ABSTRACT
BACKGROUND: Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. METHODS: Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 106 receptors/cell) at 24 h p.i. of 70 MBq (10 µg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 µg) of 64Cu-DOTA-trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. RESULTS: 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA-trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for 64Cu-DOTA-trastuzumab Fab than 111In-DOTA-trastuzumab Fab. CONCLUSIONS: We conclude that 111In-DOTA-trastuzumab Fab was more specific than 64Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for 64Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind 64Cu may improve the association between T/B ratios and HER2 density for 64Cu-labeled trastuzumab Fab.
ABSTRACT
Previous studies of problem gamblers portray this group as being almost exclusively male. However, this study demonstrates that females comprised 46% of the population ( n = 1,520) of persons who sought assistance due to concerns about their gambling from the publicly-funded BreakEven counselling services in the state of Victoria, Australia, in one 12-month period. This suggests that the model of service delivery which is community based counselling on a non-residential basis may be better able to attract female clients than treatment centres where males predominate such as veterans centres. A comparative analysis of the social and demographic characteristics of female and male gamblers within the study population was undertaken. As with previous studies, we have found significant differences between males and females who have sought help for problems associated with their gambling. Gender differences revealed in this study include females being far more likely to use electronic gaming machines (91.1% vs. 61.4%), older (39.6 years vs. 36.1 years), more likely to be born in Australia (79.4% vs. 74.7%), to be married (42.8% vs. 30.2%), living with family (78.9% vs. 61.5%) and to have dependent children (48.4% vs. 35.7%), than males who present at these services. Female gamblers (A$7,342) reported average gambling debts of less than half of that owed by males (A$19,091). These gender differences have implications for the development and conduct of problem gambling counselling services as it cannot be assumed that models of service which have demonstrated effectiveness with males will be similarly effective with females.
