Overview and Emerging Trends in the Treatment of Osteoradionecrosis.

OPINION STATEMENT: Osteoradionecrosis (ORN) of the mandible is a rare but devastating complication which occurs following radiation therapy for head and neck malignancies. Left untreated, ORN often results in pathologic fracture of the mandible leading to pain, trismus, difficulty eating, and overall poor quality of life. Historically, early intervention relied on hyperbaric oxygen and local debridement. Patients whose disease progressed despite therapy required segmental resection of the mandible with osseous free flap reconstruction, a highly invasive operation. Patients that presented with a moderate disease without pathologic fracture were often doomed to fail non-operative management, ultimately leading to disease progression and fracture. The traditional dichotomous treatment paradigm left a void of options for patients with moderate disease. The ideal intervention for this category of patients would provide renewed vascularity to the diseased tissue bed allowing for the osteogenesis and reestablishment of strong, load-bearing bone. The innovative technique termed the vascularized fascia lata "rescue flap" has proven to be an effective treatment for moderate ORN and will likely transform dated treatment algorithms.

[Predictive factors for mandibular osteoradionecrosis after irradiation of head and neck cancers]. / Facteurs prédictifs de l'ostéoradionécrose mandibulaire après irradiation des cancers des voies aérodigestives supérieures.

The identification of the different risk factors for mandibular osteoradionecrosis (ORN) must be done before and after the management of patients with head and neck cancer. Various clinical criteria for this severe radiation-induced complication are related to the patient (intrinsic radiosensitivity, malnutrition associated with thin weight loss, active smoking intoxication, microcapillary involvement, precarious oral status, hyposalivation) and/or related to the disease (oral cavity, large tumor size, tumor mandibular invasion). Therapeutic risk factors are also associated with a higher risk of ORN (primary tumor surgery, concomitant radio-chemotherapy, post-irradiation dental avulsion, preventive non-observance with the absence of stomatological follow-up and daily installation of gutters fluoride and, non-observance curative healing treatments). Finally, various dosimetric studies have specified the parameters in order to target the dose values distributed in the mandible, which increases the risk of ORN. An mean mandibular dose greater than 48-54Gy and high percentages of mandibular volume receiving 40 to 60Gy appear to be discriminating in the risk of developing an ORN.

Is Adjunctive Hyperbaric Oxygen Treatment Alone or with Surgery the Proper Management for Active and Persistent Osteoradionecrosis?

ABSTRACT: This study enrolled patients with stage 3 osteoradionecrosis. There were three treatment modalities: antibiotics, hyperbaric oxygen therapy (HBOT), and surgery. Complete healing was the primary outcome. Multiple logistic regression analysis demonstrated that surgery with HBOT improved wound healing better than HBOT alone.

Metronidazole-induced encephalopathy caused by hyperbaric oxygen therapy in a patient with mandibular osteomyelitis.

Metronidazole (MNZ) is prescribed for the treatment of infection caused by anaerobic bacteria and protozoa. Metronidazole-induced encephalopathy (MIE) has been known to be a side-effect, although its onset ratio is unclear. However, to the best of our knowledge, MIE associated with hyperbaric oxygen therapy (HBO) has not been previously reported. Here, we present the case of a 68-year-old man with mandibular osteomyelitis who received metronidazole for 49 days and received five times HBO therapy. He visited our hospital for evaluation and treatment of peripheral neuropathy, speech disturbance, nausea, and disturbance of gait after 47 days of initiating metronidazole treatment. Brain magnetic resonance imaging revealed hyperintense lesions in the cerebellar dentate nuclei, which was consistent with MIE. The patient's ataxic symptoms improved in 15 days after the discontinuation of MNZ. This is the first report demonstrating case of MIE could be related with HBO, as far as we had searched.

Protocol for prospective randomised assessor-blinded pilot study comparing hyperbaric oxygen therapy with PENtoxifylline+TOcopherol± CLOdronate for the management of early osteoradionecrosis of the mandible.

INTRODUCTION: Osteoradionecrosis (ORN) of the mandible is a painful and debilitating condition occurring after radiotherapy to the head and neck to treat cancer. For decades, hyperbaric oxygen (HBO) has formed the mainstay of the early management of ORN. Literature about the efficacy of HBO is contentious. Recently, Oral and Maxillofacial surgical units in France and UK have trialled a combination of medications to treat ORN, also known as PENTOCLO (PENtoxifylline+TOcopherol±CLOdronate). This regime has shown promising results to date however randomised controlled trials in the area comparing HBO against PENTOCLO are lacking and there are no current trials registered in Europe, UK, Australia and the USA. The purpose of this pilot study is to generate a hypothesis that can be tested in large multi-centre controlled trials. METHODS AND ANALYSIS: For this pilot study we will recruit 16 patients who will be randomly allocated to one of either HBO or PENTOCLO. After a 4 week period of uniform 'pre-treatment' medication patients will be commenced on their allocated treatment. Standard follow-up examination, imaging and photographs will be taken and de-identified and then presented to two Oral and Maxillofacial surgeons for allocation of a Notani & Lyons classification score. Data for each patient will be tracked over the 18 months of treatment and follow-up. The results will then be analysed using descriptive statistics and all patients included in an intention to treat analysis. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the South Metropolitan Health Service HREC (PRN RGS0000001193). Data generated by conducting this study will be uploaded to an open access repository in a de-identified form. Results from this study will be disseminated at national and international conferences as well as peer reviewed medical publications. TRIAL REGISTRATION NUMBER: ACTRN12618001099213; Pre-results.

Effect of expanded bone marrow-derived osteoprogenitor cells seeded into polycaprolactone/tricalcium phosphate scaffolds in new bone regeneration of rabbit mandibular defects.

The purpose of this study was to assess and evaluate new bone formation in rabbit marginal mandibular defects using expanded bone marrow-derived osteoprogenitor cells seeded in three-dimensional scaffolds of polycaprolactone/tricalcium phosphate (PCL/TCP). Bone marrow was harvested from the rabbit ilium and rabbit bone marrow-derived osteoprogenitor cells were isolated and expanded in standard culture medium and osteogenic medium supplement. The cells were then seeded into the PCL/TCP scaffolds and the cell/scaffold constructions were implanted into prepared defects in rabbit mandibles. PCL/TCP scaffold alone and autogenous bone graft from the mandible were also implanted into the other prepared defects. The specimens were evaluated at 4 and 8 weeks after the implantation using clinical, radiographic, and histological techniques. The results of the experimental group demonstrated more newly formed bone on the surface and in the pores of the PCL/TCP scaffolds. In addition, the osteoblasts, osteocytes, and new bone trabeculae were identified throughout the defects that were implanted with the cell/scaffold constructions. The PCL/TCP alone group was filled mostly with fibrous cells particularly in the middle region with less bone formation. These results would suggest that the derived osteotoprogenitor cells have the potential to form bone tissue when seeded onto PCL/TCP scaffolds.

Cervical Necrotizing Fasciitis of Odontogenic Origin and Hyperbaric Oxygen Therapy.

Necrotizing fasciitis (NF) is an infection of the soft tissues pathology with high mortality that spreads through the fascial planes and rarely seen in head and neck region. The cause of infection is often odontogenic problems. Broad-spectrum antibiotics, surgical debridement, and hyperbaric oxygen therapy (HBO) are important for the treatment of disease. We report a case of cervical NF in a 33-year-old woman who was treated with rapid surgical debridement and simultaneous HBO.

The efficacy of hyperbaric oxygen therapy related to the clinical stage of osteoradionecrosis of the mandible.

This study aimed to evaluate the success of hyperbaric oxygen therapy (HBOT) and surgery in the treatment of mandibular osteoradionecrosis (ORN) in relation to the extent of the ORN. Twenty-seven patients with ORN were identified from a total of 509 patients with a history of primary oral or base of the tongue cancer; these patients had been treated with radiation therapy with curative intent between 1992 and 2006, with a radiation dose to the mandible of ≥50Gy. The ORN was staged according to the classification of Notani et al. The time from completion of radiation therapy to the development of ORN varied (median 3 years). Forty HBOT sessions were offered. After HBOT alone, 3 of 11 stage I lesions, 0 of 8 stage II lesions, and 0 of 8 stage III lesions had healed (P=0.0018). An absolute incidence of 5.3% ORN was found in this population. Of all sites irradiated in this study, the floor of the mouth was most associated with ORN (8.6%), whereas the cheek was least associated (0%). Based on the results of this study, HBOT can be recommended for stage I and II ORN and for selected cases of stage III ORN.

[Hyperbaric oxygen and radiotherapy: From myth to reality]. / Oxygénothérapie hyperbare et radiothérapie : entre mythe et réalité.

Worldwide, more than a million people receive each year a curative radiotherapy. While local control and overall survival are steadily increasing, 5 to 15% of patients still develop above grade 2 late toxicities. Late toxicities treatments are complex. Hyperbaric oxygenation was shown to induce revascularization and healing of injured tissues, but indications are still debated. Through a literature review, we summarized the hyperbaric oxygenation indications in radiation-induced late toxicities. We also studied the knowledge and practice of French local radiation therapists. It seems that hyperbaric oxygen therapy can be a conservative treatment of haemorrhagic cystitis and radiation-induced pain, in case of drug therapies failure. Often associated with a significant morbidity and mortality, surgery could be avoided. The risk of complications in case of tooth extraction in irradiated tissues is also reduced. However, the role of hyperbaric oxygenation for mandibular osteoradionecrosis, radiation-induced proctitis, enteritis, lymphoedema, brachial plexopathy, skin and neurological sequelae seems more questionable since studies results are conflicting. Future outcomes of phase III studies are expected to clarify the role of hyperbaric oxygenation in the management of radio-induced toxicities, including for head and necks complications.

New perspectives on the conservative management of osteoradionecrosis of the mandible: A literature review.

Over the last decades, several therapeutic options were considered in the treatment of the osteoradionecrosis (ORN) of the mandible, including supportive measures, ultrasound therapy, corticosteroids, hyperbaric oxygen, surgical resection with reconstruction, and, more recently, drugs capable of reversing the fibroatrophic process. Once established, the ORN does not spontaneously disappear and a standard treatment has not yet been defined. The clear clinical effectiveness of hyperbaric oxygen therapy (HBOT) varies according to the literature and there are some economic/logistic issues to be considered; the triplet tocopherol/pentoxifylline/clodronate demands greater evidence from randomized clinical trials and also resilience from the patient, given the long treatment duration and its possible side effects. Controversy around the ideal treatment of the initial stage ORN of the mandible persists. More rigorous randomized prospective trials are essential. The purpose of this article was to review the relevant literature on the physiopathology of ORN of the mandible and discuss the new perspectives of its conservative treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Comparison of Australian and New Zealand referral rates for hyperbaric oxygen in oro-facial osteoradionecrosis: evidence-based, funding constraint or clinician whim?

AIM: To compare Australian and New Zealand (NZ) rates of referral to hyperbaric units for patients with, or at risk of developing mandibular or maxillary osteoradionecrosis (ORN) due to a history of radiotherapy for oro-pharyngeal cancer. METHOD: Relevant patient treatment data from all hyperbaric units in Australia and NZ were collated and analysed. RESULTS: The rate of referral to hyperbaric units in Australia for treatment or prophylaxis of patients with, or at risk of oro-facial ORN, was 1.7 times the rate of referral in NZ. Within Australia, there was a greater than three-fold interstate variation. CONCLUSION: There is a significant referral rate difference both within Australia and between Australia and NZ for hyperbaric oxygen therapy for oro-facial ORN. Possible reasons for this difference include access to funding, logistical difficulties, clinician preference for an alternative treatment and clinician attitudes to hyperbaric oxygen.

Akut exazerbierende primär chronische Osteomyelitis der Mandibula im Kindesalter.

Inflammation of bone is caused either by bacterial infection or occasionally by physical stimulus. Primary chronic osteomyelitis of mandibular bone is a chronic inflammation of an unknown cause. Pain, swelling, limited mouth opening, regional lymphadenopathy and hypaesthesia are clinical symptoms at initial presentation. Results of biopsy, computed tomography and scintigraphy reveal the diagnosis of a primary chronic osteomyelitis. Its management is long-term antibiotic therapy, hyperbaric oxygen and surgical therapy, even bisphophonate treatement may be a good option. The case report presents a primary progressive chronic osteomyelitis of the manibular bone of a ten year old boy. Clinical and radiological signs are discussed as well as diagnosis, management and follow-up.

Comparison of complications in free flap reconstruction for osteoradionecrosis in patients with or without hyperbaric oxygen therapy.

BACKGROUND: Hyperbaric oxygen (HBO) therapy induces native tissue oxygenation. The hypothesis was patients with mandibular osteoradionecrosis (ORN) and a history of HBO therapy would have less free flap reconstruction complications than patients without HBO therapy. METHODS: We conducted a multisite retrospective review involving radical debridement and free flap reconstruction for ORN between January 1, 1995 and June 30, 2011. Patients were stratified based on receiving prior HBO therapy or not. RESULTS: Thirty-nine of 89 patients (43.8%) had HBO therapy whereas 50 of 89 (56.2%) did not. The HBO therapy group had significantly less patients with diabetes. There was no statistical difference in overall complication in patients between groups (p = .5478). However, there was marginal significance of increased infections in the patients with a history of HBO therapy (p = .0545). CONCLUSION: Although no significant differences in free flap reconstruction complication rates were observed between these 2 patient cohorts, there was marginal significance of increased infections in the patients with a history of HBO therapy. A prospective multi-institutional randomized study examining issues of infection would address issues inherent in this retrospective study.

Platelet-rich plasma, low-level laser therapy, or their combination promotes periodontal regeneration in fenestration defects: a preliminary in vivo study.

BACKGROUND: This study histomorphometrically analyzes the influence of platelet-rich plasma (PRP), low-level laser therapy (LLLT), or their combination on the healing of periodontal fenestration defects (PFDs) in rats. METHODS: PFDs were surgically created in the mandibles of 80 rats. The animals were randomly divided into four groups: 1) C (control) and 2) PRP, defects were filled with blood clot or PRP, respectively; 3) LLLT and 4) PRP/LLLT, defects received laser irradiation, were filled with blood clot or PRP, respectively, and then irradiated again. Animals were euthanized at either 10 or 30 days post-surgery. Percentage of new bone (NB), density of newly formed bone (DNB), new cementum (NC), and extension of remaining defect (ERD) were histomorphometrically evaluated. Data were statistically analyzed (analysis of variance; Tukey test, P <0.05). RESULTS: At 10 days, group PRP presented ERD significantly lower than group C. At 30 days, group PRP presented NB and DNB significantly greater than group C. Groups LLLT, PRP, and PRP/LLLT showed significant NC formation at 30 days, with collagen fibers inserted obliquely or perpendicularly to the root surface. NC formation was not observed in any group C specimen. CONCLUSIONS: LLLT, PRP, or their combination all promoted NC formation with a functional periodontal ligament. The combination PRP/LLLT did not show additional positive effects compared to the use of either therapy alone.

Superimposed infection in mandibular osteoradionecrosis: diagnosis and outcomes.

BACKGROUND: Radiation therapy can result in osteoradionecrosis (ORN) and mucosal ulceration predisposing to infection. METHODS: Fourteen patients presenting with infectious sequelae related to mandibular ORN were retrospectively reviewed. RESULTS: In most patients, infection followed diagnosis of ORN; but in 4 patients, ORN was not diagnosed until after the time of infection and imaging. An early imaging finding of ORN was lingual cortical defects near the last molar. Pain followed by erythema, purulent drainage, and subperiosteal abscess by imaging were the most common signs of infection. In most patients, conservative management eventually failed and segmental mandibulectomies were required. CONCLUSIONS: Soft tissue infection with characteristic bone findings such as subperiosteal abscess and cortical bone erosions helps to distinguish infected ORN from recurrent tumor or sterile ORN. In patients previously treated with radiation who present with infection, pain or an avid PET scan with bone involvement, the mandible should be scrutinized.

Orthopedic and orthodontic treatment in central giant cell granuloma treated with calcitonin.

Central giant cell granuloma of the jaw is a benign lesion of unknown etiology that occurs with very low frequency. It mainly occurs in children and young adults and is more common in the mandible. The most common treatment is surgical removal; however, alternative therapies (intralesional injections of corticosteroids, interferon alpha, and calcitonin) have been used in order to avoid undesirable damage to the jaws and teeth. The lesion may cause root resorption, tooth germ displacement, and other dental problems, as well as malocclusion that must be treated orthodontically. The orthodontic, orthopedic, and calcitonin-based treatments of one of these cases is presented.