Most lymphomas that involve the central nervous system are B-cell neoplasms that express the cell surface molecule CD20. After intravenous administration, rituximab can be reproducibly measured in the cerebrospinal fluid (CSF) in patients with primary central nervous system lymphoma; however, the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin lymphoma. Because lymphomatous meningitis is a frequent complication of nonHodgkin lymphoma, we have conducted an analysis of the safety and pharmacokinetics of direct intrathecal administration of rituximab using cynomolgus monkeys. No significant acute or delayed toxicity, neurologic or otherwise, was detected. Pharmacokinetic analysis suggests that drug clearance from the CSF is biphasic, with a terminal half-life of 4.96 hours. A phase 1 study to investigate the safety and pharmacokinetics of intrathecal rituximab in patients with recurrent lymphomatous meningitis will be implemented based on these findings. ( IntroductionCentral nervous system (CNS) involvement is associated with an adverse outcome in patients with non-Hodgkin lymphoma (NHL). 1 Most NHLs that involve the CNS are B-cell neoplasms that express CD20. 2 Dissemination within the leptomeninges represents a common pathway of progression in systemic NHL and primary CNS lymphoma and usually heralds neurologic deterioration and a fatal outcome. 3 Rituximab monoclonal antibody therapy is an effective treatment for B-cell NHL. [4][5][6][7] To date, preclinical and clinical practice involving rituximab has been limited to intravenous administration. This agent binds specifically to the antigen CD20, which is expressed on more than 90% of B-cell NHL and primary CNS lymphoma but is not expressed by normal neurons or glia in the brain.A number of preclinical models have demonstrated that therapeutic antibodies administered into the cerebrospinal fluid (CSF) are able to concentrate in and eradicate tumors within the craniospinal axis with minimal toxicity. 8,9 The primate model of drug delivery into the CSF represents a valid experimental model for the prediction of CSF drug pharmacokinetics in humans. [10][11][12][13] This is the first preclinical analysis of the safety and pharmacokinetics of rituximab administration within the craniospinal axis. Study designAll experimental procedures have been reviewed and approved by the Committee on Human Research and by the Committee on Animal Research, University of California, San Francisco.Four female cynomolgus monkeys, aged 16 to 18 years, weighing 3 to 5 kg, were obtained from Biosurg (Winters, CA). A total of 7 experiments were performed with one monkey in each experiment. Data are reported from the 4 experiments that involved suboccipital administration of rituximab. Three experiments used an Ommaya reservoir (Integra NeuroCare, Plainsboro, NJ) in the right lateral ventricle. Although intra-Ommaya administration of rituximab resulted in high CSF concentrations, the size of the res...
2006 Background: Radiotherapy with concomitant and adjuvant TMZ (TMZ/RT TMZ) is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. Compared with the standard adjuvant TMZ, dd TMZ results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial determined if intensified TMZ improves survival (OS) or progression free survival (PFS). Methods: This phase III trial was conducted by the RTOG, EORTC and NCCTG. Neurologically stable patients with adequate tissue for prospective MGMT analysis were randomized to Arm 1: standard TMZ (150-200 mg/m 2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m 2 x 21 d) q 4 wks for 6-12 cycles. Symptom, QOL and neurocognitive testing was performed in a subset of patients. The primary endpoint was OS. Secondary analyses evaluated impact of MGMT status. Eligibility criteria included age > 18 yrs, KPS 60, and tissue block with > 1cm 2 tumor. Results: A total of 833 patients were randomized from a total of 1173 registered. Inadequate tissue (n=144) and early disease progression (n =56) were the most frequent reasons for non-randomization. No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p = 0.63), or median PFS (5.5, 6.7 mo, p = 0.06), or by methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p < 0.0001), PFS (8.7, 5.7 mo, p < 0.0001) and response (p = 0.012). Cox modeling showed that MGMT status and RPA class were significant predictors of OS while the treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade 3 toxicity in Arm 2 (19%, 27%, p = 0.008); mostly lymphopenia and fatigue. Conclusions: This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM. Additionally, it demonstrated the feasibility of tumor tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial and established this as a viable clinical trial paradigm.
Using whole genome expression microarray technology to discover clinically relevant biomarkers for pilocytic astrocytoma (PA), the authors identified matrilin-2 as a unique mRNA overexpressed in PA. Matrilin-2 protein expression was similarly elevated in the majority of sporadic PA, but in only one neurofibromatosis 1-associated PA with an unusually aggressive clinical phenotype. These results suggest that matrilin-2 may be a specific and clinically useful biomarker for discriminating between indolent and clinically aggressive PA.
In this study, we test the reliability of chromogenic in situ hybridization (CISH) for the detection of epidermal growth factor receptor (EGFR) gene amplification in glioblastoma. Earlier reports have described EGFR CISH in glioblastoma multiforme, but a comparison of CISH with a "gold standard" testing method, such as fluorescence in situ hybridization (FISH), has not been described. Therapies targeting the EGFR-signaling pathway might increase the importance of assessment of EGFR-amplification status. CISH is a potential alternative to FISH as a testing method. To test its reliability, EGFR-amplification status by CISH was assessed in 89 cases of glioblastoma and compared with FISH results, and correlated with the protein expression using immunohistochemistry (IHC) for EGFR. FISH was scored as being EGFR-amplified in 47/89 tumors, CISH as being amplified in 43/89 tumors. The CISH and FISH results were in agreement in 83/89 cases (93%). Four glioblastomas were scored as being amplified by FISH, but not by CISH; whereas amplification was detected in 2 tumors by CISH that were not amplified using FISH. Forty-eight of the 89 cases were positive for EGFR expression by IHC. EGFR amplification was highly correlated with protein expression by IHC, as 40/48 (83%) EGFR IHC-positive cases were found to be EGFR-amplified. The high concordance of CISH and FISH for the assessment of EGFR gene-amplification status indicates that CISH is a viable alternative to FISH for the detection of EGFR gene amplification in glioblastoma. Detectable EGFR expression by IHC can occur in the absence of gene amplification, but is uncommon.
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