BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma

We report that B cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is expressed in the normal human brain at approximately 10% of that in lymphatic tissues (tonsils and adenoids) and is produced by astrocytes. BAFF was regularly detected by enzyme-linked immunosorbent assay in brain tissue lysates and in normal spinal fluid, and in astrocytes by double fluorescence microscopy. Cultured human astrocytes secreted functionally active BAFF after stimulation with interferon-gamma and TNF-alpha via a furin-like protease-dependent pathway. BAFF secretion per cell was manifold higher in activated astrocytes than in monocytes and macrophages. We studied brain lesions with B cell components, and found that in multiple sclerosis plaques, BAFF expression was strongly up-regulated to levels observed in lymphatic tissues. BAFF was localized in astrocytes close to BAFF-R-expressing immune cells. BAFF receptors were strongly expressed in situ in primary central nervous system (CNS) lymphomas. This paper identifies astrocytes as a nonimmune source of BAFF. CNS-produced BAFF may support B cell survival in inflammatory diseases and primary B cell lymphoma.     

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.     

Report: workshop on mediastinal grey zone lymphoma

There are several indications that classical Hodgkin lymphoma (cHL) and at least a proportion of cases of Primary Mediastinal B cell Lymphoma (PMBL) are derived from B cells at similar stages of differentiation and share common pathogenic mechanisms. The first indication was the existence of mediastinal grey zone lymphomas as identified in the 4th International Symposium on HL, with clinical, histological and immunohistochemical features intermediate between cHL and PMBL. Second, both tumor types resemble a cell that is developmentally situated in-between the germinal center reaction and a plasma cell. Third, cHL and PMBL were found to have similar gene expression profiles, including the lack of immunoglobulin expression and low levels of B cell receptor signalling molecules, and the secretion of molecules like the chemokine TARC and the prominent expression of IL-13 receptors. Fourth, both entities were found to have common genomic aberrancies, notably in 2p15 and 9p24, the sites of the REL oncogene and the tyrosine kinase gene JAK2, respectively. Further comparison of both lymphoma types may provide further insight in the pathogenic mechanisms and allow the design of diagnostic algorithms to sort out the small number of so-called mediastinal grey zone lymphomas, that appear to be intermediate between PMBL and cHL.     

Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.     

The stromal cell marker SPARC predicts for survival in patients with diffuse large B-cell lymphoma treated with rituximab

The cellular composition of the tumor microenvironment may affect survival in diffuse large B-cell lymphoma (DLBCL). We performed immunostains for 2 stromal cell markers, CD68 and SPARC (secreted protein, acidic and rich in cysteine), in 262 patients with DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapies. Patients with any SPARC+ cells in the microenvironment had a significantly longer overall survival, and patients with high SPARC positivity in the microenvironment also had a significantly longer event-free survival. Survival differences were mainly due to the prognostic effect of SPARC+ cells in activated B-cell (ABC)-type DLBCL, with no effect found in the germinal center B-cell-type DLBCL. Of clinical features examined, only the number of extranodal sites was significantly associated with SPARC expression. Multivariate analysis revealed that SPARC expression predicted patient survival independent of the International Prognostic Index or tumor cell of origin. SPARC expression in the microenvironment of DLBCL can be used for prognostic purposes, determining a subgroup of patients with ABC DLBCL who have significantly longer survival. More aggressive chemotherapy protocols should be considered for patients with ABC DLBCL without SPARC+ stromal cells. CD68 expression by cells in the microenvironment did not predict survival.     

Clinical and dosimetric analysis of 469 prostate cancer patients treated in France in 2005 by permanent implant brachytherapy using the Iodin 125 seeds IsoSeed Bebig: report to the French Economic committee of health products (CEPS)]

A French decree of February 3rd 2005, allowed the Iodin 125 seeds from several companies to be reimbursed after a permanent implantation brachytherapy for a prostate cancer. Within this frame, the French "Comité économique des produits de santé" (CEPS; Economic committee for health products) made mandatory the annual writing and publication of a follow-up study with three main aims; make sure that the seeds were used for prostate cancer patients with criterias corresponding to the national recommendations, analyze the quality of the dosimetric data, and report all side effects, complications and possible accidents. We therefore report here a clinical and dosimetric analysis of 469 patient cases treated in France in nine centers in 2005 with the Iodin 125 IsoSeed Bebig. This analysis shows that: 1) The national recommendations for selecting patients for exclusive prostate brachytherapy have been taken into account in 97% of the cases; 2) The dosimetric quality criterias totally fulfilled the recommendations in a large majority of cases; the intra-operative D90 was found to be superior to 145 Gy in 98% of the patients, and the intra-operative V100 was superior to 95% in 96% of the cases; 3) The early toxicity (mainly urinary) was found to be at the lower range of what is reported in the literature, with in particular a retention rate of 2.4%.     

Biochemical detection of novel anaplastic lymphoma kinase proteins in tissue sections of anaplastic large cell lymphoma.

The (2;5) translocation, found in many T-cell and null cell anaplastic large cell lymphomas (ALCLs), creates a hybrid gene encoding the 80-kd NPM-ALK protein. Typically neoplastic cells show labeling of both nucleus and cytoplasm for anaplastic lymphoma kinase (ALK) and for the N-terminus of nucleophosmin (NPM). However, 10-20% of cases exhibit cytoplasmic labeling only for ALK, indicating the probable presence of variants of the classical (2;5) translocation that do not involve the NPM gene. We report the detection (using Western blotting and an in vitro kinase assay) in seven such ALCL cases, of ALK proteins with molecular masses of 85 kd, 97 kd (one case exhibiting a (2;3)(p23;q21) translocation), 104 kd (one case carried a (1;2)(q21;p23) translocation), and 113 kd. Tyrosine kinase activity was detected in four of these proteins, but the N-terminal portion of NPM could not be detected. These results show how ALCL cases that express ALK proteins other than NPM-ALK can be detected by sensitive biochemical techniques using routine cryostat sections.