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Iron (Fe) is an essential element that plays a fundamental role in a wide range of cellular functions, including cellular proliferation, DNA synthesis, as well as DNA damage and repair. Because of these connections, iron has been strongly implicated in cancer development. Cancer cells frequently have changes in the expression of iron regulatory proteins. For example, cancer cells frequently upregulate transferrin (increasing uptake of iron) and down regulate ferroportin (decreasing efflux of intracellular iron). These changes increase the steady-state level of intracellular redox active iron, known as the labile iron pool (LIP). The LIP typically contains approximately 2% intracellular iron, which primarily exists as ferrous iron (Fe2+). The LIP can readily contribute to oxidative distress within the cell through Fe2+-dioxygen and Fenton chemistries, generating the highly reactive hydroxyl radical (HO•). Due to the reactive nature of the LIP, it can contribute to increased DNA damage. Mitochondrial dysfunction in cancer cells results in increased steady-state levels of hydrogen peroxide and superoxide along with other downstream reactive oxygen species. The increased presence of H2O2 and O2•− can increase the LIP, contributing to increased mitochondrial uptake of iron as well as genetic instability. Thus, iron metabolism and labile iron pools may play a central role connecting the genetic mutational theories of cancer to the metabolic theories of cancer.

Background Ultra-high dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising anti-tumor efficacy compared to conventional dose rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. Methods Cohorts of three-week-old male and female C57Bl/6 mice exposed to hypofractionated (2×10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months post-treatment. Animals were sacrificed 6 months post-irradiation and tissues analyzed for neurological and cerebrovascular decrements. Results The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin) and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and a preservation of cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. Conclusions Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlight its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins—but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.

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