Description: Despite ongoing efforts to develop new treatment options, the prognosis for patients with inoperable esophageal carcinoma is still poor and the reliability of individual therapy outcome prediction based on clinical parameters is not convincing. The aim of this work was to investigate whether PET can provide independent prognostic information in such a patient group and whether the tumor-to-blood standardized uptake ratio (SUR) can improve the prognostic value of tracer uptake values. Methods: 18 F-FDG PET/CT was performed in 130 consecutive patients (mean age ± SD, 63 ± 11 y; 113 men, 17 women) with newly diagnosed esophageal cancer before definitive radiochemotherapy. In the PET images, the metabolically active tumor volume (MTV) of the primary tumor was delineated with an adaptive threshold method. The blood standardized uptake value (SUV) was determined by manually delineating the aorta in the low-dose CT. SUR values were computed as the ratio of tumor SUV and blood SUV. Uptake values were scan-time-corrected to 60 min after injection. Univariate Cox regression and Kaplan–Meier analysis with respect to overall survival (OS), distant metastases-free survival (DM), and locoregional tumor control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. Results: In multivariate Cox regression with respect to OS, including T stage, N stage, and smoking state, MTV- and SUR-based parameters were significant prognostic factors for OS with similar effect size. Multivariate analysis with respect to DM revealed smoking state, MTV, and all SUR-based parameters as significant prognostic factors. The highest hazard ratios (HRs) were found for scan-time-corrected maximum SUR (HR = 3.9) and mean SUR (HR = 4.4). None of the PET parameters was associated with LRC. Univariate Cox regression with respect to LRC revealed a significant effect only for N stage greater than 0 ( P = 0.048). Conclusion: PET provides independent prognostic information for OS and DM but not for LRC in patients with locally advanced esophageal carcinoma treated with definitive radiochemotherapy in addition to clinical parameters. Among the investigated uptake-based parameters, only SUR was an independent prognostic factor for OS and DM. These results suggest that the prognostic value of tracer uptake can be improved when characterized by SUR instead of SUV. Further investigations are required to confirm these preliminary results.

Description: Radioimmunotherapy is considered to have great potential for efficient and highly specific treatment of tumors. The aim of this study was to determine the efficacy of radioimmunotherapy when using 90 Y-labeled cetuximab and to determine to what degree induction and repair of DNA double-strand breaks (DSBs) are decisive for this approach. Methods: This study was performed with 9 cell lines of squamous cell carcinoma of the head and neck (HNSCC) differing strongly in epidermal growth factor receptor (EGFR) expression. The radionuclide 90 Y was coupled by the chelator trans -cyclohexyl-diethylene-triamine-pentaacetic acid (CHX-A''-DTPA)/linker construct to the EGFR-directed antibody cetuximab to yield 90 Y-Y-CHX-A''-DTPA-cetuximab with a specific activity of approximately 1.2 GBq/mg. EGFR expression was determined by immunofluorescence and Western blotting, cetuximab binding by fluorescence-activated cell sorter analysis, the number of DSBs by immunofluorescence staining H2AX/53BP1-positive repair foci, and cell survival by colony formation. Results : For the 9 HNSCC cell lines, cetuximab binding correlated with the amount of EGFR present in the cell membrane ( r 2 = 0.967, P 〈 0.001). When cells were exposed to 90 Y-Y-CHX-A''-DTPA-cetuximab, the number of induced DSBs increased linearly with time ( r 2 = 0.968, P = 0.016). This number was found to correlate with the amount of membranous EGFR ( r 2 = 0.877, P = 0.006). Most DSBs were repaired during incubation at 37°C, but the small number of remaining DSBs still correlated with the amount of membranous EGFR (24 h: r 2 = 0.977, P 〈 0.001; 48 h: r 2 = 0.947, P 〈 0.001). Exposure to 90 Y-Y-CHX-A''-DTPA-cetuximab also resulted in efficient cell killing, whereby the extent of cell killing correlated strongly with the respective number of remaining DSBs ( r 2 = 0.989, P 〈 0.001) and with the amount of membranous EGFR ( r 2 = 0.967, P 〈 0.001). No cell killing was observed for UTSCC15 cells with low EGFR expression, in contrast to the strong reduction of 86% measured for UTSCC14 cells showing a strong overexpression of EGFR. Conclusion: 90 Y-Y-CHX-A''-DTPA-cetuximab affected cell survival through the induction of DSBs. This treatment was especially efficient for HNSCC cells strongly overexpressing EGFR, whereas no effect was seen for cells with low levels of EGFR expression. Therefore, EGFR-directed radioimmunotherapy using 90 Y-Y-CHX-A''-DTPA-cetuximab appears to be a powerful tool that can be used to inactivate tumors with strong EGFR overexpression, which are often characterized by a pronounced radioresistance.

Description: Author(s): F. Holzmeier, R. Y. Bello, M. Hervé, A. Achner, T. M. Baumann, M. Meyer, P. Finetti, M. Di Fraia, D. Gauthier, E. Roussel, O. Plekan, R. Richter, K. C. Prince, C. Callegari, H. Bachau, A. Palacios, F. Martín, and D. Dowek The role of the nuclear degrees of freedom in nonlinear two-photon single ionization of H 2 molecules interacting with short and intense vacuum ultraviolet pulses is investigated, both experimentally and theoretically, by selecting single resonant vibronic intermediate neutral states. This high selec... [Phys. Rev. Lett. 121, 103002] Published Fri Sep 07, 2018