An international multicenter retrospective analysis of patients with extranodal marginal zone lymphoma and histologically confirmed central nervous system and dural involvement

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty-six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26-78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2-year progression-free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2-year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas

AbstractMore active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days −8 to −3). Gemcitabine was infused continuously at 10 mg/m2/minute over 4.5 hours (days −8 and −3). Busulfan dosing targeted 4000 μM-minute/day (days −8 to −5). Melphalan was infused at 60 mg/m2/day (days −3 and −2). Patients with CD20+ tumors received rituximab (375 mg/m2, days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography–positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation

Radiation Induces Acute Alterations in Neuronal Function

Every year, nearly 200,000 patients undergo radiation for brain tumors. For both patients and caregivers the most distressing adverse effect is impaired cognition. Efforts to protect against this debilitating effect have suffered from inadequate understanding of the cellular mechanisms of radiation damage. In the past it was accepted that radiation-induced normal tissue injury resulted from a progressive reduction in the survival of clonogenic cells. Moreover, because radiation-induced brain dysfunction is believed to evolve over months to years, most studies have focused on late changes in brain parenchyma. However, clinically, acute changes in cognition are also observed. Because neurons are fully differentiated post-mitotic cells, little information exists on the acute effects of radiation on synaptic function. The purpose of our study was to assess the potential acute effects of radiation on neuronal function utilizing ex vivo hippocampal brain slices. The cellular localization and functional status of excitatory and inhibitory neurotransmitter receptors was identified by immunoblotting. Electrophysiological recordings were obtained both for populations of neuronal cells and individual neurons. In the dentate gyrus region of isolated ex vivo slices, radiation led to early decreases in tyrosine phosphorylation and removal of excitatory N-methyl-D-aspartate receptors (NMDARs) from the cell surface while simultaneously increasing the surface expression of inhibitory gamma-aminobutyric acid receptors (GABAARs). These alterations in cellular localization corresponded with altered synaptic responses and inhibition of long-term potentiation. The non-competitive NMDAR antagonist memantine blocked these radiation-induced alterations in cellular distribution. These findings demonstrate acute effects of radiation on neuronal cells within isolated brain slices and open new avenues for study

Notch1 activation confers transforming properties to primary human melanocytes and promotes human melanoma progression

The Notch signaling pathway is a highly conserved signaling pathway that was originally characterized for its function in influencing cell fate and differentiation. However, more recent evidence has well established the role of Notch activation in several cancers. Active Notch has been shown to cooperate with viral oncoproteins in the transformation of human cell lines. Despite these observations, the role of Notch signaling in human melanoma development and melanocyte transformation remains unknown. Here, we show that the Notch signaling pathway is activated in melanoma cells but not in normal melanocytes. Lentiviral mediated expression of active Notch1 in melanocytes results in altered morphology, enhanced growth, focus formation, and changes in gene expression. Constitutive Notch1 activation enhances melanoma cell proliferation in vitro and in vivo in SCID mice. Inhibition of the Notch signaling pathway suppresses the growth of melanoma cells both in vitro and in vivo while sparing normal melanocytes. Activation of Notch1 signaling also enables melanoma cells from primary lesions to acquire metastatic capability. Furthermore, the oncogenic effect of Notch1 on primary melanoma cells is mediated by β-catenin, which is upregulated following Notch1 activation. MCAM, a cell adhesion molecule that promotes melanoma progression and metastasis, is upregulated by constitutive Notch activation in both melanocytes and melanoma cells. We identified a CSL binding consensus sequence within MCAM\u27s promoter and illustrate that CSL is capable of binding an oligonucleotide based on the MCAM promoter sequence in vitro. Finally, expression of active Notch1 in normal melanocytes induces anchorage independent growth in vitro, a hallmark of transformed cells. Our data illustrate that active Notch1 protein alone is capable of conferring transforming properties to normal melanocytes in vitro and promoting the progression of primary melanoma

Notch1 activation confers transforming properties to primary human melanocytes and promotes human melanoma progression

The Notch signaling pathway is a highly conserved signaling pathway that was originally characterized for its function in influencing cell fate and differentiation. However, more recent evidence has well established the role of Notch activation in several cancers. Active Notch has been shown to cooperate with viral oncoproteins in the transformation of human cell lines. Despite these observations, the role of Notch signaling in human melanoma development and melanocyte transformation remains unknown. Here, we show that the Notch signaling pathway is activated in melanoma cells but not in normal melanocytes. Lentiviral mediated expression of active Notch1 in melanocytes results in altered morphology, enhanced growth, focus formation, and changes in gene expression. Constitutive Notch1 activation enhances melanoma cell proliferation in vitro and in vivo in SCID mice. Inhibition of the Notch signaling pathway suppresses the growth of melanoma cells both in vitro and in vivo while sparing normal melanocytes. Activation of Notch1 signaling also enables melanoma cells from primary lesions to acquire metastatic capability. Furthermore, the oncogenic effect of Notch1 on primary melanoma cells is mediated by β-catenin, which is upregulated following Notch1 activation. MCAM, a cell adhesion molecule that promotes melanoma progression and metastasis, is upregulated by constitutive Notch activation in both melanocytes and melanoma cells. We identified a CSL binding consensus sequence within MCAM\u27s promoter and illustrate that CSL is capable of binding an oligonucleotide based on the MCAM promoter sequence in vitro. Finally, expression of active Notch1 in normal melanocytes induces anchorage independent growth in vitro, a hallmark of transformed cells. Our data illustrate that active Notch1 protein alone is capable of conferring transforming properties to normal melanocytes in vitro and promoting the progression of primary melanoma

Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1

The requirement for Notch signaling in vasculogenesis and angiogenesis is well documented. In a previous study, we showed that activation of the Notch pathway in endothelial cells induces differentiation-associated growth arrest; however, the underlying mechanism remains to be elucidated. Here, we show that activation of the Notch pathway by either stimulation of cell surface Notch receptors with crosslinked soluble delta-like 4 (sDll4)/Jagged1 (sJag1) or constitutive expression of the Notch1 intracellular domain (N(IC)) suppresses endothelial cell proliferation. This suppression is mediated by the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Following Notch1 activation, both pathways were suppressed in endothelial cells, and alterations in MAPK or PI3K/Akt pathway activity reversed Notch1-induced growth inhibition. Furthermore, we found the effect of Notch1 on endothelial cells to require Mastermind-like (MAML). Overexpression of a dominant-negative mutant of MAML1 antagonized the effects of activated Notch1 on the MAPK and PI3K/Akt pathways. Ectopic expression of Hairy/Enhancer of Split 1 (HES1) consistently reproduced the inhibitory effect of N(IC) on endothelial cell proliferation. Together, our data demonstrate that the Notch/MAML-HES signaling cascade can regulate both MAPK and PI3K/Akt pathways, which suggests a molecular mechanism for the inhibitory effect of Notch signaling on endothelial cell proliferation

Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression

Cellular signaling mediated by Notch receptors results in coordinated regulation of cell growth, survival, and differentiation. Aberrant Notch activation has been linked to a variety of human neoplasms. Here, we show that Notch1 signaling drives the vertical growth phase (VGP) of primary melanoma toward a more aggressive phenotype. Constitutive activation of Notch1 by ectopic expression of the Notch1 intracellular domain enables VGP primary melanoma cell lines to proliferate in a serum-independent and growth factor-independent manner in vitro and to grow more aggressively with metastatic activity in vivo. Notch1 activation also enhances tumor cell survival when cultured as three-dimensional spheroids. Such effects of Notch signaling are mediated by activation of the mitogen-activated protein kinase (MAPK) and Akt pathways. Both pathways are activated in melanoma cells following Notch1 pathway activation. Inhibition of either the MAPK or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway reverses the Notch1 signaling-induced tumor cell growth. Moreover, the growth-promoting effect of Notch1 depends on mastermind-like 1. We further showed that Notch1 activation increases tumor cell adhesion and up-regulates N-cadherin expression. Our data show regulation of MAPK/PI3K-Akt pathway activities and expression of N-cadherin by the Notch pathway and provide a mechanistic basis for Notch signaling in the promotion of primary melanoma progression