Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 81
Filter
1.
Int J Hematol ; 119(6): 647-659, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38532078

ABSTRACT

OBJECTIVES: NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML. METHODOLOGY: This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60-75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351. RESULTS: In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7-74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated. OUTCOMES: NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Cytarabine , Daunorubicin , Leukemia, Myeloid, Acute , Liposomes , Humans , Daunorubicin/administration & dosage , Daunorubicin/pharmacokinetics , Cytarabine/administration & dosage , Cytarabine/pharmacokinetics , Leukemia, Myeloid, Acute/drug therapy , Middle Aged , Aged , Male , Female , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Japan , Treatment Outcome , Asian People , East Asian People
2.
Blood Cell Ther ; 6(3): 80-86, 2023 Aug 25.
Article in English | MEDLINE | ID: mdl-38146355

ABSTRACT

The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have reported copy number variants of genes such as IKZF1, CDKN2A/2B, and PAX5. These gene mutations can be analyzed using multiplex ligation-dependent probe amplification (MLPA), which is less costly and easier to perform than large-scale gene mutation analyses. In this study, we performed copy number variant analysis of leukemia cells at the first onset of Ph+ALL in a case series of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the MLPA method. We analyzed how it influenced allo-HSCT prognosis together with MRD information. CDKN2A/2B copy number variations significantly increased the rate of post-transplant recurrence (P=0.025) and significantly reduced disease-free survival (P=0.015). Additionally, patients with IKZF1 deletions had a significantly higher post-transplant recurrence rate (P=0.042). Although they were positive for pre-transplant MRD, no relapse was observed in patients with wild-type copy number variations in IKZF1 or CDKN2A/2B. CDKN2A/2B copy number variation is a crucial factor that can be confirmed at initial onset as a post-transplant prognostic factor of Ph+ALL.

3.
Int J Hematol ; 118(6): 711-717, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37728705

ABSTRACT

Venetoclax (VEN) combination regimens are now recognized as effective against acute myeloid leukemia (AML). However, the prognosis of patients who do not attain a composite complete response (cCR) is extremely poor, and clinical determinants of response remain unknown. Medical records of 57 patients with AML treated with VEN combination regimens from April 2021 to March 2022 at six institutions were retrospectively analyzed. The primary endpoint was cCR, complete remission, or complete remission with incomplete hematologic recovery after one cycle of VEN combination regimen. Five patients had previously relapsed after allogeneic hematopoietic stem cell transplantation (allo-SCT). The treatment regimen was azacitidine-VEN in 48 patients (84%) and low-dose cytarabine-VEN in 9 patients (16%). Thirty patients (53%) achieved cCR after one cycle of a VEN regimen. In univariate analysis, the number of prior chemotherapy regimens, post-allo-SCT relapse, and cytogenetic risk category were associated with a decreased likelihood of achieving cCR. In multivariate analysis, second-line chemotherapy remained a significant predictor of response. Patients who received anthracycline immediately before the VEN regimen had a higher cCR rate than patients who did not receive anthracycline. In this study, prior chemotherapy/allo-SCT and cytogenetic risk were associated with VEN treatment outcomes.


Subject(s)
Anthracyclines , Leukemia, Myeloid, Acute , Humans , Anthracyclines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/etiology , Retrospective Studies , Treatment Outcome , Antineoplastic Agents/therapeutic use
4.
Int J Hematol ; 117(5): 684-693, 2023 May.
Article in English | MEDLINE | ID: mdl-36574168

ABSTRACT

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5 years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS (n = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.


Subject(s)
Fetal Hemoglobin , Myelodysplastic Syndromes , Humans , Retrospective Studies , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/drug therapy , Prognosis , Azacitidine
5.
Curr Oncol ; 29(11): 8529-8539, 2022 11 09.
Article in English | MEDLINE | ID: mdl-36354732

ABSTRACT

The prognosis of patients with multiple myeloma (MM) has improved dramatically with the introduction of new therapeutic drugs, but the disease eventually becomes drug-resistant, following an intractable and incurable course. A myeloma niche (MM niche) develops in the bone marrow microenvironment and plays an important role in the drug resistance mechanism of MM. In particular, adhesion between MM cells and bone marrow stromal cells mediated by adhesion molecules induces cell adhesion-mediated drug resistance (CAM-DR). Analyses of the role of mitochondria in cancer cells, including MM cells, has revealed that the mechanism leading to drug resistance involves exchange of mitochondria between cells (mitochondrial transfer) via tunneling nanotubes (TNTs) within the MM niche. Here, we describe the discovery of these drug resistance mechanisms and the identification of promising therapeutic agents primarily targeting CAM-DR, mitochondrial transfer, and TNTs.


Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Cell Adhesion , Drug Resistance, Neoplasm , Mitochondria/metabolism , Tumor Microenvironment
6.
Am J Surg Pathol ; 46(8): 1017-1024, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35848760

ABSTRACT

Although the alteration of the 9p24.1 chromosome locus and PD-L1 overexpression is found in nodular sclerosis classic Hodgkin lymphoma, whether these aberrations occur in CHL and Hodgkin-like lesion (HLL) of methotrexate-associated lymphoproliferative disorder (MTX-CHL and MTX-HLL) is unknown. We compared the clinicopathologic features, the genomic status of the 9p24.1 locus and PD-L1 expression in a series of 34 patients including 17 with Epstein-Barr virus-positive de novo CHL, 7 with MTX-CHL, 10 with MTX-HLL using an immunofluorescence in situ hybridization method and immunohistochemistry. The proportions of cells with 9p24.1 genetic alteration in CD30-positive Hodgkin/Reed-Sternberg cells of de novo CHL, MTX-CHL and MTX-HLL were 55%, 68%, and 24%, respectively. The positive rates of PD-L1 measured by immunohistochemical H-scores of de novo CHL, MTX-CHL and MTX-HLL were 142±38, 157±75, and 70±42, respectively. Alteration of the 9p24.1 gene and expression of PD-L1 protein were correlated with all 3 diseases (correlation coefficient, 0.731). Both alteration of the 9p24.1 gene and overexpression of PD-L1 protein were observed in Epstein-Barr virus-positive de novo CHL and MTX-CHL but not in MTX-HLL. In conclusion, MTX-CHL has similar pathogenesis-like de novo CHL, but MTX-HLL seems to be a different disease from de novo CHL and MTX-CHL.


Subject(s)
Epstein-Barr Virus Infections , Hodgkin Disease , B7-H1 Antigen/metabolism , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/genetics , Hodgkin Disease/drug therapy , Hodgkin Disease/genetics , Humans , Methotrexate/adverse effects
7.
J Infect Chemother ; 28(9): 1279-1285, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35691863

ABSTRACT

INTRODUCTION: Influenza virus infection (IVI) is frequent in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, and reports from several countries indicate high morbidity and mortality from progression to lower respiratory tract disease (LRTD). However, there have been no reports on IVI clinical characteristics, treatment outcomes, and risk factor for progression to LRTD among allo-HSCT recipients in Japan. METHODS: We retrospectively reviewed the medical charts of allo-HSCT recipients who developed IVI between 2012 and 2019. RESULTS: Forty-eight cases of IVI following allo-HSCT were identified at our institution. The median age was 42 years, and median time from allo-HSCT to IVI was 25 months. Thirty-seven patients (77.1%) were administered neuraminidase inhibitors (NAIs) as antiviral therapy within 48 h of symptom onset (early therapy), whereas 11 (22.9%) received NAI over 48 h after onset (delayed therapy). Subsequently, 12 patients (25.0%) developed LRTD after IVI. Multivariate analysis identified older age (hazard ratio [HR], 7.65; 95% confidence interval [CI], 2.22-26.3) and bronchiolitis obliterans (HR, 5.74; 95% CI, 1.57-21.0) as independent risk factors for progression to LRTD. Moreover, land-mark analysis showed that early therapy prevented progression to LRTD (11.8% vs. 45.5%, P = 0.013). The IVI-related mortality rate was 2.1%. CONCLUSIONS: Early NAI treatment is recommended for reducing the risk of LRTD progression due to IVI in allo-HSTC recipients, particularly for older patients and those with bronchiolitis obliterans.


Subject(s)
Bronchiolitis Obliterans , Communicable Diseases , Hematopoietic Stem Cell Transplantation , Influenza, Human , Adult , Bronchiolitis Obliterans/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Influenza, Human/complications , Influenza, Human/epidemiology , Retrospective Studies , Risk Factors
8.
Int J Hematol ; 115(2): 233-243, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34741230

ABSTRACT

RAS/RAF/MEK/ERK pathway inhibitors exhibit significant anti-tumor effects against various tumor types, including multiple myeloma (MM), and they are predicted to play a pivotal role in precision medicine. The XPO1 inhibitor KPT-330 has also exhibited promising efficacy in combination with other novel drugs in treating relapsed/refractory MM (RRMM). In this study, we explored the anti-tumor effects of a combination of the pan-RAF inhibitor TAK-580 and KPT-330. Importantly, TAK-580 enhanced KPT-330-induced cytotoxicity and apoptosis in human myeloma cell lines and primary myeloma cells from RRMM patients. Moreover, TAK-580 and KPT-330 synergistically inhibited nuclear phospho-FOXO3a and enhanced cytoplasmic phospho-FOXO3a in MM cells, leading to cytoplasmic enhanced Bim expression and finally apoptosis. This indicates that TAK-580 enhances KPT-330-induced cytotoxicity and apoptosis primarily via the FOXO3a-Bim axis. In addition, TAK-580 enhanced the cytotoxicity of KPT-330 against MM cells even in the presence of IGF-1. Taken together, our results demonstrate that a combination of pan-RAF inhibitor and XPO1 inhibitor is a potential therapeutic option in treating MM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Hydrazines/pharmacology , Multiple Myeloma/drug therapy , Triazoles/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Drug Synergism , Humans , Tumor Cells, Cultured
9.
Ann Hematol ; 100(10): 2479-2486, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34247299

ABSTRACT

The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has improved dramatically. Although measurable residual disease (MRD) kinetics during pretransplant treatment has been recently reported to correlate with patient outcomes, it is unclear whether prognosis is better if the MRD falls below the detection sensitivity soon after induction therapy. We retrospectively analyzed data of 37 Ph + ALL patients who were treated with autologous or allogeneic stem cell transplantation (auto-SCT, allo-SCT) at our institute from 2003 to 2019. Based on MRD kinetics, patients were divided into three groups: early responders (MRD became negative after induction therapy [n = 10, 27.0%]); late responders (MRD remained positive after induction therapy and became negative just before SCT [n = 12, 32.4%]); and poor responders (MRD was positive until just before SCT [n = 15, 40.5%]). The 5-year disease-free survival (DFS) rates for the three groups were 80.0%, 60.0%, and 29.9%, respectively (P = 0.037). The 5-year overall survival rates were not significantly different. The 5-year relapse rates were 0.0%, 31.7%, and 49.5%, respectively (P = 0.045). Non-relapse mortality (NRM) rates were similar among the three groups. Subgroup analysis for the cases that received posttransplantation tyrosine kinase inhibitor maintenance therapy revealed that DFS was similarly dependent on MRD kinetics (P = 0.022). This study clarified that MRD kinetics was a significant prognosticator for DFS and relapse rate in Ph + ALL.


Subject(s)
Neoplasm, Residual/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Adult , Female , Humans , Male , Middle Aged , Neoplasm, Residual/genetics , Neoplasm, Residual/therapy , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prognosis , Retrospective Studies , Stem Cell Transplantation , Transplantation, Homologous , Treatment Outcome , Young Adult
10.
Int J Hematol ; 113(4): 606-610, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33389657

ABSTRACT

The Janus kinase/signal transducers and activators of transcription signaling pathway induces programmed death ligand-1 (PD-L1) expression. JAK2 mutation at position 617 (JAK2V617) is a frequent driver of myeloproliferative neoplasms (MPN) through PD-L1 expression. Although PD-1 inhibitors should be effective against MPN with JAK2V617F mutation, this has not yet been reported in humans. Thus, we assessed the efficacy of a PD-1 inhibitor in a lung cancer patient with JAK2V617F-positive essential thrombocythemia (ET). A 71-year-old man was diagnosed with ET, and with lung carcinoma 3 years later. After right lobectomy and postoperative chemotherapy, pembrolizumab [a PD-1 inhibitor (200 mg, every 3 weeks)] was initiated for refractory lung carcinoma. Lung cancer progression did not occur for 1.5 years under treatment. Most megakaryocytes were PD-L1-positive, and after pembrolizumab initiation, platelet count remained below 45 × 104/µL without the need for other cytoreductive therapies for ET. The JAK2V617F allele burden gradually decreased from 11.5% at diagnosis to 2.9% after 17 months of pembrolizumab treatment. Other peripheral blood lineages did not decrease, and pembrolizumab treatment was continued without any adverse events. This is the first report demonstrating the effectiveness of pembrolizumab in an MPN patient with JAK2V617F mutation.


Subject(s)
Alleles , Gene Frequency/drug effects , Immune Checkpoint Inhibitors/pharmacology , Janus Kinase 2/genetics , Mutation , Thrombocythemia, Essential/genetics , Aged , Amino Acid Substitution , B7-H1 Antigen/antagonists & inhibitors , Biomarkers , Bone Marrow/pathology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunohistochemistry , Male , Platelet Count , Thrombocythemia, Essential/diagnosis , Thrombocythemia, Essential/drug therapy
11.
Clin Lymphoma Myeloma Leuk ; 21(4): e321-e327, 2021 04.
Article in English | MEDLINE | ID: mdl-33127326

ABSTRACT

INTRODUCTION: The risk factors for bleomycin-induced lung injury (BLI), a fatal complication of cancer chemotherapy, are not well-established. The renin-angiotensin-aldosterone system (RAAS) has recently been suggested to play a role in the development of lung injury. This study clarified the impact of hypertension (HTN) and the administration of RAAS inhibitors on BLI occurrence in patients treated with bleomycin-containing regimens. PATIENTS AND METHODS: We retrospectively analyzed the data of 190 patients treated with a bleomycin-containing regimen for Hodgkin lymphoma or germ cell tumors at our institutions from 2004 to 2018. RESULTS: Overall, 190 patients received bleomycin, and symptomatic BLI occurred in 21 (11.1%) cases. In the multivariate analysis, age ≥ 65 years (odd ratio, 10.90; 95% confidence interval, 3.72-32.20; P < .001) and history of HTN (odds ratio, 3.32; 95% confidence interval, 1.07-10.30; P = .04) were found to be significant risk factors for BLI onset. BLI occurred in 3.6% (n = 5) of patients with no risk, 11.8% (n = 2) of those whose only risk factor was HTN, 31.6% (n = 6) of those whose only risk factor was age ≥ 65 years, and 57.1% (n = 8) of those with both risk factors (P < .001). BLI-induced mortality rates in each group were 0.0% (n = 0), 5.9% (n = 1), 10.5% (n = 2), and 42.9% (n = 6) (P < .001), respectively. Among 31 patients with HTN, BLI incidence was 12.5% in patients who were administered RAAS inhibitors and 53.3% in those who were not (P = .02). CONCLUSION: Older age and history of HTN were independent risk factors for the development of BLI, and the administration of RAAS inhibitors might reduce the onset of BLI.


Subject(s)
Angiotensin II Type 2 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Bleomycin/adverse effects , Hypertension/epidemiology , Lung Injury/epidemiology , Administration, Intravenous , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin II Type 2 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Bleomycin/administration & dosage , Child , Female , Hodgkin Disease/drug therapy , Humans , Hypertension/drug therapy , Incidence , Lung Injury/chemically induced , Lung Injury/prevention & control , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/drug therapy , Renin-Angiotensin System/drug effects , Retrospective Studies , Risk Assessment/statistics & numerical data , Risk Factors , Young Adult
12.
Oncotarget ; 11(44): 3984-3997, 2020 Nov 03.
Article in English | MEDLINE | ID: mdl-33216827

ABSTRACT

Many RAS pathway inhibitors, including pan-RAF inhibitors, have shown significant anti-tumor activities in both solid and hematological tumors. The pan-RAF inhibitor, TAK-580, is a representative of the novel RAF inhibitors that act by disrupting RAF homo- or heterodimerization. In this study, we examined the anti-tumor effects of TAK-580 used as monotherapy or in combination with bortezomib, lenalidomide, or other novel agents in multiple myeloma (MM) cells in vitro. TAK-580 monotherapy potently targeted proteins in the RAS-RAF-MEK-ERK signaling pathway and induced potent cytotoxicity and apoptosis in MM cell lines and myeloma cells from patients with newly diagnosed and relapsed and/or refractory MM, compared with a representative RAF inhibitor, dabrafenib. Normal donor peripheral blood B lymphocytes and cord blood CD34-positive cells were not affected. Importantly, TAK-580 significantly inhibited phospho-FOXO3 and induced upregulation of BimL and BimS in a dose-dependent manner, finally leading to apoptosis in MM cells. Moreover, TAK-580 enhanced bortezomib-induced cytotoxicity and apoptosis in MM cells via the FOXO3-Bim axis and the terminal unfolded protein response. Importantly, TAK-580 also enhanced lenalidomide-induced cytotoxicity and apoptosis in MM cells. Taken together, our results provide the rationale for TAK-580 monotherapy and/or treatment in combination with novel agents to improve outcomes in patients with MM.

13.
J Clin Exp Hematop ; 60(4): 159-168, 2020 Dec 15.
Article in English | MEDLINE | ID: mdl-33148934

ABSTRACT

Some patients diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) develop spontaneous regression upon the discontinuation of MTX, whereas others require chemotherapy. The mechanisms underlying this differential response and the capacity to spontaneously regress are not clearly understood. We evaluated numerous clinicopathological features in 63 patients diagnosed with MTX-LPD, with a special focus on those with Epstein-Barr virus (EBV)-positive mucocutaneous lesions (EBVMCL). The diagnosis of EBVMCL included cases of both EBV-positive mucocutaneous ulcers (EBVMCU) and diffuse gingival swelling associated with proliferation of EBV-positive large B-cells. Of the four subgroups of MTX-LPD, one-year treatment-free survival (TFS) after the discontinuation of MTX was achieved among those with EBVMCL (100%), diffuse large B-cell lymphoma (57%), Hodgkin-like lesions (60%), or classical Hodgkin lymphoma (29%); a significant difference in TFS was observed when comparing the responses of patients with EBVMCL to the those diagnosed with other subtypes. Multivariate analysis revealed predictive factors for prolonged TFS that included EBV-positive lesions and comparatively low levels of serum LDH. Taken together, our study suggests that a diagnosis of EBVMCL is related to the overall clinical outcome after the discontinuation of MTX.


Subject(s)
Epstein-Barr Virus Infections , Herpesvirus 4, Human/metabolism , Hodgkin Disease , Lymphoma, Large B-Cell, Diffuse , Methotrexate/adverse effects , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Epstein-Barr Virus Infections/chemically induced , Epstein-Barr Virus Infections/metabolism , Epstein-Barr Virus Infections/mortality , Epstein-Barr Virus Infections/therapy , Female , Hodgkin Disease/chemically induced , Hodgkin Disease/metabolism , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Humans , Lymphoma, Large B-Cell, Diffuse/chemically induced , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Methotrexate/administration & dosage , Middle Aged , Retrospective Studies , Survival Rate
14.
Int J Hematol ; 112(5): 690-696, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32770478

ABSTRACT

Even though the hematopoietic stem cell transplantation (HSCT) procedure has been improved, oral mucositis (OM) is still a severe complication of the conditioning regimen. We investigated the association between OM severity and the alteration of oral bacterial flora using 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) analysis in 19 consecutive patients undergoing HSCT. Oral samples were collected at pre-transplantation, at the peak of mucositis and post-engraftment. T-RFLP profiles for each timepoint were constructed into an X-Y matrix, and the distances between timepoints were calculated. Patients with severe and moderate OM had larger changes in their oral bacterial flora from before HSCT to peak of mucositis than controls (p = 0.031 and 0.016, respectively). Moreover, severe mucositis was significantly associated with an extended period of fever until engraftment, high maximum C-reactive protein levels, and prolonged periods of opioid treatment and intravenous hyper-alimentation. These findings suggest that mucositis severity is associated with the magnitude of change in the oral bacterial flora. This novel finding may help advance strategies for the prevention or treatment of OM after HSCT.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Microbiota , Polymorphism, Restriction Fragment Length , Stomatitis/etiology , Stomatitis/microbiology , Transplantation Conditioning/adverse effects , Adult , Aged , Female , Humans , Immunocompromised Host , Male , Microbiota/genetics , Middle Aged , RNA, Ribosomal, 16S , Severity of Illness Index , Stomatitis/prevention & control , Young Adult
15.
Tokai J Exp Clin Med ; 45(2): 92-96, 2020 Jul 20.
Article in English | MEDLINE | ID: mdl-32602108

ABSTRACT

A 69-year-old man was referred to the hematology department for the evaluation of pancytopenia. He had been treated with radiation and epirubicin for hepatocellular carcinoma, and with docetaxel and pembrolizumab for lung adenocarcinoma. Bone marrow smears exhibited markedly increased promyelocytes, and polymerase chain reaction (PCR) study demonstrated chimeric fusion genes of PML-RARA. He was diagnosed with therapy-related acute promyelocytic leukemia (t-APL) and treated with all trans-retinoic acid (ATRA). After 30 days of ATRA treatment, complete hematological response was achieved. To the best of our knowledge, this case represents the first description of successfully treated t-APL diagnosed after treatment with pembrolizumab.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Hepatocellular/drug therapy , Carcinoma/drug therapy , Docetaxel/adverse effects , Epirubicin/adverse effects , Leukemia, Promyelocytic, Acute/chemically induced , Leukemia, Promyelocytic, Acute/drug therapy , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Neoplasms, Multiple Primary , Tretinoin/therapeutic use , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Docetaxel/therapeutic use , Epirubicin/therapeutic use , Humans , Male , Treatment Outcome
17.
Case Rep Gastroenterol ; 13(2): 336-341, 2019.
Article in English | MEDLINE | ID: mdl-31543755

ABSTRACT

A 47-year-old woman visited Tokai University Hospital complaining of left cervical lymph node swelling in 2007. The laboratory data were almost normal except for slight anemia (Hgb 10.5 g/dL), elevation of serum soluble interleukin (IL)-2 receptor levels (645 U/mL [normal range 220-530 U/mL]), and positive hepatitis C virus (HCV) antibody. Serum transaminase and lactated dehydrogenase levels were normal. Contrast-enhanced computed tomography (CT) showed lymph node swelling with a diameter of 3 cm at the left supraclavicular fossa and mild splenomegaly, and 18F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT) revealed abnormal uptake in the left supraclavicular fossa. The patient was diagnosed as having indolent nodal marginal zone B-cell lymphoma by lymph node biopsy. After 9 years with no progression of lymphoma, the patient received 12-week ledipasvir/sofosbuvir therapy for HCV infection and achieved sustained virologic response without any adverse effects. The left supraclavicular mass disappeared in the FDG-PET/CT performed 5 months after antiviral therapy indicating complete response. The serum soluble IL-2 receptor concentration decreased to 244 U/mL. Thereafter, her lymphoma was in remission for 3 years.

18.
Neoplasia ; 21(8): 788-801, 2019 08.
Article in English | MEDLINE | ID: mdl-31276931

ABSTRACT

Hematological malignancies harboring various ABL1 fusions are expected to be sensitive to tyrosine kinase inhibitors (TKIs), similar to those with BCR-ABL1. However, SEPT9-ABL1 exhibits TKI resistance both in vitro and in vivo. SEPT9-ABL1 has the same ABL1 region as seen in BCR-ABL1 but no point mutation in its kinase domain, which is one of the main mechanisms underlying TKI resistance in the leukemic cells harboring BCR-ABL1. The purpose of this study was to reveal the mechanism underlying TKI resistance induced by SEPT9-ABL1. We focused on the TP53 status because TKI-induced apoptosis in BCR-ABL1-positive cells is achieved through TP53. Mouse TP53 homologue TRP53 was downregulated and less phosphorylated in the cells expressing SEPT9-ABL1 than in those with BCR-ABL1, resulting in the prevention of apoptosis induced by TKIs. The CRM1 inhibitor KPT-330 accumulated nuclear TRP53 and NFKB1A (also known as IκBα), which is thought to capture TRP53 in the cytoplasm, and induced apoptosis in the hematopoietic cells expressing SEPT9-ABL1. In addition, the combination treatment of KPT-330 and imatinib, which induced the marked nuclear accumulation of PP2A and SET, reactivated PP2A through its dephosphorylation and inhibited SET expression, resulting in the effective induction of the apoptosis in the cells expressing SEPT9-ABL1. The combination treatment with KPT-330 and imatinib successfully reduced the subcutaneous masses expressing SEPT9-ABL1 and extended the survival of the mice intraperitoneally transplanted with SEPT9-ABL1-expressing cells. These results show that therapy with CRM1 inhibitors may be effective for overcoming TKI resistance induced by SEPT9-ABL1.


Subject(s)
Drug Resistance, Neoplasm/genetics , Oncogene Proteins, Fusion/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/genetics , Septins/genetics , Animals , Apoptosis/drug effects , Cell Line, Transformed , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Gene Expression , Humans , Mice , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
19.
Int J Hematol ; 109(6): 657-664, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30915717

ABSTRACT

This multicenter, phase I, open-label dose escalation study evaluated safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of inebilizumab in Japanese patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), or multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplantation. Patients received inebilizumab 2, 4, or 8 mg/kg intravenously on days 1 and 8 of the first 28-day cycle, and once every 28 days thereafter, with a 12 mg/kg cohort added. Twenty patients (11 FL, six DLBCL, two CLL, and one MM) received inebilizumab at four dose levels (2 mg/kg cohort, n = 3; 4 mg/kg cohort, n = 7; 8 mg/kg cohort, n = 4; 12 mg/kg cohort, n = 6). Three patients experienced dose-limiting toxicities: grade 4 neutropenia/grade 3 leukopenia (n = 1, 12 mg/kg) and grade 3 infusion reaction (n = 1 each, 4 mg/kg and 12 mg/kg); the maximum tolerated dose was 8 mg/kg. Four (three FL and one DLBCL) patients achieved complete response; eight (six FL and two DLBCL) achieved partial response. Overall response rate was 60%. Over the dose ranges evaluated, the pharmacokinetic profile of inebilizumab in Japanese patients was generally dose proportional. This phase I study showed acceptable toxicity and preliminary and promising efficacy of inebilizumab in patients with relapsed/refractory FL and DLBCL.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antigens, CD19/immunology , Lymphoma, B-Cell/drug therapy , Multiple Myeloma/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Asian People , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Recurrence , Treatment Outcome
20.
J Clin Exp Hematop ; 59(1): 34-39, 2019.
Article in English | MEDLINE | ID: mdl-30918142

ABSTRACT

Composite lymphoma (CL) is defined as the occurrence of two distinct types of lymphoma within the same patient. Most cases of CL involve Hodgkin and non-Hodgkin lymphomas or two distinct types of B-cell lymphomas; true CL is a composite B-cell and T-cell lymphoma, and is rare. We herein report a case involving concurrent extranodal NK/T-cell lymphoma, nasal-type and diffuse large B-cell lymphoma, which has not been previously reported. As the mechanisms and treatments of composite B-cell and T-cell lymphomas are unclear, further studies are required to improve the prognosis.


Subject(s)
Composite Lymphoma/pathology , Lymphoma, Extranodal NK-T-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Nose Neoplasms/pathology , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Invasiveness
SELECTION OF CITATIONS
SEARCH DETAIL