Increased Cancer Risk in Canine Radiation Chimeras - Blood Journal

Increased Cancer Risk in Canine Radiation Chimeras - Blood Journal

From www.bloodjournal.org by guest on December 30, 2017. For personal use only. Increased By H. Cancer Joachim Deeg, Rainer Risk Storb, Ross ...

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From www.bloodjournal.org by guest on December 30, 2017. For personal use only.

Increased By

H.

Cancer

Joachim

Deeg,

Rainer

Risk Storb,

Ross

Theodore One-hundred R/min

and

eight

delivered

dogs

from

of various

2 opposing

breeds

10 mg/kg

i.v..

in a single

dose.

Radiation

chimeras

were

observed

for

incidence

of malignant

61

Seven

).

carcinoma, control

tumors

malignancies

were (2),

dogs.

These

and

a number

risk

of developing

solid

gives

a significance

The

increased

risk

in the

M malignant poietic

conditioning

given

of p

0.001

<

among for

marrow

has with

hemopoietic

about graft

analyzes

the

(chimeras) study many

cancer

risk

tion that have cancer incidence I 5 chemotherapy

in are

are known for present study graft

recipients

been used transplanta-

to

AND

dogs

for

123

chimenas

Hutchinson

Wash.

They

and

51 control

Cancer

Research

consisted

of

New

Virginia, untreated Argonne, beagles beagles

York,

beagles

the

111,21 served and

27 were

and

I 8 were

and 62 female,

controls.

with

approximately 1 2 with

and

the

Sixty-one

to I 19 males were

In

followed

addition,

chimenas, dogs,

164

I 500 were

intervals

were

for at least

I 80 days

after

kennel

the

maintenance

Vol. 55,

were

feeding,

comparable

No. 2 (February),

vaccination

at the

1980

FHCRC

schedule, and

ANL.

and Dogs

dog at

be

sacrifice

pcntobanbital of

post-

died.221

littenmate

and by the 109-ENG-38

Submitted

(c) /980

10

Fred

autologous

I 500

R at 5 R/min

in 200-R

description

iv.

in

of the

prepared dose,

a

and School

Center,

18047.

by the National

13

dose.2’

69 were I

Seattle,

Medicine Argonne. CA

Cancer

the

(Division

of Medicine,

Laboratory, CA

single

dogs,

by

and

DLA-nonidentical,

Research

Washington National

of

Seattle, Ill.

15704.

CA

Institute.

18/05, DHEW;

of Energy under Contract W-31is afellow ofthe Leukemia Society of in part Cancer

Award

Al

by a Junior Faculty Clinical Society. ED. T. is a recipient

O242Sfrom

the National

Institute

Diseases. accepted

October

to H. Joachim

Hutchinson Wash.

2 were

in a single

10

(‘ancer

by Grants

requests

Seattle,

receiving

in TBI-treated

Pathology.

7. /979;

by Grune

and

mg/kg

DLA-identical,

Infectious July

at 9.3 R/min

dogs,

is supported the American

reprint

to

TBI

Dogs

iv.

transplants

of

Career

were

corresponding

(6 dogs),

100 mg/kg

U.S. Department (T.E.F). HiD.

and

beam.

in air,

rad) at 9.3 R/min

awarded

Research

ofAl/ergy

RPHM

central

A detailed

and the Argonne 18221

to the

3 hr (4 dogs).

Hutchinson

in part

or

2000

transplantation

dose)

at 5 R/min.

ofBiostatistics. University

opposing

marrow dose

108 was

in a polyurethane

two

tissue

for

Irradiation

previously.24

(58

the Fred

Oncology,

housed

perpendicular

(DMB),

grafts

dogs.

R (1500-2000

the 96 allogeneic

CA

dogs between

(midline

(CY), busulfan

ofTBl

consisted

5

I

I 5 chemotherapy-conditioned

dimethyl

Among

bia Street, conditions,

of

cyclophosphamide

Address

among

or until

examinations

that

for

R at 9.3 R/min

has been given

ofa

96 females

histologic

axis

R

I 200

at

96

of the chimenas and

a

chimeras.

deaths

on all dogs

allogeneic

R ( I I 50 rad)

America. G.E.S. Fellowshipfrom

were

and

nad midline

on 2000-2800

Wash.,

long

1200

given

(ANL), I 97 were

have incidence should

intravenous

transplantation

with

fractions

and

by

midway

the

900

Supported

retrievers,

Laboratory

of the control

breeds.

dogs

Alberta.

Among

breeds;

compared

Transplanted

Labrador

National

as controls.

of other

at the

natural

unanesthetized

(2 dogs)

Seattle,

German shonthains, Irish setters, and from kennels in Washington, Oregon,

Argonne

of other

maintained (FHCRC),

transplantation.

Blood.

conditioned

From

were

Center basenjis,

Oklahoma,

at

dogs

beagles.

Dalmatians, ned bone hounds, various crossbneeds, obtained

The

dogs

Oncology).

All

male

with

Eighty-four

Departments

Fred

chimeras of these

irradiation

their

regimen

placed

#{176}Co sources

METHODS

Dogs

marrow

to the cage

dosimetry

observed

in 25

carcinomas,

chemotherapy

space)

performed

for

aluminum

by

until

a chemotherapy

administered

Of

gland

seen

diseases.

autopsies

were

The

(median

Transplantation

and

grafts

been applied to man. Specifically, the among 108 radiation chimeras and chimeras observed from 6- 1 2 I mo is

MATERIALS

tissues

radiation

total-body

kennel

of

Complete

mortem

dogs

that has of marrow

observed lack

Conditioning

by high doses drugs and/or

2 I 5 normal

of

mo

were

of equality

1 5 canine

nonmalignant

been

malignancies patients

in the

with

there

has

analysis.

grafts. 28).

perianal

4 intestinal

patients

were

87

carcinomas.

high-dose

FHCRC

2-1

tumors

A test

dimethyl

(median

hypernephroma.

that

(because

for

or

marrow

mo

Twenty-five

dogs.

at 5-9.3

i.v..

dogs)

6-97

observed

suggests

Marrow

in marrow

compared to that among similar periods of time.

observed

mg/kg (12

for

included

regression

been

irradiation

100

dogs

tumor.

of control

injection.

E. Sale,

total-body

or autologous

tumors

that

mcimice

(TBI), which potential.”2#{176} The

in a canine model of the principles

hemoby

in air)

2 mammary

a high F1 hybrid

for marrow transplantation and immunosuppressive

total-body irradiation their carcinogenic

as yet

George

chimeras

Brenner hazards

of human

#{176} of

the development of recipients. Furthermore,

The and

chimeras

been used inotherwise fatal

grafts,

(1 1 1 dogs)

in 21 5 untreated

times

has

nonmalignant disorders of the ‘ Ever since the observations

parental

conditioned of cytotoxic

tumor

radiation

dose

to that

of a proportional

transplantation

and Beldotti7 and otherst malignant lymphomas in

concern marrow

No

.

canine

L. Weiden,

cyclophosphamide.

chemotherapy

chimeras.

to be 6.90

Paul

R (midline given

3 lymphosarcomas,

basis

Chimeras

Thomas

1 5) and

carcinoma,

is estimated

transplantation to treat patients

and system.’

Schwartz dence of

level

5 radiation

On the

that

compared

carcinomas,

tumors.

of cancer

ARROW creasingly

in

500

were allogeneic

(median

mammary

8 thyroid

a malignancy

rates avoided

observed seminoma,

included

of other

was

received

E. Fritz,

E. Donnall

1200-1

1 5 dogs

then mo

Radiation

Thomas and

given

and

21

in chimeras

mastocytoma

were

They 6-1

Prentice,

C. Graham,

#{176}Co sources,

busulfan.

in Canine

Cancer

Research

4, 1979. Deeg.

M.D.,

Center.

Division

of

1 1 24 (‘olum-

98/04.

& Stratton.

Inc.

0006-497//80/5502--0013$0/.00/0

233

From www.bloodjournal.org by guest on December 30, 2017. For personal use only.

DEEG

234

unknown),

and

matched, conditioned

mates.

dogs

The

were

were

day

Sixty-six the

27

grafts

given

and

an

(GVHD).27 the cell

and

assessment

clinical

fluid,

and

histologic

were for

treated

102

with

days

and

for

after

genetic

markers,

GVHD

have

been

described.2223’26

Statistical

and

control

malignant

log-rank

Dogs

“malignant

methods should

bone

log-rank to

test

chimera

at

proportional

dependent

covariates,

associated

with

risk

on age

techniques

have

transplant statistical competing

risks

This

the

to

used at

transplantation. example,

the (deaths

A

the observation transplantation,

Controls

period of

5

7 malignant complication,

surviving.

None

chimeras,

observed

of the

developed

a malignancy

risk

of

tumors (Table while one (A859)

the

I 5 chemotherapy-conditioned

for

6-97

mo

as yet.

to

(median 2). Figure

28),

has

2 1 5 control 6), 25 have 1 illustrates

curves.

timerisk of

because ments.

statistical

analysis

of

meaning

of has

of death

among

in Table and controls of lack Deaths

dogs

in the

3. A large at FHCRC

of kennel space from infectious

such of

insufficiency been seen

been

published.’ 1 . Malignancies

in Radiation

two

number were

colonies

are

of marrow killed either

or use in other complications

equally distributed between controls. Deaths from chronic insufficiency were restricted

heart

presence

of Death

summarized recipients

closely

dependence

Table

the

Kaplan-Meier

Causes

cancer

malignancy)

(median

Among

in cancer hazard between radiation control dogs, presented in the form of

Causes

of

from

with

in the

I). is

the difference chimeras and

a “time-

Similar

of

time

changed

the

estimates

unrelated

all Seattle

relative

of 6-1 2 1 mo (median the 108 radiation

More

The

in the

discussion

relative

use

to examine

for

data.35

the

the

used,

killed

the

method,3234

on age

been

until

transplantation.

to estimate and

that

dogs

membership

regression

transplantation

and

led

of

or were

at and

calculations.

the fact

group

time

to age plots28

cancer

in these

as control

in which

was

survival tests

without

to accommodate

hazards

and

in respect

Kaplan-Meier

times”

be regarded

associated

this

died

transplantation.

dependent” control

that

used

compared using

tumor

were

properly

marrow

were

diagnosis

statistics!ui

refined dogs

dogs

tumor

have censored

During after

and

dogs, followed for 2-1 87 mo developed malignancies (Table

Methods

Chimeras first

in Chimeras

chimeras developed Four died of this

antibiotic

by peripheral

blood

criteria

15)

disease

engraftment and

Malignancies

0.

electrolyte,

examinations,

RESULTS

litter-

day

graft-versus-host

of hemopoietic

marrow

DLA-

DLA-identical

(MTX)

prevent

(6

15 chemotherapy-

chimeras

of postgrafting

counts,

the

from

methotnexate to

dogs

All

was designated

I 3 chemotherapy

attempt

Details

therapy,

transplants

infusion

immunosuppressant in

unrelated

7 unknown).

of marrow

TBI

grafting

blood

from

14 DLA-mismatched,

ET AL.

experiwere

marrow recipients and GVHD and pancreatic to chimeras. Pancreatic

appears to be radiation-related; in dogs with autologous grafts

it has not in

but

Chimeras Interval

Date of

Do No.

Sex

Breed

755C

M

Beagle

Birth

3/6 1

Transplant

Radiation Dose

3/62

1 500

Marrow Donor (Sex)

R

Nonlittermate

(F)

MTX Post grafting

No

Tumor

Hypernephroma to lung,

977C

M

Beagle

2/6 1

2/64

1 500

R

Nonlittermate

(F)

No

metastatic

liver,

ileum,

paraaortic cord

spleen. Mongrel

8/68

2/69

1 500

R

Littermate

(F)

No

2,467

to liver, inguinal

paraaortic M

nodes,

gland carcinoma

metastatic

655

2,920

spleen,

spinal Perianal

From

Transplantation to Tumor Diagnosis in Days

and

nodes

1 . Mastocytoma

3,308

right

hind leg

2.

Seminoma,

metastatic

to lymph spleen, D7

F

Beagle

3/69

10/69

1200

R

Littermate

(M)

Yes

1.

nodes,

liver,

lungs 1,394

Mammary

gland

carcinoma

metastatic

to liver,

spleen.

bladder,

skin,

pericardium.

and

peritoneum 2. A859

M

Beagle

4/72

6/73

1200

R

Littermate

(M)

Yes

Brennan

Recurrent right

The marrow

donors

for dogs 6 55, D7. and A 859

were

DLA-identical

done.

tNo

immunosuppressive

drugs

other

than

Methotrexate

were

given.

with

the recipients.

In dogs

755C

tumor

of ovary

mastocytoma

of

2,708

hind leg

and 977C.

no histocomp

atibility

typing

was

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CANCER

RISK

IN RADIATION

Table Dogs:

2.

CHIMERAS

Malignancies

235

in Contro

I Dogs

3.

Causes

o f Death

Age of Dogs

#{149}

Group

at Diagnosis

Number

With

Table

Tumor

Tumor

Sex

5

M

3

F

Thyroid

Controls

in Days

carcinoma

Cause

3, 168, 3,454, 3,675.

3,961,

Malignancy

4.171,

4,321,

Killedt

4,568.

4,674

of Death

ANL

FHCRC

22 1

Infections

Chimeras

3

4

20

40 18

26

-

-

-

7

-

-

5

3

F

Lymphosarcoma

246,

1

M

Reticulum

cell sarcoma

4.7 1 1

2

F

Mammary

carcinoma

3,738.

5,603

inanition Pancreatic

2

F

Intestinal

2,844,

2,858,

CNSdisorders*

12

-

1

M

MiscelIaneous

12

-

7

1

M

Unknown

-

-

8

1

M

carcinomat

357,

3.568,

Salivary

gland

5,01

1

5,006

2,995

Chronic

GVHD

lncludes

+

insufficiency

both

radiation

dogs

entered

and chemotherapy

-

chimeras.

carcinoma 1

F

Pituitary

carcinoma

1

M

Melanoma

3,870

1

M

Bronchoalveolar

5,023

tlncludes

4.680

Hydrocephalus, §lncludes

Angiosarcoma

F

Carotid

1

F

Chondrosarcoma

All but one dog (hound) tlncludes

intestine,

liver,

body

were

tumor

chimeras.

central

nervous

390

biliary

among autopsy

controls studies,

Deaths

system

from were

disorders observed

of the only

In 8 chimeras, detailed bacteriologic examinations,

failed to provide information of death. However, examinations done on all FHCRC dogs.

and acute heat

nicketts,

causes.

Increased

Cancer

Risk

seizure

prostration,

gastric

and other

Table

tree.

(CNS)

at ANL. including

renal

fights,

ossification,

control number chemotherapy

than

other

marrow

trans-

foreign

disorders. circulatory

body,

failure.

peptic

ulcer.

Cushing pulmonary

3.267

beagles.

pancreas,

epilepsy,

dog

syndrome.

3,364

M

1

experiments

plantation.

carcinoma 1

into

about

the possible cause of the CNS were not

4

gives

Among

the

Radiation

number

of

dogs with cancer along under the hypothesis

between between gives a

cancer

incidence

observed (log-rank)

and

and expected significance

based on all dogs, or p For the reason given comparison is somewhat

=

Chimeras

TBI-treated

with of

the no

TBI.

The

cases level

and

“expected” association difference

of malignancies of p 0.008, =

0.01 2, based on beagles only. in the methods section, this biased toward underestimat-

ing the significance of the increased risk. More specifically, marrow transplantation took place when dogs were anywhere from 3 mo to several years of age (median Table

9.4 4.

mo). Cancer

Very Incidence

Conditioned Group

early

cancers

in Marrow

Graft

by TBI and in Control Dogs

then, Recipients Dogs

W ith Cancer

INumber

of Dogs) All Dogs

Observed

almost

Expected

Log-Rank Significance Level

TBI-treated (108)

5

2.07

0.008

Controls (215)

Beagles

I::

(83)

,‘

-

-..

Controls (198)

Chirneras Confrols

All 3-yr survivors

25

28.93

TBI-treated 4 25

1.53

0.0122

28.47

TBI-treated (50)

5

1.05

0.001

Controls (156) Beagles

AGE

IN DAYS

3-yr

TBI-treated

22

26.95

4

0.64

22

26.36

(37)

survivors Fig. 1 . Cumulative cancer hazard in radiation chimeras (solid line) and normal control dogs (dotted line) shown in form of Kaplan-Meier curves.

Controls (151)

0.001

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236

DEEG

necessarily,

occurred

in control

dogs.

A simple

proce-

exponentially

dure to avoid this problem is to restrict attention to long-term survivors. For example, by 3 yr of age, all but two TBI-treated beagles had received their marrow grafts. Table 4 gives the observed and expected numbers significance levels dence rates among levels

are

less

than

beagles alone. A more refined

0.001

for

all

dogs

and

of taking

identical

account

would permit from control marrow grafting.

significance

levels

The

log-rank idea

time

of

significance

level

of group

membership

transplantation

can

proportional the magnitude radiation

hazards regression of the increased chimeras.

(instantaneous) dogs. Suppose

r(t)

of cancer following

risk the

parameter, function

on

have

a cancer

incidence

represents

on Cancer

In spite of the radiation chimeras dependence

The of

assumption to data

6.90

times

of the

relative

of cancers was made

risk

that

on both

among to study

age

and

indication that the and transplantation

increasing as the dogs transplanted

ages though

these

sample

the relative risk following relative

animal late,

on

of

sizes.

Age(yr): Relative

risk:

age

the the at

risk assomay be

and may be higher in neither trend is clear

More

explicitly,

to vary as a power risk estimates: 4

5

3.55

5.59

permitting

of age

6

6.28

7.61

of a test

11.17

for no association

Dose,

is p

=

Degree

or G VHD

in Table

1, two

given was

between (p

chimeras

with

malignan-

I 200 R, and three had received no significant difference in cancer dogs 0.82).

=

given Also,

I 200 and in allogeneic

plants, dence

there was no correlation between and the degree of donor-recipient

bility

or presence/absence

This

I 500 R, trans-

tumor mcihistocompati-

of G V H D.

gave

7

=

shows

that

long-term

0.16. to vary

canine

radiation

risk of developing to nonirradiated

maligdogs. No

observed in a smaller number of chimeras followed for simi-

lar periods of time. The tumors chimeras fail to show a predilection

observed in TBI for the hemo-

poietic or lymphoreticular systems. Rather, they fall within the spectrum of malignancies seen in control dogs. There may be an increase in cancer risk with age at transplantation tion. Because of

the

and

number

the

group ment,

and

large

that were a statistical account

with

greatly

varying

of animals

killed upon approach

these

time

after

transplanta-

observation in the

times

experimental

termination of an experihad to be chosen that took

differences

as well

as the

waiting

time of experimental animals plantation. This was important nonirradiated dogs occurred

from

tumor in an irradiated at which many dogs

diagnosed, and at ages waiting for irradiation

dog was were still

birth until transas three tumors in long before the first

and transplantation, and thus, were not yet at risk for posti rradiation complications. Ti me-dependent versions of the log-rank test and the proportional hazards regression

the

8.1 1 11.10

significance level of a test for trend is p Similarly, if the relative risk is permitted

study

tumor has as yet been chemotherapy-conditioned

into

transplant. There is an ciated with irradiation

The

the

Risk

small number an attempt

5.19

chimeras have an increased nant tumors when compared

and 198 control beagles of 6.90, with an associated interval of 1.97-24.13. dogs are estimated to of

4.28

3

DISCUSSION

control the

age t becomes kr(t). permits the estimation

rate

2

Incidence

incidence respectively

a

dogs.

Effect ofAge

with

in

to estimate risk among

k, without any r(l). Application

the 83 TBI-treated beagles gave a relative risk estimate approximate 95(; confidence This means that TBI-treated control

of Radiation

at the

at age t among transplantation,

cancer incidence rate at any proportional hazards method the relative concerning

changes

incorporated analysis cancer

Suppose

rate that

1.5

of <0.001.

that be

1

of Histocompatibility,

cies had been I 500 R. There

3-yr survivors. For example, the observed and “expected” number ofcancers for all TBI-treated beagles was 4 and 0.9 1 , respectively, with an associated (timedependent)

one obtains:

0.5

level

As shown

the group to radiation This gave based

risk:

significance

Effect

for

of waiting

to those

age at transplant,

0.09.

on Tumor method

time to transplantation membership to change chimera at the time of almost

both

Relative The

of dogs with cancer and log-rank for test of equality of cancer mci3-yr survivors. The significance

with

Age (in yr at transplant):

ET AL.

features

methods

accommodated

these

special

of the data.

A high incidence of lymphoreticular tumors of both host and donor type has been described in irradiated and nonirradiated F1 mice of various strains given grafts of parental spleen cells.8 0,37 It has been postulated that the donor cells were chronically stimulated by the histocompatibility antigens of the host and that

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CANCER

RISK

IN RADIATION

CHIMERAS

this chronic stimulation leukemia virus which,

237

led to activation of murine in turn, would infect host or

donor cells, whichever would be susceptible to the virus.9’38 The development of malignant lymphomas following allogeneic or xenogeneic transplants has been described in other incidence of malignant graft recipients might genie

stimulation

antigens in the immu nosuppression Finally, patient

with

host

graft

in

has

acute

by

the

of

sarcoma course

been

one

TBI

who

incomplete

on

a for

developed

shortly after was complicated

doses

report

conditioned

an

of corticosteroids

and

immunosuppressed patients lymphocyte transformation Also, several patients have single

and

times marrow various ered

multiple

may lead resembling been observed

extramedullary

human

immunoThis treated

to reactive lymphoma to develop

before

the

diagnosis of

of a second

tumors

in

the

.

malignancy

contrast

to

humans

with

rodents organ

chimeras

have

not

although

lymphoma

in dogs.46 An increased

with shown

is a common risk

spontaneous

system,

has

also

been

of the

reported

in

human patients with various congenital immunodeficiencies.47 Canine chimeras experience a severe combined immunodeficiency during the first 200-300 days after transplantation,48 a period during which no malignancy has as yet been observed. Thereafter, they regain normal immunologic reactivity, which makes it unlikely that the development of tumors diagnosed 1394-3308 days (46-1 10 mo) after transplantation is related to immunologic It appears that TBI increased

cancer

nogenicity have been man.’6’9

risk

dysfunction. is the most in radiation

and leukemogenicity shown beyond

Dose

rate

and

total

Thus,

cause

chimeras.

The

of exposure

own

exposure in

to

different of myelo-

in beagle Whatever

dogs the

may be, hemopoietic likely in our radiation

hemopoietic

system

has

been

of radiation, destroying inducing damage that of abnormal clones.50

that gave rise to however, has never the development

of chemotherapy periods of time. in the present study part

of

their

times

ty-four

human

their been

current exposed

of nonhemopoietic

chimeras have

natural are

CY

been observed malignancy3

followed

been

lives.

for

observed

for a

Comparably

not available

long

for human

marrow

chimeras

human

for the

transplanted

between and an

4 and additional

in Seattle 8 yr 52

after have

from I to 4 yr without development of a (and unpublished observation). Twenty

radiation

chimeras

twin

(including

grafts)

transplantation, 16 syngeneic

are

living

six patients between

and an additional radiation chimeras

with

4 and

9 yr

59 allogeneic have been

observed from I to 4 yr.l Two of the human radiation ch i meras developed non hematologic malignancies approximately I yr after grafting (unpublished observations). generally tumor whether

Whether increased

these risk

in patients they are

present. cancer suggests avoided,

with related

malignancies of developing

are due to a secondary

hematologic to irradiation

malignancies is unknown

a or at

Despite this uncertainty, the increased risk of in canine radiation chimeras reported here that TBI, at least at high doses, should be if possible, in the conditioning for marrow

transplantation likely

of human

patients

with

nonmalignant

diseases.

carci-

of ionizing radiation doubt in animals and dose

to radiation.

after and

tumor

primarily

marrow system,

monozygous

neoplasms,

for malignancies,

lympho-hemopoietic

and

radiation

lymphoreticular

their

are long-term survivors marrow transplantation

from In

grafts canine

induction not be

carcino-

transplant recipients, and it is not clear whether the finding of an increased cancer incidence among canine radiation chimeras can be extrapolated to man. Twen-

radiation

hemopoietic

transplants,

since

after

irradiation the development

has been shown low dose rates.49

of tumor should

observation

is

chimeras presented here is likely to be different virus activation or chronic antigenic stimulation.

syndromes at very

The donor hemopoietic

great

at variable

canine

TBI

not be estabbreast

to be increased

dose range of 8 More recently,

number prolonged Dogs

after marrow transplantation and before relapse.”44’45 These chloromas may suggest differential diagnoses and should be consid-

established. The etiology

found

could and

tumors was more likely and, in fact, could be confirmed by our findings. It is of interest that no tumor has as yet been observed among the smaller

No other has been in severely

tumors

been

a threshold

bronchogenic,

exposed to very high doses precursor cells rather than might lead to the development

antithymocyte

globulin. He died 84 days after grafting. similar case had been reported. Evidence presented, however, that viral infections

have

a broad settings.’6

chimeras

marrow

transplantation.42 by GVHD

mas

although

Thyroid,

mechanism malignancies

histocompatibility

presence

leukemia

by

high

cells

lished.’5

proliferative following

I

transplantation blastic patient’s

of

there with

species as well.39 Also, the high lymphomas in human organ be the result of chronic anti-

be important,

seem

to

ACKNOWLEDGMENT We wish Raff,

Lisa

to thank

Ray

Gerhard-Millen,

Colby, Joni

Pat Manek,

Susan

Whitefleld,

Janis

DeRose, Korbol,

Robert and

the

From www.bloodjournal.org by guest on December 30, 2017. For personal use only.

DEEG

238

technicians

of the

tories

at the

thank

at ANL

of canine

pathology,

FHCRC

for

Dr.

Louise

tumors,

in compiling

hematology, their

and

for

Bell

data.

We

bacteriology

technical

Lombard

Laverne

survival

and

expert

diagnosis

and

are

and

Donald

for their

to Lederle

Pearl

also

gle

help

ratonies,

We

Park,

Pfizer

classification

Doyle

indebted

nies,

labora-

assistance.

River,

N.Y.,

NC.,

Schening New

Evansville,

Wellcome

Corporation,

Pharmaceuticals,

Puninethol,

Laborato-

Burroughs

Ind.

Garamycin,

N.Y.,

and

generous

Geopen,

Research

Bboomfield,

York,

for their

Co.,

ET AL.

Tnian-

N.J.,

Mead

supply

Roenig-

Johnson

Labo-

of Methotrexate,

and Cytoxan.

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1980 55: 233-239

Increased cancer risk in canine radiation chimeras HJ Deeg, R Storb, R Prentice, TE Fritz, PL Weiden, GE Sale, TC Graham and ED Thomas

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