An overview of the current approaches to the management of patients with primary central nervous system lymphoma (PCNSL) is provided. Although accumulating evidence demonstrates that PCNSL is a curable type of brain tumor, in many cases establishing the diagnosis and overcoming chemotherapeutic resistance remain significant obstacles. The issue of treatment-related neurotoxicity is also a central consideration in treatment planning. The introduction of highly active antiretroviral therapy has had a major impact on this disease in that the incidence of AIDS-related central nervous system lymphoma, once highly prevalent in the 1980s and 1990s, has now virtually disappeared. However, the problem of diagnostic delays secondary to steroid effects, radiation-induced neurotoxicity and methotrexate resistance represent unique and important problems in this disease. The use of anti-CD20 antibody in this disease represents the first application of biologically based targeted therapies for PCNSL; however, the overall impact of this modality in brain lymphoma awaits further evaluation in ongoing studies The application of proteomic as well as gene expression technologies is yielding insights into PCNSL pathogenesis, in particular specific oncogenic pathways, which may be exploited to develop new therapies.
"Unlike systemic lymphoma, primary cerebral lymphoma (PCL) and primary intraocular lymphoma (PIOL) are subsets of primary central nervous system lymphoma (PCNSL), and they affect immunologically privileged organs. Both usually appear as a diffuse large B-cell non-Hodgkin lymphoma in which malignant lymphoid cell types not normally present in the brain or eye are detected . The internal tissues of the brain and eye are usually protected from the inflammatory processes mediated by the immune system. "
[Show abstract][Hide abstract] ABSTRACT: Background
Toll-like receptor (TLR) agonists have important properties that can be exploited for immunotherapy against tumors. Locally injected immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG-ODNs), which are TLR9 agonists, have shown promise in cancer models. Several studies have demonstrated that these motifs have immunologic effects similar to those of bacterial DNA and can stimulate monocytes, macrophages, dendritic, and B cells, which then produce several proinflammatory cytokines. However, these CpG-ODNs appear to produce opposite effects on tumor B cells.
In this study, we investigated the direct effects of a murine class B CpG (1826) ODNs on lymphoma B cells in vitro and in vivo, using mouse models of non-Hodgkin B lymphomas developing in immunoprivileged sites, specifically the brain and the eye, and in subcutaneous sites.
In vitro, CpG-ODNs produced antiproliferative and proapoptotic effects on lymphoma B cells. In vivo, it had an antitumor effect when injected into tumors in murine models of subcutaneous lymphoma (SCL) and primary cerebral lymphoma (PCL). However, its intravitreal administration into a primary intraocular lymphoma (PIOL) mouse model did not produce an antitumor effect. In vitro experiments using supernatant from mouse PIOL samples demonstrated that the PIOL molecular microenvironment inhibits the antiproliferative effect of CpG-ODNs on lymphoma B-cells.
Responsiveness to CpG stimulation differs in subcutaneous, cerebral, and ocular tumors, according to the tumoral and molecular microenvironment, and this should be considered for further therapeutic approaches.
Journal of Experimental & Clinical Cancer Research 04/2013; 32(1):18. DOI:10.1186/1756-9966-32-18 · 4.43 Impact Factor
"Primary central nervous system lymphoma has received more attention in recent years, especially for its unsatisfactory therapy and poor prognosis, resulting in increasing scientific awareness [4–6]. It is clear that its unsatisfactory therapy and poor prognosis are connected with the chemosensitivity and radiosensitivity [7, 8]. Special attention has been paid in recent years to factors related to the molecular biological characteristics of the tumor, in an attempt to predict and improve the prognosis. "
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to detect the expression of Ku80 in primary central nervous system lymphoma and to evaluate the relationship between Ku80 expression level and clinical outcomes. Thirty-eight patients with primary central nervous system lymphoma (PCNSL) were included in this retrospective study. The expression of Ku80 in tumor samples was determined by immunohistochemistry. One thousand neoplastic cells per specimen were counted. The expression levels were compared with the clinical data and statistically analyzed. The results of this study show that the expression of Ku80 can be found in the majority of PCNSLs. The mean expression level of Ku80 in 38 PCNSL is 64.1 ±24.5. A significant difference in Ku80 expression could be found between the age < 65 years group and age ≥ 65 years group (P = 0.006). Kaplan-Meier analysis revealed that patients who showed a high Ku80 expression had a significantly shorter median survival time (MST) than patients who had low Ku80 expression (P = 0.036). Patients' age, tumor location, and treatment protocol were significantly related to prognosis in PCNSL (P < 0.05). The expression of Ku80 was observed in the majority of PCNSLs. Ku80 was a predictive factor for survival in this study. In addition to Ku80, other clinical variables including age, tumor location and therapeutic protocol are correlated significantly with overall survival.
"Primary CNS lymphoma (PCNSL) is an aggressive brain tumor, representing 4% of intracranial neoplasms and 4–6% of extra-nodal lymphomas with a yearly incidence of 0–5 cases per 100,000 people, even if some registry studies suggest that its incidence in immunocompetent patients is progressively increasing. Its outcome remains unsatisfactory with a survival of less than 20–30% at 5 years and a median survival of 10–20 months  . This is caused by the little knowledge of the biologic and molecular features and by the small number of published clinical trials. "
[Show abstract][Hide abstract] ABSTRACT: Primary CNS lymphoma (PCNSL) is a rare and aggressive brain tumor with an unsatisfactory outcome. Therapeutic progress in this field is strongly conditioned by the limited biology and the molecular knowledge about this disease, which hamperizes the identification of new targeted therapies and the poor clinical conditions and performance status of patients, rendering very difficult their enrollment in prospective trials. Chemoradiation therapy is the most commonly used strategy for patients with PCNSL, which is associated with better efficacy rates, but also with high incidence of severe neurotoxicity. As a consequence, a dilemma in PCNSL treatment is the choice between strategies designed to intensify therapy to improve the cure rate, versus strategies of treatment de-escalation to avoid severe neurotoxicity. The efficacy of chemotherapy is strongly limited by the special functional and microenvironmental characteristics of the CNS, which is variably protected by the blood-brain barrier (BBB) and includes extensive chemotherapy sanctuaries where tumor cells grow undisturbed. Drugs exhibiting a good capability to cross the BBB and drugs that can be safely administered at high doses to obtain therapeutic concentrations in the CNS are the most commonly used in the treatment of PCNSL. Consolidation after chemotherapy represents the best role for radiotherapy. Since this tumor has an infiltrative nature, the whole brain should be irradiated, with increased risk of severe neurotoxicity. Some authorities are investigating in randomized trials the impact on outcome and neurotolerability of replacing consolidation radiotherapy with other strategies, like high dose chemotherapy supported by autologous stem cell transplantation. The rationale for the use of this strategy is the administration of high doses of cytostatics to achieve therapeutic concentrations in sanctuaries, CNS organs and lymphoma tissues and to overcome drug resistance mechanisms. Future therapeutic progresses in PCNSL will be based on the expansion of molecular and biological knowledge, the improvement of therapeutic efficacy and the prevention of iatrogenic neurotoxicity.
Best practice & research. Clinical haematology 03/2012; 25(1):119-30. DOI:10.1016/j.beha.2011.12.001 · 2.12 Impact Factor
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