This survey at a whole institution underlines the high number of cases of invasive aspergillosis among nonneutropenic patients, with an overall mortality rate that was significantly higher than that for neutropenic patients.

IntroductionSeveral subsets of stromal cells, in particular follicular dendritic cells (FDCs) and fibroblastic reticular cells (FRCs), are found within secondary lymphoid organs where they play a key role in the initiation and maintenance of efficient immune responses. FDCs are restricted to germinal centers (GCs) and allow B-cell migration, selection, and differentiation through a complex set of survival factors including BCR-mediated signal, chemokines, cytokines, and adhesion molecules. 1 B-cell selection relies on an affinitybased competition for the fixation of antigen, presented as immune complexes by CD21 hi CD35 hi FDCs. Only B cells with high-affinity BCR receive survival signals from FDCs, capture antigen, and present it to CD4 ϩ T cells that deliver additional survival and maturation signals. 2,3 Conversely, FRCs are less well characterized. They are tightly interconnected in the paracortex of lymph nodes (LNs) where they secrete and ensheath various extracellular matrix components, thus building an intricate network of conduits, connecting afferent lymphatic vessels to high endothelial venules (HEVs). 4 This conduit system allows the rapid transport of soluble antigens from the periphery to the resident myeloid immature dendritic cells (DCs). 5 In addition, part of this reticular network called cortical ridge favors B, T, and DC recruitment and reciprocal interactions, in particular through the production of constitutive and inflammatory chemokines. 6,7 CCL19, CCL21, and CXCL12 are involved in the migration of mature myeloid DCs and naive B and T cells, whereas CXCL9, CXCL10, and CCL5 are crucial for the migration of activated T cells and plasmacytoid DCs. [8][9][10] Strikingly, CCL19 and CCL21 are not synthesized by human HEVs but rather by stromal cells in the T-cell zone. 11,12 These chemokines further reach luminal surface of HEVs by endothelial uptake and transcytosis. FRCs provide therefore a favorable and highly specialized lymphoid environment for immune cell migration and activation.The ontogeny of FRCs and FDCs remains unclear, but these cells are supposed to be of mesenchymal origin. LN organogenesis in the mouse relies on the interaction between CD45 Ϫ VCAM-1 ϩ ICAM-1 ϩ mesenchymal cells and CD45 ϩ CD4 ϩ CD3 Ϫ lymphoid tissue inducer cells in the LN anlagen. 13 A prominent role is attributed to lymphotoxin-␤ receptor (LT␤R) triggering by membrane-bound LT␣1␤2 (LT) and to tumor necrosis factor receptor 1 (TNFR1)/tumor necrosis factor-␣ (TNF). 14,15 Adult lymphoid tissues are highly dynamic structures that retain several features of embryonic organization. 16 Functional mouse FRCs able to construct a reticular meshwork and to secrete inflammatory chemokines could be generated in vitro by stimulation of LN-derived stromal cell lines using a combination of TNF and LT. 17 In vivo, transgenic expression of LT or injection of newborn LN-derived The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefo...

The blastic variant (BV) form of mantle cell lymphoma (MCL) is considered to be a very aggressive subtype of non-Hodgkin's lymphoma (NHL). In order to determine its clinico-biological features and response to therapy we studied 33 patients (17%) out of 187 suffering from MCL who were diagnosed with a BV of MCL. Blastic variant was diagnosed according to histopathological patterns, immunophenotyping, and bcl1 gene rearrangement and/or cyclin D1 overexpression. Three patients initially diagnosed with large cell NHL were classified as BV. Patients received front-line therapy including CHOP-like regimen or CVP (n = 29), or chlorambucil (n = 4) and CHOP or ESAP as second-line therapy. High-dose intensification with stem cell transplantation (SCT) was performed in 11 cases (autoSCT, n = 8; alloSCT, n = 3). All but two patients were in complete remission (CR) at the time of transplant (CR1, n = 5; CR2, n = 4). Clinical and biological characteristics did not differ from those of the common form of MCL. The median age was 62 years (29-80), with a sex ratio (M/F) of 2.6:1. Of the 33 patients, 66% had extranodal site involvement, 85% had an Ann Arbor stage IV, and 82% had peripheral lymphadenopathy. Circulating lymphomatous cells were seen in 48% of cases. Twelve patients (36%) entered a CR1 with a median duration of 11 months. Fifteen patients (46%) failed to respond and rapidly died of progressive disease. Second-line therapy led to a 26% (6/23) CR2 rate. Nine patients relapsed after high-dose therapy. Twenty-two of the 33 patients (66%) died of refractory or progressive disease. Median overall survival (OS) time was 14.5 months for the 33 BV patients as compared to 53 months for the 154 patients with a common form of MCL, P Ͻ0.0001. In the univariate analysis, OS was influenced by age, extranodal site involvement, circulating lymphomatous cells, and international prognosis index (IPI). In the multivariate analysis, only IPI affected OS: patients with IPI у2 had 8 months median OS as compared to 36 months median OS for patients with IPI Ͻ2, P = 0.003. Blastic variant is one of the worst forms of NHL. An improved recognition of BV of MCL is required, particularly in high-grade CD5 + NHL using immunophenotyping and bcl1 molecular study. Standard therapy using anthracycline or even high-dose intensification produce poor results and an alternative treatment should be proposed to such patients. Leukemia (2001) 15, 1785-1791.

Bleomycin-induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals were intranasally instilled with saline or bleomycin (0.5 mg in 100 microl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor-beta (TGF-beta) in BAL. Batimastat treatment was effective in reducing MMP-2 and MMP-9 activity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease.

A b s t r a c tRecent studies suggest that the incidence of primary central nervous system lymphomas (PCNSLs) is increasing. A few decades ago, PCNSLs accounted for only 1% of all primary intracranial neoplasms. Today, however, they represent between 2% and 6% of all primary brain neoplasms and more than 1% of all non-Hodgkin lymphomas. This trend does not seem totally explained by improved diagnostic techniques or by HIV infection. A substantial increase in PCNSLs among immunocompetent patients has been observed.'"* Most PCNSLs are characterized by a diffuse proliferation of large B cells. 7 Follow-up usually shows a rapid local relapse. Systemic dissemination has been described only rarely. The prognosis remains poor even though some long-term survival has been reported. 38The frequency of each histologic subtype is variable from 1 series to another, and little is known about their biologic characteristics. In a previous article, 9 we reported the major features of 51 AIDS-related PCNSLs. In the present study, we reviewed 72 PCNSLs occurring in immunocompetent patients and studied their clinical and morphologic characteristics, immunophenotype (including expression of bcl-2 and p53), and Epstein-Barr virus (EBV) status. We also studied the impact of these different variables on patient survival. Material and Methods PatientsSeventy-two PCNSLs were studied, including 40 in patients who were part of the lymphomes cerebraux primitifs

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Repeated exposure of mice to an aerosol of LPS can lead to pulmonary interstitial fibrosis and MMPs seem to be associated with this process.

CD56 expression has been reported previously in some non-Hodgkin's lymphoma (NHL) characterization. They principally involve the nasopharynx, are related to Epstein-Barr virus (EBV), and may be classified as either T- or non–T-natural killer (NK) cells according to CD3/T-cell receptor (TCR) status at the genomic or protein level. The present study reports three cases of non-nasal NK-NHL with the following characteristics: an agressive clinical behavior, heterogenous morphological data evoking pleomorphic T-cell malignant lymphoma, a non–T-NK phenotype using flow cytometry, and immunochemistry. The three cases were CD56+ without membrane expression of specific T markers (CD3, CD5, and TCR). Heterogenous results were observed concerning different antigens: CD2, CD4, CD8, CD16, CD94, CD122, TiA1, perforin, and granzyme B. There was no evidence of detectable clonal TCR gene rearrangement with polymerase chain reaction. No NK activity was detected in the two tested cases, and no relation was found with EBV. Multidrug resistance investigations suggest that agressive clinical findings could be related to MDR1 gene expression as confirmed by MDR1 mRNA detection, MDR1 gene product (Pgp) expression, and a functional multidrug resistance study using rhodamine efflux by flow-cytometry.