Complex housing partially mitigates low dose radiation-induced changes in brain and behavior in rats.

PURPOSE: In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain's ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure. METHODS: We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing. RESULTS: Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions. CONCLUSIONS: Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.

A quantitative assessment of the consequences of allowing dose heterogeneity in prostate radiation therapy planning.

Target dose uniformity has been historically an aim of volumetric modulated arc therapy (VMAT) planning. However, for some sites, this may not be strictly necessary and removing this constraint could theoretically improve organ-at-risk (OAR) sparing and tumor control probability (TCP). This study systematically investigates the consequences of PTV dose uniformity that results from the application or removal of an upper dose constraint (UDC) in the inverse planning process for prostate VMAT treatments. OAR sparing, target coverage, hotspots, and plan complexity were compared between prostate VMAT plans with and without the PTV UDC optimized using the progressive resolution optimizer (PRO, Varian Medical Systems, Palo Alto, CA). Removing the PTV UDC, the median D1cc reached 144.6% for the CTV and the PTV, and an average increase of 3.2% TCP was demonstrated, while CTV and PTV coverage evaluated by D99% was decreased by less than 0.6% with statistical significance. Moreover, systematic improvement in the rectum dose volume histograms was shown (a 5-10% decrease in the volume receiving 50% to 75% prescribed dose), resulting in an average decrease of 1.3% (P < 0.01) in the rectum normal tissue complication probability. Additional consequences included potentially increased dose to the urethra as evaluated by PTV D0.035cc (median: 153.4%), delivering 283 extra monitor units (MUs), and slightly higher degrees of modulation. In general, the results were consistent when a different optimizer (Photon Optimizer, Varian Medical Systems) was used. In conclusion, removing the PTV UDC is acceptable for localized prostate cases given the systematic improvement of rectal dose and TCP. It can be particularly useful for cases that do not meet the rectum dose constraints with the PTV UDC on. This comes with the foreseeable consequences of increased dose heterogeneity in the PTV and an increase in MUs and plan complexity. It also has a higher requirement for reproducing the position and size of the target and OARs during treatment. Finally, with the PTV UDC completely removed, in some cases the maximum doses within the PTV did approach levels that may be of concern for urethral toxicity and therefore in clinical implementation it may still be necessary to include a PTV UDC, but one based on limiting toxicity rather than enforcing dose homogeneity.

Profound and Sexually Dimorphic Effects of Clinically-Relevant Low Dose Scatter Irradiation on the Brain and Behavior.

Irradiated cells can signal damage and distress to both close and distant neighbors that have not been directly exposed to the radiation (naïve bystanders). While studies have shown that such bystander effects occur in the shielded brain of animals upon body irradiation, their mechanism remains unexplored. Observed effects may be caused by some blood-borne factors; however they may also be explained, at least in part, by very small direct doses received by the brain that result from scatter or leakage. In order to establish the roles of low doses of scatter irradiation in the brain response, we developed a new model for scatter irradiation analysis whereby one rat was irradiated directly at the liver and the second rat was placed adjacent to the first and received a scatter dose to its body and brain. This work focuses specifically on the response of the latter rat brain to the low scatter irradiation dose. Here, we provide the first experimental evidence that very low, clinically relevant doses of scatter irradiation alter gene expression, induce changes in dendritic morphology, and lead to behavioral deficits in exposed animals. The results showed that exposure to radiation doses as low as 0.115 cGy caused changes in gene expression and reduced spine density, dendritic complexity, and dendritic length in the prefrontal cortex tissues of females, but not males. In the hippocampus, radiation altered neuroanatomical organization in males, but not in females. Moreover, low dose radiation caused behavioral deficits in the exposed animals. This is the first study to show that low dose scatter irradiation influences the brain and behavior in a sex-specific way.

Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour.

Radiation therapy can not only produce effects on targeted organs, but can also influence shielded bystander organs, such as the brain in targeted liver irradiation. The brain is sensitive to radiation exposure, and irradiation causes significant neuro-cognitive deficits, including deficits in attention, concentration, memory, and executive and visuospatial functions. The mechanisms of their occurrence are not understood, although they may be related to the bystander effects.We analyzed the induction, mechanisms, and behavioural repercussions of bystander effects in the brain upon liver irradiation in a well-established rat model.Here, we show for the first time that bystander effects occur in the prefrontal cortex and hippocampus regions upon liver irradiation, where they manifest as altered gene expression and somewhat increased levels of γH2AX. We also report that bystander effects in the brain are associated with neuroanatomical and behavioural changes, and are more pronounced in females than in males.

Two primary seminomas in a patient with polyorchidism.

We report the clinical, radiographic and pathological findings of polyorchidism and a right-sided abdominal seminoma found in a 28-year-old man who presented with cryptorchidism in childhood and who later underwent an orchiectomy for a left-sided seminoma. Pathological analysis of the abdominal tumour revealed the existence of a classic seminoma bordered by a rim of non-tumour tissue and remnants of epididymis. We propose that patients who present with cryptorchidism be assessed for polyorchidism as this might be the source of additional primary tumours.