Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
1.
Cureus ; 16(6): e61944, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38978909

ABSTRACT

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy affecting multiple sites, most commonly the skin. About 10-20% of BPDCN cases are accompanied by hematological neoplasms. A 71-year-old male was diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP) 11 years prior (at 60 years of age), and dasatinib treatment was initiated. A major molecular response (MMR) was achieved 18 months after diagnosis, and the molecular response (MR)4.0 lasted beyond 36 months. Due to pancytopenia, dasatinib was discontinued at 74 months, but the CML-CP remained undetectable. One hundred and twenty-two months after the diagnosis, the patient presented with cutaneous lesions on the forehead and abdomen. Immunological and histological analyses of the skin biopsy showed infiltration of atypical cells from the deep epidermis to the entire dermis, expressing clusters of differentiation (CD) 4, CD56, and CD123 without any other markers. The same cells were observed in bone marrow samples. BPDCN was diagnosed, followed by chemotherapy and possibly autologous or allogeneic hematopoietic stem cell transplantation (HSCT). To the best of our knowledge, this is the first case report of the development of BPDCN in a patient with CML in molecular remission. Further studies are required to clarify the pathogenesis of BPDCN in patients with hematological malignancies in remission.

2.
Blood Adv ; 7(4): 508-524, 2023 02 28.
Article in English | MEDLINE | ID: mdl-35930695

ABSTRACT

Extramedullary disease (EMD) is known to be associated with chemoresistance and poor prognosis in multiple myeloma (MM); however, the mechanisms of its development are not fully understood. Elucidating the mechanism of EMD development and its therapeutic targeting would greatly contribute to further improvement of treatment outcome in patients with MM. Here, we show that bone marrow stroma cell-derived hyaluronan (HA) elicits homophilic interactions of MM cells by binding to surface CD44, especially long-stretch variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of HA in a syngeneic murine MM model in a CD44-dependent manner. HA-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) in vitro and in murine models via γ-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Treatment of HA-injected mice with anti-CD44 antibody or γ-secretase inhibitors readily suppressed the development of EMD from transplanted MM cells and significantly prolonged the survival of recipients by overcoming PI resistance. The HA-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the prediction, prevention, and treatment of EMD in patients with MM.


Subject(s)
Hyaluronic Acid , Multiple Myeloma , Mice , Animals , Hyaluronic Acid/metabolism , Hyaluronic Acid/pharmacology , Amyloid Precursor Protein Secretases
3.
Rinsho Ketsueki ; 64(12): 1514-1518, 2023.
Article in Japanese | MEDLINE | ID: mdl-38220151

ABSTRACT

Here we present the case of a 50-year-old woman with chronic myeloid leukemia who received nilotinib as initial treatment. After about 2 years of nilotinib therapy, she developed headache, blurred vision, impaired consciousness, and marked hypertension. Posterior reversible encephalopathy syndrome (PRES) was diagnosed, and was strongly suspected to be a vascular adverse event caused by nilotinib. Nilotinib was withheld and the patient was treated with antihypertensive drugs under ventilator management. Her symptoms resolved quickly. The most likely cause of PRES is systemic arterial hypertension and endothelial dysfunction due to direct injury leading to dysfunction at the level of the blood-brain barrier, along with the resultant vasogenic edema. PRES has been reported with some tyrosine kinase inhibitors, but this is the first case of PRES during nilotinib treatment.


Subject(s)
Hypertension , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid , Posterior Leukoencephalopathy Syndrome , Humans , Female , Middle Aged , Posterior Leukoencephalopathy Syndrome/chemically induced , Posterior Leukoencephalopathy Syndrome/drug therapy , Hypertension/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid/complications
4.
Intern Med ; 61(22): 3329-3334, 2022 Nov 15.
Article in English | MEDLINE | ID: mdl-35466165

ABSTRACT

Objective Currently, treatment of relapsed or refractory multiple myeloma is challenging. Although bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide (VTD-PACE), a potent combination of a proteasome inhibitor, immunomodulatory drug, and conventional chemotherapeutics, is a widely used regimen, its efficacy and safety are unclear. Methods We retrospectively analyzed the clinical data of 35 patients treated with VTD-PACE. Results The overall response rate was 65.7% (complete response, 5.7%). The median progression-free survival (PFS) and overall survival (OS) were 8.0 [95% confidence interval (CI), 0.9-15.0] and 20.0 (95% CI, 17.5-22.5) months, respectively. Twenty-two (62.9%) patients developed grade 3-4 infections, and no therapy-related deaths occurred. Sixteen of 25 patients (64%) underwent stem cell harvest successfully with more than 2.0×106/kg of CD34 cells after VTD-PACE. Twenty-two patients underwent autologous or allogeneic stem cell transplantation (SCT). The response and survival durations were short in patients without SCT after VTD-PACE [median PFS: 4.0 (95% CI, 2.7-5.3) months; OS: 14.0 (6.9-21.0) months]; however, these responses significantly improved with SCT following VTD-PACE. The PFS was 8.0 (NA) months (p=0.024), and the OS was 21.0 (19.1-22.8) months (p=0.019). Conclusion VTD-PACE is an effective and tolerable salvage regimen and feasible bridging therapy for SCT.


Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Humans , Bortezomib/therapeutic use , Thalidomide/therapeutic use , Multiple Myeloma/drug therapy , Etoposide/therapeutic use , Cisplatin/therapeutic use , Retrospective Studies , Dexamethasone/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Transplantation, Autologous , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Treatment Outcome
5.
Gan To Kagaku Ryoho ; 47(5): 789-796, 2020 May.
Article in English | MEDLINE | ID: mdl-32408321

ABSTRACT

Autologous stem cell transplantation(ASCT)for newly-diagnosed multiple myeloma(NDMM)has underwent recent improvements in combination with novel agents-containing induction and post-ASCT therapy. Since the approval of bortezomib for NDMM in Japan, we conducted the following regimen(BD arm)in transplant-eligible patients with NDMM: BD (bortezomib and dexamethasone)induction, ASCT, VRD consolidation, and maintenance therapy with immunomodulatory drugs(IMIDs). The efficacy and safety of the BD arm were compared to those of patients treated with vincristine, doxorubicin, and dexamethasone(VAD)induction followed by ASCT(VAD arm)retrospectively. Thirty-three patients were treated with the BD arm, and 92 patients with the VAD arm. Thirty-one patients in the BD arm proceeded to ASCT. Thereafter, 23 and 17 patients received VRD consolidation and IMIDs maintenance therapy, respectively. The rates of complete response/Bvery good partial response after ASCT, consolidation, and maintenance therapy were 43%/61%, 76%/90% and 87%/93%, respectively. The response rates after ASCT did not differ between BD and VAD arms. The median PFS was 46.2 months(BD arm)and 30.6 months(VAD arm)(HR 0.48[0.27-0.85], p=0.0106). The median OS was not-reached(BD arm)and 90.6 months(VAD arm)(HR 0.21[0.05-0.87], p=0.0172). VRD consolidation and IMIDs maintenance therapies improved disease status after ASCT and prolonged PFS and OS.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Peripheral Blood Stem Cell Transplantation , Bortezomib , Consolidation Chemotherapy , Dexamethasone , Disease-Free Survival , Humans , Lenalidomide , Multiple Myeloma/therapy , Retrospective Studies , Thalidomide , Transplantation, Autologous
6.
Intern Med ; 57(24): 3521-3528, 2018 Dec 15.
Article in English | MEDLINE | ID: mdl-30101910

ABSTRACT

Objective Although R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is a standard therapy for diffuse large B-cell lymphoma (DLBCL), the optimal dose for elderly patients remains unclear. Methods and Patients We retrospectively verified our R-CHOP dose-attenuation system implemented from 2005 for DLBCL patients. Among the 115 DLBCL patients treated during 2001-2010, 33 patients treated during 2001-2005 received R-CHOP doses adjusted according to physicians' decisions (PHY group). Eighty-two patients treated after 2005 received adjusted R-CHOP doses according to a unified dose-attenuation system (UNI group). Patients aged <60, 60-69, 70-79, and ≥80 years received the standard R-CHOP, 100% R-CHO+P (50 mg/m2), 100% R+75% CHO+P (40 mg/m2), and 100% R+50% CHO+P (30 mg/m2), respectively. We compared the responses, survival, and treatment cessation between the PHY and UNI groups. Results The patients' characteristics between both groups were closely comparable. All PHY patients received randomly adjusted R-CHOP doses; 94% of UNI patients received scheduled doses. The complete response rates differed significantly between the UNI (77%) and PHY patients (50%) (p=0.011). The two-year event-free survival rates were 50% and 32% in the UNI and PHY groups, respectively (p=0.0083). The two-year OS rates were 77% and 72% in the UNI and PHY group (p=0.16). Among the patients aged >70 years (n=59) overall survival was shorter in the PHY group (62%) than in the UNI group (72%; p=0.02). The UNI group received higher anti-tumor agent doses than the PHY group. The therapy discontinuation rates were 5% in the UNI group and 24% in the PHY group. Conclusion Carrying out unified dose reduction may improve the efficacy and prognosis among elderly DLBCL patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoma, Large B-Cell, Diffuse/drug therapy , Adult , Age Factors , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Drug Administration Schedule , Female , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Male , Middle Aged , Prednisone/administration & dosage , Prognosis , Retrospective Studies , Rituximab , Vincristine/administration & dosage
7.
Int J Hematol ; 107(5): 559-567, 2018 May.
Article in English | MEDLINE | ID: mdl-29388164

ABSTRACT

Two regimens are commonly used for peripheral blood hematopoietic stem cell harvesting (PBSCH) in multiple myeloma: high-dose cyclophosphamide (HD-CY) + granulocyte-colony stimulating factor (G-CSF), and G-CSF alone. The objective of the present study was to evaluate the anti-myeloma effect of the PBSCH regimen including HD-CY. We retrospectively assessed harvesting efficiency, complications, and anti-myeloma effects in 115 patients receiving HD-CY + G-CSF (HD-CY group) and 32 patients receiving G-CSF alone (G-alone group). We collected > 2 × 106 CD34-positive cells/kg from 93 and 75% of patients in the HD-CY and G-alone groups, respectively (P = 0.0079). The mean HSC count was also higher in the HD-CY group. No severe complications were observed in the G-alone group, whereas 66% of patients in the HD-CY group were treated with intravenous antibiotics. The median progression-free and event-free survival (PFS and EFS) were longer in the HD-CY group than in the G-alone group (28 vs. 18 months and 25 vs. 13 months, respectively; P = 0.0127 and 0.0139), with no difference in median overall survival. HD-CY showed anti-myeloma effect, as verified by prolonged EFS and PFS, when a vincristine, doxorubicin, and dexamethasone regimen was administered as induction before PBSCH.


Subject(s)
Cyclophosphamide/administration & dosage , Granulocyte Colony-Stimulating Factor/administration & dosage , Immunosuppressive Agents/administration & dosage , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Peripheral Blood Stem Cell Transplantation , Antigens, CD34 , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Count , Combined Modality Therapy , Dexamethasone/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Drug Therapy, Combination , Female , Hematopoietic Stem Cells , Humans , Induction Chemotherapy , Male , Middle Aged , Pulse Therapy, Drug , Retrospective Studies , Time Factors , Vincristine/administration & dosage
8.
Cancer Sci ; 102(12): 2109-17, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21848808

ABSTRACT

The p210Bcr/Abl and p190Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. Crk-associated substrate lymphocyte type (Cas-L)/human enhancer of filamentation-1 (HEF1)/neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is an adapter protein at focal adhesions known to be associated with solid tumor metastasis. Crk-associated substrate lymphocyte type has also been reported to be tyrosine phosphorylated by p190Bcr/Abl. We demonstrated that Cas-L was expressed in murine granulocytes, as well as in lymphocytes, and that Cas-L-deficient (Cas-L(-/-) ) granulocytes had increased migratory activity and decreased adhesiveness. To examine whether Cas-L was involved in leukemogenesis by p210Bcr/Abl, we generated Cas-L(-/-) p210Bcr/Abl transgenic mice. The mice displayed early development of myeloproliferative neoplasm seen in the chronic phase of CML, which resulted in the early death of the mice. Pathologically, increased infiltration of myeloid cells into several tissues was detected in the absence of Cas-L. In a hematopoietic reconstitution assay, Cas-L(-/-) p210Bcr/Abl transgenic cells showed a low population in the spleen, although only their myeloid cell population was normal. Thus, Cas-L seems to regulate the progression of CML in a negative way, presumably by attenuating extramedullary hyperplasia.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Fusion Proteins, bcr-abl/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/physiopathology , Myeloid Cells/physiology , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Apoptosis , Cell Movement , Cell Proliferation , Crk-Associated Substrate Protein/metabolism , Disease Progression , Female , Fusion Proteins, bcr-abl/genetics , Genes, abl , Granulocytes/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemic Infiltration , Lymphocyte Count , Lymphocytes/metabolism , Lymphocytes/pathology , Male , Mice , Mice, Transgenic , Myeloid Cells/metabolism , Myeloid Cells/pathology , Myeloid Progenitor Cells/metabolism , Myeloid Progenitor Cells/pathology , Neoplasm Metastasis , Phosphorylation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
9.
Cancer Sci ; 99(7): 1407-13, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18452556

ABSTRACT

Evi-1 is a zinc-finger transcriptional factor whose inappropriate expression leads to leukemic transformation in mice and humans. Recently, it has been shown that Evi-1 regulates proliferation of hematopoietic stem/progenitor cells at embryonic stage via GATA-2 up-regulation; however, detailed mechanisms underlying Evi-1-mediated early hematopoiesis are not fully understood. We therefore evaluated hematopoietic potential of Evi-1 mutants using a cultivation system of murine para-aortic splanchnopleural (P-Sp) regions, and found that both the first zinc finger domain and the acidic domain were required for Evi-1-mediated hematopoiesis. The hematopoietic potential of Evi-1 mutants was likely to be related to its ability to up-regulate GATA-2 expression. We also showed that the decreased colony forming capacity of Evi-1-deficient P-Sp cells was successfully recovered by inhibition of TGF-b signaling, using ALK5 inhibitor or retroviral transfer of dominant-negative-type Smad3. Our findings suggest that Evi-1 promotes hematopoietic stem/progenitor expansion at the embryonic stage through up-regulation of GATA-2 and repression of TGF-beta signaling.


Subject(s)
DNA-Binding Proteins/physiology , GATA2 Transcription Factor/physiology , Hematopoiesis , Proto-Oncogenes/physiology , Transcription Factors/physiology , Transforming Growth Factor beta/physiology , Animals , Cells, Cultured , Female , GATA2 Transcription Factor/genetics , MDS1 and EVI1 Complex Locus Protein , Mice , Mice, Inbred C57BL , Signal Transduction , Up-Regulation
10.
J Immunol ; 180(7): 4402-8, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18354160

ABSTRACT

Transcription factor AML1/Runx1, initially isolated from the t(8;21) chromosomal translocation in human leukemia, is essential for the development of multilineage hematopoiesis in mouse embryos. AML1 negatively regulates the number of immature hematopoietic cells in adult hematopoiesis, whereas it is required for megakaryocytic maturation and lymphocytic development. However, it remains yet to be determined how AML1 contributes to homeostasis of hematopoietic stem cells (HSCs). To address this issue, we analyzed in detail HSC function in the absence of AML1. Notably, cells in the Hoechst 33342 side population fraction are increased in number in AML1-deficient bone marrow, which suggests enrichment of quiescent HSCs. We also found an increase in HSC number within the AML1-deficient bone marrow using limiting dilution bone marrow transplantation assays. These results indicate that the number of quiescent HSCs is negatively regulated by AML1.


Subject(s)
Core Binding Factor Alpha 2 Subunit/metabolism , Hematopoiesis , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Animals , Bone Marrow/metabolism , Colony-Forming Units Assay , Core Binding Factor Alpha 2 Subunit/deficiency , Core Binding Factor Alpha 2 Subunit/genetics , Gene Expression Regulation , Mice , Mice, Knockout , Myeloid Cells/cytology , Myeloid Cells/metabolism
11.
Am J Hematol ; 72(3): 220-2, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12605397

ABSTRACT

A male patient had a relapse of myelodysplastic syndrome (MDS) 2 years after BMT from a female matched unrelated donor. Conventional cytogenetics, FISH, and short-tandem repeat chimerism analysis proved a relapse of donor origin. He underwent reduced-intensity BMT after a conditioning with fludarabine and busulfan, since he had impaired renal, liver, and pulmonary functions. Chimerism analysis on day 28 after the second BMT showed mixed chimerism of the first and the second donors, which later turned to full second-donor chimerism on day 60. He developed grade II acute GVHD of the skin and cytomegalovirus reactivation, but both were improved with methylprednisolone and ganciclovir, respectively. He remains in complete remission 6 months after the second BMT. Reduced-intensity second BMT from an alternative donor appeared to be a tolerable treatment option for donor-derived leukemia/MDS after the first conventional transplantation.


Subject(s)
Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/methods , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/therapy , Tissue Donors , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclosporine/therapeutic use , Graft vs Host Disease/diagnosis , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Male , Methotrexate/therapeutic use , Myelodysplastic Syndromes/genetics , Recurrence , Remission Induction , Transplantation Chimera , Transplantation Conditioning
12.
Am J Hematol ; 72(1): 27-30, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12508264

ABSTRACT

Polymerase chain reaction (PCR) is a sensitive method for detection of Aspergillus DNA in bronchoalveolar lavage fluid, but it has not yet been able to distinguish infection from contamination. We have established a technique to quantify Aspergillus DNA using a real-time PCR method to resolve this problem, and we report herein a successful application of real-time PCR to diagnose invasive pulmonary aspergillosis by comparing the amount of Aspergillus DNA in bronchial lavage fluid from an affected area to that from an unaffected area. This novel tool will provide rapid, sensitive, and specific diagnosis of pulmonary aspergillosis.


Subject(s)
Aspergillosis/diagnosis , Aspergillus fumigatus/isolation & purification , Bronchoalveolar Lavage Fluid/chemistry , DNA, Fungal/analysis , Lung Diseases, Fungal/diagnosis , Polymerase Chain Reaction , Adult , Aspergillosis/etiology , Aspergillosis/genetics , Aspergillosis/pathology , Aspergillus fumigatus/genetics , Bone Marrow Transplantation/adverse effects , Computer Systems , Cryptogenic Organizing Pneumonia/etiology , Female , Graft vs Host Disease/etiology , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Leukemia, Myeloid, Acute/complications , Lung Diseases, Fungal/etiology , Lung Diseases, Fungal/genetics , Lung Diseases, Fungal/pathology , Opportunistic Infections/diagnosis , Opportunistic Infections/etiology , Opportunistic Infections/genetics , Opportunistic Infections/pathology , Sensitivity and Specificity , Transplantation, Homologous
SELECTION OF CITATIONS
SEARCH DETAIL
...