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Keywords:

  • neoplasms staging;
  • primary androgen deprivation therapy;
  • prognostic grouping;
  • prostate;
  • validation studies

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Objective

In the TNM seventh edition, a prognostic grouping for prostate cancer incorporating prostate-specific antigen and Gleason score was advocated. The present study was carried out to evaluate and validate prognostic grouping in prostate cancer patients.

Methods

The 15 259 study patients treated with primary androgen deprivation therapy were enrolled in the Japan Study Group of Prostate Cancer. Overall survival was stratified by tumor–nodes–metastasis, Gleason score and prostate-specific antigen, and extensively analyzed. The accuracy of grouping systems was evaluated by the concordance index.

Results

The 5-year overall survival in prognostic grouping-I, IIA, IIB, III and IV was 90.0%, 88.3%, 84.8%, 80.6% and 57.1%, respectively. When considering subgroup stratification, the 5-year overall survival of subgroups prognostic grouping-IIA, IIB, III and IV was 80.9∼90.5%, 75.4∼91.8%, 75.7∼89.0% and 46.9∼86.2%, respectively. When prognostic grouping-IIB was subclassified into IIB1 (except IIB2) and IIB2 (T1–2b, prostate-specific antigen >20, Gleason score ≥8, and T2c, Gleason score ≥8), the 5-year overall survival of IIB2 was significantly lower than that of IIB1 (79.4% and 87.3%, P < 0.0001). Also, when prognostic grouping-IV was subclassified into IV1 (except IV2) and IV2 (M1, prostate-specific antigen >100 or Gleason score ≥8), the 5-year overall survival of prognostic grouping-IV1 was superior to that of IV2 (72.9% and 49.5%, P < 0.0001). Prognostic groupings were reclassified into modified prognostic groupings, divided into modified prognostic grouping-A (prognostic grouping-I, IIA, and IIB1), modified prognostic grouping-B (prognostic grouping-IIB2 and III), modified prognostic grouping-C (prognostic grouping-IV1) and modified prognostic grouping-D (prognostic grouping-IV2). The concordance index of prognostic grouping and modified prognostic grouping for overall survival was 0.670 and 0.685, respectively.

Conclusion

Prognostic grouping could stratify the prognosis of prostate cancer patients. However, there is considerable variation among the prognostic grouping subgroups. Thus, the use of a modified prognostic grouping for patients treated with primary androgen deprivation therapy is advisable.


Abbreviations & Acronyms
ADT

androgen deprivation therapy

AJCC

American Joint Committee on Cancer

c-index

concordance index

CSS

cancer-specific survival

GS

Gleason score

J-CaP

Japan Study Group of Prostate Cancer

mPG

modified prognostic grouping

OS

overall survival

PADT

primary androgen deprivation therapy

PC

prostate cancer

PFS

progression-free survival

PG

prognostic grouping

PSA

prostate-specific antigen

SG

stage grouping

TNM

tumor–nodes–metastasis

UICC

Union for International Cancer Control

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

The TNM classification system by the UICC and the AJCC is used worldwide for the stage classification of malignancies, including PC. This TNM classification correlates the prognoses for PC and is used to select the treatment modalities. However, serum levels of PSA and a histological scoring system known as GS correlate strongly with the prognosis, as well as with TNM staging. Thus, several risk classification systems have been developed for localized or locally advanced PC in combination with multifactorial prognostic factors.[1-3] D'Amico's classification was a system of risk stratification originally developed to guide in the selection of radiation therapy for localized or locally advanced PC.[4] D'Amico's classification has also been validated for surgical treatment in several studies.[5] Based on this historical background, the UICC and AJCC developed PG for PC in the TNM seventh edition by incorporating PSA and GS into TNM SG in 2011.[6, 7] The PG classifies localized PC (SG-I and II) into three groups (PG-I, IIA and IIB) using PSA cut-off values of 10 and 20 ng/mL, and GS cut-off values of 6 or less, 7 and 8 or more. This classification system is almost identical to the risk classification by D'Amico, where low, intermediate and high risk correspond to PG-I, PG-IIA and PG-IIB/III, respectively.

As PC is an androgen-sensitive malignant tumor, PADT is used worldwide for patients with metastatic disease or locally advanced PC. Surgical treatment or radiation therapy is the gold standard for treating localized PC, and PADT is an option to provide sufficient outcomes. To improve the prognosis for these patients, ADT in combination with such definitive therapies is recommended as combination therapy.[8-10] PADT is also a reasonable alternative option for local or locally advanced disease in various patient conditions, such as in elderly patients, those with poor performance status or those with particular hopes (rejection for operation and radiation therapy).[11, 12] In fact, PADT including complete androgen blockade, castration, anti-androgen agent monotherapy and intermittent administration is used in 14.1–49.8% of patients with localized PC in Japan and Western countries.[13-16] Thus, ADT plays crucial roles in the treatment of various stages of PC; however, mostly in metastatic disease and not in all stages, and it is important to elucidate the clinical outcomes of PADT.

To understand the reality and treatment outcomes of ADT, we have started a nationwide longitudinal cohort study called the J-CaP study. In the J-CaP study, more than 26 000 PC patients treated by ADT were enrolled between 2001 and 2003, and have been followed up until now. Several crucial findings have been reported from this study.[17-19] In particular, we provided a new risk-scoring system known as J-CAPRA for patients treated with PADT in combination with the Cancer of the Prostate Strategic Urologic Research Endeavor database in the USA.[19]

In the present study, we validated the PG of the TNM seventh edition using this J-CaP database, to elucidate whether the PG could stratify the prognosis of PC patients. Furthermore, we provided mPG for PADT patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Patient backgrounds

A total of 26 272 men were enrolled in J-CaP; of these, 19 265 were treated with PADT.[17-19] Clinical variables available from this database include patient age, PSA value, GS, clinical TNM stage, details of ADT and follow-up data until 31 December 2011. The 4006 patients who had a missing value in this database were excluded, and we finally analyzed 15 259 patients. The patient backgrounds are described in Table 1. The median age was 75 years (range 35–99 years). The median PSA level at diagnosis was 24.5 ng/mL (range 0.01–30789).

Table 1. Patient background
 n%
Age (years)  
–693 16020.7
70–743 86025.3
75–794 44729.1
80–3 79224.9
Total15 259100
Gleason score  
2–65 38035.3
74 38428.7
8–105 49536
Total15 259100
PSA  
0–103 76424.7
10–203 03819.9
20–1004 61830.3
100–3 83925.2
Total15 259100
T stage (7th)  
T13 19921.0
T2b2 50516.4
T2c2 43516.0
T35 58336.6
T41 53710.1
Total15 259100
N stage  
N012 86584.3
N12 39415.7
Total15 259100
M stage  
M011 15073.1
M14 10926.9
Total15 259100

Classification and subgrouping of patients

In the J-CaP database, T stage was determined according to the TNM fifth edition, because the patients were enrolled from 2001 to 2003. To validate the PG, we had to convert from the fifth edition to the seventh edition in the patients of T2 stage. To avoid underestimation when applied to the grouping system, the T2a of the fifth edition was converted to T2b of the seventh edition.

In this database, the clinical stage was used, because they were diagnosed by biopsy specimen and imaging modalities, such as transrectal ultrasonography, magnetic resonance imaging, computed tomography and so on.

The patients were divided into subgroups by TNM stage, GS and PSA value using the cut-off values of PSA at 10 and 20 ng/mL, and GS of 6 or less, 7 and 8 or more. The OS was calculated in each subgroup by Kaplan–Meier analysis (Table 2). mPG were developed depending on similar 5-year OS of these subgroups.

Table 2. Five-year OS of subgroups stratified by TNM, PSA, GS
 TPSAGSn5-year OS (%)CISubclassified PGmPG
  1. T2a and T2b (TNM5th) were converted into T2b and T2c (TNM7th), respectively. A slash part is IIB2 and a bold letter part is IV2.

PG ITotal  115690.0(87.6–92.1)  
 T1≤10≤6115690.0(87.6–92.1)IA
PG IIATotal  244288.4(86.6–90.0)  
 T1≤10734088.8(83.3–92.6)IIAA
 T110<, ≤20719690.1(82.3–94.7)
 T110<, ≤20≤653189.0(85.1–92.1)
 T2b≤10≤656290.5(86.7–93.3)
 T2b10<, ≤20≤640688.8(83.9–92.4)
 T2b≤10720985.5(78.0–90.7)
 T2b10<, ≤20719880.9(72.2–87.4)
PG IIBTotal  369885.5(83.9–87.0)  
 T120<≤621987.4(80.3–92.2)IIB1A
 T2b20<≤625891.4(85.8–95.0)
 T120<714785.2(76.4–91.1)
 T2b20<718583.5(74.5–89.7)
 T1≤10≥818487.5(79.9–92.5)
 T2b≤10≥813387.8(79.1–93.2)
 T110<, ≤20≥814186.4(75.0–93.1)
 T2b10<, ≤20≥813991.8(81.8–96.6)
 T120<≥813580.4(69.6–88.0)IIB2B
 T2b20<≥818583.8(74.3–90.2)
 T2c≤10≤626391.4(84.5–95.4)IIB1A
 T2c10<, ≤20≤624488.6(82.1–92.9)
 T2c20<≤628786.1(79.4–90.8)
 T2c≤10713084.0(74.4–90.5)
 T2c10<, ≤20720386.2(78.7–91.3)
 T2c20<735285.1(79.5–89.4)
 T2c10≥88582.8(70.5–90.6)IIB2B
 T2c10<, ≤20≥811578.0(65.9–86.6)
 T2c20<≥829375.4(67.4–81.9)
PG IIITotal  291980.6(78.6–82.4)  
 T3≤10≤611689.0(78.9–94.6)IIIB
 T310<, ≤20≤616784.4(75.0–90.7)
 T320<≤641482.2(76.7–86.6)
 T3≤10712080.3(69.3–88.1)
 T310<, ≤20714688.5(80.1–93.6)
 T320<775281.7(77.9–85.0)
 T3≤10≥813079.9(70.4–87.0)
 T310<, ≤20≥817975.7(67.0–82.6)
 T320<≥889576.7(72.8–80.1)
PG IVTotal  504457.1(55.2–58.9)  
 T4N1≤100≤69586.2(74.3–93.1)IV1C
 T4N1≤100715675.8(65.6–83.7)
 T4N1≤100≥829066.3(58.6–73.2)
 T4N1100<≤63877.2(47.8–92.6)
 T4N1100<712070.9(59.5–80.2)
 T4N1100<≥823675.1(67.8–81.2)
 M1≤100≤633075.3(67.9–81.4)
 M1≤100739669.9(63.4–75.6)
 M1≤100≥873751.1(46.2–55.9)IV2D
 M1100<≤629461.4(53.4–68.8)
 M1100<773449.1(44.3–54.0)
 M1100<≥8161846.9(43.8–50.1)

Statistical analysis

OS, CSS and PFS were assessed by the Kaplan–Meier methods. Differences among groups were assessed by the log–rank test. P < 0.05 was considered statistically significant. When calculating the survival, the first day of endocrine therapy was counted as the starting point. Events taken into account in calculation of the PFS were PSA failure, clinical failure and death. If multiple events occurred in the same patient, the time of appearance of the first of these events was deemed as the time of event in this patient.[17, 18]

The accuracy of grouping systems was evaluated by the c-index. These statistical analyses were carried out using JMP9 (SAS Institute, Cary, NC, USA) and STATA11 (Stata Corp, College Station, TX, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Comparison of risk classification by SG and PG

The number of patients in SG-I, II, III and IV were 3049 (20.0%), 4247 (27.8%), 2919 (19.1%) and 5044 (33.1%), respectively; whereas those in PG-I, IIA, IIB, III and IV were 1156 (7.6%), 2442 (14.7%), 3690 (24.2%), 2919 (19.1%) and 5044 (33.1%), respectively. Kaplan–Meier analysis showed the 5-year OS of SG and PG (Fig. 1). The OS of SG-I, II, III and IV was 88.6% (95% CI 87.0–90.0%), 86.3% (95% CI 84.8–87.6), 80.6% (95% CI 78.6–82.4) and 57.1% (95% CI 55.2–58.9), respectively. The 5-year OS of PG-I, IIA, and IIB was 90.1% (95% CI 87.6–92.1), 88.4% (95% CI 86.6–90.0) and 85.5% (95% CI 83.9–87.0), respectively.

figure

Figure 1. Kaplan–Meier curve of OS, CSS and PFS according to SG and PG. (a) SG OS, (b) SG CSS, (c) SG PFS, (d) PG OS, (e) PG CSS and (f) PG PFS. image, SG-I; image, SG-II; image, SG-III; image, SG-IV; image, PG-I; image, PG-IIA; image, PG-IIB; image, PG-III; image, PG-IV.

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We also evaluated CSS and PFS as secondary end-points using SG and PG (Fig. 1). The 5-year CSS in SG-I, II, III and IV was 98.6%, 97.8%, 93.2% and 66.7%, respectively; whereas that in PG-I, IIA and IIB was 99.6%, 99.1% and 97.1, respectively. The 5-year PFS in SG-I, II, III and IV was 70.2%, 64.6%, 53.7% and 24.8%, respectively; whereas that in PG-I, IIA and IIB was 75.9%, 69.5% and 62.3%, respectively. Thus, PG could stratify the prognosis of patients treated by PADT based on OS, CSS and PFS. However, the OS of PG-I and IIA were relatively close, and that of PG-IV was far poorer than that of PG-I to III.

Subclassification of PG by TNM, PSA and GS

To clarify the heterogeneity of prognosis in each PG, we subclassified the patients of PG-I, IIA, IIB and III by PSA and GS, using PSA cut-off levels of 10 and 20 ng/mL, and GS cut-off levels of 6 or less, 7 and 8 or more. PG-IV was subclassified according to a PSA cut-off level of 100 ng/mL, on the basis of J-CAPRA score,[19] and GS as the same as above, and the presence or absence of distant metastasis (Table 2). Kaplan–Meier analysis showed that the 5-year OS of subgroups belonging to PG-I, IIA, IIB, III and IV were 90.0%, 80.9–90.5%, 75.4–91.8%, 75.7–89.0% and 46.9∼86.2%, respectively (Fig. 2 and Table 2). There was considerably wide variation among the subgroups in each PG. Interestingly, PG-IIB could be divided into IIB1 (IIB except IIB2) and IIB2 (T1 or T2b, PSA >20 ng/mL, GS ≥8, and T2c, GS ≥8), based on the poorer 5-year OS of the latter subgroups. The 5-year OS of IIB2 was significantly lower than that of IIB1 (79.4% and 87.3%, P < 0.0001). In contrast, there was no statistically significant difference between IIB1 and I (5-year OS 87.3% and 90.1%, P = 0.1856) or IIA (5-year OS 87.3% and 88.4%, P = 0.2340). Also, there was no statistically significant difference between PG-IIB2 and III (79.4% and 80.6%, P = 0.2950). Similarly, Table 2 shows that there were two distinct groups in PG-IV. When PG-IV was divided into IV1 (IV except IV2) and IV2 (M1, PSA >100 ng/mL or GS ≥ 8), the 5-year OS of PG-IV2 was significantly lower than that of PG-IV1 (49.5% and 72.9%, P < 0.0001). There was no statistically significant difference between PG-III and IV1 (5-year OS 80.6% and 72.9%, P = 0.2950).

figure

Figure 2. Kaplan–Meier curve of OS for each PG. (a) OS, (b) CSS and (c) PFS. image PG-I; image, PG-IIA; image, PG-IIB1; image, PG-IIB2; image, PG-III; image, PG-IV1; image, PG-IV2.

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Development of a novel PG (mPG) for patients treated with PADT

Based on the aforementioned analysis, we developed mPG for patients treated with PADT, with patients classified into four groups: A (PG-I, IIA, IIB-1), B (IIB-2, III), C (IV1) and D (IV2) (Table 3). Kaplan–Meier analysis of OS, CSS and PFS is shown in Figure 3. The 5-year OS of mPG-A, B, C and D was 88.2% (95% CI 87.1–89.2), 80.3% (95% CI 78.6–82.0), 72.9% (95% CI 70.0–75.7), and 49.5% (95% CI 47.2–51.7), respectively. In addition, CSS and PFS, as secondary end-points, were analyzed using the mPG (Fig. 3). The 5-year CSS in mPG-A, B, C and D was 98.7%, 93.3%, 82.0% and 59.2%, respectively. The 5-y PFS in mPG-A, B, C and D was 68.6%, 53.6%, 39.7% and 17.8%, respectively. To estimate the effects of age, we divided the patients into groups using 75 years as the median age. The number of patients in the younger group (less than 75 years) and the older group (75 years or older) were 8329 and 7020, respectively. PG and mPG showed similar survival curves in both the younger and older groups (Fig. 4).

figure

Figure 3. Kaplan–Meier curves of OS, CSS and PFS for mPG are shown. (a) OS, (b) CSS and (c) PFS. image, A; image, B; image, C; image, D.

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figure

Figure 4. Kaplan–Meier curve of OS for PG and mPG for each group. (a) PG in the younger group (less than 75 years), (b) PG in the older group (75 years or more), (c) mPG in the younger group and (d) mPG in the older group. image, PG-I; image, PG-IIA; image, PG-IIB; image, PG-III; image, PG-IV; image, A; image, B; image, C; image, D.

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Table 3. Classification of mPG
Subclassified PGmPG
 PSAGS ≤ 6GS = 7GS ≥ 8 PSAGS ≤ 6GS = 7GS ≥ 8
T1≤10IIIAIIB-1T1≤10AAA
10<, ≤20IIAIIAIIB-110<, ≤20AAA
20<IIB-1IIB-1IIB-220<AAB
T2a,b≤10IIAIIAIIB-1T2a, b≤10AAA
10<, ≤20IIAIIAIIB-110<, ≤20AAA
20<IIB-1IIB-1IIB-220<AAB
T2c≤10IIB-1IIB-1IIB-2T2c≤10AAB
10<, ≤20IIB-1IIB-1IIB-210<, ≤20AAB
20<IIB-1IIB-1IIB-220<AAB
T3≤10IIIIIIIIIT3≤10BBB
10<, ≤20IIIIIIIII10<, ≤20BBB
20<IIIIIIIII20<BBB
T4N1≤100IV-1IV-1IV-1T4N1≤100CCC
100<IV-1IV-1IV-1100<CCC
M1≤100IV-1IV-1IV-2M1≤100CCD
100<IV-2IV-2IV-2100<DDD

The c-index was calculated to evaluate the accuracy of SG and PG in the risk classification of PC patients treated by PADT. The c-index of SG, PG and mPG for OS was 0.668, 0.670 and 0.685, respectively. Similarly, the c-indexes of SG, PG and mPG were 0.798, 0.801 and 0.825 for CSS, and 0.680, 0.683 and 0.694 for PFS, respectively.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

In the present study, the use of PG in the TNM seventh edition was validated using the data of PC patients who were treated with PADT from the J-CaP database. Our data showed that PG could stratify the prognosis of patients, including OS, CSS and PFS for the patients who were treated with PADT. However, the OS of PG-I to III were relatively close. In contrast, the OS of PG-IV was far poorer than those of PG-I to III. One of the features of the present study was that the prognosis of subgroups stratified by TNM, PSA and GS could be analyzed, because our database included 15 259 patients treated with PADT, and each subgroup consisted of a median of 206 patients (range 86–1618). Through these analyses, it became clear that the prognosis of the subgroups in each PG varied widely. Interestingly, our data clearly showed that there were two groups with distinct prognosis in PG-IIB and IV, which were subclassified as PG-IIB1/IIB2 and PG-IV1/IV2. The OS of PG-IIB1 was almost equivalent to those of PG-I and IIA, whereas the OS of PG-IIB2 was almost equivalent to that of PG-III. Similarly, the patients of T4N0M0 and TXN1M0 showed almost equivalent survival to those of PG-III. Even if they had metastatis, the patients of GS 7 or less and PSA 100 ng/mL or less showed a relatively better prognosis, which was similar to that of PG-III. Furthermore, we developed a modified PG for the patients treated with PADT, based on our findings. The c-index of mPG was higher than that of SG and PG in the analysis of all kinds of end-points, including OS, CSS and PFS.

The survival of patients with localized PC who were treated by radical prostatectomy or radiation therapy was stratified by the D'Amico classification.[20-24] Generally, the prognosis of patients with high-risk PC was clearly worse than those of patients with low- or intermediate-risk PC, when they were treated by operation or radiation monotherapy. To improve the clinical outcomes of these patients, optimization of treatment protocols depending on the risk group was carried out, such as dose escalation of radiotherapy, introduction of new radiation techniques or combination use of ADT.[25, 26] Long-term adjuvant therapy using ADT was believed to be especially important for high-risk PC, which had possibly concomitant micrometastasis. Our data showed that the 5-year OS and CSS of PG-I, PG-IIA and PG-IIB/III who were treated by PADT were slightly worse, but almost comparable with those of the patients with the same risk of PC treated by radical prostatectomy or radiation therapy.[20-24] Our data also showed that PADT was more effective for patients with low GS PC than for those with high GS. These data provide useful information for predicting the effect of ADT before or after radical therapy.

Generally, PADT is the gold standard of the treatment for PG-IV PC. As shown in the present study, however, the patients of PG-IV have various clinical backgrounds, and the treatment results of PADT also differ greatly. To improve the clinical outcomes, recent new approaches in addition to PADT or other than PADT have been developed for this group. There are some reports of the combination use of ADT with radiotherapy for N1 cases and of prostatectomy after ADT or chemotherapy for T4 or N1 cases to improve clinical outcomes.[27-29] In contrast, PADT is also effective for patients with metastasis at first, but the problem was to become castration-resistant prostate cancer at shorter duration. The PG-IV is a very heterogenous population and probably needs more subdivision than just PG-IV1 and IV2. The present results indicated that among metastatic disease, PC such as PG-IV2 presented a very poor prognosis, and we should improve the clinical outcomes of this subpopulation if possible. For this population, the introduction of new agents, including docetaxel, cabazitaxel and molecular target drugs, in the early phase of treatment has been reported.[30] The patients of PG-IV2 (M1, PSA >100 ng/mL or GS ≥ 8) might be chosen first in the future for the use of those drugs. Thus, it might be important to stratify the risk of PG-IV to develop new treatments or compare the outcomes of these treatments. Although there are few reports about classifying PG-IV so far, the results of the present study are very useful and applicable for choosing the treatment and evaluating the prognosis when considering the medical treatment that ranks second to PADT.

When interpreting the results of this research, there are some points that should be noted. First, in the present study, we validated the use of PG only for the cohort of patients treated by PADT; therefore, further studies are required to validate the study results for the cohort treated by definitive treatments. The second point was that patients were registered to the database by the TNM fifth edition in the present study, and we had to substitute to the seventh edition from the fifth edition for patients in the T2 stage. Although we tried to classify the T2a and T2b of the fifth edition as T2b of the seventh edition, the patients of T1, T2a and T2b had actually almost the same prognosis. The third point was that the present study involved large-scale research with many institutions, and as diagnosis is not based on the work of a central pathologist, pathological assessment might not be unified.

The present study is the first report that verified the validity of the PG of the TNM seventh edition using a large-scale database. Although this classification could appropriately stratify the prognosis, each group still consisted of subgroups with a wide variety in prognosis of patients treated with PADT. The mPG might provide improved accuracy in predicting prognosis in PC treated by PADT and should be validated using a large database of PC patients treated by other modalities.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References
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