Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL).

BACKGROUND: Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. PATIENTS AND METHODS: A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. RESULTS: None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab.

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

Suppression of genetic resistance to bone marrow grafts and natural killer activity by administration of fat emulsion.

Graft rejection is one of the major obstacles to successful bone marrow transplantation (BMT). If resistance to marrow grafting could be avoided, BMT could be used widely in treatment of hematological and immunological disorders. There has been evidence that natural killer (NK) cells play a major role in genetic resistance to BMT and that macrophages are also involved in genetic resistance. Agents toxic to macrophages such as silica and carrageenan have been found to have a suppressive effect on genetic resistance to BMT. Parenteral fat emulsions are known to accumulate in macrophages and to impair various functions of macrophages and those of the reticuloendothelial system. We show here that the administration of a fat emulsion, Intralipos 20%, to recipient mice can suppress genetic resistance to bone marrow grafts and NK cell activity probably through the impairment of the macrophage function. The administration of the fat emulsion might be a new tactic in conditioning protocols for human BMT in the future.

Several marker analyses of T-lymphoma cells in eight Japanese adults.

Lymphoma cells in eight adult Japanese patients with no evidence of overt leukemia throughout their clinical course were demonstrated to be of T-cell nature by combining studies of various immunologic cell surface markers and cytochemistry. The histologic diagnosis of these patients was diffuse histiocytic lymphoma in four patients, poorly differentiated lymphocytic lymphoma in two patients and mixed histiocytic and lymphocytic lymphoma in two patients, according to Rappaport's classification. In seven of the eight patients, the malignant appearance and the large number of E-rosetting cells readily led to the diagnosis of T-cell lymphoma. Human Ia-like antigens were unexpectedly detected on the malignant T cells in seven of the eight patients. TdT activity was elevated in two of the four patients tested. Acid phosphatase activity was always observed in the neoplastic T-cells, and this activity was tartrate resistant. Focal activity of acid alpha-naphthyl acetate esterase was detected in the malignant cells with somewhat mature appearances, but large immature cells had no or weak dispersed activity. Except for E-rosetting ability, malignant T-cells showed such variable properties that multiple marker analyses seem to be necessary in the diagnosis and the prediction of prognosis of these disorders. Frequent occurrence of T-cell malignancy in Japan was also discussed.

Immunohistochemical analysis of peripheral T-cell lymphoma in Japanese patients.

The authors immunohistochemically analyzed the phenotype of 40 cases of peripheral T-cell lymphoma, including 12 adult T-cell leukemia/lymphoma (ATL) cases. Molecular genetic analysis of the T-cell receptor beta-chain and immunoglobulin heavy chain genes were also applied to cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-like lymphoma and so-called Lennert's lymphoma. Twenty non-ATL lymphomas expressed a helper/inducer phenotype, whereas only one extranodal case expressed a suppressor/cytotoxic phenotype. Three cases had a CD4-CD8- phenotype, and two cases a CD4+CD8+phenotype. No specific relationship between morphologic characteristics (LSG classification) and phenotype was found among non-ATL lymphomas. Six of eight AILD-like lymphomas had a helper/inducer phenotype. Monoclonality of neoplastic T-cells was demonstrated in six of the seven cases of AILD-like lymphoma by molecular genetic analysis. Two cases of Lennert's lymphoma also showed a helper/inducer phenotype and rearrangement of the T-cell receptor beta-chain gene. Serologically defined ATL cases had a helper/inducer phenotype except in one case that expressed both CD4 and CD8. None of the ATL cases had the CD7 antigen in this study using WT 1 as a CD7 antibody, which is in contrast with the non-ATL lymphomas in which 13 of 25 cases expressed CD7. CD25, strongly detectable in all ATL cases, was negative or weakly expressed in non-ATL lymphomas. These facts suggest that non-ATL and ATL are in the different biologic state, probably resulting from the integration of human T-cell leukemia virus type I (HTLV-I), although both are derived from helper/inducer T-cells.

Primary mediastinal large B-cell lymphoma: a comparative study with nodular sclerosis-type Hodgkin's disease.

The clinicopathological features of 10 patients with primary mediastinal large B-cell lymphoma (PMLBCL) are described. The patients were aged 19 to 63 years, with a median age of 25.5 years. There were 5 men and 5 women. All patients presented with chest symptoms, and 6 presented with superior vena cava syndrome. Nine patients had bulky mediastinal tumors. The disease was confined within the thorax and contiguous lymph nodes, although multiple liver tumors were observed in 1 patient. Laboratory findings included high lactate dehydrogenase levels and elevated C-reactive protein levels. The soluble interleukin 2-receptor level was high in 6 patients tested. A comparative study of PMLBCL and nodular sclerosis-type Hodgkin's disease (NS-HD) with a mediastinal mass revealed substantial overlap in clinical features. Histopathological examination of biopsy specimens of PMLBCL revealed clusters of CD20+ large cells; however, CD30+ Hodgkin/Reed-Sternberg-like cells were occasionally seen, raising the potential to misdiagnose PMLBCL as NS-HD. The patients with PMLBCL were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), biweekly CHOP, or MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin) regimen, and 6 received consolidation radiotherapy to the involved field. With the exception of 1 patient who was primarily refractory to therapy, 9 patients (90%) achieved complete response and 7 (70%) remain in continuous remission with a mean follow-up of 24 months.

Establishment of a near-tetraploid B-cell lymphoma line with duplication of the 8;14 translocation.

The neoplastic cells of a patient with diffuse histiocytic lymphoma were grown in three systems: Soft agar, liquid culture, and by heterotransplantation into the nude mouse. In each case, the growing cells were shown to bear the same immunoglobulin heavy and light chain type as the original neoplastic cells (IgM-lambda). In both the liquid culture and nude mouse heterotransplant tumors, karyotypic analysis revealed the presence of pseudodiploid and near-tetraploid metaphases bearing one and two copies of an 8;14 translocation, respectively. From the liquid culture separate clones of pseudodiploid and near-tetraploid cells were isolated in soft agar, and separate cell lines SK-DHL2A and SK-DHL2B were established. Studies comparing the proliferative characteristics of the two lines showed no difference in cell population doubling time or clonigenicity in soft agar. Hence, the presence of two copies of the translocated material did not confer a proliferative advantage on cells containing it. Theses lines may be valuable in future studies of cell proliferation and oncogenesis in the human immune system.

An efficient screening approach for anti-Microcystis compounds based on knowledge of aquatic microbial ecosystem.

To improve the efficiency of screening for anti-Microcystis compounds, we planned to use algae-lysing bacteria that kill the organisms of water blooms. A two step-screening process was carried out, i.e., the screening of algae-lysing bacteria and the selection of anti-Microcystis producers from the bacteria. Sources for the isolation of the bacteria were a co-cultivated fluid of a water sample with axenic Microcystis viridis, a water sample collected in a water bloom season, and a water bloom sample. The water bloom sample was the best source for the isolation of the algae-lysing bacteria and such bacteria were shown to exhibit potent activity. Seventeen strains out of 20 isolated algae-lysing bacteria produced anti-Microcystis activities, and one of the principles was the previously reported argimicin A. These results indicate that algae-lysing bacteria in water blooms may be good sources for potent and selective anticyanobacterial compounds.

[Angiocentric lymphoma associated with anemia secondary to parvovirus B19 infection].

A 50-year-old woman was admitted to our hospital in May 1993 because of papules, cervical lymphadenopathy and interstitial pneumonia. Oxygen inhalation and pulse therapy of corticosteroid were started. A biopsy of the left inguinal lymphnode showed T zone enlargement and marked vascularization with polymorphous atypical lymphoblasts, consistent with angiocentric lymphoma (immunohistochemically T cell type). In situ hybridization with EBER-1 did not show association of EB virus. She was subsequently treated with ProMACE-CytaBOM successfully, but anemia had progressed before that treatment showing a reticulocyte count 0/1000, LDH 870 U/l, positive direct Coombs test. Bone marrow aspiration revealed red cell aplasia and the existence of giant pronormoblasts. The hemoglobin dropped to the level of 4.7 g/dl, requiring anabolic steroid and frequent blood transfusion. Parvovirus B19-specific antibodies were negative initially by western blot assay, but IgM antibody appeared after 35 days and IgG after 71 days. In August anemia improved following a reticulocyte burst and recovery of bone marrow erythroblasts. This patient is the first reported case of angiocentric lymphoma complicated with severe anemia, perhaps resulting from autoimmune hemolytic process and parvovirus B19 infection.

[Malignant lymphoma following operation and chemotherapy of small cell lung carcinoma].

A 57-year-old man was admitted with systemic lymphadenopathy. He had undergone resection for small cell lung carcinoma and received chemotherapy 6 years previously. A specimen of swollen lymph nodes showed malignant lymphoma. Surface marker analysis revealed the lymphoma to have the same characteristics as lymphoblastic lymphoma (LBL). He received combination chemotherapy, but marked resistance was recognized. His condition deteriorated rapidly and died. Having the characteristics of LBL on lymphoma at an older age and severe drug-resistance suggests that this lymphoma might have been a second malignancy due to preceding chemotherapy.

Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b(+)/F4/80(+) myeloid cell recruitment.

Activation of the fibrinolytic system during lymphoma progression is a well-documented clinical phenomenon. But the mechanism by which the fibrinolytic system can modulate lymphoma progression has been elusive. The main fibrinolytic enzyme, plasminogen (Plg)/plasmin (Plm), can activate matrix metalloproteinases (MMPs), such as MMP-9, which has been linked to various malignancies. Here we provide the evidence that blockade of Plg reduces T-cell lymphoma growth by inhibiting MMP-9-dependent recruitment of CD11b(+)F4/80(+) myeloid cells locally within the lymphoma tissue. Genetic Plg deficiency and drug-mediated Plm blockade delayed T-cell lymphoma growth and diminished MMP-9-dependent CD11b(+)F4/80(+) myeloid cell infiltration into lymphoma tissues. A neutralizing antibody against CD11b inhibited T-cell lymphoma growth in vivo, which indicates that CD11b(+) myeloid cells have a role in T-cell lymphoma growth. Plg deficiency in T-cell lymphoma-bearing mice resulted in reduced plasma levels of the growth factors vascular endothelial growth-A and Kit ligand, both of which are known to enhance myeloid cell proliferation. Collectively, the data presented in this study demonstrate a previously undescribed role of Plm in lymphoproliferative disorders and provide strong evidence that specific blockade of Plg represents a promising approach for the regulation of T-cell lymphoma growth.