Preclinical dosimetry: exploring the use of small animal phantoms

Biglin, Emma R.; Price, Gareth J; Chadwick, Amy L.; Aitkenhead, A.; Williams, Kaye J.; Kirkby, K.J.

doi:10.1186/s13014-019-1343-8

Cited by 28 publications

(25 citation statements)

References 36 publications

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“…Small animal radiation delivery to the whole heart or regions of the heart and/or lung, requires careful planning of dose distribution [82,83]. However, no standards have been followed for the performance and reporting of radiation dosimetry in small animal studies, which has made it difficult to reproduce previously published results [84].…”

Section: Inconsistencies In Radiation Dose Deliverymentioning

confidence: 99%

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Schlaak

SenthilKumar

Boerma

et al. 2020

Cancers

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Radiation therapy (RT) is an important component of cancer therapy, with >50% of cancer patients receiving RT. As the number of cancer survivors increases, the short-and long-term side effects of cancer therapy are of growing concern. Side effects of RT for thoracic tumors, notably cardiac and pulmonary toxicities, can cause morbidity and mortality in long-term cancer survivors. An understanding of the biological pathways and mechanisms involved in normal tissue toxicity from RT will improve future cancer treatments by reducing the risk of long-term side effects. Many of these mechanistic studies are performed in animal models of radiation exposure. In this area of research, the use of small animal image-guided RT with treatment planning systems that allow more accurate dose determination has the potential to revolutionize knowledge of clinically relevant tumor and normal tissue radiobiology. However, there are still a number of challenges to overcome to optimize such radiation delivery, including dose verification and calibration, determination of doses received by adjacent normal tissues that can affect outcomes, and motion management and identifying variation in doses due to animal heterogeneity. In addition, recent studies have begun to determine how animal strain and sex affect normal tissue radiation injuries. This review article discusses the known and potential benefits and caveats of newer technologies and methods used for small animal radiation delivery, as well as how the choice of animal models, including variables such as species, strain, and age, can alter the severity of cardiac radiation toxicities and impact their clinical relevance.

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Section: Inconsistencies In Radiation Dose Deliverymentioning

confidence: 99%

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Schlaak

SenthilKumar

Boerma

et al. 2020

Cancers

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“…A similar approach using an equivalent radiation system has been used previously (52,53). Multiple groups have used dose rate measurements in solid water phantoms, cross calibrated with EBT3 lms to gauge doses delivered for a particular experimental setup (54). Herein the dose rate for our small animal irradiator (SAI) at isocenter and an open eld was determined to be 3.62 Gy/min, consistent with dose rates for similar eld sizes (52).…”

Section: Discussionmentioning

confidence: 81%

Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Sprowls

Arsiwala

Kielkowski

et al. 2020

Preprint

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Background Brain metastasis is a devastating stage of cancer progression, occurring in ~30% of metastatic breast cancer patients. Two-year survival rates for these patients is low, and most typically survive less than one year. Treatments for these women are limited by the blood-brain barrier, but include cytotoxic chemotherapy, surgical resection, and radiation therapy (whole-brain radiotherapy or stereotactic radiosurgery). Radiotherapy is considered to be capable of inducing disruption of the blood-brain barrier and eliciting an abscopal response to extracranial tumors. Methods A combination of ionization chamber and Gafchromic film dosimetry was used to commission and determine dose outputs for our experimental design. Dose deposition in-vivo was verified by immunohistochemistry. To evaluate the effects of ionizing radiation at the normal blood-brain barrier and the blood-tumor barrier, athymic nude and FVB mice were used. Athymic nude mice were injected with MDA-MB-231Br cells. Lesions were allowed to develop for ~28 days. Mice were then irradiated at the prescribed dose. Prior to tissue collection, mice were injected with Texas red, followed by a vascular washout with physiological buffer. Fluorescence in normal and diseased brain was quantified by fluorescent microscopy. Results Using a 10mmx10mm collimator, determined to have adequate field homogeneity as determined by Gafchromic film analysis, we were able to successfully treat a single hemisphere in mice. The blood-brain-barrier remained undisrupted in athymic nude mice at doses up to 12Gy compared to untreated brain and radiation naïve controls. Immune competent FVB mice treated with radiation showed significant blood-brain barrier disruption at a dose of 12Gy only. The blood-tumor barrier showed significant disruption at 24hrs following radiation treatment (6 or 12Gy). Conclusion Our study demonstrated that radiation therapy disrupts the blood-tumor barrier, but fails to disrupt the normal blood-brain barrier in athymic nude mice. However, in FVB immune competent mice, the blood-brain barrier was disrupted at a dose of 12Gy, suggesting an abscopal-like response impacts extent of barrier leakage.

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“…1c-f). Discrepancies in backscatter conditions originating from phantom size and material apparently were responsible for these differences [16], because they were largely abrogated when the characteristics of our inhouse phantom were modelled into the supplier's depth dose curve (Fig. 1e).…”

Section: Resultsmentioning

confidence: 99%

Contrast-enhanced, conebeam CT-based, fractionated radiotherapy and follow-up monitoring of orthotopic mouse glioblastoma: a proof-of-concept study

et al. 2020

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Background: Despite aggressive treatment regimens comprising surgery and radiochemotherapy, glioblastoma (GBM) remains a cancer entity with very poor prognosis. The development of novel, combined modality approaches necessitates adequate preclinical model systems and therapy regimens that closely reflect the clinical situation. So far, image-guided, fractionated radiotherapy of orthotopic GBM models represents a major limitation in this regard. Methods: GL261 mouse GBM cells were inoculated into the right hemispheres of C57BL/6 mice. Tumor growth was monitored by contrast-enhanced conebeam CT (CBCT) scans. When reaching an average volume of approximately 7 mm 3 , GBM tumors were irradiated with daily fractions of 2 Gy up to a cumulative dose of 20 Gy in different beam collimation settings. For treatment planning and tumor volume follow-up, contrast-enhanced CBCT scans were performed twice per week. Daily repositioning of animals was achieved by alignment of bony structures in native CBCT scans. When showing neurological symptoms, mice were sacrificed by cardiac perfusion. Brains, livers, and kidneys were processed into histologic sections. Potential toxic effects of contrast agent administration were assessed by measurement of liver enzyme and creatinine serum levels and by histologic examination. Results: Tumors were successfully visualized by contrast-enhanced CBCT scans with a detection limit of approximately 2 mm 3 , and treatment planning could be performed. For daily repositioning of the animals, alignment of bony structures in native CT scans was well feasible. Fractionated irradiation caused a significant delay in tumor growth translating into significantly prolonged survival in clear dependence of the beam collimation setting and margin size. Brain sections revealed tumors of similar appearance and volume on the day of euthanasia. Importantly, the repeated contrast agent injections were well tolerated, as liver enzyme and creatinine serum levels were only subclinically elevated, and liver and kidney sections displayed normal histomorphology.

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Preclinical dosimetry: exploring the use of small animal phantoms

Cited by 28 publications

References 36 publications

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Contrast-enhanced, conebeam CT-based, fractionated radiotherapy and follow-up monitoring of orthotopic mouse glioblastoma: a proof-of-concept study

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