Predictive value of early and late residual 18F-fluorodeoxyglucose and 18F-fluorothymidine uptake using different SUV measurements in patients with non-small-cell lung cancer treated with erlotinib

Purpose

To evaluate the predictive value of early and late residual ¹⁸F-fluorodeoxyglucose (FDG) and ¹⁸F-fluorothymidine (FLT) uptake using different SUV measurements in PET in patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib.

Methods

We retrospectively reviewed data from 30 patients with untreated stage IV NSCLC who had undergone a combined FDG PET and FLT PET scan at 1?week (early) and 6?weeks (late) after the start of erlotinib treatment. Early and late residual FDG and FLT uptake were measured in up to five lesions per scan with different quantitative standardized uptake values (SUV_max, SUV_2Dpeak, SUV_3Dpeak, SUV₅₀, SUV_A50, SUV_A41) and compared with short-term outcome (progression vs. nonprogression after 6?weeks of erlotinib treatment). Receiver-operating characteristics (ROC) curve analysis was used to determine the optimal cut-off value for detecting nonprogression after 6?weeks. Kaplan-Meier analysis and the log-rank test were used to evaluate the association between residual uptake and progression-free survival (PFS).

Results

Nonprogression after 6?weeks was associated with a significantly lower early and late residual FDG uptake, measured with different quantitative parameters. In contrast, nonprogression after 6?weeks was not associated with early and late residual FLT uptake. Furthermore, patients with a lower early residual FDG uptake measured in terms of SUV_max and SUV_2Dpeak had a significantly prolonged PFS (282?days vs. 118?days; p?=?0.022) than patients with higher values. Similarly, lower late residual FDG uptake and early residual FLT uptake measured in terms of SUV_3Dpeak, SUV_A50 and SUV_A41, and late FLT uptake measured in terms of SUV_3Dpeak and SUV_A50 was associated with an improved PFS.

Conclusion

Early and late residual FDG uptake, measured using different quantitative SUV parameters, are predictive factors for short-term outcome in patients with advanced NSCLC treated with erlotinib. Additionally, low residual FDG and FLT uptake early and late in the course of erlotinib treatment is associated with improved PFS.     

Induction and repair of DNA double-strand breaks in blood lymphocytes of patients undergoing 18F-FDG PET/CT examinations

Purpose

The purpose of this study was to evaluate DNA double-strand breaks (DSBs) in blood lymphocytes of patients undergoing positron emission tomography (PET)/CT using γ-H2AX immunofluorescence microscopy and to differentiate between ¹⁸F-fluorodeoxyglucose (FDG) and CT-induced DNA lesions.

Methods

This study was approved by the local Ethics Committee and complies with Health Insurance Portability and Accountability Act (HIPAA) requirements. After written informed consent was obtained, 33 patients underwent whole-body ¹⁸F-FDG PET/CT (3?MBq/kg body weight, 170/100 reference mAs at 120?kV). The FDG PET and CT portions were performed as an initial CT immediately followed by the PET. Blood samples were obtained before, at various time points following ¹⁸F-FDG application and up to 24?h after the CT scan. Distinct foci representing DSBs were quantified in isolated lymphocytes using fluorescence microscopy after staining against the phosphorylated histone variant γ-H2AX.

Results

The DSB values at the various time points were significantly different (p?<?0.001). The median baseline level was 0.08/cell (range 0.06–0.12/cell). Peaks of radiation-induced DSBs were found 30?min after ¹⁸F-FDG administration (median excess foci 0.11/cell, range 0.06–0.27/cell) and 5?min after CT (median excess foci 0.17/cell, range 0.05–0.54/cell). A significant correlation between CT-induced DSBs and dose length product was obtained (ρ?=?0.898, p?<?0.001). After 24?h DSB values were still slightly but significantly elevated (median foci 0.11/cell, range 0.10–0.14/cell, p?=?0.003) compared to pre-exposure levels.

Conclusion

PET/CT-induced DSBs can be monitored using γ-H2AX immunofluorescence microscopy. Peak values may be obtained 30?min after ¹⁸F-FDG injection and 5?min after CT. The radionuclide contributes considerably to the total DSB induction in this setting.     

MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors

The apoptosis inhibitor protein survivin is overexpressed in many tumors, making it a candidate target molecule for various forms of immunotherapy. To explore survivin as a target antigen for adoptive T cell therapy using lymphocytes expressing survivin-specific transgenic T cell receptors (Tg-TCRs), we isolated HLA-A2-allorestricted survivin-specific T cells with high functional avidity. Lymphocytes expressing Tg-TCRs were derived from these T cells and specifically recognized HLA-A2+ survivin+ tumor cells. Surprisingly, HLA-A2+ but not HLA-A2- lymphocytes expressing Tg-TCRs underwent extensive apoptosis over time. This demise was caused by HLA-A2-restricted fratricide that occurred due to survivin expression in lymphocytes, which created ligands for Tg-TCR recognition. Therefore, survivin-specific TCR gene therapy would be limited to application in HLA-A2-mismatched stem cell transplantation. We also noted that lymphocytes that expressed survivin-specific Tg-TCRs killed T cell clones of various specificities derived from HLA-A2+ but not HLA-A2- donors. These results raise a general question regarding the development of cancer vaccines that target proteins that are also expressed in activated lymphocytes, since induction of high-avidity T cells that expand in lymph nodes following vaccination or later accumulate at tumor sites might limit themselves by self-MHC-restricted fratricide while at the same time inadvertently eliminating neighboring T cells of other specificities.