Outcome and prognostic factors for atypical meningiomas after first recurrence

Journal of Clinical Neuroscience 63 (2019) 100–105

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Clinical study

Outcome and prognostic factors for atypical meningiomas after first recurrence Guobin Zhang a,1, Yunsheng Zhang a,b,1, Guijun Zhang a,1, Da Li a, Zhen Wu a, Yonggang Wang a,⇑, Junting Zhang a,⇑ a b

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing 100050, PR China Department of Neurosurgery, Civil Aviation General Hospital, Peking University, Chaoyang District, Beijing 100023, PR China

a r t i c l e

i n f o

Article history: Received 19 August 2018 Accepted 18 January 2019

Keywords: Atypical meningioma Recurrence Prognostic factors Surgery Gamma knife radiosurgery

a b s t r a c t Atypical meningioma (AM) tends to be tumor with high rates of recurrence and mortality. In this retrospective study, 131 recurrent AM patients underwent AM surgery in Beijing Tiantan Hospital between January 2008 and December 2015. Of the 131 cases collected, 61 were male (46.6%), and 70 (53.4%) were female. 53 (40.5%) patients chose observation instead of therapy, 53 (40.5%) received repeat surgery and 25 patients (19.0%) received gamma knife surgery (GKS). The median overall survival (OS) was 34.6 months and actuarial OS of patients at 1, 3 and 5 years were 88.6%, 48.8%, 36.0%, respectively. In the treatment group including 78 patients with surgery and GKS group, a tumor progression happened to 35 patients (44.9%). The median duration of progression-free survival (PFS) was 34.5 months and the median OS was 61.7 months. Second PFS at 1, 3 and 5 years were 84.1%, 46.5% and 24.0%, respectively; the corresponding OS was 98.5%, 75.1%, 57.9%, respectively. Multivariate analysis revealed treatment strategy was the only independent factor (P < 0.001). In the treatment group, non-peritumoral edema (P = 0.002), preoperative KPS (per 10 scores increase) (P < 0.001) and GKS (P = 0.042) was related to better OS. Short interval (<24 months) from symptoms onset to intervention was related to better PFS (P = 0.004) in univariate analysis. This retrospective study presents the largest cohort of recurrent AM patients, surgical treatment is recommended in patients with tumor recurrence, and GKS is considered a promising therapeutic option of recurrence atypical meningioma. Ó 2019 Published by Elsevier Ltd.

1. Introduction Meningiomas, which are thought to arise from arachnoid capcells, account for more than 30% of all intracranial neoplasms. According to the 2016 World Health Organization (WHO) classification criteria, they can be classified into three types: WHO grade I (benign), WHO grade II (atypical), and WHO grade III (anaplastic or malignant) [1]. Atypical meningiomas (AMs), which account for approximately 20–30% of all meningiomas diagnosed, is an aggressive subtype of meningioma associated with a high recurrence rates following surgical resection [2–4]. Histopathologically, they Abbreviations: AM, atypical meningiomas; CI, confidence interval; GKS, gamma knife radiosurgery; KPS, Karnofsky performance scale; PRT, postoperative radiotherapy; GTR, gross total resection; STR, subtotal resection; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; MRI, magnetic resonance imaging. ⇑ Corresponding authors. E-mail addresses: [email protected] (Y. Wang), [email protected] (J. Zhang). 1 Joint first authors: Guobin Zhang, Yunsheng Zhang and Guijun Zhang contributed equally to the work. https://doi.org/10.1016/j.jocn.2019.01.032 0967-5868/Ó 2019 Published by Elsevier Ltd.

could be defined in as follows: 4–19 mitotic index figures per 10 high-power field, exhibiting three of the following histological features: increased cellularity, small cells with a high nuclear-tocytoplasmic ratio, large and prominent nucleoli, patternless or sheetlike growth, or foci of spontaneous necrosis [1]. Many recurrent studies have reported on the treatment and prognosis of atypical meningiomas, which had a greater rate of recurrence compared with benign tumors at 5 years [4–6]. However, few studies have been reported in detail that prognostic factors and treatment regarding outcome in recurrence atypical meningioma. Surgery appears to be the preferred choice for recurrence atypical meningioma, however, the benefits of other treatments including radiotherapy for patient survival is still need to be explored. To increase our understanding of risk factors in recurrence atypical meningiomas and to guide their treatment, we aimed to investigate appropriate management strategies and to identify predictors of better survival for recurrent AM.

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2. Materials and methods

3. Results

2.1. Patient selection

3.1. Population description

In this study, 330 patients underwent AM resection in Beijing Tiantan Hospital between January 2008 and December 2015. In these cases, 131 patients experienced recurrences at final followup. All patients had the pathologically identified AM by the neuropathology department of our hospital. Approval of this study was granted by the Beijing Tiantan hospital committee on human research.

Of the 131 cases collected, 61 were male (46.6%), and 70 (53.4%) were female. The mean ages at first recurrence was 49 ± 20 years (range, 7–73 years). 100 cases (76.3%) were primary AM and 31 cases (23.7%) were secondary tumor. The first symptoms of patients attributed to tumor location. The major initial preoperative symptoms in recurrent AM patients were headache (n = 41, 31.3%), and the probability of motor and walking impairment and epilepsy were closely followed. Tumor location was divided into two parts: skull base (n = 35, 26.7%) and non-skull base (n = 96, 73.3%). The median preoperative KPS score was 80. The mean maximum tumor diameter was 5.0 ± 2.0 cm (range, 1.5– 10 cm). According to preoperative MRI and operative records, 56 patients (42.7%) had peritumoral edema (including 24 males and 32 females). Bone invasion occurred in 40 patients (59.7%) of the patient cohort (including 22 males and 18 females). 17 patients with bone invasion received surgery, 10 patients received GKS and 13 patients chose observation. The patient characteristics were listed in Table 1.

2.2. Data collection The patient data were collected from the patient data management system. The following characteristics were noted: age at first recurrence of AM; gender; preoperative Karnofsky performance scale (KPS) score; tumor groups were divided into primary tumor (the first diagnosis was atypical meningiomas) and secondary tumor (the prior surgery for WHO grade I meningioma and then transformed to atypical meningioma); interval (we defined the time between initial surgery to first recurrence); tumor location (at the skull base vs. non-skull base); size (tumor size was measured as the maximum diameter); peritumoral edema; bone invasion; boundary; extent of resection; administration of GKS and administration of postoperative radiotherapy (PRT). The tumor characteristics were deduced from the operative records and preoperative magnetic resonance imaging (MRI). The extent of resection was identified by the operative records and postoperative MRI. Those patients routinely received postoperative contrasted MRI within 3 to 7 days after surgery when they were stable. Surgical resection was graded according to the Simpson grades. We defined Simpson grade I-II as gross total resection (GTR) and Simpson III-IV as subtotal resection (STR). Bone invasion was defined that tumor massed into bone, hyperostosis and/or bone destruction. Progression-free survival (PFS) as the time from the date of surgery for the first recurrence to a second tumor progression in postoperative MRI, and overall survival (OS) as the time from the first recurrence to the date of death, noting if the patient instead survived or was lost to follow-up. Recurrence was defined as tumor regrowth or reappearance within the previous surgical field or a new distant lesion as documented by recent follow-up MRI findings. Patients’ status was obtained from the follow-up by outpatient or telephone interview. Recurrent AM patients chose three different therapies: observation, surgery and GKS. We could not justify if the tumor progression for patients who chose observation because most of them did not perform MRI routinely, only get the OS for the entire cohort.

2.3. Statistical analysis The analysis was conducted using SPSS version 22.0 software (IBM Corporation, Armonk, NY, USA). Data reported as mean ± SD or median. Univariate analysis was used to determine better prognostic factors for favorable second PFS and OS following first recurrence. Potential significant factors in the univariate analysis were then included in a multivariate Cox regression analysis to determine the independent factors. Patients were classified into 2 groups: observation group and treatment group. For observation group, only OS were analyzed. And second PFS and OS were analyzed for patients who underwent surgical treatment and GKS after their first recurrence. All P value <0.05 was considered significant.

Table 1 Clinical and treatment characteristic for overall patients with atypical meningioma. Clinical characteristics

No. of patients (%)

Overall Gender Male Female Age, yrs Range Mean Median Preoperative symptoms Headache Epilepsy Motor and walking impairment Others Preoperative KPS Range Mean Median 80 <80 Tumor group Primary Secondary Location Skull base Non-skull base Tumor size (Diameter, cm) Range Mean Median Interval (months) Range Mean Median Peritumoral edema Bone invasion Treatment strategies Observation Surgery GKS Treatment group Second-recurrence Death

131

(%) is the percentage of the proportion in this group.

61 (46.6) 70 (53.4) 7–73 49 51 41 14 24 52

(31.3) (10.7) (18.3) (39.7)

50–100 79 80 97 (74.1) 34 (25.9) 100 (76.3) 31 (23.7) 35 (26.7) 96 (73.3) 1.5–10.0 5 5.0 1.4–94.6 27.7 23.6 56 (42.8) 40 (59.7) 53 (40.5) 53 (40.5) 25 (19.0) 35 (44.9) 19 (24.4)

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3.2. Outcome in the recurrent AM patients In 131 recurrence AM patients, the median follow-up period for the entire cohort was 23.6 months (range, 0.7–84.8 months). Treatment strategies for recurrent AM patients varied widely: 53 patients (40.5%) chose observation instead of therapy, 53 patients (40.5%) received repeat surgery of their recurrent AM, and 25 patients (19.0%) received GKS. Of 131 patients, 56 patients died at the end of follow-up, including 37 patients died in observation group, 16 patients died in surgery group and 3 patients died in GKS group. The median OS was 34.6 months and actuarial OS of patients at 1, 3 and 5 years were 88.6%, 48.8%, 36.0%, respectively (Fig. 1). 3.3. Outcome in the tumor subgroups (primary vs. secondary) In 131 recurrence AM patients, 100 cases (76.3%) were primary AM and 31 cases (23.7%) were secondary tumor. These two groups patient characteristics were listed in Table 2. In the two groups, there were significant differences in tumor size. The mean tumor size of secondary group was larger than the primary group (mean size: 5.3 vs. 5.1 cm). And in the secondary group, the ratio of tumors larger than 5 cm was 74.2%, which was higher than the primary group (51.0%). There were no significant different distributions between two subgroups in gender, age, preoperative KPS, tumor location, peritumoral edema and invasiveness (both in bone and brain invasion). The Cox regression analysis also showed that no significant different in OS between two subgroups (Supplement figure). 3.4. Risk factors of OS in the recurrent AM patients In the entire group, according to univariate analysis, the preoperative KPS score (greater or equal to 80) (HR = 0.403, 95% CI = 0.237–0.685; P = 0.001), peritumoral edema (HR = 2.083, 95% CI = 1.218–3.563; P = 0.007), and tumor groups (HR = 0.540, 95% CI = 0.299–0.976; P = 0.041) and types of treatment at the first

Table 2 Clinical characteristics of 131 cases of primary and secondary atypical meingioma. Clinical characteristics

Primary

Secondary

P

Overall n (%) Male Female Age, yr Range Mean Median Preoperative KPS Range Mean Median Tumor size Range Mean Median Location Skull base Non-skull base Peritumoral edema Invasive group Brain invasion Bone invasion

100 (76.3) 50 (50.0) 50 (50.4)

31 (23.7) 11 (35.5) 20 (64.5)

0.157

7–73 49 51

18–72 49 51

50–100 80 80

60–100 80 80

1.0–9.0 5.1 5

3.0–10.0 5.3 5

58 (58.0) 42 (42.0) 47 (47.0)

23 (74.4) 8 (25.6) 9 (29.0)

0.077

29 (29.0) 30 (30.0)

9 (29.0) 10 (32.3)

0.997 0.811

0.030*

0.624

0.023*

0.105

P* values are statistically significant; (%) is the percentage of the proportion in this group.

recurrence (HR = 0.214, 95% CI = 0.133–0.346; P < 0.001) were shown to be significant favorable predictors of OS (Table 2). Multivariate analysis revealed treatment strategy was only an independent factor (HR = 0.236, 95% CI = 0.146–0.381; P < 0.001) (Fig. 2). The OS of the observation group was significantly shorter than the treatment group (both surgery and GKS). Other variables, including gender, age at first recurrence diagnosis, tumor location, bone invasion, and tumor diameter have no impact on the OS (Table 3). 3.5. Risk of outcome in treatment group Next, we analyzed the patients who received the treatment. In the treatment group including 78 patients with surgery and GKS,

Fig. 1. Kaplan–Meier estimated overall survival of AM after first recurrence.

Fig. 2. Kaplan-Meier curves of overall survival after first recurrence for patients who received surgery, GKS, and observation, respectively.

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G. Zhang et al. / Journal of Clinical Neuroscience 63 (2019) 100–105 Table 3 Univariate and multivariate analysis prognostic factors in recurrent atypical meningioma. Variable

OS Univariate Analysis

Male KPS 80 Age 35yrs Diameter 5 cm Convexity Interval 24 months Peritumor edema Tumor groups Bone invasion No treatment

Multivariate Analysis

P

HR

95% CI

P

HR

95% CI

0.937 0.001 0.473 0.469 0.318 0.156 0.007 0.041 0.387 0.000

0.979 0.403 1.129 1.223 0.847 0.676 2.083 0.540 0.777 0.214

0.572–1.675 0.237–0.685 0.700–2.156 0.709–2.109 0.611–1.173 0.394–1.161 1.128–3.563 0.299–0.976 0.439–1.375 0.133–0.346

0.000*

0.236

0.146–0.381

*

CI, confidence interval; HR, hazard ratio; KPS, Karnofsky performance scale; OS, overall survival. P values are statistically significant.

Table 4 Univariate and multivariate analysis prognostic factors in recurrent atypical meningioma after treatment. Variable

Univariate Analysis

Multivariate Analysis

PFS

Male KPS (per 10 scores increase) KPS 80 Age 60yrs Convexity Diameter 5 cm Bone invasion Interval 24 months Tumor groups Peritumor edema Treatment (Surgery vs. GKS)

OS

PFS

P

HR

95% CI

P

HR

95% CI

0.879 0.094 0.444 0.563 0.528 0.967 0.968 0.004 0.887 0.124 0.450

1.053 0.981 0.756 1.230 1.144 1.014 0.986 0.357 0.938 1.698 1.298

0.539–2.060 0.959–1.003 0.369–1.549 0.609–2.485 0.753–1.737 0.521–1.974 0.495–1.963 1.178–0.714 0.389–2.266 0.866–3.329 0.659–2.557

0.786 0.000 0.499 0.734 0.944 0.677 0.618 0.099 0.337 0.002 0.042

1.137 0.957 1.464 1.186 1.020 1.225 1.261 0.431 0.575 5.780 0.276

0.449–2.878 0.936–0.979 0.485–4.417 0.442–3.184 0.590–1.761 0.471–3.187 0.508–3.131 0.158–1.171 0.186–1.780 1.869–17.873 0.080–0.953

P

OS HR

95% CI

P

HR

95% CI

0.024*

0.974

0.952–0.997

0.011* 0.025*

4.829 0.237

1.436–16.325 0.067–0.832

CI, confidence interval; HR, hazard ratio; KPS, Karnofsky performance scale; PFS, progression-free survival; OS, overall survival; GKS, gamma knife radiosurgery. P* values are statistically significant.

35 patients (44.9%) happened to a second recurrence. The median duration of PFS was 34.5 months and the median OS was 61.7 months. Second PFS at 1, 3 and 5 years were 84.1%, 46.5% and 24.0%, respectively; the corresponding OS was 98.5%, 75.1%, 57.9%, respectively. We wanted to know whether postoperative radiotherapy (PRT) or not will affect the patient’s survival in surgery group. There were 15 patients (28.3%) underwent PRT, tumor progression happened to 6 patients and then 3 patients died. 38 patients (71.7%) declined PRT, 15 patients happened to tumor

progression and then 10 patients died. PRT after surgery for AM recurrence was not related to outcome (both PFS and OS; P > 0.05). The significantly association between PRT and outcome was not observed in our study. As shown in Table 4, recurrent AM patients with a time that interval 24 months had improved PFS compared with patients with a time that interval <24 months (49.4 months vs. 18.9 months, the median PFS; P = 0.004) (Fig. 3A), no other factors were associated with PFS according to univariate analysis. For the OS, patients with

Fig. 3. Survival curves. (A) Kaplan-Meier curves of progression-free survival after first recurrence for interval 24 months and <24 months. (B) Kaplan-Meier curves of overall survival after first recurrence for peritumoral edema (yes or no). (C) Kaplan-Meier curves of overall survival after first recurrence for patients who received surgery and GKS.

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Table 5 Clinical characteristics of 78 cases with surgery and GKS. Clinical characteristics Overall n (%)

Surgery 53 (67.9)

GKS 25 (32.1)

P

Male Age, yrs Range Mean Median Preoperative KPS Range Mean Median Diameter Range Mean Median Skull base

26 (49.1)

13 (52.0)

0.500 0.631

21–72 49 51

7–72 47 53

50–100 80 80

70–90 78 80

0.8–8.2 4.4 4.0 9 (17.0)

1.4–4.7 2.8 3.1 8 (32.0)

0.422

0.137

0.115

(%) is the percentage of the proportion in this group.

higher preoperative KPS (per 10 scores increase) had longer OS compared with patients with lower preoperative KPS (HR = 0.957, 95% CI = 0.936–0.979; P < 0.001). And peritumoral edema was significantly related to shorter OS (HR = 5.780, 95% CI = 1.869–17.873; P = 0.002) (Fig. 3B). In addition, patients who received GKS had better OS compared with patients who received surgery (64.7:50.3 months, the mean OS; P = 0.042) (Fig. 3C). 3.6. Favorable treatment of survival for recurrent AM patient We analyzed the differences between the different treatments. There were no significantly different clinical behaviors between two groups (GKS group and surgery group) were observed in our study (Table 5).

because the complications and damage related to surgery might be irreversible when tumor recurrence. So it was still difficult for surgeons to choose appropriate treatments for patients with recurrent AMs [12]. In this study, some patients declined treatment and chose observation, we could only evaluate the OS among patients chose strategies at their recurrence including: surgery, GKS and observation. We found that the treatment strategy was only an independent factor for the prognosis of the patient. Compared with the observation group, the survival of patients who received treatment was significantly longer than those who choose to observation, this result is consistent with the previous report [13,14]. 4.2. Surgery and outcome Few previous studies details reported the association between extent of resection and outcome in patients with recurrent AM. Our study displayed that the gross total resection (GTR) for recurrent AM was associated with longer OS compared with STR. A lot of previous studies agreed with ours. Like Karol et al. report found that STR is an independent predictor of early progression [15]. Cao et al. also found that surgery Simpson I and II can improve the PFS and OS of tumors and total resection is a most suitable treatment strategy [13]. In our study, there was no significantly association between GTR and improved PFS. But in Ross et al. report, they found that GTR was related to better PFS, not OS. Similar conclusions are also mentioned in Anil’s report [14,16]. However, although there is ample evidence that GTR has a significant effect on prolonging patient survival, sometimes GTR is not easily achieved due to tumor location or patient physical limitations, and the role of other adjuvant therapies needs to be considered. 4.3. Postoperative radiotherapy and outcomes

Atypical meningioma was an aggressive subtype of meningioma associated with a high recurrence rate. Previous retrospective studies have shown that compared with benign meningiomas, AMs patients have a much shorter median PFS [7]. Most investigators attempted to find some factors related to AM management to improve the therapeutic effect. However, few publications regarding clinical information and outcomes following first recurrence were reported [8–10]. The optimal management of atypical meningioma in the recurrent cases is also not clearly defined. In this study, we retrospectively analyzed 131 patients who underwent surgery at their first recurrence and detected some useful predict factors and effective management of this recurrent tumor.

Postoperative radiotherapy after surgical resection of AMs was still controversial. Some series demonstrate that the addition of postoperative radiotherapy should be recommended in AMs. For example, Hae et al. reported that compared with surgery alone patients, surgical resection followed by adjuvant radiotherapy led to better local control. Ayal et al. showed patients who have had GTR of an atypical meningioma should be considered for adjuvant radiation therapy given the improvement in local control. Wang et al. analyzed patients who underwent STR found adjuvant radiation therapy is significantly associated with improved OS compared with no adjuvant radiation therapy. And Zhi also recommended patients who undergo STR for newly diagnosed AM should receive PRT based on improvements in local control and PFS [12,17–19]. However, most neurosurgeons would not advocate postoperative radiotherapy if the tumor was excised completely in Ams [20]. And some research results support this view. Benedito analyzed the database and included articles in which the anatomic pathological classification of atypical meningiomas, they got the conclusion that no evidence to suggest that PRT decreases the rate of recurrence in patients with atypical meningiomas. [21] These results are variably in agreement with those in our department. In our study, a total of 28.3% of our patients underwent adjuvant radiotherapy followed surgery. Surgery with or without PRT did not reach statistical significance. By analyzing patients with or without PRT after surgery, we found that the prognosis of patients with no significant relationship. However, PRT after surgery had better PFS (49 vs. 24 months, the median PFS) and OS (61 vs. 41 months; the median OS).

4.1. Treatment strategy and outcome

4.4. GKS and outcome

Surgery was the first choice of treating primary AMs [11]. However, the management offered to patients should be cautious

Despite the significant efficacy of surgery for meningiomas, the role of GKS in certain meningioma, especially the wrapping of

3.7. Other factors In our study, 53 patients underwent surgery when tumor recurred, GTR was performed in 34 (64.2%) of patients who underwent surgery and STR in 19 (35.8%). In GTR groups, 8 patients subsequently suffered tumor progression; in STR groups, 13 patients recurrence. Patients who received GTR at recurrent surgery experienced longer OS than those who treated STR (55.0 months vs. 41.4 months, median OS; P < 0.05). There was no significantly association between GTR and improved PFS, however, GTR trend towards improved PFS. 4. Discussion

G. Zhang et al. / Journal of Clinical Neuroscience 63 (2019) 100–105

vascular nerve structures such as optic nerve sheath or cavernous sinus, has become a first line option [22]. But the role of GKS in OS for recurrent AM patients is still controversy. Previous studies like Haliry et al.’s report showed no difference was also observed in local control for patients who received stereotactic radiosurgery (SRS) and adjuvant radiotherapy [9]. In our study, patients with GKS showed the better survival than others. Like as Tania et al. reported that GKS for recurrence was associated with improved PFS [23]. And Nanda et al.’s report also proved that GKS can affect patient survival, but they found that better survival for patients who received surgery at recurrence [14]. We then analyzed the differences between the surgery and GKS and found no significantly different clinical behaviors between two groups. But through data analysis, we found that the GKS group had smaller tumors than the surgery group. This data is also the same as the consensus. To avoid radiation-related secondary damage, GKS treatment usually limit the size of tumors to within 3 cm. Recent studies proved beneficial to patients with a high tumor control rate varying from 85 to 100% at 5 years when people received GKS treatment [24,25]. Further detailed research to explore this conclusion in the future. 4.5. Other factors and outcomes Our study revealed that patients with interval less than 24 months had significantly improved PFS, Cao et al.’ s study was consistent with ours [13]. In the treatment group, patients with preoperative KPS (per 10 scores increase) had better survival and peritumoral edema was related to worse OS. Budohoski et al. study also found that peritumoral edema is an independent factor for tumors [15]. Prognostic factors regarding recurrent AM were not reported in detail according to review published literature review. 4.6. Limitation This was a retrospective study, with patients’ selection bias and unequal patient group. It was a limitation of this study that we did not prove the effect of chemotherapy on OS/PFS, the type of therapy may be feasible but need to be verified in the future, especially chemotherapy would be a salvage therapy for repeated recurrences. 5. Conclusion This study provides the risk factors and treatment strategy for PFS and OS of patients who developed recurrence after first surgery. Surgical treatment is recommended in patients with tumor recurrence, and GKS is considered a promising therapeutic option for recurrence atypical meningioma. Acknowledgments Not applicable. Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.01.032.

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