Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept.

BACKGROUND: Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier. OBJECTIVE: The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI. METHODS: After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed. RESULTS: The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced. DISCUSSION: Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury. CONCLUSION: Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.

Androgen blockade enhances response to melanoma vaccine.

BACKGROUND: Because preclinical studies suggest an interaction between androgens and the immune system, we used a murine model to determine whether androgen blockade with flutamide might enhance the immunogenicity of an irradiated melanoma cell vaccine. MATERIALS AND METHODS: Forty C57BL/6 male mice were randomly assigned to four treatment groups: flutamide + RPMI (Group A), flutamide + irradiated B16 murine melanoma cells (Group B), placebo + RPMI (Group C), and placebo + irradiated B16 cells (Group D). Splenocyte proliferation and secretion of interleukin-2 and interferon-gamma were assayed after coculturing splenocytes with irradiated B16 cells. Antibody-dependent cellular cytotoxicity (ADCC) against B16 cells was determined using peripheral blood lymphocytes. To examine the effect of treatment on tumor growth, a second set of 40 mice assigned to Groups A, B, C, and D underwent tumor challenge 7 days after the last treatment. RESULTS: Splenocyte proliferation was significantly higher in the two groups receiving flutamide at 50 mg/kg x 7 days (29% in Groups A and B vs 3% in Group C and 7% in Group D). Secretion of interferon was significantly higher in mice receiving flutamide + irradiated B16 cells (15.2 pg/ml in Group B vs 0, 1.7, and 4 pg/ml in Groups A, C, and D, respectively; P = 0.0024). Differences in interleukin secretion were not significant. ADCC was 26% in Group B vs 15, 8, and 22% in Groups A, C, and D, respectively (P = 0.0001). In the tumor challenge experiment, the rate of survival was 10% higher in mice receiving irradiated B16 + flutamide than in mice receiving irradiated B16 alone. CONCLUSION: Flutamide can enhance immune responses to an irradiated whole-cell melanoma vaccine. A clinical study of immunotherapeutic androgen blockade is warranted.