Abstract
Purpose
The RefleXion X1 Medical Radiotherapy System (RefleXion Medical) is a novel radiation therapy (RT) device capable of delivering real-time positron emission tomography (PET) scan-guided or biology-guided RT (BgRT). The purpose of this pilot study was to evaluate the performance of its PET imaging subsystem to detect 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyl) prostate-specific membrane antigen [PSMA] PET scan signal as the foundation for BgRT in patients with prostate cancer.
Methods and Materials
Patients underwent a standard diagnostic 18F-DCFPyl PSMA PET scan. If at least 1 PET-scan-avid tumor was identified, the patient was then scanned on the RefleXion X1 unit. The target volume, activity concentration, and normalized target signal were determined, and BgRT planning was performed.
Results
In 20 patients, at least 1 PSMA PET-scan-avid tumor was identified for BgRT planning (5 lymph node metastases, 7 bone metastases, 7 prostate glands, and 1 prostate bed). In 18 patients, the PET-scan-avid tumor was visualized on the RefleXion X1 PET scan, whereas in 2 patients, the tumor was too close to the PET scan activity in the bladder to be clearly visualized. BgRT planning was feasible and met stereotactic body RT organ dose constraints in 8 (40%) patients (3 prostate glands, 3 bones, and 2 lymph nodes). BgRT was not feasible in 12 (60%) patients because of low target activity concentration (<5 kBq/mL), low normalized target signal intensity (<2.7), or proximity of the PET-scan-avid tumor to the bladder.
Conclusions
This is the first study to demonstrate the feasibility of using 18F-DCFPyl scan imaging for BgRT planning on the RefleXion X1 system in patients with prostate cancer. BgRT using targeted PET scan radiopharmaceuticals to guide RT represents a promising new dimension in radiation oncology and warrants further investigation.
Introduction
The RefleXion X1 Medical Radiotherapy System (RefleXion Medical) is a hybrid imaging-therapy system.1, 2, 3 The system consists of a flattening filter-free 6 MV photon beam linear accelerator, multileaf collimator, dual 90° arcs of solid-state Silicon Photomultiplier-Positron Emission Tomography (PET) scan detectors, a fan-beam 16-slice kilovoltage computed tomography, and a megavoltage detector, all mounted on an O-ring gantry capable of rotating continuously at 60 RPM.4 PET scan detectors allow for real-time dynamic guidance of radiation therapy directed at PET scan emissions from the tumor and the potential to deliver radiation therapy (RT) to a smaller volume with greater sparing of normal tissue.4 This enables radiation delivery directly guided using the PET scan signal originating from the tumor itself, thus introducing a pioneering approach referred to as biology-guided RT (BgRT).
Prostate-specific membrane antigen (PSMA) PET scan with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyl) has been approved for imaging PSMA-positive tumors in men with prostate cancer with either (1) suspected metastasis who are candidates for initial definitive therapy or (2) suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.5,6 In the future, the potential for BgRT guided by 18F-DCFPyl as a biological fiducial holds promise in treating patients with prostate cancer.
However, a prerequisite for such advancements is a comprehensive understanding of the PET scan imaging subsystem’s performance on the Reflexion X1 system, particularly in detecting PET scan signals derived from 18F-DCFPyl. This prospective study aimed to better assess the performance of the PET scan imaging subsystem for the detection of 18F-DCFPyl PET signals as a foundation to evaluate 18F-DCFPyl-based BgRT treatment planning and delivery in future studies. Data from this study would allow assessment of the technical performance of the PET scan imaging subsystem in patients with prostate cancer undergoing standard-of-care (SOC) imaging with 18F-DCFPyl for diagnostic purposes, as well as supplement and enhance technical understanding of the potential for 18F-DCFPyl-guided BgRT delivery in the future. The patient population eligible for this investigation represents the spectrum of cases, with respect to motion and radiographic environments, that a radiation oncologist may encounter in practice.
Methods and Materials
Trial design
This was a single-institution prospective trial that was approved by the institutional review board of (City of Hope; [NCT06580015). The primary objective of this study was to determine the imaging performance of the PET scan imaging subsystem of the RefleXion Medical Radiotherapy System Device (Reflexion X1) in patients undergoing SOC 18F-DCFPyl PET-computed tomography (CT) scan on the same day. Patients with prostate cancer scheduled for a diagnostic 18F-DCFPyl PSMA PET scan as part of SOC were eligible for this study (Fig. 1). Diagnostic PSMA PET-CT scans were performed on a Siemens Biograph128_Vision 600 Edge. Diagnostic PET-CT scan images were then transferred to Eclipse (Siemens, Inc) for target and organs at risk (OARs) contouring. If at least one PET-avid tumor was identified, the radiation oncologist contoured one of these tumors as the gross target volume (GTV) for BgRT planning. A planning target volume (PTV) and biological tracking zone (BTZ) were then contoured. The PTV was defined as the GTV with a 5 mm symmetrical margin. The BTZ represents the tumor’s full range of motion plus margin. The RefleXion X1 RT delivery is limited only to PET scan-avid tumors within the BTZ. For purposes of this study, the BTZ was defined as the PTV with a 5 mm symmetrical margin. Patients then underwent an additional imaging-only session the same day to acquire PET scan images on the RefleXion X1 without additional radiotracer administration. The study timeline estimated the time from injection to the start of the SOC diagnostic scan to be approximately 60 minutes, and the time from injection to the start of the RefleXion X1 scan to be approximately 120 minutes (Fig. 1).
Figure 1.
Study flowchart. Patients first underwent a standard of care 18F-DCFPyl PET-CT scan. If at least 1 PET-scan-avid tumor was identified, then the patient would undergo a PET scan on the RefleXion X1 unit.
Abbreviations:18F-DCFPyl = 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid; CT = computed tomography; PET = positron emission tomography.
RefleXion X1 PET scan performance evaluation and BgRT planning
BgRT planning was attempted for cases where tumors were detectable on the RefleXion X1 PET scan images. Images and volumes were transferred into the RefleXion X1 treatment planning system (TPS). BgRT planning was performed on the RefleXion X1 TPS, with the prescription dose determined by the location of treatment sites. The planning objectives of OARs were established in accordance with the 2018 Timmerman guidelines.7 The objective for target coverage was for the prescribed dose to cover 95% (D95%) of the PTV. The following parameters were analyzed: PTV D95%, the minimal dose to the GTV, plan maximum dose, conformity index (CI), gradient index (GI), and maximum point dose (D0.03 cc) to the nearest OARs. The RefleXion X1 BgRT planning system also generated dose-volume histogram boundaries, which model variations in BgRT delivery.
In addition to dosimetric parameters, activity concentration (AC) within BTZ and normalized target signal (NTS) were calculated using the RefleXion X1 TPS during BgRT plan generation (Fig. 2). As illustrated in Fig. 2, the target signal was identified as the mean signal value of all voxels falling above 80% of the maximum PET voxel within the BTZ. A 3 mm shell around the BTZ was automatically generated by the system and defined as the “background” region. The mean background was calculated using voxels within this background shell. The activity concentration (AC) metric was the difference between the mean target signal and the mean background. The NTS value was the AC value divided by the standard deviation of the voxels within the background shell. The creation of successful and feasible BgRT plans required that the target AC value exceeded 5 kBq/mL and the NTS value surpassed 2.7.8
Figure 2.
Definition of activity concentration (AC) and normal target signal (NTS).
Comparisons between feasible and nonfeasible cases were performed using the Wilcoxon rank-sum test in MATLAB (MathWorks). Continuous variables are presented as median (range), and a 2-sided P-value < .05 was considered statistically significant.
Results
Thirty-two patients underwent 18F-DCFPyl PET scans from August 29, 2022, to March 29, 2023, for the following indications: rising PSA after surgery or RT in 16 (50%) patients, metastatic disease in 9 (28%) patients, and newly diagnosed patients with high-risk prostate cancer in 7 (22%). The mean time from injection to 18F-DCFPyl PET scan was 70 minutes (range, 59-93). The mean time from injection to RefleXion X1 scan was 173 minutes (range, 142-218). In twenty-three (72%) patients, at least 1 PET-scan-avid tumor was identified on the 18F-DCFPyl PSMA PET scan. Three of these patients did not have modeling on the RefleXion X1 system. Two patients declined the subsequent RefleXion X1 scan, and 1 patient was not scanned because of a technical issue. In the remaining 20 patients, PET-scan-avid tumors were identified and contoured for PET scan imaging on RefleXion X1 (5 in lymph nodes, 7 in bones, 7 in the prostate glands, and 1 in the prostate bed) as listed in Table 1. BgRT plans were feasible in 8 patients, yielding a 40% feasibility rate.
Table 1.
Characteristics and RefleXion X1 positron emission tomography (PET) scan imaging metrics for patients scanned on the RefleXion X1 PET scan subsystem
| Patient trial ID | Site imaged | PSA | PET/CT SUV(max) | GTV volume (cc) | Injection to X1 scan (min) | X1 AC (kBq/mL) | X1 NTS | BgRT Rx dose (cGy) |
|---|---|---|---|---|---|---|---|---|
| 001 | Lymph node | 61 | 107.3 | 50.9 | 151 | 48.04 | 24.66 | 900 × 3 |
| 002 | Lymph node | 0.898 | 47.86 | 18 | 159 | 7.32 | 7.45 | 900 × 3 |
| 003 | Lymph node | 0.427 | 80.25 | 1.2 | 156 | 13.05 | 1.96 | 1000 × 3 |
| 007 | Prostate | 4.786 | 13.98 | 0.5 | 143 | 5.46 | 3.88 | 900 × 5 |
| 008 | Prostate | 0.038 | 22.46 | 2.1 | 142 | 6.9 | 4.44 | 900 × 5 |
| 011 | Prostate | 9.75 | 7.54 | 1 | 151 | 2.89 | 2.41 | 900 × 5 |
| 012 | Prostate Bed | 0.226 | 11.01 | 0.9 | 177 | NA | NA | NA |
| 013 | Bone | 0.242 | 4.94 | 0.3 | 150 | 1.07 | 2.72 | 900 × 3 |
| 014 | Bone | 4.189 | 26.5 | 0.5 | 175 | 1.92 | 2.68 | 900 × 3 |
| 015 | Bone | 0.771 | 34.42 | 3.1 | 177 | 14.33 | 21.04 | 900 × 3 |
| 017 | Bone | 122 | 31.06 | 3.4 | 165 | 14.23 | 13.99 | 900 × 3 |
| 019 | Prostate | 2 | 12.13 | 2.5 | 189 | 2.8 | 3.32 | 900 × 5 |
| 020 | Lymph node | 27.151 | 9.02 | 0.1 | 218 | 1.1 | 3.09 | 900 × 3 |
| 021 | Bone | 12.665 | 51.29 | 9 | 205 | 22.87 | 33.87 | 1000 × 3 |
| 023 | Prostate | 2.6 | 10.8 | 0.4 | 199 | 1.74 | 1.96 | 900 × 5 |
| 026 | Prostate | 7.611 | 27.85 | 2.5 | 152 | 6.04 | 4.36 | 900 × 5 |
| 030 | Lymph node | 0.646 | 8.91 | 0.2 | 202 | NA | NA | NA |
| 031 | Bone | 0.838 | 5.65 | 5.1 | 170 | 4.29 | 4.73 | 800 × 3 |
| 032 | Prostate | 13.131 | 39.35 | 15.7 | 146 | 46.86 | 2.2 | 900 × 5 |
| 034 | Bone | 0.271 | 3.05 | 0.1 | 177 | 0.61 | 1.19 | 900 × 3 |
Abbreviations: AC = activity concentration; BgRT = biology-guided radiation therapy; CT = computed tomography; GTV = gross tumor volume; NA = not applicable; NTS = normal target signal; PSA = prostate-specific antigen; Rx = therapy; SUVmax = maximum standardized uptake value.
Plans were defined as successfully generated on X1 TPS if Timmerman dose constraints were met.7 BgRT plans were successfully generated for 18 patients scanned on X1. The prescription dose was 2700 or 3000 cGy in 3 fractions for lymph node tumors, 2400 to 3000 cGy in 3 fractions for bone metastasis, and 4500 cGy in 5 fractions for tumors in the prostate gland. For tumors in the prostate gland, an initial attempt was made to generate plans with a prescription dose of 3625 cGy in 5 fractions. However, these plans did not meet the minimum 5 gantry revolutions per beam station requirement of the RefleXion X1 TPS, and consequently, the prescription was changed to 4500 cGy in 5 fractions.9
Table 2 presents the dosimetric parameters of the generated BgRT plans. The median (range) maximal dose, PTV D95%, and GTV minimal doses were 129% (122.3%-155.4%), 101.5% (97.0%-104.6%), and 112.8% (92.0%-119.2%), respectively. The median (range) CI and GI were 1.20 (1.06-1.48) and 8.72 (5.20-12.49), respectively. The median (range) D0.03 cc to the nearest OARs was 81.9% (31.9%-116.6%).
Table 2.
Dosimetric parameters of generated biology-guided radiation therapy (BgRT) plans (n = 18)
| Dosimetric parameters | Median | Range |
|---|---|---|
| PTV volume (cc) | 7.0 | 2.0-96.6 |
| PTV D95% | 101.5% | 97.0%-104.6% |
| GTV Dmin | 112.8% | 92.0% 119.2% |
| Dmax | 129.0% | 122.3%-155.4% |
| CI | 1.20 | 1.06-1.48 |
| GI | 8.72 | 5.20-12.49 |
| OAR D0.03cc | 81.9% | 31.9%-116.6% |
Abbreviations: CI = conformity index; Dmax = maximum dose; Dmin = minimum dose; GI = gradient index; GTV = gross tumor volume; OAR = organ at risk; PTV = planning target volume.
Feasible and deliverable BgRT plans were possible if AC and NTS values met the requirements for BgRT delivery. Of the 18 generated plans, 8 were feasible for BgRT. For the 8 patients with feasible BgRT plans, AC and NTS values were 10.78 (5.5-48) kBq/mL and 10.72 (3.88-33.87), respectively. The mean values (95% confidence intervals) for AC and NTS values were 15.65 (3.63-27.67) kBq/mL and 14.21 (4.80-23.62), respectively. In contrast, among the 12 patients for whom BgRT plans were not feasible, AC and NTS values were 2.36 (0.61-46.86) kBq/mL and 2.55 (1.99-4.73), respectively. The mean values (95% confidence intervals) for AC and NTS values were 7.63 (0-17.83) kBq/mL and 2.63 (1.94-3.31), respectively. Notably, the 95% CI for the mean AC values of nonfeasible cases, calculated using the t-distribution, was (−2.56, 17.83). However, because AC values are strictly nonnegative, the interval was truncated at 0.
Median (range) values for PSA, PET scan maximum standardized uptake value (SUVmax), and GTV volumes were 6.20 (0.04-122.0), 32.74 (13.98-107.30), and 3.3 (0.5-50.9) cc in feasible cases and 1.41 (0.23-27.15), 9.91 (3.05-80.25), and 0.7 (0.10-15.7) cc in nonfeasible cases. PET scan SUVmax value and GTV volume were significantly higher in feasible cases (P = .02 and p = .03), whereas PSA values showed no significant difference (P = .45). The median time interval between activity injection and RefleXion X1 scan was 156 (142-205) minutes for feasible and 177 (150-218) minutes for nonfeasible cases, with no significant difference (P = .34). Detailed data were summarized in Table 3. The estimated treatment time for feasible BgRT plans was 11.5 (9.2-22.9) minutes. A typical successful BgRT plan is illustrated in Fig. 3.
Table 3.
Patient characteristics
| Characteristic | All patients scanned on X1 (N = 20) median (range) | BgRT plan successful (N = 8) median (range) | BgRT plan not successful (N = 12) median (range) |
|---|---|---|---|
| Age (y) | 72 (54-89) | 74 (57-89) | 70 (54-86) |
| PSA | 2.30 (0.04 –122.0) | 6.20 (0.04-122.0) | 1.41 (0.23-27.15) |
| Administered activity 18F-DCFPyl (mCi) | 9.61 (8.13-10.65) | 9.78 (8.91-10.19) | 9.58 (8.13-10.65) |
| Time from 18F-DCFPyl injection to start of X1 scan (min) | 173 (142-218) | 156 (142-205) | 177 (150-218) |
| PET-scan-avid tumors selected for BgRT planning | bones (7), lymph nodes (5), prostate (7), prostate bed (1) | bone (3), lymph nodes (2), prostate (3) | bone (4), lymph nodes (3), prostate (4), prostate bed (1) |
| Tumor size (GTV) (cc) | 1.65 (0.10-50.9) | 3.25 (0.5-50.90) | 0.70 (0.10-15.7) |
| Tumor SUVmax | 18.22 (3.05-107.3) | 32.74 (13.98-107.30) | 9.91 (3.05-80.25) |
| AC concentration kBq/mL | 5.90 (0.617-48.04) | 10.78 (5.46-48.04) | 2.36 (0.61-48.86) |
| NTS value | 3.60 (1.19-33.87) | 10.72 (3.88-33.87) | 2.55 (1.99-4.73) |
Abbreviations:18F-DCFPyl = 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid; AC = activity concentration; BgRT = biology-guided radiation therapy; GTV = gross tumor volume; NTS = normal target signal; PET = positron emission tomography; PSA = prostate-specific antigen; SUVmax = maximum standardized uptake value.
Figure 3.
An example of a typical biology-guided radiation therapy (BgRT) plan. (A) Positron emission tomography (PET) scan on diagnostic PET-computed tomography (CT) scan and (B) RefleXion X1 PET-Linac scan for patient 15 with a PET-scan-avid rib metastasis with gross tumor volume (GTV) volume = 3.1 cc, planning target volume (PTV) = GTV + 5 mm, BTZ (biological tracking zone) = PTV + 5 mm, activity concentration (AC) concentration = 14.33 kBq/mL, and normal target signal (NTS) value = 21.04. Red, magenta, and green contours represent GTV, PTV, and BTZ. (C) The dose distribution and (D) the bounded dose-volume histogram (DVH) of a BgRT plan are displayed for the same patient. The bounded DVH models variations in BgRT delivery, encompassing fluctuation in target-background signal variation, target localization, and dose delivery uncertainties.
In 2 patients (patients 12 and 30), BgRT plans were not feasible because the tumor signal was indistinguishable from the bladder. Figure 4 illustrates an example of a patient with a tumor close to a high-uptake organ, the bladder. Consequently, the NTS value falls below the safe delivery threshold of 2.7.
Figure 4.
Positron emission tomography (PET) scan on diagnostic PET-computed tomography (CT) scan (left) and RefleXion X1 PET-Linac (right) for a patient with a PET-scan-avid node in the left anterior low pelvic fat, consistent with metastasis. Increased bladder filling on the RefleXion X1 scan resulted in the tumor appearing closer to the bladder on the RefleXion X1 scan, leading to a normal target signal (NTS) value lower than the safe delivery threshold of 2.7.
Discussion
This study represents the first prospective investigation into the viability of using 18F-DCFPyl scan imaging for BgRT plan generation on the RefleXion X1 system in patients with prostate cancer. Of 20 patients with a PET-scan-avid tumor identified on a diagnostic scanner, the same tumor was identified on 18 of them on the RefleXion X1 system, sufficient to develop BgRT plans. Among the 18 patients with plans generated, 8 were deemed feasible for BgRT. Plans that were not feasible stemmed from 4 primary factors: (1) PET-scan-avid tumors of small size, (2) PET-scan-avid tumors with low SUVmax values, (3) tumors located in proximity to the bladder, and (4) a longer time interval between the diagnostic PET scan and the RefleXion X1 PET scan.
For tumors smaller than 1 cm in dimension (equivalent to a size of about 0.5 cc), a weak target AC value was observed in the corresponding BgRT plans, attributable to the PET scan system characteristics of the RefleXion X1 system. Hu et al10 demonstrated that PET scan image contrast diminishes significantly when PET-scan-avid tumors are less than 13 mm in size. Despite protocol instructions for patients to empty their bladder before the RefleXion X1 PET scan, the urinary bladder’s high PET scan signal posed challenges. For tumors near the bladder, such as in the prostate gland, prostate bed, and adjacent lymph nodes, NTS values fell short because of substantial background noise from the bladder.
The median (range) time from 18F-DCFPyl injection to the RefleXion X1 scan exceeded the proposed 120-minute interval in the protocol, registering at 173 (142-218) minutes. Several factors contributed to this. There were delays from infusion to completion of the diagnostic scan. The diagnostic PET scanner was located in a separate building at a distance requiring prearranged shuttle transportation to the RefleXion X1 unit. The diagnostic scans then needed to be uploaded to the radiation oncology systems for contouring and plan generation. Positioning patients on the Reflexion X1 system required more time than regular RT sessions because of the absence of localization markers on patients' bodies and the discrepancy between the curved diagnostic PET-CT scan couch and the flat Reflexion X1 couch. These factors are expected to have less of an impact as this investigational imaging workflow becomes more established. Shortening this interval could potentially enhance target AC and NTS values, facilitating successful BgRT plans in a larger cohort of patients undergoing this type of exploratory imaging study. For example, in a clinical BgRT setting, however, where patients undergo dedicated RefleXion X1 scans for BgRT planning and treatment delivery without relying on acquisition of a SOC diagnostic PET-CT scan, the injection-to-scan interval should be limited to approximately 60 minutes for optimal treatment outcomes.
This study also demonstrated that the dose fall-off of BgRT plans was less pronounced compared to conventional stereotactic body RT (SBRT), evidenced by higher CI and GI values than typically observed for conventional SBRT. This discrepancy can be attributed to the radiation delivery mode of BgRT, which convolves the PET scan signal inside the BTZ with optimized photon fluence masks obtained during treatment planning. Consequently, some photon beamlets may be directed onto nontarget areas within the BTZ, resulting in heightened dose spillage, which can be mitigated by future improvements in imaging detection systems or enhanced signal tracking modes.
Conclusion
This is the first study to prospectively investigate the feasibility of using 18F-DCFPyl PET scan imaging for BgRT plan generation on the RefleXion X1 system in patients with prostate cancer. Tumors that are relevant to the RT of prostate cancer can be well visualized in various locations, including lymph nodes and bones, the most common sites of metastasis. A dedicated BgRT workflow with PSMA PET scan imaging on the RefleXion X1 at 60 minutes after injection may result in higher target AC values and will optimize BgRT planning. Small PET-scan-avid tumors or those close to the bladder may make BgRT planning challenging. This pilot study demonstrated the potential feasibility of using 18F-DCFPyl for BgRT on the RefleXion X1 unit in patients with prostate cancer. A larger multicenter trial is planned to confirm these results and generalizability. Potential future applications include SBRT 18F-DCFPyl PET scan-based BgRT to PET-scan-avid lymph nodes, visceral metastases, local recurrences within the prostate bed, and intraprostatic tumors. 18F-DCFPyl-guided BgRT is technically feasible using RefleXion X1. A larger multicenter study is planned to obtain US Food and Drug Administration clearance to deliver 18F-DCFPyl-guided BgRT. With the rapidly growing interest in the field of radiopharmaceuticals, this technology can be an important convergence platform for radiation oncologists to innovatively integrate theranostic PET scan-guided RT and targeted radiopharmaceutical therapy. BgRT using current and potentially future targeted PET scan radiopharmaceuticals to biologically direct external beam RT warrants further investigation and represents a promising new dimension in radiation oncology and nuclear oncology.
Disclosures
Jeffrey Y.C. Wong received trial and grant support from RefleXion Medical and grants from Varian, Accuray, Blue Earth Diagnostics, and NIH. Angela J. Da Silva and Karine A. Al Feghali are employees of RefleXion Medical. Terence Williams received an honorarium from RefleXion Medical, grant funding from NIH, ASTRO, and ACS, and travel support from the Alliance for Clinical Trials. Other authors have nothing to disclose. AI was not used in preparation of this manuscript.
Acknowledgments
We thank Jessica Liu, CRN, Aidalyn Carino, CRN, and Jennifer Simpson, CRC, for their dedication and support to this trial.
Footnotes
Sources of support: This study was funded by RefleXion Medical, Inc, Hayward, California, USA.
Data supporting the findings of this study are available from the corresponding author upon reasonable request.
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