Control and Prevention
of Hemorrhage:
ISAAC
Children's
Cancer
Research
Foundation
DJERASSI2
AND SIDNEY
Platelet Transfusion'
FARBER
and the Department
of Pathology,
Harvard
Boston, Massachusetts
Medical
School
at The Children's
Hospital,
SUMMARY
Platelet transfusions are effective in the control of hemorrhages in thnombocyto
penic patients with acute leukemia.
They are especially valuable as a supportive
measure during intensive chemotherapy.
Availability of large amounts of platelets
permits the administration
of chemotherapeutic
agents in amounts many times greater
than the conventional doses.
Platelets
concentrated
from freshly
collected
acid-citrate-dextrose
in thnombocytopenic
recipients.
(ACD)
Their
blood
are
capable
of circulation
in vivo survival
critically
effective.
ill patients is relatively short.
Repeated
infusions, however, are consistently
A dose of 8 platelet concentrates
per 100 lb of body weight is recommended.
in
Repeated infusions should be given if optimal results are not obtained.
Immune reactions and resistance to transfused platelets appear to be of little practi
cal significance.
Preservation of platelets in the frozen state without loss of viability
has been demonstrated.
A practical
method for storage
tribute greatly to the routine use of platelet transfusions.
The chemotherapy of Patients with acute leukemia may
be complicated by preexisting or induced thrombocyto
penia.
With this in view, a study of the nature and con
trol of bleeding iii thrombocytopenia
was initiated in 1948.
In the early stages of this investigation Freeman empha
sized the role of platelets
in the pathogenesis
of bleeding in
acute
leukemia
(ii).
Subsequently
he
method for the separation
arid concentration
developed
a
of platelets
from whole blood utilizing ion-exchange
indicated
that. the large-scale
resins (12), which
preparation
of human
plate
lets for clinical use was possible.
A practical technique
for platelet separation by differential centrifugation
(19)
was later developed
by Klein et al. (17, 18) to obtain sepa
rated platelets as a by-product
of ordinary
blood banking.
Transfusion of platelets in whole blood to thrombocyto
penic patients was reported by Duke in 1910 (9). Early
reports on transfusions
of concentrated
platelets failed
(16, 19), however, to encourage the use of this procedure in
routine blood banking.
The need for exceedingly large
amounts of blood and the possibility of immune reactions
suggested
of viable
that
maintenance
separable
intact
platelets
the function
of vascular
components
platelets
(18).
will con
of platelets
integrity
related
to the
may be associated
rather
than
In the
course
with
with the activity
of these
of
studies,
it
became apparent that transfusions of fresh platelets may
be valuable for supportive management
of children with
acute leukemia (5, 6, 10). The National Cancer Institute
has reported similar experience with platelet-rich plasma
(13).
A number
platelet
years
of questions
transfusions
at
The
pertaining
to the optimal
were investigated
Children's
Cancer
use of
during the last 10
Research
Foundation.
These studies may be summarized as follows:
Hemostatic effects of platelet transfusions in patients with
acute leuk@mia.—The association of platelet deficiency with
a tendency to bleed has been known for many years.
The
major role of thrombocytopenia
in bleeding in l)atients
with acute leukemia was demonstrated more recently (11).
The experience with transfusion of platelets at The Chil
dren's
Cancer
Research
Foundation
(6, 10) was supported
to multiple platelet transfusions were some of the factors
by the study of Freireich et al. in 1959 (14) on the value of
responsible for this delay.
The closed system of plastic
bags designed by Klein et al. (17) for the procurement of
platelet preparations
as a by-product
of blood banking
transfusions
of fresh versus banked blood in the manage
ment of bleeding in patients with acute leukemia.
made available large amounts of platelet material for
penia is coml)licated by the inherent variability
of the
course of bleeding caused by lack of platelets.
Severe
hemorrhages may cease or reappear spontaneously,
with
out detectable
cause. Carefully controlled studies are
therefore required to evaluate the effects of any hemostatic
clinical investigation and use. Studies of the mechanism
of platelet action using frozen and lyophilized platelets
1 This
investigation
was
supported
in part
by
research
contract
AT(30-1) from the Atomic Energy Commission and a grant C-6516
from the National Cancer Institute, NIH, USPHS.
2 Present
address:
1740 Bainbridge
Street,
The
Children's
Philadelphia,
Hospital
of
Pennsylvania.
Philadelphia,
The evaluation of hemostatic agents in thrombocyto
agent,
including
fresh
platelets.
Such
evaluations
have
been made in several separate series of patients at The
Children's Cancer Research Foundation on numerous oc
1499
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1965 American Association for Cancer Research.
Cancer
1500
Vol.25,October1965
Research
casions since 1954. The hemostatic effects of the various
preparations were evaluated according to the following cri
tenia: Arrest of epistaxis was attributed to a hemostatic
agent if it occurred within 30 miii of its administration
and
lasted for at least 8 hr. When epistaxis was intermittent,
freedom of bleeding for 24 hr following administration was
considered
to
be
associated
with
induced
[email protected]@4A- $P*@flEN13
P@TTE@N
B-8
@TIENTS
hemostasis.
Similar rules were applied for the evaluation of bleeding
from gingival, oral, anal, on other visible sites. These
rules were also used in evaluating hematemesis.
Arrest of
hematunia was considered to be related to the administra
l00
tion of the agent if it occurred after no more than 2 con
secut.ive pa.ssings of urine.
Evaluation of hemostatic ef
fects on nielena was particularly
difficult.
Normal ap
pearance of stool within 48 hr was considered to be due to
the induction of hemostasis.
According to these criteria, the incidence of hemostasis
C)
F-
following administration of fresh platelets to leukemic pa
tients varied with the number of platelets or platelet con
centrates given and the increments in the number of cm
culating platelets.
Table 1 summarizes the hemostatic
effects observed in 2 separate groups of patients studied in
this
respect.
consistently
In both
in patients
studies
hemostasis
occurred
most
whose platelet count was increased
12
24
by 40,000 platelets/cu
mm or more.
However,
bleeding
was occasionally
arrested
in the absence of a significant
in the management
of patients with acute leukemia.—In the course of the stud
ies described in this report, it became apparent
that plate
let transfusions may indeed offer an excellent tool for sup
portive management
of patients receiving antitumor
chem
otherapy. The elimination of bleeding as a constant
threat to the patient permitted more adequate dosages
and schedules of administration of therapeutic agents.
More slowly actimig drugs could thus be employed, and
patients who responded slowly could be maintained on
treatment
until maximal chemotherapeutic
effects were
obtained.
As part of the “total care― program
for children
malignancy,
platelet
transfusions
could be credited
with
with
reducing the physical and psychologic problems
overt bleeding presents to both patient arid parents.
which
EFFECTS
OF
FRESH
PLATELET
INCREMENT
<20,000
PLATELET
TRANSFUSIONS
PLATELET
PLATELET
INCREMENT
21000—40,000
IN:@@T
Epistaxis
Hematuria
Oral mucosa
Rectal
Hematemesis
Bleeding
Occa-
Bleeding
Occa-
sions
arrested
sions
arrested
sions
1
3
6
1
7
3
3
1
2
3
1
5
0
3
1
2
1
5
8
18
12
16
1
2
24
33%
of elevation
of the platelet
count
of pa
The difficulty in making an objective evaluation of these
over-all and self-apparent
illustrated
effects of platelet transfusions
here by the lack of significant
statistical
is
infor
mation to substantiate thesestatements.
Hopefully, larger
collaborative studies currently in progress will provide the
needed
information.
Circulation of transfused plateleti separated and coneen
trated from ACD bloxl.—Early studies on transfusion of
concentrated platelets were done with materials separated
from blood with ethylenediaminetetraacetate
(EDTA) as
anticoagulant (16). It was reported that ACD caused
platelets
to clump irreversibly
rendering
chosen,
during sedimentation,
them inadequate
for transfusions
thus
when an
Bleeding
67%
a serious problem with respect to platelet trans
Should an anticoagulant
such as EDTA be
adequate
to
procurement
the
blood
of
bank.
The
platelets
blood
presents
major
components
(red
cells and,/or plasma) remaining after the removal of plate
lets from EDTA-treated
blood are unsatisfactory
for
______ routineuse. Onthe otherhand,ACD-treated
platelets
arrested
4
3
3
1
1
1
can be prepared
by the method described
by Klein et at.
(17, 18) at minimal cost as a by-product
of ordinary blood
banking.
Pheresis of platelet-rich
plasma (13) or platelet
pheresis3 programs can also be arranged for the procure
ment of platelets when ACD is used.
The ability of platelets concentrated
from ACD-treated
blood
to
circulate
in
patients
with
acute
leukemia
is
illus
13
3 1)jerassi,
Hemostasis
96
platelets.
difficulties
—
Total episodes
84
The choice of anticoagulants for the collection of blood
Occa
5
5
6
72
tients with acute leukemia after transfusions of concentrated
presents
fusions.
CoxriiTmoN
Melena
60
elevation of the l)latelet count was desired.
TABLE 1
HEMOSTATIC
48
.np@AFTER
INF1EION
(HOUF@)
CHART 1.—Duration
increase in the platelet count.
Over-all value of platelet transfusions
36
81%
I.,
and
Alvarado
J.
Plateletpheresis
and
Plasma
pheresis in the Routine Operation of a Children's Hospital Blood
Bank. Clin. Pediat., 3: 466—71,
1965.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1965 American Association for Cancer Research.
DJERASSI
AND F,@u@BER—Control
and
Prevention
1501
of Hemorrhage
TABLE 4
trated
tiated
in Chart 1. This observation was well substan
in the course of the administration
of more than
15,000
platelet
concentrates
to a large number
of patients
with thrombocytopenia
of varied origins (3, 4, 6, 10).
The occasional failure to resuspend ACD platelet con
centrates
adequately
is usually
due to 1 of 2 factors
INCREASE OF PLATELET COUNTS OF PATIENTS WITH ACUTE
LEUKEMIA FOLLOWING INFUSION OF VARIOUS AMOUNTS
OF CONCENTRATED PLATELETS
of
increase of platelet
count (±e)No.
No.
of units5!lb of body weightAverage
patients0.022-0.05
: (a)
inadequate mechanical dispersion of the sedimented plate
lets into the supernatant
plasma, caused by excessive
concern for the “fragility―of platelets, or (b) excessive
cooling of the platelet concentrate (to 1°or 2°C).
In vivo recovery of transfused ACD platelets.—Cnitically
evaluated
data on platelet preparations
obtained from
ACD-tneated blood have been reported.
Levin and Fnei
reich (personal communication)
found recently that 30%
± 7,200
33,800± 3,700
37,800± 28,000
43,000± 19,000
(avO.036)
0.051-0.079
(av0.064)
0.080
(avO.080)
0.081-0.199
(avO.124)
0.200-0.300 (av0.224)14,250
a One unit
= platelets
from
67,645
15
13
11
11
± 29,00012
500 ml of whole
blood.
TABLE 5
PLATELET RECOVERY FOLLOWING ADMINISTRATION OF VARIOUS
AMOUNTS OF CONCENTRATED PLATELETS
TABLE 2
DISTRIBUTION OF % RECOVERY OF CONCENTRATED PLATELETS
FOLLOWING INFUSION ON 34 OccAsioNs
Group of
of
dose (unit/lb of
patientsPlatelet
(%)“A
body
transfusionsNo.
weight)No.
of ra
tients with
of
maximum
inf@tionRecovery
occasions100090-99080—89270—79060—69150—59140—49530—39420—29510—19100—96Total34Median
of
Recovery
(%)“No.
B
0.051-0.96
C
0.10-0.164
D0.025-0.0380.20—0.2415
a Statistical
significance
2
10
440.8
11
11
73
between
Groups
A and
39.9
19.1
13.4
D : P < 0.01.
of platelets originally present in the blood can be recovered
and counted in the circulation of a thrombocytopenic
pa
tient with acute leukemia following infusion of concentra
ted platelets.
A median of 23 % of the platelets present
in a concentrate appeared in the circulation of 34 patients
with acute leukemia in 1 of the studies carried out at this
institution
: 23
a Percent
of
infused
platelets
found
in
circulation
after
trans
fusion.
TABLE
(Table
2).
The observation of considerably higher (up to 60 %)
in vivo recovery of similarly prepared platelets in patients
with aplastic anemia or other forms of thrombocytopenia
(3) points to the presence of unfavorable
conditions
in
leukemia
recipients.
It was further
observed
that fever
3
and infection tend to decrease the in vivo recovery of trans
fused platelets (Table 3). It is quite possible, however,
that other factors may also be involved.
Platelet trans
INFECTIONPlatelets
WITHOUT
PATIENTSWITHINFECTIONPATIENTS
fusions are given as a rule to severely ill patients, fre
quently in advanced stages of their disease.
Rapid utili
of possible recovered!
nits/Ib
of [email protected]
(units/lb
recovered!
zation or increased destruction of transfused platelets also
maximum
maximum
body
cu mm(u
cu mm―Dose
weigl@)Recovery
wegiht)Recovery
(%)“Platelets
(%)5260.0253510120.025672040.129131500.038102100.135147120.057472370
may be responsible for their failure to remain in circulation
PLATELET RECOVERY IN PATIENTS WITH ACUTE LEUKEMIA WITH
AND WITHOUT INFECTION
Dosage of platelets for patients with acute leukemia.—In
two separate studies (4) it was found that children with
acute leukemia should be given concentrated
platelets in
doses
of
4.5
X
10°
p
latelets/lb
of
body
weight
to assure a
.051801030.21071380.07297140.028472530.054176780.028454350.06529940.129613380.06589620.12847530.071502140.20014
.2001612030
moderate to good elevation of the platelet count (Table 4).
This is approximately 0.08 unit4 of platelets/lb
of body
weight.
Higher elevations of the platelet count can be
observed when larger amounts of platelet material are
given. Analysis of more recent data, however, suggests a
diminishing return with the use of very large quantities
.200103580.133243500.20023Mean:3280.1192@@7b5930.07739•3b
.066361460
of platelets (Table 5). Thus, the desirability of more fre
quent transfusions of optimal doses of platelets may war
rant further study.
a Maximum
recoverable
S p
by
0.025
the
method
= 1500 platelets/cu
of
analysis
of
mm.
variance.
4 One
unit
is
defined
as
the
platelets
separated
from
500
whole blood.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1965 American Association for Cancer Research.
ml
of
1 502
Cancer
Vol.25,October1965
Research
of platelet concentrates
usually requires materials sepa
rated simultaneously
from multiple donors.
Should a
fraction of all platelets infused be incompatible, detection
of their decreased survival may be limited by the methodol
ogy used.
The
thrombocytopenic
survival
of concentrated
platelets
in
recipients
is only 3—5days when deter
mined by direct visual counting.
Radioactively
labeled
platelets,. on the other hand, survive up to 11 days in
normal recipients
(1). Should platelets interact with
specific
5
30
60
20
8
minutes
24
hours
TIME AFTERTRANSFtJSION
°NUM@R
OFPATIENTSSTUDIED
CHART
2.—In
vivo
survival
of
transfused
fresh
platelets
in
children with acute leukemia.
Sequestration
and survival
of transfused
platelets
in len
kemic patients.—The judicious use of platelet transfusions
in patients with leukemia requires knowledge of the rate of
their appearance in the circulation, as well as their removal
on utilization.
The temporary sequestration of transfused
platelets, suggested on the basis of studies in normal re
cipierits
of radioactively
labeled
platelets
(1), was not ob
served in thrombocytopenic
patients by visual counting of
circulating platelets.
Chart 2 illustrates the rate of ap
pearance
of platelets
in the circulation
after infusion.
On
only 1 of 34 occasions did the highest. platelet count after
infusion occur after 12 hr.
The maximal elevation
served 3 hr or less after the other 33 transfusions.
was ob
Similar
survival
may not
can be given as whole fresh blood obtained
from normal
or
it is in other Patients.
In the latest series of 17 PatientS
(Chart 1) Olily 3 exhibited platelet survivals of 3—5days
Transfusions of whole fresh blood and platelet-rich l)lasma,
however, are limited by the capacity of the recipient's
circulatory system.
Freireich et al. (13) successfully used
platelet-rich plasma for the control of bleeding in thrombo
cytopenic patients.
Under certain circumstances, such as
following massive blood loss, platelet-rich plasma is indeed
the preparation of choice. Its use becomes more difficult
when daily or twice-daily infusions of 20-40 ml of plasma
the latter
is usual
for patients
with
aplastic
due in part to the relatively smaller increments of the
platelet (‘OulitS
iii leukernic patients, or perhaps to other
specific
conditions
111these recipients.
I@iiiiiUne reactions to platelet transfusions.—The
geriic composition of Platelets is but partially known.
anti
The
1reseI@ce of A arid B ty@)e-specific red cell antigens in plate
lets has been demonstrated
(15) and adequate
studies on
specific Platelet antigens, responsible
for Platelet “types,―
have
been reported
nature is desirable
fusions.
Freireich
tamed
@
shortened
polycythemic donors.
This probably is the most efficient
way of transfusing platelets.
The mere separation of fresh
platelet-rich plasma by centrifugation is associated with a
although
@
a partially
findings were obtained in patients with thrombocytopenia
of nonmalignant
origin (3).
The in vivo survival of transfused concentrated platelets
in patients with acute leukemia is generally shorter than
anemia (3).
In the majority of patients, the platelet count
returned
to preinfusion
levels within 24 hr.
This may be
@
antibodies,
be detected when they are rapidly utilized in the thrombo
cytopenic recipient.
The most important feature of the alleged immune re
sponse to platelet transfusions is the laek of systemic re
actions following administration
of potentially incompati
ble material.
The repeated administration
of platelets to
more than 500 patients with malignant or other disorders
was not associated with more than the usual side effects
of blood or plasma administration.
This also was true
when platelets obtained from random donors were given
to leukemic patients without regard to their ABO red cell
type.
The unusual character of the immune response to plate
lets is further suggested by its temporary nature.
Ac
cording to Baldini, the resistance may disappear spontane
ously or follow a course of steroids or splenectomy (2).
The antigenicity of platelets is mild and rarely compli
cates the use of platelet transfusion.
It is possible, how
ever, that further insight into the problems of platelet typ
ing may hell) to increase the efficacy of transfused platelets.
Choice of platelet preparations for transfusion.—Platelets
(20).
Further
information
from the sanie donor by pla.smapheresis
casionally
platelets
of this
for the efficient use of platelet trans
et al. (13) observed
that platelets
ob
may oc
fail to circulate in 4—5% of the recipients,
while
supplied
by other donors would increase
the
platelet
count.
previous
studies
This
observation
on smaller
numbers
was consistent
of I)atients
with
(21).
It, is of interest that resistance to platelet transfusions
developing after multiple administrations
of whole blood or
platelets
platelets
sibilities
could hot be demonstrated
when concentrated
were given repeatedly
(4, o). The following pos
may account for this observation.
Transfusion
loss as high as 30 % of the platelets
per kg of body
weight
present
are required
in whole blood.
for extensive
l)eriOds.
00
I,)
0
;
81
I-
z
61
U
I-
41
4
2C
I2units
4
8
2
6
20
24
28
32
36
40
in a patient
with
TIME AFTER INFUSION(HOURS)
CHART 3.—Circulation
of frozen
platelets
acute leukemia.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1965 American Association for Cancer Research.
DJERASSI
AND F@BER—Control
and
Prevention
1503
of Hemorrhage
amounts of fresh platelets.
Improved
clot retraction,
shortened bleeding time, and arrest of spontaneous hemor
rhages also were observed.
6(
51
REFERENCES
1. Aas, K. A., and Gardner,
x 41
F. H. Survival
of Blood Platelets
Labeled with Chromium51.J. Clin. Invest., 37: 1257, 1958.
2. Baldini, i@I., Ebbe, S., and Bridges,
Blood Platelets.
Blood,
@O:
761, 1962.
8 31
3. Djerassi,
Surgical
151 21
-J
a. II
@idunits
40 -44
IOtmi@s
@
2
4
6
8
0
12
34
6''
TIME AFTER V4FUS@N(HOURS)
CHART 4.—Circulation
of frozen
platelets
in a patient
with
acute leukemia.
Hyperproteinemia
and
the
associated
hypervolemia
may
then present an added problem.
Generalized edema, al
buminuria, retention of transfused electrolytes, and im
pending cardiac failure are potential complications.
These side effects do not occur with the use of platelet
concentrates.
The yield of recoverable platelets from con
centrates,
plasma.
reduced.
however,
is smaller
than
The survival of sedimented
from
platelet-rich
J. M.
I., and Alvarado, J. Platelet
Management
Isoimmunity
Transfusions
of Thrombocytopenic
to
in the
Patients.
Ann.
N. Y. Acad. Sci., 115: 366—77,
1964.
4. Djerassi, I., Farber, S., and Evans, A. E. Transfusions of
Fresh Platelet Concentrates
to Patients with Secondary
Thrombocytopenia.
New Engl. J. Med., p68: 221—29,1963.
5. Djerassi,I., Farber, S., Evans,A. E., and Yoshimura,II. Ob
servation on the Use of Transfusions of Fresh Human Platelet
Concentrates. Proc. Vilith Congr. Intern. Soc. Blood Trans
fusion, Tokyo, Japan, September, 1960.
6. Djerassi, I., Klein, E., Farber, S., and Toch, R. Transfusion
of Platelet Concentrates to Thrombocytopenic
Patients. Proc.
VIIth Congr. Intern. Soc. Blood Transfusion, Rome, Italy,
1958,p.1012.Basel:S.Karger1959.
7. Djerassi, I., and Roy, A. Preservation of Viable Platelets in
the Frozen State. Life Sci., 1: 327—31,1962.
8.
. A Method for Preservation of Viable Platelets: Com
bined Effects of Sugars and Dimethylsulfoxide.
Blood,
@:
703—17,1963.
9. Duke, W. W. The Relation of Blood Platelets to Hemorrhagic
Disease:
platelets may also be
Description
of
a Method
for
Determining
the
Bleed
ing Time and Coagulation Time and Report of Three Cases of
Hemorrhagic
Disease
Relieved
by Transfusion.
J. Am. Med.
fresh
The
Assoc.55:1185,1910.
10. Farber, S., and Klein, E. The Nature and Control of Bleeding
emergency nature of each transfusion and the need for
large amounts of fresh blood, usually at an inconvenient
time, have discouraged the use of fresh platelets in many
centers.
The need for a method of preservation of din
ically effective platelets is evident.
Studies on frozen arid
lyophilized platelets (18) have suggested that platelet com
Review of a 10 Year Program of Research. Ann. paediat.
Fenniae, 3: 348, 1957.
11. Freeman, G. Roles of Prothrombin Activity, Heparin-Pro
Preservation
of platelets.—The
platelets
is a heavy burden
for
ponents may be responsible
static functions
of platelets.
procurement
of
any blood bank.
for at least some of the hemo
Viable circulating
platelets,
however, remain the first choice for the control of bleeding
in thrombocytopenia,
until the hemostatic
function of
platelets
is better
understood
and active
come available.
Preservation
attempted
many
with
components
of viable platelets
varied
techniics.
the effects of hypertonic
sugar
dimethylsulfoxide,
yielded
recently
at —196°C, combining
with those of
preparations
of animal
platelets capable of circulation in thrombocytopenic
re
cipients (7, 8). Extension of this work to human material
indicated that a strictly conitolled rate of freezing was
essential.
Human platelet concentrates frozen at the rate
of 1°C/mini in the presence of 5 % dextrose arid 5 % di
methylsulfoxide
were given
to 18 j)atients
with
thrombo
cytopenia.
These preparations were consistently found to
induce significant increases of the platelet counts.
In a
series of 8 transfusions
counts were increased
levels (Charts 3, 4).
platelets
appeared
of preserved
platelets,
the platelet
by 30,000—66,000 above preinifthsion
The in vivo recovery of the frozen
to vary
12.
13.
14.
from 30 to 50 % of comparable
15.
16.
Leukemia
Titer
Blood,
and
Other
Thrombocytopenic
and Platelet
Concentration
7: 311, 1952.
States.
in Bleeding
A
of Leu
. Method for Obtaining Large Yields of Human Platelets
as
has been
Unfortunately,
solutions
tamine
kemia.
be
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Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1965 American Association for Cancer Research.
Control and Prevention of Hemorrhage: Platelet Transfusion
Isaac Djerassi and Sidney Farber
Cancer Res 1965;25:1499-1503.
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Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1965 American Association for Cancer Research.