記述言語：英語   出版者・発行元：WILEY  

AimsThe central nervous system (CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer (NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown.
Methods and resultsWe identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3 epsilon, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA (EBER), 100% and T cell receptor (TCR)- or , 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours.
ConclusionsAlthough extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy.

DOI： 10.1111/his.13223

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

CD4(+) Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44(+) CD62L(+) central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

DOI： 10.1182/blood-2016-09-741629

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記述言語：英語   出版者・発行元：ELSEVIER SCI LTD  

Background. Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. Case Report. Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. Discussion. A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. Conclusion. Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

DOI： 10.1016/j.jcyt.2016.12.007

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記述言語：英語   出版者・発行元：ELSEVIER SCI LTD  

Background. Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. Case Report. Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. Discussion. A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. Conclusion. Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

DOI： 10.1016/j.jcyt.2016.12.007

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記述言語：英語   出版者・発行元：ELSEVIER SCI LTD  

Background. Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. Case Report. Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. Discussion. A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. Conclusion. Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

DOI： 10.1016/j.jcyt.2016.12.007

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

CD4(+) Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44(+) CD62L(+) central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

DOI： 10.1182/blood-2016-09-741629

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

CD4(+) Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44(+) CD62L(+) central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

DOI： 10.1182/blood-2016-09-741629

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DOI： 10.1111/cas.13291

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記述言語：英語   出版者・発行元：WILEY  

Background. Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand.
Patients and Methods. The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of >= 65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP.
Results. A total of 836 patients with a median age of 74 years ( range, 65-96 years) were analyzed. In the SoLT-J cohort (n=555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score >= 3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n5281).
Conclusion. The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP.

DOI： 10.1634/theoncologist.2016-0260

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DOI： 10.1007/s12185-017-2391-1

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記述言語：英語   出版者・発行元：WILEY  

Background. Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand.
Patients and Methods. The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of >= 65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP.
Results. A total of 836 patients with a median age of 74 years ( range, 65-96 years) were analyzed. In the SoLT-J cohort (n=555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score >= 3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n5281).
Conclusion. The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP.

DOI： 10.1634/theoncologist.2016-0260

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DOI： 10.1111/cas.13340

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DOI： 10.1111/his.13223

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10(down)) GI-FL. The diagnosis of CD10(down) FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10(down) GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10(+) GI-FL, CD10(down) GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10(down) group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10(down) GI-FL, and an identical clone was found between CD10(down) follicles and CD10(+)BCL2(+) neoplastic follicles. In the diagnosis of cases with CD10(down) BCL2(+) follicles, careful examination with molecular studies should be carried out.

DOI： 10.1111/cas.13031

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記述言語：英語   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD.

DOI： 10.18926/AMO/54603

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記述言語：英語   出版者・発行元：SPRINGER  

Purpose The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial.
Methods In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m(2), days 1-3) and cisplatin (20 mg/m(2), days 1-3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR).
Results The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47-89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3-4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %).
Conclusions This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.

DOI： 10.1007/s00280-016-3135-2

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記述言語：英語   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD.

DOI： 10.18926/AMO/54603

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

DOI： 10.1111/pin.12439

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

DOI： 10.1111/pin.12439

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記述言語：英語   出版者・発行元：WILEY  

BACKGROUNDTransplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed.
STUDY DESIGN AND METHODSThe study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit.
RESULTSSixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p=0.52) on Day 100 after TA-TMA onset.
CONCLUSIONThis is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   出版者・発行元：WILEY  

BACKGROUNDTransplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed.
STUDY DESIGN AND METHODSThe study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit.
RESULTSSixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p=0.52) on Day 100 after TA-TMA onset.
CONCLUSIONThis is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   出版者・発行元：WILEY  

BACKGROUNDTransplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed.
STUDY DESIGN AND METHODSThe study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit.
RESULTSSixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p=0.52) on Day 100 after TA-TMA onset.
CONCLUSIONThis is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   出版者・発行元：WILEY  

BACKGROUNDTransplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed.
STUDY DESIGN AND METHODSThe study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit.
RESULTSSixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p=0.52) on Day 100 after TA-TMA onset.
CONCLUSIONThis is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   出版者・発行元：WILEY  

BACKGROUNDTransplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed.
STUDY DESIGN AND METHODSThe study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit.
RESULTSSixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p=0.52) on Day 100 after TA-TMA onset.
CONCLUSIONThis is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   出版者・発行元：WILEY  

BACKGROUNDTransplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed.
STUDY DESIGN AND METHODSThe study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit.
RESULTSSixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p=0.52) on Day 100 after TA-TMA onset.
CONCLUSIONThis is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising < 3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NF kappa B pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at Delta Ct <= 1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi's algorithm, 16/27 (59.3%) demonstrated an ABC-like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis.

DOI： 10.1097/PAS.0000000000000592

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

Background The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted.
Methods We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort.
Findings We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group.
Interpretation PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy.

DOI： 10.1016/S1470-2045(15)00533-1

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記述言語：英語   出版者・発行元：Dove Medical Press Ltd  

Background: Conditioning regimens including total body irradiation (TBI) or cyclophosphamide can mobilize high-mobility group box 1 (HMGB1) to peripheral blood. Additionally, increased plasminogen activator inhibitor (PAI)-1 levels are associated with post-allogeneic hematopoietic stem cell transplantation (aHSCT). However, changes to circulating levels of HMGB1 after aHSCT are poorly understood. Materials and methods: The study cohort included 289 patients who underwent aHSCT at one of 25 institutions in Japan. We have investigated the relationship between HMGB1 and PAI-1 following aHSCT. A significant increase in HMGB1 levels occurred after conditioning treatment. Additionally, levels of HMGB1 at day 0 were significantly increased in TBI+ patients and cyclophosphamide/TBI patients. Conclusion: Our data revealed that an increased level of HMGB1 at day 0 following aHSCT correlates with increased PAI-1 after aHSCT, which is consistent with previous reports. Increased HMGB1 at day 0 after a conditioning regimen may play a role in transplantation-associated coagulopathy following aHSCT, because PAI-1 can accelerate procoagulant activity.

DOI： 10.2147/JBM.S93008

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

BACKGROUNDDonor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI.
CASE REPORTA 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered.
DISCUSSIONWe analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-, macrophage inflammatory protein (MIP)-1, and MIP-1, which declined with the improvement of symptoms after initiation of PSL treatment.
CONCLUSIONInflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

DOI： 10.1111/trf.13283

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

BACKGROUNDDonor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI.
CASE REPORTA 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered.
DISCUSSIONWe analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-, macrophage inflammatory protein (MIP)-1, and MIP-1, which declined with the improvement of symptoms after initiation of PSL treatment.
CONCLUSIONInflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

DOI： 10.1111/trf.13283

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

BACKGROUNDDonor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI.
CASE REPORTA 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered.
DISCUSSIONWe analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-, macrophage inflammatory protein (MIP)-1, and MIP-1, which declined with the improvement of symptoms after initiation of PSL treatment.
CONCLUSIONInflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

DOI： 10.1111/trf.13283

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DOI： 10.1007/s12185-016-1976-4

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

Mantle cell lymphoma (MCL) is essentially incurable with conventional chemotherapy. The MCL International Prognostic Index (MIPI) is a validated specific prognostic index, but was derived from patients with advanced-stage disease primarily in the pre-rituximab era. We analysed 501 MCL patients (median age, 67years; range 22-90) treated with rituximab-containing chemotherapy, and evaluated the prognostic factors adjusted by the treatment. Five-year overall survival (OS) in the low, intermediate and high MIPI groups was 74%, 70% and 35%, respectively. Additional to MIPI risk factors, multivariate analysis revealed that low serum albumin and bone-marrow involvement were also significantly associated with a poor outcome. The revised-MIPI (R-MIPI) was constructed using six factors, namely age, performance status, white blood cell count, serum lactate dehydrogenase, bone-marrow involvement and serum albumin, which is divided into four prognostic groups. Five-year OS in low, low-intermediate (L-I), high-intermediate (H-I) and high R-MIPI groups was 92%, 75%, 61% and 19%, respectively. Hazard ratio for OS of L-I, H-I and high risk to low risk patients were 54, 83 and 330, respectively. R-MIPI, a new prognostic index with easy application to the general patient population, shows promise for identifying low- and high-risk MCL patients in the rituximab era.

DOI： 10.1111/bjh.13486

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記述言語：英語  

Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan

DOI： 10.1016/j.bbmt.2015.04.012

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記述言語：英語   出版者・発行元：BMJ PUBLISHING GROUP  

Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) affecting B-cells or T-cells, respectively. The serum level of soluble interleukin-2 receptor (sIL-2R) is known to reflect the immune activity and tumour volume in aggressive NHL; however, the release of sIL-2R in LBL has not been extensively studied. Further, the relationship between sIL-2R release and the expression level of IL-2R alpha subunit (CD25) remains unknown.
In the present study, we examined the serum level of sIL-2R in 23 patients with T lymphoblactic lymphoma (T-LBL) and compared these with the levels in 20 patient with T acute lymphoblastic leukaemia (T-ALL), 40 patients with diffuse large B-cell lymphoma (DLBCL) and 40 patients with peripheral T-cell lymphoma (PTCL), not otherwise specified. The release of sIL-2R into the serum in patients with T-LBL was significantly lower than that for T-ALL, DLBCL and PTCL (p<0.001).
Immunohistochemistry revealed that CD25 expression was correlated with the serum level of sIL-2R in T-LBL (p=0.0069), whereas no correlation was found to exist between serum sIL-2R levels and CD25 expression in patients with DLBCL (p=0.348) and PTCL (p=0.266). Furthermore, double immunohistochemical analysis revealed that CD25-positive cells were also found to be Foxp3-positive non-neoplastic T-cells. In conclusion, CD25-positive non-neoplastic T-cells in T-LBL are presumed to be the primary source of sIL-2R, and the low number of cells present results in a lower level of sIL-2R released into the serum compared with the other aggressive and highly aggressive lymphomas.

DOI： 10.1136/jclinpath-2015-202934

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of a-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT.

DOI： 10.1182/blood-2014-12-615781

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記述言語：英語   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-gamma/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-gamma single-positive (IL-17(-)) and IFN-gamma/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-gamma and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-gamma/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.

DOI： 10.4049/jimmunol.1400973

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/bcj.2015.6

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DOI： 10.5227/skincancer.29.323

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DOI： 10.1016/j.bbmt.2014.10.015

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記述言語：日本語   出版者・発行元：岡山医学会  

DOI： 10.4044/joma.127.133

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00175&link_issn=&doc_id=20150825270006&doc_link_id=10.4044%2Fjoma.127.133&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.127.133&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

DOI： 10.18926/AMO/53676

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記述言語：英語   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP-EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs.

DOI： 10.18926/AMO/51868

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記述言語：英語   出版者・発行元：SPRINGER JAPAN KK  

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (BCLu-DLBCL/CHL), also known as gray-zone lymphoma, has overlapping clinical and biological characteristics of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (CHL). These lymphomas are typically associated with mediastinal disease, and extranodal involvement is rare. In the present report, we describe a case of a 78-year-old woman with BCLu-DLBCL/CHL found to have extranodal lesions and no evidence of mediastinal disease. Although biopsy specimens were histologically similar to nodular sclerosis CHL, the tumor cells were positive for CD30 and mature B-cell markers, such as CD20, CD79a, PAX5, BOB.1, and OCT-2, but negative for CD15. Furthermore, the patient had extranodal lesions and an increased level of soluble IL-2 receptor. These findings are unusual in CHL. Therefore, we diagnosed the patient with BCLu-DLBCL/CHL. She received adriamycin, bleomycin, vincristine, and dacarbazine therapy and exhibited partial response. Some cases without mediastinal disease, such as our case, have been reported; however, these cases are rare and further studies are required.

DOI： 10.1007/s00795-013-0038-8

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記述言語：英語  

DOI： 10.1016/j.humpath.2013.03.002

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/leu.2012.321

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記述言語：英語   出版者・発行元：BIOMED CENTRAL LTD  

D cyclins positively regulate the cell cycle and mediate the pathogenesis of some lymphomas. Cyclin D1 overexpression is the hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 are reportedly not as specific to certain lymphomas as cyclin D1. In this study, cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive diffuse large B-cell lymphomas (DLBCLs) (50/51) and in 28% of CD5-negative DLBCLs (14/51). A statistically significant difference was observed between these two groups (p<0.0001). In contrast, no statistical difference was found in the cyclin D3 expression between CD5-positive (18/51) and CD5-negative (24/51) DLBCLs (p=0.23). Based on these findings, cyclin D2 is therefore considered to be closely associated with de novo CD5-positive DLBCLs. This insight may be useful for overcoming the inferior survival of this aggressive lymphoma. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1382856320966453

DOI： 10.1186/1746-1596-8-81

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記述言語：英語  

Impact of a single human leucocyte antigen (HLA) allele mismatch on the outcome of unrelated bone marrow transplantation over two time periods. A retrospective analysis of 3003 patients from the HLAWorking Group of the Japan Society for Blood and Marrow Transplantation.

DOI： 10.1111/bjh.12279

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：SPRINGER  

DOI： 10.1007/s00520-012-1602-9

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記述言語：英語  

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation. © 2013 USCAP, Inc.

DOI： 10.1038/modpathol.2012.127

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記述言語：英語  

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation. © 2013 USCAP, Inc.

DOI： 10.1038/modpathol.2012.127

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4(+) progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4(+) plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4(+) progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum. Modern Pathology (2012) 25, 956-967; doi:10.1038/modpathol.2012.54; published online 6 April 2012

DOI： 10.1038/modpathol.2012.54

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記述言語：英語   出版者・発行元：SPRINGER  

Here, we discuss the pathophysiology of leukemia-associated gingival enlargement based on a case of acute myelomonocytic leukemia (AML-M4) with typical gingival enlargement. Uniquely, this patient was well enough to allow full periodontal examination and incisional gingival biopsy to be performed both before and after chemotherapy. The patient was a 39-year-old Japanese woman with AML-M4 showing gingival enlargement. Histological and immunohistochemical features of gingiva and bacterial counts in the periodontal pockets were examined before and after chemotherapy. The results were as follows: (1) infiltration of myelomonocytic blasts in enlarged gingiva; (2) resolution of gingival enlargement with complete remission of AML by anticancer chemotherapy; and (3) the numbers of bacteria in the periodontal pockets were not high and were not altered before or after chemotherapy. In patients with AML-M4, remarkable mucosal enlargement is not generally observed in the body except in the gingiva. We hypothesized that antigens derived from periodontal bacteria, even if they are not present in large numbers, could act as chemoattractants for myelomonocytic leukemic cells.

DOI： 10.1007/s10266-011-0051-0

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-gamma-deficient and IL-17-deficient mice as donors. Infusion of IFN-gamma(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-beta expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD. (Blood. 2012; 119(1): 285-295)

DOI： 10.1182/blood-2011-01-332478

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DOI： 10.4044/joma.124.197

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

Follicular lymphoma is the most common low-grade lymphoma and it frequently presents with a systemic disease, often showing advanced clinical stage (III/IV). The lymphoma cells are usually growing associated with follicular dendritic cell (FDC) networks. Abnormal FDC networks have been reported in duodenal follicular lymphoma, in which cases exhibit lower clinical stages than the nodal cases. In the present study, we analyzed the FDC network distribution pattern of 242 nodal follicular lymphomas by immunohistochemistry. Out of the 242 cases, 27 cases (11%) demonstrated an atypical pattern of FDC networks, in which the CD21 staining totally or partially disappeared in the neoplastic follicles. Furthermore, we compared the clinical data of these 27 cases and 58 typical FDC network cases of follicular lymphoma. We found that in the typical cases, 52 out of 58 patients (90%) showed advanced clinical stage (III or IV), whereas 10 of 27 (37%) atypical FDC network cases showed localized clinical stage (I or II) (P < 0.01). In conclusion, nodal follicular lymphoma with total loss or partially disrupted FDC networks therefore show a lower clinical stage.

DOI： 10.1111/j.1440-1827.2011.02736.x

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記述言語：英語   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Bronchiolitis obliterans (BO) is a disease with a poor prognosis, and a key factor that limits long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). We here report a case of a 31-year woman with acute lymphatic leukemia, which was treated by chemotherapy and HSCT, and consequently developed BO 2 years after HSCT. A non-tuberculous mycobacterial infection occurred and showed gradual exacerbation. She started taking anti-mycobacterial drugs, but lost appetite, felt tired and finally lost consciousness one month after beginning medication. Arterial blood gas revealed marked hypercapnia. Using extracorporeal life support (ECLS), the carbon dioxide concentration was reduced and her consciousness recovered. To our knowledge, this is the first case in which ECLS was successfully used for hypercapnia in a patient with BO.

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

Diffuse large B-cell lymphoma (DLBCL) rarely involves the duodenum, and its clinicopathological characteristics have not been well elucidated. We performed clinicopathological examinations and identified 15 patients with duodenal DLBCL using 18 gastric or colonic DLBCL as a control. Eleven of the 15 patients (73%) were subclassified by immunohistochemical analysis according to the Choi algorithm as germinal center B-cell-like (GCB) type, whereas the 18 control gastric and colonic DLBCL were predominantly subclassified as activated B-cell-like (ABC) type. The classifications according to organ involvement were statistically significant (P= 0.011 and P= 0.035). Macroscopically, the GCB lesions were varied, while all ABC lesions were ulcerative. Fluorescence in situ hybridization analysis revealed a higher frequency of t(14;18) translocation in patients with duodenal DLBCL (3 of 13) as compared with non-duodenal gastrointestinal tract DLBCL (0 of 18), however, the difference was not significant (P = 0.064). Furthermore, the three patients with t(14;18) translocations were classified as GCB. In addition, overall survival of patients was statistically different between those with and without t(14;18) translocation (P= 0.040). In conclusion, duodenal DLBCL predominantly exhibits GCB-type tumors and the frequency of t(14;18) translocation appears to be higher in duodenal GCB-type DLBCL compared to non-duodenal tumors.

DOI： 10.1111/j.1440-1827.2011.02748.x

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

The D cyclins are important cell cycle regulatory proteins involved in the pathogenesis of some lymphomas. Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma. In the present study, we found that cyclin D2 was specifically overexpressed in the proliferation centers (PC) of all cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) examined (19/19). To examine the molecular mechanisms underlying this overexpression, we immunohistochemically examined the expression of nuclear factor (NF)-kappa B, p15, p16, p18, and p27 in the PC of six patients. Five cases showed upregulation of NF-kappa B expression, which is known to directly induce cyclin D2 by binding to the promoter region of CCND2. All six PC examined demonstrated downregulation of p27 expression. In contrast, upregulation of p15 expression was detected in five of six PC examined. This discrepancy suggests that unknown cell cycle regulatory mechanisms involving NF-kappa B-related pathways are also involved, because NF-kappa B upregulates cyclin D2 not only directly, but also indirectly through c-Myc, which is believed to downregulate both p27 and p15. In conclusion, cyclin D2 is overexpressed in the PC of CLL/SLL and this overexpression is due, in part, to the upregulation of NF-kappa B-related pathways. (Cancer Sci 2011; 102: 2103-2107)

DOI： 10.1111/j.1349-7006.2011.02046.x

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

Natural killer (NK)/T-cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T-cell lymphoma. Nineteen untreated patients with extranodal NK/T-cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P = 0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I-II and nine (47%) were stages III-IV. Using PET/CT, eight patients (42%) were in stages I-II and 11 (58%) were in stages III-IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T-cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

DOI： 10.1111/j.1600-0609.2011.01645.x

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記述言語：英語   出版者・発行元：SPRINGER  

Coagulase-negative staphylococci (CoNS) are frequently isolated from blood cultures of hematopoietic cell transplantation (HCT) patients. Generally, the use of central venous catheters is recognized as a significant risk factor for CoNS infection, while the impact of CoNS infection from oral ulcerative mucositis, which occurs frequently in HCT, may be underestimated. Here, we examined the bacteria on the buccal mucosa after HCT.
Sixty-one patients were examined for bacteria on the buccal mucosa routinely once a week from 1 week before to 3 weeks after allogeneic HCT. Subjects were divided into groups with short and long periods of antibiotic use, and differences in bacterial substitution were evaluated. The relationships between type of HCT (conventional HCT or RIST) and bacterial substitution were also evaluated.
The changes in detection frequencies of CoNS and alpha-streptococci from before to 3 weeks after HCT were significant (P < 0.05, chi (2) test): 14.5-53.3% and 92.7-53.1%, respectively. Significant bacterial substitution of CoNS for streptococci was observed in the long-term antibiotic use group (P < 0.05, chi (2) test), but also occurred in cases with short-term or no antibiotic use. No relationships between type of HCT (conventional HCT or RIST) were observed.
Bacterial substitution of CoNS for streptococci occurred frequently on the buccal mucosa after HCT. In addition to antibiotic use, environmental factors may be involved in bacterial substitution. It is important to consider the presence of oral mucositis in CoNS infection after HCT.

DOI： 10.1007/s00520-010-0923-9

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記述言語：英語   掲載種別：書評論文，書評，文献紹介等   出版者・発行元：FUTURE MEDICINE LTD  

Graft-versus-host disease (GvHD), a major complication following allogeneic hematopoietic stem cell transplantation, is mediated by donor-derived T cells. On activation with alloantigens expressed on host antigen-presenting cells, naive CD4(+) T cells differentiate into T-helper cell subsets of effector T cells expressing distinct sets of transcriptional factors and cytokines. Classically, acute GvHD was suggested to be predominantly related to Th1 responses. However, we now face a completely different and complex scenario involving possible roles of newly identified Th17 cells as well as Tregs in GvHD. Accumulating data from experimental and clinical studies suggest that the fine balance between Th1, Th2, Th17 and Tregs after transplantation may be an important determinant of the severity, manifestation and tissue distribution of GvHD. Understanding the dynamic process of reciprocal differentiation of regulatory and T-helper cell subsets as well as their interactions will be important in establishing novel strategies for preventing and treating GvHD.

DOI： 10.2217/IMT.11.51

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記述言語：英語   出版者・発行元：INFORMA HEALTHCARE  

The prognosis for patients with advanced or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is extremely poor. Thus, allogeneic stem cell transplantation (allo-HSCT) should be considered for this disease. However, reports of allo-HSCT for ENKL are limited because of the rarity of the disease. Here, we describe the clinical course of 12 cases of advanced and refractory ENKL treated with allo-HSCT, including five cases with cord blood transplant. With a median follow-up of 13 months (range, 1-168 months), seven patients are alive in remission, five have died, and one treatment-related death occurred. All patients with disease progression at transplant died of disease progression, whereas seven of eight patients with a complete or partial response are long-term survivors. Allo-HSCT is a feasible and promising consolidation therapy for advanced and relapsed ENKL. The disease status before allo-HSCT is well associated with general outcome, and thus induction treatment is very important for this disease.

DOI： 10.3109/10428194.2011.572322

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記述言語：英語   出版者・発行元：SPRINGER  

Coagulase-negative staphylococci (CoNS) are frequently isolated from blood cultures of hematopoietic cell transplantation (HCT) patients. Generally, the use of central venous catheters is recognized as a significant risk factor for CoNS infection, while the impact of CoNS infection from oral ulcerative mucositis, which occurs frequently in HCT, may be underestimated. Here, we examined the bacteria on the buccal mucosa after HCT.
Sixty-one patients were examined for bacteria on the buccal mucosa routinely once a week from 1 week before to 3 weeks after allogeneic HCT. Subjects were divided into groups with short and long periods of antibiotic use, and differences in bacterial substitution were evaluated. The relationships between type of HCT (conventional HCT or RIST) and bacterial substitution were also evaluated.
The changes in detection frequencies of CoNS and alpha-streptococci from before to 3 weeks after HCT were significant (P < 0.05, chi (2) test): 14.5-53.3% and 92.7-53.1%, respectively. Significant bacterial substitution of CoNS for streptococci was observed in the long-term antibiotic use group (P < 0.05, chi (2) test), but also occurred in cases with short-term or no antibiotic use. No relationships between type of HCT (conventional HCT or RIST) were observed.
Bacterial substitution of CoNS for streptococci occurred frequently on the buccal mucosa after HCT. In addition to antibiotic use, environmental factors may be involved in bacterial substitution. It is important to consider the presence of oral mucositis in CoNS infection after HCT.

DOI： 10.1007/s00520-010-0923-9

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

DOI： 10.1007/s12185-011-0845-4

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記述言語：英語   出版者・発行元：SPRINGER  

Oral mucositis is a common symptomatic complication associated with hematopoietic stem cell transplantation (HCT). We use simple strategies aimed to reduce oral mucositis by keeping the oral cavity clean and moist. Here, we report on the progress of oral care and the changes in the degree of oral mucositis. The purpose of this pilot study is to evaluate the effects of our strategies on the prevalence and the severity of oral mucositis.
Fifty-three consecutive patients from 2003 to 2006 administered with conventional allogeneic HCT were enrolled in this study. The degree of oral mucositis was evaluated daily in all patients. Our oral care program was divided into two periods: "examination and trial period (2003 and 2004)" and "intensive oral care period (2005 and 2006)." In the latter, an oral care regimen was carried out systematically by a multidisciplinary team.
Using our oral care strategies, the prevalence of ulcerative oral mucositis was decreased significantly. The rate was reduced from 76% (10 of 13) of patients with ulcerative oral mucositis in 2003 to only 20% (3 of 15) in 2006.
Our pilot study suggests that oral mucositis in HCT patients can be alleviated by simple strategies aimed at keeping the oral cavity clean and moist.

DOI： 10.1007/s00520-010-1002-y

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記述言語：英語  

DOI： 10.1007/s00520-010-1002-y

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients. (Blood. 2010;116(24):5119-5125)

DOI： 10.1182/blood-2010-06-289231

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients. (Blood. 2010;116(24):5119-5125)

DOI： 10.1182/blood-2010-06-289231

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記述言語：英語   出版者・発行元：FERRATA STORTI FOUNDATION  

Background
Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse.
Design and Methods
Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy.
Results
Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission.
Conclusions
We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

DOI： 10.3324/haematol.2010.027516

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記述言語：英語   出版者・発行元：FERRATA STORTI FOUNDATION  

Background
Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse.
Design and Methods
Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy.
Results
Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission.
Conclusions
We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

DOI： 10.3324/haematol.2010.027516

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL INVESTIGATION INC  

Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.

DOI： 10.1172/JCI39165

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記述言語：英語   出版者・発行元：OXFORD UNIV PRESS  

Background: A recent laboratory study indicated that statins impaired the antitumor effects of rituximab by inducing conformational changes in CD20. Although these findings raised significant concerns about statin use during rituximab treatment, their clinical significance is unclear.
Patients and methods: We conducted a retrospective study investigating the effects of statins on the prognosis of diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Newly diagnosed DLBCL patients were analyzed (n = 256), including 35 patients taking statins.
Results: The 3-year progression-free survival rates were 84% and 73% (P = 0.38), while the overall survival rates were 89% and 78% (P = 0.28) for those patients treated with and without statins, respectively. After adjusting for the International Prognostic Index and serum cholesterol level, statin use was not associated with prognosis.
Conclusions: These results indicate that statins do not influence the clinical prognosis of DLBCL treated with RCHOP. Further studies with larger numbers of patients are warranted to confirm the prognostic significance of statins for patients with DLBCL receiving rituximab-containing chemotherapy.

DOI： 10.1093/annonc/mdp490

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：JOHN LIBBEY EUROTEXT LTD  

DOI： 10.1684/ejd.2010.0908

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記述言語：英語   出版者・発行元：SPRINGER  

Severe oral mucositis induced by allogeneic hematopoietic cell transplantation (HCT) is associated with intolerable pain and risk of systemic bacteremia infection. Differences between conventional HCT and reduced-intensity regimens for allogeneic HCT (RIST) may influence the occurrence and severity of oral mucositis. Here, we evaluated oral mucositis in patients undergoing RIST and compared the results with those in conventional allogeneic HCT patients to facilitate predictive measures for mucositis.
A total of 127 consecutive patients undergoing HCT (conventional, 63; RIST, 64) were included in this study. Severity of oral mucositis during HCT period was evaluated daily. Differences in severity of mucositis among HCT types were analyzed. Use of morphine to control pain due to oral mucositis was evaluated in each HCT method.
The severity of oral mucositis was reduced in patients undergoing RIST. Worsening of oral mucositis was delayed in patients receiving RIST. Use of morphine to control pain due to oral mucositis was significantly decreased in patients undergoing RIST compared with those receiving conventional allogeneic HCT.
The severity of oral mucositis was reduced and the peak day of oral mucositis was delayed in RIST patients compared with those receiving conventional HCT.

DOI： 10.1007/s00520-009-0637-z

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記述言語：英語   出版者・発行元：SPRINGER  

Severe oral mucositis induced by allogeneic hematopoietic cell transplantation (HCT) is associated with intolerable pain and risk of systemic bacteremia infection. Differences between conventional HCT and reduced-intensity regimens for allogeneic HCT (RIST) may influence the occurrence and severity of oral mucositis. Here, we evaluated oral mucositis in patients undergoing RIST and compared the results with those in conventional allogeneic HCT patients to facilitate predictive measures for mucositis.
A total of 127 consecutive patients undergoing HCT (conventional, 63; RIST, 64) were included in this study. Severity of oral mucositis during HCT period was evaluated daily. Differences in severity of mucositis among HCT types were analyzed. Use of morphine to control pain due to oral mucositis was evaluated in each HCT method.
The severity of oral mucositis was reduced in patients undergoing RIST. Worsening of oral mucositis was delayed in patients receiving RIST. Use of morphine to control pain due to oral mucositis was significantly decreased in patients undergoing RIST compared with those receiving conventional allogeneic HCT.
The severity of oral mucositis was reduced and the peak day of oral mucositis was delayed in RIST patients compared with those receiving conventional HCT.

DOI： 10.1007/s00520-009-0637-z

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2009.22.7769

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記述言語：英語   出版者・発行元：SPRINGER  

Oral and systemic infections arising from the oral cavity are significant problems in clinical management of patients undergoing leukemia treatment. However, there is significant disparity in the reported incidences of development of periodontal infections. Evidence is limited to those showing the systemic influence of periodontal infection in neutropenic patients. This study indicated an association between febrile neutropenia (FN) and periodontitis in a case in which periodontal treatment in the intervals between chemotherapy cycles reduced FN in subsequent courses of chemotherapy and hematopoietic transplantation (HCT).
Periodontal treatment was performed in a 61-year-old man with advanced periodontitis, who received HCT following three cycles of chemotherapy. After recovery from neutropenia induced by initial chemotherapy, periodontal treatment was performed in each chemotherapy interval period. Following extraction of teeth with severe advanced periodontitis, all teeth were subjected to periodontal pocket curettage and root planning, which are common periodontal treatments to reduce periodontal pockets harboring anaerobic periodontal bacteria, before HCT.
Periodontal treatment successfully reduced periodontal pockets from 4.1 +/- 1.5 mm to 3.0 +/- 0.6 mm, which was almost within the healthy range (< 3.0 mm), before HCT. The frequency of FN decreased significantly with increasing cycles of chemotherapy, and decreases in FN corresponded to progress of periodontal treatment. Blood cultures obtained a total of 12 times throughout leukemia treatment were all negative.
The observations reported here indicate the importance of periodontal treatment in clinical management of patients undergoing leukemia treatment to prevent FN, although all blood cultures were negative.

DOI： 10.1007/s00520-008-0532-z

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in Japan. A propensity score method was used to compensate for the non-randomized study design. From January 2000 to December 2004, 378 patients who were newly diagnosed with DLBCL at 13 institutes were enrolled: 123 in the rituximab plus CHOP-based chemotherapy (R+) group, and 255 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (77.7 vs. 69.4%, P < 0.001). The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 70.5% for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43-0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited younger patients (hazard ratio 0.25, 95% CI 0.08-0.75, P = 0.013). IPI also showed significant impact for PFS (hazard ratio 1.82, 95% CI 1.55-2.14 for one score increase, P < 0.001) as well as OS (hazard ratio 2.10, 95% CI 1.71-2.57, P < 0.001). In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for Japanese DLBCL patients, particularly younger patients.

DOI： 10.1007/s12185-009-0259-8

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, -5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.

DOI： 10.1007/s12185-008-0196-y

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記述言語：英語   出版者・発行元：ELSEVIER IRELAND LTD  

CD123 has been identified as a specific surface marker for plasmacytoid dendritic cells (PDCs). However, CD123 has recently been shown to be expressed on freshly isolated or in vitro generated myeloid dendritic cells (MDCs). In this article, we investigated whether the expression of CD123 on monocyte-derived MDCs was related to their function, especially to tumor-inhibiting potential. MDCs were induced from cord blood CD14(+) monocytes with granulocyte-macro phage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 7 days, and then CD123(+) cells were isolated by positive immunomagnetic cell selection. We observed that CD123(+) cells lost monocyte CD14 expression, acquired immature myeloid dendritic cell phenotype and morphology. They exerted more significant endocytosis and less antigen-presenting function than CD123-MDCs which are often referred to as typical MDCs. Meanwhile, CD123(+) MDCs exhibited more significant tumor-inhibiting activity toward hematological tumor cell lines of U937 and Jurkat even at a low effector:target ratio. CD123(+) MDCs expressed higher level of cytoplasmic TNF-alpha-related apoptosis-inducing ligand (TRAIL), but no detectable surface TRAIL and very little soluble TRAIL. Pretreatment with recombinant human TRAIL receptor 2:Fc fusion protein significantly reduced the tumor-inhibiting effect of CD123(+) MDCs, but not of CD123(-) MDCs. Overall, our data demonstrated that CD123(+) MDCs were an early-stage immature DC subset, with a significant tumor-inhibiting activity partially via involvement of enhanced cytoplasmic TRAIL. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2008.04.048

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

The rote of T helper (Th) 1 and Th2 polarization in acute graft-vs-host-disease (GVHD) is unclear. We investigated the role of Th2 cytokine secretion by utilizing donor T cells that cannot make interleukin (IL)-4, IL-5, IL-9, and IL-13 from quadruple cytokine-deficient (Quad-KO) animals, in a well-characterized BALB/c - C57BL/6 model of allogeneic bone marrow transplantation. B6 recipients of BALB/c Quad-KO T cells demonstrated greater clinical severity, target organ damage, and mortality from GVHD than recipients of BALB/c wild-type (WT) T cells. When compared with donor T cells that are deficient in signal transducers and activators of transcription 6 signaling or the signature Th2 cytokine, IL-4, Quad-KO T cells demonstrated greater GVHD mortality. Mechanistic studies demonstrated that Quad-KO T cells demonstrated enhanced T-cell proliferation than WT T cells when stimulated with either allogeneic antigen-presenting cells or with nonspecific stimuli, such as anti-CD3 monoclonal antibody. Quad-KO T cells also secreted greater amounts of Th1 cytokines and IL-17 compared to WT T cells. Deficiency of Th2 cytokines, however, did not alter the allospecific cytotoxic responses, the numbers of immunoregulatory CD4(+)CD25(+) Foxp3(+) T cells or their suppressive functions. Our data thus unequivocally demonstrate that deficiency of the four classical Th2 cytokine enhances T-cell proliferative responses and aggravates GVHD. (c) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2008.02.010

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL INVESTIGATION INC  

Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allo-stimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2.3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition-induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.

DOI： 10.1172/JCI34712

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

Objective. T cells that undergo lymphopenia-induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naive T cells. But the ability of these T cells in causing graft-versus-host disease (GVHD) is not known.
Methods. We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naive T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT).
Results. Contrary to our hypothesis, LIP of donor T cells under either noninflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathologic, and biochemical parameters than naive T cells. Compared to naive donor T cells, LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated an increase in the CD44(hi) "memory" phenotype T cells and not the CD4(+)CD25(+) T cell subset to be critical for the reduction in GVHD.
Conclusions. These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity, or anti-tumor immunity. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2006.10.010

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

Objective. T cells that undergo lymphopenia-induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naive T cells. But the ability of these T cells in causing graft-versus-host disease (GVHD) is not known.
Methods. We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naive T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT).
Results. Contrary to our hypothesis, LIP of donor T cells under either noninflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathologic, and biochemical parameters than naive T cells. Compared to naive donor T cells, LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated an increase in the CD44(hi) "memory" phenotype T cells and not the CD4(+)CD25(+) T cell subset to be critical for the reduction in GVHD.
Conclusions. These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity, or anti-tumor immunity. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2006.10.010

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Pathogenesis of chronic graft-versus-host disease (cGVHD) is largely unknown. It is important to determine the responsible cell types and the factors that play roles to recruit these cells into sites of disease. We examined whether monocytes and chemokine fractalkine/receptor CX3CR1 axis might be involved. We found that the absolute number of CX3CR1 + monocytes in the blood was significantly decreased in patients with severe cGVHD. Immunohistochemical staining revealed the extensive infiltration of CD 14 + cells as well as strong expression of fractalkine in the cGVHD skin. The number of infiltrated CD14+ cells on the margin of fractatkine+ epidermis was larger in cGVHD skin compared to that of acute graft-versus-host disease, whereas no difference was observed in CD3 + T cells. These results suggest that CX3CR1+ monocytes may be recruited from the circulation to the fractalkine + epidermis in cGVHD, and highlight these cells and this chemokine/receptor axis as additional targets for cGVHD therapy.

DOI： 10.1097/01.tp.0000245080.71722.87

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Pathogenesis of chronic graft-versus-host disease (cGVHD) is largely unknown. It is important to determine the responsible cell types and the factors that play roles to recruit these cells into sites of disease. We examined whether monocytes and chemokine fractalkine/receptor CX3CR1 axis might be involved. We found that the absolute number of CX3CR1 + monocytes in the blood was significantly decreased in patients with severe cGVHD. Immunohistochemical staining revealed the extensive infiltration of CD 14 + cells as well as strong expression of fractalkine in the cGVHD skin. The number of infiltrated CD14+ cells on the margin of fractatkine+ epidermis was larger in cGVHD skin compared to that of acute graft-versus-host disease, whereas no difference was observed in CD3 + T cells. These results suggest that CX3CR1+ monocytes may be recruited from the circulation to the fractalkine + epidermis in cGVHD, and highlight these cells and this chemokine/receptor axis as additional targets for cGVHD therapy.

DOI： 10.1097/01.tp.0000245080.71722.87

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記述言語：英語   出版者・発行元：WILEY-LISS  

We report a case of T-cell chronic lymphoproliferative disorder (CLPD) that shows neither features of T-cell prolymphocytic leukemia nor disease progression for more than 34 months. Flow cytometric analyses of the lymphocytes revealed high expression of CD4 and CD25. Up-regulation of Foxp3, a master regulatory gene for developmental differentiation of regulatory T cells (Treg), was confirmed at mRNA and protein levels. To our knowledge, this is the first case of extremely indolent CLPD with Treg phenotype.

DOI： 10.1002/ajh.20688

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記述言語：英語   出版者・発行元：CARDEN JENNINGS PUBL CO LTD  

Peak blood concentration of cyclosporine (CsA) in renal transplantation patients was recently reported to be associated with clinical efficacy. We therefore evaluated the toxicity and efficacy of a regimen of once-daily infusion of CsA plus a short course of methotrexate as prophylaxis of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation from an HLA allele-matched, unrelated donor. Nineteen patients with hematologic malignancies received CsA, 3 mg/kg per day, as a 4-hour intravenous (IV) infusion from day -1. After engraftment, patients received CsA orally at twice the IV dose. The CsA dose was adjusted to maintain the blood trough level between 1.50 and 200 ng/mL. Methotrexate was administered IV at doses of 10 mg/m(2) on day 1 and 7 rag/rn2 on days 3,6, and 11. Bone marrow engraftment occurred in all patients. Grade 1 and grade 2 GVHD occurred in 6 (31.6%) and 7 (36.8%) of the 19 patients, respectively. No patient had grade 3 or 4 GVHD. Acute nephrotoxicity developed in 1 (5.3%) of the 19 patients, and hypertension developed in 3 (15.8%) of the 19 patients. We evaluated the pharmacokinetics of 4-hour CsA infusion in 10 patients. Tie mean trough concentration, mean peak concentration, mean time to peak concentration, and area under the curve (24 hours) were 161 +/- 43 ng/mL, 1498 +/- 387 ng/mL, 3.2 +/- 1.0 hours, and 10,848 +/- 1,991 ng(.)h/mL, respectively. This regimen was well tolerated and did not enhance the risk of severe GVHD in patients undergoing allogeneic bone marrow transplantation from an HLA allele-matched, unrelated donor.

DOI： 10.1532/IJH97.05006

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

Graft-versus-leukemia ( GVL) response after allogeneic bone marrow transplantation ( BMT) represents one of the most potent forms of immunotherapy against malignant diseases(1). Antigen-presenting cells ( APCs) are crucial for the induction of graft-versus-host disease ( GVHD)(2-6), the most serious complication of allogeneic BMT, but their role in GVL responses is unclear. Using a series of clinically relevant mouse GVL tumor models, we found that APCs and alloantigen expression on tumors are crucial for GVL. Moreover, APCs of host origin predominated in GVL responses although donor APCs contributed as the acuity of tumor burden decreased.

DOI： 10.1038/nm1309

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記述言語：英語  

DOI： 10.1182/blood-2004-10-4087

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

Fas ligand (FasL) and perforin pathways not only are the major mechanisms of T cell-mediated cytotoxicity but also are involved in homeostatic regulation of these T cells. In the present study, we tested whether CD8(+) donor T cells that are deficient in both perforin and FasL (cytotoxic double deficient [cdd]) could induce graft-versus-host disease (GVHD) in a major histocompatibility complex class I-mismatched lethally irradiated murine model. Interestingly, recipients of cdd CD8(+) T cells demonstrated significantly greater serum levels of interferon gamma and tumor necrosis factor alpha and histopathologic damage from GVHD than wild-type (wt) T cells on day 30 after allogeneic bone marrow transplantation (P < .05). Wt and either perforin-deficient or FasL-deficient CD8(+) T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8(+) T cells were eliminated. In contrast, cdd CD8(+) T cells exhibited prolonged expansion and reduced apoptosis to alloantigen stimulation in vivo and in vitro. Together these results suggest that donor cdd CD8(+) T cells expand continuously and cause lethal GVHD, and that both perforin and Fast-are required for the contraction of alloreactive CD8(+) T cells. (C) 2005 by The American Society of Hematology.

DOI： 10.1182/blood-2004-08-3036

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記述言語：英語   出版者・発行元：NATL ACAD SCIENCES  

Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent, it inhibits the activity of histone deacetylases and at low doses exhibits anti inflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.

DOI： 10.1073/pnas.0400380101

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DOI： 10.1111/j.1537-2995.2004.03078.x

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DOI： 10.1182/blood-2004-02-0763

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oilgonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD. (C) 2003 by The American Society of Hematology.

DOI： 10.1182/blood-2002-09-2748

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記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

We have recently shown that early administration of interleukin 18 (IL-18) after bone marrow transplantation (BMT) attenuates acute graft-versus-host disease (GVHD) in a lethally irradiated parent into F1 (B6-->B6D2F1) BMT model. In this study, we investigated whether IL-18 can maintain graft-versus-leukemia (GVL) effect in this context. B6D2F1 mice received transplants of T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either syngeneic (H2(b/d)) or allogeneic B6 (H2(b)) donors. Recipient mice were treated with recombinant murine IL-18 or the control diluent. Initial studies demonstrated that IL-18 treatment did not affect the proliferative responses or the cytolytic effector functions of T cells after BMT. In subsequent experiments, animals also received host-type P815 mastocytoma cells at the time of BMT. All syngeneic BM transplant recipients died from leukemia by day 18. The allogeneic BM transplant recipients effectively rejected their leukemia regardless of treatment and IL-18 significantly reduced GVHD-related mortality. Examination of the cytotoxic mechanisms with perforin-deficient donor T cells demonstrated that perforin is critical for the GVL effect. Taken together these data demonstrate that IL-18 can attenuate acute GVHD without impairing the in vitro cytolytic function or the in vivo GVL activity after allogeneic BMT.

DOI： 10.1182/blood-2002-04-1252

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DOI： 10.1007/BF02982726

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