Prognostic value of pre-transplantation total metabolic tumor volume on 18fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography in relapsed and refractory aggressive lymphoma.
International journal of hematology
Relapsed and refractory aggressive lymphoma have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is effective in chemosensitive patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is among the few options for non-chemosensitive patients. 18Fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18FDG-PET/CT) is the standard tool for evaluating response to chemotherapy and residual tumor volume. However, accurate assessment of residual tumor volume is not currently being achieved in clinical practice, and its value in prognostic and therapeutic stratification remains unclear. To answer this question, we investigated the efficacy of quantitative indicators, including total metabolic tumor volume (TMTV), in predicting prognosis after auto-HSCT and allo-HSCT. We retrospectively analyzed 39 patients who received auto-HSCT and 28 who received allo-HSCT. In the auto-HSCT group, patients with a higher TMTV had a poor prognosis due to greater risk of relapse. In the allo-HSCT group, patients with a higher TMTV had a lower progression-free survival rate and a significantly higher relapse rate. Neither Deauville score nor other clinical parameters were associated with prognosis in either group. Therefore, pre-transplant TMTV on PET is effective for prognostic prediction and therapeutic decision-making for relapsed or refractory aggressive lymphoma.
View details for DOI 10.1007/s12185-022-03394-w
View details for PubMedID 35701707
Single-cell RNA sequencing reveals immune profile and tumor cell heterogeneity of angioimmunoblastic T-cell lymphoma
WILEY. 2022: 1273
View details for Web of Science ID 000778583803149
Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions.
Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.
View details for DOI 10.1016/j.canlet.2022.215597
View details for PubMedID 35150810
A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.
View details for DOI 10.1182/bloodadvances.2021004618
View details for PubMedID 34638128
Targeting leukemia-specific dependence on the de novo purine synthesis pathway
Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
View details for DOI 10.1038/s41375-021-01369-0
View details for Web of Science ID 000680815500001
View details for PubMedID 34344987
Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway
Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST.Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated.The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action.In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.
View details for DOI 10.1159/000518103
View details for Web of Science ID 000678759300001
View details for PubMedID 34350861
Platelet decrease and efficacy of platelet-rich plasma return following peripheral blood stem cell apheresis
JOURNAL OF CLINICAL APHERESIS
2021; 36 (5): 687-696
Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis.We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis.In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 109 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 109 /L, respectively), whereas severe platelet decrease (<50 × 109 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 109 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings.Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis.
View details for DOI 10.1002/jca.21917
View details for Web of Science ID 000661969300001
View details for PubMedID 34133767
Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study
ANNALS OF HEMATOLOGY
2021; 100 (1): 197-208
Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.
View details for DOI 10.1007/s00277-020-04310-0
View details for Web of Science ID 000585844700001
View details for PubMedID 33150464
- B cell receptor signaling related to resistance to Helicobacter pylori eradication therapy in gastric diffuse large B cell lymphoma HEMATOLOGICAL ONCOLOGY 2021; 39 (1): 145-147
Increasing Diluent Volume Decreases Bendamustine-Induced Venous Irritation without Reducing the Therapeutic Efficacy
BIOLOGICAL & PHARMACEUTICAL BULLETIN
2020; 43 (3): 488-492
The intravenous injection of bendamustine often induces venous irritation, which reduces patients' QOL. We previously reported that the dilution of the final volume of bendamustine from 250 to 500 mL significantly decreased the incidence of venous irritation. However, the influence of this change on the therapeutic efficacy of bendamustine remains unclear. Therefore, the aim of this study was to evaluate the efficacy and safety profiles of bendamustine at different dilutions of the final volume, comparing with the correspondences of previous studies. Thirty-four patients, who received a total of 161 courses of bendamustine and rituximab chemotherapy, were included in this study. The overall response rate of this regimen was 94.1% in this study, which was comparable to that reported in the BRB study (94.2%, a phase II study of bendamustine plus rituximab therapy in Japanese patients). Additionally, the median progression-free survival was not inferior to that reported in the BRB study. Bendamustine-induced venous irritation was observed in 17.6% of the patients during the first treatment cycle administered at a final volume of 500 mL, and was found to be lower than that observed in the control, where bendamustine was administered at a final volume of 250 mL (85.7%). These results suggest that diluting bendamustine to 500 mL, but not to 250 mL, reduces the incidence of venous irritation without a negative impact on its therapeutic efficacy; thus, this simple strategy may be beneficial to ensure efficacy and safety in patients receiving regimens including bendamustine.
View details for Web of Science ID 000517670400019
View details for PubMedID 32115507
- Paics, a De Novo Purine Synthetic Enzyme, Is a Novel Target for AML Therapy AMER SOC HEMATOLOGY. 2019
- Paics Inhibition Is a Potential Therapeutic Strategy for MYC-Positive DLBCL AMER SOC HEMATOLOGY. 2019
- A Fast and Accurate Diagnostic Method for Ph-like ALL Using the Ncounter System AMER SOC HEMATOLOGY. 2019
Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation
ANNALS OF HEMATOLOGY
2019; 98 (11): 2579-2591
Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.
View details for DOI 10.1007/s00277-019-03801-z
View details for Web of Science ID 000491421100002
View details for PubMedID 31628517
- Genome-Wide CRISPR Screen Identifies PAICS, An Enzyme Involved in De Novo Purine Synthesis, As a Potential Target for AML Therapy CIG MEDIA GROUP, LP. 2019: S216-S217
- PAICS Inhibition is a Potential Therapeutic Strategy for MYC-Positive Aggressive DLBCL CIG MEDIA GROUP, LP. 2019: S254
Safety and Seropositivity after Live Attenuated Vaccine in Adult Patients Receiving Hematopoietic Stem Cell Transplantation
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2019; 25 (8): 1576-1585
Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.
View details for DOI 10.1016/j.bbmt.2019.04.006
View details for Web of Science ID 000483008500014
View details for PubMedID 30959161
Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma
ANNALS OF HEMATOLOGY
2019; 98 (5): 1197-1207
The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.
View details for DOI 10.1007/s00277-019-03628-8
View details for Web of Science ID 000464721200015
View details for PubMedID 30729289
- Previous exposure to bortezomib is linked to a lower risk of engraftment syndrome after autologous hematopoietic stem cell transplantation LEUKEMIA & LYMPHOMA 2019; 60 (1): 271-273
Macrophages in ascites from cancer patients are primed to transdifferentiate into fibroblasts
WILEY. 2018: 1262
View details for Web of Science ID 000453773606109
Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2018; 42 (11): 1466-1471
GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13-negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0.03). There were no significant differences in other clinicopathologic factors including histological grade, BCL2-IGH translocation, immunohistochemical phenotype, and Follicular Lymphoma International Prognostic Index. In addition, overall survival and progression-free survival were poorer in GNA13-positive cases than in GNA13-negative cases (P=0.009 and 0.005, respectively). In multivariate analysis, GNA13 positivity was found to be a poor prognostic factor for overall survival and progression-free survival. Thus, GNA13 protein expression was an independent prognostic factor and may affect disease progression in FL.
View details for DOI 10.1097/PAS.0000000000000969
View details for Web of Science ID 000447699800005
View details for PubMedID 30307409
View details for PubMedCentralID PMC6266301
Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2018; 24 (11): 2302-2309
Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.
View details for DOI 10.1016/j.bbmt.2018.06.002
View details for Web of Science ID 000453638700020
View details for PubMedID 29909153
- Expression of PD-1 and PD-L1 on cytotoxic T lymphocytes and immune deficiency in a patient with adult T cell leukemia/lymphoma ANNALS OF HEMATOLOGY 2018; 97 (2): 359-360
Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma.
2018; 9 (2): 1717-1725
Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin <120 g/l, elevated lactate dehydrogenase level, and high-risk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV-negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL (p < 0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients.
View details for DOI 10.18632/oncotarget.23138
View details for PubMedID 29416725
View details for PubMedCentralID PMC5788593
Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma
2018; 9 (2): 1717-1725
Neoantigens are the main targets of tumor-specific T cells reactivated by immune checkpoint-blocking antibodies or when using tumor-infiltrating T cells for adoptive therapy. While cancers often accumulate hundreds of mutations and harbor several immunogenic neoantigens, the repertoire of mutation-specific T cells in patients might be restricted. To bypass suboptimal conditions, which impede the reactivation of existing T cells or the priming of neoantigen-specific T cells in a patient, we employ T cells of healthy donors with an overlapping HLA repertoire to target cancer neoantigens. In this study, we focus on streamlining the process of in vitro-induction of neoantigen-specific T cells and isolating their T cell receptors (TCRs) to establish a time-efficient protocol that will allow the patient to benefit from subsequent therapy. We first optimized the priming of T cells to omit multiple restimulations and extended culturing. Neoantigen-specific T cells were enriched using specific dextramers and next-generation sequencing was applied to determine the TCR repertoire. This allowed us to circumvent the laborious process of expanding T cell clones. Using this protocol, we successfully identified HLA-A-restricted TCRs specific for neoantigens found in an esophageal cancer cell line (TE-8) and a primary ovarian cancer. To verify TCR specificity, we generated TCR-engineered T cells and confirmed recognition of the tumor-derived neoantigens. Our results also emphasize the importance of neoepitope selection in order to avoid cross-reactivity to corresponding wild-type peptide sequences. In conclusion, we established a 2-week protocol for generating and identifying neoantigen-specific TCRs from third-party donors making this strategy applicable for clinical use.
View details for DOI 10.18632/oncotarget.23138
View details for Web of Science ID 000419623200018
View details for PubMedID 29541393
View details for PubMedCentralID PMC5834292
Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS.
2018; 2 (17): 2242-2252
Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.
View details for DOI 10.1182/bloodadvances.2018018754
View details for PubMedID 30194138
View details for PubMedCentralID PMC6134219
Identification of unipotent megakaryocyte progenitors in human hematopoiesis.
2017; 129 (25): 3332-3343
The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34+CD38+IL-3RαdimCD45RA- common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41+ CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.
View details for DOI 10.1182/blood-2016-09-741611
View details for PubMedID 28336526
- Delineation of Novel Subtypes Based on Microenvironment Immune Signature Provides Prognostic Stratification Strategy in Peripheral T-Cell Lymphoma AMER SOC HEMATOLOGY. 2016
Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2016; 22 (9): 1608-1614
Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.
View details for DOI 10.1016/j.bbmt.2016.05.017
View details for Web of Science ID 000381781400011
View details for PubMedID 27220263
Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study.
[Rinsho ketsueki] The Japanese journal of clinical hematology
2016; 57 (12): 2475-2480
In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ.
View details for DOI 10.11406/rinketsu.57.2475
View details for PubMedID 28090013
- First Preclinical Report of the Efficacy and PD Results of KHK2823, a Non-Fucosylated Fully Human Monoclonal Antibody Against IL-3R alpha AMER SOC HEMATOLOGY. 2015
- Prior Use of Mogamulizumab to Allogenic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-Versus-Host Disease AMER SOC HEMATOLOGY. 2015
[Herpes simplex virus type 2 fulminant hepatitis after umbilical cord blood transplantation for acute myeloid leukemia].
[Rinsho ketsueki] The Japanese journal of clinical hematology
2014; 55 (6): 682-6
This report describes a 41-year-old patient, who developed herpes simplex virus type 2 (HSV-2)-hepatitis after umbilical cord blood transplantation (CBT). The patient had received allogeneic bone marrow transplantation from an unrelated donor for acute myeloid leukemia (AML) not in remission. AML relapsed 18 months after the first transplantation, and CBT was performed. AML relapsed again 5 months later and the patient was given chemotherapy. Although there was no active chronic graft-versus-host disease, liver dysfunction appeared, and one week later, progressed to acute liver failure. Viral screening of blood by PCR including hepatitis B and C viruses, human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, herpes simplex virus type 1 and HSV-2 revealed elevation of HSV-2 (2.34 * 10⁴ copies/ml). We diagnosed the patient as having HSV-2 acute hepatitis, and initiated treatment with antiviral drugs (acyclovir, foscarnet) and plasma exchange. However, liver functions deteriorated rapidly, and the patient died on day 6 after the onset of acute liver failure. Although HSV hepatitis is very rare after allogeneic stem cell transplantation, it is rapidly progressive and associated with a high mortality rate. Thus, early diagnosis with prompt antiviral intervention is recommended.
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