Gold nanoparticles (GNPs) have shown potential to be used as a radiosensitizer for radiation therapy. Despite extensive research activity to study GNP radiosensitization using photon beams, only a few studies have been carried out using proton beams. In this work Monte Carlo simulations were used to assess the dose enhancement of GNPs for proton therapy. The enhancement effect was compared between a clinical proton spectrum, a clinical 6 MV photon spectrum, and a kilovoltage photon source similar to those used in many radiobiology lab settings. We showed that the mechanism by which GNPs can lead to dose enhancements in radiation therapy differs when comparing photon and proton radiation. The GNP dose enhancement using protons can be up to 14 and is independent of proton energy, while the dose enhancement is highly dependent on the photon energy used. For the same amount of energy absorbed in the GNP, interactions with protons, kVp photons and MV photons produce similar doses within several nanometers of the GNP surface, and differences are below 15% for the first 10 nm. However, secondary electrons produced by kilovoltage photons have the longest range in water as compared to protons and MV photons, e.g. they cause a dose enhancement 20 times higher than the one caused by protons 10 μm away from the GNP surface. We conclude that GNPs have the potential to enhance radiation therapy depending on the type of radiation source. Proton therapy can be enhanced significantly only if the GNPs are in close proximity to the biological target.

Background Immunotherapy has demonstrated remarkable success in treating different cancers. Nonetheless, a large number of patients do not respond, many respond without immediate changes detectable with conventional imaging, and many have unusual immune-related adverse events that cannot be predicted in advance. In this exploratory study, we investigate how 3′-Deoxy-3’-¹⁸F-fluorothymidine (FLT) positron emission tomography (PET) measurements of tumor and immune cell proliferation might be utilized as biomarkers in immunotherapy. Methods Seventeen patients with metastatic castrate resistant prostate cancer were treated with combination pTVG-HP DNA vaccine and pembrolizumab. Patients underwent baseline and 12-week FLT PET/CT scans. FLT PET standardized uptake values (SUVs) were extracted from tumors, non-metastatic lymph nodes, spleen, bone marrow, pancreas, and thyroid to quantify cell proliferation in these tissues. Regional immune cell responses to pTVG-HP DNA vaccine were assessed by comparing FLT uptake changes in vaccine draining and non-draining lymph nodes. Cox proportional hazards regression was utilized to relate FLT uptake and other clinical markers (PSA and tumor size) to progression-free survival. Area under receiver operating characteristic (AUC) curves and concordance indices were used to assess the predictive capabilities of FLT uptake. Results Changes in FLT uptake in vaccine draining lymph nodes were significantly greater than changes in non-draining lymph nodes (P = 0.02), suggesting a regional immune response to vaccination. However, the changes in FLT uptake in lymph nodes were not significantly predictive of progression-free survival. Increases in tumor FLT uptake were significantly predictive of shorter progression-free survival (concordance index = 0.83, P < 0.01). Baseline FLT uptake in the thyroid was significantly predictive of whether or not a patient would subsequently experience a thyroid-related adverse event (AUC = 0.97, P < 0.01). Conclusions FLT PET uptake was significantly predictive of progression-free survival and the occurrence of adverse events relating to thyroid function. The results suggest FLT PET imaging has potential as a biomarker in immunotherapy, providing a marker of tumor and immune responses, and as a possible means of anticipating specific immune-related adverse events. Trial registration NCT02499835.

Many successful preclinical findings fail to be replicated during translation to human studies. This leads to significant resources being spent on large clinical trials, and in some cases, promising therapeutics not being pursued due to the high costs of clinical translation. These translational failures emphasize the need for improved preclinical models of human cancer so that there is a higher probability of successful clinical translation. Companion-animal cancers offer a potential solution. These cancers are more similar to human cancer than other preclinical models, with a natural evolution over time, genetic alterations, intact immune system, and a permanent adaptation to the microenvironment. These advantages have led pioneers in veterinary radiation oncology to aid human medicine by elucidating basic principles of radiation biology. More recently, the veterinary and human radiation oncology fields have increasingly collaborated to achieve advancements in education, radiotherapy techniques, and trial networks. This review describes these advancements, including significant prior research findings and the evolution of the veterinary radiation oncology discipline. It concludes by describing how companion-animal models can help shape the future of human radiotherapy. Taken as a whole, this review suggests companion-animal cancers may become widely used for preclinical radiotherapy research.

The statistical analysis of positron emission tomography (PET) standardized uptake value (SUV) measurements is challenging due to the skewed nature of SUV distributions. This limits utilization of powerful parametric statistical models for analyzing SUV measurements. An ad-hoc approach, which is frequently used in practice, is to blindly use a log transformation, which may or may not result in normal SUV distributions. This study sought to identify optimal transformations leading to normally distributed PET SUVs extracted from tumors and assess the effects of therapy on the optimal transformations. Methods . The optimal transformation for producing normal distributions of tumor SUVs was identified by iterating the Box–Cox transformation parameter ( λ ) and selecting the parameter that maximized the Shapiro–Wilk P -value. Optimal transformations were identified for tumor SUV _max distributions at both pre and post treatment. This study included 57 patients that underwent ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG) PET scans (publically available dataset). In addition, to test the generality of our transformation methodology, we included analysis of 27 patients that underwent ¹⁸ F-Fluorothymidine ( ¹⁸ F-FLT) PET scans at our institution. Results . After applying the optimal Box–Cox transformations, neither the pre nor the post treatment ¹⁸ F-FDG SUV distributions deviated significantly from normality ( P > 0.10). Similar results were found for ¹⁸ F-FLT PET SUV distributions ( P > 0.10). For both ¹⁸ F-FDG and ¹⁸ F-FLT SUV distributions, the skewness and kurtosis increased from pre to post treatment, leading to a decrease in the optimal Box–Cox transformation parameter from pre to post treatment. There were types of distributions encountered for both ¹⁸ F-FDG and ¹⁸ F-FLT where a log transformation was not optimal for providing normal SUV distributions. Conclusion . Optimization of the Box–Cox transformation, offers a solution for identifying normal SUV transformations for when the log transformation is insufficient. The log transformation is not always the appropriate transformation for producing normally distributed PET SUVs.

Anti-angiogenic therapies target tumor vasculature and tumor cells, thus a concurrent assessment of these targets would lead to a greater understanding of therapeutic resistance and facilitate development of improved therapeutic strategies. We utilize dynamic 3′-deoxy-3′- ¹⁸ F-fluorothymidine positron emission tomography ( ¹⁸ F-FLT PET) scanning to concurrently assess changes in tumor cell proliferation and vasculature during anti-angiogenic therapy, providing insight into how these therapies may be used effectively with combination chemotherapy. Thirty-three patients with advanced solid malignancies underwent treatment with vascular endothelial growth factor receptor inhibitor (VEGFR-TKI) axitinib on an intermittent schedule (two-weeks-on/one-week-off). Patients had up to three dynamic ¹⁸ F-FLT PET/CT scans: at baseline, after two weeks of continuous VEGFR-TKI treatment, and following a one week treatment break. ¹⁸ F-FLT kinetics were analyzed using a two-tissue compartment kinetic model. Kinetic parameters V _b and K ₁ were extracted to quantify changes in tumor vasculature and the ¹⁸ F-FLT flux constant K _i was calculated to quantify changes in tumor cell proliferation. Two weeks of continuous axitinib exposure led to decreases in V _b (median −21%, P = 0.07), K ₁ (median −39%, P < 0.01), and K _i (median −37%, P < 0.01), corresponding to diminished tumor vasculature and cell proliferation that may antagonize treatment with concurrent chemotherapy. Axitinib treatment breaks led to significant increases in V _b (median +42%, P < 0.01), K ₁ (median +46%, P < 0.01), and K _i (median +39%, P < 0.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rho ⩽ −0.70, P < 0.01) were found between changes in tumor vasculature during axitinib exposure weeks and changes in tumor vasculature during treatment breaks. Imaging with dynamic ¹⁸ F-FLT PET revealed new insights relating to the interplay of vascular and proliferative pharmacodynamics of axitinib therapy, facilitating a greater understanding of the mechanistic actions of VEGFR-TKIs. Increases in tumor vasculature and cell proliferation during VEGFR-TKI treatment breaks, suggests this period is an optimal time to schedule synergistic chemotherapy and warrants further investigation.

Background: The radiation‐induced abscopal effect (RIAE) is a desirable phenomenon involving radiation‐induced activation of the immune system and regression of metastatic disease after local radiotherapy. However, the majority of patients undergoing radiotherapy do not experience abscopal responses. One potential barrier to the RIAE is tumor‐associated macrophages (TAMs), which can be recruited to the tumor after radiotherapy and have an immunosuppressive effect on the tumor microenvironment (TME). Purpose: We aim to evaluate the dual capabilities of the FDA‐approved iron nanoparticle ferumoxytol for (1) enhancing the RIAE and (2) measuring TAMs by magnetic resonance imaging (MRI). We hypothesized that (1) the immunomodulating effect of ferumoxytol could enhance the RIAE by repolarizing the M2 TAMs to M1 TAMs, and (2) the TAMs could be non‐invasively imaged by ferumoxytol‐MRI. Methods: Twenty‐eight BALB/c mice were subcutaneously implanted with 4T1 primary orthotopic tumor (mammary fat pad) and flank tumor (abscopal tumor). At 14 days post‐implantation, mice were separated into four groups: control (Ctrl), radiotherapy (RT) only (8‐Gy×3), ferumoxytol only (FMX; 40 mg/kg) and combined (Comb) group (a single dose of 40 mg/kg FMX 24 h prior to 8‐Gy×3) ( n = 7 mice per group; 56 tumors). At 23‐ and 24‐day post‐implantation the pre‐ and post‐FMX injection MRI was performed for mice in FMX and Comb group. The percent change in transverse relaxation time (%T2*) from pre to post ferumoxytol injection was calculated from MR images for both tumors and lymph nodes (LNs). At 25 days post‐implantation, both tumors were harvested, and the TAMs were analyzed by flow cytometry. Results: At 25 days post‐implantation, the primary tumor volume in the RT and Comb groups was significantly lower than the Ctrl and FMX groups ( p  < 0.05). No significant size difference of abscopal tumors was observed among all groups. In addition, there was no significant difference in lung metastasis nodules. A significant decrease in %T2* values of tumors and LNs in the FMX and Comb group 24 h post‐ferumoxytol injection was observed, suggesting ferumoxytol uptake in TAMs. The flow cytometry result showed that the CD80 ⁺ CD206 ⁻ M1 macrophage population was similar among all tumors and groups. The CD80 ⁻ CD206 ⁺ M2 macrophage population was also similar in all tumors and groups, with the exception of the FMX group, where the M2 tumor macrophage levels were significantly higher when compared to the Ctrl group ( p  < 0.05). Tumors in the FMX group had a significant negative Pearson correlation between tumor %T2* change and M1 tumor macrophage levels ( r = −0.76, p  < 0.05) but this correlation was not significant in any other treatment group. Conclusions: Radiotherapy combined with ferumoxytol led to significant growth delays of irradiated tumors, but no abscopal effects were observed in non‐irradiated tumors. Additionally, our hypothesis that the immunomodulating effect of ferumoxytol could enhance the RIAE by repolarizing the M2 TAMs to M1 was not supported by our findings. However, our second hypothesis that the TAMs could be non‐invasively imaged by ferumoxytol‐MRI was supported by our findings. This includes observation of a significant negative correlation between M1 TAMs and %T2* change in tumors in the ferumoxytol treatment group.