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Late
effects
of
total
body
irradiation
Total
body
irradiation
(TBI)
is
a
powerful
but
potentially
hazardous
tool
used
in
the
eradication
of
malignant
cells
and
the
suppression
of
the
immune
system
to
enable
bone
marrow
engraftment.
The
occasion
of
its
use
is
confined
to
bone
marrow
transplantation
(BMT)
in
malignant
dis-
orders
and
some
non-malignant
haematological
and
meta-
bolic
conditions
and
is
accompanied
by
high
dose
chemotherapy.
Since
infection
and
graft
versus
host
disease
(GVHD)
may
also
complicate
BMT
untangling
factors
leading
to
late
sequelae
may
be
a
difficult
task
and
frequently
there
is
more
than
one
cause
of
any
single
pathological
event.
The
radiation
dose
employed
in
TBI
is
as
high
above
the
median
lethal
dose
(LD50)
for
'marrow
death'
as
possible
before
encountering
significant
bowel
or
lung
toxicity.
Most
early
experience
was
gained
with
single
fraction
TBI
and
doses
of
up
to
a
10
Gy
proved
effective
and
safe;
if
fast
dose
rates
were
used
the
acute
toxicity
increased
unless
the
total
dose
was
lowered.
Latterly
and
as
in
virtually
all
other
clinical
radiotherapy
the
benefits
of
fractionation
have
been
realised.
By
dividing
the
TBI
dose
in
several
fractions
over
a
number
of
days
the
acute
toxicity
is
lowered,
the
total
TBI
dose
may
be
safely
raised
(for
example
12-15
Gy
in
six
fractions),
and
dose
rate
is
less
important.'
Of
great
significance
is
the
fact
that
the
higher
total
dose
achieved
by
fractionation
probably
allows
greater
leukaemic
cell
kill
and
the
lower
doses
per
fraction
reduce
the
late
normal
tissue
morbidity.
This
forms
the
basis
for
this
review
which
will
focus
on
late
sequelae
of
TBI
usually
presenting
a
year
or
more
from
exposure.
They
can
be
grouped
into
late
effects
pertaining
to
growth
and
the
endocrine
system,
specific
organs,
and
second
malignancy.
Growth
and
the
endocrine
dysfunction
Growth
failure
after
TBI
may
be
attributed
to
a
number
of
factors
and
varies
according
to
the
type
of
fractionation
schedule.
Endocrine
dysfunction2-4
and
epiphysial
growth
plate
damage
(skeletal
dysplasia)5
are
the
main
direct
effects
of
TBI.
There
is
a
significant
decrease
in
height
SD
scores
after
both
9-10
Gy
of
TBI
in
a
single
fraction
and
12-14
Gy
TBI
given
in
6-8
fractions.
Height
is
signifi-
cantly
more
impaired
three
years
after
TBI
in
the
single
fraction
group
(height
SD
score
-0-9
compared
with
-022
respectively)
despite
the
lower
total
dose
of
radia-
tion.6
There
is
evidence
of
segmental
disproportion
in
both
groups
with
diminished
sitting
height
compared
with
subischial
leg
length.
However,
this
may
be
accounted
for
by
chemotherapy
antedating
TBI
as
there
is
now
evidence
that
this
may
have
a
disproportionate
effect
on
spinal
growth
compared
with
other
epiphyses.7
Growth
hormone
deficiency
occurs
in
patients
receiving
TBI
even
without
previous
cranial
irradiation,
although
the
mean
peak
growth
hormone
concentrations
are
usually
lower
in
those
who
have
been
previously
irradiated
(in
acute
lymphoblastic
leukaemia).
Growth
hormone
treat-
ment
after
TBI
only
maintains
a
normal
growth
rate
and
does
not
give
rise
to
catch
up
growth
or
affect
the
dispro-
portionate
spinal
growth.8
Primary
thyroid
dysfunction
is
commonplace
after
TBI
but
fractionated
schedules
give
rise
to
a
much
lower
inci-
dence
of
both
overt
hypothyroidism
and
thyroid
stimulat-
ing
hormone
abnormalities
(59-73%
compared
with
16-25%9
10).
The
risk
of
hypothyroidism,
however,
con-
tinues
over
a
life
time
and
eventually
careful
follow
up
may
reveal
an
equally
high
incidence.
Occasionally
there
is
spontaneous
recovery.4
It
is
customary
to
treat
raised
concentrations
of
thyroid
stimulating
hormone
with
replacement
thyroxine
therapy
even
if
the
patient
is
euthy-
roid
but
there
is
no
evidence
that
high
thyroid
stimulating
hormone
stimulates
neoplastic
change
in
humans."
Growth
at
puberty
is
dependent
on
the
interaction
of
growth
hormone
with
sex
steroids
and
strict
attention
should
be
paid
both
to
growth
hormone
status
and
sexual
maturation
at
adolescence.
TBI
and
alkylating
agents
such
as
busulphan
and
cyclophosphamide
all
have
an
effect
on
the
gonad
and
in
the
transplant
situation
one
cannot
be
considered
with
the
other.
It
is
recognised
that
almost
all
girls
and
boys
transplanted
before
puberty
and
in
the
young
adult
period
will
recover
normal
sexual
function
after
cyclophosphamide
alone.12-14
After
TBI,
however,
the
situation
is
different.
In
one
large
series,
30
of
42
girls
and
51
of
65
boys
currently
greater
than
12
years
of
age
but
transplanted
in
the
prepubertal
period
had
delayed
sexual
development
accompanied
by
raised
gonadotrophins
and
subnormal
sex
steroid
concentrations
indicating
gonadal
failure.
The
14
boys
developing
secondary
sexual
charac-
teristics
at
the
appropriate
age
all
had
fractionated
TBI,
whereas
of
the
12
girls
with
age
appropriate
development
six
had
received
single
fraction
and
six
fractionated
TBI.14
It
is
recommended
that
children
with
delayed
pubertal
development
should
be
given
sex
steroid
supplementation
early
not
only
to
avoid
psychological
problems
but
also
to
ensure
an
adequate
growth
velocity
during
this
important
growing
period.
Return
of
ovarian function
and
fertility
(10
out
of
380)
has
been
reported
in
the
postmenarcheal
female
trans-
planted
at
less
than
26
years
of
age
particularly
after
frac-
tionated
TBI.
The
low
incidence
of
pregnancies
and
the
high
risk
nature
of
these
pregnancies,
however,
means
that
all
patients
should
be
warned
of
the
likelihood
of
infertility
al
E
Sanders,
data
presented
at
workshop
on
female
fertil-
ity
after
BMT,
Royal
Marsden
Hospital,
19931s
14).
The
potential
for
a
normal
pregnancy
is
further
compromised
by
reduced
uterine
blood
flow
and
failure
of
the
uterus
to
increase
in
size
at
puberty
despite
adequate
oestrogenisa-
tion.'5
Of
323
adult
males
only
five
demonstrated
return
of
spermatogenesis
after
TBI.13
14
Organ
specific
damage
With
increasing
survival
of
patients
treated
with
TBI/BMT
new
late
sequelae
are
constantly
being
observed.
After
growth
failure
and
endocrine
dysfunction
damage
to
the
lungs,
cardiovascular
system,
kidney,
eye,
and
brain
are
the
commonest
sequelae
found
but
the
use
of
anthracy-
clines,
aminoglycoside
antibiotics,
and
amphotericin
and
the
occurrence
of
GVHD
are
often
contributory.'5
CARDIOVASCULAR
SEQUELAE
Survivors
of
childhood
malignancy
represent
one
of
the
largest
risk
groups
for
premature
cardiovascular
disease.'6
Late
and
perhaps
progressive
cardiotoxicity
is
a
serious
side
effect
of
mediastinal
radiation.
Much
information
has
been
gained
from
studying
patients
treated
for
Hodgkin's
disease
in
childhood.'7
They
have
had
a
higher
dose
of
mediastinal
radiation
than
would
be
delivered
during
TBI
but
in
a
greater
number
of
fractions,
which
suggests
that
TBI
may
be
just
as
damaging.
382
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Late
effects
of
total
body
irradiation
The
cardiovascular
system
may
be
directly
or
indirectly
affected
by
radiation
treatment.
The
direct
affects
are
on
the
pericardium,
myocardium,
endocardium
valves,
con-
duction
system,
and
coronary
arteries
and
may
become
clinically
significant
over
time
presenting
as
cardiomyo-
pathy,
sudden
death,
or
arrhythmias.'6
Radiation
also
damages
endothelial
cells
resulting
in
a
loss
of
capillaries
and
ischaemia
at
the
microcirculatory
level
and
fibrosis
results.
This
tends
to
present
late
and
often
in
adulthood
as
progressive
pericardial
thickening,
cardiac
valve
thickening
and
deformity,
and
fibrotic
vascular
damage
all
of
which
tend
to
pursue
a
serious
course
with
poor
prognosis.16
Sinus
node
and
atrioventricular
conduction
block
and
arterial
occlusive
disease
and
strokes
are
also
recognised
complications
of
irradiation
treatment.
16
The
role
of
anthracyclines
in
the
pathogenesis
of
dose
related
cardiotoxicity
(particularly
cardiomyopathy)
and
the
synergistic
effect
between
mediastinal
irradiation
and
these
chemotherapeutic
agents
is
well
known.'8
19
In
addi-
tion
other
drugs,
for
example
cyclophosphamide,
used
in
conditioning
prior
to
TBI
may
also
add
to
the
cardiotoxic-
ity.
A
present
there
is
no
effective
preventative
treatment
for
the
development
of
radiation
related
cardiovascular
disease
and
accurate
monitoring
of
cardiac
structure,
func-
tion,
and
pericardial
disease
by
echocardiography
and
the
detection
of
coronary
artery
disease
and
conduction
defects
by
exercise
stress
testing
and
24
hour
electro-
cardiographic
recording
should
be
vigorously
pursued.
Although
few
of
our
TBI
patients
have
presented
with
symptomatic
cardiac
dysfunction
so
far
clinicians
should
have
a
low
threshold
for
suspicious
symptoms
even
in
the
face
of
extreme
youth
of
the
patient.
I
suspect
that
many
cardiovascular
complications
may
not
yet
have
presented
in
our
young
population
but
may
be
lying
in
store
until
mid
adult
life.
PULMONARY
SEQUELAE
Pulmonary
late
effects
appear
to
be
less
common
in
the
paediatric
population
than
in
adults.
TBI
is
only
one
of
many
contributory
factors
to
lung
disease
and
cannot
be
solely
implicated
in
any
situation.
Pulmonary
interstitial
tissue
is
particularly
sensitive
to
cytotoxic
agents
as
well
as
to
radiation,
and
the
lungs
and
airways
are
also
targets
for
microbial
and
fungal
infection
and
GVHD
causing
addi-
tional
severe
structural
and
functional
damage.
As
a
result
delayed
and
chronic
pulmonary
complications
may
occur.
Restrictive
defects
of
ventilatory
function
are
common
in
marrow
recipients,
even
those
who
are
healthy
long
term
survivors.
Springmeyer
et
al
found
that
20%
of
their
popu-
lation
showed
a
reduction
in
total
lung
capacity,
vital
capacity,
and
impairment
of
diffusing
capacity
one
year
after
BMT.20
Lung
function
tends
to
improve
over
the
subsequent
3-4
years
and
may
stabilise
or
completely
normalise.
This
is
confirmed
by
Tait
et
al
who
also
found
the
occurrence
of
permanent
subclinical
obstructive
defects
but
these
were
worse
and
continued
to
increase
beyond
two
years
in
patients
with
GVHD.2'
Severe
obstructive
airways
disease
is
uncommon
except
in
those
in
whom
GVHD
is
manifested
by
obliterative
bronchio-
litis.
Patients
who
experience
idiopathic
interstitial
pneu-
monitis
early
after
BMT
have
greater
defects.20
22
Idiopathic
interstitial
pneumonia
where
diffuse
pul-
monary
infiltrates
(alveolar
or
interstitial)
and
no
microbial
agents
are
detected
is
usually
an
early
event
after
BMT
within
100
days
but
uncommonly
presents
late.
It
may
be
insidious
presenting
with
changes
on
routine
chest
radio-
graphy
or
lung
function
tests
but
the
usual
clinical
picture
is
one
of
hypoxaemia,
tachypnoea,
non-productive
cough,
with
or
without
fever.
The
prognosis
is
poor
and
there
is
no
known
effective
treatment.
The
host
of
risk
factors
include
increased
dose
of
TBI
and
dose
delivery
rate
and
single
fractionation.23
RENAL
SEQUELAE
Although
early
renal
toxicity,
often
due
to
nephrotoxic
agents
and
related
to
the
transplant
period,
has
been
recog-
nised
for
some
long
time,
late
nephrotoxicity
is
a
relatively
newly
reported
phenomenon
in
children.
Radiation
nephropathy
occurring
at
higher
doses
than
those
given
in
TBI
is
well
documented.
Generally,
20
Gy
of
once
daily
fractionated
radiation
to
both
kidneys
has
been
considered
the
tolerance
level
before
the
onset
of
significant
radiation
injury.24-26
Lately
there
have
been
several
publications
indicating
a
syndrome
of
late
onset
renal
dysfunction
consistent
with
radiation
nephritis.27-29
It
tends
to
occur
within
one
year
of
BMT
in
children
conditioned with
intensive
multiagent
chemotherapy
and
TBI.
Presentation
is
often
as
the
haemolytic
uraemic
syndrome
or
as
progres-
sive
renal
failure.
Most
patients
show
anaemia,
increased
concentrations
of
creatinine
and
blood
urea
and
micro-
scopic
haematuria
with
evidence
of
microvascular
haemolysis.
Renal
biopsy
specimens
consistently
show
intraglomerular
mesangiolysis,
mesangioproliferation,
and
arteriolonecrosis.
Recovery
or
stabilisation
of
function
occur
in
some
while
in
others
there
is
progressive
renal
failure.27-29
In
our
practice,
late
renal
sequelae
are
unusual
and
it
is
generally
assumed
that
radiation
nephropathy
has
been
precipitated
by
unusually
intensive
conditioning
in
the
reported
patients,
lowering
the
threshold
of
the
kidney
to
radiation
injury.28
We
have
seen
late
onset
hypertension
requiring
thera-
peutic
intervention
in
adolescents
up
to
eight
years
after
BMT
but
with
otherwise
normal
renal
function.
NEUROPSYCHOLOGICAL
Marrow
transplantation
is
now
a
common
treatment
for
leukaemic
relapse
and
TBI
conditioning
may
lead
to
undesirable
neurological
sequelae.
Many
children
with
relapsed
acute
lymphoblastic
leukaemia
already
will
have
received
cranial
irradiation
with
regular
intrathecal
methotrexate
as
part
of
central
nervous
system
directed
therapy
for
their
initial
disease.
Such
a
combination
is
known
to
be
associated
with
a
spectrum
of
neurological
deficits
from
subtle
learning
difficulties,30
31
attentional
deficits,32
and
low
or
declining
IQ
scores
and
memory
impairment32-34
through
to
severe
necrotising
leuco-
encephalopathy
with
progressive
neurological
deteriora-
tion.35
Changes
on
computed
tomography
frequently
appear
as
attenuation
of
the
white
matter,
ventricular
dilatation,
and
intracerebral
calcifications,
which
are
thought
to
reflect
demyelination,
cerebral
atrophy,
and
mineralising
microangiopathy.36
Young
age
of
the
patient
is
shown
to
be
associated
with
poorer
educational
attain-
ment37
and
a
greater
incidence
of
changes
on
computed
tomography,
fits,
and
low
IQ
on
completion
of
treat-
ment.38
Female
sex
also
mitigates
against
good
educational
performance.39
Little
has
been
written
about
the
effects
of
TBI
on
neurological
function
but
a
recent
report
from
our
centre
indicated
that
of
14
patients
receiving
a
second
course
of
brain
irradiation
either
as
TBI
or
as
cranial
irra-
diation,
all
suffered
from
a
variety
of
neurological
deficits
presenting
with
at
least
one
soft
neurological
sign,
such
as
diminished
fine
motor
control
and
poor
coordination.40
The
vast
majority
of
patients
showed
selective
reduction
in
verbal
IQ
attention
and
concentration
and
girls
showed
383
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greater
impairment
than
boys.40
Although
no
difference
in
cognitive
outcome
has
been
found
between
doses
of
18
and
24
Gy
of
cranial
irradiation
a
shorter
interval
between
two
radiation
exposures
and
higher
cumulative
doses
of
radiotherapy
all
correlated
with
poorer
cognitive
function
in
our
recent
publication.40
In
addition
to
neurological
and
cognitive
deficits,
psy-
chological
distress
born
of
prolonged
hospitalisation,
intensive
treatment,
and
the
threat
of
disease
recurrence
should
be
addressed
with
equal
effort
and
sympathy
as
with
physical
sequelae.
OPHTHALMIC
COMPLICATIONS
Radiation
has
long
been
known
to
be
a
cause
of
cataracts
of
the
posterior
subcapsular
type
in
a
dose
related
fashion.4'
The
cataractogenic
nature
of
steroids
is
also
proved,4243
and
more
recently
it
has
been
suggested
that
antineoplastic
drugs
may
induce
cataracts.44
In
one
large
study
from
Seattle
a
comparison
was
made
in
the
incidence
of
cataracts
among
patients
conditioned
for
BMT
with
single
fraction
TBI,
and
fractionated
TBI.
The
risk
of
developing
cataracts
was
estimated
to
be
80%
for
single
fraction
and
18%
for
fractionated
TBI,
suggesting
a
significant
sparing
effect
of
fractionated
irradiation.45
A
more
recent
study
looking
at
development
of
cataracts
in
children
echoes
our
own
experience
showing
that
almost
all
(94%)
patients
with
leukaemia
receiving
single
fraction
TBI
develop
cataracts
by
three
years
from
exposure.
The
progression
of
the
cataract
was
most
pronounced
during
the
first
four
year
period
and
the
mean
time
to
onset
of
cataract
formation
was
2-2
years
(range
1-3
years).
No
relationship
was
found
between
age
and
onset
of
treatment,
sex
of
the
patient,
or
steroid
treatment
given
for
GVHD
unlike
in
the
Seattle
study.46
Surgery
is
well
tolerated
and
successful
but
seems
to
be
more
often
necessary
when
single
dose
TBI
is
given.45
Various
other
syndromes
after
BMT
have
been
described
such
as
keratoconjunctivitis
sicca
and
obstruction
of
the
nasolacrimal
duct
which
may
be
a
manifestation
of
GVHD
or
be
due
to
TBI.
TEETH
Radiation
to
the
head
and
neck
can
cause
impairment
of
growth
of
deciduous
or
permanent
teeth
and
diminished
secretion
of
saliva.47
It
may
also
impair
dentine
and
enamel
formation
and
lead
to
hypoplasia
of
the
mandible
and/or
maxilla.
In
addition,
it
may
give
rise
to
tooth
and
root
shortening
and,
in
some
cases,
complete
lack
of
tooth
development
depending
on
the
age
of
the
patient
at
the
time
of
irradiation.
Tooth
decay
is
common
and
often
presents
uniquely
on
surfaces
which
are
usually
immune
to
decay
as
well
as
at
characteristic
sites.47
Chemotherapy
administration
alone
can
produce
significant
alteration
in
dental
development
and
cause
decay
and
a
combination
of
both
treatment
modalities
may
severely
affect
dentition.47
Regular
dental
examination
and
attention
to
oral
hygiene
and
diet
is
mandatory.
BONE
Growth
impairment
by
radiation
has
already
been
mentioned
in
sections
relating
to
growth
and
the
endocrine
system
and
the
teeth.
The
appearance
of
benign
exostoses
are
alluded
to
in
the
section
on
second
neoplasms.
The
diagnosis
of
avascular
necrosis
of
bone
is
traditionally
linked
to
the
use
of
steroids,
but
it
is
a
relatively
common
condition
among
the
transplant
population
and
may
present
insidiously,
often
after
a
variable
degree
of
delay.
The
contribution
from
TBI
to
this
condition
is
unknown.
Second
malignancy
Individuals
with
a
history
of
childhood
cancer
have
been
estimated
to
have
10-20
times
the
life
time
risk
of
a
second
malignancy
compared
with
age
matched
controls.48
The
incidence
within
20
years
of
diagnosis
appears
to
vary
from
3-12%
reflecting
variability
in
intensity
and
the
type
of
regimen
of
chemoradiotherapy.49
50
The
aetiology
of
secondary
cancer
is
multifactorial
with
evidence
pointing
at
reduction
of
immune
surveillance
due
to
immuno-
suppression,
genetic
predisposition,
and
the
oncogenic
potential
of
chemotherapy,
particularly
alkylating
agents
and
epipodophyllotoxins.51-53
Radiotherapy
also
plays
a
large
part
and
second
tumours
that
may
occur
in
a
dose
related
fashion
are
often
found
within
the
radiation
field.52
Brain
tumours
have
been
reported
in
association
with
radiotherapy
in
childhood
acute
lymphoblastic
leukaemia
and
tineacapitis54
and
thyroid
neoplasms
after
radio-
therapy
for
Hodgkin's
disease.55
Dogs
given
dog
leucocyte
antigen
identical
marrow
after
TBI
have
an
incidence
of
second
tumours
five
times
higher
than
that
of
unirradiated
controls,56
and
it
is
reasonable
to
suppose
that
secondary
cancer
may
be
commoner
after
BMT
conditioned
with
TBI
than
with
chemotherapy
alone.
In
a
large
series
from
Seattle
of
2246
bone
marrow
recipients
with
leukaemia
and
aplastic
anaemia
Witherspoon
et
al
reported
an
incidence
of
secondary
malignancy
6-69
times
higher
than
primary
cancer
in
the
general
population.57
In
multivariate
analysis
TBI,
among
other
factors,
was
a
predictor
for
secondary
malignancy.
Those
patients
conditioned
with
TBI
had
a
relative
risk
of
3
9
compared
with
those
who
remained
unirradiated.
Recently,
a
French
study
found
a
cumulative
incidence
of
second
solid
tumours
at
eight
years
of
22%
in
patients
with
aplastic
and
Fanconi's
anaemia
conditioned
with
cyclophosphamide
and
thorocoabdominal
irradiation.58
This
contrasted
strongly
with
an
incidence
of
1-4%
at
10
years
in
the
Seattle
experience
using
cyclophosphamide
alone
before
marrow
transplantation
in
similar
patients.59
The
implication
that
radiation
has
played
a
part
in
the
development
of
these
tumours
is
strong
and
where
possible
TBI
should
be
excluded
from
conditioning
regimens
before
BMT
for
non-malignant
disorders.
The
type
of
second
malignancies
found
are
non-Hodgkin's
lymphomas
often
of
B
lymphocyte
origin,
known
to
be
Epstein-Barr
virus
and
immune
suppression
associated,
leukaemias,
gliomas,
melanoma,
squamous
cell
carcinomas,
bone
and
soft
tissue
sarcomas,
and
thyroid
neoplasms,2
57
all
of
which
can
be
associated
with
radiotherapy.
Multiple
benign
exostoses
and
widespread
pigmented
naevi
are
commonly
found
in
association
with
TBI
and
chemotherapy.60
The
tendency
of
these
towards
malig-
nancy
is
as
yet
unknown
but
the
risks
of
melanoma
are
higher
in
patients
with
multiple
naevi
and
great
care
should
be
taken
to
protect
the
skin
from
the
sun's
carcinogenic
potential.
Between
5
and
25%
of
multiple
exostoses
undergo
malignant
change
to
chondrosarcoma
and
more
rarely
to
osteosarcoma6l
but
so
far
these
have
not
been
reported
after
TBI.
Conclusion
Survival
after
BMT
for
malignant
disease
is
an
expanding
field
and
the
beneficial
effects
of
TBI
are
clear
for
all
to
see.
The
deleterious
effects,
however,
are
often
delayed
and
may
be
of
insidious
onset
and
there
is
no
room
for
com-
placency
when
monitoring
these
patients.
New
late
sequelae
are
constantly
attracting
the
limelight
when
trans-
plantation
has
been
carried
out
in
childhood
and
there
is
strong
suspicion
among
oncologists
that
we
have
not
yet
384
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Late
effects
of
total
body
irradiation
385
seen
the
last.
Vigilance
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attention
to
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is
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ALISON
D
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Department
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doi: 10.1136/adc.72.5.382
1995 72: 382-385Arch Dis Child
A D Leiper
Late effects of total body irradiation.
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