De novo CD5 ؉ diffuse large B-cell lymphoma (CD5 ؉ DLBCL) is known to have phenotypically and genotypically different characteristics than CD5 ؊ DLBCL and mantle cell lymphoma (MCL). To further characterize CD5 ؉ DLBCL, 109 patients with CD5 ؉ DLBCL were reviewed, and the results were compared with those of 384 CD5 ؊ DLBCL and 128 cyclin D1 ؉ MCL patients. Patients with CD5 ؉ DLBCL showed a higher age distribution (median, 66 years; P ‫؍‬ .0083) and a female predominance (male-female ratio, 49:60, P ‫؍‬ .011) compared with those with CD5 ؊ DLBCL. CD5 ؉ DLBCL was more closely associated with many aggressive clinical features or parameters than CD5 ؊ DLBCL: 69% older than 60 years (P ‫؍‬ .039), 34% with performance status greater than 1 (P ‫؍‬ .0016), 69% with serum lactate dehydrogenase level higher than normal (P < .0001), 62% with stage III/IV disease at diagnosis (P ‫؍‬ .0023), 35% with more than one extranodal site (P ‫؍‬ .023), and 40% with B symptoms (P ‫؍‬ .0031). The overall International Prognostic Index score was thus significantly higher for the patients with CD5 ؉ DLBCL than for those with CD5 ؊ DLBCL (P ‫؍‬ .00005). The most frequent site of extranodal involvement was bone marrow (28%), a higher frequency than that for CD5 ؊ DLBCL (P < .0001) but lower than that for cyclin D1 ؉ MCL (P ‫؍‬ .0015). Histopathologically, CD5 ؉ DLBCL showed centroblastic morphology except for 3 patients with immunoblastic disease, and interfollicular growth pattern (7%) and intravascular or intrasinusoidal infiltration (19%) were observed. Immunophenotypically, CD5 ؉ DLBCL was characterized by a CD5 ؉ CD10 ؊ CD19 ؉ CD20 ؉ CD21 ؊ CD23 ؊ cyclin D1 ؊ phenotype and a predominance of surface IgM. Of particular interest is that CD5 ؉ DLBCL was characterized by a survival curve significantly inferior to that for patients with CD5 ؊ DLBCL (P ‫؍‬ .0026). These findings suggest that CD5 ؉ DLBCL may constitute a unique subgroup of DLBCL.

BackgroundDe novo CD5-positive diffuse large B-cell lymphoma (CD5 + DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5

Transcription factor NF-B plays a significant role in regulating genes involved in immune response, cell growth and differentiation, and even viral activity (reviewed by Siebenlist et al. (1) and Baeuerle and Henkel (2)). The gene expression of human immunodeficiency virus (HIV) 1 is also regulated by NF-B, suggesting that NF-B plays a critical role in acquired immunodeficiency syndrome (AIDS) (3), and a great effort has been made to analyze the activating mechanisms of NF-B. In many cells, NF-B is usually present as a latent form bound to IB, preventing NF-B from entering into the nucleus. Among IB molecules, IB-␣ is the most well-characterized because of its wide expression and the fact that it has been initially cloned among IB. The activation of NF-B is induced by a variety of extracellular stimuli including cytokines such as tumor necrosis factor ␣ (TNF␣), phosphatase inhibitors such as okadaic acid, protein synthesis inhibitors such as cycloheximide, cellular stress such as ultraviolet irradiation, and viral infection (1, 2). Some of these stimuli cause the degradation and disappearance of . Accumulating data also show that the disappearance of the IB-␣ is critical for the signal-dependent activation of NF-B and that phosphorylation and ubiquitination of IB-␣ precedes the degradation (9 -17). Unfortunately, however, the signaling pathways for these events are poorly understood, although the participation of some signaling molecules such as Ras (18,19), Raf (18,20,21), and protein kinase C isozymes nPKC⑀ (22, 23) and aPKC (19,24,25) have been reported to activate B site-dependent gene expression.MEK kinase is an activator of SAPKs/JNK1 (26,27). SAPKs/ JNK1 are distantly related members of the MAP kinase family, which are enzymes activated by stress and inflammatory cytokines, but only slightly or not at all by growth factors or phorbol esters (28,29).The similarity between the agents that cause the activation of SAPKs/JNK1, such as TNF␣ or UV irradiation (28,29), and those that cause the activation of NF-B (1, 2) prompted us to examine the involvement of MEK kinase in the activation of NF-B and the disappearance of IB-␣. MATERIALS AND METHODSPlasmids-MEK kinase cDNA was isolated by a reverse transcription-polymerase chain reaction procedure using mouse brain mRNA as a template following the published sequence information (30). The cDNA was inserted into the EcoRI site of the vector SRD, a derivative of SR␣-296 (31). The kinase-negative mutant of MEK kinase (KM-MEKK), where bases 1780 -1782 are changed from AAA to ATG resulting in an amino acid substitution at 432 of Lys to Met (27), was inserted into the EcoRI site of SRD vector. Human MAD3 cDNA (32) from base 1 to 1128 was isolated following a standard procedure and inserted into the EcoRI site of SRD vector. All of the protein coding region of CAT from pSV2-CAT (33) was inserted into SRD vector yielding SRD-CAT. B-CAT (p-55A2) and mutant B-CAT (p-55A3) plasmids were described previously (34). HIV-LTR-luciferase plasmid (35) 13234by guest on May 13, 2...

Background. Although colony-stimulating factors have been shown to accelerate recovery from severe neutropenia after intensive chemotherapy or bone marrow transplantation, their use in acute leukemia has been controversial because in vitro they stimulate leukemic colonies as well as normal granulocyte colonies. Methods. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of recombinant human granulocyte colony-stimulating factor (CSF) after a standard course of intensive therapy in 108 patients with relapsed or refractory acute leukemia (67 with acute myelogenous leukemia, 30 with acute lymphocytic leukemia, 9 in blast crisis from chronic myelogenous leukemia, and 2 with acute leukemia arising from myelodysplastic syndromes). Treatment with granulocyte CSF (200 micrograms per square meter of body-surface area per day in a 30-minute infusion) was begun two days after the end of the chemotherapy and continued until the neutrophil count rose above 1500 per cubic millimeter. Results. Treatment with granulocyte CSF accelerated the recovery of neutrophils significantly (P less than 0.01), shortening it by about a week, but it had no effect on platelet recovery. Although the incidence of febrile episodes was almost the same, documented infections were significantly less frequent in the group treated with granulocyte CSF (P = 0.028). There was no evidence that granulocyte CSF accelerated the regrowth of leukemic cells. Fifty percent of 48 patients in the CSF group who could be evaluated and 36 percent of 50 controls had complete remission. The rate of relapse was almost the same in the two groups. Conclusions. It appears that recombinant human granulocyte CSF is safe in acute leukemia, accelerating neutrophil recovery and thereby reducing the incidence of documented infection without affecting the regrowth of leukemic cells. It should be used with caution, however, pending further confirmation of these early results.

The human serotonin transporter (5-HTT) gene has a polymorphism in the 5'-flanking promoter region that is called the serotonin transporter gene-linked polymorphic region (5-HTTLPR). In lymphoblast cell lines, the promoter activity of the 5-HTT gene is dependent on 5-HTTLPR allelic variants. The transcriptional activity of the l allele was more than twice as high as that of the s allele. The s allele is considered to be associated with mood disorders and anxiety-related personality traits. To evaluate the functional differences of 5-HTTLPR in the brain in vivo, we examined the allelic variations of 5-HTTLPR and measured 5-HTT binding in the living human brain using positron emission tomography (PET) with C(11)-labeled trans-1, 2, 4, 5, 6, 10-beta-hexahydro-6-[4-(methylthio) phenyl]pyrrolo[2,1-a]isoquinoline (McN5652) as a ligand. Twenty-seven healthy male subjects participated in this study. Although the human lymphoblast cells with the l/l genotype was reported to produce higher concentrations of both mRNA and protein of 5-HTT than those with the l/s or s/s genotype in a human lymphoblast in vitro study, 5-HTT binding in vivo was not significantly different among subjects with the three genotypes (l/l: 0.842 +/- 0.184, l/s: 0.708 +/- 0.118, s/s: 0.825 +/- 0.209). In conclusion, this study does not support the assumption that the genotype-dependent differences of 5-HTTLPR directly contributes to the regulation of the 5-HTT binding site in the living human brain.

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.

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. (Cancer Sci

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.