Purpose:To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. Experimental Design: Fifty-six patients with relapsed GBM (WHO grade IV) were treated with at least three vaccinations. Children and adults were treated similarly in three consecutive cohorts, with progressively shorter vaccination intervals per cohort. Feasibility and toxicity were assessed as well as effect of age, extent of resection, Karnofsky Performance Score, and treatment cohort on the progression-free (PFS) and overall survival (OS) using univariable and multivariable analysis. Results: Since the prevaccine reoperation, the median PFS and OS of the total group was 3 and 9.6 months, respectively, with a 2-year OS of 14.8%. Total resection was a predictor for better PFS both in univariable analysis and after correction for the other covariates. For OS, younger age and total resection were predictors of a better outcome in univariable analysis but not in multivariable analysis. A trend to improved PFS was observed in favor of the faster DC vaccination schedule with tumor lysate boosting. Vaccine-related edema in one patient with gross residual disease before vaccination was the only serious adverse event. Conclusion: Adjuvant DC-based immunotherapy for patients with relapsed GBM is safe and can induce long-term survival. A trend to PFS improvement was shown in the faster vaccination schedule. The importance of age and a minimal residual disease status at the start of the vaccination is underscored.In spite of multimodal therapy, including maximal safe neurosurgical resection followed by radiochemotherapy and maintenance chemotherapy, malignant or high-grade gliomas (HGG) continue to have a dismal prognosis (1). Prognosis after relapse is even worse (2, 3), with a median progression-free survival (PFS) of 2 months, and virtually all patients being dead 18 months after the relapse. Even in pediatric patients with relapsed HGG, the prognosis is poor (4).The rationale, the preclinical, and the early clinical evidence to develop dendritic cell (DC)-based immunotherapy for HGG has been reviewed by our research group (5, 6) and by others (7 -14). Vaccination is done with autologous mature monocyte-derived ex vivo generated DC loaded with autologous tumor lysate. The characteristics and in vitro function of the vaccine have been analyzed (15, 16). We described some early clinical experience on feasibility and toxicity that we obtained in a small group of patients (17,18).For the implementation of immunotherapy in clinical practice for patients with relapsed HGG, an observational prospective cohort comparison trial, HGG-IMMUNO, was designed, in which adjuvant autologous DC vaccination is done in patients with relapsed HGG after maximal new resection of the relapsed tumor. Except for the time window in cohort A, which was the

In several studies lactation has been shown to be associated with a hypothalamic-pituitary-adrenal axis hyporesponsiveness to physical and psychological stressors. As it is not known whether the marked blunting of endocrine stress reactivity in women can be ascribed to suckling as a short-term effect or to lactation in general, the acute effects of suckling on the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system responses to mental stress were investigated in lactating women.Forty-three lactating women were randomly assigned either to breast-feed or to hold their infants for a 15-min period with the onset 30 min before they were exposed to a brief psychosocial stressor (Trier Social Stress Test). Both breastfeeding and holding the infant yielded significant decreases in ACTH, total plasma cortisol, and salivary free cortisol (all P < 0.01). There were no significant differences in baseline hormone levels between the groups 1 min before the stress test. In response to stress exposure, ACTH, total plasma cortisol, salivary free cortisol, norepinephrine, and epinephrine were significantly increased in all lactating women (all P < 0.001). However, total cortisol and free cortisol responses to stress were attenuated in breast-feeding women (P ‫؍‬ 0.001 and P ‫؍‬ 0.067, respectively), who also showed significantly decreasing PRL levels during the stress test (P ‫؍‬ 0.005). In addition, there was no change in plasma oxytocin or vasopressin in response to the stressor. Breast-feeding as well as holding led to decreased anxiety (P < 0.05), whereas, in contrast, stress exposure worsened mood, calmness, and anxiety in the total group (all P < 0.001).From these data we conclude that lactation in women, in contrast to that in rats, does not result in a general restraint of the hypothalamic-pituitary-adrenal axis response to a psychosocial stressor. Rather, suckling is suggested to exert a short-term suppression of the cortisol response to mental stress. (J Clin Endocrinol Metab 86: 4798 -4804, 2001) E VIDENCE FROM ANIMAL and human studies has suggested that suckling is associated with significant alterations in the reactivity of the hypothalamic-pituitaryadrenal (HPA) axis during the postpartum period (1, 2). Observations in the lactating rat have shown an endocrine hyporesponsiveness to physical and psychological stressors, including attenuated secretion of ACTH (3-7), corticosterone (3-5, 8 -11), catecholamines (12), oxytocin (9, 13-15), and PRL (12, 16).In humans, the effect of lactation on stress-responsive neurohormonal systems has been explored, to date, only for treadmill exercise. Altemus and associates (17) found significantly attenuated plasma ACTH, cortisol, and glucose responses to physical stress in lactating compared with nonlactating women. However, the effects of suckling on endocrine as well as behavioral responses to a psychosocial stress paradigm in humans have not yet been investigated. More important, it is not known whether the marked blunting of endocrine stress responsi...

Malignant progression in gliomas is correlated with increased migratory capacity which involves metalloproteolytic activity. Here, we report that ectopic expression of BCL-2 in two malignant glioma sublines markedly promoted glioma cell migration from spheroids and invasion into Matrigel-coated membranes. Invasion of fetal rat-brain aggregates was enhanced by BCL-2. Zymography revealed activation of matrix metalloproteinase-2 (MMP-2) in BCL-2-expressing cells. BCL-2 expressing cells showed an increase in MMP-2/-3/-12 (LN-18), and MMP-9/-12 and cell surface urokinase-type plasminogen activator (u-PA) (LN-229) mRNA and a reduction in tissue inhibitors of metalloproteinases (TIMP)-2 mRNA (LN-229). Taken together, we propose a novel function for BCL-2 in the malignant phenotype of glioma cells, that is, to enhance migration and invasion by altering the expression of a set of metalloproteinases and their inhibitors.z 1998 Federation of European Biochemical Societies.

Interleukin 10 (IL‐10) expression has been found to be correlated with the extent of malignancy in gliomas. In vitro, IL‐10 increases proliferation and migratory capacity in human glioma cell lines. In this study, we localized the site of IL‐10 synthesis in gliomas to cells of microglial origin. Biopsy specimens from 11 patients with malignant glioma were processed on native tissues and at early cell culture passages (0–4). IL‐10 mRNA was analyzed by RT‐PCR and in situ hybridization. Protein was quantitatively assessed by ELISA in cell culture supernatants, and cells expressing IL‐10 were determined by a combination of immunohistochemistry for CD68 (specific for microglia/macrophage lineage) and IL‐10 in situ hybridization. IL‐10 mRNA decreased from passage 0 to 4 in all samples and was undetectable beyond passage 5. Such downregulation of mRNA leads to a steep decrease of IL‐10 protein in culture supernatants (below detection level, 0.05 ng/ml, beyond passage 1). The combination of in situ hybridization for IL‐10 and CD68 immunostaining revealed that only cells of the microglia/macrophage lineage produced IL‐10 mRNA. Our results identify microglia/macrophage cells as the major source of IL‐10 expression in gliomas which decreases markedly during early passages of primary cultures of human gliomas due to a progressive reduction of microglia/macrophages present. Int. J. Cancer 82:12–16, 1999. © 1999 Wiley‐Liss, Inc.

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Endothelial cells of blood vessels forming the interphase between systemic circulation and tissues are crucial for maintenance of homeostasis and organ-related functions. Recent experiments support organ-specific endothelial differentiation and suggest differential gene expression patterns in endothelial cells. Here, we compared gene expression in primary human cerebral endothelial cells (HCEC), which are major constituents of the blood brain barrier (BBB), with human umbilical vein endothelial cells (HUVEC) by using cDNA array analysis of 375 genes. Under basal culture conditions, 35 genes were expressed only in HCEC, whereas 20 gene transcripts were detected only in HUVEC. A total of 78 genes were expressed in both endothelial cell types partly with distinct expression levels. Genes expressed by cerebral endothelial cells are important in vasculo- and angiogenesis (VEGF, erbB1) and immunoregulation (OSM-Rbeta, decorin, IL-6) or have growth-supporting properties (brain-derived neurotrophic factor, stem cell factor, transforming growth factor-beta). The differential gene expression profiles were confirmed at the protein level of cell cultures (ELISA, immunoblotting) and human tissues (immunohistochemistry). Identification and further functional characterization of genes specifically expressed by cerebral endothelial cells will have important impact on our understanding of endothelial function at the BBB.

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Irradiation is an effective element for the treatment of pontine gliomas. Intensive chemotherapy seems to be important in achieving a better OS.