ASTRO 2023 (1,2,3,26-32) Flashcards

Question

A mutation in which of the following genes is LEAST likely to cause an increase in sensitivity to ionizing radiation: A. NBS1(NBN) B. BRCA1 C. ATM D. MRE11 E. XPC

Answer 1

XPC is a gene whose product is involved in nucleotide excision repair (NER). Mutations in XPC result in the human genetic disease xeroderma pigmentosum, which is characterized by extreme sensitivity to ultraviolet light. Mutations in all of the other genes result in human genetic diseases characterized by sensitivity to ionizing radiation, including Nijmegen breakage syndrome (NBS1), familial breast cancer (BRCA1), ataxia telangiectasia (ATM), and ataxia telangiectasia-like disorder (MRE11).

Answer 2

-People diagnosed with LIG4 syndrome are radiation sensitive because these individuals are deficient in the DNA ligase IV enzyme (LIG4), which plays a central role in non-homologous end joining (NHEJ) of double-strand breaks. -Cells deficient in nucleotide excision repair exhibit normal sensitivity to ionizing radiation, since this repair process plays little or no role in the repair of damages induced by ionizing radiation, but are very sensitive to UV radiation (Answer Choice A). -Base excision repair (BER), not mismatch repair, involves the action of a DNA glycosylase and an AP endonuclease (Answer Choice C). -People with Fanconi anemia are highly sensitive to DNA cross-linking agents due to inhibition of the mono ubiquitination of FANCD2, a downstream Fanconi anemia protein, following genotoxic stress (Answer Choice D). -The immune deficient phenotype in SCID mice is caused by a defect in XRCC7 (DNA-PKcs), which is critical for NHEJ as well as V(D)J rejoining. As a result, a defect in XRCC7 leads to a radiosensitive phenotype as well as the immune deficits seen in the SCID mouse. Defects in several genes are now known to cause SCID phenotypes; the mutation in the common human disease of the same name (severe combined immunodeficiency) differs from that in the well-known mouse strain.

Answer 3

MSH2 and MLH1 play a central role in mismatch repair. XPA/XPG are involved in nucleotide excision repair (Answer Choice D). DNA Ligase IV, Ku70, and DNA-PKcs all play roles in NHEJ (Answer Choices B, C, and E)

Answer 4

-An exonuclease cleaves one nucleotide at a time beginning at the end of a DNA strand. -Ligases seal breaks in the DNA strand (Answer choice A). -DNA polymerases add a new nucleotide to the end of DNA during DNA synthesis (Answer choice B). -Endonucleases produce nicks within intact DNA strands (Answer choice C). -RNA polymerase generates new species of mRNA (Answer choice D).

Answer 5

-Defects in base excision repair (BER) may increase mutation rate but generally do not alter cell survival after ionizing radiation with the exception of mutation of the XRCC1 gene, which would confer a slight increase in radiation sensitivity, as it is also involved in single-stranded DNA break repair. -Defects in nucleotide excision repair (NER) increase sensitivity to UV radiation but not to ionizing radiation (Answer Choice B). -The xeroderma pigmentosum (XP) and Cockayne Syndrome (CS) genes are involved in NER (Answer Choice C). -BER acts to remove damaged bases from DNA, including those damaged by ionizing radiation, but NER acts on pyrimidine dimers, single-strand breaks, and bulky adducts (Answer Choice D). -The gene defective in most patients with Li-Fraumeni Syndrome is p53, although some patients with that condition have mutations in CHK2 (Answer Choice E).

Answer 6

Two principal recombinational DNA repair pathways have been identified, homologous recombination (HR) and non-homologous endjoining (NHEJ), each of which employs separate protein complexes. DSB repair by HR requires an undamaged template molecule that contains a homologous DNA sequence, typically derived from the sister chromatid in the S and G2 phase cells. In contrast, NHEJ of double-stranded DNA ends, which can occur in any cell-cycle phase, does not require an undamaged partner and does not rely on extensive homologies between the recombining ends (typically 2-6 bp of microhomology are used). Defective HR can be causally linked to impaired DNA replication, genomic instability, human chromosomal instability syndromes, cancer development, and cellular hypersensitivity to DNA damaging agents. Cells with genetic defects in NHEJ (such as mutation of DNA-PK, XRCC4, or DNA ligase IV) display a more pronounced hypersensitivity to ionizing radiation than cells defective in HR (such as mutation of BRCA1, BRCA2, or RAD51)

Answer 7

Several DNA repair pathways, including translesional DNA synthesis (TLS), nucleotide excision repair (NER), and homologous recombination (HR) can be mobilized at stalled DNA replication forks depending on the type of fork-blocking lesion. Chemotherapy-induced DNA lesions, such as interstrand crosslinks, interfere with the progress of the replicative DNA helicase or DNA polymerases, thereby leading to replication fork blockage or demise and producing DNA gaps or one-sided DNA doublestrand breaks (DSBs). Uncoupling of the replicative DNA helicase from the polymerases may occur generating excessive single-stranded DNA, which could in turn be the target of endonucleoytic processing, resulting in a one-sided DSB. In addition, single stranded breaks induced by endogenous and exogenous sources may lead to the formation of onesided DSBs due to runoff of the replication fork. In the repair of one-sided DSBs, HR appears to be the only pathway leading to their productive resolution. This entails resection of the DSB to form a 3′-tailed end for Rad51 filament assembly and DNA strand invasion and ultimately reconstruction of the replication fork.

Answer 8

Xeroderma pigmentosum is a genetic disorder due to mutation in genes involved in nucleotide excision repair (NER). This phenotype is characterized by extreme sensitivity to ultraviolet light.

Answer 9

BRCA1 and BRCA2 predominantly regulate homologous recombination (HR) as opposed to non-homologous end joining (NHEJ). Fewer than 10% of patients with breast cancer are found to have mutations in these breast cancer susceptibility genes. Due to the negative effect that BRCA1 mutation has on HR, BRCA1-deficient cells are more SENSITIVE, not resistant, to mitomycin C and other DNA crosslinking agents (Answer choice A). The prevalence of BRCA1 mutation is slightly lower than that of BRCA2 mutations in the general US population (1:500 for BRCA1 vs 1:222 for BRCA2). The breast cancer risks for carriers of BRCA1 and BRCA2 mutations are similar at about 70% by the age of 80, but with earlier age of disease onset for the BRCA1 mutation (peaks in 4th decade) compared to BRCA2 carriers (peaks in 5th decade).

Answer 10

Among the 5 genes listed, all may affect radiation or DSB sensitivity at different levels. However, DNA-PKcs is directly involved in DSB repair and DNA-PKcs mutation is known to cause hypersensitivity to DSB damage and radiation.

Answer 11

p21 inhibits CDK-cyclin activity, which has the effect of decreasing the phosphorylation of RB1. ATM, and not p21, phosphorylates NBS1 thereby stimulating homologous recombinational repair. p53-mediated G1 arrest results from transactivation of p21 by p53. An increase in the amount of p53 can result in apoptosis or G1 arrest. DNA damage does initiate a signal transduction pathway that results in increased amounts of p53, however this occurs by stabilization of the existing protein, rather than by increased transcription of the gene that encodes it.

Answer 12

The ATM protein contains a highly conserved C-terminal kinase domain resembling a phosphatidylinositol-3 kinase (PI(3)K); this kinase is an important component of a number of DNA damage repair pathways. Both ATM and ATR are required for IR-induced Chk1 phosphorylation. ATM is recruited to double strand breaks by the Mre11-Rad50-Nbs1 complex. ATR is recruited to single stranded DNA at sites of stalled replication forks by ATR-interacting protein (ATRIP). Cells derived from patients with AT typically display decreased levels of p53 phosphorylation. Irradiation causes autophosphorylation of ATM which converts it from an inactive dimer into the active monomeric form, not vice versa. ATM activation and Nbs1 recruitment to damaged DNA occurs prior to ATR recruitment and Chk1 phosphorylation

Answer 13

B The process by which tumor cells change phenotype in response to an immune response (cytotoxicity or inflammation) in an attempt to avoid recognition (i.e. the induction of PD-1, PD-L1, and IDO following antigen recognition and the production of IFNγ) is characteristic of an adaptive immune response

Answer 14

D Section 1: Regulation of T Cell Activation by CD28-CTLA4 Naive and memory T cells express high levels of CD28 but lack surface CTLA4. CTLA4 is initially sequestered within intracellular vesicles. Upon TCR activation, CTLA4 is transported to the cell surface. The strength of TCR signaling determines the level of CTLA4 expression. Stronger signals lead to higher CTLA4 surface expression. Role of CTLA4: Acts as a negative regulator of T cell activation. Dampens T cell responses to maintain appropriate activation levels despite varying antigen stimulation. Prevents excessive T cell activation in response to strong TCR signals. Section 2: Role of PD-1 Pathway in T Cell Regulation PD-1 pathway primarily regulates T cell function in peripheral tissues, not during initial activation. Activated T cells express PD-1. Inflammatory signals, particularly IFN-γ produced by TH1 cells, induce the expression of PD-L1 on target cells. Binding of PD-1 on T cells to PD-L1 on target cells downregulates T cell activity. This limits tissue damage and maintains immune homeostasis. Chronic Antigen Exposure: Excessive PD-1 signaling in the context of chronic antigen exposure can lead to T cell exhaustion or anergy, impairing their function.

Answer 15

C Inhibitors of programmed cell death 1 (PD-1) receptor: pembrolizumab and nivolumab. Inhibitors of programmed death ligand 1 (PD-L1): atezolizumab, durvalumab, and avelumab. Ipilimumab is an example of a Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitor.

Answer 16

A The abscopal effect describes a situation whereby a patient being treated with radiation therapy to a site of metastatic disease experiences concurrent regression of a distant site of metastatic disease that is not being directly irradiated. The abscopal hypothesis was first described in 1953 to refer to the effects of ionizing radiation occurring "at a distance from the irradiated volume but within the same organism.” In contrast, the bystander effect describes the induction of biologic effects in cells that are in close proximity to cells that are directly traversed by a charged particle

Answer 17

B. T cells recognizes antigenic determinants presented in the MHC cleft by the T cell receptor Pattern recognition receptors (PPRs) such as Toll-like receptors (TLRs) are predominantly found on APCs and other innate immune cells and are used for the detection of danger signals such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The engagement of PPRs initiates the maturation of APCs, especially dendritic cells, thereby allowing them to stimulate T cells by providing the first signal (signal 1: antigen) to the TCR and the second signal (signal 2: co-stimulation) to CD28, which then amplifies signal 1. PD-1 is an immune checkpoint that inhibits proximal signaling of the TCR by sequestering Src Homology Region-Containing Protein Tyrosine Phosphatase-2 (SHP-2) and facilitating Csk-mediated inhibitory phosphorylation of Lck.

Answer 18

D Lymphocyte Activating 3 (LAG3) is a cell surface immune checkpoint receptor protein that is expressed on activated T cells and negatively regulates cellular prol and is activated by (MHC) II. Programmed cell death protein (PD)-1 is a cell surface immune checkpoint receptor protein that is bound by its two ligands, PD-L1 and PD-L2 and functions to suppress T cell inflammatory activity and promotes self tolerance. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is another immune checkpoint receptor protein that is activated by CD80 and CD86 and functions to downregulate the immune response. A potential immune checkpoint target, T-cell immunoglobulin and mucin domain-3 (TIM-3) is activated by Galectin-9 (Gal-9), Phosphatidylserine, HMGB-1, and Cecam-1 and plays a role in T cell exhaustion. LAG3, PD-1, CTLA-4, and TIM3 all act as co inhibitory receptors that limit or inhibit the activation of T cells even if the TCR is engaged. OX40 (OX40L) is a co-stimulatory receptor that does promotes T cell activation by driving T-cell proliferation, memory, cytotoxic effector function, and cytokine production. Other examples of co-stimulatory molecules are 4-1BB, CD40L, GITR, ICOS, and CD27. CTLA4 counteracts the activity of the T cell co-stimulatory receptor, CD28, both sharing identical ligands: namely, CD80 (B7.1) and CD86 (B7.2). Although CTLA-4 is active on CD8+ T cells, it seems that most of its effects are derived from down-modulation of helper T cell activity and enhancement of Treg immunosuppressive activity. PD-1 limits the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and functions to limit autoimmunity. PD-1 expression is induced following T cell activation. When engaged by one of its ligands, PD-1 inhibits kinases that are involved in T cell activation through the phosphatase SHP250, although additional signaling pathways are also likely induced. The general concept is that blocking CTLA-4 affects early T cell activation whereas blockade of PD-1 signaling is more relevant later, at the tissue site, thereby explaining why the CTLA-4 inhibitors are associated with more significant toxicity.

Answer 19

B Regulatory (suppressor) T cells are a subset of CD4+ T cells that express the transcription factor foxhead box P3 (FOXP3). FOXP3 is a potent suppressor of immune responses to self and non-self and is essential to the maintenance of peripheral immunological tolerance. Tregs suppress the activation, proliferation, and cytokine production of CD4+ and CD8+ T cells, and are additionally thought to suppress B cells and dendritic cells. They exert their suppressive activity through cell-to-cell contact and via the production of soluble suppressive/inhibitory messengers (i.e. TGF-beta, IL-10 and adenosine). Loss of function mutations in the Foxp3 gene underlie the lymphoproliferative disease of the Scurfy mouse and the homologous autoimmune lymphoproliferative disorder in man, termed Immune dysregulation Polyendocrinopathy Enteropathy−X (IPEX) linked syndrome. Of note, despite the immune suppressive function, the infiltration of tumors by Tregs doesn’t necessarily indicate worse prognosis as it is also an indicator for a T cell inflamed tumor phenotype, (i.e. a (positive) sign for immune reactivity). Antigen presentation without signal 2 can cause T cell anergy. Epitope spreading (or antigen cascade, antigen spread, determinant spread) describes a phenomenon where the immune response evolves and expands from focusing on a single antigenic epitope, into a multi-epitopic response be it naturally or following therapeutic intervention e.g. vaccination or radiotherapy. This process is dynamic and may continue to expand over time. Antigen spreading of the anti-tumor immune response from one antigen to another antigen has been linked to superior clinical outcome with the assumption that it counteracts tumor immune evasion

Answer 20

A MHC class I molecules are heterodimers made of two, noncovalently linked polypeptide chains, α and B2M. The conformation of the MHC class I protein is highly dependent on the presence of B2M. B2M is essential for proper MHC class I folding and transport to the cell surface.

Answer 21

A. Programmed cell death 1 receptor

Answer 22

The Hounsfield unit scale is a standardized approach to interpreting reconstructed images obtained with a computerized tomography (CT) scanner. CT is a technique that relies on differential levels of X-ray attenuation by tissues within the body to produce digital images reflecting anatomy. Hounsfield units (HU) are numerical values that reflect these differences in density and composition, and thus X-ray attenuation, between various tissue types. Radiologists use software that automatically assigns HUs to every voxel of a CT scan to enable efficient scan interpretation. In oral radiology, approximate HUs can be derived using grayscale levels in cone beam CT (CBCT) images.

Answer 23

C cumulative doses from 2-3 head CTs to the brain are 5-6 cGy. For comparison, X-ray doses from chest radiography are 0.01 cGy (0.1 mGy) and X-ray doses from mammography are 0.04 cGy (0.4 mGy). B- barium E- FDA

Answer 24

C The standard uptake value (SUV) is a standard method of quantifying the radioactive uptake observed in a positron emission tomography (PET) scan image. As a cancer detection method, (FDG) PET is based on the observation that in normoxic conditions tumor cells primarily use glycolysis for energy production instead of mitochondrial oxidative phosphorylation as normal cells do. This phenomenon is known as the Warburg effect. SUV scores of >15 g/mL usually indicate a tumour that is highly dependent on glucose metabolism and is therefore more aggressive rather than indolent. It therefore follows that SUV scores inversely correlate with local tumor control The SUV is calculated as follows: SUV [g/ml] = (Tissue activity (mCi/ml))/(injected dose (mCi)) × patient’s body weight (g). SUV score values are therefore proportional to a patient’s body weight SUV values increase in value if the PET scan is delayed after FDG injection. The typical dose of FDG administered to adult patient is approximately 10-18 mCi.

Answer 25

D PSMA is expressed in certain non-prostate tissues, such as the kidneys, small intestine and salivary glands, consequently these tissues also demonstrate uptake on PET-PSMA scan. Conversely, On PET-FDG scans physiological uptake is seen in the brain, heart and urinary system and other metabolically active tissues. PSMA stands for Prostate-specific membrane antigen. PSMA is a membrane- bound antigen that is highly specific for benign and malignant prostatic epithelium, although endothelial cells in multiple organs are also immunoreactive. PET PSMA is not reliable for lesions less than 5 mm in size. The radionuclide gallium-68 (68Ga) decays through positron emission to the stable isotope zinc-68 (68Zn). The tracer is indeed based upon the peptidomimetic Glu-NH-CO-NH-Lys(Ahx)-HBED-CC combined with the radionuclide 68Ga.

Answer 26

E The use of microRNAs (miRNAs) and small interfering RNAs (siRNAs): important tool for “gene silencing” or RNA interference (RNAi). miRNAs and siRNAs bind to and inhibit the transcription of specific genes and/or they can silence cytoplasmic mRNAs either by stimulating their cleavage or by inhibiting translation. miRNAs are produced from transcripts that form stem-loop structures, whereas siRNAs are produced from long double-stranded RNA precursors. In the initiation phase of RNAi, the ribonuclease-III enzyme Dicer cleaves double-stranded RNA molecules into 21–23-nt short interfering siRNA duplexes. In the effector phase of RNAi, the siRNA becomes unwound and assembles into RISC (RNA-induced silencing complex). The activated effector complex recognizes the target by siRNA–mRNA base pairing and cleaves the mRNA strand with its endoribonuclease activity.

Answer 27

D The radioactive half-life of 18F is 110 minutes, PET imaging cameras detect the 0.51 MeV photons produced by the annihilation resulting from the interaction of a positron and electron.

Answer 28

A In gel electrophoresis, DNA molecules are negatively charged and therefore migrate towards the positive electrode. Sodium dodecyl sulfate (SDS), a detergent, is used to denature proteins, not DNA, so that the proteins can be separated by size on a gel. The higher the concentration of agarose in the gel, the slower DNA molecules will migrate. Polyacrylamide gels are generally used to separate small DNA molecules whereas agarose gels are used for large sized DNA. The lower the molecular weight of the molecule, the more rapidly it will migrate through a gel.

Answer 29

A Capillary sequencing requires in vivo cloning and amplification whereas next generation sequencing (NGS) utilizes adaptor ligation of DNA fragments and binding to a matrix for DNA sequencing.

Answer 30

C Northern blotting is used to study RNA.

Answer 31

A Wild-type p53 protein is not detectable, because its mRNA is short-lived (T½ = 8 min) in unstressed cells. The induction of DNA double strand breaks by X-ray irradiation initiates a p53-dependent signal transduction cascade. One downstream target of this cascade includes the induction of WAF1/CIP1 mRNA, which encodes the p21 protein. Upregulation of WAF1/CIP1 protein inhibits the cyclin E/cyclin-dependent kinase 2 complex, an event that is able to stop cells from progressing through G1. Phosphorylation of p53 at serine-15 in response to ionizing radiation correlates with both accumulation of total p53 as well as its transactivation of downstream genes

Answer 32

D A clonogenic survival assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony (~50 cells). This approach is commonly used by radiation biologists to assess 248 reproductive death after ionizing radiation or treatment with other cytotoxic agents. Following treatment with radiation and/or cytotoxic agents, only a fraction of cells retain reproductive capacity and can form colonies. A feeder layer consists of cells (fibroblasts) that have been irradiated (typically ~30 Gy) and can no longer divide but still produce growth factors for the colony forming cells. Trypsin is a protease that breaks down cellular adhering proteins to facilitate release of cells from each other and detach cells from a tissue culture dish. Survival curves are semi-log plots, with the survival fraction (logarithmic scale) on the Y-axis and therapeutic dose on the X-axis (linear scale).

Answer 33

C A radiation worker is permitted either 50 mSv per year for each year that the person was engaged in radiation work or else a lifetime dose equal to his/her age multiplied by 10 mSv, whichever is less. Based on the lifetime dose rule, this woman would have been permitted 200 mSv as of her 20th birthday. The 50 mSv per year rule dictates that her maximum allowable dose would be only 100 mSv.

Answer 34

E The NCRP recommendations state that a worker who has declared a pregnancy may receive a maximum dose of 0.5 mSv per month to the mother’s fetal monitor worn at the mother’s waist, under any protective apron worn by the woman.

Answer 35

D NCRP recommendations: A radiation worker is currently permitted 50 mSv to the eye and 500 mSv to the skin in any given year & annual dose equivalent limit for the lens the eye was 150 mSv. The ICRP recommends an annual equivalent absorbed dose limit for the lens of the eye to be 15 mSv for the public. For chronic occupational exposures, the ICRP recommends an equivalent dose limit for the lens of the eye of 20 mSv in a year, averaged over defined periods of 5 years, with no single year exceeding 50 mSv.

Answer 36

B A member of the general public is permitted 1 mSv per year for “chronic” radiation exposure over extended periods of time, or 5 mSv per year for an infrequent exposure. Radiation workers, including radiation oncologists and nuclear power plant employees, may receive 50 mSv per year A person under the age of 18 may be exposed to radiation up to 1 mSv per year if the potential exposure occurs as part of an educational or training program A patient’s relative transporting a patient to and from radiotherapy treatment, presumably an infrequent event, would be considered to be a member of the general public and therefore would be allowed 5 mSv per year

Answer 37

C The Maximum Permissible Dose (MPD) defines the recommended occupational exposure dose limits and does not include any dose received from medical procedures or natural background radiation. Radiation workers (including residents) are considered subject to occupational exposure limits. Medical students are considered subject to the education and training exposure limits. In nearly all cases, the MPD is greater than the dose that would be obtained with strict adherence to the principles of ALARA, which stipulate that personnel should receive doses “as low as reasonably achievable”. The MPD recommendations for radiation workers are typically 10-50 fold higher than for members of the general public. The NCRP and ICRP guidelines treat age differently in establishing the MPD. The effective dose limit for occupational exposure per the NRCP guidelines is 10 mSv per year of age or 50 mSv per year and per the ICRP guidelines is 20mSv per year (averaged over 5 years) or 50mSv per year. The MPD for younger workers is therefore greater under NCRP guidelines than under ICRP guidelines, but the MPD for older workers is greater under ICRP guidelines than under the NCRP guidelines.

Answer 38

B The “committed dose equivalent” is the dose equivalent to a tissue or organ that will be received over a 50-year period from the ingestion of radioactive material(s)

Answer 39

A The maximum dose with fluoroscopy is to the skin. Early transient erythema may occur with doses of 2 Gy, dry desquamation with single doses of 14 Gy, and moist desquamation with single doses of 18 Gy or more.

Answer 40

A Dose and dose-rate effectiveness factor is used to take into consideration dose and dose-rate when considering exposures for cancer risk. LNT is the linear non-threshold model. HSR is the hypoxia sensitizer radio. LDRR is a usual abbreviation for low dose rate radiation.

Answer 41

A The most sensitive period during gestation is when radiation exposure may cause embryonic lethality. Based on animal studies, this period of time occurs immediately following conception but prior to implantation within the uterine wall.

Answer 42

C Irradiation during the early fetal period, corresponding to weeks 8-15 of gestation in humans, is associated with the greatest risk for mental retardation. The main risks during preimplantation, organogenesis, and the late fetal period are prenatal death, congenital malformations, growth retardation and carcinogenesis, respectively. There is an increased risk of carcinogenesis following irradiation throughout the gestation period. Preimplantation (0-1.5 weeks) Prenatal Death Organogenesis (1.5-6 weeks) Congenital Malformations Early Fetal Period (6-8 weeks) NIL 8-15 weeks Mental Retardation (High Risk) (Risk ~0.4 per Gy ~25 IQ points per Gy) additional risk: Microcephaly Late Fetal Period (16-25) weeks Mental Retardation (Lower Risk) Risk ~0.1 per Gy additional risk: Growth Retardation, Carcinogenesis

Answer 43

B Spina bifida is a neural tube defect typically associated with folate deficiency, not ionizing radiation exposure.

Answer 44

A The LD50 for oocytes has been shown to be approximately 0.5 Gy

Answer 45

C Low dose radiation of the fetus during the third trimester, not the first trimester, causes an increased risk of childhood cancers, especially leukemias. The Oxford Survey of Childhood Cancers suggested an association between childhood cancer and in utero exposure to diagnostic x-rays. This was a retrospective case-controlled study of 7,649 children who died of leukemia of childhood cancers. The relative cancer risk estimate assuming radiation to be the causative agent was estimated at 1.52 (Lancet 1:1185, 1970).

Answer 46

C The genetically significant dose (GSD) is the annual average gonadal dose to a population adjusted for the relative child expectancy of that population. Exposure to radon does not contribute significantly to the GSD because the decay products of radon are deposited almost entirely in the lung. The GSD resulting from medical procedures performed annually in the United States is estimated to be 0.3 mSv, not 1 Sv. Although the GSD can be utilized to estimate the number of children born each year with a radiation-induced mutation, the GSD itself is an estimate of the average gonadal dose to the population (including potential parents), not an estimate of the effects on offspring The GSD is an annual population dose, not an individual lifetime dose

Answer 47

D The dose required to double the incidence of mutations in humans has been estimated to be approximately 1-2 Sv. Radiation does not induce characteristic mutations; it only increases the incidence of mutations that are known to occur spontaneously A higher incidence of genetic abnormalities was not found in the children with at least one parent who previously received treatment with ionizing radiation prior to conception. The best estimates are that no more than 1-6% of spontaneous mutations in humans are due to exposure to background radiation The absolute mutation rate for humans has been estimated to be approximately 0.1-0.6% per Sv.

Answer 48

A ‘Studies of the Japanese A-bomb survivors by RERF have served as a “gold standard” for radiation epidemiology. One of the key findings is that there has NOT been found to be a statistically significant increase in mutations identified in the F1 generation (approximately 70,000 individuals), despite the original expectation that there might be based on animal experiments. The doubling-dose estimate for radiation-induced genetic mutations in humans is therefore based on mouse data coupled with estimates of human spontaneous mutation rates. A majority of the survivor cohort received relatively low radiation exposure of less than 100 mSv. A recently revised dosimetry model (DS02) provides improved estimates of individual exposures received by individuals who survived the Japanese A-bomb. The Adult Health Study cohort members even today continue to undergo a thorough clinical exam every two years. By providing data and biological samples these participants remain an important resource for future analyses

Answer 49

B The mutation rate decreased significantly when the dose rate was reduced. This was attributed to repair processes that take place during irradiation at low dose rates. Interestingly, this is different than what was observed in the fruit fly study, which demonstrated that dose rate had no effect on the mutagenesis rate. The dose response curve for radiation-induced mutagenesis was found to be linear WITHOUT a threshold. Males were found to be MORE susceptible to radiation induced mutation than females. Mutation rates at the different loci studied DID vary widely The estimated doubling dose for mutations was approximately 1 Gray

Answer 50

D The dose that will lead to oligospermia and reduced fertility in the male is estimated to be 0.15 Gy. There is neither a latent period nor temporary sterility in the female following exposure to radiation. Radiation sterility does not affect hormone balance, libido, or physical capability in the male, but can induce permanent ovarian failure and menopausal symptoms in the female The dose that will lead to permanent sterility in the female is 12 Gy in the prepubertal woman and 2 Gy in the premenopausal (mature) woman

Answer 51

D Low dose-rate exposure usually results in fewer mutations than the same dose given at a high dose rate. T to A transitions are usually found following exposure to ultraviolet (UV) light, but not to ionizing radiation High LET radiation tends to cause large deletions, while low LET radiation tends to cause small deletions The types of mutations observed following exposure to ionizing radiation can differ from the spectrum of mutations observed following exposure to UV radiation The relative dose to double the rate of mutagenesis is estimated to be 1 Gy

Answer 52

B Testis is a dose-rate sensitive organ with low dose rates causing more damage than the same dose at a high dose rate. A dose-rate effect is described as occuring when a decreased response is observed following a decreased dose rate. Exposure of the fetus in utero causes more damage if the exposure is at a low dose rate than if the same dose is given at a high dose-rate; this is likely due to the fact that more stages of gestation are affected at a low dose-rate. FLASH technology is based on using an ultra-fast dose-rate to enhance tumor killing and somehow lowering normal tissue toxicity.

Answer 53

A Cancer survivors constitute 3.5% of the US population, but second primary malignancies among this high-risk group now account for 16% of all cancers diagnosed. A high frequency of second primary tumors among patients diagnosed with soft tissue sarcoma patients has been reported, with a particularly high risk of developing a new soft tissue sarcoma Radiotherapy to the breast or chest wall of young women is associated with long-term cardiotoxicity and an increased risk of second breast cancers. Genetic factors, as well as the potential carcinogenic effects of treatment, can affect the probability of second cancers in survivors. Patients with the BRCA2 mutation demonstrate an increased risk of subsequent ovarian cancer, as well as cancers in the irradiated and unirradiated breast. Patients with Li-Fraumeni syndrome and other familial cancer syndromes would likewise be at increased risk of developing second malignancies unrelated to the carcinogenic effects of their initial treatments. Children who receive cranial irradiation as part of their treatment for leukemia are at a significant increased risk for developing meningiomas.

Answer 54

D Both benign nodules and malignant tumors of the thyroid can be induced by radiation. None of the other sites shows such an increased incidence of benign tumors following treatment with ionizing radiation.

Answer 55

C Approximately 15% of the fatal cancers diagnosed among patients previously treated with total body irradiation are leukemias.

Answer 56

C Among the population of children who were treated for tinea capitis (ringworm) using ionizing radiation, an excess incidence was not detected for head and neck cancers. Brain cancers, thyroid cancers, adenomas, (non-CLL) leukemias, and late development of breast cancer were all observed at an excess incidence among children that were previously treated with X-Rays compared with children who only received topical medications.

Answer 57

E The susceptibility to radiation-induced cancer decreases with increasing age at the time of irradiation. Radium dial painters ingested significant quantities of radium-containing paint by repeatedly licking the paint brushes they used. These women subsequently developed an excess number of osteosarcomas due to the incorporation of radium into their growing bones and the continuous low dose-rate irradiation received by these tissues over the next decades. At this time, cancers induced by radiation cannot be distinguished from cancers that occur naturally, although molecular markers for radiation exposure may eventually be identified The current consensus among radiation protection organizations is that the most appropriate dose response curve for radiation carcinogenesis is one that increases linearly with increasing radiation dose and without a dose threshold (linear no-threshold or LNT model). This hypothesis, however, has been challenged by those who believe that exposure to low radiation doses may be less harmful than what is predicted by the LNT model, and possibly even beneficial (often referred to as hormesis). The LNT model has also been criticized by those who believe that bystander effects may result in an increased risk at low doses over those predicted by the LNT model Hematological malignancies have shorter latency periods compared to solid tumors

Answer 58

D Statistically significant increases in non-cancer disease mortality with increasing radiation dose have been observed, particularly for diseases of the circulatory, digestive, and respiratory systems. Survivors who received less than 5 Gy demonstrate an increased risk of heart disease. Among the Japanese A-bomb survivors, susceptibility to radiation induced breast cancer was found to dramatically decrease with increasing age at time of exposure, with women over 50 years of age showing little or no excess. The latency period for the appearance of most radiation-induced solid tumors is far greater than 1-3 years, ranging from 10-60 years post exposure. It is estimated that 8% of people exposed to 1 Sv would die from a radiation-induced cancer. Thus, in a population of 1,000 people, approximately 80 would develop and die from a fatal cancer

Answer 59

C The risk estimates based on the Radiation Effects Research Foundation (RERF) analyses for solid tumors are well-fit using a linear model; a linear-quadratic model provides a much better fit to the leukemia dose response data. Although the BEIR VII Committee conducted an analysis of the data related to the DDREF, and used a value of 1.5 for its own risk estimations, the factor of 2.0 has historically been applied to adjust for lower doses and dose-rates. RERF data clearly indicate that radiation risk is dependent on gender, as well as age at exposure and time since exposure Population studies frequently have more limitations compared to more quantitative case-control studies, including smaller population sizes and uncertainties associated with dose estimations, confounding factors, and lack of relevant control populations The BEIR VII estimates the lifetime additional cancer risk is about 1% following 100 mSv

Answer 60

C Development of cancer after high dose radiation is an example of a stochastic effect. A stochastic effect fulfills two criteria: 1) the probability of an outcome of interest increases with increasing dose, typically without a threshold dose; and 2) the severity of an outcome of interest is not altered by dose (all or none) In contrast, deterministic effects, such as mental retardation, cardiac toxicity, cataracts and acute toxicity, have a threshold dose below which it does not occur and have increased severity with increased dose.

Answer 61

C Administration of potassium iodide (KI) to the children that had been exposed to 131 Iodide (131I) as a result of the accident would have reduced the number of thyroid cancers by decreasing exposure to the radioactive iodide. While 137 Cesium (137Cs) was released as part of the accident, 131I was the cause of the thyroid cancers that occurred. Most of the tumors demonstrated rearrangements of the RET and PTC genes The majority of the tumors occurred predominantly in children within 7- 10 years following exposure.

Answer 62

D Data from the atomic bomb survivors demonstrate that breast cancer, thyroid cancer, bladder cancer, and non-CLL leukemia were all significantly induced following exposure to radiation Cancer of the cervix is tightly linked to HPV viral infection and is not considered to be a highly radiogenic tumor

Answer 63

A Medical exposure contributes more than 50% of the average annual effective radiation dose, slightly higher than that contributed by environmental exposures, and has significantly increased since the 1980s. The average annual effective dose related to population and occupational exposure from nuclear reactors remains minimal, at 0.0005 mSv to 0.005mSv Following medical exposures, natural background radiation is the next largest contributor to the average annual effective dose, contributing approximately 37% of all radiation exposure The US population has a higher average annual effective dose from medical procedures compared to that of other developed countries. CT scans represent the greatest contributer followed by nuclear medicine procedures.

Answer 64

C Alpha-particles are emitted during the decay of radionuclides, such as radon, that occur in nature. Radon gas escapes from the soil and builds up inside homes where it is inhaled and can cause lung cancer.

ASTRO 2023 (1,2,3,26-32) Flashcards

(101 cards)