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Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts

Elodie Melsens, Elly De Vlieghere (UGent) , Benedicte Descamps (UGent) , Christian Vanhove (UGent) , Ken Kersemans (UGent) , Filip De Vos (UGent) , Ingeborg Goethals (UGent) , Boudewijn Brans (UGent) , Olivier De Wever (UGent) , Wim Ceelen (UGent) , et al.
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Abstract
Background: Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with F-18-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. Methods: In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 mu L PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 mu l NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. F-18-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). Results: A T/B= 3.59 on pre-treatment F-18-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B = 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. Conclusions: Tumor tissue hypoxia as measured with F-18-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.
Keywords
Radioresistance, F-18-FAZA pet/CT, Tumor hypoxia, Predictive biomarker, Esophageal adenocarcinoma xenografts, Nimorazole, SQUAMOUS-CELL CARCINOMA, PROGNOSTIC VALUE, TUMOR HYPOXIA, F-18-FLUOROAZOMYCIN ARABINOSIDE, RADIATION-THERAPY, NECK-CANCER, BASE-LINE, IN-VIVO, NIMORAZOLE, HEAD

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Chicago
Melsens, Elodie, Elly De Vlieghere, Benedicte Descamps, Christian Vanhove, Ken Kersemans, Filip De Vos, Ingeborg Goethals, et al. 2018. “Hypoxia Imaging with 18F-FAZA PET/CT Predicts Radiotherapy Response in Esophageal Adenocarcinoma Xenografts.” Radiation Oncology 13.
APA
Melsens, E., De Vlieghere, E., Descamps, B., Vanhove, C., Kersemans, K., De Vos, F., Goethals, I., et al. (2018). Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts. RADIATION ONCOLOGY, 13.
Vancouver
1.
Melsens E, De Vlieghere E, Descamps B, Vanhove C, Kersemans K, De Vos F, et al. Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts. RADIATION ONCOLOGY. 2018;13.
MLA
Melsens, Elodie, Elly De Vlieghere, Benedicte Descamps, et al. “Hypoxia Imaging with 18F-FAZA PET/CT Predicts Radiotherapy Response in Esophageal Adenocarcinoma Xenografts.” RADIATION ONCOLOGY 13 (2018): n. pag. Print.
@article{8556118,
  abstract     = {Background: Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with F-18-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. 
Methods: In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic ({\textlangle} 1\%) conditions: control (100 mu L PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 mu l NaCl 0.9\% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. F-18-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). 
Results: A T/B= 3.59 on pre-treatment F-18-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3\%, specificity 71.4\%). Radiation was less effective in hypoxic tumors (T/B = 3.59) compared to normoxic tumors (T/B {\textlangle} 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P {\textlangle} 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. 
Conclusions: Tumor tissue hypoxia as measured with F-18-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.},
  articleno    = {39},
  author       = {Melsens, Elodie and De Vlieghere, Elly and Descamps, Benedicte and Vanhove, Christian and Kersemans, Ken and De Vos, Filip and Goethals, Ingeborg and Brans, Boudewijn and De Wever, Olivier and Ceelen, Wim and Pattyn, Piet},
  issn         = {1748-717X},
  journal      = {RADIATION ONCOLOGY},
  language     = {eng},
  pages        = {8},
  title        = {Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts},
  url          = {http://dx.doi.org/10.1186/s13014-018-0984-3},
  volume       = {13},
  year         = {2018},
}

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