Early Prediction and Monitoring of Treatment Response in Gastrointestinal Stromal Tumors by Means of Imaging: A Systematic Review

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms. Tyrosine kinase inhibitor (TKI) therapy is currently part of routine clinical practice for unresectable and metastatic disease. It is important to assess the efficacy of TKI treatment at an early stage to optimize therapy strategies and eliminate futile ineffective treatment, side effects and unnecessary costs. This systematic review provides an overview of the imaging features obtained from contrast-enhanced (CE)-CT and 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) PET/CT to predict and monitor TKI treatment response in GIST patients. PubMed, Web of Science, the Cochrane Library and Embase were systematically screened. Articles were considered eligible if quantitative outcome measures (area under the curve (AUC), correlations, sensitivity, specificity, accuracy) were used to evaluate the efficacy of imaging features for predicting and monitoring treatment response to various TKI treatments. The methodological quality of all articles was assessed using the Quality Assessment of Diagnostic Accuracy Studies, v2 (QUADAS-2) tool and modified versions of the Radiomics Quality Score (RQS). A total of 90 articles were included, of which 66 articles used baseline [F-18]FDG-PET and CE-CT imaging features for response prediction. Generally, the presence of heterogeneous enhancement on baseline CE-CT imaging was considered predictive for high-risk GISTs, related to underlying neovascularization and necrosis of the tumor. The remaining articles discussed therapy monitoring. Clinically established imaging features, including changes in tumor size and density, were considered unfavorable monitoring criteria, leading to under- and overestimation of response. Furthermore, changes in glucose metabolism, as reflected by [F-18]FDG-PET imaging features, preceded changes in tumor size and were more strongly correlated with tumor response. Although CE-CT and [F-18]FDG-PET can aid in the prediction and monitoring in GIST patients, further research on cost-effectiveness is recommended

Cell Proliferation and DNA Breaks Are Involved in Ultraviolet Light-induced Apoptosis in Nucleotide Excision Repair-deficient Chinese Hamster Cells

UV light targets both membrane receptors and nuclear DNA, thus evoking signals triggering apoptosis. Although receptor-mediated apoptosis has been extensively investigated, the role of DNA damage in apoptosis is less clear. To analyze the importance of DNA damage induced by UV-C light in apoptosis, we compared nucleotide excision repair (NER)-deficient Chinese hamster ovary cells (lines 27-1 and 43-3B mutated for the repair genes ERCC3 and ERCC1, respectively) with the corresponding DNA repair-proficient fibroblasts (CHO-9 and ERCC1 complemented 43-3B cells). NER-deficient cells were hypersensitive as to the induction of apoptosis, indicating that apoptosis induced by UV-C light is due to unrepaired DNA base damage. Unrepaired lesions, however, do not activate the apoptotic pathway directly because apoptosis upon UV-C irradiation requires DNA replication and cell proliferation. It is also shown that in NER-deficient cells unrepaired lesions are converted into DNA double-strand breaks (DSBs) and chromosomal aberrations by a replication-dependent process that precedes apoptosis. We therefore propose that DSBs arising from replication of DNA containing nonrepaired lesions act as an ultimate trigger of UV-C–induced apoptosis. Induction of apoptosis by UV-C light was related to decline in the expression level of Bcl-2 and activation of caspases. Decline of Bcl-2 and subsequent apoptosis might also be caused, at least in part, by UV-C–induced blockage of transcription, which was more pronounced in NER-deficient than in wild-type cells. This is in line with experiments with actinomycin D, which provoked Bcl-2 decline and apoptosis. UV-C–induced apoptosis due to nonrepaired DNA lesions, replication-dependent formation of DSBs, and activation of the mitochondrial damage pathway is independent of functional p53 for which the cells are mutated