Novel Combination Treatment for Melanoma: FLASH Radiotherapy and Immunotherapy Delivered by a Radiopaque and Radiation Responsive Hydrogel.

Immunotherapies have become the standard treatment for melanoma. To further improve patient responses, combinations of immunotherapies and radiotherapy (RT) are being studied, since radiotherapies can potentially provide additional immune stimulation, in addition to direct antitumor effects. FLASH-RT is a novel, ultrahigh dose rate, radiation delivery approach, with the potential of at least equivalent tumor control efficacy and reduced damage to healthy tissue. However, the effects of combining FLASH-RT and immunotherapy have not been extensively studied in melanoma. Toll-like receptor (TLR) agonists, such as imiquimod (IMQ), are potent immunostimulatory agents, although their utility is limited due to poor solubility and systemic side effects. We therefore developed a novel combination therapy for melanoma consisting of IMQ delivered to the tumor via a radiopaque and radiation responsive hydrogel combined with FLASH-RT. We found that FLASH was able to effectively stimulate IMQ release from the hydrogel. In addition, we found that the combination of FLASH and released IMQ resulted in synergistic melanoma cell killing in vitro. The combination therapy reduced tumor growth compared to controls, enhanced survival, and resulted in remarkable enhancements in certain tumor cytokine levels. CT imaging allowed the hydrogel to be monitored in vivo. In addition, no adverse effects of the treatment were observed. Overall, this IMQ-gel and FLASH-RT combination may have potential as an improved treatment for melanoma and indicates that the interactions of FLASH-RT and TLR agonists merit further study.

Ytterbium Nanoparticle Contrast Agents for Conventional and Spectral Photon-Counting CT and Their Applications for Hydrogel Imaging.

Significant work has been done to develop nanoparticle contrast agents for computed tomography (CT), with a focus on identifying safer and more effective formulations. Contrast agents for spectral photon-counting computed tomography (SPCCT), a fast-growing imaging modality derived from conventional CT, have also recently gained considerable attention. In this study, we explored the synthesis of ultrasmall ytterbium nanoparticles (YbNP) and demonstrated that, potentially, they can be used as conventional CT and SPCCT contrast agents. These nanoparticles were tested in vitro for their cytotoxicity and contrast-generating properties with a variety of imaging systems. When scanned with conventional CT and SPCCT at clinically relevant energies, YbNP are significantly more attenuating than gold nanoparticles (AuNP), the contrast agents that have been most well studied. Furthermore, YbNP were studied for their potential application for labeling and monitoring hydrogels. The presence of the YbNP payload in hydrogels allowed for hydrogel localization and tracking in vivo. Additionally, the in vivo imaging results revealed that YbNP generate higher contrast when compared to AuNP used as a label. In summary, this is the first research study to examine ultrasmall YbNP as conventional CT and SPCCT contrast agents, as well as using them in a hydrogel system to make it radiopaque. These findings underscore YbNP's utility as CT and SPCCT contrast agents, as well as their potential for tracking hydrogels in vivo.

Frontal lobe hypometabolism associated with Sudden Unexpected Death in Epilepsy (SUDEP) risk: An objective PET study.

OBJECTIVE: Abnormalities of brain structures and neuronal networks have been identified in MRI studies of patients with Sudden Unexpected Death in Epilepsy (SUDEP) as well as in those at elevated risk. The goal of this study was to identify common patterns of objectively detected brain glucose metabolic abnormalities associated with SUDEP patients and those at high SUDEP risk. METHODS: Patients with refractory epilepsy (n = 78, age: 16-61 years, 44 females), who underwent comprehensive presurgical evaluation, were assessed for their risk of SUDEP using the revised SUDEP-7 inventory. From the 57 patients with low SUDEP risk, 35 were selected to match their demographic and clinical characteristics to those with high SUDEP risk (n = 21). [18F]fluoro-deoxy-glucose positron emission tomography (FDG-PET) abnormalities were evaluated in the high- and low-SUDEP risk subgroups compared to FDG-PET scans of a healthy adult control group using statistical parametric mapping (SPM). Individual FDG-PET scans of 4 additional patients, who died from SUDEP, were also analyzed by SPM. RESULTS: Mean SUDEP-7 score was 6.1 in the high and 2.7 in the low SUDEP risk group. MRI showed no lesion in 36 patients (64%). Statistical parametric mapping analysis of the high SUDEP risk subgroup showed bilateral medial frontal and inferior frontal hypometabolism as a common pattern. The low-risk group showed no specific common metabolic abnormalities on SPM group analysis. Individual PET scans of all 4 patients who died from SUDEP also showed bilateral frontal lobe hypometabolism. CONCLUSIONS: These data show that bilateral frontal lobe involvement on FDG-PET, especially the medial and inferior frontal cortex, may be a common metabolic pattern associated with high SUDEP risk and SUDEP itself, in patients with refractory focal epilepsy.

Evolution of Brain Glucose Metabolic Abnormalities in Children With Epilepsy and SCN1A Gene Variants.

Three children with drug-refractory epilepsy, normal magnetic resonance image (MRI), and a heterozygous SCN1A variant underwent 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) scanning between age 6 months and 1 year and then at age 3 years 6 months to 5 years 5 months. Regional FDG uptake values were compared to those measured in age- and gender-matched pseudo-controls. At baseline, the brain glucose metabolic pattern in the SCN1A group was similar to that of the pseudo-controls. At follow-up, robust decreases of normalized FDG uptake was found in bilateral frontal, parietal and temporal cortex, with milder decreases in occipital cortex. Children with epilepsy and an SCN1A variant have a normal pattern of cerebral glucose metabolism at around 1 year of age but develop bilateral cortical glucose hypometabolism by age 4 years, with maximal decreases in frontal, parietal, and temporal cortex. This metabolic pattern may be characteristic of epilepsy associated with SCN1A variants and may serve as a biomarker to monitor disease progression and response to treatments.