In vivo validation and tissue sparing factor for acute damage of pencil beam scanning proton FLASH.

BACKGROUND AND PURPOSE: Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. Most data so far are based on electron beams with limited utility for human treatments. This study validates the effect of proton FLASH delivered with pencil beam scanning (PBS) in a mouse leg model of acute skin damage and quantifies the normal tissue sparing factor, the FLASH factor, through full dose response curves. MATERIALS AND METHODS: The right hind limb of CDF1 mice was irradiated with a single fraction of proton PBS in the entrance plateau of either a 244 MeV conventional dose rate field or a 250 MeV FLASH field. In total, 301 mice were irradiated in four separate experiments, with 7-21 mice per dose point. The endpoints were the level of acute moist desquamation to the skin of the foot within 25 days post irradiation. RESULTS: The field duration and field dose rate were 61-107 s and 0.35-0.40 Gy/s for conventional dose rate and 0.35-0.73 s and 65-92 Gy/s for FLASH. Full dose response curves for five levels of acute skin damage for both conventional and FLASH dose rate revealed a distinct normal tissue sparing effect with FLASH: across all scoring levels, a 44-58% higher dose was required to give the same biological response with FLASH as compared to the conventional dose rate. CONCLUSIONS: The normal tissue sparing effect of PBS proton FLASH was validated. The FLASH factor was quantified through full dose response curves.

Comparison of Coding Transcriptomes in Fibroblasts Irradiated With Low and High LET Proton Beams and Cobalt-60 Photons.

PURPOSE: To identify differential cellular responses after proton and photon irradiation by comparing transcriptomes of primary fibroblasts irradiated with either radiation type. METHODS AND MATERIALS: A panel of primary dermal fibroblast cultures was irradiated with low and higher linear energy transfer (LET) proton beams. Cobalt-60 photon irradiation was used as reference. Dose was delivered in 3 fractions of 3.5 Gy (relative biological effectiveness) using a relative biological effectiveness of 1.1 for proton doses. Cells were harvested 2 hours after the final fraction was delivered, and RNA was purified. RNA sequencing was performed using Illumina NextSeq 500 with high-output kit. The edgeR package in R was used for differential gene expression analysis. RESULTS: Pairwise comparisons of the transcriptomes in the 3 treatment groups showed that there were 84 and 56 differentially expressed genes in the low LET group compared with the Cobalt-60 group and the higher LET group, respectively. The higher LET proton group and the Cobalt-60 group had the most distinct transcriptome profiles, with 725 differentially regulated genes. Differentially regulated canonical pathways and various regulatory factors involved in regulation of biological mechanisms such as inflammation, carcinogenesis, and cell cycle control were identified. CONCLUSIONS: Inflammatory regulators associated with the development of normal tissue complications and malignant transformation factors seem to be differentially regulated by higher LET proton and Cobalt-60 photon irradiation. The reported transcriptome differences could therefore influence the progression of adverse effects and the risk of developing secondary cancers.

Plasma proteins as prognostic biomarkers in radiotherapy treated head and neck cancer patients.

BACKGROUND: Blood-based protein biomarkers can be a useful tool as pre-treatment prognostic markers, as they can reflect both variations in the tumor microenvironment and the host immune response. We investigated the influence of a panel of plasma proteins for the development of any failure defined as recurrent disease in the T-, N-, or M-site in HNSCC. METHODS: We used a multiplex bead-based approach to analyze 19 proteins in 86 HNSCC patients and 15 healthy controls. We evaluated the associations between the biomarkers, loco-regional failure, failure in the T-, N-, or M-site, overall survival (OS), p16 status, and hypoxia. RESULTS: In 41 p16 positive oropharynx cancer patients we identified a profile of biomarkers consisting of upregulation of IL-2, IL-4, IL-6, IL-8, eotaxin, GRO-a, and VEGF and downregulation of VEGFR-1 and VEGFR-2 with a significantly reduced risk of failure (p < 0.01). None of the individual proteins were associated with outcome. CONCLUSION: The identified plasma profile potentially reflects an activated immune response in a subgroup of the p16 positive patients.

The relative biological effectiveness of antiprotons.

BACKGROUND AND PURPOSE: Aside from the enhancement of physical dose deposited by antiprotons annihilating in tissue-like material compared to protons of the same range a further increase of biological effective dose has been demonstrated. This enhancement can be expressed in an increase of the relative biological effectiveness (RBE) of antiprotons near the end of range. We have performed the first-ever direct measurement of the RBE of antiprotons both at rest and in flight. MATERIALS AND METHODS: Experimental data were generated on the RBE of an antiproton beam entering a tissue-like target consisting of V79 cells embedded in gelatin with an energy providing a range of approximately 10cm. RESULTS: The RBE in the entrance channel (the "plateau") is only slightly above the value for a comparable proton beam, and remains low until the proximal edge of the spread-out Bragg peak (SOBP). A steep increase of RBE is seen starting from the onset of the SOBP. CONCLUSIONS: This paper reports the final results of the experiment AD-4/ACE at CERN on the first-ever direct measurement of RBE of antiprotons and constitutes the first step toward developing treatment plans.