Dexamethasone Mediated Inhibition of Local IL-2 Immunotherapy is Dose Dependent in Experimental Brain Tumors

Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the role of systemic immunosuppression using dexamethasone on the efficacy of local IL-2 immunotherapy in treating experimental murine CNS tumors.An endothelial cell line secreting hIL-2 (NTC-121) was injected intracranially in C57BL/6 mice (n= 10/group) along with B16/F10 (wild type) melanoma cells. A separate set of animals also received daily injections of either 1 mg/k or 10 mg/kg of dexamethasone. Sixty percent of mice treated with IL-2 (P < 0.001 vs. control) vs. 55%(P < 0.005) of mice treated with IL-2 and 1 mg/kg of dexamethasone were long-term survivors (LTS) of >120 days. There was no difference in survival between control animals that received only wild type cells or animals that were treated with IL-2 and 10 mg/kg of dexamethasone. Histopathological examination of brains from animals sacrificed at different times showed an accumulation of CD8 + T-cells around the site of the injected tumor only in the IL-2 group and the group that received 1 mg/kg of dexamethasone.These results suggest that while high doses of dexamethasone can completely inhibit the immune response observed with IL-2, lower and more likely therapeutic doses of dexamethasone do not inhibit local IL-2 immunotherapy.     

Recent Advances in Brain Tumor Therapy: Local Intracerebral Drug Delivery by Polymers

New approaches to malignant glioma are being actively investigated. Local drug delivery directly to the site of the tumor is one novel approach that has been approved by the US FDA and other regulatory agencies worldwide. This agent, Gliadel, delivers the chemotherapeutic drug carmustine (BCNU) from a biodegradable polymer placed in the resection cavity after brain tumor surgery. Gliadel represents the first clinical application of polymer delivery for brain tumors, but the potential for this new methodology is far greater. In this review, we will briefly summarize the development of Gliadel from a laboratory idea to its current role as an approved treatment for gliomas. Then we will present the most recent work being done to expand the potential benefits of polymeric delivery for brain tumors. This work includes trials for its use as the initial therapy for gliomas, as well as its use against metastasis. Further clinical trials exploring the maximum-tolerated dose and the combination of Gliadel with systemic chemotherapeutic treatments such as temozolamide and O(6)-benzylguanine will be reviewed. Finally, we will present preclinical work on the efficacy of polymeric methods for delivering other chemotherapeutic agents, and a variety of novel compounds that modify brain tumor biology. This latter work represents potential future clinical applications of local polymeric drug delivery to the brain and other sites where cancers can occur.     

Outcome and cost of craniotomy performed to treat tumors in regional academic referral centers

OBJECTIVE: Improved clinical and economic outcomes for high-risk surgical procedures have been previously cited in support of regionalization. The goal of this study was to examine the effects of regionalization by analyzing the cost and outcome of craniotomy for tumors and to compare the findings in academic medical centers versus community-based hospitals. METHODS: Outcomes and charges were analyzed for all adult patients undergoing craniotomy for tumor in 33 nonfederal acute care hospitals in Maryland using the Maryland Health Service Cost Review Commission database for the years 1990 to 1996. A total of 4723 patients who underwent craniotomy for tumor were selected on the basis of Diagnostic Related Group 1 (craniotomy except for trauma, age 18 or older) and International Classification of Diseases-9th Revision diagnosis code for benign tumor, primary malignant neoplasm, or secondary malignant neoplasm (codes 191, 192, 194, 200, 225, 227, 228, 237, and 239). Hospitals were categorized as high-volume hospitals (>50 craniotomies/yr) or low-volume hospitals (相似文献   

The surgical bed after BCNU polymer wafer placement for recurrent glioma: serial assessment on CT and MR imaging

OBJECTIVE: The objective of our study was to describe the CT and MR imaging appearances of the surgical bed in the brains of patients receiving biodegradable polymers impregnated with N, N'1, 3-Bis-(2-chloroethyl)-N-nitrosourea (BCNU) for recurrent glioma and to determine whether patients receiving placebos could be differentiated from those receiving BCNU based on the pattern and growth kinetics of tumor recurrence. MATERIALS AND METHODS: The CT and MR images of 20 patients who underwent surgery for resection of recurrent high-grade gliomas and placement of intratumoral wafers (11 received BCNU polymer wafers, nine received control wafers) were analyzed for wafer appearance, volume of gas in the tumor bed, and volume of enhancement on serial scans. RESULTS: Wafers appeared as linear hyperdense structures on CT and as linear low-signal-intensity structures on MR imaging and caused no significant enhancement. In the BCNU polymer group, gas volume was 4.0 +/- 3.4 cm(3) (mean +/- SD), whereas gas volume was 1.6 +/- 3.0 cm(3) for the placebo group (Mann-Whitney test, p = 0.03). A trend toward linear rather than exponential recurrent tumor growth was identified for the BCNU polymer group but not for the placebo group. CONCLUSION: BCNU polymer wafers have a specific appearance on CT and MR imaging with which radiologists should be familiar: gas in the surgical bed is an expected transient finding, and tumor regrowth in patients receiving BCNU polymer wafers appeared to occur at a slower rate than in those receiving the placebo.     

Gene therapy for experimental brain tumors using a xenogenic cell line engineered to secrete hIL-2

Summary Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the feasibility and efficacy of using a rat endothelial cell line (NTC-121) transfected with the human interleukin-2 (IL-2) gene in treating experimental murine CNS tumors. The NTC-121 cells were injected intracranially in C57BL/6 mice (N = 10/group) along with non-irradiated, non-transfected B16/F10 (wild type) melanoma cells. Sixty percent of mice treated with IL-2 (p<0.001 vs. control) were long-term survivors (LTS) of >120 days. Control animals that received only wild type cells had a median survival of 18 days (range 15–20). Histopathological examination of brains from animals sacrificed at different times showed no tumor growth in the non-irradiated NTC-121 group, moderate (1–2 mm) tumor growth in the irradiated group, and gross tumor invasion (>2 mm) and tissue necrosis in the control group. Moreover, animals treated with IL-2 showed an accumulation of CD8+ T cells around the site of the injected tumor. The use of a xenogenic cell line to deliver hIL-2 stimulates a strong immunologic cytotoxic anti-tumor response that leads to significant prolongation of survival in mice challenged with the B16/F10 intracranial melanoma tumor. Our findings demonstrate that the use of a xenogenic cell line can provide a potent vehicle for the delivery of gene therapy and may therefore represent a new approach for brain tumor therapy.     

Advancing the field of drug delivery: taking aim at cancer

Drug delivery systems for cancer therapeutics have now been used by millions of patients and have resulted in the creation of new therapies as well as significantly improving existing ones. Here we discuss a number of the drug delivery systems that have been approved by regulatory authorities and that are currently in clinical use, such as controlled delivery of cancer therapeutics, local chemotherapy, polymer drug conjugates, liposomal systems, and transdermal drug delivery patches. The next generation of "smart" drug delivery approaches such as controlled release microchips are discussed as are some of the future challenges and directions in this field.     

Recurrent ectopic craniopharyngioma

A 66-year-old woman developed an asymptomatic mass in the right frontal lobe 5 years after undergoing a right frontal craniotomy and removal of a craniopharyngioma. The mass progressively enlarged over the next 3 years, during which time it became multiloculated and partially cystic. Repeat craniotomy was performed 8 years after the original operation, at which time the mass was found to be an ectopic craniopharyngioma. The lesion probably resulted from seeding of tumour cells along the surgical tract at the time of the initial surgery.