User:Nicoespi/sandbox

Intro Scrap
Osteoradionecrosis (ORN) is a serious complication of radiation therapy in the management of cancer where radiated bone becomes necrotic and exposed. ORN occurs most commonly in the mouth during the treatment of head and neck cancer, and can arise over 5 years after treatment. Common signs and symptoms include pain, difficulty chewing, trismus, mouth-to-skin fistulas and non-healing ulcers.

The pathophysiology of ORN is fairly complex and involves drastic changes to bone tissue as a result of DNA damage and cell death caused by radiation treatment. Radiation therapy targeting tumor cells can affect normal cells as well, which can result in the death of bone tissue. Advances in radiation therapy have decreased the incidence of ORN, estimated at around 2% Certain risk factors including the size and location of tumor, history of smoking or diabetes , and presence of dental disease  can affect the chances of developing ORN.

Osteoradionecrosis is difficult to prevent and treat. Current prevention strategies are aimed at avoiding excess doses of radiation as well as maintaining excellent dental hygiene. Treatments are variable depending on the provider and disease severity, and can range from medical treatment with antibiotics to hyperbaric oxygen therapy (HBO) to surgical debridement or reconstruction.

Epidemiology
The epidemiology of osteoradionecrosis has proven difficult to estimate, with previous studies reporting incidence of disease between 4.74-37.5%. More recent reports have estimated the incidence to 2%, which is likely attributable to improvements in radiation therapy.

Pathophysiology
Radiation therapy destroys tumor cells primarily by causing DNA damage that promotes cell death. Tumor cells are especially susceptible to damage by radiation as they frequently develop mutations in the DNA repair mechanisms that allow normal, healthy tissues to recover from radiation damage. However, excessive radiation doses can cause even normal tissue to be overwhelmed by DNA damage and lead to local tissue changes and necrosis. Scientists have been conducting investigations into the exact mechanisms of these changes to help create treatments since osteoradionecrosis (ORN) was first described by Regaud in 1922. Various competing theories have emerged over the years with resultant changes to accepted treatments. Initially, it was believed that ORN arose from a combination of radiation, trauma and infection. According to this belief, radiation damage to the bone caused the bone to weaken, making it susceptible to traumatic microfractures and allowing bacteria to invade. This theory placed ORN on a spectrum of disease with osteomyelitis, so it was primarily treated with antibiotics. In 1983, Robert E. Marx, a prominent oralmaxillofacial surgeon, refuted the notion that trauma and infection were prerequisites in the development of ORN based on his review of Meyer's work. Marx proposed that ORN was the result of cumulative tissue damage secondary to ionizing radiation, causing disturbances in tissue metabolism and homeostasis that resulted in cell death and hypocellular tissues. In addition, radiation causes injury to the endothelial cells of local vasculature, creating a hypovascular environment which leads to decreased oxygen delivery resulting in hypoxic tissues. The loss of vasculature helps explain why the mandible is more commonly affected than than maxilla, as the mandible is served primarily by the inferior alveolar artery, and has a far less robust blood supply than the maxilla. In sum, Marx believed that ORN was essentially hypocellular-hypovascular-hypoxic tissues behaved much like chronic non-healing wounds. Initial reports by Marx and others showing that treatment with hyperbaric oxygen (HBO) prevented ORN helped support this theory. However, later studies began to raise doubts about the effectiveness of HBO therapy and question whether Marx's theory was comprehensive enough to guide treatment.

The Marx theory of ORN prevailed until around 2004, when Delanian and Lefaix proposed the radiation-induced fibroatrophic (RIF) process. Advances in lab techniques allowed scientists to perform more detailed studies of ORN specimens. Analysis of samples showed that tissues undergoing ORN underwent three phases of disease: 1) prefibrotic, 2) constitutive organized and 3) late fibroatrophic phases . During the prefibrotic phase, injury to endothelial cells secondary to radiation causes destruction of local vasculature, and recruitment of inflammatory cells and fibroblasts via pro-inflammatory cytokines like TNF-α, FGF-β and TGF-β1 . In addition, osteoblasts within the bone are damaged and destroyed, leading to decreased production of normal bone tissue . In the constitutive organized phase, fibroblasts persist and are converted to myofibroblasts by these same cytokines, that begin to fibrous extracellular matrix (ECM) within the affected bone . Consequently, the increased production of ECM by myofibroblasts coupled with decreased production of osteoid by osteoblasts results in weakened bony tissue. Finally, during the late fibroatrophic phase, the affected bone becomes hypocellular as myofibroblasts begin to die and leave behind weak, fibrotic tissue. Ultimately, these tissues are fragile and susceptible to damage by trauma or infection with little ability to repair or defend themselves due to the lack of vasculature caused during the pre-fibrotic phase. Given this understanding of the pathophysiology of ORN, current treatments are targeted at decreasing inflammatory cytokines and reducing free radical damage to DNA.

Risk Factors
Risk factors for osteoradionecrosis include:


 * Size and location of tumor; the risk of developing ORN increases with larger tumors, since they require higher doses of radiation to achieve cure, subsequently exposing nearby tissues to higher doses . While radiation therapy has become more targeted and precise, patients with tumors located closer to the mandible (e.g. oral cavity) or maxilla (e.g. nasopharynx) will more commonly develop ORN since the bone is more likely fall within the radiation field.
 * Dose and delivery of radiation; generally speaking, higher doses of radiation are more likely to result in ORN, especially when doses exceed 65 Gy . While minimizing radiation doses and avoiding excess radiation to bone can reduce ORN, there does not appear to much evidence that different radiation strategies (i.e. conventional radiotherapy, IMRT, brachytherapy) reduce risk.
 * Smoking; tobacco use is associated with significant increases in risk of developing ORN . This increased risk is attributed to the vasoconstrictive properties of nicotine, which coupled with damage to endothelium by radiation, exacerbate the decreased perfusion of affected tissues.
 * Diabetes mellitus; diabetes is a known cause of microvascular disease, which similar to smoking, can worsen the blood supply and perfusion to tissues affected by radiation.
 * Dental disease and extractions; patients with poor oral hygiene and dental disease prior to radiation, including edentulous patients, are more susceptible to developing ORN . Diseased teeth near the radiation field may need to be extracted, and should be evaluated prior to radiation treatment.

SCRAP SECTION

Excess exposure of these healthy tissues to radiation has been shown to cause ORN, and scientists have Since its first description in 1922 (Regaud 1922), advances in technology and laboratory techniques have led to various theories regarding the pathophysiology of ORN.

DNA damage is achieved through direct effects of radiation on DNA or via indirect pathway where radiation creates free radicals and reactive oxygen species which alter the DNA.

, coupled with other risk factors (link here to RF section), ** Add this to Pathophys section in third sentence once risk factor section is done

Diagnosis tab before?

Management
Prevention

Treatment