Normal Tissue Radiation Responses

With respect to the morphologic changes associated with radiation-induced liver disease, notably veno-occlusive disease (VOD), this may be observed

- The Kupffer cells, hepatic-specific phagocytes, often increase in size during the progression of VOD and can contain large amounts of hemosiderin, a pigment that is a breakdown product of hemoglobin - The morphologic hallmark of VOD is the presence of lesions with severely congested sinusoids in the central zones of the lobules, and an accompanying atrophy of the central portion of the liver plates. The lumen of the central and sublobular veins are filled with a dense network of reticulin fibers that frequently contain trapped red cells.

What is the approximate D₀ for oocytes?

0.1 Gy Oocytes are extremely radiosensitive, and like lymphocytes, will undergo apoptosis after exposure to approximately 0.12 Gy (12 cGy).

For pre-pubescent patients, what is the minimum dose (Gy) to the epiphyseal growth plate which can result in reductions in height?

10 Doses greater than 10 Gy are associated with abrogation of height. The dose response relationship may most steep between 15-20 Gy, but continues as a function of higher doses.

At what testicular dose is surveillance for testosterone deficiency recommended for childhood and young adult survivors of cancer?

12 Gy 1 - 3 Gy exposure is associated with possibly reversible azoospermia; 3 - 6 Gy is associated with possibly but unlikely reversible azoospermia; > 6 Gy, azoospermia is probably permanent; > 12 Gy is associated with increased risk of testosterone deficiency.

Which of the following is the lowest dose likely to lead to permanent sterility in a male?

6 Gy single dose A single dose or 6 Gy, of 2.5 - 3 Gy fractionated dose over 2 - 4 weeks can cause permanent sterility in males. Induction of sterility does not affect hormone balance, libido or physical capability in males, unlike in females where radiation sterility produces hormonal changes like those seen in natural menopause.

The time interval between radiation therapy and clinical manifestation of injury to slow or non-proliferating normal tissues can be as long as:

>10 years. There is no evidence to suggest that the incidence of late normal tissue complications reaches a plateau. Patients can be at risk for certain complications even > 10 years after exposure.

Which characteristic makes cancer stem cells an important determinant of resistance to RT?

Ability to repopulate during treatment Cancer stem cells are pluripotent cells with a high replicative potential, that give rise both to more stem cells and to tumor progenitor cells that become heterogeneous genotypically and phenotypically. Not only are they thought to be resistant to conventional therapies, but also they have the ability to repopulate an entire tumor with progenitors. Cancer stem cells are implicated in the metastatic process and may be enriched in sites of metastatic disease

TGF-beta protein levels in the plasma of patients exposed to radiotherapy has been extensively correlated to what

Acute radiation lung injury Plasma TGF-β levels have extensively been evaluated as a measure of and predictor for acute and chronic radiation lung injury.

The Quantitative analysis of normal tissue effects in the clinic (QUANTEC) suggested that prevent of severe xerostomia (long term salivary function <25% of the pre-treatment baseline) requires which of the following dose constraints on the parotid glands:

At least one parotid gland should receive a mean dose <20 Gy For severe xerostomia, the recommendation was that one parotid should receive a mean dose less than 20 Gy or both parotid glands should receive a mean dose less than 25 Gy.

Which of the following effects is typically observed within a week following irradiation of the small intestine?

Atrophic villi Atrophic villi would likely be observed within a week following the start of irradiation of the small intestine, since the cells lining the villi have relatively short life spans.

Which of the following organs has the highest tissue weighting factor (Wₜ) used for calculation of effective dose?

Breast

Which of the following intermediates is thought to play a critical role in the pro-fibrotic signaling of TGF-beta?

CTGF CTGF, or connective tissue growth factor, is a downstream effector of TGF beta signaling. It is known to be involved in wound repair, fibrosis, and several pathologic states associated with increased extracellular matrix production.

How would the liver be classified in the Casarett and Michalowski systems for normal tissue responses to radiation exposure?

Casarett Group III, Michalowski F-type (flexible) Liver cells do not divide regularly and are variably differentiated and are therefore characterized as "reverting post-mitotic" / group III in the Casarett system. They are considered flexible in the Michalowski system as they have no compartment and no strict hierarchy.

Radiation-induced epilation occurs before dermatitis because:

Cells in the germinal matrix of the hair bulb have shorter cell cycle times than the basal cells of the epidermis

As the dose to an organ increases, the latency period prior to the development of a late complication generally:

Decreases The latent period prior to the manifestation of a late effect generally decreases with increasing dose to the irradiated organ.

Following radiation injury, the extent of neutrophil infiltration into the irradiated volume is positively correlated with the severity of the late complication, T/F?

False

Re-irradiation tolerance of the kidney increases with increasing time interval between treatments, indicating continuous repair of sub-threshold damage, T/F?

False In the kidney, the tolerance to retreatment decreases with time, indicating a continuous progression of renal injury in the interval between treatments.

Members of the TNF-α family of cytokines are important mediators of fibrosis, T/F?

False It is the TGF-β family of cytokines, not the TNF-α family, that are associated with the development of fibrosis.

bFGF (FGF2) enhances radiation-induced apoptosis of endothelial cells, T/F?

False bFGF protects against, rather than enhances, radiation-induced apoptosis of endothelial cells.

Length irradiated is a critical factor in determining the tolerance dose for the esophagus, T/F?

False despite being a serially arranged tissue like rectum and spinal cord, several recent studies have shown that increasing the length of esophagus in the treatment field does not predict for severity or duration of radiation-induced esophagitis.

According to Michalowski's tissue classification system, bone marrow would be classified as which of the following types of tissue?

Hierarchical

The cells thought to be responsible for radiation-induced cognitive dysfunction reside in:

Hippocampus

Historically, what are the reported toxicities for patients with ataxia telangiectasia following RT?

Increased acute and increased late toxicity AT patients experienced severely increased acute AND late toxicities following radiation, indicating that the efficiency of DNA repair is important across both categories of toxicity.

The TD₅ as a function of length of spinal cord irradiated:

Initially decreases with increasing cord length, and then remains relatively constant for higher total doses

Which of the following cytokines is generally considered both anti-inflammatory and immunosuppressive?

Interleukin 10 It is a major anti-inflammatory cytokine that inhibits the initiation and effector phases of cellular immune responses as well as a variety of inflammatory responses. The other cytokines (IL-1, IL-6, IL-8, and TNFα¬) are all considered proinflammatory.

What describes the LENT/SOMA scoring system?

It standardizes assessments of the severity of late effects. The Late Effects Normal Tissue (LENT) Task Force -Subjective, Objective, Management, Analytic (SOMA) scale is intended to standardize the assessments of the incidence and severity of late radiation effects.

Of the following, the organ/tissue least able to tolerate re-irradiation is the:

Kidney The kidney exhibits little or no re-irradiation tolerance, whereas the other organs, including the spinal cord, exhibit at least some recovery following irradiation.

Assuming that the target cells do not have a pro-apoptotic tendency, the time to the expression of radiation damage in early-responding tissues typically correlates best with the:

Lifespan of the mature functional cells of the tissue

Which of the following organs has a TD5/5 of approximately 30 Gy for whole-organ irradiation using conventional fractionation?

Liver The TD5/5 (total dose associated with a 5% probability of a complication within 5 years after radiation therapy) for whole-liver irradiation is approximately 30 Gy for conventional fractionation with x-rays. The TD5/5 is 17.5 Gy for the whole lung, 23 Gy for the whole kidney, and 45 Gy for the whole brain.

Which of the following types of blood cells is most radioresistant?

Macrophages

Renal irradiation can lead to the development of radiation nephropathy, which is characterized by proteinuria, anemia, hypertension and a chronic, progressive decrease in renal function. The decline in kidney function characteristic of radiation nephropathy can be:

Mitigated using drugs that block the renin-angiotensin system

Renal irradiation can lead to the development of radiation nephropathy, which is characterized by proteinuria, anemia, hypertension and a chronic, progressive decrease in renal function. The decline in kidney function characteristic of radiation nephropathy can be;

Mitigated using drugs that block the renin-angiotensin system.

The probability that a given dose distribution will cause a specific complication in an organ at risk is denoted as the _____.

NTCP

Radiation effects in the nervous system typically arise as a consequence of damage to:

Oligodendrocytes and glial cells

How do a tissue's progenitor cells compare to its stem cells?

Only progenitor cells can migrate to the site of a normal tissue injury.

The lacrimal gland is comparable to which of the following organs/glands in terms of its radioresponse?

Parotid The lacrimal gland is comparable to the parotid in terms of both its structure and the tendency of secreting cells to undergo radiation-induced interphase death.

A drug used to treat fibrosis and osteoradionecrosis is:

Pentoxifylline

RILD is rarely observed earlier than six months following the completion of radiotherapy, T/F?

RILD typically occurs between 2 weeks and 3 months after completion of radiotherapy.

What is the response and location of stem cells in the intestinal epithelium after fractionated radiation?

Relatively radioresistant and located at the base of the crypt The intestinal stem cells, now known to be identifiable by the LGR5 marker are relatively radioresistant due to increased reliance on homologous recombination and subsequently regenerate the crypts and villi following radiation. They are located in the crypt. Normal stem cells, in hierarchical tissues, are dividing cells and are radiosensitive.

The tolerance dose for xerostomia resulting from treatment of a head and neck tumor with 3 Gy fractions compared to 2 Gy fractions would be expected to:

Remain about the same Serous acinar cells undergo apoptotic cell death. Altering the fraction size will not change the rate of xerostomia, rather the volume needs to be decreased in order to minimize the rate of xerostomia.

TGF-β leads to the activation of which downstream signaling pathway primarily involved with epithelial-mesenchymal transition (EMT) and tissue fibrosis?

SMAD

The inhibition of what protein blocks epithelial-mesenchymal transition (EMT) to reduce pulmonary fibrosis?

SMAD3 Smad (receptor-regulated Smads) proteins are involved in downstream signaling after TGFβ (SMAD1, 2, 3, 5 and 8). There are two inhibitory Smads (SMAD6 and 7) that antagonize TGFβ signaling. TGFβ promotes terminal differentiation along a lineage from proliferation- capable progenitor fibroblasts to postmitotic functional fibrocytes. Epithelial-mesenchymal transition (EMT) recognized in fibrogenesis. Loss of SMAD3 blocks EMT and reduces fibrogenesis.

The shape of the dose response curve for the induction of late effects is best described as:

Sigmoidal

What portion of the gastrointestinal tract generally exhibits the greatest acute radiation-induced injury for a given dose?

Small intestine In documented cases of humans dying from gastrointestinal syndrome after whole-body irradiation, the small intestine typically showed the most denudation relative to the other sites, likely due to the greater presence of radiosensitive crypt cells.

How does radiation affect spermatogenesis?

Spermatogenesis is more sensitive to fractionated doses Dependent on location in maturation pathway, radiation sensitivity decreases as sperm mature. Recovery of spermatogenesis is dose-dependent and takes between 1-5 years. Onset of azoospermia occurs more rapidly with higher doses.

Following radiation therapy for breast cancer, the rate of major coronary events increases linearly by 7.4% per gray, without any threshold. This is an example of a _____ ?

Stochastic effect Radiation carcinogenesis is considered to be a stochastic effect. In a stochastic effect, probability of cancer increases with dose, but the severity is dose independent. A stochastic effect has no threshold dose and the probability of the effect increases with dose. However, the severity of a stochastic effect is not effected by dose. This is in comparison to a deterministic effect which has a threshold dose, and the severity of the effect is related to the dose

Over-expression of which of the following proteins is most closely associated with the development of cancer cachexia?

TNFα

Adult stem cells lack which characteristic?

Totipotency Adult stem cells can be unipotent, multipotent, or in some cases, even pluripotent; however, only extremely early-stage embryonic stem cells are considered to be totipotent (that is, able to generate all embryonic and adult cell types). Adult stem cells do self-renew (as well as give rise to progenitor cells), are largely undifferentiated

In general, B cells are more radiosensitive than T cells, T/F?

True

Temporary epilation can be caused by a 3 Gy acute exposure, and is observed around 3 weeks after irradiation T/F?

True

Dose fractionation increases the risk for sterility in the male, T/F?

True Dose fractionation increases the risk for sterility in the male; the TD5 and TD50 for sterility are 2 Gy and 8 Gy, respectively, for a single dose of X-rays, whereas these values decrease to 1 Gy and 2 Gy for fractionated irradiation. This effect results from spreading the dose over time permitting reassortment sensitization to occur for spermatogonia, which have a large variation in radiation sensitivity through the course of their cell cycle, and more than compensating for any repair that might occur between fractions. Spermatids and spermatozoa are relatively radioresistant, whereas spermatogonia are radiosensitive.

It is often possible to distinguish a radiation-induced cataract from an age-induced one, T/F?

True It is often possible to distinguish a radiation-induced cataract from an age related cataract as a radiation-induced cataract usually begins at the posterior portion of the lens and an age-related cataract more commonly appears in the anterior portion of the lens. The threshold dose for cataract formation is now known to be well below 10 Gy.

radiation induced liver disease RILD is rarely observed earlier than six months following the completion of radiotherapy, T/F?

True RILD typically occurs between 2 weeks and 3 months after completion of radiotherapy.

The pro-fibrotic activities and role in radiation-induced fibrosis of TGFβ1 are mediated by SMAD3, T/F?

True TGF- β1 plays a central role in radiation-induced fibrosis as it causes epithelial to mesenchymal cell trans-differentiation and promotes the influx of fibroblasts and production of extracellular matrix. TGF- β1 activates SMAD proteins, including SMAD3, which modulates the transcription of target genes with pro-fibrotic activities.

Radiation-induced fibrosis is generally irreversible, T/F?

True The emphasis therefore is on prevention.

The majority of patients who develop radiation pneumonitis go on to develop pulmonary fibrosis, T/F?

True The majority of patients who develop clinically-detectable pneumonitis will progress to fibrosis. It is strongly suspected that many of the patients who develop lung fibrosis in the apparent absence of pneumonitis did, in fact, have pneumonitis, but that it was asymptomatic and had gone unrecognized. Lung is a very sensitive, dose-limiting organ with a steep dose response curve for single dose, whole organ irradiation, characterized by a TD5/5 of 7 Gy (the TD5/5 for fractionated radiotherapy using a conventional dose per fraction is about 17.5 Gy).

The serous acinar cells of the parotid and submaxillary glands are considered the target cells for radiation-induced salivary gland damage, T/F?

True The serous acinar cells of the parotid and submaxillary glands are considered to be the targets for radiation-induced salivary gland damage. Serous acinar cells typically die by apoptosis and not mitotic catastrophe following irradiation. Mucous cells are more radioresistant than serous cells.

The kidney has a relatively low tolerance dose because of the limited number of clonogens within each nephron, T/F?

True although the cells comprising the functional subunits of the kidney are not particularly radiosensitive. The kidney exhibits substantial sparing with fractionation and displays little or no tolerance to re-irradiation. A much longer latent period than 3 months is required before the appearance of radiation nephropathy.

According to the Rubin and Casarett tissue classification system, which of the following classes includes intestinal crypt cells?

Vegetative intermitotic (VIM)

The functional subunit (FSU) concept is relevant to normal tissue toxicity after irradiation because:

clonogenic cells from outside a structurally undefined FSU that survive irradiation are capable of migrating to and repopulating it. In most cases, the structurally undefined functional subunits (FSUs) benefit from migration of surviving clonogens from surrounding FSUs for their continued survival and function (not the structurally defined ones).

The whole-organ radiation tolerance dose for the kidney is low, whereas small volumes can tolerate much higher doses. This is because the kidney:

contains functional subunits that are arranged in parallel.

What type of tissues tend to tolerate re-treatment better?

early responding tissues Early responding tissues tend to tolerate re-treatment better. Early responding tissues have a rapidly proliferating stem cell compartment. If the stem cells are able to migrate to the irradiated area, and restore the tissue architecture, they may possibly be able to tolerate re-treatment to nearly the full dose. However, late responding tissues tend to have a slowly proliferating stem cell compartment with incomplete functional recovery and also incomplete proliferative capacity recovery. Therefore, late responding tissue has more difficulties with re-treatment.

If the dose-limiting, normal tissue toxicity of interest is characterized by an α/β ratio of 10 Gy, and the corresponding tumor possesses an α/β ratio of 2 Gy, it is most likely that a patient being treated for this type of cancer would benefit from:

hypofractionation In prostate cancer, HDR treatment radiobiologically makes sense because having a low α/β indicates that fraction size has a large impact.

Based on the current Response Evaluation Criteria in Solid Tumors (RECIST), a partial response (PR) is defined as a decrease in the:

longest target lesion dimension by 30%.

Withers' skin colony assay requires that a "moat" of necrosis surround an "island" of keratinocytes to be irradiated because the:

moat prevents the migration of cells from outside the radiation field into the island. In order for the skin colony assay to properly assess clonogenic survival of irradiated epithelial cells, it is necessary to minimize artifacts that could interfere with the measurement of inherent radiosensitivity. Migration and proliferation of clonogenic cells from outside the radiation field would artificially increase the surviving fraction of cells in the irradiated island. To prevent this from happening, a moat of necrosis is used to isolate the island.

How is the radiosensitivity of the jejunum quantified?

number of regenerating crypts

In which of the following organs would you expect to see a binary radiation damage response?

spinal cord

What organ has the highest sensitivity for radiation carcinogenesis in children?

thyroid The thyroid gland is the most sensitive organ to radiation carcinogenesis in children. These malignancies tend to be well-differentiated, indolent tumors, often managed by surgery alone. Historic examples of high incidences of radiation-induced thyroid cancer include survivors of the atomic bomb attacks on Hiroshima and Nagasaki, children who ingested radioactive iodine after the chernobyl accident, and children treated with x-rays for various conditions including enlarged thymus and tinea capitis. Thryoid cancer is the most common type of cancer found in children who lived near the Chernobyl nuclear power plant in 1986. High concentrations of radioactive iodine were released into the environment, which was preferentially taken up by the thyroid.

For radiation-induced normal tissue toxicity, the term TD50/5 refers to the:

total radiation dose for which there is a 50% probability of developing toxicity within 5 years of irradiation. The definition of the term "TD50/5" (or "50% Tolerance Dose at 5 Years") is the total radiation dose that would yield an approximately 50% probability of causing an unacceptable normal tissue complication within 5 years of the completion of radiotherapy.

The Laws of Bergonié and Tribondeau state that normal tissues should be radiosensitive if they contain a significant proportion of cells that are:

undifferentiated, with a high mitotic rate and a long mitotic future.