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Summary Background Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. Methods PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20–79 years, had an Eastern Cooperative Group performance status of 0–3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1–5 of cycle one and days 2–6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. Findings Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5–5·5). 2-year progression-free survival was 76% (95% CI 58–87). The most frequent adverse events of grade 3–4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. Interpretation R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. Funding The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients’ fitness for steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65–75%) and 34% (95% CI, 21–47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P

The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose ((18) F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine-rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of (18) F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The (18) F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value-volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine-rituximab.

The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis. Here, we examined the relationship between EDG2 and NM23 expression during myeloid differentiation of leukemia cells. NM23 expression decreased and EDG2 expression increased during all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60, NB4, and THP-1 leukemia cells. Moreover, this inverse correlation was more evident when myeloid differentiation was enhanced by ellagic acid, an inhibitor of NM23 activity. In contrast, there was no inverse correlation between EDG2 and NM23 expression during erythroid differentiation of HEL and K562 cells. ATRA plus LPA enhanced the motility of leukemia cells as well as breast cancer cells in an EDG2-dependent manner. These results suggest a common molecular mechanism between myeloid differentiation of leukemia cells and migration of breast cancer cells depending on NM23 and EDG2 expression levels.

The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2(nd)- or 3(rd)-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48-12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37-17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.

nm23-H1 was originally identified as a protein that is expressed at a lower than usual level in metastatic cancer cells. The nm23 genes play critical roles in cellular proliferation, differentiation, oncogenesis, and tumor metastasis. Peripheral T-cell lymphoma (PTCL) is relatively rare, accounting for only 10% to 15% of non-Hodgkin's lymphomas. We examined whether nm23-H1 is a prognostic factor of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). PTCL is more aggressive and has a poorer prognosis than diffuse large B-cell lymphoma. nm23-H1 was positive in 44.1% of PTCL-NOS patients. nm23-H1 expression was not correlated with age, performance status (PS), lactate dehydrogenase (LDH) level, or stage. The nm23-H1-positive group had significantly shorter overall survival (OS). OS was significantly shorter in patients with the following clinicopathologic features: age ＞ 60 years, PS of 2-4, LDH ＞ normal, bone marrow involvement, or nm23-H1-positive lymphoma. The nm23-H1 protein may be an important prognostic factor in PTCL-NOS. Because our results suggest that nm23-HI is produced by lymphoma cells, we expect to see the development of new treatments targeting nm23 overexpression.

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity characterized by selective growth of lymphoma cells in the lumina of small vessels. IVLBCL has been listed in the WHO classification, which improves recognition of the disease. However, no standard therapy has been established based on the results of prospective studies. We previously reported promising efficacy of rituximab (R)-containing chemotherapy for IVLBCL (JCO 2008) and a high incidence of central nervous system (CNS) recurrence (25% at 3 y) after R-chemotherapy (Lancet Oncol 2009, Cancer Sci 2010). To explore a more effective first-line treatment, we conducted a phase 2 trial of R-CHOP combined with CNS prophylaxis including R-high-dose methotrexate (R-HDMTX) and intrathecal chemotherapy with MTX, cytarabine (Ara-C), and prednisolone (PSL) (IT). Methods: Major inclusion criteria were untreated, histologically confirmed IVLBCL, age 20-79 y, ECOG PS 0-3, and no apparent CNS involvement at diagnosis. Patients received 3 cycles of R-CHOP followed by 2 cycles of R-HDMTX (3.5 g/m2; 2 g/m2 for ≥70 y) every 2 weeks, and 3 additional cycles of R-CHOP. IT (MTX 15 mg, Ara-C 40 mg, PSL 10 mg) was performed twice during the first 3 cycles of R-CHOP and twice during the final 3 cycles of R-CHOP (4 times in total). If patients achieved complete response (CR), they were observed without any therapy until relapse or disease progression. The primary endpoint was 2-y progression-free survival (PFS), and secondary endpoints included 2-y overall survival (OS), CR rate, cumulative incidence of CNS recurrence at 2 y, patterns of progression, and adverse events. The threshold 2-y PFS was estimated to be 35%, with expected 2-y PFS estimated to be 60%. With a statistical power of 90% and a one-sided, type I error of 5%, a projected sample size of 37 was calculated in anticipation of 10% ineligible patients. The trial was registered in the UMIN Clinical Trials Registry (UMIN000005707). Results: 38 IVLBCL patients were enrolled between June 2011 and July 2016. One patient was found to be ineligible after completion of the protocol treatment due to a past history of lymphoma. The protocol treatment was completed in 34 (89%) of 38 patients. The diagnosis of IVLBCL was histologically confirmed by central pathological review in all enrolled patients. The baseline characteristics of the 37 eligible patients were: male sex, 16 (43%); median age, 66 (range 38-78) y; ECOG PS >1, 15 (41%); stage IV, 37 (100%); serum LDH >ULN, 36 (97%); WBC Conclusion: This phase 2 trial met its primary endpoint and showed favorable outcomes with a low cumulative incidence of CNS recurrence and acceptable toxicity profiles. These results indicate that R-CHOP combined with CNS prophylaxis including R-HDMTX and IT could be a reasonable treatment option for untreated IVLBCL without apparent CNS involvement at diagnosis. Disclosures Shimada: Takeda Pharmaceutical: Honoraria; MSD: Research Funding; Otsuka Pharmaceutical: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Consultancy, Honoraria; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Honoraria. Yamaguchi:Ono Pharmaceutical: Research Funding; Teijin Pharma: Honoraria; MSD: Honoraria; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Astellas Pharma: Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding. Atsuta:Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Matsue:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Nagai:Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; AstraZeneca: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical: Research Funding; SymBio Pharmaceuticals Limited: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; IQVIA: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria; Novartis Pharma: Honoraria; Mundi Pharma: Honoraria, Research Funding; Bayer Pharma: Honoraria, Research Funding; AbbVie: Research Funding. Fukuhara:Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Miyazaki:Eisai: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Takeda: Honoraria; SymBio Pharmaceuticals: Honoraria; Nippon Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria. Okamoto:Kyowa Kirin Co., Ltd.: Other: Scholarship donation; Chugai Pharmaceutical Co., Ltd.: Other: Scholarship donation; Takeda Pharmaceutical Co., Ltd.: Other: Scholarship donation; Taiho Pharmaceutical Co., Ltd.: Other: Scholarship donation. Uchida:Eisai: Honoraria. Tsukasaki:Daiichi Sankyo: Consultancy; Kyowa Kirin: Honoraria; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Mundi Pharma: Honoraria; Ono Pharmaceutical: Consultancy; Eisai: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Masaki:Tanabe Mitsubishi: Research Funding; Taiho: Research Funding; Kyowa Kirin: Research Funding; Astellas Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Taisho Toyama: Research Funding; Daiichi Sankyo: Research Funding; Teijin: Research Funding; Takeda Pharmaceutical: Research Funding. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding. Suzuki:Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Novartis: Honoraria.

Introduction: Aberrant expression of T-cell markers is occasionally observed in B-cell lymphomas. We conducted a retrospective study to establish its incidence and to determine its relationship with clinical features of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods: We reviewed DLBCL patients diagnosed between January 2002 and April 2009. Patients fulfilled the following criteria: (1) age >18 years, (2) HIV negative, (3) B-cell lymphoma confirmed by restricted expression of surface immunoglobulin light chains by flow cytometry (FCM). Aberrant T-cell marker expression (ATCME) was defined as positivity for CD2, CD3, CD4, CD7, and/or CD8 on DLBCL cells by FCM. Phenotyping was also performed by immunohistochemistry (IHC). Patients were grouped according to positive or negative ATCME and their clinical features including survival were compared. Results: Of 150 patients, 11 (7.3%) showed ATCME; CD2 and CD7 were most often expressed. ATCME was less often detected and the signal was weaker using IHC. There were no statistically significant differences in clinical features between the two groups. Conclusions: FCM may be useful to detect ATCME in a small amount of lymphoma cells. The mechanism responsible for ATCME, and whether it contributes in any way to the pathogenesis of B-cell neoplastic transformation, requires clarification.

Background Classical Hodgkin’s lymphoma is characterized by Hodgkin and Reed Sternberg cells, which are of B-cell origin in many cases. We recently highlighted the adverse prognostic significance of cytotoxic molecule expression in patients with classical Hodgkin’s lymphoma. However, the clinical characteristics of cytotoxic molecule-positive classical Hodgkin’s lymphoma remain controversial. Design and Methods We investigated the clinicopathological profiles of 32 patients with cytotoxic molecule-positive Hodgkin’s lymphoma, comprising 23 with nodular sclerosis and 9 with mixed cellularity, and compared these profiles with those of 55 patients with cytotoxic molecule-positive nodal peripheral T-cell lymphoma, not otherwise specified and 439 patients with cytotoxic molecule-negative Hodgkin’s lymphoma. Results The patients with cytotoxic molecule-positive Hodgkin’s lymphoma consisted of 20 men and 12 women with a median age of 50 years (range, 19 to 81). All these patients had lymphadenopathy at presentation, and 14 showed mediastinal involvement. Physical findings included hepatomegaly and splenomegaly in six patients each. Four patients had a bulky mass, and nine showed stage IV disease. The tumor cells of patients with cytotoxic molecule-positive Hodgkin’s lymphoma had a prototypic immunophenotype of CD15+ CD30+ CD45RO− fascin+, with positivity for Epstein-Barr virus in 39% of cases. All patients were negative for Pax5. In comparison with patients with cytotoxic molecule-positive nodal peripheral T-cell lymphomas, not otherwise specified, patients with cytotoxic-positive Hodgkin’s lymphoma had relatively mild clinical symptoms, similar to those of patients with cytotoxic molecule-negative Hodgkin’s lymphoma. Regarding prognosis, the survival of patients with cytotoxic molecule-positive Hodgkin’s lymphoma was worse than that of patients with cytotoxic molecule-negative Hodgkin’s lymphoma ( P =0.0003) but better than that of patients with cytotoxic molecule-positive peripheral T-cell lymphomas, not otherwise specified ( P =0.002). Conclusions Cytotoxic molecule-positive Hodgkin’s lymphoma is characterized by an unfavorable prognosis, even if its clinicopathological features are within the boundaries of classical Hodgkin’s lymphoma. More effective chemotherapy for cytotoxic molecule-positive Hodgkin’s lymphoma is clearly required.

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 Recently, there have been reports of hepatitis B virus (HBV) reactivation after rituximab combination chemotherapy in hepatitis B surface antigen (HBsAg) –negative patients with B-cell lymphoma. In this prospective study, the frequency of and risk factors for HBV reactivation in patients who were receiving rituximab chemotherapy were examined. Patients and Methods A total of 314 HBsAg-negative patients with diffuse large B-cell lymphoma were treated with rituximab chemotherapy. Antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured. Results Of the 314 patients, 51 (16.2%) were HBV carriers. HBV reactivation occurred during or after rituximab chemotherapy in six patients (12%). All six patients who developed HBV reactivation were anti-HBc positive, and three of them were also anti-HBs positive. In these six patients, the pretreatment anti-HBs titer was low. Entecavir administration was started when serum HBV DNA became positive, and serum HBV-DNA became negative within 1 to 3 weeks. Rituximab chemotherapy was then continued. Risk factors for HBV reactivation were being male and having a low anti-HBs titer. Conclusion HBV reactivation occurred in some patients who had been anti-HBs negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of rituximab chemotherapy, but rituximab chemotherapy could be continued after entecavir administration reduced the serum HBV-DNA level. Entecavir (BMS 200495) prophylaxis was not performed when rituximab chemotherapy was started, and it was thought that entecavir could be started when serum HBV-DNA increased.

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.

Among methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPD), diffuse large B-cell lymphoma (DLBCL) accounts for about half. We studied the clinicopathological characteristics and prognosis of patients with DLBCL in MTX-LPD. This study included 29 patients who developed DLBCL after receiving MTX for rheumatoid arthritis. MTX was discontinued in all patients. Their median age was 62 years. Elevated lactate dehydrogenase (LDH) level was observed in 97% of the patients, bone marrow involvement in 17%, and involvement of extranodal sites in 41%. As for the cellular immunophenotype, CD20 was positive in 93%, CD5 in 3%, CD10 in 31%, BCL2 in 21%, BCL6 in 69%, and Epstein-Barr virus (EBV)-encoded small non-polyadenylated RNA (EBER) in 24%. Chemotherapy was started within 2 months after MTX withdrawal in 23 patients, of whom 12 patients received combination with rituximab. Spontaneous remission occurred in the remaining six patients. The EEBV-positive rate was 67% (4/6), and the four EBV-positive patients achieved complete response. Among the 23 DLBCL patients treated with chemotherapy, 20 patients achieved complete response. The 5-year overall survival was 74% and the 5-year progression-free survival was 65%. After the development of DLBCL, withdrawal of MTX was the first choice of treatment. Germinal center B-cell type and EBER-positive patients tended to show spontaneous remission. The utility of rituximab should be examined in future studies.

Rituximab, a genetically engineered chimeric monoclonal antibody that specifically binds to CD20, is the first monoclonal antibody approved for the treatment of B-cell lymphoma. The addition of rituximab to chemotherapy has improved progression-free survival and overall survival for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Rituximab-CHOP therapy is the new standard therapy in elderly and young, low-risk DLBCL patients. For young, high-risk DLBCL patients, treatment that incorporates rituximab and hematopoietic stem cell transplantation has been administered in clinical studies. Rituximab maintenance therapy for DLBCL is not effective at present. On the other hand, when active treatment is required in patients with follicular lymphoma, rituximab-chemotherapy is now the optimal treatment. In follicular lymphoma, randomized controlled trials of rituximab-chemotherapy show lengthened time to progression but, as yet, no improvement in overall survival.

The clinical efficacy of COP-BLAM chemotherapy combined with human recombinant granulocyte colony-stimulating factor (G-CSF) was evaluated in 104 previously untreated patients with non-Hodgkin's lymphoma (NHL). According to the method of Laurence et al., a modified COP-BLAM regimen was administered every 21 days. G-CSF was added when the granulocyte count fell below 1000 x 10 9 /l. Ninety-eight of 104 (94.2%) patients achieved a complete remission ; the 4-year survival rate was 82.4% with a median duration of observation of 26 months. Survival was significantly longer in patients with low serum LDH levels, B-cell type or low CRP or in earlier clinical stages, than in patients with high serum LDH levels, T-cell type or higher CRP levels or in advanced clinical stages. The mean duration of administration of G-CSF was 5.4 days. Twelve patients developed infections during treatment. The adverse effects of G-CSF included interstitial pneumonia, bone pain and fever. Patients administered COP-BLAM combined with G-CSF achieved a high rate of remission and had a low incidence of infection. Nearly all the patients could be treated in 21-day cycles. The results suggest that G-CSF combined with COP-BLAM was effective in treating NHL, because the patients can tolerate a higher dose of the anticancer agents.

A 61-year-old Japanese man was referred to our hospital in 2002 due to severe pancytopenia. Bone marrow and peripheral blood findings indicated he had severe aplastic anemia (AA). A whole-body CT scan and Ga scintigraphy revealed no abnormal findings. Antithymocyte globulin and cyclosporine A (CyA) were administered and he got transfusion independently. In September 2004, he complained of abdominal fullness and a skin eruption in the lower abdomen. An abdominal CT revealed a spleen mass and lymphoadenopathy of the pancreas head. Splenectomy was done, and he was diagnosed with a diffuse large B cell lymphoma (DLBCL) of the spleen and skin. His karyotype was associated with t(14; 18). CyA was stopped, all lesions disappeared, and then his AA relapsed. In January 2007, antithymocyte globulin/CyA was readministered. In May 2007, he complained of acute swelling in his right thigh. A biopsy from the tumor revealed DLBCL. CyA was stopped again, yet the lymphoma did not regress. He was given R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone), followed by 5 cycles of R-VP (rituximab, vincristine, prednisolone) and radiation therapy, resulting in a partial remission. We report DLBCL after immunosuppressive therapy for AA. Although this is a rare complication, it should be considered before beginning immunosuppressive therapy.

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.

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.

Rhabdomyosarcoma is exceedingly rare in adults. A 62-year-old woman was referred to our hospital because of general pain. Computed tomography revealed a solid tumor in the right nasal cavity. Histopathological examination showed solid proliferation of atypical small round cells, having cytologic features reminiscent of lymphomas, and lacking the fibrovascular stroma. The cells were CD56(+), desmin(+), vimentin(+), HHF35(+), myogenin(+) and MyoD1(+). The patient was positive for the PAX3-FKHR fusion gene. The patient was diagnosed as having alveolar rhabdomyosarcoma. We conclude that rhabdomyosarcoma should be included in the differential diagnoses of CD56(+) small round cell tumor, and immunohistochemical and cytogenetic studies should be performed.

Background: We studied the clinicopathological characteristics and prognoses of localized stage thyroid diffuse large B-cell lymphoma (DLBCL). Patients and methods: This study included 32 patients with stage I/IIE thyroid DLBCL. Their median age was 66 years, the male/female ratio was 10/22. Results: As to the cellular immunophenotype, CD20 was positive in 31/32, CD5 in 0/32, CD10 in 4/32, CD23 in 1/32, BCL2 in 14/30, and BCL6 in 24/32. Twelve cases showed abnormal karyotypes: two cases with t(8;14)(q24;q32), four cases with 3q27, two cases with 17p11, and four cases with other abnormal karyotypes. As for treatment, eight cases were treated with chemotherapy alone and 24 cases were treated with chemotherapy followed by radiotherapy. Complete response was achieved in 94%. The 5-year progression-free survival was 84% and the 5-year overall survival was 90% with a median follow-up period of 62 months. The germinal center B-cell (GCB) type had a significantly better prognosis than the non-GCB type. Conclusion: Localized stage thyroid DLBCL is a disease with a relatively good prognosis. It is, however, a heterogeneous disease with regard to histological type and pathological state. Localized stage thyroid DLBCL has a good prognosis and it is that there are more GCB-type DLBCL lymphomas.

Diffuse large B-cell lymphoma (DLBCL) with the 8q24 translocation is occasionally seen in the gastrointestinal tract, but has rarely been reported in the thyroid gland. We experienced two cases of primary thyroid DLBCL having t(8;14)(q24;q32). The immunophenotype and karyotype of Case 1 (66-year-old female) and Case 2 (70-year-old female) were: CD10-, CD20+, BCL-2+/add(13)(q34), t(8;14)(q24;q32) and CD10-, CD20-, CD79a+, BCL-2-/t(8;14)(q24;q32), respectively. Although long-term complete remission could be achieved in both of our patients by conventional chemotherapy with/without radiation therapy, accumulation of further such cases is necessary to develop a standard treatment protocol and also to elucidate the pathogenesis of t(8;14)(q24;q32)-positive primary thyroid DLBCL.

A 35-year-old man was referred to our hospital because of left supraclavicular and cervical lymphadenopathies. Histopathological examination of the lymph nodes revealed reactive lymphadenopathy. He visited our hospital three years after the initial diagnosis because of enlarged left cervical lymph nodes. Histopathologically, both Hodgkin/Reed-Sternberg (H/RS) and lymphocyte-predominant (LP) cells were found in the lymph node. We first suspected nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), because these cells were CD15(-) and CD30(-). However, the diagnosis of lymphocyte-rich classical Hodgkin lymphoma (LRCHL) was finally confirmed, because these cells were found to be CD20(-), Bob.1(+), Oct.2(-), and BCL6(-) by additional immunostaining. The patient was treated with six cycles of ABVD chemotherapy, and a complete response was achieved. However, he underwent autologous stem-cell transplantation after high-dose chemotherapy owing to a relapse 10 months after primary treatment. Distingushing LRCHL from NLPHL was difficult in this patient, because histopathological examination showed both H/RS and LP cells, and immunostaining revealed these cells to be triple negative (CD15(-), CD30(-) and CD20(-)). Accumulation of such cases are necessary to establish better criteria for the differential diagnosis and assessment of clinical behavior.

Standard treatment for elderly patients with relapsed or refractory DLBCL has not been established. CPT-11 has a broad spectrum of anticancer activities including a cytotoxic effect in a variety of malignant tumors. The results of combined treatment with CPT-11 and rituximab have not been reported. The R-CMD regimen was given to elderly patients with relapsed or refractory DLBCL. The safety and efficacy of this regimen were studied. In addition, the serum nm23-H1 level was determined to study whether or not it can serve as a prognostic factor. Thirty elderly patients with DLBCL were studied. The main non-hematological toxicities were infusion-related adverse events. Grade 3/4 hematological toxicity was seen in 19 patients. Following R-CMD treatment, the BNP and troponin T levels did not increase. The CR rate was 57%, PR rate was 17%, 2-year survival rate was 45.2%, and PFS rate was 37.2%. Patients with serum nm23-H1 levels of higher than 80 ng/mL before the treatment showed significantly poorer prognosis. The serum nm23-H1 level of the 30 subjects before the treatment was elevated at 39.4 +/- 41.3 ng/mL, but it significantly decreased only in the subset of patients who achieved CR. The R-CMD regimen was safe in elderly patients with DLBCL. No new signs of cardiotoxicity were observed with this regimen. It was also effective in patients with relapsed or refractory DLBCL who had previously used DXR.

A 71-year-old woman was referred to our hospital because of hyperproteinemia and serum M-protein (IgG-lambda type). Chest computed tomographic (CT) scan revealed a tumor in each lung and transbronchial lung biopsy was performed. Histopathological examination showed monotonous medullary proliferation of morphologically mature plasma cells. These cells were cIgG+, cIg-lambda+, CD 20+, CD 79 a+, CD 138+, cIg-kappa-, and CD3-. Since there were very few non-neoplastic plasma cells and small lymphocytes in addition to the absence of reactive lymph follicles and fibrosis, the patient was diagnosed as having plasmacytoma. There was no proliferation of plasma cells in the bone marrow. Thus, the lesion was finally characterized as primary pulmonary plasmacytoma. Treatment with melphalan/prednisolone resulted in considerable decrease in the serum IgG level and regression of the pulmonary tumors. The effectiveness of the chemotherapy could confirm our diagnosis, although MALT-type lymphoma with plasmacytic differentiation cannot be completely ruled out.

Lymphomas rarely develop during pregnancy, but hepatosplenic gammadelta T-cell lymphoma (HSgammadeltaTCL) is extremely rare. We encountered a case of T-cell intracellular antigen-1 (TIA-1) positive and granzyme B-positive HSgammadeltaTCL that developed early during the course of pregnancy. The patient was a 31-yr-old female who was referred to our hospital because of pancytopenia and splenomegaly at the time of the14th week of her gestation. Her pancytopenia and hepatosplenomegaly worsened and she became fibril at the 27th week of gestation and Cesarean section was performed at the 29th week. Histopathological examination of the spleen, which was resected 28 d after delivery for a diagnostic purpose, revealed medium to large-sized nodules composed of dense proliferation of lymphoid cells having round to oval-shaped nuclei and abundant weakly eosinophilic cytoplasm. They were CD3epsilon+, mCD3+, CD4-, CD8-, CD56+, CD79a-, T-cell receptor (TCR)-gammadelta protein+, TIA-1+, and granzyme B+ by either immunohistochemistry or flow cytometry. Clonal rearrangement of TCR-gamma genes without such rearrangement of TCR-delta and TCR-beta genes was confirmed by Southern blot hybridization. Thus, the patient was diagnosed as having HSgammadeltaTCL, and combination chemotherapy was initiated. She is currently in partial remission. To our knowledge, this is the first case report of HSgammadeltaTCL that developed during pregnancy. Pathogenesis of pregnancy-associated lymphoma is not known, but it is possible that maternal immunity during pregnancy or a hormonal imbalance, such as a change in the progesterone level, induces the development of lymphoma. Pregnancy-associated lymphoma is resistant to standard chemotherapy and is associated with poor prognosis. Therefore, it is important to accumulate clinicopathologic data of such cases for the development of a treatment modality.

Purpose: Rituximab is an anti-CD20 monoclonal antibody, and it is used to treat B-cell lymphomas. Antibody-dependent cellular cytotoxicity (ADCC) is considered one of the mechanisms through which rituximab exerts its effects. Granulocyte colony-stimulating factor (G-CSF) enhances the cytotoxicity of neutrophils through ADCC, and it can be speculated that a combination of rituximab and G-CSF may augment the treatment efficacy of rituximab. Experimental Design: We administered rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) treatment with G-CSF to 15 patients with follicular lymphoma, and we investigated the safety and efficacy of this regimen. We investigated ADCC activity in neutrophils and the expression of cell surface antigens including Fcγ receptor type I [FcγRI (CD64)] on neutrophils to determine the optimal dose of G-CSF. Results: Adverse reactions occurred in 14 of 15 patients and consisted mainly of grade 3/4 hematological toxicity. The response rate was 100%, with complete remission in 12 patients (80%) and partial remission in 3 patients (20%). At 14 months, the median length of the observation period, 2 of 12 patients had relapsed. G-CSF administration increased both FcγRI expression and ADCC activity. There were no significant differences in the levels of FcγRI expression or ADCC activity between the 2 μg/kg G-CSF and 5 μg/kg G-CSF groups, indicating that the optimal dose of G-CSF was 2 μg/kg. Conclusions: We conclude that the combination of rituximab-CHOP and G-CSF is well tolerated. We plan to carry out a randomized trial to compare efficacy between rituximab-CHOP treatment and treatment with a combination of rituximab-CHOP and G-CSF.

Acute leukemia patients with MLL (mixed linage leukemia) rearrangements tend to respond poorly to conventional therapies. We examined differentiation of human myeloid leukemia cells displaying the MLL-AF9 gene, using several differentiation agents. When MOLM-14 cells were treated with all-trans retinoic acid (ATRA) or 1beta,25-dihydroxyvitamin D3, significant induced differentiation was observed. Trichostatin A (TSA), an inhibitor of histone deacetylase, demonstrated enhance effects with ATRA in regard to growth inhibition and differentiation induction in MOLM-14 cells. Pretreatment with TSA before exposure to ATRA displayed increased effect. Based on these findings, combined treatment with ATRA and TSA may be clinically useful in therapy for acute leukemia displaying MLL-AF9 fusion gene.

Purpose: Recently, we established an ELISA technique for measuring nm23-H1 protein in serum and found that the serum nm23-H1 level is a potential prognostic factor for patients with non-Hodgkin’s lymphoma. Experimental Design: We used immunohistochemistry to examine the expression of nm23-H1 by the lymphoma cells in patients with diffuse large B-cell lymphoma (DLBCL). Results: By analyzing a consecutive series of 172 untreated DLBCL patients, we found that 100 (58.1%) were strongly positive. The cytoplasmic nm23 expression in lymphoma cells correlated significantly with the serum nm23-H1 level. There was a significant correlation between patients with cytoplasmic nm23-positive lymphoma and those with performance status 2–4, stage III/IV, bulky mass, B symptoms, elevated serum level of soluble interleukin 2 receptor, and elevated serum level of C-reactive protein. Overall and progression-free survival rates were significantly lower in patients with nm23-H1-positive lymphomas than in those with nm23-H1-negative lymphomas. Similar difference was seen between patients with high and low serum levels of nm23-H1. Thus, the correlation between presence or absence of cytoplasmic nm23-H1 expression and serum nm23-H1 levels suggests that serum nm23-H1 is produced directly by lymphoma cells. Conclusion: We suggest that nm23-H1 expression is a prognostic factor for DLBCL, and that it is as important as serum nm23-H1, both of which are useful for planning a treatment strategy.

Summary. We have reported previously that the serum nm23-H1 level is a prognostic factor for non-Hodgkin's lymphoma. In this study, we examined nm23-H1 expression in T- and natural killer (NK)-cell lymphoma in order to evaluate whether lymphoma cells produce the protein. The clinical significance of the cytotoxic molecules, T-cell intracellular antigen-1 (TIA-1) and granzyme B and nm23-H1 expression were also examined. Expression of nm23-H1, TIA-1, or granzyme B was examined by immunohistochemistry in 137 previously untreated lymphoma patients. The relationship between the results and clinical outcome was examined in 81 patients with angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma, unspecified. The neoplastic cells of some lymphomas produced nm23-H1 and the expression rates of nm-23-H1, TIA-1 and granzyme B were 36·5%, 78·8% and 32·8% respectively. The nm23-H1-positive or TIA-1-positive groups had significantly shorter overall and disease-free survivals. Multivariate analysis confirmed nm23-H1 expression to be an independent prognostic factor. The nm23-H1 protein can be an important prognostic factor in the lymphomas studied here. New treatments that target nm23 overexpression could be developed as a result of nm23-HI production by lymphoma cells.

Serum levels of the nm23-H1 protein and their clinical implication in extranodal NK/T-cell lymphoma

Objective Although all-trans retinoic acid (ATRA) can bring about complete remission of acute promyelocytic leukemia (APL), the incidence of early recurrence is considerably high. Thus, chemotherapeutic agents, such as anthracycline agents or cytosine arabinoside (AraC), are generally co-administered with ATRA. The therapeutic outcome of APL patients has significantly improved by chemo-differentiation therapy. Late-phase toxicities, such as cardiotoxicity and secondary carcinogenesis, are becoming clinically important. Therefore, we must identify the most suitable chemotherapeutic agents for the treatment of APL. Methods We examined the effects of ICRF-193 and several other anticancer drugs on the growth and differentiation of APL cell lines (NB4 and HT-93) and other myeloid leukemia cell lines (HL-60 and U937). Results If anticancer agents were available that not only inhibited the proliferation of APL cells but also induced their differentiation, they would be very useful for the treatment of APL. DNR slightly induced the differentiation of APL cells. On the other hand, other DNA topoisomerase II inhibitors, such as ICRF-154 and ICRF-193, significantly induced the differentiation of APL cell lines and leukemia cells freshly isolated from APL patients. These drugs effectively cooperated with ATRA in inhibiting the growth and inducing the differentiation of APL cells, whereas DNR did not. The incidence of cardiotoxicity and secondary carcinogenesis associated with ICRF-193 are much lower than that with DNR. Conclusion These results suggest that ICRF-193 may be useful in the treatment of patients with APL.

Nasal and nasal-type natural killer (NK) lymphoma is a distinct clinicopathological entity mostly associated with Epstein-Barr virus. Cases that have widespread lesions are resistant to ordinary anti-cancer therapy and take a highly aggressive course. To date, there are no available data on the relationships between the localization, clinical outcome and expression of adhesion molecules in such cases. We examined the expression of cutaneous lymphocyte antigen (CLA) in 52 cases of NK-cell lymphoma. CLA was highly expressed in cutaneous cases. Also, the CLA+ group (n=29) had a much worse prognosis than the CLA- group (n=23), regardless of the primary site or clinical staging. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors showed that the expression of CLA was an independent prognostic indicator. In conclusion, the present findings established that CLA is an independent and important prognostic factor in patients with NK-cell lymphomas.

We measured soluble CD44 (sCD44) by enzyme-linked immunosorbent assay in 216 patients with non-Hodgkin's lymphoma (NHL). The sCD44 level was significantly elevated in patients with NHL. A sCD44 level of ≥500 ng/ml showed a significantly decreased overall survival (OS) rate and progression free survival (PFS) rate. In the high–intermediate+high risk group (international prognostic index (IPI)), both the OS rate and the PFS rate were significantly decreased when the sCD44 level was ≥1000 ng/ml. Moreover, the results of a multivariate analysis showed that the five IPI prognostic factors and the sCD44 level were independent prognostic factors, thus suggesting that sCD44 levels could be a useful prognostic marker for aggressive lymphoma

Therapeutic approaches for non-Hodgkin's lymphoma (NHL) are currently based on the International Prognostic Index (IPI). Research on biological prognostic factors has been actively pursued in recent years, with serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) being identified as prognostic factors for NHL. Here, we determined that serum VEGF and IL-6 levels are independent prognostic factors for aggressive lymphoma. Compared with normal controls, serum VEGF and IL-6 levels were significantly higher in patients with aggressive lymphoma or adult T-cell leukemia/lymphoma. Furthermore, overall and disease-free survival rates for patients with high levels of VEGF or IL-6 were significantly poorer than for patients with low levels. In addition, the prognosis for patients with high levels of both serum VEGF and IL-6 was significantly poorer than that for patients with high levels of either VEGF or IL-6 or with low levels of both VEGF and IL-6. Multivariate analyses of a variety of prognostic factors, including the five IPI factors, revealed that serum VEGF and IL-6 were both independent prognostic factors for overall survival of aggressive lymphoma. Therefore, a combination of VEGF and IL-6 represents a useful prognostic factor for aggressive lymphoma.

Rituximab, a genetically engineered chimeric monoclonal antibody that specifically binds to CD20, is the first monoclonal antibody approved for the treatment of B-cell lymphoma. It has been shown that rituximab exerts cytotoxic activities through CDC and ADCC, and that it directly induces apoptosis. The CD20 protein has four transmembrane domains (tetraspan structure) and is not internalized following antibody binding, and is not shed or secreted into the circulation. Therefore, CD20 can serve as a target of antibody therapy. As the other anti-CD20 antibodies, there are ofatumumab and obinutuzumab, and clinical development is expected. In addition, histone deacetylate inhibitor or proteasome inhibitor as a new drugs for lymphoma in the future.

We assessed the efficacy and safety of full-dose CHOP regimen plus granulocyte colony-stimulating factor to treat aggressive non-Hodgkin's lymphoma in elderly patients. Forty-two patients with untreated disease were included in this study, aged 70-79 years, with stage II or higher disease and a performance status of 0-3, without severe organ dysfunction. Of the 40 patients who could be evaluated 87.5% achieved complete remission, with a 4-year survival rate of 69% and a 3-year progression-free survival rate of 49%. When stratified by the International prognostic Index, the 4-year survival rate was 90.9% for the low and low-intermediate risk group and 41.3% for the high-intermediate and high risk group, whereas the 3-year progression survival rate was 87.7% and 11.3%, respectively. Grade 3 or 4 hematological toxicity was found in 31 instances of granulocytopenia (77.5%) and 7 of anemia (17.5%). Nonhematological toxicity of grade 3 or 4 included pneumonia in two patients, heart failure in one, and gastrointestinal bleeding in one. Full-dose CHOP regimen with granulocyte colony-stimulating factor support could achieve a high-dose intensity in elderly patients whose general physical condition was good and hence achieved a high complete remission rate, but the disease often recurred within 2 years. Consequently, a new therapeutic strategy needs to be established, particularly for patients with high-intermediate or high risk.

Standard chemotherapy has been ineffective for improving the poor 10-year survival rate of patients with indolent lymphoma. However, a wider choice of therapeutic modalities has become recently available, including immunotherapy with monoclonal antibodies and allogeneic peripheral blood stem cell transplantation. Accordingly, a sensitive prognostic indicator is required to identify high-risk patients and to help design new therapeutic approaches for them. We previously reported that the serum nm23-H1 protein level was an independent prognostic factor for aggressive lymphoma. The present study was performed to assess the clinical implications of this protein on indolent lymphoma and whether it can be used to classify the aggressiveness of the disease in order to assist in the individualization of therapy. A total of 130 patients with indolent lymphoma were enrolled in this multicenter study. The serum nm23-H1 protein level was significantly higher in patients with indolent lymphoma than in a normal control group. In addition, indolent lymphoma patients with higher nm23-H1 levels had worse overall and progression-free survival rate than those with lower nm23-H1 levels. Therefore, nm23-H1 in serum may be useful for identifying a distinct group of patients at high risk.

Advances in chemotherapy have led to a favorable long-term prognosis in approximately 50% of patients with aggressive non-Hodgkin lymphoma (NHL). However, the remaining patients do not enjoy such prolonged survival after standard treatment. New prognostic factors are needed to define this poor-prognosis group and to plan an appropriate treatment strategy. It has been reported that serum nm23-H1 protein may be a new prognostic factor for aggressive NHL. In the present study involving multiple institutions and a large number of patients, the level of nm23-H1 protein was compared among different types of lymphoma; it was lowest for indolent lymphoma, followed by aggressive lymphoma and then highly aggressive lymphoma. In addition, patients with aggressive NHL and higher nm23-H1 levels had worse overall and progression-free survival rates than those with lower nm23-H1 levels. The nm23-H1 level was also compared between patients with diffuse large B-cell lymphoma and patients with peripheral T-cell lymphoma. The results suggest that the level of nm23-H1 could serve as a prognostic factor in both groups. Moreover, the prognosis of lymphoma patients could be ascertained even more precisely by combining soluble interleukin-2 receptor or soluble CD44 and nm23-H1 levels. A multivariate analysis confirmed that the nm23-H1 level is an independent and important prognostic factor in aggressive NHL. Therefore, it may provide useful information for clinicians to determine the appropriate therapy for each type of lymphoma.

Most chromosomal abnormalities associated with breakage at 11q23 in acute leukaemia involve the MLL gene, and the presence of this breakage strongly predicts a poor clinical outcome. We assessed the possibility of differentiation-inducing therapy for acute leukaemias with chromosomal translocations involving 11q23. Among the cell lines with MLL translocations that we examined, KOCL48 and KOPN-1 cells were induced to differentiate into granulocytes by all-trans retinoic acid (ATRA) or into monocytes by 1α,25-dihydroxyvitamin D3 (VD3). These cells expressed p16 mRNA before treatment with 5-aza-2′-deoxycytidine (5-AZA), an inhibitor of DNA methylation. On the other hand, differentiation was not induced in SN-1, KOCL33, KOCL51 or KOCL44 cells by ATRA or VD3, and these cells did not express mRNA of this gene. However, these cells were effectively induced to differentiate by ATRA or VD3 in the presence of 5-AZA, and concomitantly exhibited p16 gene expression, suggesting an association between DNA demethylation and restoration of sensitivity to differentiation-inducing activity of ATRA or VD3 in leukaemia cells with MLL abnormalities. Based on these findings, combined treatment with ATRA or VD3 plus 5-AZA may be clinically useful in therapy for acute leukaemia with MLL abnormalities.

Soluble interleukin-2 receptor (sIL-2R) is produced by activated T and B cells, and the level of this receptor is elevated in patients with non-Hodgkin's lymphoma (NHL). The present study demonstrated that the sIL-2R level was high in the following groups of patients with aggressive NHL; those aged > or = 60 yr, those with a poor PS, those in Ann Arbor stage III or IV, and those in the high intermediate or high risk group according to the International Prognostic Index (IPI). Overall survival was significantly poorer when the sIL-2R level was 2000 U/ml or more. In addition, the overall survival of patients in the low (L) and low-intermediate (L-I) risk groups with an sIL-2R level of 3000 U/ml or more was significantly poorer, suggesting that the sIL-2R level could be particularly useful for identifying patients with a poor prognosis among the L and L-I risk groups. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors plus the five IPI prognostic factors showed that the sIL-2R level was an independent prognostic indicator. In conclusion, the present findings established that the sIL-2R level is a significant independent prognostic factor in patients with aggressive NHL.

A variant form of CD44 that has additional amino acids in the common protein backbone (CD44-v6) seems to play a role in the metastasis of malignancies. We measured soluble CD44-v6 (sCD44-v6) by ELISA in 201 patients with malignant lymphoma. The sCD44-v6 level was significantly elevated in patients with non-Hodgkin's lymphoma (NHL) (n = 184). The sCD44-v6 level was correlated significantly with the standard sCD44 and soluble interleukin-2 receptor levels, but only weakly with serum lactate dehydrogenase (LDH). In 149 patients with aggressive NHL, the sCD44-v6 level was elevated in the subgroups with a high LDH level, stage III/IV disease, T-cell lymphoma, and high-intermediate or high risk group as identified by the International Prognostic Index (IPI). When the sCD44-v6 level was > or = 800 ng/ml the overall survival rate was significantly decreased (p = 0.0001). In the low + low-intermediate risk group (IPI) both overall survival rates (log-rank p = 0.0005, Wilcoxon p =0.002) were significantly decreased when the sCD44-v6 level was > or = 800 ng/ml. In multivariate analysis, sCD44-v6 was shown to be independent of the five prognostic factors in the IPI (age, performance status, number of extranodal sites, Ann Arbor stage and LDH level), so it may be useful for predicting the outcome of aggressive NHL.

We conducted a multi-institutional collaborative study to examine the usefulness and safety of third-generation chemotherapy CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) combined with granulocyte colony-stimulating factor (G-CSF) in the treatment of aggressive non-Hodgkin's lymphoma (NHL). Subjects included patients with aggressive NHL who were 60 yr of age or younger and had been diagnosed as having a low–intermediate, high–intermediate, or high risk using the International Prognostic Index (IPI). A total of 24 patients were enrolled in the study between May 1997 and March 1998, including 9 low–intermediate-risk cases, 13 high–intermediate-risk cases and 2 high-risk cases. Although all 24 patients were originally enrolled in the study, one adult T-cell leukemia/lymphoma case was subsequently excluded. Thus, in the end, 23 cases were evaluated. Evaluation of the efficacy of therapy revealed complete remission in 20 patients (87%). Of these 20 patients, 8 were low–intermediate-risk cases (89%) and 12 were either high–intermediate- or high-risk cases (86%). Partial remission was achieved in 2 patients (8.7%). The 2-yr survival rate was 91.3%, and the 2-yr disease-free survival rate was 81.8%. Grade 3 or higher adverse reactions were granulocytopenia (87%), thrombocytopenia (17.4%) and liver dysfunction (4.3%). CyclOBEAP therapy has been associated with a high remission rate for aggressive NHL. When combined with G-CSF, a high relative dose intensity was maintained for each drug administered (0.94–0.97). Furthermore, although the observation period was short, both the survival rate and disease-free survival rate were good. Hence, we concluded that there were no problems associated with the procedure in terms of safety.

A previous study reported that a nondifferentiating myeloid leukemia cell line produced differentiation-inhibiting factors. One of the factors was purified as a homologue of the nm23 genes. Thenm23 genes were overexpressed in acute myelogenous leukemia (AML) cells, and a higher level of nm23 gene expression was correlated with a poor prognosis in AML. The present study determined the plasma levels of nm23-H1 protein by enzyme-linked immunosorbent assay and assessed the association between this level and the clinical outcome in 102 patients with AML. The plasma concentration of nm23-H1 was higher in patients with AML than in normal controls (P = .0001). Plasma nm23-H1 levels were correlated with the product of the intracellular nm23 messenger RNA (mRNA) level and the white blood cell count, but not with the mRNA level alone. Therefore, nm23-H1 plasma levels probably depend on the total mass of leukemic cells overexpressing the nm23-H1 gene. Overall survival was lower in patients with higher plasma nm23-H1 levels than in those with lower levels. Multivariate analysis using the Cox proportional hazard model showed that elevated plasma nm23-H1 levels significantly contributed to the prognosis of AML patients. Furthermore, the plasma nm23-H1 levels were investigated in 70 patients with other hematologic neoplasms, including 6 with acute lymphoblastic leukemia, 13 with chronic myelogenous leukemia, and 12 with myelodysplastic syndrome. Plasma nm23-H1 levels were significantly higher in all of these hematologic neoplasms than in normal controls. Increased plasma levels of nm23-H1 may have prognostic value in these hematologic malignancies as well as in AML.

Pivalyloxymethyl butyrate (AN9) is an anticancer derivative of butyric acid. In this study, doxorubicin (DXR) and AN9 synergistically inhibited the growth of lymphoma and lung carcinoma cells, whereas there was no synergy between AN9 and antimetabolites. AN9 did not affect the intracellular uptake of DXR. Among anthracyclines and their derivatives, the synergistic effect was prominent in compounds with a daunosamine moiety, suggesting that AN9 may affect the catabolism of these compounds. The degradation of DXR in the extract from AN9-treated cells was much less than that in extract from untreated cells. AN9 did not directly inhibit the enzyme activity but rather suppressed expression of the enzyme. With respect to the expression of drug resistance-related genes, there was no significant difference between untreated and AN9-treated cells. However, AN9 significantly down-regulated the levels NADPH-cytochrome P450 reductase and DT-diaphorase mRNA in the presence of DXR but not the level of xanthine oxidase mRNA. The enhancement of the sensitivity to anthracyclines was closely associated with the suppression of the mRNA expression.

The outcome of patients with non-Hodgkin’s lymphoma has been improved by current approaches to treatment. Nevertheless, many patients either do not have a complete remission or ultimately relapse. To identify such patients, it is important to be able to predict the outcome. We previously found that the differentiation inhibitory factor/nm23 was correlated with the prognosis of acute myeloid leukemia. To examine the prognostic effect of nm23 on non-Hodgkin’s lymphoma, we established an enzyme-linked immunosorbent assay procedure to determine nm23-H1 protein levels in plasma and assessed the association of this protein level with the response to chemotherapy, overall survival, and progression-free survival in patients with aggressive non-Hodgkin’s lymphoma. The plasma concentration of nm23-H1 was significantly higher in patients with malignant lymphoma than in normal controls, especially in aggressive non-Hodgkin’s lymphoma. The complete remission rate in patients with higher nm23-H1 levels was significantly worse than that in patients with lower nm23-H1 levels. Overall survival and progression-free survival were also lower in patients with higher nm23-H1 levels than in those with lower levels. The 3-year survival rates in patients with low and high nm23-H1levels were 79.5% and 6.7% (P = .0001). A multivariate analysis of prognostic factors showed that the plasma nm23-H1level was independently associated with the survival and progression-free survival. An elevated plasma nm23-H1concentration predicts a poor outcome of advanced non-Hodgkin’s lymphoma. Therefore, nm23-H1 in plasma may be useful for identifying a distinct group of patients at very high risk.