Val M. Runge, Fred Carolan,
MD MD
#{149} Daphna #{149} Gene
Y. Geiblum, Heard, MD
Gd-HP-DO3A of the Brain’
terms:
Gadolinium #{149} Head and neck 10.36, 10.38 #{149} Head and neck neoMR studies, 10.1214 #{149} Magnetic reso(MR), contrast enhancement, 10.1214
neoplasms, plasms.
nance Radiology
1990;
177:393-400
C
L Pacetti,
RN
enhancement
travenously
with
administered
ingado-
pentetate dimeglumine has rapidly become accepted in magnetic resonance (MR) imaging of the brain for improved lesion detection and diagnostic specificity. Limitations encountered in early clinical applications of MR imaging included suboptimal characterization of disease type and activity. Furthermore, MR imaging proved less sensitive for detecting disease in some cases, compared with enhanced computed tomography
(CT),
despite
significantly
great-
er soft-tissue contrast. The impact of contrast agents on CT provided a historical precedent for the development of paramagnetic chelates for similar
use
in MR
imaging;
thus,
many of these limitations were alleviated. The in vitro and in vivo characteristics of gadopentetate were first described in 1984 (1). The agent demonstrated strong Ti relaxation, high in vivo stability, rapid renal excretion, and high tolerance (2). These characteristics,
bond al ion
#{149}
MR Imaging
ONTRAST
made
between and
the
possible
the
by
the
chelating
agent,
of gadopentetate,
metde-
pharmaceutical
Center, University of Kentucky, Tufts University, Boston (D.Y.C., June 26; revision received July
search focused on the synthesis of additional agents that might demonstrate more favorable safety and imaging characteristics. This work led to the synthesis and initial evaluation of gadolinium 1,4,7-tris(carboxymethyl)-iO-(2’-hydroxypropyl)1,4,7,iO-tetraazacyclododecane
(HP-
DO3A) in animals, followed by clinical trials. This article elucidates the initial clinical experience with Gd-HP-DO3A
referral
in a neurologic
disease
center.
MATERIALS
AND
This study was part open-label, dose-ranging
METHODS
of a multicenter, clinical trial
that examined safety and efficacy. Adult patients (aged 18-75 years) with presumed intracranial neoplastic disease, cither primary or metastatic, were enrolled. Diagnosis was established by means of tissue
pathology
or CT.
Exclusion
criteria
included pregnancy, lactation, and a history of clinically significant hemolytic anemia. Written informed consent was obtained from each patient after a complete explanation of the nature of the study.
tight
paramagnetic
fined a new class of contrast agents for MR imaging. From this group, gadopentetate became the first agent to reach clinical trials (3,4). After approval by the U.S. Food and Drug Administration, gadopentetate gained widespread acceptance for improved diagnosis of head and spine disease with MR imaging. Subsequently, an additional agent in this class, gadolinium tetraazacyclododecanetetraacetic acid (DOTA), has been evaluated in Europe (5). After the successful development
From the Magnetic Resonance Imaging and Spectroscopy HM1O3 Medical Center, Lexington, KY 40536 (V.M.R.), and M.L.P., F.C., G.H.). Received May 24, 1990; revision requested cepted July 9. Address reprint requests to V.M.R. C RSNA, 1990 I
#{149} Martha
in Clinical
As part of a phase II clinical trial, 14 patients with presumed intracranial neoplastic disease underwent magnetic resonance (MR) imaging before and after intravenous injection of gadolinium 1,4,7-tris(carboxymethyl)-10-(2’-hydroxypropyl)1,4,7,10-tetraazacyclododecane (HPDO3A). This neutral (nonionic) gadolinium chelate has lower osmolality, when formulated at equimolar concentrations, and superior in vitro stability compared with gadopentetate dimeglumine. The safety profile of Gd-HP-DO3A permitted administration of doses up to 0.3 mmol/kg, three times the dose of gadopentetate dimeglumine approved by the U.S. Food and Drug Administration. In this limited dinical trial, Gd-HP-DO3A proved to be a safe and efficacious agent in MR imaging of the head. The only change documented in patient monitoring was that of slight skin redness at the injection site immediately after administration in two patients. No statistically significant changes due to administration of the agent were noted in laboratory evaluations. These results differ from those obtained with gadopentetate, which induces a transient rise in serum iron and bilirubin levels in up to 26% of patients. Administration of higher doses of Gd-HPDO3A, either 0.2 or 0.3 mmol/kg, appeared to provide improved enhancement. No decrease in efficacy at these high doses was noted. Index
MS
Before
the
initiation
gation, the study protocol form were reviewed and Institutional
Review
of this
investi-
and consent approved by the
Board.
Gd-HP-DO3A (SQ 32,692; Squibb Diagnostics, Princeton, NJ) (Fig 1) was provided as a clear, stable aqueous solution in 20-mL mol/L
vials. The solution contained 0.5 Gd-HP-DO3A, 0.25 mmol/L Ca[Ca(HP-DO3A)]2 (to act as a scavenging
agent for any free gadolinium ion or chelating agent), and 10 mmol/L tris(hydroxymethyl)aminomethane (a buffer to maintain pH). At 25#{176}C, the osmolality of Cd-HP-DO3A is 0.63 osm per kilogram of water, the viscosity is 1.8 cp, and the specific gravity is 1.141. The contrast material was administered intravenously as a slow infusion, with an injection rate not
re-
3; ac-
Abbreviations DOTA = tetraazacyclododecanetetraacetic acid, DTPA = diethylenetniaminepentaacetic acid, ECC electrocardiography, HP-DO3A l,4,7-tris(carboxymethyl)-l0(2’-hydroxypropyl)-l,4,7,lO-tetraazacyclododecane.
393
Table 1 Clinical Data, Dose with MR Imaging
of Gd-HP-DO3A,
Patient! Age(y)/
HPDO3A
(SQ Figure
32,692)
1. Cd-HP-DO3A gadolinium chelate.
philic
achieved
hydrois the +3 charge of the the cumulative -3 carboxyl groups. Con-
by balancing
gadolinium charge from
ductivity
ion with the three
is a neutral Neutrality
measurements
have
osmolality
than
uncharged in charge allows solutions with
that
of gadopentetate.
the
repeat
nosis
was
logic
evaluation
established
surgery
or
was
1. Diag-
means
of histo-
of specimens
biopsy
two patients,
in Table by
in
obtained
1 1 of
at
14 patients.
In
a solitary enhancing lesion at both CT and MR imaging, a
noted
finding consistent in patients in whom
was originally
with metastatic the primary
established
tissue biopsy. of sarcoidosis
disease disease
by means
In patient 14, was presumptive,
the
of
diagnosis with no
1/53/F 2/68/F 3/37/M 4/46/F 5/76/F 6/20/M 7/42/M
0.1 0.2 0.3 0.05 0.1 0.2 0.3
8/57/F 9/7l/M 10/70/F 1 1 /36/M
0.2 0.1 0.05 0.3
Astrocytoma (grade 3/3)* Astrocytoma (grade 3/3)* Poorly differentiated neuroectodermal Meningioma5 Astrocytoma (grade 3/3)5 Eosinophilic granuloma5 Acute and chronic inflammation plexus from CNS toxoplasmosis5 Metastatic melanoma5 Astrocytoma (grade 3/3)5 Astrocytoma (grade 3/3)5 Metastatic renal cell carcinoma
12/62/F
0.3
Astrocytoma(grade3/3)5
13/32/F l4/22/M
0.2 0.2
Astrocytoma Sarcoidosis
= central established
nervous system. by means of histologic
study
and
administration The 24-hour
4 and
24 hours
of the contrast examination also
physical
examination.
Laboratory values al with Gd-HP-DO3A with those obtained
from this clinical triwere compared from a phase II clini-
cal trial with gadopentetate performed by the principal investigator (V.M.R.) in 1984. The entry criteria of the 1984 study were similar to those of the present study and required that patients have a presumed intracranial tumor. All laboratory studies
were
performed
immediately
be-
history,
physical
examination,
vital
12-lead extensive
electrocardiography laboratory tests.
(ECG), Analysis
tems, Iselin, NJ). Before the contrast material was administered, T2-weighted (repetition time [msec]/echo time [msec] = 3,000/45, 90) and Ti-weighted (650/20) images were obtained. The Ti-weighted acquisitions were repeated approximately 2, 15, 30, and 45 minutes after contrast material administration. In both imaging techniques, a small bandwidth was used, with first-order gradient moment nulling
consisted
blood
hemoglobin
level,
mean corpuscular count (including
matocnit,
leukocyte and
of a complete
including
platelet
cluding nitrogen,
count;
chemistry,
levels of glucose, creatinine, calcium, phosphorus, uric
total
cholesterol,
total
total
bilirubin,
alkaline
partate
signs,
and of he-
volume, total differential),
blood
protein,
inurea acid,
lactic
Magnetom
(in
albumin,
phosphatase,
aminotransferase,
as-
dehydro-
both
axes)
unit
the
Medical
section-select
applied
nation
(Siemens
in
only.
the
and
ada
Sys-
thickness
images
obtained
sis
including
levels, and
included
gravity, protein and microscopic ment,
394
blood,
Radiology
#{149}
iron levels, iron bindferritin levels. Urinalyof pH,
levels, and examination and
prothrom-
partial thromboplasmetabolism, including
evaluation
ketones.
specimens.
specific
glucose levels of sediImmediately
and
any was
the coronal
one
was
kept One
patient. for
plane
during
spin
excitation
for all T2-weighted
section
thickness),
for Ti-weighted
or more
in
section
citations
for 3-mm
primary
plane
T2-weighted
were
studies with
images
one
cx-
of 4 mm
thickness,
and
sections.
Images
supplemented
images
The
constant
in a single
citation
and
in one
examination.
acquired
(3-8-mm
plane
orthogonal planes, according to the disease visualized. Image evaluation included both qualitative and quantitative measurements. Images were reviewed by the principal investigator and assessed relative to the
detailed
in Figure
terest measurements normal tissues) were
from the images, culated according
2. Region-of-in-
(of normal obtained
and abdirectly
with enhancement to the formula:
calpercent-
age of enhancement (SI postcontrast SI precontrast)/(SI precontrast), where = signal intensity. Of the 14 patients, five had undergone enhanced imaging with gadopentetate
within
2 weeks
-
SI
of the Gd-HP-DO3A
study, without intervening therapy that might have affected lesion enhancement. In each patient, administration of the two agents was separated by at least 48 hours. In two patients, the correlative examination with gadopentetate was performed at an outside institution from which quantitative data could not be derived. In the other three patients, both studies were acquired with the same MR imaging instrumentation and pulse sequences, which permitted quantitative comparison of the
enhancement tate
relative
achieved to that
with
achieved
gadopentewith
Gd-HP-
DO3A.
RESULTS
section
transferrin ing capacity,
of biopsy
sequences,
clotting
and iron
of choroid
2/3)
exami-
For all imaging
the field of view was 250 mm, with 256 phase-encoding steps. These images were obtained in the axial plane in 13 patients
bin, thrombin, tin times; and
tumor5
readout
T2-weighted
genase, and alanine aminotransferase; electrolyte evaluation, including sodium, potassium, and chloride levels; hepatic function, consisting of evaluation of the gamma glutamyl transpeptidase level; functions,
(grade
criteria a
fore and 2, 4, 8, 24, and 48 hours after ministration of gadopentetate. Imaging was performed at 1 T with
count,
evaluation
after
medium. included
contemplated because of the indolent nature of the disease. Patient monitoting included (within the immediate 24 hours before administration of the agent)
biopsy
blood
Examined
Diagnosis
before administration of Gd-HP-DO3A, vital signs and ECG results were again checked. Vital signs, ECG, and all laboratory tests were subsequently repeated immediately after completion of the postcontrast
studied
(mmol/kg)
Note.-CNS S Diagnosis
exceeding 10 mL/min. The specifics of age, sex, dose of GdHP-DO3A, and diagnosis are provided for 14 patients
in 14 Patients
confirmed
that the compound remains solution. The lack of overall the formulation of 0.5-mol/L
lower
Diagnosis
Dose
Sex
Gd
and
two
cx-
in the
by Tiin the other two
Clinical following
monitoring drug-related
revealed changes.
the In
one patient, the injection site appeared red immediately after contrast material injection. This resolved in approximately 45 minutes. In another patient, the injection site was observed to be slightly red initially after injection subsequent abnormalities
(the site examination). represent
changes noted were thought
was
normal These the only
from baseline to be attributable November
at two
that to 1990
Image 1. Wsa
abnonn.J
noted
enhancement
on any Image
14/l4yes 2. If the
aiaw
qusetion
to
& Rate the degree
4.
Were
all lmsge
IfUse
szwer rank
Information
ssn
the
set(*.
14/14
E
set
B
12/14
C
12/14
D
11/14
E
B
2/14
C
2/14
D
3/14
B
C
In tern
ofprovldlng
yes
be
Image
inage
D
2/14
equal
to the
nostic
for seth
which
14/14
B sets
Please
specl
C
12/14
0/14
5.
uiybe
or u*ybe. 14/14
B
oferthancement
Marlcedlyenhanced Sllghtlyenbanced Noenbancement
set?
r
1 1s ye
14/14
set
and
W
In tern 1 providing
D
dlsgnosUc
B
lnforndon?
r
14/14
quselion
tion. No changes related to drug administration were found at ECG. Nine of 14 patients had normal ECG results both before and after contrast material administration. Five patients entered the study with abnormal ECG findings. These were unchanged after drug administration. Ten of i4 patients had no laboratory abnormalities. In four patients, minor changes were noted in serum assays that were thought to be unrelated to contrast material administralion. In one patient who was
Evaluation
plae
ofdlagnostlc the leset.
complete
questlora
thfornition
with
Inages
ciequal
5 through a rankofV
dlgnoIc
receiving dexamethasone, crease in blood glucose noted. In two patients,
7. providing the tdlagshould be assigned the
vshse
iron level was found to decrease on follow-up examinations, a result attributed to surgery performed during the 24-hour period after drug administration (one of these patients was the one in whom the abnormal blood glucose value was also noted). In one
value. Image A
Diagnostic
5 4
Information
3
Rank
2
Set B
C
D
K
13/14
11/14 2/14
11/14 2/14
10/14 2/14
1/14
1/14
1/14
2/14
14/14 6.
ComparIng In a change
the motdiagnostlc
5/14
7. Ifanyofthe
image
tlon?Pleaie
dMgnesls.
image setto the paUent tbersy.
yes
8/14
In *t1ent
Indicate
leset dapoUc sM/or
no
homage set. would
patient,
result
4/5 3/5 2/5
Informedon, Information.
Dgnosls TheiaW Outcome
whetse
the r*tw
ofthls
thformes-
rial Lesion
detection
4 2 10
Nunmberofleslons Improved DbsostIc Distinction Distinction
visuallestlon cIty ofedema of lesion
B-E
6 7 11
borders
Figure 2. Criteria for image evaluation. Numbers image sets. A unenhanced images, B immediate postcontrast images, D 30-45-minute postcontrast
represent
number
postcontrast
images,
E
of answers/number
images, 45-60-minute
C
of
15-30-minute postcontrast
images.
140 1.2
120 1.0
-o 100 E
I
.#{149}0
.-:74::a#{149}#{149}
o”_
0.6
0
340
t
#{176}
(
0.2
ScREEN
IHR
2HR
4116
5116
24/40
46I
53ZN
lime
186
21/8
41
686
241
461
TIm#{149}
b.
a.
Figure 3. Safety profiles. Mean changes from baseline after intravenous injection of contrast material in serum iron (a) and total bilirubin (b) levels. Results from the phase II dm1cal investigation with Gd-HP-DO3A (#{149}) in 14 patients are compared with data from a previ0505 phase II investigation with gadopentetate (0) in 30 patients with intracranial neoplastic disease. There were no statistically significant laboratory changes demonstrated with GdHP-DO3A administration. Specifically, serum iron and total bilirubin levels remained with-
in normal limits after Gd-HP-003A levels after gadopentetate injection.
injection, contrary to the common elevation of these Concentration values are in conventional units, not SI
units.
drug administration. site appeared normal material administration 12 patients. Results at physical Volume
177
#{149} Number
The injection after contrast in the other examination 2
serum
iron
binding
ca-
administration.
In a previous phase II investigation performed by the author, 1 1 of 28 and nine of 30 patients demonstrated abnormally high serum iron and total bilirubin levels, respectively, within 48 hours after administration of 0.i mmol/kg of gadopentetate. The time scale of these changes is presented in Figure 3. This abnormal result was not observed in the patients receiving Gd-HP-DO3A. Gd-HP-DO3A, like gadopentetate, enhances Ti relaxation and thus causes an increase in signal intensity on Ti-weighted images. Contrast material enhancement, in this limited clinical trial, did improve lesion characterization
#{149}___#{149}_____#{149}____#{149}______t#______#{149} 0 0
the
pacity was decreased 24 hours after contrast material administration. In another patient, the partial thromboplastin time was decreased at 4 hours and the aspartate aminotransferase level at 24 hours after contrast mate-
outcome?
WIdth?
sets provided addltionaldtsgnostic the urage set(s) which psuvided
th1.thfcrmmthn
an invalue was the serum
were unchanged from baseline in all i4 patients. Assessment of vital signs (heart rate, blood pressure) revealed no significant changes from baseline attributable to Gd-HP-DO3A injec-
(Fig
2). For
example,
findings on the T2-weighted image in a patient with an astrocytoma (Fig 4) were abnormal. However, only the postcontrast image allowed recognition of disruption of the blood-brain barrier, which can also be used to dired stereotaxic biopsy. In eight of 14 patients,
delayed
postcontrast
images
demonstrated slightly improved lesion enhancement relative to the immediate postcontrast image (Fig 5). Qualitatively, enhancement provided improved distinction of the lesion border, as assessed with disruption of the blood-brain barrier in ii of 14 patients, with improved differentiation of the lesion from surrounding edema in seven of i4 patients (Fig 2). Radiology
#{149} 395
The
disease
entities
studied
clinical trial included tracranial lesions with characteristics similar mal brain. Such lesions
in this
examples relaxation to those can be
of inof nordiffi-
cult to identify on nonenhanced MR images. Lesion detection was improved in this manner after enhancement in four of 14 patients, with an increased number of lesions visualized
on
postcontrast
patients
(Fig
Four
images
in two
2).
patients
received
Gd-HP-
DO3A at a dose of 0.3 mmol/kg (breakdown of other doses: two patients received 0.05 mmol/kg, three received 0.1 mmol/kg, and five received 0.2 mmol/kg). Despite the potential for T2 shortening at high doses, intense enhancement was
demonstrated
in each
case.
One
lesion, a grade 3 astrocytoma, trated in Figure 6. Prominent hancement was also observed desmoplastic medulloblastoma
7) at a dose side
MR
is illusenin a (Fig
of 0.3 mmol/kg.
image
mmol/kg
with
of gadopentetate same
duced
enhancement.
studies
patient
with
Figure
4. Grade 3 astrocytoma. (a) Precontrast axial T2-weighted image. (b) Axial Tiweighted images obtained before (top left) and 2 (top right), 15 (bottom left), and 30 (bottom right) minutes after intravenous administration of 0.1 mmol/kg Gd-HP-DO3A. Enhancement is seen in the portion of the lesion (arrow) demonstrating disruption of the bloodbrain barrier. The thickness of the garlandlike rings, and thus apparent lesion enhancement, increases with time.
0.1
(Fig
7d)
demonstrated
marked
re-
In the
nine
lesion
enhance-
#{149}-#{149}------.----#{149}.--.--.----.#{149} 600
despite the varied disease (Fig 8). Results in the three patients in whom both examinations (gadopentetate and Gd-HP-DO3A) were performed at our institution confirm improved enhancement at higher doses (Table 2). In patients 1 and 3, the low dose was 0.1 mmol/kg for was
0.2
Patient sone
and
mmol/kg
2 was when
for
possible
was performed, influencing the and
dose
0.05
and
mmol/kg
for
Radiology
#{149}
POST
15M69
POST
3OMSN
POST
45606 POST
1000 900 600 -
900
700
;/
500 400
high
gadopentetate.
ter
5. Quantitation of signal-intensity change in the primary administration of 0.05 (a), 0.1 (b), 0.2 (c), and 0.3 (d) mmol/L
additional
mmol/kg In a patient
lesion in each Gd-HP-DO3A.
patient
af-
2,
mmol/kg
the
d.
c.
Figure
for
dose
was In a
seizures of unknown enhanceon the examina-
ophilic granuloma, hancement of both
patients Gd-HP-DO3A with eosin-
prominent enthe soft-tissue
mass and adjacent meningeal mation was visualized at MR
(images not ment of the less
intense,
the
meningeal
inflamimaging
shown). At CT, enhancebulk of the lesion was with
nonvisualization
portion.
of
Significant
lesion enhancement was noted in a patient with metastatic melanoma (Fig 1 1), despite the hyperintensity of this mass relative to normal brain on precontrast Ti-weighted images.
Detection contrast
receiving 0.2 were of note.
396
any
9). In a patient with a proved meningioma, adof 0.05 mmol/kg Gdresulted in statisticalenhancement, compared mmol/kg gadopentetate
in two
2604
1O1
a factor degree
limiting
patient with longstanding and a meningeal process cause (presumed sarcoid), ment was best recognized higher-dose Gd-HP-DO3A
Results
SCREEN
b.
a.
dose
In patient
was
Gd-HP-DO3A,
tion (Fig surgically ministration HP-DO3A ly poorer with 0.1 (Fig 10).
(
dexametha-
conclusions.
low
400
0
Gd-HP-DO3A.
receiving
of enhancement
0.1
high
.z
Gd-HP-DO3A-enhanced
MR imaging potentially
the
the
700
____1
!E
ment, the increase in signal intensity immediately after contrast material administration correlated with dose,
gadopentetate
D.
An out-
enhanced
in the
such
.
HP-DO3A) diagnosis helped
of enhancement images
(0.2
permitted
on post-
mmol/kg
Gd-
a more
certain
of metastatic disease exclude the possibility
and of a
nonneoplastic hemorrhage. Qualitative image evaluation (single observer, nonblinded) of the entire patient population resulted in the following additional findings (Fig 2). There was abnormal enhancement in each patient, with the postcontrast image providing significant additional diagnostic information in all 14 patients. Delayed imaging (subsequent to the initial postcontrast image) did not improve visualization of enhancement. In 13 of 14 patients, the immediate postcontrast image was thought to be most diag-
nostic. mediate thought
In one of 14 patients, postcontrast image to be diagnostically
the imwas equal to
November
1990
of normal
tigation proved
\
\
brain
tissue
(14)
and
of gadopentetate imaging of human
inves-
for imbrain in-
farction (15). Subsequent studies demonstrated conclusively that contrast enhancement improved detection of intracerebral metastatic lesions (16,17). In the absence of signif-
icant
edema,
small
metastatic
lesions
can be missed on unenhanced MR images. Likewise, lesions adjacent to cerebrospinal fluid in the subarachnoid space or ventricular system can I
be overlooked.
b.
a.
Figure
6.
Grade
3 astrocytoma.
(a) Precontrast
images DO3A. tissues
before (left) and immediately after This high dose of contrast material surrounding the necrotic center on
T2-weighted
MR image.
(right) administration provided prominent immediate postcontrast
(b) Tl-weighted
of 0.3 mmol/kg enhancement images.
MR
Gd-HPof neoplastic
In this clinical trial, there was no change in blood or urine parameters, physical examination findings, vital signs, or ECG results that could be attributed to Gd-HP-DO3A administration. The laboratory abnormalities encountered with gadopentetate may be due in part to the osmolality of the
solution Table 2 Percentage Gadopentate-
of Contrast Enhancement and Gd-HP-DO3A-enhanced
Patient No.
High
Sarcoid Meningioma Glioblastoma
dose
was twice
the other delayed cases, information postcontrast thought diagnosis,
that
of low dose
images.
In five
The
pattern
of 14
of con-
improved the ability diagnosis (diagnostic specificity) in six of 14 patients. Region-of-interest measurements demonstrated that the degree of enhancement of soft tissue with Gd-HPDO3A paralleled the dose, with statistically greater enhancement of muscle at a dose of 0.3 mmol/kg, compared with that achieved at 0.1 and 0.2 mmol/kg (P < .02 in each case). Data for the 0.05mmol/kg dose were not considered in this statistical comparison because of to make
a specific
the limited Table
group
size (two
patients).
3 presents
data derived from precontrast and immediate postcontrast images. Although enhancement of normal gray matter increased with dose, this result was not statistically signifi-
cant.
clinical evaluation has established the of disease entities for
of gadopentetate wide spectrum
177
Number
#{149}
2
18 48 118
early
1980s
by other
those
altering
the
investigators
blood-brain
barn-
disease
ial lesions, tration was
(7-10).
contrast material demonstrated
For
intraax-
administo improve
tumor delineation by highlighting the region of blood-brain barrier
dis-
trials
indicated
the
experience. series
describing
Also
po-
of investigations
the
enhancement
included was
in work
patterns
were
kiloand a
given
acid
ligand
(18).
receiving had adlocalized
nausea, paresthesias, and were the major complaints
not
in this trial. In our current such adverse reactions
reported
after
Gd-HP-
DO3A administration. However, the reporting and recording of such reactions can differ greatly from institution to institution. Only more extensive evaluation of Gd-HP-DO3A can help determine whether such minor adverse reactions will be reported with any frequency after administration of this agent. In the same trial of gadopentetate administration, a tran-
rise in serum was reported
iron and bilirubin in 26% of men
and 18% of women. A study conducted in 12 healthy male volunteers with 0.2 mmol/kg gadopentetate further quantitated this change in serum iron and total bilirubin levels, which could be observed 3-4 hours after injection and were at a maximum at 612 hours (20). This study suggested that slight hemolysis immediately afto be
for improved imaging of pitulesions (13), a finding that has confirmed with subsequent
clinical this
also
per
The potential for also exists when
chelating
ter gadopentetate
ruption. This identification of bloodbrain barrier disruption can be vital for proper diagnosis (11,12). Initial
clinical
solution). exchange is the
of patients investigation,
sient levels
er. Clinical trials with gadopentetate in imaging brain neoplasia rapidly followed. Early publications elucidated the improved detection of extraaxial tumors such as meningiomas, as well as intraaxial lesions including
metastatic
osm
for gadopentetate respectively,
In a trial of 1,068 patients gadopentetate (19), 19.9% verse reactions. Headache,
strongly suggested that agents such as gadopentetate would increase the diagnostic potential of MR imaging in neurologic diseases, particularly
been
and
(DTPA)
which contrast material administration is efficacious. Early work with a brain abscess model (6) demonstrated lesion detectability in certain instances only on postcontrast MR images. This and similar experience in
the
vs 0.63
diethylenetriaminepentaacetic
coldness, dizziness
itary
DISCUSSION
Volume
10 26 62
tential
Experimental
0.5-mol/L metal ion
High Dose5
in all cases.
resulting from the images was qualitatively to be critical in determining therapy, or outcome. The lesion was thought to be better on the postcontrast images
primary visualized in 10 of 14 patients. trast enhancement
with
Low Dose
Diagnosis
1 2 3 S
in Three Patients Examined MR Imaging
(1.94
gram of water Gd-HP-DO3A,
the
injection
cause
of these
was changes.
likely Al-
though this side effect was described as resulting in no recognizable clinical consequence, it is significant that such a change was not observed in
the
present
injection. Under Cul+ and
trials certain Zn2+
after
Gd-HP-DO3A
conditions may react
with
in vitro, the
Radiology
397
#{149}
I
.:..
a.
b.
C.
Figure 7. Desmoplastic medulloblastoma (poorly differentiated neuroectodermal tumor). (a) Precontrast T2-weighted MR image. (b) Tiweighted axial MR images obtained at 1.0 T (650/20) before and immediately after (right) administration of 0.3 mmol/kg Gd-HP-DO3A. Intense lesion enhancement is noted (arrow). Five days before, an MR image was obtained at a private outpatient clinic. In the interval between imaging procedures, an intraventricular shunt was placed. (c) Ti-weighted image at 1.5 T (583/15) after intravenous administration of 0. 1 mmol/kg possible due
gadopentetate. Visual inspection to lack of long-term data archiving
DTPA complex. In tests in which a phosphate solution equimolar in metal ion to gadolinium chelate (25 mmol/L) was monitored for release of Gd3, replacement of the gadolinium ion occurred with the DTPA com-
plex.
Such
reactivity
demonstrated Gd-DO3A and Gd-HP-DO3A sult illustrates
ion
substitution
such
has
vivo.
The
has
with
not
been
serves
the
imaging
MR
studies
(Fig
all improved
higher Thus,
than this
ing.
Despite patient
ence suggests characteristics quite similar
398
Radiology
#{149}
Lesion
enhancement
in each
of Gd-HP-DO3A
dose
(average
category)
characteris-
2). For exam-
on postcontrast
dose.
The
was calculated
as described
in Materials and from the immediate
Methods, with postcontrast
use of data image.
Figure tate. This conclusion is not surprising, given the similarities in relaxivity and tissue distribution. More definitive comments with respect to efficacy await enrollment and scientific reporting of significantly larger patient populations. The following observations can be inferred from the enhancement observed in this clinical trial relative to the administered dose of contrast material. With high doses of Gd-HPDO3A, there was no direct evidence to suggest decreased enhancement, which would be a theoretical consideration due to T2 shortening. The sta-
9.
clearly demarcated study at a higher
sarcoid
(presumptive
on the Gd-HP-DO3A dose (arrow).
the contrast enhancement of a lesion markedly improve on delayed images. This would have been anticipated if a high dose had resulted in mitial high concentrations of the agent in the lesion, causing sufficient shortening of T2 to reduce the signal intensity of the lesion on immediate
conclusion is provided by the time course of enhancement curves for the 14 patients (Fig 5). In no instance did
demonstrate
to the
Intracranial
diagnosis). Postcontrast Ti-weighted MR images obtained after intravenous injection of 0.1 mmol/kg gadopentetate (top) and 0.2 mmol/kg Gd-HP-DO3A (bottom). Although contrast enhancement along the meninges was noted on the postcontrast study enhanced with gadopentetate, it was more
that the enhancement of Gd-HP-DO3A are to those of gadopente-
this
.
I’
experi-
due
not
percentage
of enhancement
postcontrast A dose
population,
was
for
tistics gathered suggest continued increased enhancement at the highest dose evaluated, 0.3 mmol/kg. Further indirect evidence supporting this
limitations
comparison
as a func-
as a “stress
images. However, it must be recognized that this clinical trial did not enroll a population representative of that typically referred for MR imagsmall
c. Statistical
(70,,.I./kg)
Do..
tion
plc, lesion characterization, identification of the lesion border, differentiation from surrounding edema, and prospective lesion identification
were
in b than
I
ions
de-
tics of Gd-HP-DO3A in patients with intracranial neoplastic disease appear to mirror those of gadopentetate when dose is not considered. In this clinical trial, Gd-HP-DO3A significantly improved the diagnostic yield
of the
intense
I
in
test” illustrating the greater kinetic inertia of the Gd-HP-DO3A complex compared with that of gadopentetate.
Overall,
is more
F
Figure 8. all patients
of metal
more
enhancement clinic.
and such as this refor metal
demonstrated
concentration
that contrast outpatient
been
gadopentetate,
employed in the experiment scribed was substantially that encountered in vivo.
evaluation
not
with Gd-DOTA its derivatives (18). Although the potential
reveals at the
duce (Fig
routine lesion
Ti-weighted of 0.05 mmol/kg
relatively 10), even
poor enhancement in lesions known strong
MR
images. can pro-
imaging
enhancement
to
enhancement
at
or CT. Greater was
noted,
November
de-
1990
1S\
Such lesions potentially
#{248}_
might at doses
also be missed of 0.1 mmol/kg
or lower due to relatively hancement and partial-volume fects. Such findings would
much aging is
.
.4
9..
1
dependent technique
tential
for
higher
contrast
clearly clinical
defines trials.
faint
enefbe very
on the specific employed. The
improved
diagnosis
agent
impoat
concentration
the need for further A dose administration
trial with gadopentetate (21) concluded that intravenous injection of 0.2 mmol/kg could increase diagnosb.
a.
Figure 10. Meningioma. weighted MR images immediate postcontrast pentetate. Enhancement dopentetate.
(a) Precontrast (left) and immediate postcontrast (right) Tienhanced with 0.05 mmol/kg Gd-HP-DO3A. (b) Precontrast (left) and (right) Ti-weighted MR images enhanced with 0.1 mmol/kg gadowas approximately twofold higher at the 0.i-mmol/kg dose of ga-
tic yield nately,
in selected U.S. Food
tration
approval
and
of this
been granted only mmol/kg. Perhaps with Gd-HP-DO3A to imaging metastatic
brain,
and
that
of different
cases. UnfortuDrug Adminis-
agent
has
for a dose of 0.1 a clinical trial that is restricted disease in the
examines
the
administered
efficacy
doses
use of the model of the dose tration trial of gadopentetate, be definitive
in clarifying
with
adminiscould the
appro-
priate dose for examinations of the head. In any such work, large groups will be needed, with quantitation of blinded reader interpretation of the MR images and statistical evaluation by means surements ministration
of region-of-interest of enhancement of the agent.
after
The findings of improved hancement at higher doses gest
that
Gd-HP-DO3A
cacious and
diagnostic
Figure 11. (b) Precontrast tamed with tense relative This illustrates higher doses
Left
frontal melanoma metastasis. (a) Precontrast T2-weighted MR image. (top) and postcontrast (15 minutes) (bottom) Ti-weighted MR images ob0.2 mmol/kg Gd-HP-DO3A. Although the metastasis (arrow) is slightly hyperinto normal brain on the precontrast image, prominent enhancement is seen. one potential application for intravenous contrast material administration at in MR imaging.
Table 3 Percentage of Enhancement with MR Imaging
with
0.05 Tissue
Graymatter Muscle (masseter)
Dose
mmol/kg (n 2) 4 34
spite the varied diseases, at higher doses of Gd-HP-DO3A (up to 0.3 mmol/kg). Unfortunately, this result does not reflect a rigorous comparison of the efficacy of different doses
Volume
177
Number
#{149}
2
of Gd-HP-DO3A 0.1 mmol/kg
in 14 Patients
Examined
3)
0.2 mmol/kg (n 5)
0.3 mmol/kg (n 4)
4±3 30 ± 2
7±4 35 ± 2
8±5 47 ± 8
(ii
specificity
intensity
on
that high
precontrast
Ti-
Metastatic
in particular
may
effi-
of lesions
signal
images.
be
detection
central nervous system demonstrate relatively
ma b.
the
in the might weighted a.
enalso sug-
might
for improving
meaad-
melano-
demonstrate
hypermntensity on precontrast weighted images due to the
Tipresence
of either hemorrhage or melanin. In such cases, a higher dose of contrast material might improve the certainty with which the diagnosis of neoplas-
tic disease is made with MR imaging (Fig 11). Lesion enhancement was sufficient for clinical diagnostic purposes in all cases
at a dose
of 0.1
mmol/kg.
How-
ever, unlike gadopentetate, Gd-HPDO3A can be administered at higher doses without any demonstrable ill
of the
effects. In the central nervous system, doses of 0.2-0.3 mmol/kg should find application for improved detection of meningeal disease, small enhancing lesions, metastatic disease confined to bone, and soft-tissue ab-
nary
normalities.
contrast agent. These prelimidata, however, suggest that certam lesions, such as meningeal disease or small metastatic lesions, could be better visualized at higher doses.
in the
future
turboFLASH also
might
Brain
perfusion
with
techniques
(fast
low-angle
benefit
from
studies such
as
shot) high
Radiology
dose
399
#{149}
administration. Two applications in areas other than the central nervous system that might be improved with a high dose of contrast material in MR imaging are the delineation of myocardiai ischemia and detection of metastatic disease to the liver. In summary, Gd-HP-DO3A offers four potential advantages over intravenous gadopentetate for contrast enhancement on MR images. This new agent is neutral, inert to chemical substitution by copper or zinc ions, does not cause biochemical abnormaiities (in initial limited experience), and can be administered at doses up to 0.3 mmol/kg. These represent preliminary findings based on a small patient population. Expanded clinical trials with further evaluation of the role of high doses of Gd-HPDO3A are warranted. #{149} Acknowledgment: tarial
Miller
and
administrative
We appreciate assistance
in the completion
the secreof Lisa
of this study.
3.
Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadoliniumDTPA complex: a potential NMR contrast agent. AJR 1984; 142:619-624.
2.
Gries
H, Miklautz
H.
Some
4.
MRI: tients.
5.
6.
7.
8.
9.
10.
16:105-112.
400
Radiology
#{149}
11.
12.
13.
M, Mutzel
14.
W.
of GdDTPA/dimeglu-
as a contrast
agent
Kilgore
DP,
Breger RK, Daniels DL, et al normal MR appearance afinjection of Gd-DTPA. Radiology 1986; 160:757-761. Virapongse C, Mancuso A, Quisling R. Human brain infarcts: Gd-DTPA-enhanced MR imaging. Radiology 1986; 161:785-794. Russell EJ, Geremia GK, Johnson CE, et al. Multiple cerebral metastases: detectability with Gd-DTPA-enhanced MR imaging. Radiology 1987; 165:609-617. Healy ME, Hesselink JR, Press GA, Middleton MS. Increased detection of intracranial metastases with intravenous GdDTPA. Radiology 1987; 165:619-624. Tweedle MF, Hagan JJ, Dose LV, et al. Reaction of Gd complexes with endogenously available ions (abstr). In: Book of abstracts: Society of Magnetic Resonance in Medicine 1987. Berkeley, Calif: Society of Magnetic Resonance in Medicine, 1987; 477. Goldstein HA, Kashanian FK, Blumetti RF, et al Safety assessment of gadopentetate dimeglumine in U.S. clinical trials. Radiology 1990; 174:17-23. Niendorf HP, Seifert W. Serum iron and serum bilirubin after administration of
Cranial tissues: ter intravenous
mine after intravenous injection into healthy volunteers. Physiol Chem Phys Med NMR 1984; 16:167-172. Carr DH, Brown J, Bydder GM, et al.
Gadolinium-DTPA
physico-
chemical properties of the gadoliniumDTPA complex: a contrast agent for MRI. Physiol Chem Phys Med NMR 1984;
HJ, Laniado
Pharmacokinetics
References 1.
Weinmann
15.
in
initial clinical experience in 20 paAJR 1984; 143:215-224. Parizel PM, Degryse HR, Chevens J, et al. Gadolinium DOTA enhanced MR imaging of intracranial lesions. J Comput Assist Tomogr 1989; 13:378. Runge VM, Clanton JA, Price AC, et al. Evaluation of contrast-enhanced MR imaging in a brain abscess model. AJNR 1985; 6:139-147. Bydder C, Kingsley F, Brown J, Niendorf H, Young I. MR imaging of meningiomm including studies with and without gadolinium-DTPA. J Comput Assist Tomogr 1985; 9:690-697. Felix R, Schoerner W, Laniado M, et al. Brain tumors: MR imaging with gadolinium-DTPA. Radiology 1985; 156:681-688. Runge VM, Schoerner W, Niendorf HP, et al. Initial clinical evaluation of gadoliniuni DTPA for contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 1985; 2:27-35. Breger RK, Papke RA, Pojunas KW, et al. Benign extraaxial tumors: contrast enhancement with Gd-DTPA. Radiology 1987; 163:427-429. Graif M, Bydder GM, Steiner RE, et al. Contrast-enhanced MR imaging of malignant brain tumors. AJNR 1985; 6:855-862. Brant-Zawadzki M, Berry I, Osaki L, Brasch R, Murovic J, Norman D. GdDTPA in clinical MR of the brain. I. Intraaxial lesions. AJR 1986; 147:1223-1230. Berry I, Brant-Zawadzki M, Osaki L, Brasch R, Murovic J, Newton TH. GdDTPA in clinical MR of the brain. II. Extraaxial lesions and normal structures. AJR 1986; 147:1231-1235.
16.
17.
18.
19.
20.
Gd-DTPA-dimeglumine: a pharmacologic study in healthy volunteers. Invest Radiol 21.
1988; 23(suppl 1):275-280. Niendorf HP, Laniado M, Semmler W, Sch#{246}rner W, Felix R. Dose administration of gadolinium-DTPA in MR imaging of intracranial tumors. AJNR 1987; 8:803815.
November
1990
MD MD
#{149} Daphna #{149} Gene
Y. Geiblum, Heard, MD
Gd-HP-DO3A of the Brain’
terms:
Gadolinium #{149} Head and neck 10.36, 10.38 #{149} Head and neck neoMR studies, 10.1214 #{149} Magnetic reso(MR), contrast enhancement, 10.1214
neoplasms, plasms.
nance Radiology
1990;
177:393-400
C
L Pacetti,
RN
enhancement
travenously
with
administered
ingado-
pentetate dimeglumine has rapidly become accepted in magnetic resonance (MR) imaging of the brain for improved lesion detection and diagnostic specificity. Limitations encountered in early clinical applications of MR imaging included suboptimal characterization of disease type and activity. Furthermore, MR imaging proved less sensitive for detecting disease in some cases, compared with enhanced computed tomography
(CT),
despite
significantly
great-
er soft-tissue contrast. The impact of contrast agents on CT provided a historical precedent for the development of paramagnetic chelates for similar
use
in MR
imaging;
thus,
many of these limitations were alleviated. The in vitro and in vivo characteristics of gadopentetate were first described in 1984 (1). The agent demonstrated strong Ti relaxation, high in vivo stability, rapid renal excretion, and high tolerance (2). These characteristics,
bond al ion
#{149}
MR Imaging
ONTRAST
made
between and
the
possible
the
by
the
chelating
agent,
of gadopentetate,
metde-
pharmaceutical
Center, University of Kentucky, Tufts University, Boston (D.Y.C., June 26; revision received July
search focused on the synthesis of additional agents that might demonstrate more favorable safety and imaging characteristics. This work led to the synthesis and initial evaluation of gadolinium 1,4,7-tris(carboxymethyl)-iO-(2’-hydroxypropyl)1,4,7,iO-tetraazacyclododecane
(HP-
DO3A) in animals, followed by clinical trials. This article elucidates the initial clinical experience with Gd-HP-DO3A
referral
in a neurologic
disease
center.
MATERIALS
AND
This study was part open-label, dose-ranging
METHODS
of a multicenter, clinical trial
that examined safety and efficacy. Adult patients (aged 18-75 years) with presumed intracranial neoplastic disease, cither primary or metastatic, were enrolled. Diagnosis was established by means of tissue
pathology
or CT.
Exclusion
criteria
included pregnancy, lactation, and a history of clinically significant hemolytic anemia. Written informed consent was obtained from each patient after a complete explanation of the nature of the study.
tight
paramagnetic
fined a new class of contrast agents for MR imaging. From this group, gadopentetate became the first agent to reach clinical trials (3,4). After approval by the U.S. Food and Drug Administration, gadopentetate gained widespread acceptance for improved diagnosis of head and spine disease with MR imaging. Subsequently, an additional agent in this class, gadolinium tetraazacyclododecanetetraacetic acid (DOTA), has been evaluated in Europe (5). After the successful development
From the Magnetic Resonance Imaging and Spectroscopy HM1O3 Medical Center, Lexington, KY 40536 (V.M.R.), and M.L.P., F.C., G.H.). Received May 24, 1990; revision requested cepted July 9. Address reprint requests to V.M.R. C RSNA, 1990 I
#{149} Martha
in Clinical
As part of a phase II clinical trial, 14 patients with presumed intracranial neoplastic disease underwent magnetic resonance (MR) imaging before and after intravenous injection of gadolinium 1,4,7-tris(carboxymethyl)-10-(2’-hydroxypropyl)1,4,7,10-tetraazacyclododecane (HPDO3A). This neutral (nonionic) gadolinium chelate has lower osmolality, when formulated at equimolar concentrations, and superior in vitro stability compared with gadopentetate dimeglumine. The safety profile of Gd-HP-DO3A permitted administration of doses up to 0.3 mmol/kg, three times the dose of gadopentetate dimeglumine approved by the U.S. Food and Drug Administration. In this limited dinical trial, Gd-HP-DO3A proved to be a safe and efficacious agent in MR imaging of the head. The only change documented in patient monitoring was that of slight skin redness at the injection site immediately after administration in two patients. No statistically significant changes due to administration of the agent were noted in laboratory evaluations. These results differ from those obtained with gadopentetate, which induces a transient rise in serum iron and bilirubin levels in up to 26% of patients. Administration of higher doses of Gd-HPDO3A, either 0.2 or 0.3 mmol/kg, appeared to provide improved enhancement. No decrease in efficacy at these high doses was noted. Index
MS
Before
the
initiation
gation, the study protocol form were reviewed and Institutional
Review
of this
investi-
and consent approved by the
Board.
Gd-HP-DO3A (SQ 32,692; Squibb Diagnostics, Princeton, NJ) (Fig 1) was provided as a clear, stable aqueous solution in 20-mL mol/L
vials. The solution contained 0.5 Gd-HP-DO3A, 0.25 mmol/L Ca[Ca(HP-DO3A)]2 (to act as a scavenging
agent for any free gadolinium ion or chelating agent), and 10 mmol/L tris(hydroxymethyl)aminomethane (a buffer to maintain pH). At 25#{176}C, the osmolality of Cd-HP-DO3A is 0.63 osm per kilogram of water, the viscosity is 1.8 cp, and the specific gravity is 1.141. The contrast material was administered intravenously as a slow infusion, with an injection rate not
re-
3; ac-
Abbreviations DOTA = tetraazacyclododecanetetraacetic acid, DTPA = diethylenetniaminepentaacetic acid, ECC electrocardiography, HP-DO3A l,4,7-tris(carboxymethyl)-l0(2’-hydroxypropyl)-l,4,7,lO-tetraazacyclododecane.
393
Table 1 Clinical Data, Dose with MR Imaging
of Gd-HP-DO3A,
Patient! Age(y)/
HPDO3A
(SQ Figure
32,692)
1. Cd-HP-DO3A gadolinium chelate.
philic
achieved
hydrois the +3 charge of the the cumulative -3 carboxyl groups. Con-
by balancing
gadolinium charge from
ductivity
ion with the three
is a neutral Neutrality
measurements
have
osmolality
than
uncharged in charge allows solutions with
that
of gadopentetate.
the
repeat
nosis
was
logic
evaluation
established
surgery
or
was
1. Diag-
means
of histo-
of specimens
biopsy
two patients,
in Table by
in
obtained
1 1 of
at
14 patients.
In
a solitary enhancing lesion at both CT and MR imaging, a
noted
finding consistent in patients in whom
was originally
with metastatic the primary
established
tissue biopsy. of sarcoidosis
disease disease
by means
In patient 14, was presumptive,
the
of
diagnosis with no
1/53/F 2/68/F 3/37/M 4/46/F 5/76/F 6/20/M 7/42/M
0.1 0.2 0.3 0.05 0.1 0.2 0.3
8/57/F 9/7l/M 10/70/F 1 1 /36/M
0.2 0.1 0.05 0.3
Astrocytoma (grade 3/3)* Astrocytoma (grade 3/3)* Poorly differentiated neuroectodermal Meningioma5 Astrocytoma (grade 3/3)5 Eosinophilic granuloma5 Acute and chronic inflammation plexus from CNS toxoplasmosis5 Metastatic melanoma5 Astrocytoma (grade 3/3)5 Astrocytoma (grade 3/3)5 Metastatic renal cell carcinoma
12/62/F
0.3
Astrocytoma(grade3/3)5
13/32/F l4/22/M
0.2 0.2
Astrocytoma Sarcoidosis
= central established
nervous system. by means of histologic
study
and
administration The 24-hour
4 and
24 hours
of the contrast examination also
physical
examination.
Laboratory values al with Gd-HP-DO3A with those obtained
from this clinical triwere compared from a phase II clini-
cal trial with gadopentetate performed by the principal investigator (V.M.R.) in 1984. The entry criteria of the 1984 study were similar to those of the present study and required that patients have a presumed intracranial tumor. All laboratory studies
were
performed
immediately
be-
history,
physical
examination,
vital
12-lead extensive
electrocardiography laboratory tests.
(ECG), Analysis
tems, Iselin, NJ). Before the contrast material was administered, T2-weighted (repetition time [msec]/echo time [msec] = 3,000/45, 90) and Ti-weighted (650/20) images were obtained. The Ti-weighted acquisitions were repeated approximately 2, 15, 30, and 45 minutes after contrast material administration. In both imaging techniques, a small bandwidth was used, with first-order gradient moment nulling
consisted
blood
hemoglobin
level,
mean corpuscular count (including
matocnit,
leukocyte and
of a complete
including
platelet
cluding nitrogen,
count;
chemistry,
levels of glucose, creatinine, calcium, phosphorus, uric
total
cholesterol,
total
total
bilirubin,
alkaline
partate
signs,
and of he-
volume, total differential),
blood
protein,
inurea acid,
lactic
Magnetom
(in
albumin,
phosphatase,
aminotransferase,
as-
dehydro-
both
axes)
unit
the
Medical
section-select
applied
nation
(Siemens
in
only.
the
and
ada
Sys-
thickness
images
obtained
sis
including
levels, and
included
gravity, protein and microscopic ment,
394
blood,
Radiology
#{149}
iron levels, iron bindferritin levels. Urinalyof pH,
levels, and examination and
prothrom-
partial thromboplasmetabolism, including
evaluation
ketones.
specimens.
specific
glucose levels of sediImmediately
and
any was
the coronal
one
was
kept One
patient. for
plane
during
spin
excitation
for all T2-weighted
section
thickness),
for Ti-weighted
or more
in
section
citations
for 3-mm
primary
plane
T2-weighted
were
studies with
images
one
cx-
of 4 mm
thickness,
and
sections.
Images
supplemented
images
The
constant
in a single
citation
and
in one
examination.
acquired
(3-8-mm
plane
orthogonal planes, according to the disease visualized. Image evaluation included both qualitative and quantitative measurements. Images were reviewed by the principal investigator and assessed relative to the
detailed
in Figure
terest measurements normal tissues) were
from the images, culated according
2. Region-of-in-
(of normal obtained
and abdirectly
with enhancement to the formula:
calpercent-
age of enhancement (SI postcontrast SI precontrast)/(SI precontrast), where = signal intensity. Of the 14 patients, five had undergone enhanced imaging with gadopentetate
within
2 weeks
-
SI
of the Gd-HP-DO3A
study, without intervening therapy that might have affected lesion enhancement. In each patient, administration of the two agents was separated by at least 48 hours. In two patients, the correlative examination with gadopentetate was performed at an outside institution from which quantitative data could not be derived. In the other three patients, both studies were acquired with the same MR imaging instrumentation and pulse sequences, which permitted quantitative comparison of the
enhancement tate
relative
achieved to that
with
achieved
gadopentewith
Gd-HP-
DO3A.
RESULTS
section
transferrin ing capacity,
of biopsy
sequences,
clotting
and iron
of choroid
2/3)
exami-
For all imaging
the field of view was 250 mm, with 256 phase-encoding steps. These images were obtained in the axial plane in 13 patients
bin, thrombin, tin times; and
tumor5
readout
T2-weighted
genase, and alanine aminotransferase; electrolyte evaluation, including sodium, potassium, and chloride levels; hepatic function, consisting of evaluation of the gamma glutamyl transpeptidase level; functions,
(grade
criteria a
fore and 2, 4, 8, 24, and 48 hours after ministration of gadopentetate. Imaging was performed at 1 T with
count,
evaluation
after
medium. included
contemplated because of the indolent nature of the disease. Patient monitoting included (within the immediate 24 hours before administration of the agent)
biopsy
blood
Examined
Diagnosis
before administration of Gd-HP-DO3A, vital signs and ECG results were again checked. Vital signs, ECG, and all laboratory tests were subsequently repeated immediately after completion of the postcontrast
studied
(mmol/kg)
Note.-CNS S Diagnosis
exceeding 10 mL/min. The specifics of age, sex, dose of GdHP-DO3A, and diagnosis are provided for 14 patients
in 14 Patients
confirmed
that the compound remains solution. The lack of overall the formulation of 0.5-mol/L
lower
Diagnosis
Dose
Sex
Gd
and
two
cx-
in the
by Tiin the other two
Clinical following
monitoring drug-related
revealed changes.
the In
one patient, the injection site appeared red immediately after contrast material injection. This resolved in approximately 45 minutes. In another patient, the injection site was observed to be slightly red initially after injection subsequent abnormalities
(the site examination). represent
changes noted were thought
was
normal These the only
from baseline to be attributable November
at two
that to 1990
Image 1. Wsa
abnonn.J
noted
enhancement
on any Image
14/l4yes 2. If the
aiaw
qusetion
to
& Rate the degree
4.
Were
all lmsge
IfUse
szwer rank
Information
ssn
the
set(*.
14/14
E
set
B
12/14
C
12/14
D
11/14
E
B
2/14
C
2/14
D
3/14
B
C
In tern
ofprovldlng
yes
be
Image
inage
D
2/14
equal
to the
nostic
for seth
which
14/14
B sets
Please
specl
C
12/14
0/14
5.
uiybe
or u*ybe. 14/14
B
oferthancement
Marlcedlyenhanced Sllghtlyenbanced Noenbancement
set?
r
1 1s ye
14/14
set
and
W
In tern 1 providing
D
dlsgnosUc
B
lnforndon?
r
14/14
quselion
tion. No changes related to drug administration were found at ECG. Nine of 14 patients had normal ECG results both before and after contrast material administration. Five patients entered the study with abnormal ECG findings. These were unchanged after drug administration. Ten of i4 patients had no laboratory abnormalities. In four patients, minor changes were noted in serum assays that were thought to be unrelated to contrast material administralion. In one patient who was
Evaluation
plae
ofdlagnostlc the leset.
complete
questlora
thfornition
with
Inages
ciequal
5 through a rankofV
dlgnoIc
receiving dexamethasone, crease in blood glucose noted. In two patients,
7. providing the tdlagshould be assigned the
vshse
iron level was found to decrease on follow-up examinations, a result attributed to surgery performed during the 24-hour period after drug administration (one of these patients was the one in whom the abnormal blood glucose value was also noted). In one
value. Image A
Diagnostic
5 4
Information
3
Rank
2
Set B
C
D
K
13/14
11/14 2/14
11/14 2/14
10/14 2/14
1/14
1/14
1/14
2/14
14/14 6.
ComparIng In a change
the motdiagnostlc
5/14
7. Ifanyofthe
image
tlon?Pleaie
dMgnesls.
image setto the paUent tbersy.
yes
8/14
In *t1ent
Indicate
leset dapoUc sM/or
no
homage set. would
patient,
result
4/5 3/5 2/5
Informedon, Information.
Dgnosls TheiaW Outcome
whetse
the r*tw
ofthls
thformes-
rial Lesion
detection
4 2 10
Nunmberofleslons Improved DbsostIc Distinction Distinction
visuallestlon cIty ofedema of lesion
B-E
6 7 11
borders
Figure 2. Criteria for image evaluation. Numbers image sets. A unenhanced images, B immediate postcontrast images, D 30-45-minute postcontrast
represent
number
postcontrast
images,
E
of answers/number
images, 45-60-minute
C
of
15-30-minute postcontrast
images.
140 1.2
120 1.0
-o 100 E
I
.#{149}0
.-:74::a#{149}#{149}
o”_
0.6
0
340
t
#{176}
(
0.2
ScREEN
IHR
2HR
4116
5116
24/40
46I
53ZN
lime
186
21/8
41
686
241
461
TIm#{149}
b.
a.
Figure 3. Safety profiles. Mean changes from baseline after intravenous injection of contrast material in serum iron (a) and total bilirubin (b) levels. Results from the phase II dm1cal investigation with Gd-HP-DO3A (#{149}) in 14 patients are compared with data from a previ0505 phase II investigation with gadopentetate (0) in 30 patients with intracranial neoplastic disease. There were no statistically significant laboratory changes demonstrated with GdHP-DO3A administration. Specifically, serum iron and total bilirubin levels remained with-
in normal limits after Gd-HP-003A levels after gadopentetate injection.
injection, contrary to the common elevation of these Concentration values are in conventional units, not SI
units.
drug administration. site appeared normal material administration 12 patients. Results at physical Volume
177
#{149} Number
The injection after contrast in the other examination 2
serum
iron
binding
ca-
administration.
In a previous phase II investigation performed by the author, 1 1 of 28 and nine of 30 patients demonstrated abnormally high serum iron and total bilirubin levels, respectively, within 48 hours after administration of 0.i mmol/kg of gadopentetate. The time scale of these changes is presented in Figure 3. This abnormal result was not observed in the patients receiving Gd-HP-DO3A. Gd-HP-DO3A, like gadopentetate, enhances Ti relaxation and thus causes an increase in signal intensity on Ti-weighted images. Contrast material enhancement, in this limited clinical trial, did improve lesion characterization
#{149}___#{149}_____#{149}____#{149}______t#______#{149} 0 0
the
pacity was decreased 24 hours after contrast material administration. In another patient, the partial thromboplastin time was decreased at 4 hours and the aspartate aminotransferase level at 24 hours after contrast mate-
outcome?
WIdth?
sets provided addltionaldtsgnostic the urage set(s) which psuvided
th1.thfcrmmthn
an invalue was the serum
were unchanged from baseline in all i4 patients. Assessment of vital signs (heart rate, blood pressure) revealed no significant changes from baseline attributable to Gd-HP-DO3A injec-
(Fig
2). For
example,
findings on the T2-weighted image in a patient with an astrocytoma (Fig 4) were abnormal. However, only the postcontrast image allowed recognition of disruption of the blood-brain barrier, which can also be used to dired stereotaxic biopsy. In eight of 14 patients,
delayed
postcontrast
images
demonstrated slightly improved lesion enhancement relative to the immediate postcontrast image (Fig 5). Qualitatively, enhancement provided improved distinction of the lesion border, as assessed with disruption of the blood-brain barrier in ii of 14 patients, with improved differentiation of the lesion from surrounding edema in seven of i4 patients (Fig 2). Radiology
#{149} 395
The
disease
entities
studied
clinical trial included tracranial lesions with characteristics similar mal brain. Such lesions
in this
examples relaxation to those can be
of inof nordiffi-
cult to identify on nonenhanced MR images. Lesion detection was improved in this manner after enhancement in four of 14 patients, with an increased number of lesions visualized
on
postcontrast
patients
(Fig
Four
images
in two
2).
patients
received
Gd-HP-
DO3A at a dose of 0.3 mmol/kg (breakdown of other doses: two patients received 0.05 mmol/kg, three received 0.1 mmol/kg, and five received 0.2 mmol/kg). Despite the potential for T2 shortening at high doses, intense enhancement was
demonstrated
in each
case.
One
lesion, a grade 3 astrocytoma, trated in Figure 6. Prominent hancement was also observed desmoplastic medulloblastoma
7) at a dose side
MR
is illusenin a (Fig
of 0.3 mmol/kg.
image
mmol/kg
with
of gadopentetate same
duced
enhancement.
studies
patient
with
Figure
4. Grade 3 astrocytoma. (a) Precontrast axial T2-weighted image. (b) Axial Tiweighted images obtained before (top left) and 2 (top right), 15 (bottom left), and 30 (bottom right) minutes after intravenous administration of 0.1 mmol/kg Gd-HP-DO3A. Enhancement is seen in the portion of the lesion (arrow) demonstrating disruption of the bloodbrain barrier. The thickness of the garlandlike rings, and thus apparent lesion enhancement, increases with time.
0.1
(Fig
7d)
demonstrated
marked
re-
In the
nine
lesion
enhance-
#{149}-#{149}------.----#{149}.--.--.----.#{149} 600
despite the varied disease (Fig 8). Results in the three patients in whom both examinations (gadopentetate and Gd-HP-DO3A) were performed at our institution confirm improved enhancement at higher doses (Table 2). In patients 1 and 3, the low dose was 0.1 mmol/kg for was
0.2
Patient sone
and
mmol/kg
2 was when
for
possible
was performed, influencing the and
dose
0.05
and
mmol/kg
for
Radiology
#{149}
POST
15M69
POST
3OMSN
POST
45606 POST
1000 900 600 -
900
700
;/
500 400
high
gadopentetate.
ter
5. Quantitation of signal-intensity change in the primary administration of 0.05 (a), 0.1 (b), 0.2 (c), and 0.3 (d) mmol/L
additional
mmol/kg In a patient
lesion in each Gd-HP-DO3A.
patient
af-
2,
mmol/kg
the
d.
c.
Figure
for
dose
was In a
seizures of unknown enhanceon the examina-
ophilic granuloma, hancement of both
patients Gd-HP-DO3A with eosin-
prominent enthe soft-tissue
mass and adjacent meningeal mation was visualized at MR
(images not ment of the less
intense,
the
meningeal
inflamimaging
shown). At CT, enhancebulk of the lesion was with
nonvisualization
portion.
of
Significant
lesion enhancement was noted in a patient with metastatic melanoma (Fig 1 1), despite the hyperintensity of this mass relative to normal brain on precontrast Ti-weighted images.
Detection contrast
receiving 0.2 were of note.
396
any
9). In a patient with a proved meningioma, adof 0.05 mmol/kg Gdresulted in statisticalenhancement, compared mmol/kg gadopentetate
in two
2604
1O1
a factor degree
limiting
patient with longstanding and a meningeal process cause (presumed sarcoid), ment was best recognized higher-dose Gd-HP-DO3A
Results
SCREEN
b.
a.
dose
In patient
was
Gd-HP-DO3A,
tion (Fig surgically ministration HP-DO3A ly poorer with 0.1 (Fig 10).
(
dexametha-
conclusions.
low
400
0
Gd-HP-DO3A.
receiving
of enhancement
0.1
high
.z
Gd-HP-DO3A-enhanced
MR imaging potentially
the
the
700
____1
!E
ment, the increase in signal intensity immediately after contrast material administration correlated with dose,
gadopentetate
D.
An out-
enhanced
in the
such
.
HP-DO3A) diagnosis helped
of enhancement images
(0.2
permitted
on post-
mmol/kg
Gd-
a more
certain
of metastatic disease exclude the possibility
and of a
nonneoplastic hemorrhage. Qualitative image evaluation (single observer, nonblinded) of the entire patient population resulted in the following additional findings (Fig 2). There was abnormal enhancement in each patient, with the postcontrast image providing significant additional diagnostic information in all 14 patients. Delayed imaging (subsequent to the initial postcontrast image) did not improve visualization of enhancement. In 13 of 14 patients, the immediate postcontrast image was thought to be most diag-
nostic. mediate thought
In one of 14 patients, postcontrast image to be diagnostically
the imwas equal to
November
1990
of normal
tigation proved
\
\
brain
tissue
(14)
and
of gadopentetate imaging of human
inves-
for imbrain in-
farction (15). Subsequent studies demonstrated conclusively that contrast enhancement improved detection of intracerebral metastatic lesions (16,17). In the absence of signif-
icant
edema,
small
metastatic
lesions
can be missed on unenhanced MR images. Likewise, lesions adjacent to cerebrospinal fluid in the subarachnoid space or ventricular system can I
be overlooked.
b.
a.
Figure
6.
Grade
3 astrocytoma.
(a) Precontrast
images DO3A. tissues
before (left) and immediately after This high dose of contrast material surrounding the necrotic center on
T2-weighted
MR image.
(right) administration provided prominent immediate postcontrast
(b) Tl-weighted
of 0.3 mmol/kg enhancement images.
MR
Gd-HPof neoplastic
In this clinical trial, there was no change in blood or urine parameters, physical examination findings, vital signs, or ECG results that could be attributed to Gd-HP-DO3A administration. The laboratory abnormalities encountered with gadopentetate may be due in part to the osmolality of the
solution Table 2 Percentage Gadopentate-
of Contrast Enhancement and Gd-HP-DO3A-enhanced
Patient No.
High
Sarcoid Meningioma Glioblastoma
dose
was twice
the other delayed cases, information postcontrast thought diagnosis,
that
of low dose
images.
In five
The
pattern
of 14
of con-
improved the ability diagnosis (diagnostic specificity) in six of 14 patients. Region-of-interest measurements demonstrated that the degree of enhancement of soft tissue with Gd-HPDO3A paralleled the dose, with statistically greater enhancement of muscle at a dose of 0.3 mmol/kg, compared with that achieved at 0.1 and 0.2 mmol/kg (P < .02 in each case). Data for the 0.05mmol/kg dose were not considered in this statistical comparison because of to make
a specific
the limited Table
group
size (two
patients).
3 presents
data derived from precontrast and immediate postcontrast images. Although enhancement of normal gray matter increased with dose, this result was not statistically signifi-
cant.
clinical evaluation has established the of disease entities for
of gadopentetate wide spectrum
177
Number
#{149}
2
18 48 118
early
1980s
by other
those
altering
the
investigators
blood-brain
barn-
disease
ial lesions, tration was
(7-10).
contrast material demonstrated
For
intraax-
administo improve
tumor delineation by highlighting the region of blood-brain barrier
dis-
trials
indicated
the
experience. series
describing
Also
po-
of investigations
the
enhancement
included was
in work
patterns
were
kiloand a
given
acid
ligand
(18).
receiving had adlocalized
nausea, paresthesias, and were the major complaints
not
in this trial. In our current such adverse reactions
reported
after
Gd-HP-
DO3A administration. However, the reporting and recording of such reactions can differ greatly from institution to institution. Only more extensive evaluation of Gd-HP-DO3A can help determine whether such minor adverse reactions will be reported with any frequency after administration of this agent. In the same trial of gadopentetate administration, a tran-
rise in serum was reported
iron and bilirubin in 26% of men
and 18% of women. A study conducted in 12 healthy male volunteers with 0.2 mmol/kg gadopentetate further quantitated this change in serum iron and total bilirubin levels, which could be observed 3-4 hours after injection and were at a maximum at 612 hours (20). This study suggested that slight hemolysis immediately afto be
for improved imaging of pitulesions (13), a finding that has confirmed with subsequent
clinical this
also
per
The potential for also exists when
chelating
ter gadopentetate
ruption. This identification of bloodbrain barrier disruption can be vital for proper diagnosis (11,12). Initial
clinical
solution). exchange is the
of patients investigation,
sient levels
er. Clinical trials with gadopentetate in imaging brain neoplasia rapidly followed. Early publications elucidated the improved detection of extraaxial tumors such as meningiomas, as well as intraaxial lesions including
metastatic
osm
for gadopentetate respectively,
In a trial of 1,068 patients gadopentetate (19), 19.9% verse reactions. Headache,
strongly suggested that agents such as gadopentetate would increase the diagnostic potential of MR imaging in neurologic diseases, particularly
been
and
(DTPA)
which contrast material administration is efficacious. Early work with a brain abscess model (6) demonstrated lesion detectability in certain instances only on postcontrast MR images. This and similar experience in
the
vs 0.63
diethylenetriaminepentaacetic
coldness, dizziness
itary
DISCUSSION
Volume
10 26 62
tential
Experimental
0.5-mol/L metal ion
High Dose5
in all cases.
resulting from the images was qualitatively to be critical in determining therapy, or outcome. The lesion was thought to be better on the postcontrast images
primary visualized in 10 of 14 patients. trast enhancement
with
Low Dose
Diagnosis
1 2 3 S
in Three Patients Examined MR Imaging
(1.94
gram of water Gd-HP-DO3A,
the
injection
cause
of these
was changes.
likely Al-
though this side effect was described as resulting in no recognizable clinical consequence, it is significant that such a change was not observed in
the
present
injection. Under Cul+ and
trials certain Zn2+
after
Gd-HP-DO3A
conditions may react
with
in vitro, the
Radiology
397
#{149}
I
.:..
a.
b.
C.
Figure 7. Desmoplastic medulloblastoma (poorly differentiated neuroectodermal tumor). (a) Precontrast T2-weighted MR image. (b) Tiweighted axial MR images obtained at 1.0 T (650/20) before and immediately after (right) administration of 0.3 mmol/kg Gd-HP-DO3A. Intense lesion enhancement is noted (arrow). Five days before, an MR image was obtained at a private outpatient clinic. In the interval between imaging procedures, an intraventricular shunt was placed. (c) Ti-weighted image at 1.5 T (583/15) after intravenous administration of 0. 1 mmol/kg possible due
gadopentetate. Visual inspection to lack of long-term data archiving
DTPA complex. In tests in which a phosphate solution equimolar in metal ion to gadolinium chelate (25 mmol/L) was monitored for release of Gd3, replacement of the gadolinium ion occurred with the DTPA com-
plex.
Such
reactivity
demonstrated Gd-DO3A and Gd-HP-DO3A sult illustrates
ion
substitution
such
has
vivo.
The
has
with
not
been
serves
the
imaging
MR
studies
(Fig
all improved
higher Thus,
than this
ing.
Despite patient
ence suggests characteristics quite similar
398
Radiology
#{149}
Lesion
enhancement
in each
of Gd-HP-DO3A
dose
(average
category)
characteris-
2). For exam-
on postcontrast
dose.
The
was calculated
as described
in Materials and from the immediate
Methods, with postcontrast
use of data image.
Figure tate. This conclusion is not surprising, given the similarities in relaxivity and tissue distribution. More definitive comments with respect to efficacy await enrollment and scientific reporting of significantly larger patient populations. The following observations can be inferred from the enhancement observed in this clinical trial relative to the administered dose of contrast material. With high doses of Gd-HPDO3A, there was no direct evidence to suggest decreased enhancement, which would be a theoretical consideration due to T2 shortening. The sta-
9.
clearly demarcated study at a higher
sarcoid
(presumptive
on the Gd-HP-DO3A dose (arrow).
the contrast enhancement of a lesion markedly improve on delayed images. This would have been anticipated if a high dose had resulted in mitial high concentrations of the agent in the lesion, causing sufficient shortening of T2 to reduce the signal intensity of the lesion on immediate
conclusion is provided by the time course of enhancement curves for the 14 patients (Fig 5). In no instance did
demonstrate
to the
Intracranial
diagnosis). Postcontrast Ti-weighted MR images obtained after intravenous injection of 0.1 mmol/kg gadopentetate (top) and 0.2 mmol/kg Gd-HP-DO3A (bottom). Although contrast enhancement along the meninges was noted on the postcontrast study enhanced with gadopentetate, it was more
that the enhancement of Gd-HP-DO3A are to those of gadopente-
this
.
I’
experi-
due
not
percentage
of enhancement
postcontrast A dose
population,
was
for
tistics gathered suggest continued increased enhancement at the highest dose evaluated, 0.3 mmol/kg. Further indirect evidence supporting this
limitations
comparison
as a func-
as a “stress
images. However, it must be recognized that this clinical trial did not enroll a population representative of that typically referred for MR imagsmall
c. Statistical
(70,,.I./kg)
Do..
tion
plc, lesion characterization, identification of the lesion border, differentiation from surrounding edema, and prospective lesion identification
were
in b than
I
ions
de-
tics of Gd-HP-DO3A in patients with intracranial neoplastic disease appear to mirror those of gadopentetate when dose is not considered. In this clinical trial, Gd-HP-DO3A significantly improved the diagnostic yield
of the
intense
I
in
test” illustrating the greater kinetic inertia of the Gd-HP-DO3A complex compared with that of gadopentetate.
Overall,
is more
F
Figure 8. all patients
of metal
more
enhancement clinic.
and such as this refor metal
demonstrated
concentration
that contrast outpatient
been
gadopentetate,
employed in the experiment scribed was substantially that encountered in vivo.
evaluation
not
with Gd-DOTA its derivatives (18). Although the potential
reveals at the
duce (Fig
routine lesion
Ti-weighted of 0.05 mmol/kg
relatively 10), even
poor enhancement in lesions known strong
MR
images. can pro-
imaging
enhancement
to
enhancement
at
or CT. Greater was
noted,
November
de-
1990
1S\
Such lesions potentially
#{248}_
might at doses
also be missed of 0.1 mmol/kg
or lower due to relatively hancement and partial-volume fects. Such findings would
much aging is
.
.4
9..
1
dependent technique
tential
for
higher
contrast
clearly clinical
defines trials.
faint
enefbe very
on the specific employed. The
improved
diagnosis
agent
impoat
concentration
the need for further A dose administration
trial with gadopentetate (21) concluded that intravenous injection of 0.2 mmol/kg could increase diagnosb.
a.
Figure 10. Meningioma. weighted MR images immediate postcontrast pentetate. Enhancement dopentetate.
(a) Precontrast (left) and immediate postcontrast (right) Tienhanced with 0.05 mmol/kg Gd-HP-DO3A. (b) Precontrast (left) and (right) Ti-weighted MR images enhanced with 0.1 mmol/kg gadowas approximately twofold higher at the 0.i-mmol/kg dose of ga-
tic yield nately,
in selected U.S. Food
tration
approval
and
of this
been granted only mmol/kg. Perhaps with Gd-HP-DO3A to imaging metastatic
brain,
and
that
of different
cases. UnfortuDrug Adminis-
agent
has
for a dose of 0.1 a clinical trial that is restricted disease in the
examines
the
administered
efficacy
doses
use of the model of the dose tration trial of gadopentetate, be definitive
in clarifying
with
adminiscould the
appro-
priate dose for examinations of the head. In any such work, large groups will be needed, with quantitation of blinded reader interpretation of the MR images and statistical evaluation by means surements ministration
of region-of-interest of enhancement of the agent.
after
The findings of improved hancement at higher doses gest
that
Gd-HP-DO3A
cacious and
diagnostic
Figure 11. (b) Precontrast tamed with tense relative This illustrates higher doses
Left
frontal melanoma metastasis. (a) Precontrast T2-weighted MR image. (top) and postcontrast (15 minutes) (bottom) Ti-weighted MR images ob0.2 mmol/kg Gd-HP-DO3A. Although the metastasis (arrow) is slightly hyperinto normal brain on the precontrast image, prominent enhancement is seen. one potential application for intravenous contrast material administration at in MR imaging.
Table 3 Percentage of Enhancement with MR Imaging
with
0.05 Tissue
Graymatter Muscle (masseter)
Dose
mmol/kg (n 2) 4 34
spite the varied diseases, at higher doses of Gd-HP-DO3A (up to 0.3 mmol/kg). Unfortunately, this result does not reflect a rigorous comparison of the efficacy of different doses
Volume
177
Number
#{149}
2
of Gd-HP-DO3A 0.1 mmol/kg
in 14 Patients
Examined
3)
0.2 mmol/kg (n 5)
0.3 mmol/kg (n 4)
4±3 30 ± 2
7±4 35 ± 2
8±5 47 ± 8
(ii
specificity
intensity
on
that high
precontrast
Ti-
Metastatic
in particular
may
effi-
of lesions
signal
images.
be
detection
central nervous system demonstrate relatively
ma b.
the
in the might weighted a.
enalso sug-
might
for improving
meaad-
melano-
demonstrate
hypermntensity on precontrast weighted images due to the
Tipresence
of either hemorrhage or melanin. In such cases, a higher dose of contrast material might improve the certainty with which the diagnosis of neoplas-
tic disease is made with MR imaging (Fig 11). Lesion enhancement was sufficient for clinical diagnostic purposes in all cases
at a dose
of 0.1
mmol/kg.
How-
ever, unlike gadopentetate, Gd-HPDO3A can be administered at higher doses without any demonstrable ill
of the
effects. In the central nervous system, doses of 0.2-0.3 mmol/kg should find application for improved detection of meningeal disease, small enhancing lesions, metastatic disease confined to bone, and soft-tissue ab-
nary
normalities.
contrast agent. These prelimidata, however, suggest that certam lesions, such as meningeal disease or small metastatic lesions, could be better visualized at higher doses.
in the
future
turboFLASH also
might
Brain
perfusion
with
techniques
(fast
low-angle
benefit
from
studies such
as
shot) high
Radiology
dose
399
#{149}
administration. Two applications in areas other than the central nervous system that might be improved with a high dose of contrast material in MR imaging are the delineation of myocardiai ischemia and detection of metastatic disease to the liver. In summary, Gd-HP-DO3A offers four potential advantages over intravenous gadopentetate for contrast enhancement on MR images. This new agent is neutral, inert to chemical substitution by copper or zinc ions, does not cause biochemical abnormaiities (in initial limited experience), and can be administered at doses up to 0.3 mmol/kg. These represent preliminary findings based on a small patient population. Expanded clinical trials with further evaluation of the role of high doses of Gd-HPDO3A are warranted. #{149} Acknowledgment: tarial
Miller
and
administrative
We appreciate assistance
in the completion
the secreof Lisa
of this study.
3.
Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadoliniumDTPA complex: a potential NMR contrast agent. AJR 1984; 142:619-624.
2.
Gries
H, Miklautz
H.
Some
4.
MRI: tients.
5.
6.
7.
8.
9.
10.
16:105-112.
400
Radiology
#{149}
11.
12.
13.
M, Mutzel
14.
W.
of GdDTPA/dimeglu-
as a contrast
agent
Kilgore
DP,
Breger RK, Daniels DL, et al normal MR appearance afinjection of Gd-DTPA. Radiology 1986; 160:757-761. Virapongse C, Mancuso A, Quisling R. Human brain infarcts: Gd-DTPA-enhanced MR imaging. Radiology 1986; 161:785-794. Russell EJ, Geremia GK, Johnson CE, et al. Multiple cerebral metastases: detectability with Gd-DTPA-enhanced MR imaging. Radiology 1987; 165:609-617. Healy ME, Hesselink JR, Press GA, Middleton MS. Increased detection of intracranial metastases with intravenous GdDTPA. Radiology 1987; 165:619-624. Tweedle MF, Hagan JJ, Dose LV, et al. Reaction of Gd complexes with endogenously available ions (abstr). In: Book of abstracts: Society of Magnetic Resonance in Medicine 1987. Berkeley, Calif: Society of Magnetic Resonance in Medicine, 1987; 477. Goldstein HA, Kashanian FK, Blumetti RF, et al Safety assessment of gadopentetate dimeglumine in U.S. clinical trials. Radiology 1990; 174:17-23. Niendorf HP, Seifert W. Serum iron and serum bilirubin after administration of
Cranial tissues: ter intravenous
mine after intravenous injection into healthy volunteers. Physiol Chem Phys Med NMR 1984; 16:167-172. Carr DH, Brown J, Bydder GM, et al.
Gadolinium-DTPA
physico-
chemical properties of the gadoliniumDTPA complex: a contrast agent for MRI. Physiol Chem Phys Med NMR 1984;
HJ, Laniado
Pharmacokinetics
References 1.
Weinmann
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