Clinically Relevant Normal Tissue

Responses to RT

Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu

WMcB2008

www.radbiol.ucla.edu
• In 1901, Becquerel reported that a radium source that he
obtained from Marie Curie and kept in his vest pocket for
demonstration purposes caused a radiation burn that appeared
after 10days.
• Pierre Curie, the co-discoverer of radium with Marie, deliberately
produced a similar burn on himself. This radiobiology experiment
ignited interest in the medical uses of radioactive sources.

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 Latency
Different tissues take different times to express damage (latency). This
depends on their turnover time.
On this basis, normal tissues can be divided into

ACUTE RESPONDING
• Gut
• Skin
• Bone Marrow
• Mucosa
LATE RESPONDING
• Brain
• Spinal Cord
• Kidney
• Lung
• Bladder

Defined by the standard 6wks clinical treatment time

Acute responding tissues are generally “hierarchical” and

late responding tissues “flexible”.
WMcB2008

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 The importance of this distinction lies in the differing
effects of dose fractionation on the two tissue types
1

.1

S.F.
fractionated
.01 late effects

fractionated
.001 acute effects

Single dose
Single dose
acute effects
.0001 late effects
0 2 4 8 10 12

Dose (Gy)

WMcB2008

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 There is no Relationship between
Latency and Tolerance
100%

BONE
PERCENT MARROW
LETHALITY Day 30 GUT
Day 7
LUNG
Day 180

0%
0 2 4 6 8 10 12 14 16 18
Dose (Gy)

• Different tissues have different tolerances to irradiation and fail at

different times (latency) after irradiation
• Latency is determined by cell turnover kinetics in a tissue. It is NOT an
indicator of radiosensitivity.
• After moderate doses, gut fails first, then bone marrow, then lung, but
the hematopoietic system is the most radiosensitive
• In these experiments, mice were given varying doses of whole body, abdominal,
or thoracic irradiation, and the dose and time to failure assessed.
WMcB2008

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• Other examples,
• In testis, it takes 60 days to produce 1000 sperm per spermatogenic stem
cell. Sperm counts remain normal for many weeks after irradiation and
then fall precipitously.
• Tolerance is 0.1 - 0.15 Gy for temporary sterility.
• 6 - 8 Gy in 2 Gy fractions for permanent sterility.
• In gut, symptoms appear rapidly (2 weeks). This is the time taken for
epithelial cells to traverse the villus and be shed into the lumen.
• Tolerance is about 50 Gy in 2 Gy fx for the small intestine and slightly
higher for the large intestine.
• Lag time before the onset of radiation-induced proliferation in jejunum
may be less than 24 hours. In colon and stomach, slightly longer.

WMcB2008

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 Tolerance Doses Vary Widely
Organ Injury TD5%/5yr
TD50%/5yr
Bone marrow aplasia 2.5 4.5
Intestine perforation 40 55
Liver hepatitis 30 40
Brain necrosis 45 60
Lung pneumonitis 17 24
Kidney nephrosclerosis 23 28
Skin dermatitis 55 65
Rectum ulcer, fistula 60 80
Saliv. glands xerostomia 32 46
Testes sterilization 1 2
Ovaries sterilization 2-3 6-12
Bone (child) growth arrest 10 30
Bone (adult) necrosis 60 100
P. nerves neuritis 60 100
Muscle fibrosis 60 80
Breast atrophy 50 100

How Important is Dose, Anyway?

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Clinicians’ View of Tolerance Dose -
CNS
45Gy in 2Gy fractions
gives a 0.2% incidence of myelopathy
57 - 61Gy in 2Gy fractions
gives a 5% incidence of myelopathy

Fowler 1998 survey of radiation oncologists

• 41% felt tolerance of spinal cord 40-44Gy
• 33% 45-49Gy
• 24% 50Gy+

Does this variation matter?

WMcB2008

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 Segment of Mouse Gut Irradiated with Varying Doses

XRT

a b c d
12.5Gy 14.0Gy 15.5Gy 17.0Gy
Day 13
Overt tissue response (e.g. ulceration) is dose-dependent with a threshold followed by a rapid
increase in severity.
a. Patchy breakdown of mucosa except in shielded mucosa at top of specimen.
b. Ulcerated mucosa being resurfaced by near-confluent nodules regenerated from a large number
of independently surviving jejunal clonogens.
c. Severe ulceration but with about 60 discrete clonogenically-derived mucosal nodules.
d. As for c. but only 4 regenerated nodules.
WMcB2008

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 100
90
Probability of damage (%) 80 Small differences in dose can have
major biological effects

60 ~ 7.5%
per Gy

40
37
D10
20

0
0 10 20 30 40 50 60 70 80
Dose (Gy)
• Curves for the probability of a normal tissue complication NTCP in the clinic are
generally steep compared with TCP curves

• A 20% increase in dose could cause a large increase in the incidence of

complications
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 • Probability of a normal tissue complication

NTCP = 1/(1+(D/ED50)-k
• where k is sensitivity - typically about 7 for most normal tissues
• ED50 is typically 50-60 Gy

• Probability of complication free cure

= [TCP][1-NTCP]

WMcB2008

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 Acceptable Unacceptable

An unacceptably severe skin reaction caused by dose-inhomogeneity in a mastectomy case 6 weeks

after RT, illustrating clonal regrowth of epithelium of chest wall. The lack of surviving clonogens in
some areas leads to slow healing ulceration and consequently poor long-term function. However, the
survival and regeneration by even as few as about 5 clonogens per cm2 can maintain a tolerable skin
reaction. This illustrates the steepness of the normal tissue complication probability curve once a
certain tissue-specific threshold is exceeded.
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 Double Trouble
• If an area is treated to the 95% rather than the 75% isodose
line, it will be overdosed by 95/75 or 1.27 fold
• If 50Gy is given in 2Gy fractions, in reality a dose of 50 x 1.27
= 63.3Gy physical dose will be given in 2.53Gy fractions
• For a tissue with an  value = 3Gy, the biological dose
equivalent is 70Gy

i.e. small differences in physical

dose are amplified in late
responding tissues, which are
more subject to change with dose
per fraction than are acute effect
tissue

WMcB2008

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 Tissue Tolerance Doses
Tissue tolerance doses take account of many factors
• Intrinsic cellular radiosensitivity and ability to repair
• Regeneration
• Structural organization of tissues
• Wound healing ability
• Non-radiobiologically determined factors, for example
medicolegal, psychological, and socioeconomic
considerations

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 Gut Microcolony Assay
Fingerlike villi

Branching crypt
containing
stem cells and
proliferative
compartment at
positions 5-10

Control Control Day 2.5 after 13 Gy

There are about 106 crypts and 15 crypts/villus in a mouse intestine, each with about 250
cells, of which 150 cycle rapidly and 16 slowly (stem cells?). Tc = 16hrs (24hrs on man) WMcB2008
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 Murine Small Intestine
Normal 24hrs 10Gy

48hrs 10Gy 72hrs 10Gy

• Normal: All mitotic activity is in crypts (dark staining): villous cells are post-mitotic (pink)
• At 24hrs, proliferating cells (blue color) lost. About 5 of 130 cells/crypt survive
• At 48hrs, start of crypt regeneration, minimal change in villi
• At 72hrs, short villi. Repopulation of crypts well-established but no cell migration to villi. Cell cycle
time and clonogenic cell doubling time are both 8 hours, WMcB2008

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 4days 10Gy 5days 10Gy

13days - regeneration from one stem cell

• At 4dys, “Over-shoot” in crypt
repopulation and early
reconstruction of villi and good
reconstruction by day 5
• Abnormal structures can be
found as even one stem cell can
repopulate a large area

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 Murine Testis

5 weeks after 14 Gy: spermatogenesis has returned in one

Normal mouse testis with spermatogonia and a spectrum of
differentiating spermatogenic cells in the lumen of tubules, and
Sertoli cells in the walls.
tubule, the others being depopulated except for the non-
proliferative Sertoli cells. There is no regeneration. Surviving
spermatogonial stem cells continue their steady-state pattern. The
WMcB2008
sperm count reflects the proportion of stem cells that survived.

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 Dose-response for skin epithelium
Withers 1966: Skin remains intact if clonogen survival is higher than
about 5 per 10-6 per cm2. Higher doses will cause moist
desquamation.

Two clonally-derived islands of epithelium in a 1 cm diameter

radiation-induced ulcer of the skin on the back of a mouse.
Rapid regrowth on epithelial surfaces such as skin and
mucosa provide a reason for protracting radiation therapy
over several weeks.
20 days after 15Gy

Dose-survival curves for muse skin epithelial clonogenic

(stem) cells in conditions of hyperbaric oxygen, air breathing
or ischemic hypoxia induced by compression. hypoxia

air
oxygen
WMcB2008

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 The time to, and extent of regeneration can be
measured in fractionation experiments

The total dose necessary to

Regeneration reduce survival to 50 crypts per
colonic circumference from a
single dose as a function of
duration of a course of 2, 3, 5 or
10 dose fractions. The more
Repair repopulation the higher the dose
required for an isoeffect. For
example, excluding the overall
time in which 10 dose fractions
are delivered from 1 day to 9
days requires an average
increment of 20 Gy for the
isoeffect, that is, more than 2 Gy
per day. The curves also
illustrate that there is negligible
regenerative response until after
a lag period of 2 days

WMcB2008

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 Effect of Dose
Fractionation on
Clonogen Survival in
Jejunum
Regeneration is a
major factor
contributing to
increased tolerance of Redistribution
acute responding Repopulation
tissues during
fractionation
Repair

WMcB2008

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 STEADY STATE REGENERATION

differentiated

stem cells

cell loss factor f = 1 cell loss factor f = ?

In growing or regenerating normal tissues, and in cancer, the
cell loss factor (f) is < 1.0, i.e. It grows! WMcB2008

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Gut
• Latency = 14days - time taken for epithelial cells to move up the villus
and be shed into the lumen.
• Tolerance is about 50 Gy in 2 Gy fx for the small intestine and slightly
higher for the large intestine.
• Regeneration occurs with a lag time of <24hrs
• Cell loss factor f becomes 0, it regenerates rapidly

Testis
• Latency = 60 days - time for 1 spermatogenic stem cell to give 1000
sperm. This is why sperm counts remain normal for weeks after
irradiation and then fall precipitously.
• Tolerance is about 6 - 8 Gy in 2 Gy fractions can cause permanent
sterility. 0.1 - 0.15 Gy can cause temporary sterility.
• Regeneration: Unlike the gut, where recovery can be complete, sperm
counts may not recover for years - there is little regeneration!
• Cell loss factor f remains 1.0, it does not regenerate This is why sperm
counts remain low for years after radiation exposure.

In skin, f becomes 0.5, it regenerates slowly and often incompletely

WMcB2008

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 Clinical Relevance of Regeneration
• Mucositis appears 2 to 3 weeks after the start of a
standard RT course.

• Regeneration begins at about 10 to 12 days, before

evident mucositis. This can increase the tolerance of
the mucosa by about 1Gy/day, which is equivalent to
clonogenic cell number doubling every 2 days.

WMcB2008

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 Time to Regeneration Varies with Tissue

Kinetics of tissue regeneration. Withers and McBride

in Perez Principles and Practice of Radiation Oncology. WMcB2008

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 ACUTE LATE
EXTRA
DOSE
NEEDED
TO
COUNTERACT start of proliferation
PROLIFERATION

therapy time TIME

WMcB2008

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 Clinical Relevance
Because of regeneration/repopulation in acute, but not late,
normal tissue reactions during treatment:
– protracting overall treatment time beyond the
conventional 6 weeks may result in sparing (but tumors
may also be spared)
– decreasing overall treatment time to less than the
conventional 6 weeks may result in more acute normal
tissue reactions
– treatment time has relatively little effect on responses in
late effects tissues

Regeneration/repopulation in late, normal tissue

reactions after treatment, may allow recovery and make
retreatment possible
WMcB2008

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 Spinal Cord
Regeneration may be important in recovery of late
responding tissues and retreatment tolerance
initial treatment as % of tolerance
100 dose
Retreatment 50%
ED50 as a % 80
of initial
70%
ED50
60

40
95%
20

0
0 100 200

Time between treatments (days)

If the initial dose is close to the ED50,

Recovery also depends on time
the remembered dose is high but if it is van der Kogel and Fawcett
75% of the ED50, only 25% is
‘remembered’. Mason et al., Int J
Radiat Biol Phys 26:643, 1993
WMcB2008

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 Tissue Tolerance Doses
Tissue tolerance doses take account of many factors
• Intrinsic cellular radiosensitivity and repair
• Regeneration
• Structural organization of tissues
• Wound healing ability
• Non-radiobiologically determined factors, for example
medicolegal, psychological, and socioeconomic
considerations

WMcB2008

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 Functional Subunits

• The number of clonogens make up a

FSU and their organization in series or in
parallel in a tissue, can affect “tolerance”
• By definition, for an FSU to survive, at
least one clonogen must survive
• FSUs can be discrete structures, such as
a nephron in kidney or a liver lobule, or
diffuse with no clear demarcation, eg skin

WMcB2008

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168 clonogens in 12 FSUs 168 clonogens in 4 FSUs

Which is more radiation resistant and by how much?

WMcB2008

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Examples:
• Epilation occurs at a lower dose than
desquamation - because hair has fewer
clonogenic cells per FSU
• Hair depigmentation occurs at a lower dose than
skin depigmentation because follicles contain
fewer melanocytes.

WMcB2008

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 FSUs
• A tumor can be considered as being 1
FSU - all clonogenic cells have to be
killed for cure

A regenerating
clonogen 16dys
post-RTx, with
volume doubling
time of 4days
(from Hans
Kummermeir)
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 FSUs and Volume Effects
FSUs can be arranged in parallel eg. lung, liver, kidney
• In tissues that are intrinsically radiosensitive and rely on a large
functional reserve:
• A low dose to a large volume can be hazardous but
• A high dose to small volume can be innocuous
• This is because function is determined by the amount of
tissue that is not irradiated I.e. the “reserve function
determines the “volume” effect, which will be large.
FSUs can also be arranged in series eg. spinal cord, nerves
• In tissues that are intrinsically radioresistant, and where cell
migration may help tissue recovery:
• A low dose to a large volume may be innocuous but
• A high dose to a small volume may be hazardous
• i.e. a strong volume effect over a short distance
• This is a ‘true’ volume effect

WMcB2008

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 Rat Spinal Cord Volume Effect
100

ED50 2 mm 88 Gy
4 mm 54 Gy
8 mm 25 Gy
50
20 mm 20 Gy
Dose
(Gy)

white matter necrosis

20
vascular damage

10
0 1 2 3 4 5 6 7

Hopewell, van der Kogel CORD LENGTH (cm) WMcB2008

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 Dose Volume Histograms
• The dose of radiation delivered can be distributed in a 3-D
volume with smaller subunits each receiving different doses of
radiation.
• May be a useful guide in comparing treatment plans to predict
development of normal tissue complications, but there are
potential pitfalls

100
Lung (Duke)
80 V30 <18Gy - 6% pneumonitis
% Volume
60
V30 >18Gy - 24% pneumonitis

40 V30

20

10

0
Dose (Gy) WMcB2008

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 Problems with DVH

• 2-D representation of 3-D data

• May hide “hot spots” resulting from dose heterogeneity
• Ignores structural heterogeneity within tissues
• Varies with endpoint
• The “volume” may not be the most relevant e.g. bladder
surface may be more important than whole bladder
• The effects of changes in DVH will vary with the tissue,
depending on FSU structure (series/parallel), physiological
reserve, etc.

WMcB2008

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Hierarchical

Stem cells Progenitor cells Differentiated cells

Low proliferation Rapid proliferation No proliferation
Non-Functional Non-Functional Functional
Flexible

Stem cells Progenitor/functional cells

Low proliferation Slow proliferation but Functional
Non-Functional Proliferate on Demand

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 Hierarchical Tissues
• Rich in stem cells and highly proliferative progenitor cells that
differentiate into functional differentiated cells. They have a
high turnover rate and a high rate of cell loss. They respond
rapidly to irradiation and fail when the precursor pool fails to
generate enough differentiated cells.
• Examples are Gut, Skin, Bone Marrow, Mucosa

• Flexible tissues have a slow turnover rate and respond

slowly to irradiation. They fail when there is enough cell
loss to induce regeneration, which triggers an avalanche
of cell death, generally after a long lag period.
• Examples are Brain, Spinal Cord, Kidney, Lung, Bladder

WMcB2008

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Spinal cord 15 months after 22 Gy. Demyelination of long tracts is the outstanding lesion.
The unmyelinated grey matter and blood vessels are, at this stage, relatively normal
suggesting that functional changes reflect the loss of oligodendrocytes which are responsible
for myelination in the central nervous system and optic nerves.
WMcB2008

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 Late Effects

• Late effects can be considered as

dysregulated or failed healing. Molecular and
cellular responses that are involved in healing
the tissue occur during the latent period.

WMcB2008

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 Acute and Late Effects Occur in One Tissue
• For example - Skin fluoroscopic exposures
• Acute erythema - within 1 dy after 2 Gy
• Main erythema reaction - 1.5 wks after 6 Gy
• Temporary epilation - 3 wks after 3 Gy; permanent after 7 Gy
• Dry desquamation - 4 weeks after 14 Gy
• Moist desquamation - 4 weeks after 18 Gy
• Re-epithelialization - after 6-8 weeks
• Late effects
• > 8-12 weeks after >10 Gy erythema, atrophy;
• > 1 yr atrophy (2nd phase), fibrosis, necrosis, telangiectasia

Erythema Moist Desquamation Telangiectasia

WMcB2008

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 Late Effects

• Most late effects assays are mainly functional, rather

than clonogenic - e.g. paralysis, fibrosis
• An exception is the kidney - tubules can regenerate
from a single stem cell

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 Tubule Clones in Mouse Kidney
Normal mouse kidney showing a
glomerulus and adjacent proximal
convoluted tubules.
KA Mason and HR Withers
www.radbiol.ucla.edu
Regenerating tubule
Clones
Degenerating
tubule
15 months after 15 Gy showing glomerulus still intact but
extensive depopulation of tubule epithelium. The plane of
section transects 3 times the proximal tubule regenerated
from a surviving clonogenic cell. Although a single
clonogenic cell can regenerate the epithelium of the
proximal tubule of its own nephron, it is unable to migrate
and restore it in adjacent nephrons. Therefore, the
“tolerance dose” of the kidney is low. WMcB2008
 Late Effects are Complex

For example:
• Lung expresses damage in two major waves -
pneumonitis and fibrosis.
– In mice, these vary with the strain and are
genetically determined

• In brain, demyelination with white matter

necrosis, edema, hemorrhagic necrosis, and
atrophy are variably found.

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 Late Effects Involves Wound Healing

• Wound healing involves cytokines and growth factors

that mediate cellular responses including tissue
regeneration
• They may also contribute to the pathogenesis of
complications and may be responsible for some side
effects of irradiation, such as
• Fatigue
• Erythema
• Somnolence
• Nausea

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 Wound Healing Involves Cytokines
and Growth Factors

• Inflammatory Cytokines
– Tumor Necrosis Factor (TNF-), Interleukin-1 (IL-1)
• Angiogenesis
– Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast
Growth Factor (bFGF), TNF-
• Immune Cytokines
– IL-2 and IL-4
• Fibrotic Cytokines
– Transforming Growth Factor beta (TGF-), bFGF, IL-6
• Growth Factors
– Colony Stimulating Factors - G-CSF, GM-CSF, IL-3, EPO, SCF
– Epidermal Growth Factor (EGF), TGF-, bFGF

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 Cytokines

• Cytokines are soluble protein factors that drive regulatory crosstalk

between cells and tissues. They function as ligands within a
network to communicate and co-ordinate mesenchymal and
epithelial responses so as to effect healing of damaged tissues and
restore homeostasis

• Cytokines are expressed in tissues within hours of irradiation

• Over subsequent weeks and months there is a “perpetual (cyclical)

cascade” of cytokines released that is aimed at tissue regeneration.

• Complications arise when the regenerative process is unsuccessful.

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 Cytokine Gene Expression After Brain
Irradiation
3.0
SUB-
ACUTE LATE
2.5 TNF
Relative
Intensity 2.0

1.5
Age-Control
1.0 range

0.5

0.0
.1 1 10 100 1000
TIME (Log Days)

WMcB2008

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 Roles of TNF in the Brain

• Gliosis
– Stimulates proliferation in astrocytes
– Stimulates proliferation in microglia
– Induces reactive changes in microglia
(superoxide production)
• Demyelination
– Cytotoxic to oligodendrocytes
– Either neurotrophic or neurotoxic in culture
• Edema
– induces vascular changes/increase blood
brain barrier permeability

WMcB2008

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 Alterations in oligodendrocytes in
irradiated brain
SUB-ACUTE LATE
1.2

1.1
CNPase
Ratio of CONTROL
control1.0
20 GY
0.9

0.8 45 GY

0.7 30 GY

0.6
1 10 100 1000
Days (log)
WMcB2008

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 Radiation Fibrosis
• Fibrosis is a common complication of radiation
exposure that is a response of tissues to cell loss

• TGF-
• Is the pro-fibrotic cytokine par excellence.
• Causes fibroblast differentiation, senescence,
and collagen production.
• Needs to be activated by proteolytic cleavage.
• Is being targeted to reduce lung damage
following RT

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 Cytokines in Radiation-Induced
Fibrosis
Patients with persistent high serum levels of TGF-, before and during a
course of RT for lung cancer have a higher risk of developing pneumonitis.

This may be mediated not

only by locally produced
TGF- , but also circulating
TGF-  produced by tumor
cells that may be activated
at sites of RT.

Anscher et al Int J Radiat Oncol Biol Phys 30: 671, 1994

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 Fibrosis Involves Induced Fibroblast
Senescence
Progenitor Fibroblasts Irradiation drives
differentiation of
fibroblasts through
Mitotic fibroblast I a cytokine cascade
in which TGF-
figures prominently
Fibroblast
MFII TNF-
Proliferation
IL-1
Differentiation
PDGF
Matrix production
MFIII TGF-

Post-mitotic Fibrocytes

WMcB2008

Rodemann et al.
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 Cytokines and Radiation
• Cytokines delivered exogenously or produced endogenously can
protect or sensitize cells and tissues to the effects of radiation.
– Often, cytokines that activate cells to undergo cell cycle progression
and survival tend to radioprotect.
– Often, cytokines that inhibit cell cycle progression and apoptosis
tend to steer cells towards radiosensitization.
• Cytokines and growth factors produced endogenously are important in
tissue remodeling
• Radiation effects can be considered to result from disturbance of the
spatial and temporal organization and integrative tissue functions required
for wound healing

WMcB2008

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 Modification of Late Effects

• Late Effects were once considered:

– Progressive
– Irreversible
– Difficult to manage

• However, if the molecular , cellular and tissue based

responses of normal tissue to irradiation can be
identified, modifications of these pathways which
allow reductions in side effects and normal tissue
damage and/or increased therapeutic effect for
tumors should be possible.

WMcB2008

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 Possible Strategies for Modification of
Late Effects
• Angiotensin converting enzyme (ACE) inhibitors
• NSAIDs, Steroids, COX inhibitors
• Pentoxifylline family
• Anti-oxidants (MnSOD, Vit E)
• Manipulation of Cytokine/Growth Factors or Associated
Pathways
– PDGF-AA, aFGF, bFGF, EGF, IGF-1, CNTF
• Anti-apoptotic Pathways
– NF-kB, MAP kinase
• Stem/Progenitor Cell Transfer

WMcB2008

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 “Striking
Regression of Chronic Radiotherapy
Damage in a Clinical Trial of PTX and Tocopherol”
Delanian et al. J.Clin.Oncol. 17:3282, 1999

%
of
RIF

0-24% 25-49%
50-74%
75-100% Time
(months)

Response Rate - % of RIF Regression SOMA Scores with Time (Months)

WMcB2008

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 Genetics of Radiation
Response
Do genes other than repair genes influence
clinical response to RT?
– C57/C3H mice differ in acute and late responses
– Genes involved in inflammatory processes
– Genes involved in regenerative processes
– ATM and others
– Fibroblast SF2Gy correlates with late effects
– Single Nucleotide polymorphisms (SNP)

WMcB2008

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 Conclusions
• The time to a normal tissue complication depends on the tissue
turnover time. It is relatively independent of dose for hierarchical,
but not flexible, tissues
• The time to and extent of regeneration in normal tissues also
determines how much dose can be tolerated
• Tissue tolerance depends not only on intrinsic radiosensitivity of
clonogens, but also on organization into FSUs, and the number
of clonogens per FSU
• Volume effects are complex, but a major volume effect may be
due to differences in FSU organization
• Late effects are complex, but there is some reason to think they
may, to an extent, be reversible. The balance of cytokines and
growth factors determine both regeneration and normal tissue
complications

WMcB2008

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 Structural Organization of Tissues

• Tissues are sometimes considered as being

hierarchical or flexible
– This is a rather false distinction, but the
concept that different tissues have different
responses to damage is useful
– The distinction lies in their content of
pluripotent stem cells

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 Questions:
Clinically Relevant Normal Tissue Responses to Radiotherapy

WMcB2008

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66. Which of the following best reflects the
range of normal tissue tolerance for
fractionated doses at TD5%/5yr
– 2-60 Gy
– 20-60 Gy
– 40-60 Gy
– 20-100 Gy

#1 – tissue tolerance doses are highly variable and

obviously not solely determined by intrinsic radiation
responsiveness

WMcB2008

www.radbiol.ucla.edu
67. What is the dose range that would give a
5% incidence in myelopathy in 2Gy fractions
– 40-44 Gy
– 45-49 Gy
– 49-54 Gy
– 55-69 Gy
– 70-74Gy

#4 – not that one would work to a 5% incidence!

WMcB2008

www.radbiol.ucla.edu
67. Based on radiobiological theory, normal
tissue complications could increase per Gy
dose increase by what percent
– 2.5%
– 5%
– 7.5%
– 10%

#3 – this depends upon whether the FSUs are in series

or in parallel as well as many other factors, but the
NTCP curve has a steep slope reflecting the loss of the
last clonogen from individual FSUs
WMcB2008

www.radbiol.ucla.edu
68. The cell loss factor for steady state normal
tissues is
–0
–1
–2
–5
– Variable depending on the tissue

#2 – unless a tissue is growing, as in cancer or a fetus,

one cell must be lost for every cell division. If not, even
adults would double in size every few months.

WMcB2008

www.radbiol.ucla.edu
69. After RT the cell loss factor during active
regeneration in the testis is
–0
–1
–2
–5
– Variable depending on the tissue

#2 – the testis does not seem to change its kinetics of

cellular production following radiation exposure

WMcB2008

www.radbiol.ucla.edu
70. After RT the cell loss factor during active
regeneration in the small intestine is
–0
–1
–2
–5
– Variable depending on the tissue

#1 – unlike the testis, the precursor cells at the base of

the crypt replicate and increase in number before
repopulating the villus. This lag may result in clinical
symptoms.
WMcB2008

www.radbiol.ucla.edu
71. Mucosal regeneration during a standard
course of RT begins
– Immediately
– At 2-3 days
– At 10-12 days
– At 14-21 days

#3 – regeneration is initiated before there are clinical

signs of mucositis

WMcB2008

www.radbiol.ucla.edu
 72. Which of the following is correct for
functional subunits (FSUs)
– They are arranged in series in lung
– For an FSU to survive it must have one
surviving clonogen
– They must be discrete structures for the
concept to be useful
– Each tumor cell is an FSU

#3 – the dose needed to sterilize an FSU will depend

upon the number of clonogens it contains

WMcB2008

www.radbiol.ucla.edu
73. Which of the following is true for flexible
tissues
– They contain no stem cells
– Functional cells can be induced to
proliferate on demand
– Latency is dose-independent
– They are highly proliferative

#2 – when they divide they may express latent damage

and die, triggering another round of proliferation and an
‘avalanche’ of death

WMcB2008

www.radbiol.ucla.edu
74. The most classic pro-inflammatory cytokine
in the list below is
– VEGF
– TNF-alpha
– TGF-beta
– IL-2

#1 – tumor necrosis factor alpha is responsible for many

of the symptoms of inflammation – rubor, calor, dolor,
tumor

WMcB2008

www.radbiol.ucla.edu
75. The most classic pro-fibrotic cytokine in the
list below is
– VEGF
– TNF-alpha
– TGF-beta
– IL-2

#3 – transforming growth factor beta drives fibrosis and

collagen production

WMcB2008

www.radbiol.ucla.edu
76. The most classic pro-angiogenesis cytokine
in the list below is
– VEGF
– TNF-alpha
– TGF-beta
– IL-2

#1 – VEGF is induced by HIF-1 and targeted by Avastin

in cancer therapy

WMcB2008

www.radbiol.ucla.edu
77. The most classic immune cytokine in the list
below is
– VEGF
– TNF-alpha
– TGF-beta
– IL-2

#4 – interleukin 2 is a growth factor for T cells and, with

IL-4, regulates many T cell responses

WMcB2008

www.radbiol.ucla.edu