Christopher M. Walker

PURPOSE: The purpose is to investigate whether aggressive basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) differ from nonaggressive BCC and SCC with respect to the p53 mutation spectrum and whether specific mutations can serve as prognostic indicators of tumor aggressiveness. EXPERIMENTAL DESIGN: We analyzed 342 tissues from patients with aggressive and nonaggressive BCCs and SCCs for p53 mutations by single-strand conformation polymorphism and nucleotide sequencing. RESULTS: p53 mutations were detected in 33 of 50 aggressive BCCs (66%), 37 of 98 nonaggressive BCCs (38%), 28 of 80 aggressive SCCs (35%), 28 of 56 nonaggressive SCCs (50%), and 3 of 29 samples of sun-exposed skin (10%). About 71% of the p53 mutations detected in aggressive and nonaggressive BCCs and SCCs were UV signature mutations. The frequency of CC to TT mutations in aggressive (36%) and nonaggressive SCCs (39%) was 2-fold higher than in aggressive (18%) and nonaggressive (14%) BCCs. In contrast, aggressive BCCs had a higher frequency (24%) of transversions than nonaggressive BCCs (8%) and aggressive (14%) and nonaggressive (11%) SCCs did. CONCLUSIONS: Our results indicate that UV radiation is responsible for the induction of p53 mutations and perhaps for the initiation of both aggressive and nonaggressive BCCs and SCCs. Although some differences in p53 mutation frequency, types of mutation, and hot spots were seen between aggressive and nonaggressive BCCs and SCCs, these factors do not constitute as clear-cut diagnostic or prognostic indicators of tumor aggressiveness. Tumor aggressiveness may be attributable to other genetic changes or events that occur during tumor progression.

Hyperpolarized [1-(13)C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison with alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly undersampled imaging data from tumor-bearing animals. Compared with naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements.