This analysis suggests that immutable factors, such as age and complexion, have a significant impact on BCC and SCC. However, specific treatment (radiotherapy) and transplantation complications (GVHD) may modify that risk. These additional risk factors suggest the contribution of immunologic mechanism DNA and tissue repair in the development of BCC and SCC. We confirm previous reports that exposure to ionizing radiation increases the risk of BCC but not SCC. Survivors of HCT should be monitored for the development of BCC and SCC and use preventive strategies.

Previous studies identified radiation therapy as a key modifier of basal cell carcinoma (BCC) risk in survivors of hematopoietic cell transplantation (HCT). In the present analysis, risk of BCC was analyzed in relation to age at transplant, attained age, race, total-body irradiation (TBI), and radiation fractionation in 6,306 patients who received HCT at ages 0–65 years after conditioning regimens with (n = 3870) or without (n = 2436) TBI, and who were followed from 100 days to 36.2 years after HCT. While age-specific BCC rates in the unirradiated patient population were higher than those reported for two non-patient populations, the general characteristics were similar; rates increased with attained age, were eightfold lower for non-white patients, and were higher in more recent birth cohorts. After adjusting for these effects, risk in unirradiated patients did not vary significantly with age at HCT. The additional BCC risk associated with radiation exposure was largest for the youngest ages at exposure to radiation, with relative risks exceeding 20 for those transplanted at ages less than 10 years, and decreased with increasing age at exposure until age 40 years, above which no excess risk was identified. Relative risk in the irradiated population did not vary significantly with attained age, dose fractionation or race. Risks per unit dose in HCT patients were similar to other populations exposed under clinical settings to similar radiation doses and were more than 10-fold lower than seen in the atomic bomb survivors, 97% of whom were exposed to doses < 1 Sv.

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Supplementation of the culture media of human MCF-7 breast carcinoma cells or mouse fibroblasts with low levels of selenium (30 nM) provided as sodium selenite was shown to protect these cells from ultraviolet (UV)-induced chromosome damage, as quantified by micronucleus assay. Selenium supplementation was also effective in reducing UV-induced gene mutations as measured in the lacI shuttle vector model. Protection was dependent on functional BRCA1 activity, a protein implicated in breast cancer risk and DNA damage repair. In addition, overexpression of GPx-1, a selenoprotein with antioxidant activity, also attenuated UV induced micronuclei formation in the absence of selenium supplementation. Combining selenium supplementation with GPx-1 overexpression further reduced UV-induced micronucleus frequency. These data provide evidence that the benefits of selenium supplementation might be either through the prevention or repair of DNA damage, and they implicate at least one selenoprotein (GPx-1) in the process.

There are many unknowns in the radiobiology of proton beams and other particle beams. We describe the development and testing of an image-guided low-energy proton system optimized for radiobiological research applications. A 50 MeV proton beam from an existing cyclotron was modified to produce collimated beams (as small as 2 mm in diameter). Ionization chamber and radiochromic film measurements were performed and benchmarked with Monte Carlo simulations (TOPAS). The proton beam was aligned with a commercially-available CT image-guided x-ray irradiator device (SARRP, Xstrahl Inc.). To examine the alternative possibility of adapting a clinical proton therapy system, we performed Monte Carlo simulations of a range-shifted 100 MeV clinical beam. The proton beam exhibits a pristine Bragg Peak at a depth of 21 mm in water with a dose rate of 8.4 Gy min (3 mm depth). The energy of the incident beam can be modulated to lower energies while preserving the Bragg peak. The LET was: 2.0 keV µm (water surface), 16 keV µm (Bragg peak), 27 keV µm (10% peak dose). Alignment of the proton beam with the SARRP system isocenter was measured at 0.24 mm agreement. The width of the beam changes very little with depth. Monte Carlo-based calculations of dose using the CT image data set as input demonstrate in vivo use. Monte Carlo simulations of the modulated 100 MeV clinical proton beam show a significantly reduced Bragg peak. We demonstrate the feasibility of a proton beam integrated with a commercial x-ray image-guidance system for preclinical in vivo studies. To our knowledge this is the first description of an experimental image-guided proton beam for preclinical radiobiology research. It will enable in vivo investigations of radiobiological effects in proton beams.

The basis for the use of nucleoside tracers in PET is that activity of the cell-growth–dependent enzyme thymidine kinase 1 is the rate-limiting factor driving tracer retention in tumors. Recent publications suggest that nucleoside transporters might influence uptake and thereby affect the tracer signal in vivo. Understanding transport mechanisms for different nucleoside PET tracers is important for evaluating clinical results. This study examined the relative role of different nucleoside transport mechanisms in uptake and retention of [methyl-3H]-3′-deoxy-3′-fluorothymidine (3H-FLT), [methyl-3H]-thymidine (3H-thymidine), and 3H-1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-methyluracil (3H-FMAU). Methods Transport of 3H-FLT, 3H-thymidine, and 3H-FMAU was examined in a single human adenocarcinoma cell line, A549, under both nongrowth and exponential-growth conditions. Results 3H-Thymidine transport was dominated by human equilibrative nucleoside transporter 1 (hENT1) under both growth conditions. 3H-FLT was also transported by hENT1, but passive diffusion dominated its transport. 3H-FMAU transport was dominated by human equilibrative nucleoside transporter 2. Cell membrane levels of hENT1 increased in cells under exponential growth, and this increase was associated with a more rapid rate of uptake for both 3H-thymidine and 3H-FLT. 3H-FMAU transport was not affected by changes in growth conditions. All 3 tracers concentrated in the plateau phase, nonproliferating cells at levels many-fold greater than their concentration in buffer, in part because of low levels of nucleoside metabolism, which inhibited tracer efflux. Conclusion Transport mechanisms are not the same for 3H-thymidine, 3H-FLT, and 3H-FMAU. Levels of hENT1, an important transporter of 3H-FLT and 3H-thymidine, increase as proliferating cells enter the cell cycle.

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