University of Groningen Exploring new molecular imaging concepts of prostate cancer Wondergem, Maurits

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University of Groningen

Exploring new molecular imaging concepts of prostate cancer

Wondergem, Maurits

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Focal

18

_{F-Fluorocholine uptake}

on early dynamic PET/CT imaging

of the prostatic region;

What does it mean?

Maurits Wondergema,b

Friso M. van der Zanta

Remco J.J. Knola

Jan Pruimc,d

Igle J. de Jongb

a_{Department of Nuclear Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The}

Netherlands

b_{Department of Urology, University Medical Center Groningen, University of Groningen,}

Groningen, The Netherlands

c_{Department of Nuclear Medicine and Molecular Imaging, University Medical Center}

Groningen, University of Groningen, Groningen, The Netherlands

d _{Department of Nuclear Medicine, Tygerberg Hospital, Stellenbosch University,}

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ABSTRACT

Introduction

Detection rates of 18_{F-fluorocholine PET/CT for local recurrence of prostate carcinoma}

in case of biochemical recurrence after radical prostatectomy generally range between 6 and 15%. However detection rates of local relapse of up to 76% have been reported. These favourable detection rates are attributed to increased activity in the prostatic fossa seen on early images only. Aim of this retrospective study was to evaluate the occurrence rate of focally increased 18_{F-fluorocholine uptake in and near the prostatic}

fossa in two patient populations on both early and late images and to determine whether increased tracer uptake in this area on early images only represents prostate cancer lesions.

Material and methods

Patients that received 18_{F-fluorocholine PET/CT for biochemical recurrence after radical}

prostatectomy (cohort 1) or for primary staging (cohort 2) were retrospectively studied.

Baseline patient characteristics were collected and 18_{F-fluorocholine PET/CT images}

were re-analysed for presence of increased uptake in the prostate, in the direct vicinity of the prostate/prostatic fossa, in lymph nodes and in bone lesions. Early dynamic

data was used to construct 18_{F-fluorocholine time activity curves for lesions with}

increased uptake.

Results

On early images only, focally 18_{F-fluorocholine uptake was seen in 28 patients (70.0%)}

and 11 patients (45.0%) for cohort 1 and 2 respectively. All those foci were localised in the penile bulb. In both cohorts the time-activity pattern of these lesions showed rapid increase of activity followed by decreasing activity after the second minute, while the activity pattern in histologically proven prostate tumours in cohort 2 and in suspected lymph nodes and bone lesions from both cohorts demonstrated rapid uptake in the first 2 minutes after which the activity remained stable. In cohort 1 persistent activity suspicious for local recurrence was found in up to 10% of the patients.

Conclusion

Focally increased 18_{F-flurocholine activity in the prostatic region on early images only is}

found in a high number of patients referred for evaluation after biochemical relapse and those referred for primary staging. According to our data, this represents physiological uptake in the penile bulb. Therefore early dynamic imaging of the prostatic bed region with 18_{F-Fluorocholine PET/CT does not favour the detection rate of local prostate cancer}

recurrence in comparison to late images in patients with biochemical recurrence after prostatectomy.

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INTRODUCTION

Radical prostatectomy is a widely used treatment procedure with curative intent for patients with localised prostate cancer. However, recurrences after radical prostatectomy are seen in 27 to 53% (1-3). Recurrences are generally detected by rising serum PSA-levels, which obviously does not reveal the localisation of disease. Positron

Emission Tomography/Computed Tomography (PET/CT) with 18_{F-fluorocholine has}

a high specificity and moderate sensitivity for detection and localisation of prostate cancer in patients with a biochemical relapse (4-6). After radical prostatectomy disease detection and localisation is clinically relevant for patients with low PSA values, since salvage therapeutic options with curative intent are found to be most effective in PSA ranges between 0,2 – 0,5 ng/ml (7). Generally literature reports a poor to moderate sensitivity and detection rate of 18_{F-fluorocholine PET/CT for detection of relapse after}

prostatectomy in patients with such relatively low serum PSA levels. For PSA levels ≤1.0 ng/ml a detection rate of 20% is reported and detection rates for PSA levels ≤2.0 ng/ml vary between 20 and 55% (8, 9). The reported variability in detection rates of

18_{F-fluorocholine may be due to a lack of standardisation of acquisition protocols (10).}

Timing of image acquisition may significantly influence the detection rate and significantly increased detection of local prostate cancer recurrence is seen with an acquisition protocol including an early dynamic study of the pelvis starting immediately after intravenous injection of 18_{F-fluorocholine (collected in list mode, 60 s per frame}

during 8 min) followed by late image acquisition of the pelvis 30 min following tracer administration. In patients with PSA ≤1.0 ng/ml a detection rate of 76% was found (111/146

patients) in a study by Simone et al. Of those 111 scans 99 showed 18_{F-fluorocholine}

uptake in the surgical bed only, which was interpreted as local recurrence. In the majority of those 99 patients (84%), 18_{F-fluorocholine uptake was seen on early dynamic}

images only (11).

In our daily clinical practice we did not notice such high detection rates of local recurrence with 18_{F-flurocholine PET/CT in patients with biochemical recurrence after}

radical prostatectomy, despite standard image acquisition of the pelvis immediately after injection of 18_{F-fluorocholine (collected in list mode, 60 s per frame during 10 min),}

completed by late static total body images 45-60 minutes after injection. Therefore

18_{F-fluorocholine PET/CTs of all patients with a biochemical relapse after radical}

prostatectomy were reviewed. Additionally a second cohort, which included patients

that received 18_{F-fluorocholine PET/CT for primary staging, was studied in order to}

evaluate whether focally increased activity on early images only is also present in a totally different patient population. Aim of this study was to evaluate the occurrence rate of focally increased 18_{F-fluorocholine uptake in and near the prostatic fossa on}

both early and late images and to determine whether increased tracer uptake on early images only represents prostate cancer lesions.

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MATERIAL AND METHODS

Patients

Since May 2013 data of all 18_{F-fluorocholine PET/CTs conducted in patients with}

histologically proven prostate cancer in our institution have been prospectively entered in a local database that is used for scientific, educational and quality purposes, unless no written consent was obtained from the patient for the use of their anonymous data. From the database all patients referred for 18_{F-fluorocholine PET/CT because of}

biochemical relapse after prostatectomy (cohort 1) or for diagnostic staging of primary prostate cancer without any treatment (cohort 2) till May 2016 were selected and included in the present study. Follow up scans of already included patients were excluded as well as patients with missing data. All scans were performed for clinical diagnostic work-up of patients. The study passed the local scientific board and approval of the local ethical committee for the present retrospective study was waived since the study does not fall within the scope of the Medical Research Involving Human Subjects Act (section 16.2 WMO, 26th_{February 1998).}

Imaging

18_{F-fluorocholine PET/CT scans were acquired at an early and a late time point. Patients}

were instructed to drink one litre of water within one hour before 18_{F-fluorocholine}

injection. In attempt to avoid high bladder activity concentrations in the bladder at the early-acquired images, patients were encouraged not to void until completion of the early scan sequence.

18_{F-fluorocholine was produced and synthesised by an on-site cyclotron facility}

according to the Bis(tosyloxy)methane method (Trasis Pharmacy Instruments, Ans,

Belgium). Immediately after injection of 179 MBq 18_{F-fluorocholine (mean; range}

126-221 MBq) the early scan of the pelvic area was performed in list mode (event-by-event) during 10 minutes on a Siemens Biograph-16 TruePoint PET/CT (Siemens Healthcare, Knoxville, U.S.). The late scan was acquired at 45-60 minutes after injection, with 4 min/ bed position, from the proximal femurs to the base of the skull.

From the list mode data, 10 x 1 min frames were reconstructed by means of a TrueX algorithm using 4 iterations and 8 subsets and a 5 mm Gaussian filter. The data from the late phase were reconstructed by means of an iterative 3D algorithm using 4 iterations and 8 subsets and a 5mm Gaussian filter. Reconstructed images of both time points had an image matrix size of 168 x 168, a voxel size of 4.07 x 4.07 mm and a slice thickness of 3 mm for the early dynamic images and 5mm for the late static images.

For attenuation correction of the early scan, a low-dose CT was acquired using a tube current of 25 mAs at 130 kV, collimation 16 x 1.2 mm and a pitch of 0.95. A CT with intravenous contrast administration using a tube current of 110 mAs at 110-130 kV, collimation 16 x 1.2 mm and pitch 0.95 was used for attenuation correction of the late images. Both CTs were reconstructed using a matrix size of 512 x 512 resulting in voxel sizes of 1.37 x 1.37 mm and a slice thickness of 5 mm.

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119 Data extraction and image analysis

For all included patients basic patient characteristics were extracted from the database. For cohort 1 surgical margin status of the prostatectomy specimens, time from prostatectomy to biochemical recurrence, received salvage radiation therapy, and time to PSA progression after salvage radiation therapy were extracted from medical records. Thereby a biochemical relapse was defined by two consecutive PSA values of 0.2 ng/ ml and rising after radical prostatectomy (12). PSA progression after salvage radiation therapy was defined by rising PSA in two consecutive measurements.

The 18_{F-fluorocholine PET/CT images were all reread by two experienced nuclear}

medicine physicians (M.W. and F.Z.) and findings in the pelvis on both the early and late phase, including uptake in the prostate, uptake in the direct vicinity of the prostate/ prostatic bed region and uptake suspected for lymph node and bone metastasis, were retrospectively entered in the database. Fused PET/CT images were used for anatomical mapping. Uptake in the prostatic fossa or in structures in the immediate vicinity, above the uptake in the direct surrounding, were included in the analysis. Lymph nodes with uptake higher than uptake in surrounding adipose tissue and bone lesions with elevated tracer uptake compared to adjacent bone marrow and without signs of degenerative disease on CT were considered malignant and were included in the analysis. Since it

is known that increased 18_{F-fluorocholine in the prostate may be due to malignant as}

well as benign processes, only areas with increased 18_{F-fluorocholine activity in which}

prostate cancer was found at biopsy in patients in cohort 2 were included in the analysis. Early LIST mode data was used to reconstruct time activity curves from the areas of

increased 18_{F-fluorocholine uptake and the blood pool time-activity pattern was}

measured in a standard Volume of Interest (VOI) in the left external iliac artery. Blood pool time activity was measured in order to get insight in tracer availability. Lesions directly adjacent to organs or tissues with normal tracer uptake with higher intensity than uptake in the target lesion were excluded from the analysis. Kinetic data of

18_{F-fluorocholine uptake was extracted by measuring the SUV}

max at one minute intervals

after injection of the tracer in the selected lesion of interest by means of VOI analysis using the VOI isocontour tool (cut-off 40% from maximum) in the syngo.via software package (Siemens Healthcare, Knoxville, USA).

RESULTS

Scans of 44 patients with a biochemical relapse after prostatectomy and 26 patients with primary prostate cancer were included in the study. Three scans were excluded because they proved to be follow-up scans of already included patients and of these, only the first scan was used. Another 2 other scans were excluded since early list mode data was incomplete. As a result 40 patients with a biochemical relapse and 25 patients with primary prostate cancer were analysed (Table 1).

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Table 1. Patients characteristics

Biochemical relapse after prostatectomy Staging of primary prostate cancer No. of patients 40 25 Age (years) 69.4* (56-79)‡ _{69.7* (52-80)}‡ PSA at scan (ng/ml) 2.6†_(0.3-50.0)‡ ₂₀†_(1.9-246)‡

PSA doubling time (months) 3†_(1-18)‡

-Gleason-score§ 6 2 3 7 10 3 8 8 5 9 14 13 10 0 1 Unknown 6 0 cT-stage at diagnosis|| x 3 7 1 1 0 2 6 5 3 30 9 4 0 4 cN-stage at diagnosis|| 0-x 33 20 1 7 5 cM-stage at diagnosis|| 0-x 40 25 1 0 0 Patients on hormone therapy at time of PET/CT

Yes 0 0

No 40 25

*Mean, †_Median,‡_Range,§_{Gleason-score from biopsy,}||_Before18_{F-fluorocholine PET/CT}

Prostatectomy pathology reports were available for 39/40 patients. Positive surgical margins were reported in 20 of those patients. Data on time from prostatectomy to biochemical recurrence were available for 35/40 patients. Fourteen patients did not reach PSA values <0,1 ng/ml after prostatectomy, of which 12 received salvage radiation

therapy before 18_{F-fluorcholine PET/CT. For 21 patients median time to biochemical}

recurrence was 26 months (range 4 - 80). Of them 16 received salvage radiation therapy before 18_{F-fluorocholine PET/CT. In total 32/40 patients (80%) received salvage radiation}

therapy before 18_{F-fluorocholine PET/CT. PSA progression immediately after salvage}

radiation therapy was seen in 17 patients. For the other patients median time to progression was 17 months (range 8 - 98).

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Figure 1. High 18_{F-fluorocholine uptake on early PET/CT (low dose) images in the penile bulb in}

a patient with biochemical relapse after radical prostatectomy (A-C), including the selected VOI (C). Time activity curve in the selected VOI during the first 10 minutes immediately after

18_{F-fluorocholine injection (D). Late PET/CT images with intravenous contrast agent show no}

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In cohort 1 clear persistent activity on both early and late images, suspected for local relapse, was detected in 1 patient (2.5%) and faint persistent activity, equivocal for local relapse, was seen in 3 patients (7.5%). On PET/CT the activity of those lesions was located in the prostatic fossa, without a clear anatomical substrate on CT. No histological proof of local recurrence was present due to the retrospective nature of the study in conjunction with presence of distant metastatic disease, which made biopsy for clinical purposes unnecessary. On early images only, focally increased 18_{F-fluorocholine uptake}

in the prostatic bed region was seen in 28/40 patients (70.0%). According to surgical margins after prostatectomy 16/20 patients (80%) and 11/19 (58%) with respectively positive and negative surgical margins showed focally increased uptake on early images only. Increased uptake on early images only was detected in 26/32 patients (81%) that already received salvage radiation therapy and in 2/8 patients (25%) that did not receive any treatment after radical prostatectomy. Fusion of PET and CT images revealed that all those lesions were located in the penile bulb (Figure 1).

In cohort 2, focally increased activity on early images only, adjacent to the prostatic fossa, was seen in 11/25 patients (44%). All those lesions were also located in the penile bulb. Persistent increased 18_{F-fluorocholine activity was present in the prostate segment}

in which tumour was found at biopsy in all 25 patients.

Signs of metastases were detected in a large number of patients in both cohorts. For respectively cohort 1 and 2, suspected lymph nodes only were found in 22 (55%) and 9 (36%) patients, suspected bone lesions only in 4 (10%) and 2 (8%) patients and both suspected lymph nodes and bone lesions in 4 (10%) and 2 (8%). For patients with focally increased activity on early images only 22/28 (79%) and 7/11 (64%) had signs of regional or distant metastases in respectively cohort 1 and 2.

Time-activity patterns of lesions in the penile bulb in both cohorts showed a similar course, with rapid uptake of activity in these lesions in the first 2 minutes immediately followed by a decrease of the activity lasting until at least the 10th_{minute after injection}

(Figure 2). No histopathological biopsies were taken of these lesions. Time activity curves of the area in which tumour was found at biopsy in cohort 2 showed rapid increase of 18_{F-fluorocholine activity in the first 2 minutes followed by a nearly stable}

concentration until the 10th_{minute. Time activity curves of the blood pool demonstrated}

a rapid decline in blood pool activity directly after tracer injection (Figure 3). Time activity patterns of lymph nodes and bone lesions suspected for metastases were acquired from respectively 51 and 16 lesions. Both curves indicated rapid uptake of

18_{F-fluorocholine in the first 2 minutes followed by a nearly stable concentration until}

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Figure 2. Time activity curves during the first 10 minutes after injection of 18_{F-fluorocholine. Blue and}

green lines represent the activity pattern in focal lesions seen on only early images in patients with biochemical relapse after prostatectomy and primary staging, respectively. Orange line represents the activity pattern in prostate tumours in patients, which are primarily staged for prostate cancer.

Figure 3. Time activity curves during the first 10 minutes after injection of 18_{F-fluorocholine. Purple}

and red lines represent the activity pattern in the blood pool in patients with biochemical relapse after prostatectomy and those primarily staged for prostate cancer respectively.

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Figure 4. Time activity curves during the first 10 minutes after injection of 18_{F-fluorocholine. Blue}

and green lines represent the activity pattern in suspected lymph node and bone metastases in both cohorts respectively.

DISCUSSION

Focally increased 18_{F-fluorocholine uptake on early images only is seen in a large}

number of patients and on fused PET/CT images they are located in the penile bulb. For patients with a history of radical prostatectomy (cohort 1) it can be postulated these focal activities, which are seen in 70% of these patients, are a sign of local recurrence at the vesicoureteral anastomosis. However, our data shows that these early focal activity depositions in the penile bulb are also seen in a high number of patients (44%) that were referred for staging of primary prostate cancer (cohort 2). Since those patients did not receive any treatment for prostate cancer it is highly unlikely that those findings represent prostate cancer depositions located in the penile bulb.

Furthermore, the time activity curve of the observed activity in the penile bulb in patients after radical prostatectomy shows a similar pattern compared to patients that did not receive any treatment suggesting that those observations represent the same substrate. Blood pool activity shows a similar pattern as compared to the pattern found for the focal activities in the penile bulb (Figure 2 and 3). Since the penile bulb is a highly perfused structure, physiological 18_{F-fluorcholine uptake in this structure is expected to}

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The time activity pattern in the area of prostate that was positive for prostate cancer at biopsies in patients of cohort 2 shows a pattern similar to that of lymph nodes suspicious of metastasis as well as bone lesions in both cohorts. In these, rapid uptake of 18_{F-fluorocholine is seen in the first 2 minutes followed by a more or less stable}

concentration until the 10th_{minute after activity injection, which differs from the}

activity pattern found in focal activity depositions present on early images only in the penile bulb. It is unlikely that prostate cancer lesions at the site of a local relapse after

prostatectomy show a different 18_{F-fluorocholine uptake pattern than prostate cancer}

cells in the prostate in patients staged for primary prostate cancer and prostate cancer cells in lymph node and bone metastases.

In addition to the abovementioned findings which provide strong arguments against the postulation that focally increased 18_{F-fluorocholine activity on early images only}

is a sign of local recurrence, metastases were found in 79% of patients in cohort 1 with focally increased activity on early images only. Presence of distant metastatic disease in a large number of patients strengthens the argument that local uptake is physiological since concurrent regional and/or distant metastases and local recurrence is unlikely, especially in patients with low PSA values. Moreover, early focally increased uptake was found in the majority of patients after radical prostatectomy irrespective to presence of positive or negative surgical margins, while presence of local recurrence is unlikely in patients with negative surgical margins. In addition it must be noticed that a large number of patients in cohort 1 (80%) already received salvage radiation therapy before

18_{F-fluorocholine PET/CT.}

In line with the findings of Simone et al. we also found focal 18_{F-fluorocholine uptake}

on early images only in a high number of patients with biochemical relapse after prostatectomy (76% and 70% respectively). Simone et al. considered positive findings in the prostatic bed region on 18_{F-fluorocholine PET/CT true positive for local recurrence}

when one of the following criteria was met: positive histology of vesicoureteral anastomosis biopsy, or disease progression confirmed by increasing PSA values and imaging, or a PSA nadir value <0.1 ng/ml after salvage radiation therapy without androgen deprivation therapy (11). The number of patients for which a histological biopsy was present in this study is unclear and, to our opinion, a decreasing PSA below 0.1 ng/ml after salvage radiation therapy does not prove that the found activity deposition on early 18_{F-fluorocholine images represents a local recurrence. The pre-test likelihood of}

a local recurrence in this patient population is high and in absence of any pathological

18_{F-fluorocholine deposition outside the prostatic bed region it can be expected that a}

high number of patients will benefit from salvage radiation therapy, thereby reaching a PSA nadir below 0.1 ng/ml (2). In contrast to the studied population of Simone et al. we included a high number of patients that already received salvage radiation therapy for suspicion of local recurrence before 18_{F-fluorocholine PET/CT. Even in those patients}

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Correct interpretation of focal 18_{F-fluorocholine uptake on early images only may have}

consequences for clinical management. Especially in patients that already received salvage radiation therapy after radical prostatectomy, renewed signs of local recurrence will prohibit any treatment with curative intent. Therefore, incorrect diagnoses of local recurrence in patients that also have lymph node metastases may withhold them from lymphadenectomy with curative intent. Eight patients in cohort 1 (20% of the entire cohort and 25% of patients that already received salvage radiation therapy) that already received salvage radiation therapy on the prostate, had focally increased activity on early images only and signs of lymph node metastases in the pelvis (N1M0 according to TNM 7), another 6 patients (15% of the entire cohort and 19% of patients that already received salvage radiation therapy) had signs of metastases in both the pelvic lymph nodes as well as abdominal retroperitoneal nodes (N1M1a). There is a wide variability between indications for salvage lymphadenectomy between medical centers; in some only patients with a limited number of lymph node metastases in the pelvis are operated, while other centers perform extensive lymphadenectomies of pelvic and retroperitoneal nodes. As a result the impact of incorrect diagnosis of local recurrence on clinical management differs between medical centers. However, from our data it can be estimated that incorrect diagnosis of local recurrence may affect clinical management in 25 to 44% of patients in cohort 1 that already received salvage radiation therapy.

In cohort 1 we found signs of local recurrence in the prostatic bed in 4 patients (10%). Suspicion of local recurrence in 10% of the patients is in resemblance with other cohorts that included patients with biochemical recurrence after prostatectomy, in which this varied between 6.4 and 14.6% (9, 13-16). The imaging protocols of the reports by Mazola et al. and Heninger and colleagues included early image acquisition, while the protocols of others only included late imaging acquisition. Mazola et al. found evidence for local recurrence in 15/233 (6.4%) of patients scanned 5 to 10 minutes post injection and 60 minutes post injection. Heninger et al. found local recurrence in 1/10 patients with a dynamic scan of the pelvis acquired 1 minute post injection including 8 acquisitions lasting 60 seconds each followed by a whole-body scan from head to knees.

A limitation of the present study is the relatively low number of included patients. However, the incidence of focal 18_{F-fluorocholine activity on early images only in the}

penile bulb in our series is high in both cohorts and the similarities between the activity patterns in the penile bulb between both cohorts on the one hand and the malignant lesions on the other hand are clear. Another limitation is the lack of histopathological proof of presumed absence of malignant tissue at the site of observed focal early

18_{F-fluorocholine activity in the penile bulb, which is a result of the retrospective clinical}

nature of the study. At time of clinical decision making early phase activity only at the penile bulb was considered a physiological phenomenon and therefore biopsies were not considered relevant.

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Furthermore, it must also be noticed that at present it is recommended to use the 2014 International Society of Urological Pathology consensus for Gleason grading of prostate cancer, especially for differentiation between 3+4 and 4+3, since the latter tumours have significant worse prognosis (17). Our cohort includes a large number of patients that are graded following older criteria, since for many patients Gleason grading was performed before 2014.

CONCLUSION

Focally increased 18_{F-flurocholine activity in the prostatic region seen on early images}

only is found in a high number of patients referred for evaluation after biochemical relapse and those referred for primary staging and, according to our data, represents physiological uptake in the penile bulb. Therefore early dynamic imaging of the prostatic bed region with 18_{F-Fluorocholine PET/CT does not appear to increase the detection rate}

of local prostate cancer recurrence in comparison to late images only in patients with a biochemical recurrence after prostatectomy.

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