ALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.
S100A1 may be a potentially powerful marker to differentiate the chromophobe RCC from renal oncocytoma.
Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a ‘liquid biopsy’ is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment.
The widespread mobile phone use raises concerns on the possible cerebral effects of radiofrequency electromagnetic fields (RF EMF). Reactive astrogliosis was reported in neuroanatomical structures of adaptive behaviors after a single RF EMF exposure at high specific absorption rate (SAR, 6 W/kg). Here, we aimed to assess if neuronal injury and functional impairments were related to high SAR-induced astrogliosis. In addition, the level of beta amyloid 1-40 (Aβ 1-40) peptide was explored as a possible toxicity marker. Sprague Dawley male rats were exposed for 15 min at 0, 1.5, or 6 W/kg or for 45 min at 6 W/kg. Memory, emotionality, and locomotion were tested in the fear conditioning, the elevated plus maze, and the open field. Glial fibrillary acidic protein (GFAP, total and cytosolic fractions), myelin basic protein (MBP), and Aβ1-40 were quantified in six brain areas using enzyme-linked immunosorbent assay. According to our data, total GFAP was increased in the striatum (+114 %) at 1.5 W/kg. Long-term memory was reduced, and cytosolic GFAP was increased in the hippocampus (+119 %) and in the olfactory bulb (+46 %) at 6 W/kg (15 min). No MBP or Aβ1-40 expression modification was shown. Our data corroborates previous studies indicating RF EMF-induced astrogliosis. This study suggests that RF EMF-induced astrogliosis had functional consequences on memory but did not demonstrate that it was secondary to neuronal damage.
Purpose: The diagnostic test of ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine needle aspirations. The present study was designed to evaluate -1) whether ALK-rearrangement diagnosis could be performed using circulating tumor cells (CTCs), -2) whether CTCs harboring ALK-rearrangement could be monitored in ALK-positive patients treated by crizotinib. Patients and Methods: CTCs were isolated in 18 ALK-positive and 14 ALK-negative patients by blood filtration using ISET (Isolation by Size Epithelial Tumor cells) and tested by filter adapted-fluorescence in situ hybridization (FA-FISH), a FISH method optimized for filters. Numbers of ALK-rearranged cells and patterns of ALK-rearrangement were determined in CTCs and compared to those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratin, E-cadherin) and mesenchymal (vimentin, N-cadherin) markers expression. ALK-rearranged CTCs were monitored in ALK-positive patients treated by crizotinib. Results: ALK-rearranged CTCs [ranging from 4 to 34 CTCs /1mL] were detected in all ALK-positive patients, while no or only one ALK-rearranged CTCs was detected in blood samples obtained from ALK-negative patients. ALK-rearranged CTCs harboured a unique (3’ 5’) split pattern while heterogeneous patterns (3’ 5’, only 3’) of splits were present in tumors. ALK-rearranged CTCs exclusively expressed a mesenchymal phenotype and contrasted with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in levels of ALK-rearranged CTCs and in CTCs harboring a gain of ALK native copies were detected under crizotinib treatment. Conclusion: We report that ALK-rearrangement can be detected in CTCs of ALK-positive NSCLC patients using ISET and FA-FISH, enabling diagnostic testing for crizotinib treatment. Our results suggest that CTCs harboring a unique ALK-rearrangement and mesenchymal phenotype may arise from the clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC. The molecular characterization of CTCs in patients undergoing crizotinib treatment might provide new insights into mechanism of resistance to ALK tyrosine kinase inhibitors, and possible strategies to overcome this resistance. Citation Format: Emma Pailler, Julien Adam, Amélie Barthelemy, Marianne Oulhen, Nathalie Auger, Alexander Valent, David Planchard, Melissa Taylor, Isabelle Borget, Fabrice Andre, Jean-Charles Soria, Philippe Vielh, Benjamin Besse, Françoise Farace. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1470. doi:10.1158/1538-7445.AM2013-1470
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