Paradoxical embolism to the central nervous system after sexual intercourse in a young woman with a complex atrial septal abnormality.

Ischemic stroke during sexual intercourse is an unusual occurrence. We report the evaluation and treatment of a young woman on oral contraceptives, with a complex atrial septal abnormality and right lower extremity deep vein thrombus, who had an ischemic stroke during sexual intercourse. Successful treatment was accomplished with administration of intra-arterial tissue plasminogen activator and subsequent transvascular occlusion of the atrial septal abnormality.

A safety and efficacy study of local delivery of interleukin-12 transgene by PPC polymer in a model of experimental glioma.

Interleukin-12 (IL-12) triggers an antitumoral immune response and an antiangiogenic effect against cancer. In this study, we tested a novel polymeric vehicle for IL-12 gene therapy along with adjuvant local biodegradable carmustine (BCNU) chemotherapy for the treatment of malignant glioma. Highly concentrated DNA/PPC (polyethylenimine covalently modified with methoxypolyethyleneglycol and cholesterol) complexes were used to deliver a murine plasmid encoding IL-12 (pmIL-12). For toxicity assessment, mice received intracranial injections with different volumes of pmIL-12/PPC. For efficacy, mice with intracranial GL261 glioma were treated with local delivery of pmIL-12/PPC and/or BCNU-containing polymers. Intracranial injections of 5-10 microl of pmIL-12/PPC were well tolerated and led to IL-12 expression in the brains of treated animals. Treatment with pmIL-12/PPC led to a significant increase in survival compared with untreated mice (median survival 57 days; 25% long-term survival >95 vs. 45 days for control; P<0.05). Treatment with BCNU led to a significant increase in survival compared with untreated mice, with 75% of treated mice having a long-term survival >95 days, (P<0.05). Most importantly, the combination of BCNU and pmIL-12/PPC led to a survival of 100% of the mice for 95 days after treatment (P<0.0001). This novel strategy is safe and effective for the treatment of malignant glioma. The synergy resultant from the combination of locally administered pmIL-12/PPC and BCNU suggests a role for this approach in the treatment of malignant brain tumors.

Cross-priming of T cells to intracranial tumor antigens elicits an immune response that fails in the effector phase but can be augmented with local immunotherapy.

Central nervous system (CNS) tumors are thought to be poorly immunogenic. However, whether defective anti-tumor immunity is a consequence of a relative failure of T cell priming versus a deficient effector phase of the anti-tumor immune response is not clear. We utilized a well-defined model system of B16 melanoma expressing the model antigen SIY-GFP to evaluate tumor antigen cross-priming and tumor rejection from the CNS versus subcutaneous compartments. We observed that B16-SIY cells implanted in the CNS were capable of inducing T cell priming as measured by IFN-gamma ELISPOT in the spleen. Cross-priming occurred in the absence of detectable systemic dissemination of the tumor. Despite the induction of a T cell response, CNS tumors grew progressively and were fatal, whereas the same tumor implanted in the flank was rejected. To study the effector phase of the immune response in more detail, in vitro primed 2C/RAG2-/- TCR transgenic CD8+ cells, which recognize the SIY peptide, were adoptively transferred. In addition, the CNS microenvironment was modulated by intracranial delivery of IL-2. While mice that received primed 2C cells alone showed an increase in survival, co-administration of intracranial IL-2 led to a marked prolongation of survival, with 20% of mice surviving at least 120 days. Our results demonstrate that CD8+ T cell cross-priming does indeed occur in response to a CNS tumor, but that manipulation of the brain tumor microenvironment may be necessary to support the effector phase of the anti-tumor immune response.