Treatment Of CNS Disease Research Articles

715 Multipotent Astrocytes Mature into Neurons in the Adult Mammalian Brain

INTRODUCTION: For the past decade, neural stem/precursor cells native to the adult mammalian subventricular zone (SVZ) have been studied as an inducible source to generate newborn neurons and glia. Until now, however, there has been a surprising shortage of data characterizing the cellular nature of these multipotent precursors. In this study, we used morphological and electrophysiological methods to characterize the transitional events of neurogenesis as an astrocyte-like SVZ cell population developed into functional neurons. METHODS: Young postnatal and adult rats were killed, and astrocyte-like cells from the SVZ were harvested and cultured in media containing fibroblast-derived growth factor and epidermal growth factor. Under these conditions, these cells maintain their multipotentiality and proliferative capacity for extended passages in culture. Upon withdrawal of growth factors, however, spontaneous differentiation occurs. Immunohistochemical and whole-cell patch-clamp techniques were used to evaluate their differentiation into neuronal phenotypes over a period of 4 weeks. RESULTS: Withdrawal of growth factors resulted in both a dramatic change in morphologies and characteristic membrane property alterations. Within 2 to 3 days after withdrawal, multiple rapid cell divisions generated a cell phenotype similar to primitive neuroblasts. CONCLUSION: We describe here morphological and functional cellular transitions of neurogenic multipotent astrocytes. Large numbers of these self-renewing SVZ cells can be generated, and subsequently, these cells may eventually serve as a potential donor source in the treatment of CNS disease.

Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis.

To investigate the value of antemortem cognitive functioning in predicting postmortem evidence of HIV encephalitis (HIVE). Thirty-nine subjects were assessed during life with a comprehensive neuropsychological battery and went on to autopsy within 18 months of testing. Cognitive impairment was determined by blind clinical ratings, based on demographically corrected test scores. Presence of HIVE was based on postmortem immunocytochemical detection of the viral protein gp41 or by measurement of HIV RNA by PCR in multiple brain areas as well as by histopathologic evidence such as microgliosis, presence of multinucleated giant cells, and myelin pallor in several brain regions. The sensitivity and specificity of neurocognitive impairment in detecting the occurrence of HIVE were 67 and 92%. Eighteen of 19 subjects with antemortem neurocognitive impairment had evidence of HIV-related brain disease (positive predictive value = 95%). Neuropsychological assessment can help select HIV-positive patients for treatment of CNS disease.

Meningeosis leukaemica in adult acute lymphoblastic leukaemia.

This review addresses diagnosis of CNS involvement, incidence and treatment of CNS disease at time of diagnosis, prophylaxis and treatment of CNS relapse and risk factors for meningeal recurrence in adult acute lymphoblastic leukaemia (ALL). At the time of diagnosis meningeosis leukaemica is present in about 6% (1-10%) of the adult ALL patients with a higher incidence in ALL subgroups T-ALL (8%) and B-ALL (13 %). With the invention of early additional CNS directed therapy it no longer represents an unfavourable prognostic factor. In the absence of prophylaxis meningeal relapses occur in approximately one third of adults with ALL. A literature review including more than 4000 adult ALL patients showed for the different prophylactic treatment approaches the following CNS relapse rates: intrathecal therapy alone 13% (8-19%), intrathecal therapy and CNS irradiation 15% (6-22%), high dose chemotherapy 14% (10-16%), high dose chemotherapy and intrathecal therapy 8% (2-16%) and high dose chemotherapy, intrathecal therapy together with CNS irradiation 5% (1-12%). It became obvious that the early onset of intrathecal therapy and CNS irradiation and the continuation of intrathecal administrations throughout maintenance are essential. The most favourable results where achieved with high dose chemotherapy combined with intrathecal therapy and/or CNS irradiation. The majority of treatment regimens in adult ALL already include high dose chemotherapy in order to reduce the risk of bone marrow relapse. The outcome of patients with CNS relapse is still poor. Although a remission can be induced in the majority of patients (> 60%) it is usually followed by a bone marrow relapse and the survival is poor (< 5-10%). Bone marrow transplantation might be in adults at present the only curative approach.

High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia.

The application of high-dose treatment elements has an increasing importance in the therapy of acute lymphoblastic leukemia (ALL). High-dose methotrexate (HDMTX) has been introduced in clinical trials more than 20 years ago, since it has several theoretical advantages compared to conventional dose methotrexate. These trials revealed that the efficacy and toxicity of HDMTX depends on features such as dose level, infusion time, combination regimen and schedule of leucovorin rescue. Particularly the application of controlled leucovorin rescue and improved supportive care enabled the application of increasing doses of HDMTX in the treatment of childhood and adult ALL within a variety of schedules and at dose levels mostly ranging between 0.5 g/m2 and 5.0 g/m2. In childhood ALL, first devised to replace CNS irradiation in the prophylaxis of CNS relapse HDMTX has contributed to the reduction of bone marrow relapses particularly in low risk B-lineage ALL. In addition it proved to be an effective therapy element for prophylaxis and treatment of CNS disease. At least in low risk ALL CNS irradiation could be safely replaced by repeated cycles of HDMTX with additional intrathecal therapy. In adult ALL only few of the successful treatment approaches with HDMTX have been investigated up to now. The results indicate that HDMTX has a beneficial effect with regard to overall outcome in adult B-lineage ALL. It provides effective CNS prophylaxis in combination with intrathecal therapy. In mature B-ALL HDMTX proved to be one of the most effective treatment elements and contributed to an impressive improvement of outcome in this subgroup. For T-ALL however sufficient data do not exist either in childhood or in adult ALL. Since HDMTX is an effective treatment element with manageable acute and long-term toxicity, its role in the management of adult ALL should be explored more intensively.

Clinical significance of p53 mutations in newly diagnosed Burkitt's lymphoma and acute lymphoblastic leukemia: a report of 48 cases.

To correlate the presence of p53 mutations and initial characteristics, response to chemotherapy, and survival in newly diagnosed Burkitt's lymphoma (BL) and Burkitt's acute lymphoblastic leukemia (L3 ALL). Forty-eight patients with newly diagnosed BL or L3 ALL, most of whom were treated with very intensive regimens, including early CNS disease treatment, were studied. Detection of p53 mutations was made by single-strand conformation polymorphism (SSCP) analysis of exons 5 to 8 of the gene, and mutations were determined by direct sequencing of exons with abnormal SSCP findings. Comparison of outcome between mutated and nonmutated cases was made in all patients and also after excluding five patients who received therapeutic regimens considered as suboptimal and one patient who died of AIDS while in complete remission (CR), as those six patients had no p53 mutations. A point mutation was found in nine patients (19%), and consisted of a missense mutation in seven and a chain-terminating mutation in two. SSCP, sequence, and cytogenetic analysis strongly suggested that eight of nine patients with mutations had retained the normal p53 allele, which had been lost in the remaining patient. These findings were confirmed by fluorescence-in-situ hybridization (FISH) with a p53-specific probe in two patients, including the one who had lost the normal p53 allele. Unexpectedly, mutations were significantly less frequent in patients with disseminated disease, ie, L3 ALL or stage IV BL (four of 35, 11%), than in more localized forms, ie, BL stage I, II, or III (five of 13, 38%) (P = .03). CR rates were similar in mutated (78%) and nonmutated cases (78%). The actuarial disease-free interval (DFI) after 12 months and actuarial survival rates after 24 months were 49% and 66%, respectively, in patients with mutations, and 73% and 48%, respectively, those without mutations. The differences were not significant. Our findings suggest that, contrary to what is seen in most other neoplasias, p53 mutations in newly diagnosed BL and L3 ALL are not associated with extensive tumor mass or poor response to intensive therapeutic regimens. It is hypothesized that this difference with most tumors could be due to the fact that p53 mutations in BL and L3 ALL are generally associated with persistence of a normal residual p53 allele, contrary to what is observed in the majority of tumors.

Treatment-Related Leukoencephalopathy

The etiology and pathogenesis of treatment-related leukoencephalopathy remain obscure. The evidence is substantial, however, that radiation therapy in combination with higher cerebral concentrations of certain chemotherapeutic agents such as MTX increases the likelihood of permanent damage. There is no therapy of apparent benefit for treatment-related leukoencephalopathy, but reasonable alternatives include 1) withholding chemotherapy and/or radiation, 2) administering calcium leucovorin in high doses intravenously in methotrexate-induced leukoencephalopathy (26), or 3) perfusing the subarachnoid space (2) from above through an Ommaya reservoir and out from below through a lumbar puncture needle or lumbar subarachnoid catheter. Because CT scan abnormalities and subtle mental or intellectual changes are often noted before the full-blown clinical presentation, a prospective study involving periodic CT scanning as well as formal neuropsychologic testing appears worthwhile in all patients who are to receive cranial irradiation and/or chemotherapy in the prophylaxis or active treatment of CNS disease in order to detect and perhaps even to prevent this adverse side effect of cancer therapy.