.

J Hematol Oncol 2021 Mar 30;14(1):52. Epub 2021 Mar 30.

Department of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Frameshifts in the Calreticulin (CALR) exon 9 provide a recurrent driver mutation of essential thrombocythemia (ET) and primary myelofibrosis among myeloproliferative neoplasms (MPNs). Here, we generated knock-in mice with murine Calr exon 9 mimicking the human CALR mutations, using the CRISPR-Cas9 method. Knock-in mice with del10 [Calr mice] exhibited an ET phenotype with increases of peripheral blood (PB) platelets and leukocytes, and accumulation of megakaryocytes in bone marrow (BM), while those with ins2 (Calr mice) showed a slight splenic enlargement. Phosphorylated STAT3 (pSTAT3) was upregulated in BM cells of both knock-in mice. In BM transplantation (BMT) recipients from Calr mice, although PB cell counts were not different from those in BMT recipients from Calr mice, Calr BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calr mice developed more severe pulmonary hypertension (PH)-which often arises as a comorbidity in patients with MPNs-than BMT recipients from Calr mice, with pulmonary arterial remodeling accompanied by an accumulation of donor-derived macrophages in response to chronic hypoxia. In conclusion, our murine model with the frameshifted murine Calr presented an ET phenotype analogous to human MPNs in molecular mechanisms and cardiovascular complications such as PH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-021-01064-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011226PMC
March 2021

Weight Loss Intervention before Cord Blood Transplantation in an Obese Patient with Acute Myeloid Leukemia: A Case Study.

Prog Rehabil Med 2021 19;6:20210018. Epub 2021 Mar 19.

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Background: A severely obese woman (39.8 kg/m) with relapsed acute myeloid leukemia was admitted to our hospital to undergo salvage chemotherapy followed by cord blood transplantation (CBT).

Case: During the salvage chemotherapy period, a 70-day weight loss program addressing diet and exercise was administered. After the 70-day intervention, the patient's body weight and body fat mass had decreased (8.6% and 15.0%, respectively) without any adverse events. The number of available cord blood units with total nucleated cells per body weight greater than 2 × 10/kg was zero at admission and two after weight loss; therefore, CBT could be performed.

Discussion: Considering this case, we suggest that a weight loss program combining exercise and nutrition therapy may help patients scheduled for hematopoietic stem cell transplantation by focusing on risk management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2490/prm.20210018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972948PMC
March 2021

loss in CD19 B cells promotes megakaryocytopoiesis via IL-6/STAT3 signaling-mediated thrombopoietin production.

Theranostics 2021 4;11(10):4655-4671. Epub 2021 Mar 4.

The Department of Hematology, Fukushima Medical University, Fukushima, Japan.

: Aurora kinase A (Aurora-A), which is required for mitosis, is a therapeutic target in various tumors. Targeting Aurora-A led to an increase in the differentiation and polyploidization of megakaryocytes both and . However, the mechanisms involved in controlling megakaryocyte differentiation have not been fully elucidated. Conditional knockout mice were generated. B cell development, platelet development and function were subsequently examined. Proplatelet formation, response to mTPO, post-transfusion experiment, colony assay, immunofluorescence staining and quantification, and ChIP assay were conducted to gain insights into the mechanisms of loss in megakaryocytopoiesis. Loss of in CD19 B cells impaired B cell development in association with an increase in the number of platelets in peripheral blood (PB). Surprisingly, thrombopoietin (TPO) production and IL-6 were elevated in the plasma in parallel with an increase in the number of differentiated megakaryocytes in the bone marrow (BM) of mice. Interestingly, compared with that of the mice, a higher number of CD19 B cells close to megakaryocytes was observed in the BM of the mice. Moreover, loss in CD19 B cells induced signal transducer and activator of transcription-3 (STAT3) activation. Inhibition of STAT3 reduced the mRNA levels. ChIP assays revealed that STAT3 bound to the TPO promoter. Additionally, STAT3-mediated TPO transcription was an autocrine effect provoked by IL-6, at least partially. Deletion of in CD19 B cells led to an increase in IL-6 production, promoting STAT3 activation, which in turn contributed to TPO transcription and megakaryocytopoiesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.49007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978311PMC
March 2021

Chromosomal translocation t(11;14) and p53 deletion induced by the CRISPR/Cas9 system in normal B cell-derived iPS cells.

Sci Rep 2021 Mar 4;11(1):5216. Epub 2021 Mar 4.

Department of Radiation Life Sciences, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Multiple myeloma (MM) cells are derived from mature B cells based on immunoglobulin heavy chain (IgH) gene analysis. The onset of MM is often caused by a reciprocal chromosomal translocation (cTr) between chr 14 with IgH and chr 11 with CCND1. We propose that mature B cells gain potential to transform by reprograming, and then chromosomal aberrations cause the development of abnormal B cells as a myeloma-initiating cell during B cell redifferentiation. To study myeloma-initiating cells, we have already established normal B cell-derived induced pluripotent stem cells (BiPSCs). Here we established two BiPSCs with reciprocal cTr t(11;14) using the CRISPR/Cas9 system; the cleavage site were located in the IgH Eμ region of either the VDJ rearranged allele or non-rearranged allele of IgH and the 5'-upsteam region of the CCND1 (two types of BiPSC13 with t(11;14) and MIB2-6 with t(11;14)). Furthermore, p53 was deleted using the CRISPR/Cas9 system in BiPSC13 with t(11;14). These BiPSCs differentiated into hematopoietic progenitor cells (HPCs). However, unlike cord blood, those HPCs did not differentiated into B lymphocytes by co-culture with BM stromal cell. Therefore, further ingenuity is required to differentiate those BiPSCs-derived HPCs into B lymphocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-84628-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933289PMC
March 2021

Hypofibrinogenemia is associated with a high degree of risk in infectious diseases: a post-hoc analysis of post-marketing surveillance of patients with disseminated intravascular coagulation treated with thrombomodulin alfa.

Thromb J 2021 Feb 25;19(1):12. Epub 2021 Feb 25.

Department of Surgery, Center for Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Fukuoka, Japan.

Background: In patients with infectious diseases, disseminated intravascular coagulation (DIC) is often diagnosed without the fibrinogen value. The relationship between hypofibrinogenemia and outcomes of DIC in infectious diseases has thus remained unclear.

Methods: We analyzed 3204 patients who received with thrombomodulin alfa (TM-α) for DIC and suspected DIC. Hypofibrinogenemia was defined by a fibrinogen level < 1.5 g/L.

Results: Hypofibrinogenemia was observed in 10.3% of patients with infectious diseases. The frequencies of both bleeding and organ failure symptoms, and the scores for organ failure or the DIC diagnostic criteria were significantly higher in infectious disease patients with hypofibrinogenemia, suggesting that in patients with infectious diseases, hypofibrinogenemia is associated with more progressive and severe DIC. Although the 28-day survival rate and the DIC resolution rate were both significantly lower for infectious disease patients with DIC with hypofibrinogenemia than for those without hypofibrinogenemia, this difference was not observed in DIC patients with hematological diseases.

Conclusions: Hypofibrinogenemia among infectious disease patients with DIC may reflect increased consumption of fibrinogen due to accelerated coagulation reactions, while hypofibrinogenemia among hematological disease patients with DIC may be caused by fibrinogenolysis due to hyperfibrinolysis, and frequently results in bleeding and multiple-organ failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12959-021-00264-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908729PMC
February 2021

Mutation Promoted IL-6 Production and Glycolysis Mediating PKM1 Stabilization in Macrophages.

Front Immunol 2020 8;11:589048. Epub 2021 Feb 8.

The Department of Hematology, Fukushima Medical University, Fukushima, Japan.

A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 () gene ( ) has been detected in myeloid cells of some individuals with higher levels of proinflammatory cytokine production such as interleukin (IL)-6. However, the mechanisms by which mutation mediating those cytokines remain unclear. We, therefore, established -expressing murine macrophages ( macrophages) and found that the levels of p-STAT3 were markedly elevated in macrophages in association with an increase in IL-6 production. However, inhibition of STAT3 by C188-9 significantly decreased the production of IL-6. Furthermore, the mutation endowed macrophages with an elevated glycolytic phenotype in parallel with aberrant expression of PKM1. Interestingly, silencing of PKM1 inactivated STAT3 in parallel with reduced IL-6 production. In contrast, ectopic expression of PKM1 elevated IL-6 production STAT3 activation. Importantly, the mutation contributed to PKM1 protein stabilization blockade of lysosomal-dependent degradation chaperone-mediated autophagy (CMA), indicating that the mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.589048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897702PMC
February 2021

Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.

Int J Hematol 2021 Mar 7;113(3):320-329. Epub 2021 Feb 7.

Department of Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Background: Disseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported.

Objective: The aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19.

Methods: We used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020.

Results: Seven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies.

Conclusion: Studies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-021-03084-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868079PMC
March 2021

Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib.

Int J Hematol 2021 Mar 3;113(3):441-455. Epub 2021 Jan 3.

Department of Hematology, Fukushima Medical University, Hikariga-oka 1, Fukushima, 960-1295, Japan.

Adverse vascular events have become a serious clinical problem in chronic myeloid leukemia (CML) patients who receive certain BCR/ABL1 tyrosine kinase inhibitors (TKIs). Studies have shown that endothelial-to-mesenchymal transition (EndMT) can contribute to various vascular diseases. We investigated the effects of TKIs on the development of EndMT in human vascular-endothelial cells (VECs). Exposure of VECs to dasatinib, but not to other TKIs, produced a significant increase in the formation of spindle-shaped cells. This effect was accompanied by a significant increase in expression of the EndMT inducer transforming growth factor-β (TGF-β) and mesenchymal markers vimentin, smooth muscle alpha-actin, and fibronectin, as well as a significant decrease in expression of vascular-endothelial markers CD31 and VE-cadherin attributable at least in part to activation of ERK signaling. Inhibitors of TGF-β and ERK partially attenuated dasatinib-induced EndMT. Interestingly, bosutinib efficiently counteracted dasatinib-induced EndMT and attenuated dasatinib-induced phosphorylation of ERK. Taken together, these results show that dasatinib induces EndMT, which might contribute to the development of vascular toxicity, such as the pulmonary hypertension observed in CML patients receiving dasatinib. Bosutinib could play a distinct role in protecting VECs from EndMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-03034-1DOI Listing
March 2021

Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies.

Authors:
Takayuki Ikezoe

Int J Hematol 2021 Jan 9;113(1):34-44. Epub 2020 Sep 9.

Department of Haematology, Fukushima Medical University, Fukushima, 960-1295, Japan.

Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02992-wDOI Listing
January 2021

Assessment of dysplasia in bone marrow smear with convolutional neural network.

Sci Rep 2020 09 7;10(1):14734. Epub 2020 Sep 7.

Department of Hemato-Oncology, International Medical Center, Saitama Medical University, Saitama, Japan.

In this study, we developed the world's first artificial intelligence (AI) system that assesses the dysplasia of blood cells on bone marrow smears and presents the result of AI prediction for one of the most representative dysplasia-decreased granules (DG). We photographed field images from the bone marrow smears from patients with myelodysplastic syndrome (MDS) or non-MDS diseases and cropped each cell using an originally developed cell detector. Two morphologists labelled each cell. The degree of dysplasia was evaluated on a four-point scale: 0-3 (e.g., neutrophil with severely decreased granules were labelled DG3). We then constructed the classifier from the dataset of labelled images. The detector and classifier were based on a deep neural network pre-trained with natural images. We obtained 1797 labelled images, and the morphologists determined 134 DGs (DG1: 46, DG2: 77, DG3: 11). Subsequently, we performed a five-fold cross-validation to evaluate the performance of the classifier. For DG1-3 labelled by morphologists, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 91.0%, 97.7%, 76.3%, 99.3%, and 97.2%, respectively. When DG1 was excluded in the process, the sensitivity, specificity, PPV, NPV, and accuracy were 85.2%, 98.9%, 80.6%, and 99.2% and 98.2%, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71752-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477564PMC
September 2020

Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients.

Int J Hematol 2020 Oct 31;112(4):466-476. Epub 2020 Aug 31.

Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab's efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab's efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02934-6DOI Listing
October 2020

Severe Antithrombin Deficiency May be Associated With a High Risk of Pathological Progression of DIC With Suppressed Fibrinolysis.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620941112

Department of Surgery, Center for Gastroenterology and Liver Disease, 13780Kitakyushu City Yahata Hospital, Fukuoka, Japan.

The frequency of severe antithrombin deficiency (SAD) was examined in the hematopoietic disorder-, infectious-, and basic-types of the disseminated intravascular coagulation (DIC). A posthoc analysis of 3008 DIC patients (infectious-type, 1794; hematological disorder-type, 813; and basic-type, 401) from post-marketing surveillance data of thrombomodulin alfa was performed. The clinical features of patients and outcomes were compared between patients with and without SAD, using an antithrombin cutoff value of 50%. Patients with SAD accounted for 40.4% of infectious-type DIC, 8.0% of hematopoietic disorder-type DIC, and 26.7% of basic-type DIC. There was no significant difference in thrombin-antithrombin complex levels between patients with and without SAD. The decreased fibrinogen level and differences in clinical features were significantly greater but the increases in fibrinolytic markers were significantly lower in patients with SAD than in those without. The 28-day survival rate was significantly lower in patients with SAD than in those without. Severe antithrombin deficiency was observed in all types of DIC, including hematopoietic disorders. Both hypofibrinolysis and hypercoagulability in patients with SAD may cause multiple organ failure and poor outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1076029620941112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448134PMC
June 2021

Treatment of T-Cell Prolymphocytic Leukemia with Central Nervous System Involvement Using Intrathecal Alemtuzumab Administration.

Case Rep Hematol 2020 27;2020:8822172. Epub 2020 Jul 27.

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

T-cell prolymphocytic leukemia (T-PLL) is a rare hematologic cancer with a dismal prognosis. Although a small number of patients have central nervous system (CNS) involvement, a standard treatment approach for these patients has not been established. Herein, we present a case of T-PLL with CNS involvement that was treated with a higher dose of intrathecal alemtuzumab than that previously reported. A 66-year-old man who had T-PLL with CNS involvement was admitted to our hospital. Intravenously administered alemtuzumab, a monoclonal antibody against the CD52 antigen, successfully reduced leukemia cells in peripheral blood; however, intrathecal treatment with methotrexate, cytarabine, and prednisone had a limited effect on the CNS involvement. Therefore, we intrathecally injected alemtuzumab as an experimental treatment. Although we escalated the dose of intrathecal alemtuzumab up to 5 mg, no adverse reaction was noted; however, this treatment did not completely clear the leukemia cells from the patient's cerebrospinal fluid (CSF). We performed whole brain and whole spinal irradiation therapies and subsequently performed allogeneic transplantation from a human leukocyte antigen-matched sibling donor with a conditioning regimen containing total body irradiation. At 21 days after transplantation, leukemia cells remained in his CSF. Although intrathecal alemtuzumab did not eliminate the CNS-invading leukemia cells, it was well-tolerated in our case. Further accumulation of similar cases is needed to determine the benefits and safety of intrathecal alemtuzumab administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8822172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403948PMC
July 2020

Inhibition of Aurora-A Promotes CD8 T-Cell Infiltration by Mediating IL10 Production in Cancer Cells.

Mol Cancer Res 2020 10 26;18(10):1589-1602. Epub 2020 Jun 26.

The Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Intratumoral tumor-specific activated CD8 T cells with functions in antitumor immune surveillance predict metastasis and clinical outcome in human colorectal cancer. Intratumoral CD8 T cells also affect treatment with immune checkpoint inhibitors. Interestingly, inhibition of Aurora kinase A (Aurora-A) by its selective inhibitor alisertib obviously induced infiltration of CD8 T cells. However, the mechanisms by which inhibition of Aurora-A promotes infiltration of intratumoral CD8 T cells remain unclear. Our recent results demonstrated that conditional deletion of the gene or blockade of Aurora-A by alisertib slowed tumor growth in association with an increase in the infiltration of intratumoral CD8 T cells as well as the mRNA levels of their IL10 receptor α (IL10Rα). The antitumor effects of targeting Aurora-A were attenuated in the absence of CD8 T cells. In addition, antibody-mediated blockade of IL10Rα dramatically decreased the percentage of intratumoral CD8 T cells. In further experiments, we found that the levels of IL10 were elevated in the serum of azoxymethane/dextran sodium sulfate-treated mice. Unexpectedly, we found that in addition to Aurora-A's mitotic role, inhibition of Aurora-A elevated IL10 transcription, which in turn increased the IL10Rα mRNA levels in CD8 T cells. Thus, inhibition of Aurora-A could be a useful treatment strategy for recruiting tumor-specific intratumoral CD8 T cells. IMPLICATIONS: Understanding the mechanisms by which inhibition of Aurora-A promotes CD8 T-cell infiltration and activation, as mediated by the IL10 pathway could provide a potential strategy for tumor immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-19-1226DOI Listing
October 2020

Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using At-CXCR4 monoclonal antibody.

Sci Rep 2020 04 22;10(1):6810. Epub 2020 Apr 22.

Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan.

To explore stem-cell-targeted radioimmunotherapy with α-particles in acute myelogenous leukemia (AML), pharmacokinetics and dosimetry of the At-labeled anti-C-X-C chemokine receptor type 4 monoclonal antibody (At-CXCR4 mAb) were conducted using tumor xenografted mice. The biological half-life of At-CXCR4 mAb in blood was 15.0 h. The highest tumor uptake of 5.05%ID/g with the highest tumor-to-muscle ratio of 8.51 ± 6.14 was obtained at 6 h. Radiation dosimetry estimated with a human phantom showed absorbed doses of 0.512 mGy/MBq in the bone marrow, 0.287 mGy/MBq in the kidney, and <1 mGy/MBq in other major organs except bone. Sphere model analysis revealed 22.8 mGy/MBq in a tumor of 10 g; in this case, the tumor-to-bone marrow and tumor-to-kidney ratios were 44.5 and 79.4, respectively. The stem-cell-targeted α-particle therapy using At-CXCR4 mAb for AML appears possible and requires further therapeutic studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-63557-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176675PMC
April 2020

Optimal timing of apheresis for the efficient mobilization of peripheral blood progenitor cells recruited by high-dose granulocyte colony-stimulating factor in healthy donors.

Transfus Apher Sci 2020 Jun 5;59(3):102737. Epub 2020 Feb 5.

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Predictors of peripheral blood stem cell (PBSC) yield can potentially improve the comfort, safety, and efficacy of CD34+ cell collection from donors treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We investigated 181 apheresis procedures on 109 healthy allogeneic donors to identify factors correlating with efficient PBSC collection. Apheresis started on Day 4 or 5 and continued up to Day 6 of G-CSF administration. CD34+ cell yields on Days 4 and 5 were comparable, and significantly higher than on Day 6. This suggests that starting apheresis on Day 4 rather than Day 5 may be preferable, to reduce G-CSF exposure and optimize yield, even if multi-day collection is required. More CD34+ cells were collected from male and cytomegalovirus (CMV)-seronegative donors than from female and CMV-seropositive donors, respectively. The yields of CD34+ cells were similarly high in both male and female donors aged 20-29 years; yields decreased in female donors in their thirties, and were comparably low in both male and female donors in their forties and thereafter. These findings should guide decision-making about when to begin apheresis, and encourage careful consideration of donor factors such as gender, age, and CMV serostatus when collecting PBSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.transci.2020.102737DOI Listing
June 2020

Analysis of the association between resolution of disseminated intravascular coagulation (DIC) and treatment outcomes in post-marketing surveillance of thrombomodulin alpha for DIC with infectious disease and with hematological malignancy by organ failure.

Thromb J 2020 7;18. Epub 2020 Feb 7.

Department of Surgery, Center for Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Fukuoka, Japan.

Background: Although disseminated intravascular coagulation (DIC) is life-threatening, any organ failure associated with DIC resolution and outcomes have been unclear.

Patients And Methods: A total of 2795 DIC patients (infection: 1990, hematological malignancy: 805) were analyzed in the post-marketing surveillance of thrombomodulin alpha (TM-α). The background factors of sequential organ failure assessment (SOFA) and antithrombin (AT) were investigated in DIC with infectious disease for their association with DIC resolution and outcome using κ statistics, indicating DIC resolution and survival or DIC non-resolution and non-survival. The same analyses were performed for total bilirubin, creatinine, lactate dehydrogenase, and underlying disease in DIC with hematological malignancy.

Results: In DIC with infectious disease, higher SOFA score severity was closely correlated with lower overall survival in both the DIC resolution and non-resolution groups, but AT activity was not. κ coefficients were 0.234, 0.295, and 0.311 for the SOFA score 0-6, 7-12, and 13-24 groups, respectively. In DIC with hematological malignancy, κ coefficients of total bilirubin were 0.251 and 0.434, and those of creatinine were 0.283 and 0.437 in the normal and abnormal groups, respectively, showing better concordance in the abnormal group than in the normal. Other factors had poor concordance.

Conclusion: In DIC with infectious disease, DIC resolution is an important therapeutic target in patients who have higher SOFA score severity. In DIC with hematological malignancy, DIC resolution is similarly important in patients with abnormality of bilirubin and/or creatinine.

Trial Registration: The clinical characteristics and treatment outcomes of patients with DIC treated with TM-α between May 2008 and April 2010 were retrospectively analyzed by subgroup analysis of the post-marketing surveillance data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12959-020-0216-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006199PMC
February 2020

Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial.

Lancet Haematol 2020 Mar 21;7(3):e218-e225. Epub 2020 Jan 21.

Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan.

Background: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year.

Methods: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099).

Findings: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia.

Interpretation: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed.

Funding: Epidemiological and Clinical Research Information Network.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(19)30235-2DOI Listing
March 2020

Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia.

Int J Hematol 2020 Mar 17;111(3):378-387. Epub 2019 Dec 17.

Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima, Fukushima, 960-1295, Japan.

Intranuclear proteins, including high mobility group box 1 (HMGB1) and histone H3, released from inflammatory cells activate platelets and the coagulation systems, leading to development of disseminated intravascular coagulation (DIC) in individuals with sepsis. These observations prompted us to hypothesize that HMGB1 and histone H3 liberated from leukemia cells undergoing apoptosis after chemotherapy might play a role in development of DIC. To test this hypothesis, we prospectively measured plasma levels of coagulation markers and intranuclear proteins in patients with newly diagnosed acute leukemia (n = 17) before and after chemotherapy. Ten of 17 patients were diagnosed with DIC at the time of diagnosis of leukemia. Serum levels of HMGB1 and histone H3 were significantly higher in patients with DIC than in non-DIC patients. Of note, seven patients developed DIC or experienced exacerbation of coagulopathy after administration of anti-leukemic agents. Intriguingly, an increase in levels of HMGB1 and histone H3 were detected in five of seven patients. These findings suggest that intranuclear proteins spontaneously released from leukemia cells may play a role in development of leukemia-related DIC. Additionally, remission induction chemotherapy causes apoptosis of leukemia cells, leading to forced release of intranuclear proteins, which may exacerbate coagulopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02798-5DOI Listing
March 2020

Intestinal Behçet disease associated with myelodysplastic syndrome accompanying trisomy 8 successfully treated with abdominal surgery followed by hematopoietic stem cell transplantation: A case report.

Medicine (Baltimore) 2019 Nov;98(46):e17979

Department of Rheumatology.

Rationale: Intestinal Behçet disease (BD) with myelodysplastic syndrome (MDS) is a rare condition that is resistant to various immunosuppressive therapies. Several cases in which hematopoietic stem cell transplantation (HSCT) was effective for intestinal BD with MDS accompanying trisomy 8 have been reported.

Patient Concerns: We report an 18-year-old female with a 7-year history of BD. Colonoscopy demonstrated a huge ulcer in the cecum. Chromosomal examination revealed a karyotype of trisomy 8 in 87% of cells. Bone marrow examination revealed dysplastic cells in multilineages.

Diagnoses: A diagnosis of intestinal BD associated with MDS accompanying trisomy 8 was made.

Interventions: The patient underwent ileocecal resection due to microperforations of ileocecal ulcers; she then underwent allogeneic peripheral blood stem cell transplantation (PBSCT) with her mother as a donor.

Outcomes: After the PBSCT, the patient's symptoms due to BD (fever, oral aphthae, abdominal pain, and genital ulcers) completely disappeared, with no severe adverse events.

Lessons: The present case demonstrates that HSCT including PBSCT might be an effective new therapeutic option for refractory intestinal BD with MDS when immunosuppressive therapy has achieved insufficient efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000017979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867715PMC
November 2019

A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD.

Blood Adv 2019 07;3(14):2128-2143

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, d-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650735PMC
July 2019

[Overview].

Authors:
Takayuki Ikezoe

Rinsho Ketsueki 2019;60(6):646

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.60.646DOI Listing
January 2019

[Management of transplant-associated thrombotic microangiopathy].

Authors:
Takayuki Ikezoe

Rinsho Ketsueki 2018;59(10):2307-2314

Fukushima Medical University.

The clinical features of transplant-associated thrombotic microangiopathy (TA-TMA) include microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ dysfunction caused by thrombi in microvessels. The pathogenesis of TA-TMA is based on vascular endothelial insults caused by various factors, including chemotherapy and total-body irradiation used for transplant pre-conditioning, calcineurin inhibitors, cytokines release associated with infection, and complement factors. The incidence of TA-TMA is approximately 15-30% among allogeneic transplant patients, and the mortality rate reaches 100% in severe cases with multi-organ dysfunction. This review describes the current understanding of the pathogenesis, diagnostic criteria, and treatment strategies of this potentially lethal transplant-associated complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.59.2307DOI Listing
July 2019

miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2.

Exp Hematol 2018 12 5;68:80-88.e2. Epub 2018 Sep 5.

Department of Hematology, Fukushima Medical University, Fukushima, Japan. Electronic address:

BCR-ABL1-independent mechanisms had been thought to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). The pro-oncogenic anterior gradient 2 (AGR2) mediates drug resistance of cancer cells. In this study, we observed an increased level of AGR2 in TKI-resistant CML cells. Silence of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced upregulation of AGR2 in K562 cells, which indicated a probable treatment-related drug resistance. We further investigated the potential interaction between microRNA (miRNA) and AGR2 in K562DR cells and found that downregulation of miR-217 was associated with overexpression of AGR2 in K562DR cells. Luciferase reporter assay identified that miR-217 negatively regulated expression of AGR2 through binding the 3'-untranslated region of AGR2. Hypermethylation of the CpG island on the promoter region of the MIR217 gene is a probable reason for the downregulation of miR-217 in dasatinib-treated K562 cells. Forced expression of miR-217 led to decreased expression of AGR2 as well as compromised TKI-resistant potential of K562DR cells. Similarly, overexpression of miR-217 resensitized K562DR cells to dasatinib treatment in a murine xenograft transplantation model. TKI treatment-induced drug resistance is correlated with a decrease of miR-217 and upregulation of AGR2. The miR-217/AGR2 interaction might be a potential therapeutic target in treating CML patients with TKI resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exphem.2018.09.001DOI Listing
December 2018

[Airway obstruction due to localized tracheal lesion of extranodal NK/T-cell lymphoma, nasal type].

Rinsho Ketsueki 2018;59(8):1012-1015

Department of Hematology, Fukushima Medical University.

A 76-year-old man presented with a tracheal tumor associated with severe respiratory obstruction. A tracheotomy was performed due to respiratory failure. F-fluorodeoxyglucose (FDG) -positron emission tomography/computed tomography revealed an abnormal accumulation of FDG (maximum standardized uptake value: 16) in the trachea. A histopathological examination of the tracheal biopsy revealed extranodal NK/T-cell lymphoma, nasal type (ENKL). He was treated with concurrent radiotherapy (50 Gy) for the tracheal tumor and three courses of two-thirds dose ofdexamethasone, etoposide, ifosfamide, and carboplatin. Although the tumor responded remarkably well to this therapy, the patient died of an ENKL recurrence in the lungs and liver 11 months post therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.59.1012DOI Listing
July 2019

Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2019 05 20;54(5):674-680. Epub 2018 Aug 20.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n  =  24) or rhTM (n  =  41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-018-0304-4DOI Listing
May 2019