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1.
Am J Hematol ; 93(9): 1161-1168, 2018 09.
Article in English | MEDLINE | ID: mdl-30015379

ABSTRACT

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, extravascular fluid overload, M protein, and a myriad of skin changes. The pathogenesis is poorly understood, but monoclonal plasma cells are λ-restricted and these immunoglobulin λ light chain variable (IGLV) region genes are derived from only two germlines, either IGLV1-44 or 1-40. Here we analyzed the clonal IGLV gene rearrangements of genomic DNA samples of bone marrow mononuclear cells using next-generation sequencing (NGS) to understand the clonal composition of IGLV genes in patients with POEMS syndrome (n = 30). The dominant IGLV gene rearrangement of POEMS syndrome-specific germline sequences were significantly increased in 11 POEMS patients (36.7%; IGLV1-44: n = 9, IGLV1-40: n = 2). In some cases, IGLV gene rearrangement clone was not detected as significant increase but was detected using cDNA samples by heteroduplex (HD) analysis and Sanger sequencing, suggesting that the quite small number of monoclonal plasma cells may produce large quantity of mRNA of monoclonal proteins. However, significant increase of dominant clone sizes was not directly linked to the initial disease status. On the other hand, in cases with significantly increased dominant clones, they decreased and increased accompanying with disease remission and relapse. These data demonstrate that monoclonal plasma cells are related to the pathogenesis of POEMS syndrome.


Subject(s)
Gene Rearrangement , High-Throughput Nucleotide Sequencing/methods , Immunoglobulin lambda-Chains/genetics , POEMS Syndrome/genetics , Bone Marrow Cells , Clone Cells , Humans , POEMS Syndrome/diagnosis , POEMS Syndrome/immunology , POEMS Syndrome/pathology , Plasma Cells/pathology , RNA, Messenger/analysis
3.
Ann Hematol ; 97(4): 655-662, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29332223

ABSTRACT

Thrombopoietin-receptor agonists have been recently introduced for a second-line treatment of immune thrombocytopenia (ITP). Splenectomy has tended to be avoided because of its complications, but the response rate of splenectomy is 60-80% and it has still been considered for steroid-refractory ITP. We performed partial splenic embolization (PSE) as an alternative to splenectomy. Between 1988 and 2013, 91 patients with steroid-resistant ITP underwent PSE at our hospital, and we retrospectively analyzed the efficacy and long-term outcomes of PSE. The complete response rate (CR, platelets > 100 × 109/L) was 51% (n = 46), and the overall response rate (CR plus response (R), > 30 × 109/L) was 84% (n = 76). One year after PSE, 70% of patients remained CR and R. The group with peak platelet count after PSE ≥ 300 × 109/L (n = 29) exhibited a significantly higher platelet count than the group with platelet count < 300 × 109/L (n = 40) at any time point after PSE. The failure-free survival (FFS) rates at 1, 5, and 10 years were 78, 56, and 52%, respectively. Second PSE was performed in 20 patients who relapsed (n = 14) or had no response to the initial PSE (n = 6), and the overall response was achieved in 63% patients. There were no PSE-related deaths. These results indicate that PSE is a safe and effective alternative therapy to splenectomy for patients with steroid-resistant ITP as it generates long-term, durable responses.


Subject(s)
Embolization, Therapeutic , Purpura, Thrombocytopenic, Idiopathic/therapy , Spleen/blood supply , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Drug Resistance , Drug Resistance, Multiple , Embolization, Therapeutic/adverse effects , Female , Follow-Up Studies , Hospitals, University , Humans , Japan , Male , Middle Aged , Organ Size , Purpura, Thrombocytopenic, Idiopathic/diagnostic imaging , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/pathology , Retrospective Studies , Spleen/diagnostic imaging , Spleen/drug effects , Spleen/pathology , Steroids/therapeutic use , Young Adult
4.
Intern Med ; 56(3): 353-356, 2017.
Article in English | MEDLINE | ID: mdl-28154282

ABSTRACT

Infections of the central nervous system (CNS) with varicella zoster virus (VZV) is a rare occurrence after allogeneic hematopoietic stem cell transplantation. We herein report a case of VZV meningitis, radiculitis and myelitis that developed 8 months after cord blood transplantation, shortly after the cessation of cyclosporine and low-dose acyclovir. Although treatment with acyclovir did not achieve a satisfactory response, the patient was successfully treated with foscarnet. Our report indicates that VZV infection should be considered in allo-hematopoietic stem cell transplantation (HSCT) patients with CNS symptoms and that foscarnet may be effective for the treatment of acyclovir-resistant VZV infections of the CNS. The development of optimal prophylactic strategies and vaccination schedules may eradicate post-transplant VZV disease.


Subject(s)
Antiviral Agents/therapeutic use , Foscarnet/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Herpes Zoster/etiology , Meningitis, Viral/etiology , Acyclovir/therapeutic use , Graft vs Host Disease/immunology , Herpes Zoster/diagnosis , Herpes Zoster/drug therapy , Herpesvirus 3, Human/isolation & purification , Humans , Meningitis, Viral/diagnosis , Meningitis, Viral/drug therapy , Transplantation, Homologous/adverse effects
5.
Biol Blood Marrow Transplant ; 23(2): 361-363, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27840209

ABSTRACT

Although autologous stem cell transplantation can achieve excellent responses in patients with POEMS syndrome, the optimal regimen for peripheral blood stem cell (PBSC) collection is still controversial. We retrospectively investigated the safety and efficacy of 41 PBSC collecting procedures in 37 patients with POEMS syndrome. PBSC mobilization was performed using cyclophosphamide + granulocyte colony-stimulating factor (G-CSF) (CG, n = 14) or G-CSF alone (G, n = 27). Twelve (85.7%) patients in the CG group and all (100%) patients in the G group received induction chemotherapy before PBSC collection. The proportions of good mobilizers (≥2.0 × 106 CD34+ cells/kg) were comparable between the 2 groups (CG versus G: 78.6% versus 70.4%, P = .71). Two (14.3%) patients in the CG group developed severe capillary leak symptoms during the PBSC mobilization period, whereas no patient in the G group experienced severe adverse events. Appropriate induction therapies followed by the G-CSF monotherapy compose an optimal strategy for PBSC collection.


Subject(s)
Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization , POEMS Syndrome/therapy , Peripheral Blood Stem Cell Transplantation , Adult , Aged , Ascites/chemically induced , Blood Cell Count , Drug Evaluation , Female , Fever/chemically induced , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/pharmacology , Humans , Male , Middle Aged , Pleural Effusion/chemically induced , Retrospective Studies
6.
Leuk Res ; 50: 85-94, 2016 11.
Article in English | MEDLINE | ID: mdl-27697661

ABSTRACT

Expression of the tumor suppressor gene NR4A3 is silenced in the blasts of acute myeloid leukemia (AML), irrespective of the karyotype. Although the transcriptional reactivation of NR4A3 is considered to have a broad-spectrum anti-leukemic effect, the therapeutic modalities targeting this gene have been hindered by our minimal understanding of the transcriptional mechanisms regulating its expression, particularly in human AML. Here we show the role of intragenic DNA hypermethylation in reducing the expression of NR4A3 in AML. Bisulfite sequencing analysis revealed that CpG sites at the intragenic region encompassing exon 3 of NR4A3, but not the promoter region, are hypermethylated in AML cell lines and primary AML cells. A DNA methyltransferase inhibitor restored the expression of NR4A3 following a reduction in DNA methylation levels at intragenic CpG sites. The in silico data revealed an enrichment of H3K4me1 and H2A.Z at exon 3 of NR4A3 in human non-malignant cells but that was excluded specifically in leukemia cells with CpG hypermethylation. This suggests that exon 3 represents a functional regulatory element involved in the transcriptional regulation of NR4A3. Our findings improve the current understanding of the mechanism underlying NR4A3 silencing and facilitate the development of NR4A3-targeted therapy.


Subject(s)
DNA Methylation , DNA-Binding Proteins/genetics , Gene Silencing , Leukemia, Myeloid, Acute/genetics , Receptors, Steroid/genetics , Receptors, Thyroid Hormone/genetics , Adult , Aged , Antimetabolites, Antineoplastic , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Blast Crisis/genetics , Blast Crisis/pathology , Case-Control Studies , Cells, Cultured , CpG Islands , Decitabine , Exons/genetics , Female , Gene Expression Regulation, Leukemic , Genes, Tumor Suppressor , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged
7.
Rinsho Ketsueki ; 57(6): 765-70, 2016 06.
Article in Japanese | MEDLINE | ID: mdl-27384858

ABSTRACT

A 34-year-old man who had been referred to our hospital was diagnosed with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA), oral administration, was initiated. On day 25, he developed fever and respiratory distress with bilateral pulmonary infiltrates, suggesting differentiation syndrome (DS) caused by ATRA. These symptoms showed amelioration after discontinuing ATRA and initiating methylprednisolone. ATRA was re-started on day 29 at half the original dose because of residual APL blasts. The patient subsequently developed fever, severe stomatitis, and oropharyngeal ulcers, which persisted even after discontinuing ATRA. On day 48, he suddenly developed severe abdominal pain with free air, observable on an abdominal X-ray, and underwent emergency ileocecal resection. Pathological examination of the resected ileocecal intestines revealed multiple ulcers and perforations. No leukemic cell infiltration was observed. In this case, only ATRA was administered for APL treatment. These findings suggest that ileocecal ulcerations and perforations, as well as oropharyngeal ulcers, might have been caused by DS or ATRA. Furthermore, DNA typing of the HLA-B locus revealed that the patient had HLA-B51 associated with Behçet's disease. Therefore, hypercytokinemia with DS might have induced Behçet's disease-like symptoms, including stomatitis and ileocecal perforation, complications that are particularly observed in patients with HLA-B51.


Subject(s)
Antineoplastic Agents/adverse effects , Cecal Diseases/chemically induced , Ileum , Intestinal Perforation/chemically induced , Leukemia, Promyelocytic, Acute/drug therapy , Stomatitis/chemically induced , Tretinoin/adverse effects , Adult , Antineoplastic Agents/therapeutic use , Cecal Diseases/pathology , HLA-B51 Antigen/immunology , Humans , Ileum/pathology , Leukemia, Promyelocytic, Acute/immunology , Male , Tretinoin/therapeutic use
8.
Rinsho Ketsueki ; 57(5): 624-9, 2016 05.
Article in Japanese | MEDLINE | ID: mdl-27263789

ABSTRACT

A 23-year-old woman presented with a persistent fever and shortness of breath. Computed tomography showed marked pericardial effusion, hepatosplenomegaly, and cervical and mediastinal lymph node swelling. Epstein-Barr virus (EBV) antibody titers were abnormally elevated, and the copy number of EBV-DNA was increased in peripheral blood. Based on these observations, she was diagnosed with chronic active EBV infection (CAEBV). The EBV-infected cells in her peripheral blood were CD4(+)T lymphocytes. Fever and pericardial effusion improved following treatment with a combination of prednisolone, etoposide, and cyclosporine; however, peripheral blood EBV-DNA levels remained high. The patient underwent allogeneic peripheral blood stem cell transplantation from an EBV-seronegative, HLA-matched sibling donor, with fludarabine and melphalan conditioning. The post-transplantation course was uneventful, except for mild skin acute graft-versus-host disease (grade 2). EBV-DNA became undetectable in peripheral blood 98 days post transplantation. She has since been in good health without disease recurrence. CAEBV is a potentially fatal disease caused by persistent EBV infection of T lymphocytes or natural killer cells, thus requiring prompt treatment and allogeneic transplantation. Pericardial effusion is rarely observed in CAEBV and can impede its diagnosis. Therefore, we should be aware that patients may present with marked pericardial effusion as an initial manifestation of CAEBV.


Subject(s)
Epstein-Barr Virus Infections/therapy , Herpesvirus 4, Human/physiology , Pericardial Effusion/etiology , Peripheral Blood Stem Cell Transplantation , Chronic Disease , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Female , Humans , Transplantation, Homologous , Young Adult
9.
J Clin Exp Hematop ; 55(3): 163-8, 2015.
Article in English | MEDLINE | ID: mdl-26763365

ABSTRACT

Severe acute lung injury is a rare but life-threatening complication associated with bortezomib. We report a patient with multiple myeloma who developed a severe diffuse alveolar hemorrhage (DAH) immediately after the first bortezomib administration. The patient was suspected to have pulmonary involvement of myeloma, which caused DAH after rapidly eradicating myeloma cells in the lungs with bortezomib. Rechallenge with bortezomib was performed without recurrent DAH. In patients with multiple myeloma who manifest abnormal pulmonary shadow, we should be aware of early-onset severe DAH after bortezomib administration, which might be due to pulmonary involvement of myeloma cells.


Subject(s)
Hemorrhage/diagnosis , Hemorrhage/etiology , Lung Neoplasms/complications , Lung Neoplasms/secondary , Multiple Myeloma/pathology , Pulmonary Alveoli/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease Progression , Fatal Outcome , Humans , Lung Neoplasms/drug therapy , Multiple Myeloma/drug therapy , Radiography, Thoracic , Severity of Illness Index , Tomography, X-Ray Computed
11.
Intern Med ; 53(11): 1159-64, 2014.
Article in English | MEDLINE | ID: mdl-24881741

ABSTRACT

Myeloid sarcoma (MS) is an extramedullary myeloid tumor that sometimes presents with antedating systemic leukemia, leading physicians to the misdiagnosis of lymphoma. CD25 is expressed in 13% of patients with acute myeloid leukemia (AML), and its expression is associated with FLT3-ITD mutations, an elevated serum soluble interleukin 2 receptor (sIL-2R) level and a lower survival rate. However, there are no reports concerning the relationship between MS and the CD25 expression. We herein report a case of AML accompanied by thoracic epidural MS with a high CD25 expression, the FLT3-ITD mutation and an extremely elevated serum sIL-2R level in a 59-year-old man who presented with paraplegia.


Subject(s)
Interleukin-2 Receptor alpha Subunit/metabolism , Leukemia, Myeloid, Acute , Neoplasms, Multiple Primary , Sarcoma, Myeloid , Spinal Neoplasms , fms-Like Tyrosine Kinase 3/genetics , Bone Marrow/pathology , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Male , Middle Aged , Mutation , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/metabolism , Paraplegia/etiology , Radiography , Sarcoma, Myeloid/diagnostic imaging , Sarcoma, Myeloid/pathology , Spinal Neoplasms/diagnostic imaging , Spinal Neoplasms/pathology , Thoracic Vertebrae/diagnostic imaging
12.
Exp Mol Med ; 46: e89, 2014 Apr 04.
Article in English | MEDLINE | ID: mdl-24699135

ABSTRACT

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.


Subject(s)
ADAM Proteins/metabolism , LDL-Receptor Related Proteins/metabolism , Leukocytes/metabolism , Membrane Transport Proteins/metabolism , Tetraspanin 29/metabolism , ADAM17 Protein , Cell Line, Tumor , Humans , LDL-Receptor Related Proteins/genetics , Macrophages/metabolism , Membrane Transport Proteins/genetics , Proteolysis , Tetraspanin 29/genetics
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