Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) ؉ cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R ؉ highdose cytarabine. Responders received highdose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progressionfree survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.

Key Points Germline activating STAT3 mutations were detected in 3 patients with autoimmunity, hypogammaglobulinemia, and mycobacterial disease. T-cell lymphoproliferation, deficiency of regulatory and helper 17 T cells, natural killer cells, dendritic cells, and eosinophils were common.

Proteolysis is an intrinsic component of cutaneous wound repair and several matrix metalloproteinases have been shown to participate in various stages of this process. Therefore, we investigated the expression of a novel metalloproteinase, collagenase-3 (MMP-13), in normally healing cutaneous wounds and chronic venous ulcers. MMP-13 was expressed abundantly by fibroblasts deep in the chronic ulcer bed but was not detected in epidermis and all the acute wounds. The spatial expression of MMP-13 differed from that of collagenase-1 (MMP-1), which was prominently expressed by migrating keratinocytes and dermal cells located just beneath the wound surface. Northern blot hybridization did not reveal expression of MMP-13 by fibroblasts cultured on tissue culture plastic. In accordance with our in vivo findings, however, fibroblasts grown in a collagen gel produced MMP-13 mRNA abundantly. Our results suggest that MMP-13 can be induced in skin during wound repair after altered cell-matrix interactions. Although both MMP-1 and MMP-13 have the unique ability to degrade fibrillar collagens, their regulation and role during wound repair seem different. Collagenase-1 is critical for re-epithelialization, and MMP-13 most likely plays a role in the remodeling of collagenous matrix in chronic wounds.

Background and Purpose-Activation of transcription factor nuclear factor-B (NF-B) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-B after permanent MCAO (pMCAO) was investigated. Methods-Mice transgenic for a NF-B-driven ␤-globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-B and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate (PDTC), an NF-B inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-B. Results-pMCAO increased NF-B transcriptional activity to 260% (36.9Ϯ4.5 compared with 14.4Ϯ2.6; nϭ10; PϽ0.01) in the brain; this NF-B activation was completely blocked by PDTC (17.2Ϯ2.6; nϭ9; PϽ0.05). In p50 Ϫ/Ϫ mice, pMCAO resulted in 41% (18Ϯ3.2 mm 3 ; nϭ12) smaller infarcts compared with wild-type controls (32.9Ϯ3.8 mm 3 ; nϭ9; PϽ0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6Ϯ4.2 mm 3 ; nϭ8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-B was activated in neurons in the penumbral areas. Conclusions-NF-B is induced in neurons during

SummaryMantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early -based on the median observation time of 4 years -results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median eventfree survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680.

Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low-and high-risk groups. To determine how combination of rituximab with chemotherapy influences GCassociated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P ‫؍‬ .012; FFS, 59% vs 30%, P ‫؍‬ .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P ‫؍‬ ns; FFS, 68% vs 63%, P ‫؍‬ ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low-and intermediate-risk groups (OS, 84% vs 63%, P ‫؍‬ .030; FFS, 79% vs 52%, P ‫؍‬ .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC-and non-GC phenotypes in DLBCL. (Blood. 2007;109: [4930][4931][4932][4933][4934][4935]

Purpose: Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy. The aim of this study was to determine how combination of rituximab with chemotherapy influences TAM-associated clinical outcome. Experimental Design: Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with rituximab and cyclophosphamideAdriamycin-vincristine-prednisone regimen. Of them, 71received therapy at diagnosis and 25 at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months. Fourty-five patients previously treated with chemotherapy served as a control group. Results: Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients (P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was not reached for patients with high TAM content compared with 45 months for patients with low TAM scores (P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS, 97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did not correlate with outcome. Conclusions: The data suggest that highTAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.Follicular lymphoma (FL) is the second most common subtype of all non -Hodgkin lymphomas accounting for f20% of all adult cases in the western world. FL arises from B cells in the germinal center of lymphoid tissue. It is an indolent and a chemotherapy-sensitive disease, which is, however, considered rarely curable due to its propensity to relapse. Recently, however, a significant improvement of the outcome of patients has been obtained by combining a monoclonal anti-CD20 antibody, rituximab, with induction chemotherapy (1 -3), or by prolonging the remission with rituximab maintenance therapy (4, 5). Despite the advances, response to treatment varies substantially among individual patients and outcome is often unpredictable. Treatment is also costly. These facts raise the need to identify more accurately the patients who benefit from immunochemotherapy.In FL, a specific Follicular Lymphoma International Prognostic Index (FLIPI) has been proposed (6). Although FLIPI was developed before rituximab was established in the treatment of FL, it was recently shown to be a useful predictor of the outcome also in response to rituximab and cyclophosphamideAdriamycin-vincristine-prednisone (R-CHOP) regimen (7). In estimating the prognosis of FL, FLIPI seems to distrib...

The striking upregulation of endothelial ICAM-1 expression, functioning in concert with chemotactic factors, may cause granulocyte infiltration during the first 3 days after stroke. This study may support the usage and timing of antibody infusions to block endothelial adhesion molecules in an attempt to reduce leukocyte-induced damage in stroke.