Browsing by Author "Melemenidis, Stavros"

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    Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice
    (Springer Nature, 2020-12-10) Levy, Karen; Natarajan, Suchitra; Wang, Jinghui; Chow, Stephanie; Eggold, Joshua T.; Loo, Phoebe E.; Manjappa, Rakesh; Melemenidis, Stavros; Lartey, Frederick M.; Schüler, Emil; Skinner, Lawrie; Rafat, Marjan; Ko, Ryan; Kim, Anna; Al-Rawi, Duaa H.; von Eyben, Rie; Dorigo, Oliver; Casey, Kerriann M.; Graves, Edward E.; Bush, Karl; Yu, Amy S.; Koong, Albert C.; Maxim, Peter G.; Loo, Billy W., Jr.; Rankin, Erinn B.; Radiation Oncology, School of Medicine
    Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.
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    Evaluating the Reproducibility of Mouse Anatomy under Rotation in a Custom Immobilization Device for Conformal FLASH Radiotherapy
    (BioOne, 2020-12-01) Ko, Ryan B.; Soto, Luis A.; von Eyben, Rie; Melemenidis, Stavros; Rankin, Erinn B.; Maxim, Peter G.; Graves, Edward E.; Loo, Billy W., Jr.; Radiation Oncology, School of Medicine
    The observation of an enhanced therapeutic index for FLASH radiotherapy in mice has created interest in practical laboratory-based FLASH irradiators. To date, systems capable of 3D conformal FLASH irradiation in mice have been lacking. We are developing such a system, incorporating a high-current linear accelerator to produce a collimated X-ray beam in a stationary beamline design, rotating the mouse about a longitudinal axis to achieve conformal irradiation from multiple beam directions. The purpose of this work was to evaluate the reproducibility of mouse anatomy under rotation at speeds compatible with conformal FLASH delivery. Three short-hair mice and two hairless mice were immobilized under anesthesia in body weight-specific contoured plastic molds, and subjected to three rotational (up to 3 revolutions/s) and two non-rotational movement interventions. MicroCT images were acquired before and after each intervention. The displacements of 11 anatomic landmarks were measured on the image pairs. The displacement of the anatomical landmarks with any of the interventions was 0.5 mm or less for 92.4% of measurements, with a single measurement out of 275 (11 landmarks × 5 interventions × 5 mice) reaching 1 mm. There was no significant difference in the displacements associated with rotation compared to those associated with moving the immobilized mouse in and out of a scanner or with leaving the mouse in place for 5 min with no motion. There were no significant differences in displacements between mice with or without hair, although the analysis is limited by small numbers, or between different anatomic landmarks. These results show that anatomic reproducibility under rotation speed corresponding to FLASH irradiation times appears to be compatible with conformal/stereotactic irradiation in mice.
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    FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation
    (BioOne, 2020-12-01) Soto, Luis A.; Casey, Kerriann M.; Wang, Jinghui; Blaney, Alexandra; Manjappa, Rakesh; Breitkreutz, Dylan; Skinner, Lawrie; Dutt, Suparna; Ko, Ryan B.; Bush, Karl; Yu, Amy S.; Melemenidis, Stavros; Strober, Samuel; Englemann, Edgar; Maxim, Peter G.; Graves, Edward E.; Loo, Billy W., Jr.; Radiation Oncology, School of Medicine
    Radiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.
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    Multicellular spheroids as in vitro models of oxygen depletion during FLASH irradiation
    (Elsevier, 2021) Khan, Syamantak; Bassenne, Maxime; Wang, Jinghui; Manjappa, Rakesh; Melemenidis, Stavros; Breitkreutz, Dylan Y.; Maxim, Peter G.; Xing, Lei; Loo, Billy W., Jr.; Pratx, Guillem; Radiation Oncology, School of Medicine
    Purpose The differential response of normal and tumor tissues to ultra-high dose rate radiation (FLASH) has raised new hope for treating solid tumors but, to date, the mechanism remains elusive. One leading hypothesis is that FLASH radiochemically depletes oxygen from irradiated tissues faster than it is replenished through diffusion. The purpose of this study is to investigate these effects within hypoxic multicellular tumor spheroids, through simulations and experiments. Materials and Methods Physicobiological equations were derived to model (i) the diffusion and metabolism of oxygen within spheroids; (ii) its depletion through reactions involving radiation-induced radicals; and (iii) the increase in radioresistance of spheroids, modeled according to the classical oxygen enhancement ratio and linear-quadratic response. These predictions were then tested experimentally in A549 spheroids exposed to electron irradiation at conventional (0.075 Gy/s) or FLASH (90 Gy/s) dose rates. Clonogenic survival, cell viability, and spheroid growth were scored post-radiation. Clonogenic survival of two other cell lines was also investigated. Results The existence of a hypoxic core in unirradiated tumor spheroids is predicted by simulations and visualized by fluorescence microscopy. Upon FLASH irradiation, this hypoxic core transiently expands, engulfing a large number of well-oxygenated cells. In contrast, oxygen is steadily replenished during slower conventional irradiation. Experimentally, clonogenic survival was around 3-fold higher in FLASH-irradiated spheroid compared to conventional irradiation, but no significant difference was observed for well-oxygenated 2D-cultured cells. This differential survival is consistent with the predictions of the computational model. FLASH irradiation of spheroids resulted in a dose-modifying factor of around 1.3 for doses above 10 Gy. Conclusion Tumor spheroids can be used as a model to study FLASH irradiation in vitro . The improved survival of tumor spheroids receiving FLASH radiation confirms that ultra-fast radiochemical oxygen depletion and its slow replenishment are critical components of the FLASH effect.