Validation of histologic changes induced by external irradiation in mandibular bone. An experimental animal model.

The present experimental study sought to determine the effect of high-dose irradiation on the rat mandible in order to establish an experimental model of radiogenic bone damage. The left mandibles of 20 adult Wistar rats were irradiated (single fraction 1500cGy, total dose 60Gy) by means of a hypofractionated stereotactic radiotherapy (hfSRT) over a period of 6 weeks. Follow-up was 6 weeks (group 1, n=10) and 12 weeks (group 2, n=10). The contralateral mandibles as well as 5 non-irradiated animals served as controls. Primary endpoints were fibrosis, loss of cell count, decreased immunohistochemical labelling for bone morphogenetic protein-2 (BMP-2) and osteocalcin as well as increased expression of transforming growth factor (TGF-beta). Cell loss, progressive fibrosis, and focal necrosis were detected in all irradiated sites. Quantitative measurement revealed 32.0+/-8.7% and 37.3+/-9.5% empty osteocyte lacunae for groups 1 and 2 resp., compared to 16.3+/-4.7% and 18.9+/-4.9% on the contralateral side and 7.9+/-1.7% for unirradiated controls (Mann-Whitney U test; p<.01). BMP-2 and osteocalcin labelling showed a marked decrease in irradiated and contralateral sides while TGF-beta was expressed strongly in irradiated sites only (for all p<.05). External hypofractionated irradiation with a total dose of 60Gy is feasible in rats and yields all histologic changes attributed to osteoradionecrosis (ORN) after a follow-up of 6 weeks. The irradiation protocol is suitable for an assessment of regenerative options in severe radiogenic bone damage. As a split mouth design entails major inaccuracies healthy animals have to be used as controls.

Expression of HIF-1 alpha in irradiated tissue is altered by topical negative-pressure therapy.

BACKGROUND AND PURPOSE: Despite the enormous therapeutic potential of modern radiotherapy, common side effects such as radiation-induced wound healing disorders remain a well-known clinical phenomenon. Topical negative pressure therapy (TNP) is a novel tool to alleviate intraoperative, percutaneous irradiation or brachytherapy. Since TNP has been shown to positively influence the perfusion of chronic, poorly vascularized wounds, the authors applied this therapeutic method to irradiated wounds and investigated the effect on tissue oxygenation in irradiated tissue in five patients. MATERIAL AND METHODS: With informed patients' consent, samples prior to and 4 and 8 days after continuous TNP with -125 mmHg were obtained during routine wound debridements. Granulation tissue was stained with hematoxylin-eosin, and additionally with CD31, HIF-1 alpha (hypoxia-inducible factor-1 alpha), and D2-40 to detect blood vessels, measure indirect signs of hypoxia, and lymph vessel distribution within the pre- and post-TNP samples. RESULTS: In this first series of experiments, a positive influence of TNP onto tissue oxygenation in radiation-induced wounds could be demonstrated. TNP led to a significant decrease of 53% HIF-1 alpha-positive cell nuclei. At the same time, a slight reduction of CD31-stained capillaries was seen in comparison to samples before TNP. Immunostaining with D2-40 revealed an increased number of lymphatic vessels with distended lumina and an alteration of the parallel orientation within the post-TNP samples. CONCLUSION: This study is, to the authors' knowledge, the first report on a novel previously not described histological marker to demonstrate the effects of TNP on HIF-1 alpha expression as an indirect marker of tissue oxygenation in irradiated wounds, as demonstrated by a reduction of HIF-1 alpha concentration after TNP. Since this observation may be of significant value to develop possible new strategies to treat radiation-induced tissue injury, further investigations of HIF-1 alpha regulation under TNP are warranted.

Ewing sarcoma of the mandible in a child: interdisciplinary treatment concepts and surgical reconstruction.

Ewing's sarcoma is the second most common primary bone malignancy in childhood and adolescence. We present a standardized interdisciplinary treatment protocol according to the EURO-E.W.I.N.G. 99 study, applied in the treatment of a 7-year-old patient with localized Ewing's sarcoma of the left mandible. After six blocks of VIDE (vincristine/ifosfamide/doxorubicin/etoposide) chemotherapy and stem cells rescue, intensity modulated external radiation with 48.6 Gy and subsequent high dose therapy with busulphan-melphalan were administered. Tumor resection and immediate bony reconstruction was performed using a microvascular fibula graft 10 weeks after radiation. Because of the effective neoadjuvant treatment, no extensive soft tissue resection was necessary. Healing of the osteosynthesis was uneventful. No local or systemic recurrence and no signs of significant facial deformity were found after 12 month follow-up. The presented case underlines the requirement for multidisciplinary protocols involving radiologists, pathologists, oncologists, radiation oncologists, and surgeons for accurate diagnosis and appropriate therapy. To preserve cosmetics and function within the craniofacial area after tumor resection in children, microvascular reconstructive procedures can be successfully performed with a vascularized fibular graft.