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Journal ArticleDOI

F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients.

TL;DR: The properties of 18F-PSMA-1007 are described, which show its longer half-life combined with its superior energy characteristics and non-urinary excretion overcomes some practical limitations of 68Ga-labelled PSMA-targeted tracers.
Abstract: Purpose The prostate-specific membrane antigen (PSMA) targeted positron-emitting-tomography (PET) tracer 68Ga-PSMA-11 shows great promise in the detection of prostate cancer. However, 68Ga has several shortcomings as a radiolabel including short half-life and non-ideal energies, and this has motivated consideration of 18F-labelled analogs. 18F-PSMA-1007 was selected among several 18F-PSMA-ligand candidate compounds because it demonstrated high labelling yields, outstanding tumor uptake and fast, non-urinary background clearance. Here, we describe the properties of 18F-PSMA-1007 in human volunteers and patients.

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ORIGINAL ARTICLE
F-18 labelled PSMA-1007: biodistribution, radiation dosimetry
and histopathological validation of tumor lesions in prostate
cancer patients
Frederik L. Giesel
1
& B. Hadaschik
2
& J. Cardinale
3
& J. Radtke
2
& M. Vinsensia
1
&
W. Lehnert
4
& C. Kesch
2
& Y. Tolstov
5
& S. Singer
5
& N. Grabe
6,7,8
& S. Duensing
2,5
&
M. Schäfer
3
& O. C. Neels
3
& W. Mier
1
& U. Haberkorn
1
& K. Kopka
3
& C. Kratochwil
1
Received: 2 August 2016 /Accepted: 9 November 2016 / Published online: 26 November 2016
#
The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract
Purpose The prostate-specific membrane antigen (PSMA)
targeted positron-emitting-tomography (PET) tracer
68
Ga-
PSMA-1 1 shows great promise in the detection of prostate can-
cer. However ,
68
Ga has several shortcomings as a radiolabel
including short half-life and non-ideal energies, and this has mo-
tivated consideration of
18
F-labelled analogs.
18
F-PSMA-1007
Methods Radiation dosimetry of F-PSMA-1007 was deter-
mined in three healthy volunteers who underwent whole-body
PET-scans and concomitant blood and urine sampling.
Following this, ten patients with high-risk prostate cancer
underwent
18
F-PSMA-1007 PET/CT (1 h and 3 h p.i.) and nor-
mal organ biodistribution and tumor uptakes were examined.
Eight patients underwent prostatectomy with extended pelvic
lymphadenectomy. Uptake in intra-prostatic lesions and lymph
node metastases were correlated with final histopathology, in-
cluding PSMA immunostaining.
Results W ith an effective dose of approximately 4.45.5 mSv
per 20025 0 MBq examination,
18
F-PSMA-1007 behaves sim-
ilar to other PSMA-PET agents as well as to other
18
F-labelled
PET-tracers. In comparison to other PSMA-targeting PET-
tracers,
18
F-PSMA-1007 has reduced urinary clearance enabling
excellent assessment of the prostate. Similar to
18
F-DCFPyL and
with slightly slower clearance kinetics than PSMA-11, favorable
tumor-to-backgrou nd ratios are observed 23 h after injection. In
eight patients, diagnostic findings were successfully validated by
histopathology.
18
F-PSMA-1007 PET/CT detected 18 of 19
lymph node metastases in the pelvis, including nodes as small
as1mmindiameter.
Conclusion
18
F-PSMA-1007 performs at least comparably to
68
Ga-PSMA-11, but its longer half-life combined with its su-
perior energy characteristics and non-urinary excretion over-
comes some practical limitations of
68
Ga-labelled PSMA-
targeted tracers.
Keywords
18
F-PSMA
.
F-18-PSMA
.
PSMA-1007
.
PET/
CT
.
Positron emission tomography
K. Kopka and C. Kratochwil share the senior authorship with equal
contribution
Electronic supplementary material The online version of this article
(doi:10.1007/s00259-016-3573-4) contains supplementary material,
which is available to authorized users.
* Frederik L. Giesel
frederik@egiesel.com
1
Department of Nuclear Medicine, University Hospital Heidelberg,
INF 400, 69120 Heidelberg, Germany
2
Department of Urology, University Hospital Heidelberg,
Heidelberg, Germany
3
Division of Radiopharmaceutical Chemistry, German Cancer
Research Center (dkfz), Heidelberg, Germany
4
ABX-CRO, Dresden, Germany
5
Section of Molecular Urooncology, Department of Urology, Medical
Faculty Heidelberg, University Hospital Heidelberg,
Heidelberg, Germany
6
Institute of Pathology, University Hospital Heidelberg,
Heidelberg, Germany
7
Department of Medical Oncology, National Center for Tumor
Diseases (NCT), University Hospital Heidelberg,
Heidelberg, Germany
8
Hamamatsu Tissue Imaging and Analysis Center, University of
Heidelberg, Heidelberg, Germany
Eur J Nucl Med Mol Imaging (2017) 44:678688
DOI 10.1007/s00259-016-3573-4
compounds because it demonstrated high labelling yields, out-
standing tumor uptake and fast, non-urinary background clear-
ance. Here, we describe the properties of
18
F-PSMA-1007 in
human voluntee rs and patients.
was selec ted amo ng s everal
18
F-PSMA-ligand candidate
18

Introduction
The introduction of the
68
Ga-labelled prostate-specific mem-
brane antigen (PSMA) targeted positron-emitting-tomogra-
phy/computed-tomography (PET/CT) tracer Glu-urea-
Lys(Ahx)-HBED-CC (PSMA-11) has proven highly sensitive
for the detection of disseminated prostate cancer (PCa). In two
studies (involving 319 patients and 248 patients, respectively)
sites of biochemical recurrence (BCR) were localized in 90 %
of patients including those with modest elevations in prostate
specific antigen (PSA) [
1, 2]. PSMA-11 PET/CT appears su-
perior in sensitivity to other PET agents such as Choline-PET/
CT [3, 4]. This high sensitivity could have significant clinical
implications for modifications of treatment at various stages of
prostate cancer ranging from initial diagnosis to treatment
monitoring of castration resistant metastases. For instance,
68
Ga-PSMA-11 PET/CT had a significant impact on radio-
therapy planning, resulting in meaningful changes in treat-
ment planning in over 50 % of patients [5, 6]. Although ex-
tensively studied in the recurrence and metastatic setting, there
has been relatively little attention paid to the use of PSMA-
PET in initial staging [
710]. One challenge of
68
Ga-PSMA-
11 imaging is that the agent is rapidly excreted via the urinary
tract resulting in intense accumulation in the bladder, thus,
obscuring the prostate. This has resulted in the development
of other agents with slower urinary excretion. One such can-
didate,
99m
Tc-MIP-1404, has been chosen for evaluation in
phase-2 (NCT01667536) and phase-3 (NCT02615067) stud-
ies in North America for primary staging of PC a [
11].
However,
99m
Tc is a single photon emitter and thus, has nei-
ther the sensitivity nor can gain the spatial resolution of PET-
based agents. Another challenge for
68
Ga-PSMA-11 PET/CT
is the limited availability of the
68
Ga via local radionuclide
generators. Each generator provides only one or two elutions
per day and is not only a substantial upfront investment but
requires separate syntheses at different times of the day in a
local radiopharmacy. Compared to
18
F (0.65 MeV), the posi-
tron energy of
68
Ga is higher (1.90 MeV), reducing the theo-
retical maximum spatial reso lution [12]. Finally, the short
half-life of
68
Ga relative to
18
F, (68 vs. 110 min) limits the
ability to produce agents in a central facility and ship them to
distributed imaging centers.
The first generation of
18
F-labelled PSMA-ligands, such as
18
F-DCFBC, suffered f rom high ba ckground due to slow
blood clearance [
13]. This has recently been addressed with
the introduction of the second generation compound
18
F-
DCFPyL [
14], a ligand which is characterized by fast elimi-
nation via the urinary route. However, neither
18
F-DCFBC nor
18
F-DCFPyL includes a chelator capable of binding therapeu-
tic nuclides. PSMA-617 includes a chelator for labeling with
diagnostic
68
Ga as well as β-emitting
177
Lu [15, 16]orα-
emitting
225
Ac [ 17]. Here, we present initial data on the
biodistribution, radiation dosimetry and efficacy of
18
F-
PSMA-1007, a new
18
F-labelled PSMA-ligand structurally
related to PSMA-617 (Fig. 1)[18].
Material and methods
Synthesis and quality control of
18
F-PSMA-1007
The non-radioactive reference compound
19
F-PSMA-1007
and the PSMA-1007 precursor were synthesized using solid
phase chemistry [
19].
18
F-PSMA-1007 was produced on an
automated synthesis module (Trasis AllInOne) in a two-step
synthesis using the prosthetic group 6-[
18
F]F-Py-TFP [20]for
Fig. 1 Comparison of different PSMA-ligands (
18
F-DCFBC,
18
F-DCFPyL,
68
Ga-PSMA-617,
68
Ga-PSMA-11,
18
F-PSMA-1007)
Eur J Nucl Med Mol Imaging (2017) 44:678688 679

coupling the PSMA-1007 precursor, and this was purified by
semi-preparative HPLC. The detailed description of the
radiolabelling process was published elsewhere [
21]. A direct
radiofluorination method is being developed. Radio-HPLC
was performed to determine the chemical identity and the
chemical and radiochemical purity of
18
F-PSMA-1007. The
chemical structure of
18
F-PSMA-1007 is presented in Fig. 1.
Residual solvents were determined by gas chromatography.
Radionuclide purity was controlled by half-life measurement.
Integrity of the sterile filter after filtration was assessed using
the bubble-point test. The product solution was tested for ste-
rility, bacterial endotoxins (LAL-test), pH, colorlessness and
particles.
PET/CT-imaging
All imaging was performed on a Biograph mCT Flow scanner
(Siemens, Erlangen, Germany) . PET was acquired in 3-D
mode (matrix 200 × 200) using FlowMotion (Siemens). The
emission data was corrected for randoms, scatter and decay.
Reconstruction was performed with an ordered subset expec-
tation maximization (OSEM) algorithm with two iterations/21
subsets and Gauss-filtered to a transaxial resolution of 5 mm at
full-width at half-maximum (FWHM); Attenuation correction
was performed using the unenhanced low-dose CT data. The
CT-scans were reconstructed to a slice thickness of 5 mm,
increment of 34 mm, soft tissue reconstruction kernel
(B30), using CareDose (Siemens).
Volunteers and patients
To determine initial dosimetry, three healthy volunteers
(normal PSA) underwent
18
F-PSMA-1007 PET/CT with
scansobtainedatmultipletimepointsupto6hp.i.The
healthy subjects were imaged in three blocks. Block 1
began at PET-1 (start 5 min p.i.) and extended to PET-7
(ending140minp.i.),block2beganatPET-8(start
180 min p.i.) and extended to PET-9 (240270 min p.i.)
and block 3 began at PET-10 (440480 mi n p. i.). A non-
enhanced low-dose CT (estimate 1.4 mSv, respectively)
for attenuation correction was performed at the beginning
of each block, followed by serial emission scans without
moving the volunteers in between.
All patients (n = 10) gave written informed consent to
receive
18
F-PSMA-1007 following guidelines of the
German Pharmaceuticals Act §13(2b). All patients had
newly diagnosed high-risk prostate cancer (median PSA-
level 14 ng/ml; range 5.887.3 ng/ml) with a median age
of 65 years (range 5577) and underwent
18
F-PSMA -
1007PET/CTimaging1and3hpostinjection.Theat-
tenuation correction CTs were also performed 1 and 3 h
post tracer injection. All men were treated clinically with
a multimodal approach and eight men underwent radical
prostatectomy with extended pel vic lymphadenectomy.
Two patients who were found to have metastatic disease
did not undergo prostatectomy. The data were analyzed
retrospectively w ith approval of the local ethics commit-
tee. Detailed patient characteristics and final histopatho-
logical evaluation are provided in Table
1.
Radiation dosimetry
The dosimetry analysis was performed using the QDOSE do-
simetry software suite (ABX-CRO, Germany). Automatic rig-
id co-registration and, if necessary, additional manual correc-
tion, were performed for all PET and CT data-sets. Kidneys,
Table 1 Patient characteristics
Patient
No.
Age
(y)
18
F-PSMA-1007
(MBq)
Gleason
score
Initial PSA
(ng/ml)
TNM-classification PET/CT LN-
metastases
PCa SUV
max
(1 h p.i.)
PCa SUV
max
(3 h p.i.)
1 77 356 MBq 9 40.0 pT3b, pN1 (4/41), L1, V0,
Pn1
5 54.94 76.24
2 72 347 MBq 9 15.3 cT3b, cN1, cM1 7 47.71 74.11
3 55 315 MBq 9 14.0 pT3b, pN1 (5/40), L1, V0,
Pn1
4 10.92 14.84
4 65 301 MBq 9 13.9 pT3b, pN1 (4/43), L0, V0,
Pn1
4 24.30 30.18
5 64 331 MBq 9 10.0 pT3b, pN1 (3/48 LK), L1,
V0, Pn1
3 18.85 27.49
6 64 240 MBq 7 12.2 pT3a, pN1 (3/57), L1, V1,
Pn1
3 12.98 22.57
7 62 139 MBq 8 8.5 pT3a, pN0 (0/21), L0, V0,
Pn1
0 15.53 27.45
8 69 319 MBq 8 5.8 pT3a, pN0 (0/32), L0, V0,
Pn0
0 36.69 58.56
9 61 289 MBq 7 87.3 cT3, cN1, cM1 3 35.40 58.22
10 73 111 MBq 7 31.0 pT3a, pN0 (0/27), L0, V0,
Pn1
0 16.31 19.61
680 Eur J Nucl Med Mol Imaging (2017) 44:678688

liver, spleen, whole heart, upper and lower large intestine,
parotid glands, submandibula r glands and urinary bladder
were segmented into volumes of interest (VOIs) using a per-
centage of maximum threshold between 20 and 30 % and the
corresponding CT as guidance. Afterwards the time activity
curves (TACs) were calculated for all organs. The TACs for
red marrow were derived from venous blood samples, and the
red marrow dose was calculated as described previously [
22,
23]. The urinary bladder TAC was a combination of estimated
activity in the urinary bladder VOI in PET and measured ac-
tivity of voided urine. Curve fitting was applied to all TACs
according to the software. Kidneys, salivary glands, upper and
lower large intestine and heart were fitted with a bi-
exponential function. For liver, spleen and urinary bladder
content, a mono-exponential fit to the last three time points
was performed.
The cumulative activity à between time 0 and the first
measured time point was calculated assuming a linear increase
from 0 to the first measured activity. The à between the first
measured time point and the last measured time point was
integrated numerically using trapezoidal approximation. The
à from the last measured time point to infinity was integrated
using the fitted function. The total body à was calculated
based on the injected activity assuming only physical decay
neglecting the voided urine. The à of the remainder of the
body was then automatically calculated by subtracting all
source organs from the total body activity. All source organ
residence times were calculate d by divid ing the à by the
injected activity.
Absorbed and effective dose calculations were performed
using the ICRP endorsed IDAC 1.0 package [
24]whichis
integrated into QDOSE. In addition, residence times of all
source organs and the remainder of the body were exported
as an OLINDA case file for dose calculation in OLINDA 1.1
[
25]. The absorbed doses to the salivary glands and prostate
were determined using the spherical model [
26]. The organ
masses for the salivary glands were taken from ICRP publi-
cation 89 [
27] with 25 g estimated weight for the parotid and
12.5 g for the submandibular gland.
Biodistribution
During the dosimetry evaluation, urine was collected at the
following intervals: 02h,24h,and46 h. Venous blood
samples were obtained at 2, 5, 10, 15, 30, 45, 60, 80, 120, 180,
240, and 360 min post injection. After the whole blood was
sampled, the remaining volume was centrifuged and serum
was extracted. Serum activities were measured in a well coun-
ter and corrected for decay. Activity concentrations in blood
vs. serum were compared using the individually determined
(clinical routine lab) hematocrit. Total blood volume was es-
timated from size, weight, and hematocrit.
The tracer biodistribution in patients was quantified by
SUV
mean
and SUV
max
at 1 h and 3 h post injection. For cal-
culation of the standardized uptake value (SUV), circular re-
gions of interest were drawn around the area with focally
increased uptake in transaxial slices and automatically adapted
to a three-dimensional VOI with e.soft software (Siemens) at a
40 % isocontour . Primary tumors and lymph node metastases
were evaluated separately. The normal bladder (after voiding),
background (pelvic fat), blood, brain, salivary and lacrimal
glands, lung, liver, spleen, pancreas, small intestine, and kid-
neys were evaluated with a 23cmsphereplacedinsidethe
organ parenchyma.
Histopathological evaluation
Analyses of prostatectomy specimens were performed un-
der the supervision of d edicated uropathol ogists, using
International Society of Urological Pathology nomencla-
ture [
28]. Pathologists were blinded to the PET/CT re-
sults. In addition, representative sections were stained
for immunohistochemistry. To accomplish this, sections
were deparaffinized in xylene and rehydrated in a graded
ethanol series. Antigen retrieval was performed with a
steam cooker using retrieval buffer (Target Retrieval
Solution, Dako). A mouse monoclonal antibody against
PSMA (clone 3E6, Dako) was used at a 1:100 dilution
and incubated overnight at 4 °C. Immuno detection was
performed using the Histostain-Plus detection kit
(Invitrogen) accordin g to manufacturers recommenda-
tions. Stained sections were scanned using a
Nanozoom er 2.0-HT Scansyst em (Hamam at su Photonic s)
to generate digital whole slide images.
Results
Adverse events
All patients and healthy volunteers tolerated the examination
well. No drug-related pharmacological effects or physiologic
responses occurred. All observed parameters (e.g., blood pres-
sure, heart rate, body temperature) remained normal and un-
changed during and after the examination. No patient reported
subjective symptoms.
Radiation dosimetry
Maximum intensity projection (MIP) images of the serially
performed whole-body PET-scans of one healthy volunteer
are depicted in Fig.
2a and demonstrate distinct organ uptake
for lacrimal glands, salivary glands, liver, spleen, small intes-
tine and kidneys. The fitting of these organ VOIs and blood/
plasma samples are presented in Fig.
2b and c.Accordingto
Eur J Nucl Med Mol Imaging (2017) 44:678688 681

the average of three healthy volunteers, the radiation dosime-
try revealed an effective dose of 0.022 mSv/MBq, i.e., 4.4
5.5 mSv for an injected dose of 200250 MBq. Mean values
of dedicated organ doses are presented in column 1 of Table
2.
The individual calculations of each subjects organ absorbed
doses, effective half-lives and residence times are provided as
supplemental data. As a reference, Table 2 also presents the
corresponding organ absorbed doses for the other
18
F-labelled
PSMA-ligands DCFPyL (column 5), DCFBC (column 6), the
68
Ga-labelled compounds PSMA-11 (columns 2,3) and
PSMA-617 (column 4). In addition, the mean absorbed doses
for the submandibular glands were 0.075 mGy/MBq, parotid
glands 0.09 mGy/MBq and prostate gland 0.045 mGy/MBq.
The intra-individual dose ratios are very similar for all PSMA-
targeted agents; in comparison to
18
F-DCFPyl, the effective
dose of
18
F-PSMA-1007 is slightly higher, while lower clear-
ance through the urinary route reduces dose to the bladder
wall.
Normal-organ Biodistribution and tumor uptake
In healthy subjects, the blood pool contained mean 76,
22, 12 and 8 % of the injected dose at 2 min, 1 h, 2 h
and 3 h p.i., respectively. Approximately 95 % of the
blood pool activity w as found in the serum; the blood
and serum curves converge with more complete clear-
ance. It is possible that there was a minimal and revers-
ible diffusion of the agent i nto blood cells; however,
irreversible binding to blood cells can be safely exclud-
ed. Clearance via the urinary tract was minimal and in
average only 1.2, 0.7 and 0.5 % of the injected activity
were eliminated in the urine during the 02, 24and4
6 h intervals, r espectively. In one healthy volunteer, sym-
metric tracer uptake (SUV
mean
2, perfus ion d ependen t
background <1) in the axillary lymph nodes was ob-
served. Taking into account his normal PSA-value and
an increased CRP and BSR (blood sedimentation rate),
this finding implies the potential of false-positive uptake
in inflammatory activated lymph nodes. The time-
activity-curve of the normal prostate tissue in the healthy
volunteers is provided in Fig.
3 and may serve as a
reference for future dynamic studies of primary prostate
cancer.
The uptakes in the primary tumor, lymph node metas-
tases and normal-organ biodistribution at 1 h and 3 h p.i.
in the ten patients with prostate cancer are presented in
Fig.
4. The mea n tum or-u pta ke w as 5- a n d 10- fol d hi ghe r
at1hand3hp.i.,comparedtointra-vesicalurine.The
Fig. 2 Maximum Intensity Projections (MIP) of ten serially performed
(5 min8hp.i.)
18
F-PSMA-1007 PET-scans in one healthy volunteer (a);
biodistribution correct ed for decay. Time-activity-curves of normal
organs derived from PET volume-of-interest (b). Bloo d and serum
time-activity-curves derived from serial blood-sampling, expressed as
percent injected dose in a total blood volume of 6.1 l (c)
682 Eur J Nucl Med Mol Imaging (2017) 44:678688

Citations
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Journal ArticleDOI
TL;DR: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.
Abstract: The aim of this study was to develop a treatment protocol for 225Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)-positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time-activity curves derived from serially obtained 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.

333 citations


Cites methods from "F-18 labelled PSMA-1007: biodistrib..."

  • ...PSMA Immunhistochemistry PSMA immunohistochemistry was performed with a series of tissue bank samples from salivary glands, kidneys, and prostate cancer using a standard protocol analogous to the detailed description in a previous publication (15)....

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Journal ArticleDOI
TL;DR: A molecular imaging TNM system (miTNM, version 1.0) is proposed as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI, designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions.
Abstract: Prostate-specific membrane antigen (PSMA)-ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data.

326 citations


Cites background from "F-18 labelled PSMA-1007: biodistrib..."

  • ..., 18F-PSMA1007), the spleen is recommended instead of the liver for comparison against blood-pool and salivary gland uptake (36)....

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Journal ArticleDOI
TL;DR: The high sensitivity provided by PSMA PET, with frequent identification of small-volume disease, is redefining patterns of disease spread compared with those seen at conventional imaging, demonstrating superior sensitivity and specificity compared to conventional imaging.
Abstract: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in prostate cancer. Radiolabeled small molecules that bind with high affinity to its active extracellular center have emerged as a potential new diagnostic standard of reference for prostate cancer, resulting in images with extraordinary tumor-to-background contrast. Currently, gallium 68 (68Ga)-PSMA-11 (or HBED-PSMA) is the most widely used radiotracer for PSMA positron emission tomography (PET)/computed tomography (CT) or PSMA PET/magnetic resonance (MR) imaging. Evolving evidence demonstrates superior sensitivity and specificity of PSMA PET compared to conventional imaging, with frequent identification of subcentimeter prostate cancer lesions. PSMA PET is effective for imaging disease in the prostate, lymph nodes, soft tissue, and bone in a "one-stop-shop" examination. There is emerging evidence for its clinical value in staging of high-risk primary prostate cancer and localization of disease in biochemical recurrence. The high sensitivity provided by PSMA PET, with frequent identification of small-volume disease, is redefining patterns of disease spread compared with those seen at conventional imaging. In metastatic castration-resistant prostate cancer, PSMA PET is frequently used for theranostic selection (eg, lutetium 177-PSMA radionuclide therapy), but its potential use for therapy monitoring is still under debate. However, evidence on its proper use to improve patient-related outcomes, particularly in the setting of early biochemical recurrence and targeted treatment of oligometastatic disease, is still missing. Despite the term prostate specific, PSMA functions as a folate hydrolase and is expressed in a range of normal tissues and in other benign and malignant processes. Knowledge of its physiologic distribution and other causes of uptake is essential to minimize false-positive imaging findings. ©RSNA, 2018.

238 citations

Journal ArticleDOI
TL;DR: 18F-PSMA-1007 PET/CT offers high detection rates for BCR after radical prostatectomy that are comparable to or better than those published for 68Ga-labeled PSMA ligands.
Abstract: Prostate-specific membrane antigen (PSMA)–targeted PET imaging recently emerged as a new method for the staging and restaging of prostate cancer. Most published studies investigated the diagnostic potential of 68Ga-labeled PSMA agents that are excreted renally. 18F-PSMA-1007 is a novel PSMA ligand that has excellent preclinical characteristics and that is only minimally excreted by the urinary tract, a potential advantage for pelvic imaging. The aim of this study was to investigate the diagnostic efficacy of 18F-PSMA-1007 for biochemical recurrence (BCR) after radical prostatectomy. Methods: From 3 academic centers, 251 patients with BCR after radical prostatectomy were evaluated in a retrospective analysis. Patients who had received second-line androgen deprivation therapy (ADT) or chemotherapy were excluded, but prior first-line ADT exposure was allowed. The median prostate-specific antigen (PSA) level was 1.2 ng/mL (range, 0.2–228 ng/mL). All patients underwent PSMA PET/CT at 92 ± 26 min after injection of 301 ± 46 MBq of 18F-PSMA-1007. The rate of detection of presumed recurrence sites was correlated with the PSA level and original primary Gleason score. A comparison to a subset of patients treated previously with ADT was undertaken. Results: Of the 251 patients, 204 (81.3%) had evidence of recurrence on 18F-PSMA-1007 PET/CT. The detection rates were 94.0% (79/84), 90.9% (50/55), 74.5% (35/47), and 61.5% (40/65) for PSA levels of greater than or equal to 2, 1 to less than 2, 0.5 to less than 1, and 0.2 to less than 0.5 ng/mL, respectively. 18F-PSMA-1007 PET/CT revealed local recurrence in 24.7% of patients (n = 62). Lymph node metastases were present in the pelvis in 40.6% of patients (n = 102), in the retroperitoneum in 19.5% of patients (n = 49), and in supradiaphragmatic locations in 12.0% of patients (n = 30). Bone and visceral metastases were detected in 40.2% of patients (n = 101) and in 3.6% of patients (n = 9), respectively. In tumors with higher Gleason scores (≤7 vs. ≥8), detection efficacy trended higher (76.3% vs. 86.7%) but was not statistically significant (P = 0.32). However, detection efficacy was higher in patients who had received ADT (91.7% vs. 78.0%) within 6 mo before imaging (P = 0.0179). Conclusion:18F-PSMA-1007 PET/CT offers high detection rates for BCR after radical prostatectomy that are comparable to or better than those published for 68Ga-labeled PSMA ligands.

213 citations


Cites background from "F-18 labelled PSMA-1007: biodistrib..."

  • ...One new candidate is 18F-PSMA-1007, which exhibits rapid blood clearance but only minimal amounts of activity excreted via the urinary tract (11)....

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  • ...Thus, there has been interest in the development of 18F-labeled PSMA compounds (10,11)....

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Journal ArticleDOI
TL;DR: The published literature regarding the potential pearls and technical and interpretive pitfalls of PSMA-targeted PET imaging are summarized and knowledge of these limitations can increase the confidence of interpreting physicians and thus improve patient care.
Abstract: The rapidly expanding clinical adaptation of prostate-specific membrane antigen (PSMA)-targeted PET imaging in the evaluation of patients with prostate cancer has placed an increasing onus on understanding both the potential pearls of interpretation as well as limitations of this new technique. As with any new molecular imaging modality, accurate characterization of abnormalities on PSMA-targeted PET imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants of radiotracer uptake, and potential sources of false-positive and false-negative imaging findings. In recent years, a growing number of reports have come to light describing incidental non-prostatic benign or malignant pathologies with high uptake on PSMA-targeted PET imaging. In this review, we have summarized the published literature regarding the potential pearls and technical and interpretive pitfalls of this imaging modality. Knowledge of these limitations can increase the confidence of interpreting physicians and thus improve patient care. As PSMA-targeted PET is expected to be evaluated in larger prospective trials, the dissemination of potential diagnostic pitfalls and the biologic underpinning of those findings will be of increased importance.

200 citations


Additional excerpts

  • ...This compound also takes advantage of the intrinsic positive characteristics (18)F and has been found to identify very small sites of PCa, while also having relatively low urinary excretion, which may aid visualization of intraprostatic or locally recurrent disease [61, 62]....

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References
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Book
01 Jan 2002
TL;DR: This report presents detailed information on age- and gender-related differences in the anatomical and physiological characteristics of reference individuals to provide needed input to prospective dosimetry calculations for radiation protection purposes for both workers and members of the general public.
Abstract: Preface Abstract 1. Basis of ICRP Reference Values 2. Summary of Reference Values 3. Embryo and Fetus 4. Total Body 5. Respiratory System 6. Alimentary System 7. Circulatory and Lymphatic Systems 8. Urogenital System 9. Skeletal System 10. Integumentary System 11. Additional Organs and Tissues 12. Pregnant Woman: Anatomical and Physiological Changes 13. Elemental Composition of the Body Reference

1,741 citations

Journal Article
TL;DR: The extensive testing of the OLINDA/EXM code, based on comparison with literature-established dose calculations and with the widely tested and accepted MIRDOSE3.1 code, should give users confidence in its output, and should be easy for MIRDose users to adopt and for new users to understand.
Abstract: The OLINDA/EXM version 1.0 personal computer code was created as a replacement for the widely used MIRDOSE3.1 code. This paper documents the basic function of the code and how it is similar to and different from the MIRDOSE software. Methods: After creation of the code and α- and β-testing phases, a premarket notification submission (510(k)) was filed with the Food and Drug Administration to permit marketing of the code. Permission was granted in June 2004, and the code is currently being distributed through Vanderbilt University. Not all of the technical details of the dosimetry methods have been shown here, as they have been previously documented. Results: Agreement of doses between the MIRDOSE3.1 and OLINDA/EXM codes was good, within 1%–2% in most cases. Conclusion: The extensive testing of the OLINDA/EXM code, based on comparison with literature-established dose calculations and with the widely tested and accepted MIRDOSE3.1 code, should give users confidence in its output. The OLINDA/EXM code should be easy for MIRDOSE users to adopt and for new users to understand. It will be useful in standardizing and automating internal dose calculations, assessing doses in clinical trials with radiopharmaceuticals, making theoretic calculations for existing pharmaceuticals, teaching, and other purposes.

1,265 citations

Journal ArticleDOI
TL;DR: The reference values provided needed input to prospective dosimetry calculations for radiation protection purposes for both workers and members of the general public as mentioned in this paper, and the reference values were used for both male and female subjects of six different ages: newborn, 1 year, 5 years, 10 years, 15 years, and adult.
Abstract: This report presents detailed information on age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. These reference values provide needed input to prospective dosimetry calculations for radiation protection purposes for both workers and members of the general public. The purpose of this report is to consolidate and unify in one publication, important new information on reference anatomical and physiological values that has become available since Publication 23 was published by the ICRP in 1975. There are two aspects of this work. The first is to revise and extend the information in Publication 23 as appropriate. The second is to provide additional information on individual variation among grossly normal individuals resulting from differences in age, gender, race, or other factors. This publication collects, unifies, and expands the updated ICRP reference values for the purpose of providing a comprehensive and consistent set of age- and gender-specific reference values for anatomical and physiological features of the human body pertinent to radiation dosimetry. The reference values given in this report are based on: (a) anatomical and physiological information not published before by the ICRP; (b) recent ICRP publications containing reference value information; and (c) information in Publication 23 that is still considered valid and appropriate for radiation protection purposes. Moving from the past emphasis on ‘Reference Man’, the new report presents a series of reference values for both male and female subjects of six different ages: newborn, 1 year, 5 years, 10 years, 15 years, and adult. In selecting reference values, the Commission has used data on Western Europeans and North Americans because these populations have been well studied with respect to antomy, body composition, and physiology. When appropriate, comparisons are made between the chosen reference values and data from several Asian populations. The first section of the report provides summary tables of all the anatomical and physiological parameters given as reference values in this publication. These results give a comprehensive view of reference values for an individual as influenced by age and gender. The second section describes characteristics of dosimetric importance for the embryo and fetus. Information is provided on the development of the total body and the timing of appearance and development of the various organ systems. Reference values are provided on the mass of the total body and selected organs and tissues, as well as a number of physiological parameters. The third section deals with reference values of important anatomical and physiological characteristics of reference individuals from birth to adulthood. This section begins with details on the growth and composition of the total body in males and females. It then describes and quantifies anatomical and physiological characteristics of various organ systems and changes in these characteristics during growth, maturity, and pregnancy. Reference values are specified for characteristics of dosimetric importance. The final section gives a brief summary of the elemental composition of individuals. Focusing on the elements of dosimetric importance, information is presented on the body content of 13 elements: calcium, carbon, chloride, hydrogen, iodine, iron, magnesium, nitrogen, oxygen, potassium, sodium, sulphur, and phosphorus.

1,169 citations

Journal ArticleDOI
TL;DR: In this paper, the authors investigated the detection rate of 68Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy and found that the detection rates were correlated with PSA level and PSA kinetics.
Abstract: The expression of prostate-specific membrane antigen (PSMA) is increased in prostate cancer. Recently, 68Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)]) was developed as a PSMA ligand. The aim of this study was to investigate the detection rate of 68Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy. Methods: Two hundred forty-eight of 393 patients were evaluable for a retrospective analysis. Median prostate-specific antigen (PSA) level was 1.99 ng/mL (range, 0.2–59.4 ng/mL). All patients underwent contrast-enhanced PET/CT after injection of 155 ± 27 MBq of 68Ga-PSMA ligand. The detection rates were correlated with PSA level and PSA kinetics. The influence of antihormonal treatment, primary Gleason score, and contribution of PET and morphologic imaging to the final diagnosis were assessed. Results: Two hundred twenty-two (89.5%) patients showed pathologic findings in 68Ga-PSMA ligand PET/CT. The detection rates were 96.8%, 93.0%, 72.7%, and 57.9% for PSA levels of ≥2, 1 to 6, 4–6, and

868 citations


"F-18 labelled PSMA-1007: biodistrib..." refers background in this paper

  • ...All patients had newly diagnosed high-risk prostate cancer (median PSAlevel 14 ng/ml; range 5.8–87.3 ng/ml) with a median age of 65 years (range 55–77) and underwent 18F-PSMA1007 PET/CT imaging 1 and 3 h post injection....

    [...]

  • ...Taking into account his normal PSA-value and an increased CRP and BSR (blood sedimentation rate), this finding implies the potential of false-positive uptake in inflammatory activated lymph nodes....

    [...]

  • ...5 a: Patient 2, a 72-year-old patient (PSA 15 ng/ml) diagnosed with Gleason 9 (5 + 4) prostate cancer....

    [...]

  • ...To determine initial dosimetry, three healthy volunteers (normal PSA) underwent 18F-PSMA-1007 PET/CT with scans obtained at multiple time points up to 6 h p.i....

    [...]

  • ...sites of biochemical recurrence (BCR) were localized in 90 % of patients including those with modest elevations in prostate specific antigen (PSA) [1, 2]....

    [...]

Journal ArticleDOI
TL;DR: 68Ga-PSMA-ligand PET/CT can detect recurrent PCa in a high number of patients and can help delay systemic therapy of PCa.
Abstract: Purpose Since the introduction of positron emission tomography (PET) imaging with 68Ga-PSMA-HBED-CC (=68Ga-DKFZ-PSMA-11), this method has been regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). However, published data exist for small patient cohorts only. The aim of this evaluation was to analyse the diagnostic value of 68Ga-PSMA-ligand PET/CT in a large cohort and the influence of several possibly interacting variables.

848 citations


"F-18 labelled PSMA-1007: biodistrib..." refers background in this paper

  • ...All patients had newly diagnosed high-risk prostate cancer (median PSAlevel 14 ng/ml; range 5.8–87.3 ng/ml) with a median age of 65 years (range 55–77) and underwent 18F-PSMA1007 PET/CT imaging 1 and 3 h post injection....

    [...]

  • ...Taking into account his normal PSA-value and an increased CRP and BSR (blood sedimentation rate), this finding implies the potential of false-positive uptake in inflammatory activated lymph nodes....

    [...]

  • ...5 a: Patient 2, a 72-year-old patient (PSA 15 ng/ml) diagnosed with Gleason 9 (5 + 4) prostate cancer....

    [...]

  • ...To determine initial dosimetry, three healthy volunteers (normal PSA) underwent 18F-PSMA-1007 PET/CT with scans obtained at multiple time points up to 6 h p.i....

    [...]

  • ...sites of biochemical recurrence (BCR) were localized in 90 % of patients including those with modest elevations in prostate specific antigen (PSA) [1, 2]....

    [...]

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