Radiation-Induced Oral Mucositis.

Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment.

Single-Dose Radiation-Induced Oral Mucositis Mouse Model.

The generation of a self-resolved radiation-induced oral mucositis (RIOM) mouse model using the highest possibly tolerable single ionizing radiation (RT) dose was needed in order to study RIOM management solutions. We used 10-week-old male BALB/c mice with average weight of 23 g for model production. Mice were treated with an orthovoltage X-ray irradiator to induce the RIOM ulceration at the intermolar eminence of the animal tongue. General anesthesia was injected intraperitoneally for proper animal immobilization during the procedure. Ten days after irradiation, a single RT dose of 10, 15, 18, 20, and 25 Gy generated a RIOM ulcer at the intermolar eminence (posterior upper tongue surface) with mean ulcer floor (posterior epithelium) heights of 190, 150, 25, 10, and 10 µm, respectively, compared to 200 µm in non-irradiated animals. The mean RIOM ulcer size % of the total epithelialized upper surface of the animal tongue was RT dose dependent. At day 10, the ulcer size % was 2, 5, 27, and 31% for 15, 18, 20, and 25 Gy RT, respectively. The mean relative surface area of the total epithelialized upper surface of the tongue was RT dose dependent, since it was significantly decreased to 97, 95, 88, and 38% with 15, 18, 20, and 25 Gy doses, respectively, at day 10 after RT. Subcutaneous injection of 1 mL of 0.9% saline/6 h for 24 h yielded a 100% survival only with 18 Gy self-resolved RIOM, which had 5.6 ± 0.3 days ulcer duration. In conclusion, we have generated a 100% survival self-resolved single-dose RIOM male mouse model with long enough duration for application in RIOM management research. Oral mucositis ulceration was radiation dose dependent. Sufficient hydration of animals after radiation exposure significantly improved their survival.

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been used to minimize and repair radiation-induced normal tissue injury in the intestine, salivary gland, liver, skin, lungs and cardiac muscle. This study investigated the ability of adipose tissue-derived MSCs (aMSCs) to minimize and/or repair single dose radiation-induced oral mucositis (RIOM). METHODS: Syngenic phenotypically and functionally characterized BALB/c mouse aMSCs were implanted intraperitoneally in a RIOM mouse model with different dosing protocols. Response was quantified macroscopically, microscopically and by using different histological and clinically relevant parameters. RESULTS: Irradiation at 18 Gy generated a self-resolved single-dose RIOM BALB/c mouse model with 5.6 ± 0.3 days mean duration (95% confidence interval (CI) 4.233-7.1 days) and 100% survival rate. Intraperitoneal implantation of 5 doses of 2.5 million freshly cultured syngenic aMSCs significantly and reproducibly reduced RIOM ulcer duration to 1.6 ± 0.3 days (95% CI 0.0233-3.1 days, a 72% reduction in RIOM ulcer duration), ulcer size and ulcer floor epithelial height. The therapeutic benefits were significantly dependent on dose size and frequency, number of doses, and therapy onset time. aMSCs therapy significantly minimized the RIOM-related weight loss, accelerated the weight gain and improved irradiated animals' hydration and nutritional status. aMSCs therapy did not potentiate head and neck cancer in vitro. CONCLUSIONS: Syngenic freshly cultured aMSCs significantly minimized and repaired radiation-induced oral mucositis with a 72% reduction in ulcer duration. aMSCs dose size and frequency, number of doses and therapy onset time are the main keys for optimized therapeutic outcome. aMSCs therapy did not stimulate Head and Neck cancer cell growth in-vitro.

Adipose mesenchymal stromal cells response to ionizing radiation.

BACKGROUND AIMS: This study evaluates the biological response of adipose tissue-derived mesenchymal stromal cells (aMSCs) to ionizing radiation (IR). METHODS: Irradiated BALB/c mice aMSCs were characterized for functionality and phenotype. The clonogenic capacity of irradiated aMSCs was assessed and compared with those of metastatic breast cancer cell line (4T1) and normal mouse fibroblasts (NIH3T3-wt). We investigated the IR-induced DNA damage response, apoptosis, changes in cell cycle (CC) dynamics and protein and gene expression. RESULTS: Irradiated and non-irradiated aMSCs were able to differentiate into adipocytes, chondrocytes and osteocytes with no significant difference. Irradiated aMSCs maintained the expression of mesenchymal stromal cells (MSCs) surface antigens and, as expected, were negative for hematopoietic stem cells (HSCs) surface antigens when tested up to 7 days after IR for all irradiation doses with no significant difference. Clonogenically, irradiated aMSCs had higher relative survival fraction and plating efficiency than 4T1 and NIH3T3-wt. Irradiated aMSCs expressed higher □H2AX and significantly showed faster and more time-efficient IR-induced DNA damage response evident by up-regulated DNA-PKcs and RAD51. Two hours after IR, most of aMSCs DNA damage/repair-related genes showed up-regulation that disappeared within 6 h after IR. Irradiated aMSCs showed a significant rise and an earlier peak of p-ATM-dependent and -independent (p84/5E10-mediated) G2/M CC arrest compared with 4T1 and NIH3T3-wt. CONCLUSIONS: After IR exposure, aMSCs showed a robust and time-efficient radiation-induced DNA damage repair response, stable phenotypical characteristics and multi-lineage differentiation potential, suggesting they may be reliable candidates for cell therapy in radiation oncology regenerative medicine.