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Background: Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found. Methods: One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy. Results: The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4+4.8% [95% confidence intervals (CI)] and 30.2+4.8% (95% CI), respectively. The ProMACEMOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20‐30 Gy WB, and 500 mg/m 2 of MTX dose appeared important determinants of OS. Conclusions: A modest dose of MTX (500 mg/m 2 ) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.

To cite this Article: Yamanaka, Ryuya, Homma, Junpei, Sano, Masakazu, Tsuchiya, Naoto, Yajima, Naoki, Shinbo, Yoshikatsu, Hasegawa, Akira, Onda, Kiyoshi and Tanaka, Ryuichi , 'Immuno-chemotherapy with a combination of rituximab, methotrexate, pirarubicin and procarbazine for patients with primary CNS lymphoma A preliminary report', Leukemia and Lymphoma, 48:5, 1019 1022 To link to this article: DOI: 10.1080/10428190701248009 URL: http://dx.doi.org/10.1080/10428190701248009

Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes coupled with a class prediction model could be used to define subgroups of high-grade gliomas in a more objective manner than standard pathology. RNAs from 29 malignant gliomas were analysed using Agilent microarrays. We identified 21 genes whose expression was most strongly and consistently related to patient survival based on univariate proportional hazards models. In six out of 10 genes, changes in gene expression were validated by quantitative real-time PCR. After adjusting for clinical covariates based on a multivariate analysis, we finally obtained a statistical significance level for DDR1 (discoidin domain receptor family, member 1), DYRK3 (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 3) and KSP37 (Ksp37 protein). In independent samples, it was confirmed that DDR1 protein expression was also correlated to the prognosis of glioma patients detected by immunohistochemical staining. Furthermore, we analysed the efficacy of the short interfering RNA (siRNA)-mediated inhibition of DDR1 mRNA synthesis in glioma cell lines. Cell proliferation and invasion were significantly suppressed by siRNA against DDR1. Thus, DDR1 can be a novel molecular target of therapy as well as an important predictive marker for survival in patients with glioma. Our method was effective at classifying high-grade gliomas objectively, and provided a more accurate predictor of prognosis than histological grading.

In this Phase I/II trial, the patient's peripheral blood dendritic cells were pulsed with an autologous tumour lysate of the glioma. Seven patients with glioblastoma and three patients with anaplastic glioma, ranging in age from 20 to 69 years, participated in this study. The mean numbers of vaccinations of tumour lysate-pulsed dendritic cells were 3.7 times intradermally close to a cervical lymph node, and 3.2 times intratumorally via an Ommaya reservoir. The percentage of CD56-positive cells in the peripheral blood lymphocytes increased after immunisation. There were two minor responses and four no-change cases evaluated by radiological findings. Dendritic cell vaccination elicited T-cell-mediated antitumour activity, as evaluated by the ELISPOT assay after vaccination in two of five tested patients. Three patients showed delayed-type hypersensitivity reactivity to the autologous tumour lysate, two of these had a minor clinical response, and two had an increased ELISPOT result. Intratumoral CD4+ and CD8+ T-cell infiltration was detected in two patients who underwent reoperation after vaccination. This study demonstrated the safety and antitumour effects of autologous tumour lysate-pulsed dendritic cell therapy for patients with malignant glioma.

Management of hypothalamic hamartoma with intractable gelastic epilepsy remains controversial. We have used stereotactic thermocoagulation for treatment of hypothalamic hamartoma with intractable gelastic epilepsy since 1997. Herein, we review our experience in five cases to clarify the usefulness of this treatment. A total of five patients with hypothalamic hamartoma were treated by stereotactic thermocoagulation at our hospital during the period October 1997 through February 2004. In all patients, the hamartoma was less than 10mm in diameter and was located on the floor of the third ventricle with sessile attachment to the wall. To identify ictal onset, chronic intracranial electroencephalography was performed in three patients with the use of a depth electrode implanted in the hamartoma. Attempts were made to induce gelastic seizure by electrical stimulation of the hamartoma in three patients. After magnetic resonance imaging-guided targeting, radiofrequency thermocoagulation of the boundary between the hamartoma and normal hypothalamus was performed to achieve disconnection effects. Marked reductions in seizure frequency were obtained in all cases, with three patients becoming seizure-free after the procedure. No intraoperative complications occurred except in one patient who experienced acute and transient panidrosis with hot flushes during coagulation. Our results suggest that stereotactic thermocoagulation of hypothalamic hamartoma is an acceptable treatment option for patients with intractable gelastic seizures.

Purpose: To investigate the safety and the immunologic and clinical responses of dendritic cell therapy for patients with recurrent malignant glioma.Experimental Design: Twenty-four patients with recurrent malignant glioma (6 grade 3 and 18 grade 4 patients) were evaluated in a phase I/II clinical study of dendritic cell therapy. All patients were resistant to the standard maximum therapy. The patient's peripheral blood dendritic cells were generated with granulocyte macrophage colony-stimulating factor, plus interleukin 4 with or without OK-432, and pulsed with an autologous tumor lysate. Dendritic cells were injected intradermally, or both intratumorally and intradermally every 3 weeks.Results: The protocols were well tolerated with only local redness and swelling at the injection site in several cases. Clinical responses were as follows: 1 patient with partial response, 3 patients with minor response, 10 patients with stable disease, and 10 patients with progressive disease. The patients whose dendritic cells were matured with OK-432 had longer survival times than the dendritic cells from patients without OK-432 maturation. The patients with both intratumoral and intradermal administrations had a longer survival time than the patients with intradermal administration only. Increased ELISPOT and delayed-type hypersensitivity responses after vaccination could provide good laboratory markers to predict the clinical outcome of patients receiving dendritic cell vaccination. The overall survival of patients with grade 4 glioma was 480 days, which was significantly better than that in the control group.Conclusions: This study showed the safety and clinical response of autologous tumor lysate-pulsed dendritic cell therapy for patients with malignant glioma. Dendritic cell therapy is recommended for further clinical studies in malignant glioma patients.

Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Among the new treatments currently being investigated for malignant glioma, immunotherapy is theoretically very attractive, since it offers the potential for high tumor-specific cytotoxicity. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells is capable of inducing an antiglioma response. Therefore, dendritic cell-based immunotherapy could be a new treatment modality for patients with glioma. Dendritic cell-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. The development of methods for manipulating dendritic cells for the purpose of vaccination will enhance the clinical usefulness of these cells for biotherapy for malignant glioma.

In this study, we demonstrate that tumor mRNA-loaded dendritic cells can elicit a specific CD8(+) cytotoxic T-lymphocyte (CTL) response against autologous tumor cells in patients with malignant glioma. CTLs from three patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts or EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Also, DCs-pulsed normal brain mRNA failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two patients' CD8(+) T cells expressed a modest cytotoxicity against autologous glioma cells. CD8(+) T cells isolated during these ineffective primings secreted large amounts of IL-10 and smaller amounts of IFN-gamma as detected by ELISA. Type 2 bias in the CD8(+) T-cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor mRNA-loaded DC can be an effective tool in inducing glioma-specific CD8(+) CTLs able to kill autologous glioma cells in vitro. However, high levels of tumor-specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs transfected with total tumor RNA may represent a method for inducing immune responses against the entire repertoire of glioma antigens.

In this Phase I/II trial, the patient's peripheral blood dendritic cells were pulsed with an autologous tumour lysate of the glioma. Fourteen patients with glioblastoma and 4 patients with anaplastic glioma, ranging in age from 20 to 73 years, participated in this study. The mean numbers of vaccinations of tumour lysate-pulsed dendritic cells were 4.8 times intradermally close to a cervical lymph node, and 4.2 times intratumourally via an Ommaya reservoir. The percentage of CD56-positive cells in the peripheral blood lymphocytes increased after immunization. There were 1 partial response, 2 minor responses and 7 no change cases evaluated by radiological findings. Dendritic cell vaccination elicited T-cell-mediated antitumour activity, as evaluated by ELISPOT assay after vaccination in 2 of 5 tested patients. Three patients showed DTH reactivity to the autologous tumour lysate, two of these had a minor clinical response, and two had an increased ELISPOT result. Intratumoural CD4 and CD8 T-cell infiltration was detected in two patients who underwent re-operation after vaccination. This study demonstrated the safety and antitumour effects of autologous tumour lysate-pulsed dendritic cell therapy for patients with malignant glioma.

Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Among the new treatments currently being investigated for malignant glioma, immunotherapy is theoretically very attractive, since it offers the potential for high tumor-specific cytotoxicity. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells is capable of inducing an antiglioma response. Therefore, dendritic cell-based immunotherapy could be a new treatment modality for patients with glioma. In this review, we will discuss the implications of these findings for glioma therapy. A literature review of dendritic cell-based glioma immunotherapy was used to overview the dendritic cell in immunobiology, in the central nervous system and in tumor immunology, glioma-associated antigens, dendritic cell therapy in animal glioma model, dendritic cell therapy in clinical trials and future directions in dendritic cell therapy. Dendritic cell-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. Dendritic cell therapy of glioma seems to be safe and without major side effects. Its efficacy should be further determined in randomized, controlled clinical trials. The development of methods for manipulating dendritic cells for the purpose of vaccination will enhance the clinical usefulness of these cells for biotherapy for malignant glioma.

The ECT2 (epithelial cell transforming sequence 2) proto-oncogene encodes a guanine nucleotide exchange factor for Rho GTPases, and regulates cytokinesis. ECT2 plays a critical role in Rho activation during cytokinesis, and thus may play a role in the pathogenesis of glioma. In this study, we investigated relationships between ECT2 expression, tumor histology, and prognosis in glioma patients. ECT2 mRNA expression was examined using quantitative real-time PCR, while its protein expression was examined by immunohistochemistry of 54 glioma tissue samples. Expressions of ECT2 mRNA and protein were markedly increased in high-grade gliomas compared to low-grade gliomas. Patients in whom expression of ECT2 mRNA and protein in tumor tissues was the lowest survived longer than patients who had higher expression. In vitro, ECT2 siRNA inhibited glioma cell proliferation and invasion. These data suggest that increased expression of ECT2 contribute to promotion of tumor invasiveness and progression, implying that evaluation of ECT2 expression is a prognostic marker for glioma patients.