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Radiation

Ionizing molecular damage to DNA is principal mechanism by which cells and tissues are injured.

Ionizing radiation categorized into photon radiation (X-rays or gamma-rays) and particulate radiation (protons, neutrons, and alpha-particles).

X-rays and ╬│-rays generate an intermediate ion while particulate radiation are directly ionizing.

Intermediate ion produces intermediate free radicals which break DNA chemical bonds.

Radiation also directly cause rapid cell death from mitotic arrest, point mutations in deoxyribonucleic acid (DNA), and cell membrane damage.

DNA is the primary target of therapeutic irradiation, and if not repaired, radiation induced DNA damage leads to direct cell death, cell cycle redistribution, and microenvironment changes.

DNA damaged from ionizing radiation creates double strand breaks that represents the principal damage, that if not repaired can lead the cell death.

Cell kill occurs when the cell is unable to repair the damage to DNA, which is the most critical target.

Cells that divide rapidly are most susceptible to radiation injury.

Peak sensitivity to radiation is at the M and G2 phases of the cell reproductive cycle.

Cells that are inhibited from repairing DNA damage, or are naturally deficient in DNA repair enzymes have radiosensitivity.

The therapeutic index of itradiation relies on the differential response between cancers and normal tissue, as tumor cells have lower DNA repair capability compare with normal tissue cells.

Radiation can damage one or both strands of DNA.

Single-strand radiation damage is easily repaired using the opposite strand as a template, and is not strongly related to cell death by radiation.

Double strand breaks by radiation represent the most important factor in determining cellular kill.

Chromatin is destroyed in two places with double strand breaks, ultimately resulting in cell death because of the inability to repair the damage.

Induces apoptosis, also known as programmed cell death.

Double strand breaks can cause chromosomal ab2242ations and rearrangements such that lethal changes may occur in cells when undergoing mitosis or cells may continue to divide a limited number of times before undergoing mitotic or apoptotic death, or ceasing to divide.

Certain cells including lymphocytes or salivary gland cells may die following radiation during interphase deaths by early apoptosis without attempting mitosis.

Ionizing radiation induces cell damage, often making cells lose their proliferative capacity rather than causing immediate cell death.

Ionizing radiation causes complex damage to DNA by depositing energy in spurs, regions two times the diameter of the DNA double helix.

Doses measured in Gray (Gy) units with one Gray equivalent to 1 joule of radiation energy absorbed per kilogram of body weight.

Exposure is a measure of the amount of electrical charges of all ions of one sign produced from the ionization of a unit volume of air.

One R (Roentgen), the old unit of radiation exposure, is equal the amount of radiation that will produce 2.08 x 10th to the ninth ion pairs within a cubic centimeter of air at standard temperature pressure condition.

Concept of radiation exposure applies to x-rays and gamma rays with energies less than 3 MeV.

Absorbed dose refers the amount of energy absorbed in a medium per unit mass and does not differentiate between types of medium and types of radiation.

Absorption is dependent upon radiation energy, exposure and type of medium with the traditional unit, the absorbed dose, as the rad (radiation absorbed dose)

The rad unit is utilized to express quantitatively the amount of radiation received in the tissues of the patient.

Tumor regression is not related solely to tumor cell death, as it is influenced by amount of extracellular stroma, by the rapidity rather than delayed cell death and resorption of inactivated cells.

The abscopal effect refers to a phenomenon in which localized radiation leads to tumor response distant from the site of radiation.

It is proposed that after radiation of the primary tumor, cell death leads to exposure of the intracellular contents to immune cells, and the immunogenic response involves the recruitment of cytotoxic T cells, which identify tumor derived antigens and destroy remaining tumor cells in distant lesion sites they have not been exposed to radiation.

It is suggested that radiation may lead to liberation of tumor antigens and the production of damage-associated molecular patterns, which leads to the maturation of dendritic cells and T-cell priming an immunogenic response.

Cell inactivation by ionizing radiation is random and logarithmic.

Activates cellular signaling pathways that lead to expression of proinflammaory cytokins such as IL-6 and tumor necrosis factor-alpha.

Exponential cell inactivation occurs with linear increase in dose.

Tissues that respond early are typically those which have high cell turnover rates such as skin and mucosa expressing radiation damage within 2-3 weeks after initiation of treatment.

Tissues that respond late have slow turnover or are not proliferating and express damage many years after radiation and include the kidney and spinal cord.

Optic nerves the most radiosensitive of the cranial nerves.

Ovarian dose of 400-600 rads causes sterilization and impaired or absent ovarian function in 30% of premenarchal girls, whereas almost all women over 40 years old who are exposed to that dose have sterility and ovarian failure.

4000-6000 rads are required to induce uterine fibrosis and endometrial atrophy in postpubertal women.

Risk of death from exposure to abdominal tomography is purported to be lower than the risk of cancer death from smoking cigarettes for 1 year.

A dose of 15 rad or more is necessary to result in deformities that might justify pregnancy termination.

The radiation dose for a typical cervical or intracranial arteriogram is less than 1 mrad.

External beam radiotherapy for prostate cancer-an approximate 5mm margin is typically added around the prostate to account for subclinical disease extension.

External beam radiotherapy for prostate cancer-largest long-term adverse effect is a decline in sexual function among previously potent men.

No link between exposure to low-level ionizing radiation before conception and increased risk of adverse reproductive outcome in men working in the nuclear industry.

The risk of radiation-induced breast cancer is seen primarily in women who had breast radiation exposure before the age of 30 years.

The risk of radiation induced breast cancer increases linearly with increasing doses, but decreases at the highest dosage.

Women exposed to moderate or high dose chest radiation, greater than r equal to 20 Gy, during childhood cancer therapy have an increased risk of breast cancer.

The magnitude of increased risk of breast cancer in women after being radiated during childhood is as great as that associated with BRCA mutations with a cumulative breast cancer incidence approaching 20% by age 45 years.

Breast tissue sensitive to radiation carcinogenesis with an inverse risk with age, with a very low risk when radiation exposure is given after the age of 50 years.

The risk of thyroid carcinoma in people who receive radiation is life-long.

Radiation of the breast is either not associated or minimally associated with contralateral breast cancer.

Radiation of the breast is associated with leukemia, sarcoma, lung cancer and esophageal cancer.

Radiation of the breast has a total cumulative incidence of sarcoma between 0.2-0.4% at 15 years.

Of the breast as with a 2-3 fold increase in higher risk of lung cancer.

Estimated that 1.5-2% of all cases of cancer may be attributed to CT radiation.

Fetal exposure from a CT scan of the abdomen and pelvis may increase the risk of leukemia by a factor of 1.5 over the background rate of approximately one in 3000.

A typical abdominal/pelvic CT scan deliveries 10-25 mGy of radiation with the fetal exposure of radiation as low as 4.8 mGy.

Of the breast associated with nine excess lung cancers per 10,000 patients treated.

Of the breast with modern treatments will diminish the already small risks of developing a secondary radiation-induced cancer.

Whole breast radiotherapy is associated with damage to the heart, lung, increased cardiovascular mortality, and lung cancer development, with risks that remain for 15 to 20 years after treatment.

Radiation of the breast in the supine position decreases heart volume irradiated by 85% in patients with left breast cancer (Formenti SC et al).

Excess mortality from heart disease in women administered radiation to the breast (Clarke M et al).

Increase in deaths in early BC adjuvant radiation trials, and left sided BC associated with higher mortality resulting from ischemic heart disease compared with right sided BC.

Increase of stenosis of mid and distal LAD plus distal diagonal disease in irradiated left sided breast cancer patients (Nilsson G et al).

In the above study there was a 4-7 fold increase in high grade coronary artery stenosis in mid and distal LAD, including distal diagonal branch, when comparing women with irradiated left BC with those with right sided BC.

Cardiac damage associated with the dose of radiation exposure.

Coronary artery heart disease increases 7.4% with each additional gray exposure.

These consequences occur when breast-cancer patients are treated in the supine position.

The prone position for breast cancer radiation has reduced radiation exposure to the heart and lung with similar efficacy.

Of the breast associated with disease years later, so that individuals with left breast cancers treated with radiation have a higher risk of such problems than women with right sided tumors.

Of the left breast associated with higher rates of chest pain, myocardial infarction, and coronary artery disease than women with right sided breast cancers.

Of the breast associated with increased complications in obese patients.

Adverse events are well recognized risk factors following  radio therapy in patients with local advanced lung cancers.

Radiation exposure of arterial vessels alters the natural history of coronary artery disease by inducing inflammation that subsequently triggers accelerated progression of disease.

Pathophysiology of radiation induced heart disease involves microangiography of small blood vessels and macroangiopathy of the coronary arteries, with myocardial fibrosis, coronary artery disease and ischemic heart disease.

Breast radiation associated with decline in erythrocyte levels that may be associated with fatigue, depression, impaired physical function, increased risk of local and regional recurrence and decreased survival.Exposure to prepubertal, adolescent and pregnant females may increase risk for delivery of a low-birth weight infants.

Dental radiography during pregnancy associated with low weight term infants.

Low-dose radiation exposure associated with thyroid dysfunction, thyroid cysts in females, and papillary thyroid cancers.

Low-dose exposure in utero associated with children with poor performance of intelligence tests, suggesting effects on brain development.

Pericardial disease is one of the most common manifestations of radiation induced heart injury.

Constrictive or effusion related pericardial disease ma occur months to years after radiotherapy.

Late complications include myocardial fibrosis, myocardopathy, coronary artery disease, valvular dysfunction and conduction abnormalities.

Overall incidence of detectable heart injury after chest radiation is approximately 30%, but patients treated with mantle radiation for Hodgkin’s disease have a higher risk related to the proximity of the port to structures.

To the small bowel results in diarrhea, abdominal pain, dyspepsia, bloating, cramps, and nausea.

To the small bowel results in early mucosal damage.

Administered to patients with gynecological cancers experience a 20% decrease in transit time from mouth to cecum.

Exposure to the intestine results in denudation of mucosa with loss of absorption function, barrier integrity, with increased risk of bacterial colonization, infection and inflammation.

Exposure to multiple diagnostic radiographs during childhood and adolescence for scoliosis increases the risk of breast cancer in women.

Exposure to x-rays in the United Kingdom accounts for approximately 0.6% cumulative risk of developing cancer to age 75 years. (About 700 cases per year.)

Japan attributes cumulative risk of developing cancer from diagnostic x-rays at 3.2%. (About 7587 cases per year.)

A full understanding of the mechanisms by which low-dose exposure causes cancer is not known, and any exposure is associated with some risk.

Many believe that the presence of a collagen vascular disease is a relative contraindication for radiation treatment, but controlled studies have failed to demonstrate increased acute or late complications.

In a study of 73 patients with collagen vascular disease compared to controls treated with radiation therapy no difference was noted in acute toxicity but there was a higher incidence of any late toxicity and a trend toward an increased rate of severe late toxicity (Lin).

Patients with collagen vascular disease treated with breast radiation have an increased risk of severe acute toxicity (Lin).

Treatment to the pelvis in patients with collagen vascular disease associated with increased risk of severe acute and late toxicity (Lin).

Administered to patients with Scleroderma have a higher risk of severe acute and late toxicity.

Administered to patients with SLE found to have a higher risk of severe acute and late toxicity (Lin).

Children of people exposed to atomic bombs have no indication of deleterious health effects after 62 years. (Grant EJ et al).

An alpha particle consists of two protons and two neutrons and are emitted from the decay of certain heavy radioactive nuclei, such as uranium and radium.

Alpha particles are very energetic and highly ionizing in the short range and have high linear energy transfer causing irreparable damage to cell DNA with confining damage to tumor reducing damage to nearby healthy tissues.

Alpha radiation carries little risk to the external body, who is possibly the most damaging form of radiation.

Beta-emitters have a relatively long radiation range and significant bone marrow exposure is associated with their use and it is restricted to treat bone pain for palliation.

Beta particles are electrons emitted from certain nuclei doing radioactive decay with longer range and lower linear energy transfer than alpha particles.

To cause a reversible DNA damage and induce cell death Beta particles require 102-103 tracks across a section of DNA, wheteas alpha particles require only 2-3 tracks.

Common beta emitters are carbon-14 and strontium-90.

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