Socioeconomic disparities in thyroid cancer incidence within the Surveillance, Epidemiology, and End Results (SEER) registry, 1980--2008

Background. In the past two decades, the incidence of thyroid cancer in the United States (US) has been increasing. There has been debate on whether the increase is real or an artifact of improved diagnostic scrutiny. Methods. We linked SEER9 database with 2000 US Census to obtain county-level SES (Socioeconomic Status) and compared thyroid cancer incidence trends between high and low SES counties. Joinpoint analysis was used to assess the thyroid cancer incidence trends. Annual Percentage Changes (APCs) were calculated to evaluate incidence trends. Results . The thyroid cancer incidence in high SES counties increased moderately (APC1=+2.5*, *P<0.05) before late 1990s and dramatically increased (APC2=+6.3*) after late 1990s, whereas incidence in low SES counties increased moderately (APC=+3.5*) during the entire time period (1980–2008). For smaller tumors (≤4cm), the APCs in high and low SES counties are similar to each other before late 1990s, but the incidence in high SES counties increased dramatically after late 1990s while that in low SES counties continued at a moderate increase. For large tumors (>4cm), the incidence trends in high SES counties are similar to those of low SES counties, which had a steady moderate increase. Conclusion. Our findings indicate that enhanced detection likely contributed to the increased thyroid cancer incidence in the past decades but cannot fully explain the increase, suggesting that a true increase also exists. Efforts should be made on identifying the cause of this observed increased incidence as well as more refined/selected screening and prevention measures.^

STIMULATION THROUGH TLR4 INCREASES FVIII INHIBITOR FORMATION IN A MOUSE MODEL OF HEMOPHILIA A

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses of TLR4 agonist (lipopoysaccharide; LPS). The addition of LPS combined with FVIII significantly increased the rate and the production of anti-FVIII IgG antibodies and neutralizing FVIII inhibitors. In the spleen, repeated in vivo TLR4 stimulation with LPS increased the relative percentage of macrophages and dendritic cells (DCs) over the course of 4 injections. However, repeated in vivo FVIII stimulation significantly increased the density of TLR4 expressed on the surface of all spleen antigen presenting cells (APCs). Culture of splenocytes isolated from mice revealed that the combined stimulation of LPS and FVIII also synergistically increased early secretion of the inflammatory cytokines IL-6, TNF-α, and IL-10, which was not maintained throughout the course of the repeated injections. While cytokine secretion was relatively unchanged in response to FVIII re-stimulation in culture, LPS re-stimulation in culture induced increased and prolonged inflammatory cytokine secretion. Re-stimulation with both LPS and FVIII induced cytokine secretion similar to LPS stimulation alone. Interestingly, long term treatment of mice with LPS alone resulted in splenocytes that showed reduced response to FVIII in culture. Together these results indicated that creating a pro-inflammatory environment through the combined stimulation of chronic, low-dose LPS and FVIII changed not only the populations but also the repertoire of APCs in the spleen, triggering the increased production of FVIII inhibitors. These results suggested an anti-inflammatory regimen should be instituted for all hemophilia A patients to reduce or delay the formation of FVIII inhibitors during replacement therapy.