Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.

Radiopharmaceuticals as combinatorial partners for immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple cancer types. However, only a fraction of patients with cancer responds to ICIs employed as stand-alone therapeutics, calling for the development of safe and effective combinatorial regimens to extend the benefits of ICIs to a larger patient population. In addition to exhibiting a good safety and efficacy profile, targeted radionuclide therapy (TRT) with radiopharmaceuticals that specifically accumulate in the tumor microenvironment has been associated with promising immunostimulatory effects that (at least in preclinical cancer models) provide a robust platform for the development of TRT/ICI combinations. We discuss preclinical and clinical findings suggesting that TRT stands out as a promising partner for the development of safe and efficient combinatorial regimens involving ICIs.

Clonogenic assay to measure bystander cytotoxicity of targeted alpha-particle therapy.

Radiation therapy induces targeted effects in the cells that are irradiated and also non-targeted effects (i.e. bystander effects) in non-irradiated cells that are close to or at short distance (<∼1 mm) from irradiated cells. Bystander effects are mediated by intercellular communications and may result in cytotoxic and genotoxic modifications. Their occurrence and relative contribution to the irradiation outcome are influenced by several parameters among which the particle linear energy transfer seems to be prominent. Bystander effects were first observed after external radiation therapy, but have been described also following targeted radionuclide therapy. Therefore, we propose a method to investigate their occurrence in experimental conditions where cells are exposed to radiopharmaceuticals. In this approach, clonogenic cell death is the biological endpoint of the bystander effects caused by irradiation with alpha particles (a potent inducer of the bystander response).

Rapid communication: insights into the role of extracellular vesicles during Auger radioimmunotherapy.

PURPOSE: Non-targeted effects, including bystander and systemic effects, play a crucial role during Auger targeted radionuclide therapy. Here, we investigated whether small extracellular vesicles (sEVs) produced by irradiated cells could contribute to the bystander cytotoxic effects in vitro and also to therapeutic efficacy in vivo, after their injection in tumor xenografts. MATERIALS AND METHODS: B16F10 melanoma donor cells were exposed to radiolabeled antibodies (Auger radioimmunotherapy, RIT) for 48 h or to X-rays (donor cells). Then, donor cells were incubated with fresh medium for 2 h to prepare conditioned medium (CM) that was transferred onto recipient cells for bystander effect assessment, or used for sEVs enrichment. Resulting sEVs were incubated in vitro with recipient cells for determining bystander cytotoxicity, or injected in B16F10 melanoma tumors harbored by athymic and C57BL/6 mice. RESULTS: In vitro analysis of bystander cytotoxic effects showed that CM killed about 30-40% of melanoma cells. SEVs isolated from CM contributed to this effect. Moreover, the double-stranded DNA (dsDNA) content was increased in sEVs isolated from CM of exposed cells compared to control (not exposed), but the difference was significant only for the X-ray condition. These results were supported by immunodetection of cytosolic dsDNA in donor cells, a phenomenon that should precede dsDNA enrichment in sEVs. However, sEVs cytotoxicity could not be detected in vivo. Indeed, in athymic and in immunocompetent mice that received four intratumoral injections of sEVs (1/day), tumor growth was not delayed compared with untreated controls. Tumor growth was slightly (not significantly) delayed in immunocompetent mice treated with sEVs from X-ray-exposed cells, and significantly with sEVs purified from CM collected after 48 h of incubation. These results highlight the need to determine the optimal conditions, including radiation absorbed dose and sEVs collection time, to obtain the strongest cytotoxic effects. CONCLUSIONS: This study demonstrates that sEVs could play a role during Auger RIT through bystander effects in vitro. No systemic effects were observed in vivo, under our experimental conditions. However, X-rays experiments showed that sEVs collection time might be influencing the nature of sEVs, a parameter that should also be investigated during Auger RIT.

Summary of Radiation Research Society Online 67th Annual Meeting, Symposium on "Radiation and Circulatory Effects".

PURPOSE: This article summarizes a number of presentations from a session on "Radiation and Circulatory Effects" held during the Radiation Research Society Online 67th Annual Meeting, October 3-6 2021. MATERIALS AND METHODS: Different epidemiological cohorts were analyzed with various statistical means common in epidemiology. The cohorts included the one from the U.S. Million Person Study and the Canadian Fluoroscopy Cohort Study. In addition, one of the contributions in our article relies on results from analyses of the Japanese atomic bomb survivors, Russian emergency and recovery workers and cohorts of nuclear workers. The Canadian Fluoroscopy Cohort Study data were analyzed with a larger series of linear and nonlinear dose-response models in addition to the linear no-threshold (LNT) model. RESULTS AND CONCLUSIONS: The talks in this symposium showed that low/moderate acute doses at low/moderate dose rates can be associated with an increased risk of CVD, although some of the epidemiological results for occupational cohorts are equivocal. The usually only limited availability of information on well-known risk factors for circulatory disease (e.g. smoking, obesity, hypertension, diabetes, physical activity) is an important limiting factor that may bias any observed association between radiation exposure and detrimental health outcome, especially at low doses. Additional follow-up and careful dosimetric and outcome assessment are necessary and more epidemiological and experimental research is required. Obtaining reliable information on other risk factors is especially important.

Immunostimulatory effects of radioimmunotherapy.

Radiation therapy (RT) is known for its ability to kill cancer cells in an immunogenic manner. Recent preclinical data demonstrate that targeted alpha-particle therapy shares with RT the capacity to elicit immunostimulatory effects, standing out as a promising strategy to circumvent immune checkpoint inhibitor resistance in immunologically 'cold' tumors.

Acknowledging and overcoming barriers to entry into radiation science for women.

PURPOSE: Radiation science is a unique field that brings together various disciplines to understand nature, develop new technologies, and cure diseases. Our field is a prime example of advancement through a diverse pool of competencies. Similarly, studies show that the power of diversity requires proportionate representation of sex and gender, minorities, or other groups. Nevertheless, women are still underrepresented in the radiation sciences, although disparities and underlying mechanisms were first described decades ago. This review summarizes barriers to entry and retention and suggests strategies for overcoming disparities in our field. We also highlight a concerted effort by young professionals to promote the underrepresented and underserved within the radiation science community. CONCLUSION: The radiation science community should avoid losing diverse perspectives among its ranks due to sex bias or gender disparity among others. Through targeted efforts, we can cultivate change and harness the talent of researchers, practitioners, and other professionals for the benefit of scientific progress, health-care improvement, and societal advancement overall.

From the target cell theory to a more integrated view of radiobiology in Targeted radionuclide therapy: The Montpellier group's experience.

Targeted radionuclide therapy (TRT) is used to treat disseminated or metastatic tumours in which conventional external beam radiotherapy (EBRT) would have unacceptable side effects. Unlike EBRT, TRT delivers low doses at a continuous low dose rate. In EBRT, the effect increases progressively with the dose rate, and biological effects (tumour control and normal tissue damage) are related to the dose according to a sigmoid curve model. This model is part of the so-called quantitative radiobiology that is mostly based on the target cell theory, according to which cell death is due to (lethal) radiation hits to vital cellular targets. This model was developed for EBRT, but was adapted to low dose-rate situations by including a parameter that reflects the time needed to repair tissue damage. However, a growing body of evidence indicates that the model should take into account also the biological effects, which are due to intercellular communications (bystander effects) and amplify the effects of radiation, as well as the immune system. Moreover, extranuclear targets must be considered, although induced intracellular and intercellular signalling pathways may ultimately result in DNA damage. It is likely that bystander effects and immune response always contribute to the overall response to TRT at different levels, and that dose and dose rate are key parameters in controlling their real contribution. We hypothesize that the dose rate is the key determinant in the balance between the physical and DNA-centred response on one side, and the biological response that integrates all subcellular compartments and intercellular signalling pathways on the other side.

Revisiting the Radiobiology of Targeted Alpha Therapy.

Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 µm) and their linear energy transfer (50-230 keV/µm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.

Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway.

In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.

Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner.

Long-term cognitive deficits are observed after treatment of brain tumors or metastases by radiotherapy. Treatment optimization thus requires a better understanding of the effects of radiotherapy on specific brain regions, according to their sensitivity and interconnectivity. In the present study, behavioral tests supported by immunohistology and magnetic resonance imaging provided a consistent picture of the persistent neurocognitive decline and neuroinflammation after the onset of irradiation-induced necrosis in the right primary somatosensory cortex of Fischer rats. Necrosis surrounded by neovascularization was first detected 54 days after irradiation and then spread to 110 days in the primary motor cortex, primary somatosensory region, striatum and right ventricle, resulting in fiber bundle disruption and demyelination in the corpus callosum of the right hemisphere. These structural damages translated into selective behavioral changes including spatial memory loss, disinhibition of anxiety-like behaviors, hyperactivity and pain hypersensitivity, but no significant alteration in motor coordination and grip strength abilities. Concomitantly, activated microglia and reactive astrocytes, accompanied by infiltration of leukocytes (CD45+) and T-cells (CD3+) cooperated to shape the neuroinflammation response. Overall, our study suggests that the slow and gradual onset of cellular damage would allow adaptation in brain regions that are susceptible to neuronal plasticity; while other cerebral structures that do not have this capacity would be more affected. The planning of radiotherapy, adjusted to the sensitivity and adaptability of brain structures, could therefore preserve certain neurocognitive functions; while higher doses of radiation could be delivered to brain areas that can better adapt to this treatment. In addition, strategies to block early post-radiation events need to be explored to prevent the development of long-term cognitive dysfunction.

The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest.

Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt's lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.

Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy.

PURPOSE: For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects. EXPERIMENTAL DESIGN: Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects in vitro and in vivo (in xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT). RESULTS: Between 67% and 94% (alpha RIT) and 8% and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-κB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT. CONCLUSIONS: Cell membrane-mediated nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.

Dosimetry and characterization of a 25-MeV proton beam line for preclinical radiobiology research.

PURPOSE: With the increase in proton therapy centers, there is a growing need to make progress in preclinical proton radiation biology to give accessible data to medical physicists and practicing radiation oncologists. METHODS: A cyclotron usually producing radioisotopes with a proton beam at an energy of about 25 MeV after acceleration, was used for radiobiology studies. Depleted silicon surface barrier detectors were used for the beam energy measurement. A complementary metal oxide semiconductor (CMOS) sensor and a plastic scintillator detector were used for fluence measurement, and compared to Geant4 and an in-house analytical dose modeling developed for this purpose. Also, from the energy measurement of each attenuated beam, the dose-averaged linear energy transfer (LETd ) was calculated with Geant4. RESULTS: The measured proton beam energy was 24.85 ± 0.14 MeV with an energy straggling of 127 ± 22 keV before scattering and extraction in air. The measured flatness was within ± 2.1% over 9 mm in diameter. A wide range of LETd is achievable: constant between the entrance and the exit of the cancer cell sample ranging from 2.2 to 8 keV/µm, beyond 20 keV/µm, and an average of 2-5 keV/µm in a scattering spread-out Bragg peak calculated for an example of a 6-mm-thick xenograft tumor. CONCLUSION: The dosimetry and the characterization of a 25-MeV proton beam line for preclinical radiobiology research was performed by measurements and modeling, demonstrating the feasibility of delivering a proton beam for preclinical in vivo and in vitro studies with LETd of clinical interest.

Investigation of Optimal Physical Parameters for Precise Proton Irradiation of Orthotopic Tumors in Small Animals.

PURPOSE: The lack of evidence of biomarkers identifying patients who would benefit from proton therapy has driven the emergence of preclinical proton irradiation platforms using advanced small-animal models to mimic clinical therapeutic conditions. This study aimed to determine the optimal physical parameters of the proton beam with a high radiation targeting accuracy, considering small-animal tumors can reach millimetric dimensions at a maximum depth of about 2 cm. METHODS AND MATERIALS: Several treatment plans, simulated using Geant4, were generated with different proton beam features to assess the optimal physical parameters for small-volume irradiations. The quality of each treatment plan was estimated by dose-volume histograms and gamma index maps. RESULTS: Because of its low-energy straggling, low-energy proton (<50 MeV) single-field irradiation can generate homogeneous spread-out Bragg peaks to deliver a uniform dose in millimeter-sized tumors, while sparing healthy tissues located within or near the target volume. However, multifield irradiation can limit the dose delivered in critical structures surrounding the target for attenuated high-energy beams (E > 160 MeV). CONCLUSION: Low-energy proton beam platforms are suitable for precision irradiation for translational radiobiology studies.

Diffusion MRI monitoring of specific structures in the irradiated rat brain.

PURPOSE: The analysis of biological and mesoscopic structures properties by diffusion MRI (dMRI) in brain after radiation therapy remains challenging. In our study, we described the consequences associated with an unwanted dose to healthy tissue, assessing radiation-induced brain alterations of living rats with dMRI compared to histopathology and behavioral assays. METHODS: The right primary motor cortex M1 of the rat brain was targeted by stereotactic radiosurgery with a mean radiation dose of 41 Gy. Multidirectional single b-value dMRI data of the whole brain were acquired with a 7T small-animal scanner before irradiation until 110 days post-irradiation. Diffusion tensor imaging metrics, such as fractional anisotropy (FA), mean diffusivity (MD), axial (AD), and radial diffusivity (RD) were compared to brain alterations detected by immunohistochemistry and motor performances measured by a behavioral test. RESULTS: Between days 90 and 110, radiation necrosis was observed into the white matter spreading into M1 . Results showed a reduction of FA in the corpus callosum and in the striatum, which was driven by an increase in RD from 90 to 110 days post-irradiation, whereas only RD increased in M1 . Values of RD and AD increased in the irradiated hippocampus, while FA remained constant. Moreover, an increased MD, AD and RD was observed in the hippocampus that was probably related to inflammation as well as reactive astrogliosis after 110 days post-irradiation. Finally, rats did not exhibit locomotor deficits. CONCLUSIONS: dMRI metrics can assess brain damage; the sensitivity of dMRI metrics depends on the brain region.

Analytical dose modeling for preclinical proton irradiation of millimetric targets.

PURPOSE: Due to the considerable development of proton radiotherapy, several proton platforms have emerged to irradiate small animals in order to study the biological effectiveness of proton radiation. A dedicated analytical treatment planning tool was developed in this study to accurately calculate the delivered dose given the specific constraints imposed by the small dimensions of the irradiated areas. METHODS: The treatment planning system (TPS) developed in this study is based on an analytical formulation of the Bragg peak and uses experimental range values of protons. The method was validated after comparison with experimental data from the literature and then compared to Monte Carlo simulations conducted using Geant4. Three examples of treatment planning, performed with phantoms made of water targets and bone-slab insert, were generated with the analytical formulation and Geant4. Each treatment planning was evaluated using dose-volume histograms and gamma index maps. RESULTS: We demonstrate the value of the analytical function for mouse irradiation, which requires a targeting accuracy of 0.1 mm. Using the appropriate database, the analytical modeling limits the errors caused by misestimating the stopping power. For example, 99% of a 1-mm tumor irradiated with a 24-MeV beam receives the prescribed dose. The analytical dose deviations from the prescribed dose remain within the dose tolerances stated by report 62 of the International Commission on Radiation Units and Measurements for all tested configurations. In addition, the gamma index maps show that the highly constrained targeting accuracy of 0.1 mm for mouse irradiation leads to a significant disagreement between Geant4 and the reference. This simulated treatment planning is nevertheless compatible with a targeting accuracy exceeding 0.2 mm, corresponding to rat and rabbit irradiations. CONCLUSION: Good dose accuracy for millimetric tumors is achieved with the analytical calculation used in this work. These volume sizes are typical in mouse models for radiation studies. Our results demonstrate that the choice of analytical rather than simulated treatment planning depends on the animal model under consideration.

Radiomics in precision medicine for lung cancer.

With the improvement of external radiotherapy delivery accuracy, such as intensity-modulated and stereotactic body radiation therapy, radiation oncology has recently entered in the era of precision medicine. Despite these precise irradiation modalities, lung cancers remain one of the most aggressive human cancers worldwide, possibly because of diverse genotypic alterations that drive and maintain lung tumorigenesis. It has been long recognized that imaging could aid in the diagnosis, tumor delineation, and monitoring of lung cancer. Moreover, accumulating evidence suggests that imaging information could be further used to tailor treatment type and intensity, as well as predict treatment outcomes in radiotherapy. However, these imaging tasks have been carried out either qualitatively or using simplistic metrics that doesn't take advantage of the full scale of imaging knowledge. Radiomics, which is a recent field of research that aims to provide a more quantitative representation of imaging information relating tumor phenotypes to clinical and genotypic endpoints by embedding extracted image features into predictive mathematical models. These predictive models can be a key component in the clinician decision making and treatment personalization. This review provides an overview of the radiomics application and its methodology for radiation oncology studies in lung cancer.

Understanding the continuum of radionecrosis and vascular disorders in the brain following gamma knife irradiation: An MRI study.

PURPOSE: The radiation dose delivered to brain tumors is limited by the possibility to induce vascular damage and necrosis in surrounding healthy tissue. In the present study, we assessed the ability of MRI to monitor the cascade of events occurring in the healthy rat brain after stereotactic radiosurgery, which could be used to optimize the radiation treatment planning. METHODS: The primary somatosensory forelimb area (S1FL) and the primary motor cortex in the right hemisphere of Fischer rats (n = 6) were irradiated with a single dose of Gamma Knife radiation (Leksell Perfexion, Elekta AG, Stockholm, Sweden). Rats were scanned with a small-animal 7 Tesla MRI scanner before treatment and 16, 21, 54, 82, and 110 days following irradiation. At every imaging session, T2 -weighted (T2 w), Gd-DTPA dynamic contrast-enhanced MRI (DCE-MRI), and T2*-weighted ( T2* w) images were acquired to measure changes in fluid content, blood vessel permeability, and structure, respectively. At days 10, 110, and 140, histopathology was performed on brain sections. Locomotion and spatial memory ability were assessed longitudinally by behavioral tests. RESULTS: No vascular changes were initially observed. After 54 days, a small necrotic volume in the white matter below the S1FL, surrounded by an area presenting significant vascular permeability, was revealed. Between 54 and 110 days, the necrotic volume increased and was accompanied by the formation of a ring-like region, where a mixture of necrosis and permeable blood vessels were observed, as confirmed by histology. Behavioral changes were only observed after day 82. CONCLUSION: Together, DCE-MRI and T2* w images supported by histology provided a coherent picture of the phenomena involved in the formation of new, leaky blood vessels, which was followed by the detection of radionecrosis in a preclinical model of brain irradiation. Magn Reson Med 78:1420-1431, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Gamma Knife irradiation method based on dosimetric controls to target small areas in rat brains.

PURPOSE: Targeted and whole-brain irradiation in humans can result in significant side effects causing decreased patient quality of life. To adequately investigate structural and functional alterations after stereotactic radiosurgery, preclinical studies are needed. The purpose of this work is to establish a robust standardized method of targeted irradiation on small regions of the rat brain. METHODS: Euthanized male Fischer rats were imaged in a stereotactic bed, by computed tomography (CT), to estimate positioning variations relative to the bregma skull reference point. Using a rat brain atlas and the stereotactic bregma coordinates obtained from CT images, different regions of the brain were delimited and a treatment plan was generated. A single isocenter treatment plan delivering ≥ 100 Gy in 100% of the target volume was produced by Leksell GammaPlan using the 4 mm diameter collimator of sectors 4, 5, 7, and 8 of the Gamma Knife unit. Impact of positioning deviations of the rat brain on dose deposition was simulated by GammaPlan and validated with dosimetric measurements. RESULTS: The authors' results showed that 90% of the target volume received 100 ± 8 Gy and the maximum of deposited dose was 125 ± 0.7 Gy, which corresponds to an excellent relative standard deviation of 0.6%. This dose deposition calculated with GammaPlan was validated with dosimetric films resulting in a dose-profile agreement within 5%, both in X- and Z-axes. CONCLUSIONS: The authors' results demonstrate the feasibility of standardizing the irradiation procedure of a small volume in the rat brain using a Gamma Knife.