okamoto masataka

P>Peripheral T-cell lymphoma (PTCL) has a poorer prognosis than diffuse large B-cell lymphoma (DLBCL). We administered the CyclOBEAP regimen (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) to patients with DLBCL, and reported its safety and efficacy. Here, we report the results of a multicentre phase II study of the CyclOBEAP regimen in patients with PTCL. In addition, NME1 remained a prognostic factor for survival, as shown in patients who were treated with CyclOBEAP. There were 84 eligible patients and the median age was 54 years. The 5-year overall survival (OS) rate was 72% and progression-free survival (PFS) rate was 61%. The 5-year OS was 93% among the anaplastic large-cell lymphoma cases, 74% among the angioimmunoblastic T-cell lymphoma cases, and 63% among the cases of PTCL-not otherwise specified. When the patients were divided according to the International Prognostic Index or Prognostic Index for PTCL, the 5-year OS and PFS rates did not significantly differ among the risk groups. Positivity for NME1 was found to be a significant independent prognostic factor. Grade 4 neutropenia was observed in 80 patients and thrombocytopenia in nine patients. Our results suggest that the CyclOBEAP therapy is safe and effective for PTCLs. Furthermore, the NME1 protein may be an important prognostic factor in PTCL.

Purpose: We examined whether nm23-H1 is a prognostic factor of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Experimental Design: We studied 102 consecutive, untreated PTCL-NOS patients from 1998 to 2008. The expression of nm23-H1 and TIA-1 was studied by immunohistochemistry. Results: nm23-H1 was positive in 44.1% and TIA-1 in 78.4% of the PTCL-NOS patients. nm23-H1 expression was not correlated with age, performance status (PS), lactate dehydrogenase (LDH) level, or stage but was significantly correlated with the prognostic index for T-cell lymphoma. The serum nm23-H1 level was 43.44 ng/mL in the cytoplasmic nm23-H1 strongly positive, 24.32 ng/mL in the cytoplasmic nm23-H1 moderately positive, and 13.64 ng/mL in the cytoplasmic nm23-H1-negative patients. The nm23-H1-positive group had significantly shorter overall survival (OS). TIA-1 had no prognostic impact on 5-year OS rates. OS was significantly shorter in patients with the following clinicopathologic features: age 60 or more years, PS of 2 to 4, LDH level greater than normal, bone marrow involvement, or nm23-H1-positive lymphoma. Multivariate analysis confirmed nm23-H1 expression to be an independent prognostic factor. Conclusions: The nm23-H1 protein may be an important prognostic factor in PTCL-NOS. Because our results suggested that nm23-HI is produced by lymphoma cells, we expect to see the development of new treatments targeting nm23 overexpression. Clin Cancer Res; 17(9); 2893-9. (C) 2011 AACR.

In our previous study on nm23-H1 expression with diffuse large B-cell lymphoma (DLBCL), we found that patients with positive nm23-H1 had significantly poorer prognosis than patients with negative nm23-H1. We examined whether nm23-H1 is a prognostic factor of DLBCL in the rituximab era. The subjects were 101 DLBCL patients who underwent R-CyclOBEAP (rituximab, cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone) therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, MUM1, and nm23-H1 expression by immunohistochemistry. Ninety-four DLBCL patients who underwent CyclOBEAP therapy were assumed as historical controls. Among DLBCL patients who underwent CyclOBEAP therapy, BCL2 positivity, MUM1 positivity, non-germinal center B-cell (non-GCB), and nm23-H1 positivity were associated with significantly shorter overall survival (OS) and progression-free survival (PFS). On the other hand, among DLBCL patients who underwent R-CyclOBEAP therapy, the 5-year OS rates of the nm23-H1-positive DLBCL (n = 32) and nm23-H1-negative DLBCL groups (n = 69) were 65% and 97%, respectively (p = 0.001), with 5-year PFS rates of 51% and 89%, respectively (p = 0.001). In the rituximab era, BCL2, MUM1, and non-GCB were not prognostic factors. We demonstrated that among patients with DLBCL who underwent R-CyclOBEAP therapy, patients with nm23-H1 expression had a significantly poorer prognosis than patients without nm23-H1 expression. These results suggest an important role for nm23-H1 in malignant progression and a potential therapeutic target for DLBCL.

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)

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250 mg/m(2)) in patients with newly diagnosed stage II-IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70 years were enrolled and received 6-8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1-87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5 years were 78.4% (95% CI 70.9-85.9%) and 91.3% (95% CI 86.1-96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II-IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

Patients and methods: The subjects were 607 DLBCL patients in whom cell surface markers could be analyzed, among 930 consecutive patients registered in the Adult Lymphoma Treatment Study Group between 1998 and 2008. Results: In all, 102 patients (16.8%) had CD5+ DLBCL. Compared with CD5- DLBCL, CD5+ DLBCL was more closely associated with elevated serum lactate dehydrogenase level, advanced stage, poor performance status, extranodal sites, CD10-, BCL-2+, MUM1+, and nongerminal center B-cell type. The 5-year overall survival (OS) rates of CD5+ DLBCL (n = 102) and CD5- DLBCL (n = 505) were 55% and 65%, respectively (P = 0.032), with 5-year progression-free survival (PFS) rates of 52% and 61%, respectively (P = 0.041). In the CD5+ DLBCL patients, the addition of rituximab to chemotherapy significantly improved PFS (4-year PFS, 47.4% versus 62.5%), but not OS (4-year OS, 57.8% versus 63.5%). Conclusions: For CD5+ DLBCL, the addition of rituximab to chemotherapy significantly improved the PFS, but not OS. Therefore, it is thought that a new treatment strategy is necessary for CD5+ DLBCL.

The R-CHOP regimen has been found to improve the outcome of diffuse large B-cell lymphoma (DLBCL). However, it does not provide a satisfactory treatment outcome in the high-risk group. We previously administered the CyclOBEAP regimen to patients with DLBCL, and reported its safety and efficacy. The R-CyclOBEAP regimen was administered over a total period of 12 weeks, and rituximab 375 mg/m(2) was given every 2 weeks. There were 101 eligible patients. CR was achieved in 96 patients (95%). The 5-year overall survival (OS) rate was 85% and progression-free survival (PFS) rate was 76%. When the patients were divided according to the IN, the 5-year OS and PFS rates did not significantly differ among the risk groups. The 5-year PFS of the germinal centre B-cell group was 80% and that of the non-GCB group was 74% (NS). Univariate analysis showed that the presence of B symptoms, extranodal lesions >= 2, and sIL-2R were significant poor prognostic factors. Grade 4 neutropenia was observed in 91 patients and thrombocytopenia in 9 patients. The addition of rituximab to CyclOBEAP therapy may enhance the effect of CyclOBEAP therapy for DLBCL. Copyright (C) 2010 John Wiley & Sons, Ltd.

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity with a high incidence of central nervous system (CNS) involvement at diagnosis. To evaluate CNS involvement, particularly recurrence including progression on therapy and relapse of IVLBCL, we retrospectively analyzed 109 patients with IVLBCL receiving chemotherapies with or without rituximab. In 82 patients (75%) without CNS involvement at initial diagnosis, risk of CNS recurrence at 3 years was 25% with a median follow-up in survivors of 39 months (range, 2-158 months). In 27 patients (25%) with CNS involvement at initial diagnosis, risk of CNS recurrence at 1 year was 25% with a median follow-up in survivors of 18 months (range, 10-77 months). Duration from diagnosis to CNS recurrence tended to be short in patients with CNS involvement at diagnosis. No significant difference in risk of CNS recurrence was found between patients receiving chemotherapies with or without rituximab. On multivariate analysis skin involvement at initial diagnosis was identified as a predictive factor for CNS recurrence in patients without CNS involvement at diagnosis (hazard ratio, 5.27; 95% confidence interval, 1.59-17.4; P = 0.007). Survival rate after CNS recurrence at 2 years was 12% in patients without CNS involvement at diagnosis. Central nervous system recurrence is a serious complication in IVLBCL patients and optimal strategies for CNS involvement should be established to obtain further improvements to clinical outcomes in the rituximab era. (Cancer Sci 2010).

(Cancer Sci 2010; 101: 1309-1313).

rituximabはヒト-マウスキメラ型抗CD20モノクローナル抗体で、補体依存性細胞障害作用や抗体依存性細胞介在性細胞障害作用により抗腫瘍効果を発揮する。rituximab併用化学療法では経過中に免疫グロブリンの低下が観察され、少なからぬ頻度で帯状疱疹(Herpes(H)zoster)をはじめとするウイルス再活性化が生じることが知られているが、多数例での検討結果の報告はない。rituximab併用化学療法における免疫抑制状態を評価するため、2004年4月〜2008年3月までの4年間にrituximabを併用した化学療法を実施したB細胞リンパ腫の初回治療205例について治療前、治療経過中および治療後の免疫グロブリン値の変動と、ウイルス再活性化の指標としてH.zosterの発症頻度について検討した。経時的に血清IgG値が測定可能であった89例では、治療開始時に比し終了時の血清IgG値は中央値-41.1%で、治療終了時に58例が正常値以下、22例が前値の50%以下に低下した。205例のうち17例(8.3%)にH.zosterを発症した。H.zoster発症例と非発症例の間には治療前後の血清IgG値の変化率に有意差はなかった。rituximab併用化学療法では比較的高度で遷延する液性免疫能低下が観察され、治療に際しては感染対策にも配慮が必要である。(著者抄録)

Primary CNS diffuse large B-cell lymphoma (CNS DLBCL) is confined to the CNS, and constitutes a distinct entity. In the present study a series of 40 Japanese patients with CNS DLBCL who presented with neurological, but not systemic symptoms, was reviewed. Median survival was 18.7 months. CD5, CD10, Bcl-6, MUM-1, and Bcl-2 were positive in 30%, 10%, 84%, 100%, and 93% of patients, respectively. All CD10-negative patients had non-germinal center B-cell type. There was no significant difference in survival among the immunophenotypic subgroups. CNS DLBCL appeared to be homogenous as a group, which prompted the comparison with another distinct extranodal entity, intravascular large B-cell lymphoma (IVLBCL) in Japanese patients. CNS DLBCL patients did not differ in age, sex, or immunophenotype, including CD5 positivity, from IVLBCL patients, but were significantly less likely to have poor prognostic parameters than IVLBCL patients: the international prognostic index score was low or low-intermediate in 86% of CNS DLBCL patients and high or high-intermediate in 98% of IVLBCL patients. Notably, despite this difference, their survival curves almost overlapped. The present study highlights the issue of clinical distinctiveness of aggressive extranodal lymphomas, the peculiar migration and localization of which should be further clarified.

Diffuse large B-cell lymphoma (DLBCL) has heterogeneous clinical, histological, and molecular features. We evaluated the clinical characteristics and prognoses of patients with DLBCL carrying 8q24 translocations. A total of 1864 consecutive patients with non-Hodgkin's lymphoma were treated in the Adult Lymphoma Treatment Study Group from 1998 to 2005. Of the 252 patients with DLBCL with abnormal karyotypes, 28 patients with DLBCL with the 8q24 translocation were identified. There were 14 men and 14 women, with a median age of 61 years. The 8q24 translocation was observed significantly more frequently among patients with poor performance status, among patients with high lactate dehydrogenase level, and among patients with bone marrow involvement. The 5-year overall survival was 43.9% among the patients with 8q24 translocation, and 67% among the patients with other chromosomal abnormalities. The 8q24 translocation group showed significantly poorer prognosis than the group with other translocations. In addition, patients with t(14;18) and 8q24 translocation showed significantly poorer prognosis than those with 8q24 translocation alone. It will be necessary to study whether more aggressive chemotherapy or rituximab combination chemotherapy is effective in 8q24 translocation cases. (Cancer Sci 2009; 100: 233-237).

Contraception is recommended during imatinib therapy based on the teratogenicity data in rats. However, patients may become pregnant and here we describe a successful pregnancy and labor without any congenital anomaly in a patient with chronic myeloid leukemia (CML) under treatment with imatinib. The patient had received imatinib for 53 months before she became pregnant, with a complete cytogenetic response achieved after 6 months of therapy and a major molecular response (MMR) after 28 months. CML was in MMR at discovery of pregnancy and the fetus had been exposed to imatinib for 5 weeks. Treatment was discontinued, but MMR persisted during gestation. © 2009 The Japanese Society of Internal Medicine.

We studied the clinicopathologic features and treatment outcome of patients with breast diffuse large B-cell lymphoma. As to the cellular immunophenotype, CD5 was detected in two patients, CD10 in 4, BCL2 in 20, BCL6 in 11, and MUM-1 in 17. The 5-year progression-free survival was 77% and the 5-year overall survival was 87%. Patients with the germinal center B-cell (GCB) type had a significantly better prognosis than those with the non-GCB type. The combination of anthracycline-containing chemotherapy and/or involved-field radiotherapy produced a relatively good prognosis. However, it is a heterogeneous disease with regard to histological type and pathological state. (C) 2008 Elsevier Ltd. All rights reserved.

Background: We carried out immunohistochemistry to examine the expression of nm23-H1 in Hodgkin and Reed-Sternberg cells in patients with classical Hodgkin's lymphoma (CHL). Patients and methods: We evaluated 128 patients with CHL [87 patients with nodular sclerosis (NS) and 41 patients with mixed cellularity (MC)] for CD15, CD20, Ki-67, EBER, TIA-1, and nm23-H1 by immunohistochemistry. Results: CD15 was expressed in 79%, CD20 in 11%, Ki-67 in 93%, EBER in 34%, TIA-1 in 11%, and nm23-H1 in 60% of the CHL patients. NS patients showed a significantly higher rate of nm23-H1 expression than MC patients (P < 0.001). The serum nm23-H1 level was significantly higher in patients with positive nm23 expression. Univariate analysis showed that stage IV, poor performance status, low hemoglobin level, low serum albumin level, age of 45 years or older, TIA-1-positive status, and nm23-H1-positive status were associated with significantly shorter progression-free survival. Multivariate analysis with these factors showed TIA-1 and cytoplasmic nm23-H1 expression to be significant and independent prognostic factors. Conclusions: Our results indicate that nm23-H1 expression is a prognostic factor for CHL and that it is as important as serum nm23-H1, both of which are useful for planning the treatment strategy.

We studied the clinico-pathologic features and treatment outcome of patients with peripheral T-cell lymphoma (PTCL). This study included 215 patients with T/natural killer (NK)-cell lymphoma, including 59 with PTCL-unspecified (PTCL-U), 42 with angioimmunoblastic T-cell lymphoma (AILT) and 20 with anaplastic large-cell lymphoma (ALCL). Most of the analyses were performed on patients with AILD, ALCL and PTCL-U. The patients with AILT and PTCL-U tended to be older than those with ALCL. Stage III/IV disease was seen in 90.5% of the AILT cases, 55% of the ALCL cases and 67.8% of the PTCL-U cases. In addition, 61.9% of the AILT cases had an international prognostic index (IPI) of H-I or H risk. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 72.2 and 76.1 % among the ALCL cases, 40.7 and 42.2 % among the PTCL-U cases and 31.2 and 49.3% among the AILT cases, respectively. Among the patients with PTCL-U, the 5-year PFS and OS rates in group low (L), low-intermediate (L-I), high-intermediate (H-I) or high (H) risk group of 1111 were: 47.6 and 56.1%,55.6 and 53.8%,42.4 and 40.1 % and 9.1 and 9.1 %, respectively. The 5-year PFS and OS rates in group 1, 2,3 or 4 1)), prognostic index of PTCL-U (PIT) were: 88.9 and 85.7%, 57.1 and 54.9%, 33.5 and 28.8% or 13.3 and 13.3%, respectively. The 5-year PFS and OS rates among patients who received CHOP therapy, CyclOBEAP [cyclophosphamide (CPA), vincristine (VCR), bleomycine, etoposide, doxorubicin (DXR), prednisone (PDN)] therapy or autologous stem cell transplantation were: 22 and 25.7%, 59 and 61.7% or 33.3 and 60%, respectively. Multivariate analysis revealed that the PIT score was associated with OS and PFS. These results indicate that the presence of bone marrow (BM) involvement is an independent prognostic factor which may predict both OS and PFS. PTCL-U is a heterogeneous disease with regard to histological type and pathological state. Because PTCL-U is generally not responsive to CHOP therapy, new treatment strategies need to be developed. Copyright (c) 2008 John Wiley & Sons, Ltd.

Background De novo CD5-positive diffuse large B-cell lymphoma (CD5(+) DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5(-)) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5(+) DLBCL. Design and Methods From 1984 to 2002, 120 patients with CD5(+) DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. Results Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5(+) DLBCL was more frequent than in CD53(-) DLBCL (p=0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5(+) DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5(+) DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants (p=0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. Conclusions Our study revealed the morphological spectrum of CD5(+) DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5(+) DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

Purpose To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL). Patients and Methods We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients. Results The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy. Conclusion Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.

We report here a very rare case of chronic myeloid leukemia (CML) following long-term chemotherapy with 5′-deoxy-5-fluorouridine (5′-DFUR) for gastric cancer. A 69-year-old man was diagnosed with the chronic phase of CML. Six years previously, he underwent radical subtotal gastrectomy for gastric cancer, and was subsequently treated with oral anti-metabolite 5′-DFUR as adjuvant chemotherapy for 6 years. He was placed on imatinib therapy, and achieved a major molecular response 10 months after the initiation of therapy. This is the first reported case of therapy-related CML following 5′-DFUR treatment. © 2008 The Japanese Society of Internal Medicine.