Abstract
Objective
High-grade neuroendocrine cervical cancer (HGNECC) is a rare and aggressive cervical cancer subtype. In this study, we aimed to evaluate the prognostic value of fluorodeoxyglucose-PET/computed tomography (CT) parameters for HGNECC.
Materials and methods
This single-center retrospective study included 29 patients with HGNECC who underwent fluorodeoxyglucose-PET/CT scan followed by surgery between 2006 and 2016.
Results
The median follow-up period was 40 (range, 4–184) months. After surgery, the resection margins were tumor-negative in 28 patients (96.6%), 8 (27.6%) patients had parametrial tumor invasion, and 7 patients (24.1%) tested positive for lymph node metastasis. The tumor recurred in 20 patients (69%) and 18 patients (62.1%) died during the observation period. In the univariate analyses, age and total lesion glycolysis (TLG) were associated with worse disease-free survival (DFS) (age, hazard ratio 1.056, 95% CI 1.014–1.100, P = 0.009; TLG2.5, hazard ratio 1.003, 95% CI 1–1.006, P = 0.033; and TLG3.0, hazard ratio 1.003, 95% CI 1–1.006, P = 0.034). In the multivariate analyses, older age and higher TLG3.0 were identified as independent poor prognostic factors for DFS (age, hazard ratio 1.058, 95% CI 1.014–1.104, P = 0.009; TLG3.0, hazard ratio 1.004, 95% CI 1–1.007, P = 0.033), while resection margin involvement was identified as an independent factor to predict poor overall survival (hazard ratio 20.717, 95% CI 1.289–332.964, P = 0.032).
Conclusion
Among the preoperative fluorodeoxyglucose-PET/CT parameters, TLG3.0 may be useful for predicting DFS in patients with HGNECC.
Keywords: cervical cancer, disease-free survival, fluorodeoxyglucose-PET/CT, neuroendocrine
Introduction
Neuroendocrine cervical cancer (NECC) is a rare subtype of malignant tumors of the cervix, accounting for 1.0–1.5% of all cervical malignancies [1,2]. According to the WHO classification of neuroendocrine tumors, neuroendocrine tumors of the cervix are classified as follows: low-grade neuroendocrine tumor (Grade 1 or 2), high-grade small-cell neuroendocrine carcinoma, and high-grade large cell neuroendocrine carcinoma [3,4]. Small-cell neuroendocrine carcinoma is the most common histologic subtype of cervical neuroendocrine carcinoma, followed by large-cell neuroendocrine carcinoma [5]. Similar to most neuroendocrine tumors that develop in other organs, HGNECC shows a more aggressive behavior than the usual histologic subtypes of cervical cancer such as squamous cell carcinoma and adenocarcinoma [6]. The 5-year overall survival (OS) of HGNECC (35.7%) is worse than that of squamous cell carcinoma (60.5%) and adenocarcinoma (69.7%), which show worse prognosis (hazard ratio 0.55, 95% CI 0.43–0.69 and hazard ratio 0.48, 95% CI 0.37–0.61, respectively) [7].
HGNECC is likely to show lymph node metastasis and invade the lymphovascular space at the time of diagnosis [8]. Moreover, HGNECC has a higher rate of recurrence and shows a worse 5-year survival rate [9]. Fewer studies are available owing to the rarity and aggressive behavior of this tumor. Thus, clinical markers need to be developed for predicting the prognosis of this type of tumor.
Fluorodeoxyglucose-PET/computed tomography (CT) is a tool to detect metabolically active malignant lesions [10]. In addition to conventional imaging tools such as CT and MRI, fluorodeoxyglucose-PET/CT has been increasingly used for the assessment of tumor extent, lymph node metastases, and distal metastases in various cancers [11]. Fluorodeoxyglucose-PET/CT is becoming more important in the evaluation of cervical cancer to establish an initial treatment strategy, as in patients with highly suspected lymph node metastasis or parametrial invasion in preoperative imaging, concurrent chemo-radiation therapy is initiated rather than surgery [12–14]. Fluorodeoxyglucose-PET/CT can yield quantitatively calculated parameters such as maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) [15]. Recently, these parameters are being researched to determine their association with prognosis in various cancers. Utilizing these parameters as prognostic factors for cervical cancer is still controversial; however, some reports have been published that indicate their predictive value [16]. Sarker et al. previously reported that a high SUVmax in cervical cancer patients was related to a worse prognosis, while Carpenter et al. reported that MTV and TLG can predict response to therapy and are correlated with OS of patients with cervical cancer [17,18]. However, these studies mostly included information on patients diagnosed with squamous cell carcinoma and adenocarcinoma of the cervix, and studies to determine the association between preoperative fluorodeoxyglucose-PET/CT parameters and the prognosis of HGNECC are limited.
In this study, we aimed to evaluate the prognostic value of preoperative fluorodeoxyglucose-PET/CT parameters in primary HGNECC.
Materials and methods
Study population
We enrolled 29 patients with HGNECC treated at Seoul Asan Medical Center, Seoul, Korea, between 2006 and 2016 in this retrospective study. The patients were followed-up until September 2022. This retrospective cohort study was approved by the Institutional Review Board of Seoul Asan Medical Center (IRB No. S2022-1363-0001). Patients with pathologically confirmed HGNECC and aged 20–80 years were included in this study. All patients underwent a radical hysterectomy. Among them, those who underwent preoperative fluorodeoxyglucose-PET/CT were selected. Patients who underwent previous treatment such as chemotherapy or radiation therapy were excluded.
Clinical data collection
The collected clinical data included age, BMI, parity, histologic type of tumor, and clinical stage of tumor according to the 2018 International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system. We also analyzed human papillomavirus status, initial squamous cell carcinoma antigen level, tumor size, depth of invasion, metastatic lymph node status, lymphovascular space invasion (LVSI) status, resection margin involvement, and parametrial involvement. Oncologic outcomes such as adjuvant therapy, response to adjuvant therapy, recurrence, and death were further analyzed.
Preoperative fluorodeoxyglucose-PET/computed tomography parameters
All patients underwent whole-body fluorodeoxyglucose-PET/CT before initial treatment after fasting for at least 6 h. The blood glucose level of patients was less than 150 mg/dl. Intravenous administration of fluorodeoxyglucose (5.18–7.4 MBq/kg) was performed about 60 min before PET/CT scan. Images were acquired from the top of the skull to the toe level utilizing the following devices: Biograph Sensation 16 (Siemens, Knoxville, Tennessee, USA), Biograph TruePoint 40 (Siemens, Knoxville, Tennessee, USA), Discovery Ste 8 (GE Healthcare, Milwaukee, Wisconsin, USA), Discovery 690 (GE Healthcare, Milwaukee, Wisconsin, USA), Discovery 690 Elite (GE Healthcare, Milwaukee, Wisconsin, USA), or Discovery 710 (GE Healthcare, Milwaukee, Wisconsin, USA). The obtained fluorodeoxyglucose-PET/CT images were reviewed by two certified nuclear medicine physicians. The following parameters were measured and recorded: SUVmax, SUVpeak, MTV2.5, MTV3.0, TLG2.5, and TLG3.0.
Statistical analysis
Continuous variables are expressed as the mean ± SD, while categorical variables are expressed as percentages. For analyses of the differential level of fluorodeoxyglucose-PET/CT parameters according to recurrence and survival status, the patients were subdivided into no-recurrence and recurrence groups. Next, the patients were subdivided into alive and deceased groups. The differential expression level of fluorodeoxyglucose-PET/CT parameters was analyzed among the groups. Two missing values each in MTV3.0 and TLG3.0 levels existed. Paired t-test was performed to compare the mean level of fluorodeoxyglucose-PET/CT parameters among the subdivided groups. Statistical significance was set at P < 0.05. For the survival analysis, disease-free survival (DFS) was calculated by the time elapsed between the initial treatment and confirmation of tumor progression or recurrence by radiologic tests, whereas OS was measured by the time elapsed between the initial treatment and death from any cause. Patients who were alive until the last follow-up or lost to follow-up were considered censored. Univariate and multivariate analyses were performed using the Cox proportional hazard model. Multivariate analyses were performed including variables with a P < 0.2 in univariate analysis. All statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, version 26.0; IBM Corp, Armonk, New York, USA).
Results
Clinical characteristics of the patients
The patient characteristics are listed in Table 1. The median age of patients was 45 years (range 29–70 years). The median follow-up period was 40 months (range 4–184 months). In total, 24 patients (93.1%) underwent minimally invasive surgery while 5 (6.9%) underwent open surgery. Small-cell neuroendocrine carcinoma was the most common type of tumor and was seen in 26 patients (89.7%), while FIGO stage Ib2 was the most common stage of tumor and was seen in 15 patients (51.9%). Pathologic reports after surgery revealed that a tumor size of 2–4 cm was the most common, as seen in 16 patients (55.2%), followed by >4 cm, as seen in 7 patients (24.1%). The resection margins were tumor-negative in 28 patients (96.6%). There was no FIGO stage IIb or more in preoperative image tests, but 8 patients (27.6%) had parametrial tumor invasion, and 7 patients (24.1%) were positive for lymph node metastasis in the postoperative pathologic report. Of the 27 patients who underwent adjuvant treatment, 24 (88.9%) showed a complete response while 3 (11.1%) had progressive disease. The tumor recurred in 20 patients (69%), and 18 patients (62.1%) died during the observation period.
Table 1.
Demographic and clinicopathologic characteristics of patients (n = 29)
| Characteristics | n (%) |
|---|---|
| Age at initial diagnosis (years) | |
| Median (range) | 45 (29–70) |
| Follow-up period (months) | |
| Median (IQR) | 40 (4–184) |
| BMI (kg/m2) | |
| Median (range) | 21.68 (17.51–28.81) |
| Initial SCC-Ag (units/ml) | |
| Median (range) | 0.71 (0.3–2.0) |
| HPV infection | |
| No | 3 (10.3) |
| Yes | 12 (41.4) |
| Unknown | 14 (48.3) |
| HPV type | |
| HPV 16 or HPV 18 | 11 (91.7) |
| Neither HPV 16 nor 18 | 1 (8.3) |
| Surgical type of radical hysterectomy | |
| MIS | 24 (82.8) |
| Open | 5 (17.2) |
| Histologic type | |
| Small | 26 (89.7) |
| Large | 3 (10.3) |
| FIGO stage (2018) | |
| IB1 | 5 (17.2) |
| IB2 | 15 (51.9) |
| IB3 | 2 (6.9) |
| IIA1 | 3 (10.3) |
| IIA2 | 4 (13.7) |
| Tumor size | |
| Median (range) | 3 (1–9) |
| <2 cm | 6 (20.7) |
| ≥2 cm and <4 cm | 16 (55.2) |
| ≥4 cm | 7 (24.1) |
| Resection margin involvement | |
| No | 28 (96.6) |
| Yes | 1 (3.4) |
| Parametrial invasion | |
| No | 21 (72.4) |
| Yes | 8 (27.6) |
| Lymph node metastasis | |
| No | 22 (75.9) |
| Yes | 7 (24.1) |
| LVSI | |
| No | 8 (27.6) |
| Yes | 21 (72.4) |
| Depth of invasion | |
| <1/2 | 12 (41.4) |
| ≥1/2 | 17 (58.6) |
| Vaginal extension | |
| No | 25 (86.2) |
| Yes | 4 (13.8) |
| Adjuvant treatment | |
| No | 2 (6.9) |
| Yes | 27 (93.1) |
| Adjuvant treatment method | (n = 27) |
| Chemotherapy only | 12 (44.4) |
| CCRT | 15 (55.6) |
| Response to adjuvant treatment | (n = 27) |
| CR | 24 (88.9) |
| PR | 0 (0) |
| Stable disease | 0 (0) |
| Progressive disease | 3 (11.1) |
| Recurrence | |
| No | 9 (31.0) |
| Yes | 20 (69.0) |
| Death | |
| No | 11 (37.9) |
| yes | 18 (62.1) |
CCRT, concurrent chemo-radiation therapy; CR, complete response; FIGO, International Federation of Gynecology and Obstetrics; HPV, human papillomavirus; IQR, interquartile range; LVSI, lymph-vascular space invasion; MIS, minimally invasive surgery; PR, partial response; SCC-Ag, squamous cell carcinoma antigen; SD, stable disease
Differential levels of fluorodeoxyglucose-PET/computed tomography parameters according to recurrence and survival
The mean ± SD of SUVmax and SUVpeak were 8.48 ± 5.64 and 6.24 ± 3.87, respectively. The mean ± SD of MTV2.5, TLG2.5, MTV3.0, and TLG3.0 were 19.11 ± 28.48, 105.08 ± 211.1, 16.63 ± 25.45, and 102.00 ± 201.69, respectively. None of the mean levels of these parameters showed significant differences according to the recurrence and survival status (Table 2).
Table 2.
Metabolic PET parameters of the patient according to survival outcomes
| Variables | All (n = 29) | No-recurrence (n = 9) | Recurrence (n = 20) | P value | Alive (n = 12) | Death (n = 17) | P value |
|---|---|---|---|---|---|---|---|
| SUVmax | 8.48 ± 5.64 | 7.95 ± 3.17 | 8.72 ± 6.52 | 0.670 | 7.05 ± 3.47 | 9.36 ± 6.57 | 0.228 |
| Peak SUV | 6.24 ± 3.87 | 5.88 ± 2.56 | 6.40 ± 4.39 | 0.694 | 5.22 ± 2.72 | 6.86 ± 4.38 | 0.223 |
| MTV 2.5 | 19.11 ± 28.48 | 16.19 ± 18.58 | 20.43 ± 32.31 | 0.660 | 13.36 ± 17.77 | 22.63 ± 33.4 | 0.339 |
| TLG 2.5 | 105.08 ± 211.1 | 77.11 ± 97.07 | 117.66 ± 247.32 | 0.532 | 63.41 ± 92.02 | 130.54 ± 258.08 | 0.326 |
| Variables | All (n = 27) | No-recurrence (n = 8) | Recurrence (n = 19) | P value | Alive (n = 10) | Death (n = 17) | P value |
|---|---|---|---|---|---|---|---|
| MTV 3.0 | 16.63 ± 25.45 | 14.42 ± 15.45 | 17.56 ± 29.17 | 0.731 | 12.82 ± 14.53 | 18.53 ± 30.53 | 0.531 |
| TLG 3.0 | 102.00 ± 201.69 | 76.55 ± 87.60 | 112.71 ± 237.41 | 0.583 | 68.08 ± 82.38 | 118.96 ± 249.41 | 0.449 |
Values are presented as mean ± SD.
MTV, metabolic tumor volume; peak SUV, peak standardized uptake value; SUVmax, maximum standardized uptake value; TLG, total lesion glycolysis.
Prognostic value of fluorodeoxyglucose-PET/computed tomography parameters
The results of the Cox regression analysis for DFS are shown in Table 3. In the univariate analyses, age, TLG2.5, and TLG3.0 were associated with worse DFS (age, hazard ratio 1.056, 95% CI 1.014–1.100, P = 0.009; TLG2.5, hazard ratio 1.003, 95% CI 1–1.006, P = 0.033; and TLG3.0, hazard ratio 1.003, 95% CI 1–1.006, P = 0.034). In the multivariate analyses, older age and higher TLG3.0 were identified as independent poor prognostic factors for DFS (age, hazard ratio 1.058, 95% CI 1.014–1.104, P = 0.009 and TLG3.0, hazard ratio 1.004, 95% CI 1–1.007, P = 0.033). However, the Kaplan–Meier survival curve revealed that higher TLG3.0 tended to be associated with worse DFS without statistical significance. Table 4 shows the results of the Cox regression analysis for OS. In multivariate analyses, only resection margin involvement was identified as an independent factor for predicting poor OS (hazard ratio 20.717, 95% CI 1.289–332.964, P = 0.032).
Table 3.
Cox regression analysis of disease-free survival
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | |
| Age, years | 1.056 | 1.014–1.100 | 0.009 | 1.058 | 1.014-1.104 | 0.009 |
| BMI, kg/m² | 0.923 | 0.788–1.081 | 0.319 | – | – | – |
| FIGO stage, n | 1.348 | 0.975–1.863 | 0.071 | – | – | – |
| Surgical type of radical hysterectomy | ||||||
| MIS | 1 | – | – | – | – | – |
| Open | 0.652 | 0.217–1.962 | 0.447 | – | – | – |
| Tumor size, mm | 1.160 | 0.851–1.581 | 0.348 | – | – | – |
| Depth of invasion | ||||||
| <1/2 | 1 | – | – | – | – | – |
| ≥1/2 | 1.554 | 0.615–3.926 | 0.351 | – | – | – |
| Parametrial invasion | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 2.157 | 0.841–5.533 | 0.110 | – | – | – |
| Resection margin involvement | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 1 | 1–46237.801 | 1.000 | – | – | – |
| Lymph node metastasis | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 1.226 | 0.444–3.387 | 0.694 | – | – | – |
| LVSI | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 2.401 | 0.796–7.241 | 0.120 | – | – | – |
| SUVmax | 1.050 | 0.957–1.151 | 0.302 | – | – | – |
| Peak SUV | 1.065 | 0.943–1.203 | 0.313 | – | – | – |
| MTV 2.5 | 1.017 | 0.997–1.036 | 0.097 | – | – | – |
| MTV 3.0 | 1.019 | 0.997–1.042 | 0.088 | – | – | – |
| TLG 2.5 | 1.003 | 1–1.006 | 0.033 | – | – | – |
| TLG 3.0 | 1.003 | 1–1.006 | 0.034 | 1.004 | 1–1.007 | 0.033 |
CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymph-vascular space invasion; MIS, minimally invasive surgery; MTV, metabolic tumor volume; peak SUV, peak standardized uptake value; SUVmax, maximum standardized uptake value; TLG, total lesion glycolysis.
Table 4.
Cox regression analysis of overall survival
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | |
| Age, years | 1.053 | 1.001–1.007 | 0.046 | 1.051 | 0.997-1.107 | 0.064 |
| BMI, kg/m² | 0.902 | 0.760–1.071 | 0.238 | – | – | – |
| FIGO stage, n | 1.191 | 0.878–1.615 | 0.261 | – | – | – |
| Surgical type of radical hysterectomy | ||||||
| Open | 1 | – | – | – | – | – |
| MIS | 0.589 | 0.192–1.804 | 0.354 | – | – | – |
| Tumor size, mm | 1.154 | 0.820–1.625 | 0.411 | – | – | – |
| Depth of invasion | ||||||
| <1/2 | 1 | – | – | – | – | – |
| ≥1/2 | 1.922 | 0.864–5.406 | 0.215 | – | – | – |
| Parametrial invasion | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 1.908 | 0.737–4.939 | 0.183 | – | – | – |
| Resection margin involvement | ||||||
| No | 1 | – | – | 1 | – | – |
| Yes | 27.495 | 1.720–439.634 | 0.019 | 20.717 | 1.289–332.964 | 0.032 |
| Lymph node metastasis | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 1.606 | 0.570–4.528 | 0.370 | – | – | – |
| LVSI | ||||||
| No | 1 | – | – | – | – | – |
| Yes | 2.528 | 0.701–9.113 | 0.158 | – | – | – |
| SUVmax | 1.043 | 0.956–1.137 | 0.345 | – | – | – |
| Peak SUV | 1.046 | 0.930–1.175 | 0.455 | – | – | – |
| MTV 2.5 | 1.013 | 0.994–1.032 | 0.188 | – | – | – |
| MTV 3.0 | 1.009 | 0.986–1.033 | 0.428 | – | – | – |
| TLG 2.5 | 1.002 | 1.–1.005 | 0.094 | – | – | – |
| TLG 3.0 | 1.002 | 0.999–1.005 | 0.204 | – | – | – |
CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymph-vascular space invasion; TLG, total lesion glycolysis; MIS, minimally invasive surgery; MTV, metabolic tumor volume; peak SUV, peak standardized uptake value; SUVmax, maximum standardized uptake value.
Discussion
HGNECC is a rare and aggressive subtype of cervical cancer [7]; however, due to its rarity and high aggressiveness, large-scale prospective studies to investigate this cancer have not been conducted. Therefore, the optimal treatment strategy and factors for predicting prognosis have not been fully established. In this study, we analyzed the association between the preoperative fluorodeoxyglucose-PET/CT metabolic parameters and the prognosis of HGNECC. Among the parameters, TLG3.0 was the only independent factor associated with worse DFS in patients with neuroendocrine cancer.
SUV is a well-known parameter of fluorodeoxyglucose-PET/CT, and it is defined as the ratio of the activity concentration in certain lesions to that in the whole body [19]. SUVmax is defined as the maximum voxel value of SUV in the tumor, while SUVpeak is the maximum average SUV of 1 cm3 in the tumor [20]. Some studies have previously reported that SUVs are associated with the prognosis of various cancers. Moreover, some reports have shown an association between SUV and the prognosis of cervical cancer. Takagi et al. reported that SUVmax was significantly different between stage ≤I and ≥II cervical cancer, and Yagi et al. reported that high SUVmax was associated with poor clinical outcomes in patients undergoing radical hysterectomy [21,22]. Conversely, MTV and TLG are the quantitative indexes among the fluorodeoxyglucose-PET/CT parameters that measure the metabolically active tumor volume and activity, respectively [23,24]. These parameters are also reported as prognostic factors in several types of cancers, including those of the uterine cervix. Chung et al. previously reported that MTV and TLG were significantly associated with tumor recurrence, while Calles-Sastre et al. reported that MTV and TLG were significantly associated with OS and recurrence-free survival [13,25]. However, these studies focused only on the usual histologic subtypes of cervical cancer, such as squamous cell carcinoma and adenocarcinoma, and high-grade neuroendocrine histologic subtypes were not included in these studies. Unlike previous reports, in our study, the mean expression level of each fluorodeoxyglucose-PET/CT parameter did not show significant differences between the recurrent and non-recurrent subgroups or the alive and deceased subgroups. This may be due to the difference in histologic entities, the outlying value of some of the parameters, or the small sample size. A recent study from China that included 22 patients with HGNECC reported that MTV and TLG, but not SUV, were independently associated with worse progression-free survival [26]. Our study differed in that MTV was not associated with prognosis; however, similar to the previous report, we found that TLG was an independent prognostic factor for HGNECC, while SUV was not.
Lymph node metastasis, resection margin involvement, LVSI, and large tumor size are well-known factors for predicting the poor prognosis of cervical cancer [27–29]. According to a study by Chen et al., on 172 patients with neuroendocrine cervical tumors, older age, advanced FIGO stage, large tumor size, and lymph node metastasis were all independent factors for predicting the poor prognosis [30].
In our study, we observed nodal involvement in 24% of cases and LVSI in 72%. These incidence rates were consistent with the range reported in other studies, but these factors did not affect survival outcomes [30–32]. However, in our study, age was independently associated with DFS, and resection margin involvement was associated with worse OS. Other factors such as lymph node metastasis, LVSI, and large tumor size were not found to be associated with prognosis in our study. This may be because of the small sample size in our study.
This study had several limitations. First, it was a retrospective single-center study. Thus, there might be inherent biases. Second, the sample size of this study was small due to the rarity of this cancer subtype. Nevertheless, our study is notable as, along with the study of Jiang et al., it is the first to investigate the association between fluorodeoxyglucose-PET/CT parameters and the prognosis of HGNECC. Both studies consistently showed that TLG is associated with poor prognosis in patients with HGNECC.
Our study results suggest that among the preoperative fluorodeoxyglucose-PET/CT parameters, TLG3.0 may be useful in predicting DFS in patients with HGNECC. However, future large-scale prospective studies will be necessary to validate the results of this study.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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