Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.

PURPOSE: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. EXPERIMENTAL DESIGN: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. RESULTS: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. CONCLUSIONS: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.

The effect of a PPO pay-for-performance program on patients with diabetes.

OBJECTIVES: To investigate the effectiveness of a pay-for-performance program (P4P) to increase the receipt of quality care and to decrease hospitalization rates among patients with diabetes mellitus. STUDY DESIGN: Longitudinal study of patients with diabetes enrolled in a preferred provider organization (PPO) between January 1, 1999, and December 31, 2006. METHODS: We used multivariate analyses to assess the effect of seeing P4P-participating physicians on the receipt of quality care (ie, glycosylated hemoglobin and low-density lipoprotein cholesterol testing) and on hospitalization rates, controlling for patient characteristics. RESULTS: Patients with diabetes who saw P4P-participating physicians were more likely to receive quality care than those who did not (odds ratio, 1.16; 95% confidence interval, 1.11-1.22; P <.001). Patients with diabetes who received quality care were less likely to be hospitalized than those who did not (incident rate ratio, 0.80; 95% confidence interval, 0.80-0.85; P <.001). During 1 year, there was no difference in hospitalization rates between patients with diabetes who saw P4P-participating physicians versus those who did not. However, patients with diabetes who saw P4P-participating physicians in 3 consecutive years were less likely to be hospitalized than those who did not (incident rate ratio, 0.75; 95% confidence interval, 0.61-0.93; P <.01). CONCLUSIONS: A P4P can significantly increase the receipt of quality care and decrease hospitalization rates among patients with diabetes in a PPO setting. Although it is possible that the differences observed between P4P-participating physicians and non-P4P-participating physicians were due to selection bias, we found no significant difference in the receipt of quality care between patients with diabetes who saw new P4P-participating physicians versus non-P4P-participating physicians during the baseline year. Further research should focus on defining the effect of P4Ps on intermediate outcomes such as glycosylated hemoglobin and low-density lipoprotein cholesterol levels.