PubMed · 7042147
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R Bataille. 1982. Localized Plasmacytomas.. https://pubmed.ncbi.nlm.nih.gov/7042147/
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BACKGROUND: Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes. METHODS: We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations. RESULTS: Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture. CONCLUSIONS: Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.
The ability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMCs) to induce secretion of cytokines in primary long-term marrow cultures (LTC) or in the human marrow stromal cell line HS23 was compared with that of marrow mononuclear cells. Equal numbers of G-PBMCs or marrow mononuclear cells were added to stromal cultures, supernatants were harvested at day 4 and levels of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, G-CSF, and tumor necrosis factor alpha (TNF alpha) were determined. G-PBMCs induced 21.4-fold higher levels of IL-6 and 12.5-fold higher levels of G-CSF in LTC cocultures compared with marrow mononuclear cells and induced 20.6-fold more IL-6 and 6.3-fold more G-CSF when added to HS23 cells. Experiments using sorted populations of CD20+, CD3+, and CD14+ cells showed that CD14+ cells within G-PBMCs were responsible for triggering the production of IL-6 and G-CSF. The effect did not require cell-cell contact and was inhibited when neutralizing antibodies to IL-1 alpha and IL-1 beta were used in combination. In these experiments, the greater stimulating ability of G-PBMCs is most likely attributable to the greater number of CD14+ cells in G-PBMCs (26.1+% +/- 2.3%) compared with marrow (2.5% +/- 0.8%), because equal numbers of CD14+ cells sorted from marrow and G-PBMCs showed comparable ability to induce IL-6 and G-CSF when placed directly on stromal cells.
UNLABELLED: Copper-67 (67Cu) is an attractive radionuclide for radioimmuno-therapy because of its favorable physical and biologic characteristics. Current supplies of 67Cu, however, contain as much as 60% of 64Cu at the time of delivery. Scatter photons from 64Cu enter the 67Cu energy window, affecting image resolution and counting accuracy. The radiation dose to tissue is also altered. METHODS: A line source and a small vial source of 67Cu containing varying amounts of 64Cu were used to evaluate the impact of 64Cu on image resolution and activity quantitation, respectively. Identical pharmacokinetics for 67Cu and 64Cu was assumed, and the radiation dosimetry of 64Cu was assessed using quantitative imaging data for 67Cu because the amount of 64Cu could be calculated for any time after 67Cu production. MIRD formalism was used to estimate the therapeutic index, defined as the ratio of radiation dose to tumor divided by the radiation dose to bone marrow. RESULTS: As the amount of 64Cu increased, the full width at tenth maximum of the line spread function increased, although there was no significant change in full width at half maximum. The number of scatter counts from 64Cu increased as the amount of 64Cu or the size of the source region of interest increased. When 64Cu was 25% of the total activity, less than 10% of the total 67Cu photopeak counts detected with a scintillation camera were attributable to 64Cu. Although the tumor radiation dose per unit of activity (cGy/GBq) from 67Cu was five times greater than that from 64Cu, the marrow dose (CGy/GBq) from 67Cu was only three times greater than that from 64Cu. Therefore, the therapeutic index was diminished by the presence of 64Cu. When 64Cu radioimpurity was less than 25% of the total activity, there was less than a 10% decrease in the therapeutic index. CONCLUSION: The shorter physical half-life of 64Cu relative to that of 67Cu and slower uptake and longer retention of antibody by tumor than by marrow result in a lower therapeutic index for 64Cu. The 25% radioimpurity of 64Cu causes less than 10% deviation in activity quantitation and diminution in the therapeutic index. The change in therapeutic index is predictable over time and can be used to determine the optimal time for radiopharmaceutical administration.