16 research outputs found
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Can Physicians Identify Inappropriate Nuclear Stress Tests? An Examination of Inter-Rater Reliability for the 2009 Appropriate Use Criteria for Radionuclide Imaging
Background—We sought to determine inter-rater reliability of the 2009 Appropriate Use Criteria for radionuclide imaging and whether physicians at various levels of training can effectively identify nuclear stress tests with inappropriate indications.
Methods and Results—Four hundred patients were randomly selected from a consecutive cohort of patients undergoing nuclear stress testing at an academic medical center. Raters with different levels of training (including cardiology attending physicians, cardiology fellows, internal medicine hospitalists, and internal medicine interns) classified individual nuclear stress tests using the 2009 Appropriate Use Criteria. Consensus classification by 2 cardiologists was considered the operational gold standard, and sensitivity and specificity of individual raters for identifying inappropriate tests were calculated. Inter-rater reliability of the Appropriate Use Criteria was assessed using Cohen κ statistics for pairs of different raters. The mean age of patients was 61.5 years; 214 (54%) were female. The cardiologists rated 256 (64%) of 400 nuclear stress tests as appropriate, 68 (18%) as uncertain, 55 (14%) as inappropriate; 21 (5%) tests were unable to be classified. Inter-rater reliability for noncardiologist raters was modest (unweighted Cohen κ, 0.51, 95% confidence interval, 0.45–0.55). Sensitivity of individual raters for identifying inappropriate tests ranged from 47% to 82%, while specificity ranged from 85% to 97%.
Conclusions—Inter-rater reliability for the 2009 Appropriate Use Criteria for radionuclide imaging is modest, and there is considerable variation in the ability of raters at different levels of training to identify inappropriate tests
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival