Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice.

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.

Preclinical PERCIST and 25% of SUVmax Threshold: Precision Imaging of Response to Therapy in Co-clinical 18F-FDG PET Imaging of Triple-Negative Breast Cancer Patient-Derived Tumor Xenografts.

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived xenografts (PDXs). The inter- and intratumor heterogeneity of PDXs, however, presents several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics for 18F-FDG PET to assess response to combination docetaxel and carboplatin therapy in a co-clinical trial involving triple-negative breast cancer PDXs. We characterized the reproducibility of standardized uptake value (SUV) metrics to assess response to therapy, and we optimized a preclinical PERCIST paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size, solid tumors versus tumor heterogeneity and a necrotic phenotype, and optimal selection of tumor slices versus whole tumor. Methods: A test-retest protocol was implemented to optimize the reproducibility of 18F-FDG PET SUV thresholds, SUVpeak metrics, and preclinical PERCIST parameters. In assessing response to therapy, 18F-FDG PET imaging was performed at baseline and 4 d after therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index called the Quantitative Response Assessment Score to integrate parameters of prediction and precision and thus aid in selecting the optimal image metric to assess response to therapy. Results: Our data suggest that a threshold of 25% of SUVmax (SUV25) was highly reproducible (<9% variability). The concordance and reproducibility of preclinical PERCIST were maximized at α = 0.7 and ß = 2.8 and exhibited a high correlation with SUV25 measures of tumor uptake, which in turn correlated with the SUV of metabolic tumor. Conclusion: The Quantitative Response Assessment Score favors SUV25 followed by SUVpeak for a sphere with a volume of 14 mm3 (SUVP14) as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and preclinical PERCIST SUVP14 as image metrics for response to therapy across a wide range of therapeutic regimens and PDX models.