Hall 20 - Clinical Response of Normal Tissues

Question 1

What are key determinants of tissue/organ response to radiation?

Answer 1

• Inherent radiosensitivity of the individual cells
• Kinetics of the cells in the tissue (turnover/mutation rates, lifespan)

Question 2

How are functional subunits of tissues defined?

Answer 2

Structurally defined = independent, only need one clonogen (nephrons, liver lobules)
Structurally undefined = clonogens can migrate between subunits (skin)

Question 3

What affects serial organ tissue response?

Answer 3

High-dose regions and hot spots (Dmax)

Serial = integrity of each subunit is critical to organ function, little functional reserve (spinal cord)

Question 4

What affects parallel organ tissue response?

Answer 4

Volume irradiated (or mean dose)

Parallel = sensitive to whole volume RT but large reserve capacity (kidney, lung)

Question 5

What are the most radiosensitive parenchymal cells (per Casarett’s classification)?

Answer 5

Vegetative intermitotic cells
- Classic stem cells
- No differentiation
- Ex) hematopoietic stem cells, intestinal crypt cells, spermatogonia

1. Vegetative intermitotic cells
2. Differentiating intermitotic cells
3. Reverting postmitotic cells
4. Fixed postmitotic cells

Question 6

What are the least radiosensitive parenchymal cells (per Casarett’s classification)?

Answer 6

Fixed postmitotic cells
- Do not divide
- Highly differentiated
- Ex) nerve, muscle

Question 7

What cell type breaks the rules of Casarett tissue sensitivity?

Answer 7

Lymphocytes

Highly differentiated and usually do not divide but very radiosensitive

Question 8

How does dose affect H-type populations?

Answer 8

Hierarchical model = cells compartmentalized into strict hierarchy from stem cells to maturing partially differentiated cells to functional fully differentiated non-dividing cells

Higher doses have a LONGER time to recovery

Ex) bone marrow, skin, gut epithelium

Question 9

How dose dose affect F-type populations?

Answer 9

Flexible model = cells rarely divide under normal conditions but all damaged cells can be triggered to divide

Higher doses manifest sooner but have FASTER recovery (due to higher RT dose stimulating cells to divide)

Ex) liver, glandular organs

Question 10

What is the mechanism of late tissue damage?

Answer 10

Acute inflammatory response followed by an aberrant chronic inflammatory/wound healing process

Vascular (endothelial) and parenchymal cell dysfunction and cell loss

Overproduction of particular cytokines and growth factors result in fibrosis/necrosis

Question 11

What pro-inflammatory cytokines respond to tissue damage?

Answer 11

IL-1, IL-6, IL-8, TNF-alpha

*IL-10 is anti-inflammatory

Question 12

What causes fibrosis after radiation?

Answer 12

TGF-beta
Promotes EMT, fibroblast recruitment, extracellular matrix

Question 13

What blood elements decline first after bone marrow RT?

Answer 13

Lymphocytes < granulocytes < platelets < RBCs

Question 14

What is the late effect of radiation on bone marrow?

Answer 14

Lipid infiltration (adipose) - not fibrosis

Question 15

What are symptoms of radiation induced liver disease (RILD)?

Answer 15

Anicteric ascites, hepatomegaly, isolated alk phos elevation

Question 16

What are symptoms of radiation induced liver veno-occlusive disease (VOD)?

Answer 16

Fibrosis of central and sublobular veins > congested sinusoids, atrophy of liver plates, hemosiderin in Kupffer cells (from phagocytosis of leaked RBCs)

Question 17

Why does radiation induced heart disease happen?

Answer 17

Vascular endothelial damage
» inflammation > arteriosclerosis and microvascular dysfunction

Question 18

What results from early radiation injury to nervous tissue?

Answer 18

White matter demyelination (glial injury)
May be reversible

Question 19

What results from late radiation injury to nervous tissue?

Answer 19

Gray matter vascular damage

*Tolerance of spinal cord shows little dependence on overall treatment time but depends critically on dose per fraction (low alpha-beta ratio)

Question 20

How much radiation is required to irreversibly inhibit growing cartilage?

Answer 20

20 Gy
(growth slowed at 10 Gy)

Question 21

What total body dose inhibits the immune response against a new antigen?

Answer 21

3.4-4.5 Gy

• Macrophages most resistant (up to 100 Gy)
• Plasma cells very resistant (60-90 Gy) - B cell immunity often remains intact
• Granulocytes resistant up to 50 Gy
• NK cells up to 20 Gy
• T cells sensitive at 1-5 Gy but if primed can be more resistant to >10 Gy
• B cells are very sensitive <1 Gy