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Delayed platelet engraftment (DPE) is occasionally observed despite prompt neutrophil engraftment after autologous peripheral blood stem cell transplantation (auto-PBSCT). To identify risk factors for DPE and to develop a simple and clinically applicable system for predicting the time required for platelet recovery, we conducted a multi-institutional retrospective study in 144 patients with B-cell non-Hodgkin lymphoma who underwent auto-PBSCT. In a median observation period of 930 days (range: 25-5272 days), 139 patients successfully achieved platelet engraftment (≥50.0 × 10 9 /L). The median duration for platelet engraftment was 19 days, and 130 patients had platelet engraftment within 40 days after auto-PBSCT; however, the other 14 patients failed to achieve platelet engraftment within 60 days. These 14 patients with DPE required a significantly greater number of apheresis procedures and had a lower pre-apheresis absolute lymphocyte count (PA-ALC) compared to those without DPE. Importantly, multivariate analysis revealed that the number of transplanted CD34 + cells (≤2.0 × 10 6 /kg), number of required apheresis procedures (≥3 days), and PA-ALC (≤1.0 × 10 9 /L) were independently associated with a longer time for platelet engraftment after auto-PBSCT. By incorporating these three independent factors as variables, we generated a new scoring system for prediction of the time and probability for platelet engraftment after auto-PBSCT.

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

Tumor-derived DNA is elevated in the plasma of patients with cancer. The analysis of circulating DNA may be useful for diagnosis, prognosis evaluation, and early detection of disease recurrence. In order to investigate cf-DNA as a marker during treatment, we serially quantified total cell-free (cf) and EBV plasma DNA in 30 cases of pediatric B-non-Hodgkin lymphoma by real-time PCR. The cf-DNA levels were significantly increased in patient samples at diagnosis as compared with the healthy controls (p < 0.001). At the end of treatment, a significant decrease in plasma DNA concentration was observed as compared with values observed at diagnosis (median: 94.0 copies/mL, p = 0.001). EBV was detected by ISH in 7/30 patients. Plasma EBV DNA levels were obtained from seven EBV-positive patients (median: 1278 copies/mL), while EBV DNA was not detected in 23 EBV-negative patients and 10 healthy controls. The association between the two methods of detection was statistically significant, with 100% correlation (Kappa coefficient, p = 1). In addition, the decrease of EBV viral load was associated with therapy response. Quantification of plasma EBV DNA may become a valuable source for disease detection of pediatric EBV-associated lymphomas and for monitoring treatment response.

Hepatitis C virus (HCV) infection is associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Recent evidences have also suggested that HCV infection contributes to development of autoimmune disorders and B-cell nonHodgkin's lymphoma (NHL). Mechanisms by which HCV infection promotes B-cell NHL development remain unclear. Increased serum osteopontin (OPN) levels have been associated with several autoimmune diseases as well as a variety of cancers. However, the association between OPN and B-cell NHL or HCV-associated B-cell proliferation has not previously been reported. In the present study, we determined whether serum OPN differences were associated with HCV infection, type II mixed cryglobulinemia (MC) syndrome and B-cell NHL. Serum OPN levels were measured by capture enzyme-linked immunosorbent assay. Our results show that high serum OPN levels are associated with B-cell NHL and HCV infection. Interestingly, highest serum OPN concentrations were found among HCV-infected patients with concomitant type II MC syndrome with and without B-cell NHL. These data indicate that OPN is involved in the lymphomagenesis, especially, in the context of HCV infection and autoimmune diseases.

A 53-year old man with systemic lymphadenopathy and hepatosplenomegaly was diagnosed with diffuse large B cell-lymphoma after inguinal lymph node biopsy. Anemia was noted, direct and indirect Coombs tests were positive, and the haptoglobin level was low. However, the bone marrow aspirate revealed erythroid aplasia. Co-existing autoimmune haemolytic anemia (AIHA) and pure red cell aplasia (PRCA) were diagnosed. In situ hybridization with Epstein-Barr virus (EBV) encoded small RNA (EBER) showed positive findings in lymphoma cells. Southern blot hybridization revealed immunoglobulin heavy chain gene rearrangement and a clonal EBV terminal repeat, indicating monoclonal proliferation of EBV in infected B cells. The patient was treated with CHOP, resulting in a complete remission (CR). AIHA and PRCA subsided after 3 courses of chemotherapy. In conclusion, this case demonstrates not only the association of B-cell lymphoma with autoimmune disorders but also the involvement of EBV in these conditions.

In order to analyze the involvement of gamma delta T cells in the immune surveillance against B cell lymphomas (BCL), we investigated the proportion of circulating gamma delta T cells in 52 BCL patients using two-color flow cytometry, together with tumor-infiltrating gamma delta T cells in 22 of those patients. We found that the proportion of tumor-infiltrating gamma delta T cells in BCL patients was not different from that of lymph node gamma delta T cells in reactive hyperplasia patients. However, a decreased percentage of circulating gamma delta T cells were observed in indolent lymphoma (IL) and limited aggressive lymphoma (AL) patients when compared with normal controls. In contrast, as a result of a histogram, advanced AL patients were divided into two subgroups: the patients with increased circulating gamma delta T cells and those without any increase. However, there was no difference in the clinical features of between the two AL subgroups.

Fas-ligand (FasL) is a member of the tumor necrosis factor family and transmits apoptotic cell death signal by binding to its receptor, Fas. FasL is expressed on the cell surface of activated T-cell and natural killer (NK) cell. It has been shown that the FasL can be released from the cell surface by metalloproteinase. The serum soluble FasL (sFasL) is increased in some patients with NK cell lymphoma/large granular lymphocytic leukemia. We have recently seen a patient with recurrent B-cell lymphoma accompanied with an increased serum sFasL level after autologous peripheral blood stem cell transplantation. The sFasL was markedly decreased with the tumor regression induced by the chemotherapy. We present here the first case of an elevated serum sFasL level associated with B-cell lineage malignancy and discuss the possible clinical value of sFasL.

The reasons for differences in outcome between groups of patients with diffuse large cell lymphoma (DLCL) defined by clinical prognostic factors are largely unknown. Measures of cell proliferation may offer a biological explanation for these differences. This study tested the hypothesis that these survival differences between the groups defined by established prognostic factors were due to the proliferative index. The bromodeoxyuridine labeling index (LI), a measure of the S-phase fraction, was prospectively determined on fresh tumor specimens obtained at initial diagnosis in 80 patients with DLCL seen between 1986-1993 at a single institution. Patients were grouped using prognostic factors that were significant in a univariate analysis as well as the International Index (IPI). The LI in each of these groups was compared to determine whether the differences in outcome between the groups could be explained by differences in the LI. The median LI for all patients was 5.1% (range: 0.1-25%). When the predictive effect of the LI on response and survival was analyzed, the LI did not correlate with complete response or disease-free survival (DFS). There was a trend, however, for patients with a lower LI to have a poorer overall survival (p=0.06). When the patients were analyzed using the International Index (IPI), the mean LI for patients in the low-risk, low-intermediate, high-intermediate and high risk groups was 7.1%, 10.0%, 6.4% and 6.6% respectively (p=0.41). When analyzed separately, there was no significant difference in the LI for any of the patient groups defined by significant prognostic factors. The only difference in the LI was that the median LI in patients with T-cell DLCL was significantly lower than the LI in patients with B-cell DLCL (p=0.001) and these patients had an inferior complete response rate (p=0.001), disease-free survival (p=0.003) and overall survival (p=0.015). In this study, the LI, a measure of lymphoma cell proliferation, was not a significant prognostic factor for response, disease-free survival or overall survival. Furthermore, the LI did not explain the differences in outcome between patient groups defined by the IPI. However, a lower LI seen in patients with T-cell DLCL may account for their poorer response to therapy and inferior survival when compared to patients with B-cell DLCL.

We report here a 71-yr-old Japanese woman who presented with severe anasarca and hypoalbuminemia. She had a postmortem diagnosis of intravascular large B-cell lymphoma, which is a rare type of lymphoma characterized by an intravascular proliferation of lymphoma cells. Severe generalized edema was thought to be attributed to vascular and/or lymphatic obstruction due to proliferation of lymphoma cells within the lumina and/or an increase in catabolism induced by tumor proliferation.

CD3 engagement has been used as a surrogate for antigen-specific stimulation to trigger T cell effector functions. Exogenous IL-2 has been used to prolong and amplify CD3-induced T cell activation. Previous studies have been shown that CD3 reactivity is increased in cancer patients with preactivated (> 10% HLA-DR+) T cells in the peripheral blood. In this study, we report 9 courses of a single infusion of anti-CD3 mAb (OKT3) followed by continuous infusion of intermediate dose IL-2 in 4 cancer patients [2 multiple myeloma (MM), 1 B-cell lymphoma (NHL), 1 metastatic melanoma (ME)] with advanced disease and > 10% HLA-DR+ T cells in the peripheral blood. An increase of lymphocytes, equally distributed between CD4+ and CD8+ subsets, was observed during treatment. Activation was phenotypically documented by the emergence of CD25+ cells in the peripheral blood. Unexpectedly, functional studies [including proliferation to mitogens (PHA, OKT3) and cytotoxicity assays (NK and LAK activities)] did not parallel phenotypic data and a slight decrease of all functions was observed after OKT3 and IL-2 treatment. OKT3 and IL-2 infusions were well tolerated and no limiting toxicity was observed. The treatment did not revert tumor progression in the 2 patients with progressive disease (NHL, ME) and had only minimal effects in the 2 MM patients with stable disease. These data indicate that the sequential administration of OKT3 and IL-2 had no anti-tumor activity in this small series of patients with advanced cancer who were selected for treatment because of an increased number of HLA-DR+ T cells in the peripheral blood. A discrepancy was observed between the emergence of CD25+ T cells and the clinical outcome.

Certain low grade B-cell lymphoproliferative disorders can be mistaken for each other morphologically, particularly when there is partial lymph node involvement. We encountered two cases of chronic lymphocytic leukemia, in which the interfollicular growth pattern and the pale appearance of the neoplastic proliferation in the lymph nodes led to a misclassification as monocytoid B-cell lymphoma. The correct diagnosis was established, however, when the lymph node morphology was carefully reexamined, with the knowledge of the clinical history, peripheral blood findings, and bone marrow data. The immunophenotype of the neoplastic cells in the peripheral blood (CD5, CD23, weak fluorescence intensity of surface immunoglobulin and CD22) and the lymph node immunohistochemistry (weak L26 staining, strong MT1 positivity) confirmed the diagnosis of chronic lymphocytic leukemia. These two cases demonstrate the necessity of a systematic approach to lymph node morphology and the utility of a multiparameter approach in the diagnosis of lymphoproliferative disorders.

We serially measured the serum levels of soluble interleukin-2 receptor (sIL-2R) and soluble CD8 (sCD8) in 36 patients with malignant lymphoma (33 non-Hodgkin's lymphoma cases and three Hodgkin's disease cases). The level of serum sIL-2R was significantly elevated in patients with active disease (18) compared to those in remission (18), and correlated with the clinical stage of the lymphoma. The temporal profile of the sIL-2R level reliably represented the disease status, which was judged clinically, during the course of the disease. In three patients, the tumor bulk paralleled the sIL-2R level. On the other hand, a less significant correlation was found between the serum sCD8 level and disease activity. The serial measurement of sCD8 appeared to be less useful for monitoring the disease activity, although there was a significant correlation between the sCD8 and sIL-2R levels. This study indicates that serial measurement of the serum sIL-2R level may be useful for monitoring the tumor burden in response to treatment and for early detection of disease progression in malignant lymphoma.

We have analysed the immunological profile of cells from 194 patients with a B-cell disorder associated with circulating hairy or villous lymphocytes. These included: 69 typical HCL, 25 HCL-variant and 100 splenic lymphoma with villous lymphocytes (SLVL). All cases were HLA-DR+, CD19+, CD2- and most expressed Smlg with light chain restriction. The kappa/lambda ratios were: HCL, 1.2; SLVL, 1.5; and HCL-variant, 0.55. The majority were FMC7+ (89-96% of cases) and membrane CD22+ (73-98% of cases) and often negative with CD5 and CD23, markers characteristic of chronic lymphocytic leukemia. CD24 was variably expressed ranging from 21% of cases in HCL-variant to 60% in HCL and 89% in SLVL; CD10 and CD38 were positive in one third of SLVL but usually negative in HCL and HCL-variant. Of the four markers considered typical of HCL, CD11c, CD25, HC2 and B-ly-7, CD25 and HC2 were consistently negative in HCL-variant and a minority of SLVL cases expressed CD25 or HC2+ or B-ly-7+; CD11c was positive in all three disorders (47 to 97% of cases). Based on the most common phenotype of typical HCL: CD11c+, CD25+, HC2+ and B-ly-7+, we propose a scoring system which considers the reactivity with each of these four markers and gives 1 point if positive and 0 points if negative. Scores range from 4 (typical of HCL) to 0 (atypical of HCL). 98% of HCL had high scores (3 or 4) whereas 88% of HCL-variant and 77% of SLVL scored 1 or 2 and no single case scored 3 or 4.(ABSTRACT TRUNCATED AT 250 WORDS)

A total of 541 consecutive patients treated between 1975 and 1985, 449 with B-lymphoma and 92 with peripheral T-lymphoma, excluding adult T-cell leukemia/lymphoma (ATL), termed peripheral non-ATL T-lymphoma, were analysed. Clinicopathological features that were predominantly associated with B-lymphoma were low and intermediate grades (defined by the Working Formulation), diffuse large cell type, stage II disease, bulky disease, favourable extranodal sites that are defined as a group of primary tumors such as the eye, Waldeyer's ring, thyroid, and stomach, while other features predominantly associated with peripheral non-ATL T-lymphoma were high grade pathology, diffuse mixed-cell and immunoblastic type, systemic "B" symptoms, poor performance status (PS), generalized lymphadenopathy, involvement of organs such as liver, skin, and nose, leucocytosis, and a high levels of serum alkaline phosphatase. The survival curve for B-lymphoma was better (P < 0.01) than that for peripheral non-ATL T-lymphoma. Multivariate analysis revealed that the major prognostic factors were pathology, stage, and primary site for B-lymphoma, while stage, PS, and total protein levels were important for peripheral non-ATL T-lymphoma. These results indicate that B- and peripheral non-ATL T-lymphomas appear to have different biological characteristics.

Autoreactive B cells account for a substantial part of the B-cell repertoire. They frequently secrete polyspecific natural autoantibodies, which probably bind with low affinity to the different antigens they recognize and which express germinal genes. The role of this pre-immune repertoire still remains to be defined but it has been suggested that it participates in the elimination of cell breakdown products, serves as a first barrier of defense or acts as a template upon which antigen driven selection and somatic recombinations could induce the emergence of high affinity induced antibodies. The present study, reviews the evidence favouring the idea that this autoreactive B-cell repertoire, which expresses a restricted set of V genes, frequently undergoes malignant transformation. This evidence arises from the study of the autoantibody activity and V gene usage in three different models of B-cell malignancies namely monoclonal immunoglobulins; chronic lymphocytic leukemia; and follicular non-Hodgkin's lymphomas.