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MIB Index as Predictor of Recurrence in Sporadic Vestibular Schwannomas
Original Article
MIB Index as Predictor of Recurrence in Sporadic Vestibular Schwannomas Manas Panigrahi1, Dilip Kumar1, Sudhindra Vooturi2, Shailaja Madigubba3
OBJECTIVE: Nearly 9.2% of vestibular schwannomas (VS) recur. We evaluate the association of cell proliferative markers like MIB with recurrence in VS.
-
METHODS: Retrospective data of 144 consecutive patients who underwent surgical excision for sporadic VS between January 2010 and July 2015 were collected. Comparison between groups based on recurrence of VS was done.
-
RESULTS: The average age of the study population was 43.95 12.86 years with 77 (53.5%) men. The average maximal diameter of VS was 40.25 7.23 mm. Gross total resection was done in 52 (36.1%) patients. While near total resection was performed in 81 (56.3%) patients, the remaining 11 (7.6%) patients underwent a subtotal resection. The mean follow-up period was 37.99 10.09 months (24e60). Recurrence of VS was observed in 18 (12.5%) patients. There was no difference between the groups for diameter of the tumor (42.22 8.04 vs. 39.64 7.00 mm; P [ 0.191). The average MIB index value was higher in patients with recurrence of tumor at follow-up (4.78 5.77 vs. 1.89 1.48 mm; P < 0.001). There was no difference between the groups for extent of resection or postoperative complications. MIB was the only significant predictor for recurrence (b [ 1.355 (1.07e1.78; confidence interval 95%); P [ 0.031). On receiver operating characteristic curves, a cutoff value of 3.5% for MIB showed a specificity of 84.1%.
-
CONCLUSIONS: MIB index ‡3.5% is associated with recurrence in VS. Maximal diameter of the tumor and extent of resection are perhaps not associated with recurrence of VS.
-
Key words - MIB index - Recurrence - Sporadic vestibular schwannomas Abbreviations and Acronyms EOR: Extent of resection GTR: Gross total resection ROC: Receiver operating characteristic VS: Vestibular schwannomas
WORLD NEUROSURGERY -: e1-e5, - 2018
INTRODUCTION
V
estibular schwannomas (VS) or acoustic neuromas are often benign tumors arising from Schwann cells, mostly from the superior vestibular nerve. The reported incidence of VS is 0.6 in previous studies to 1.9 per 1 million population in more recent studies.1 This increase in reported incidence is probably due to advances in neuroimaging modalities, particularly magnetic resonance imaging (MRI).2,3 Once diagnosed of VS, the treatment options include observation with the use of serial MRIs, microsurgical resection to fractionated radiotherapy. Factors that influence the choice of treatment include patient age, severity of symptoms, and tumor size. Advances in neuroanesthesia and microsurgery contribute toward minimal morbidity and mortality after complete removal of the schwannoma.4 Though long-term outcomes are favorable, recurrence rates range from 0.5% to 9.2%.5,6 Roche et al,7 in a long-term retrospective analysis after translabyrinthine approach of resection of VS, reported a recurrence rate of 9.2%. The authors attributed it to microfragments of VS that had been left along the course of the facial nerve or at the surface of the pons. Furthermore, the authors suggest that management of the recurrent VS depends on the tumor size and patient’s condition. This inconsistency in reported incidence of recurrence of VS suggests that it is poorly evaluated and hence probably underestimated. Understanding factors associated with recurrence is more important because Steinhart et al,8 in a prospective long-term follow-up study using serial MRI after resection of VS, reported tumor doubling time from residual fragments was 22 months. Furthermore, Tysome et al9 suggest that tumor recurrence happens despite gross total resection (GTR) and often occurs late, even decades after treatment. Furthermore, Nakatomi et al6 report that in patients undergoing subtotal resection of the VS, recurrence can happen as early as 2.7 years post surgical resection. The authors further suggest that it would be optimal to detect any recurrence or treatment failure early so that additional surgery, if
From the Departments of 1Neurosurgery, 2Neurology, and 3Pathology, Krishna Institute of Medical Sciences, Secunderabad, Telangana, India To whom correspondence should be addressed: Manas Panigrahi, M.Ch. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.09.039 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
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ORIGINAL ARTICLE MANAS PANIGRAHI ET AL.
MIB INDEX IN VESTIBULAR SCHWANNOMAS
required, carries a lower risk. In the context of these reports, identifying predictors of recurrence in these patients is important. Literature on factors regulating cell death and cell proliferation in VS is sparse. Marwin et al10 have previously reported that VS expressing proapoptotic factor Bax showed a higher proliferative index as measured by MIB-1 labeling index. Similarly, Antinheimo et al,11 have reported that VS due to neurofibromatosis 2, which are more invasive than sporadic VS, have higher MIB-1 indices, irrespective of age. The authors attribute the findings to probable differences in molecular biology of both tumors. In the current study, we evaluate the association of role of cell proliferative markers like MIB with recurrence of sporadic VS after surgical resection. METHODS Retrospective analysis of data collected prospectively in 144 consecutive patients who have undergone surgical excision for sporadic VS between January 2010 and July 2015 at a tertiary referral center was done. The inclusion criteria included 1) patients with VS undergoing surgical excision through retromastoid approach and 2) provisional diagnosis and histologically confirmation of vestibular schwannoma after surgery by senior neuropathologist according to the World Health Organization 2007 classification. Patients not available for follow-up and those with neurofibromatosis formed the exclusion criteria. The study was approved by institutional ethics committee; an informed consent was obtained from all the participants. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines have been implemented in our manuscript.
was excised in piecemeal using bipolar cautery and ultrasonic aspirator. Resection was guided by continuous electromyography of the facial nerve. Gross total resection was attempted in all cases; however, total excision was not achieved when the tumor was tightly adherent to the nerve complex or brainstem, if patients had excessive hemorrhage, and cerebellar edema. Mastoid air cells were packed with the fat tissue harvested from the periumbilical abdominal wall. Dura closed tightly with overlay fat-grafting, like a bath-plug technique. We perform the Valsalva maneuver to confirm the absence of cerebrospinal fluid leak from the dura. The musculopericranial flap was sutured back using 2e0 Vicryl sutures, followed by subcutaneous tissue and skin (Figure 1). MIB-1 (Ki-67) Labeling Index Sections of 5-micron thickness collected on poly-L-lysinecoated slides were subjected to immunohistochemistry immunoperoxidase technique. Briefly, the sections were dewaxed in 2 changes each in xylene and alcohol and stabilized in 0.1 M phosphate buffer saline (PBS) solution. Antigen retrieval was performed by high-temperature unmasking using a pressure cooker (125 C for 30 seconds at 25-lb pressure). Sections were then cooled to room temperature and immersed in 3% methanol hydrogen peroxide for blocking endogenous peroxidase activity. Following blockage of nonspecific binding sites using 3% casein, sections were incubated with primary antibody (Ki-67, monoclonal antibody, DAKO, Santa Clara, USA) for 1 hour, followed by incubation in secondary antibody for 30 minutes (polymer detection kit, Biogenix, Memphis, USA). The antigen-antibody complex was visualized by using diaminobenzidine as chromogen. Sections were counterstained with Harris hematoxylin, dehydrated, and mounted in DPX. At
Data Collection The variables collected included demographic profile, preoperative neurologic assessment, duration of symptoms, neurologic status, imaging features, and size of the tumor. Intraoperative tumor characteristics and immediate postoperative complications such as lower cranial nerve palsy, cerebrospinal fluid fistulas, and meningitis were noted. MIB-1 (Ki-67) labeling indices of tumors were recorded. Follow-up assessment and evaluation was done at 3 months, 12 months, and 24 months after the surgery or when the patient’s condition warranted an evaluation, such as a new-onset symptom in the postoperative period. Surgical Technique After the anesthesia and placement of electrodes, patients were positioned in supine position, with the neck extended and head turned to the opposite side so that the ipsilateral mastoid bone was at the highest point. The head was fixed to the Sugita frame system. A C-shaped curvilinear incision was made 21/2 inches from the external auditory meatus, parallel to the tragus and behind the hairline. A vascularized musculopericranial flap was raised based on the occipital artery. Retromastoid suboccipital craniotomy was done inferomedial to the transverse and sigmoid sinus junction, with a diameter of 4 cm. The dura was opened in a cruciate fashion from the center to the periphery of craniotomy. The cerebellum was retracted inferiorly, and the cerebellomedullary cistern was punctured to let out the cerebrospinal fluid and achieve laxity of the brain. The tumor
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Figure 1. Receiver operating characteristic curve for calculating specificity and sensitivity of MIB index to detect recurrence of vestibular schwannoma after surgical resection.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.09.039
ORIGINAL ARTICLE MANAS PANIGRAHI ET AL.
MIB INDEX IN VESTIBULAR SCHWANNOMAS
least 1000 nuclei were 33 counted at high magnification (40 objectives) without recounting the same areas, and the average was expressed as a percentage. Foci of necrosis were excluded. Definitions Clinical hydrocephalus—subjective symptoms of hydrocephalus along with presence of papilledema. Radiologic hydrocephalus—compression of the fourth ventricle with dilatation of third and lateral ventricles or dilated ventricles with periventricular lucency on T2-fluid-attenuated inversion recovery sequence. GTR—total macroscopic tumor excision of the tumor. Near-total resection GT—>95% macroscopic tumor excised, leaving behind a small intracanalicular part or a thin strip of tumor adherent to the nerve complex or brainstem. Subtotal resection (STR) —<95% tumor excision. Outcome Measure Regrowth/recurrence of tumor occurs when there is a >5 mm increase in the residual tumor size in the latest follow-up MRI, as compared with previous postoperative imaging. STATISTICAL ANALYSIS After confirming the homogeneity of the data, all continuous variables are expressed as mean standard deviation. Categorical
variables are expressed as percentages. The study population was divided into 2 groups on the basis of the recurrence of VS. Differences between groups for continuous variables were evaluated using the independent Student’s t-test. The chi-squared test was employed to evaluate differences between groups for categorical variables. Logistic regression analysis was done to evaluate predictors of recurrence. Receiver operating characteristic (ROC) curves were undertaken to evaluate the role of MIB index. All statistical analysis was done using SPSS version 17.0 for windows (IBM Computers, Armonk, New York, USA). P 0.05 was considered to be significant. RESULTS The average age of the study population was 43.95 12.86 (11e78) years with 77 (53.5%) men. The tumor was located on the left side in 77 (53.5%) patients and on right side in 66 (45.8%). One patient had bilateral VS, with the tumor larger on the right side. The average duration of symptoms was 11.3 11.8 (0.2e48) months. On neurologic examination, hydrocephalous was observed in 61 (42.4%) patients. Involvement of the fifth cranial nerve was observed in 55 (38.2%) patients. While signs of involvement of seventh cranial nerve were observed in 80 (55.6%) patients, 1 (0.7%) patient elicited signs involving the sixth cranial nerve. Furthermore, clinical signs of involvement of the eighth cranial nerve were observed in 136 (94.4%) patients. Involvement of the
Table 1. Comparison for Clinical Variables Between Recurrence Groups (n ¼ 144) Serial Number 1
Variable
Nonrecurrence (n [ 126)
Recurrence (n [ 18)
P Value
Age (years)
44.19 13.03
42.28 11.76
0.557
2
Women (%)
70 (55.6%)
7 (38.9%)
0.213
3
Duration of symptoms (months)
12.01 12.05
7.06 9.92
0.090
4
Maximum diameter of tumor (mm)
39.64 7.00
42.22 8.04
0.191
5
Hydrocephalus (%)
55 (63.2%)
6 (54.5%)
0.743
6
Fifth cranial nerve involved (%)
44 (34.9%)
11 (61.1%)
0.040
7
Sixth cranial nerve involved (%)
1 (0.8%)
0 (0.0%)
1.000
8
Seventh cranial nerve involved (%)
66 (52.4%)
14 (77.8%)
0.047
9
Eighth cranial nerve involved (%)
118 (93.7%)
18 (100.0%)
0.596
10
Lower cranial nerves involved (%)
12 (9.5%)
1 (5.6%)
1.000
11
Cerebellum involved (%)
63 (50.0%)
108 (55.6%)
0.802
12
Mean MIB value (%)
1.89 1.48
4.78 5.77
<0.001
13
Extent of resection Gross total (%)
48 (38.1%)
4 (22.2%)
0.293
Near total (%)
69 (54.8%)
12 (66.7%)
0.448
Subtotal (%)
9 (7.1%)
2 (11.1%)
0.629
14
Postoperative Cerebrospinal fluid leak (%)
3 (2.4%)
0 (0.0%)
1.000
Reservoir placed (%)
28 (22.3%)
2 (11.1%)
0.365
Ventriculoperitoneal shunt (%)
15 (11.9%)
2 (11.1%)
1.000
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ORIGINAL ARTICLE MANAS PANIGRAHI ET AL.
MIB INDEX IN VESTIBULAR SCHWANNOMAS
Table 2. Sensitivity and Specificity of MIB (n ¼ 131) MIB Index Cutoff Value
On evaluating specificity of MIB versus recurrence of VS on receiver operating characteristic curves (Figure 1), the area under the curve was 0.735. At a cutoff value of 2.5, the sensitivity and specificity of MIB index were 55.6% and 80.5% respectively. At a cutoff value of 3.5, the sensitivity and specificity were 44.4% and 84.1%, respectively. At a cutoff value of 4.5 for MIB index, the specificity rose up to 87.6%, and at a cutoff value of 5.5 for MIB, the specificity was 96.5% (Table 2).
Sensitivity (%)
Specificity (%)
1.5 (%)
77.8%
61.9%
2.5 (%)
55.6%
80.5%
3.5 (%)
44.4%
84.1%
4.5 (%)
33.3%
87.6%
5.5 (%)
16.7%
96.5%
DISCUSSION
7.0 (%)
16.7%
100.0%
In the current study, we evaluate the association of MIB, a cell proliferative index, with recurrence of VS in patients undergoing surgical resection. We report that a higher maximal diameter of the tumor at the initial surgery is associated with recurrence in VS. Moreover, patients with recurrence have a higher mean MIB index at initial surgery. Importantly, a cutoff value of 3% for MIB index could probably predict recurrence of VS. On the contrary, EOR of the tumor is perhaps not associated with recurrence of VS.
lower cranial nerves and cerebellum was observed in 13 (9.0%) and 73 (50.7%) patients. The average maximal diameter of the tumor was 40.25 7.23 mm (20e57). During the surgery, GTR was done in 52 (36.1%) patients. While near total resection was performed in 81 (56.3%) patients, the remaining 11 (7.6%) patients underwent a sub total resection. Post-operatively, cerebrospinal fluid leak was seen in three (2.1%) patients. While, 30 (20.9%) patients required a reservoir, ventriculoperitoneal shunt was placed in 17 (11.8%) patients. The mean follow-up period was 37.99 10.09 months (24e60). Recurrence of VS was observed in 18 (12.5%) patients. On analysis of factors affecting recurrence of VS, there was no difference between the groups for diameter of the tumor (42.22 8.04 vs. 39.64 7.00 mm; P ¼ 0.191). More number of patients with recurrence had clinical signs of involvement of fifth (61.1% vs. 34.9%; P ¼ 0.040) and seventh cranial nerve (77.8% vs. 52.4%; P ¼ 0.047) at presentation. The average MIB index value was higher in patients with recurrence of tumor at follow-up (4.78 5.77 vs. 1.89 1.48 mm; P < 0.001). There was no difference between the groups for extent of resection (EOR) or postoperative complications (Table 1). On logistic regression analysis for factors predicting recurrence, the model included variables that were significantly between the groups: involvement of fifth cranial nerve, involvement of seventh cranial nerve, maximal diameter of the VS, mean MIB value, and whether GTR was done. The model assumed statistical significance (P ¼ 0.033) with MIB as the only significant predictor for recurrence (b ¼ 1.355 [1.07e1.78; CI 95%]; P ¼ 0.031). Factors like GTR (b ¼ 0.619 [0.153e2.503; CI 95%]; P ¼ 0.501) maximal diameter of the VS (b ¼ 1.023 [0.94 to 1.11; CI 95%]; P ¼ 0.578) did not predict recurrence.
Patient and Tumor Characteristics The mean age of patients with VS in the current study was 43 years, marginally lower than that reported by Babu et al12 from a larger cohort of patients from the United States of America. This variance could be because the upper limit of range of age in the current population was 78 years, whereas that reported by Babu et al12 is 103 years. The fraction of women in the current study at 46.5% is similar to 51.98% previously reported.12 Similarly, there was no difference in the occurrence of VS due to tumor location (left or right). Importantly, the rate of recurrence of VS at 12.5% in the current study, though higher than the reported 0.5%e9.2% from the literature,13 is similar to the recurrence reported by Steinhart et al8 (Table 3). In the existing literature, the source of recurrence was usually attributed to microscopic tumor deposits left on the facial nerve, in the fundus of the internal auditory canal, or on the preserved cochlear or vestibular nerves. Furthermore, partial resection of VS is reportedly associated with regrowth in up to 44% of cases after a mean follow-up of 6.2 years.16,17 However, in the current study, we did not find a significant difference for the EOR between patients with recurrence of VS in comparison with those without recurrence. The reason for our findings could be that we analyzed EOR as 3 categories (gross total, near total, and subtotal resections), whereas all the previous studies have analyzed EOR either as gross total or subtotal groups only. Similarly, we did not find differences between groups of recurrence for the mean maximal diameter of
Table 3. Rate of Recurrence in Vestibular Schwannomas After Surgical Resection Author (Number)
Approach to Resection
Rate of Recurrence
Translabyrinthine
9.2%
Retrosigmoid-transmeatal
5.9%
Ansari et al., 2012 (n ¼ 5064)
Retrosigmoid, midcranial, translabyrinthine
7.3%
Steinhart et al., 20038 (n ¼ 50)
Transtemporal
12%
Retromastoid suboccipital
12.5%
Roche et al., 2008 (n ¼ 20) 7
14
Ramina et al., 2007
(n ¼ 252)
15
Current study (n ¼ 162)
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ORIGINAL ARTICLE MANAS PANIGRAHI ET AL.
MIB INDEX IN VESTIBULAR SCHWANNOMAS
the tumor. We also reported that patients with recurrent VS also have a higher proliferative index measured by MIB index. The association between a higher maximal diameter of VS and its proliferative index should be evaluated in more robust studies. Yanamandala et al,18 in 2013, reported the case report of a 46year-old woman with right-sided VS. The initial MRI scan showed a benign VS with a MIB of 5.7%. At 43 months after Gamma Knife surgery, the patient had a recurrent VS with an MIB of 7.4% and subsequently underwent a subtotal resection. However, a third resection was required when the VS showed frank transformation to malignancy with an MIB of 33.8%. Similarly, Steinhart et al,8 in a study of 50 patients with VS, observed for association between cellular proliferative index MIB and tumor doubling time. The authors reported 3 patients with clinical tumor growth where 1 patient had a MIB of 3.3% at presentation and the other 2 patients had a MIB of 0% at follow-up, suggesting a dip in the proliferative index just before the planned resection. Furthermore, Marwin et al10 have previously suggested that MIB is elevated in patients with sporadic VS expressing proapoptotic factor Bax. The findings of the current study that a
Strengths and Limitations The current study, a single-center experience, helped us collect data specific and more pertinent to the research hypothesis. Results of the current study reflect findings from a consistent environment and patient care protocols, with little scope for variability that is often attributed to different models of care at different institutions in multicenter studies. We included univariate comparisons; therefore the findings of our study must be interpreted with caution, but the findings seem to be clinically plausible. CONCLUSION Vestibular schwannomas with a MIB index 3.5% at initial presentation are associated with recurrence. On the contrary, maximal diameter of the tumor and EOR of the tumor are perhaps not associated with recurrence of VS. Determining proliferation through MIB index can help in decision making for future follow-up and further management in these patients.
Gamma Knife radiosurgery]. Neurochirurgie. 2004; 50:383-393.
of large and giant residual and recurrent vestibular schwannomas. Skull Base. 2007;17:109-117.
8. Steinhart H, Triebswetter F, Wolf S, Gress H, Bohlender J, Iro H. [Growth of sporadic vestibular schwannomas correlates with Ki-67 proliferation index]. Laryngorhinootologie. 2003;82:318-321.
15. Ansari SF, Terry C, Cohen-Gadol AA. Surgery for vestibular schwannomas: a systematic review of complications by approach. Neurosurg Focus. 2012; 33:E14.
REFERENCES 1. Propp JM, McCarthy BJ, Davis FG, PrestonMartin S. Descriptive epidemiology of vestibular schwannomas. Neuro Oncol. 2006;8:1-11.
cutoff value of 3.5% is associated with recurrence in VS materialize the observations made by Steinhart et al.8
2. Modan B, Wagener DK, Feldman JJ, Rosenberg HM, Feinleib M. Increased mortality from brain tumors: a combined outcome of diagnostic technology and change of attitude toward the elderly. Am J Epidemiol. 1992;135: 1349-1357.
9. Tysome JR, Moffat DA. Magnetic resonance imaging after translabyrinthine complete excision of vestibular schwannomas. J Neurol Surg B Skull Base. 73:121-124.
3. Stangerup SE, Tos M, Caye-Thomasen P, Tos T, Klokker M, Thomsen J. Increasing annual incidence of vestibular schwannoma and age at diagnosis. J Laryngol Otol. 2004;118:622-627.
10. Mawrin C, Kirches E, Dietzmann K, Roessner A, Boltze C. Expression pattern of apoptotic markers in vestibular schwannomas. Pathol Res Pract. 2002; 198:813-819.
4. Whitmore RG, Urban C, Church E, Ruckenstein M, Stein SC, Lee JY. Decision analysis of treatment options for vestibular schwannoma. J Neurosurg. 2011;114:400-413.
11. Antinheimo J, Sallinen SL, Sallinen P, Haapasalo H, Helin H, Horelli-Kuitunen N, et al. Genetic aberrations in sporadic and neurofibromatosis 2 (NF2)associated schwannomas studied by comparative genomic hybridization (CGH). Acta Neurochir (Wien). 2000;142:1099-1104.
5. Ahmad RA, Sivalingam S, Topsakal V, Russo A, Taibah A, Sanna M. Rate of recurrent vestibular schwannoma after total removal via different surgical approaches. Ann Otol Rhinol Laryngol. 2012; 121:156-161. 6. Nakatomi H, Jacob JT, Carlson ML, Tanaka S, Tanaka M, Saito N, et al. Long-term risk of recurrence and regrowth after gross-total and subtotal resection of sporadic vestibular schwannoma. J Neurosurg. 2017;19:1-7. 7. Roche PH, Regis J, Deveze A, Delsanti C, Thomassin JM, Pellet W. [Surgical removal of unilateral vestibular schwannomas after failed
16. El-Kashlan HK, Zeitoun H, Arts HA, Hoff JT, Telian SA. Recurrence of acoustic neuroma after incomplete resection. Am J Otol. 2000;21:389-392. 17. Matthies C, Samii M. Management of 1000 vestibular schwannomas (acoustic neuromas): clinical presentation. Neurosurgery. 1997;40:1-9. 18. Yanamadala V, Williamson RW, Fusco DJ, Eschbacher J, Weisskopf P, Porter RW. Malignant transformation of a vestibular schwannoma after gamma knife radiosurgery. World Neurosurg. 2013; 79:e591-e598.
12. Babu R, Sharma R, Bagley JH, Hatef J, Friedman AH, Adamson C. Vestibular schwannomas in the modern era: epidemiology, treatment trends, and disparities in management. J Neurosurg. 2013;119:121-130.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
13. Samii M, Metwali H, Gerganov V. Microsurgical management of vestibular schwannoma after failed previous surgery. J Neurosurg. 2016;125: 1198-1203.
Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.09.039
14. Ramina R, Coelho Neto M, Bordignon KC, Mattei T, Clemente R, Pires Aguiar PH. Treatment
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Received 3 August 2018; accepted 7 September 2018
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MIB Index as Predictor of Recurrence in Sporadic Vestibular Schwannomas Manas Panigrahi1, Dilip Kumar1, Sudhindra Vooturi2, Shailaja Madigubba3
OBJECTIVE: Nearly 9.2% of vestibular schwannomas (VS) recur. We evaluate the association of cell proliferative markers like MIB with recurrence in VS.
-
METHODS: Retrospective data of 144 consecutive patients who underwent surgical excision for sporadic VS between January 2010 and July 2015 were collected. Comparison between groups based on recurrence of VS was done.
-
RESULTS: The average age of the study population was 43.95 12.86 years with 77 (53.5%) men. The average maximal diameter of VS was 40.25 7.23 mm. Gross total resection was done in 52 (36.1%) patients. While near total resection was performed in 81 (56.3%) patients, the remaining 11 (7.6%) patients underwent a subtotal resection. The mean follow-up period was 37.99 10.09 months (24e60). Recurrence of VS was observed in 18 (12.5%) patients. There was no difference between the groups for diameter of the tumor (42.22 8.04 vs. 39.64 7.00 mm; P [ 0.191). The average MIB index value was higher in patients with recurrence of tumor at follow-up (4.78 5.77 vs. 1.89 1.48 mm; P < 0.001). There was no difference between the groups for extent of resection or postoperative complications. MIB was the only significant predictor for recurrence (b [ 1.355 (1.07e1.78; confidence interval 95%); P [ 0.031). On receiver operating characteristic curves, a cutoff value of 3.5% for MIB showed a specificity of 84.1%.
-
CONCLUSIONS: MIB index ‡3.5% is associated with recurrence in VS. Maximal diameter of the tumor and extent of resection are perhaps not associated with recurrence of VS.
-
Key words - MIB index - Recurrence - Sporadic vestibular schwannomas Abbreviations and Acronyms EOR: Extent of resection GTR: Gross total resection ROC: Receiver operating characteristic VS: Vestibular schwannomas
WORLD NEUROSURGERY -: e1-e5, - 2018
INTRODUCTION
V
estibular schwannomas (VS) or acoustic neuromas are often benign tumors arising from Schwann cells, mostly from the superior vestibular nerve. The reported incidence of VS is 0.6 in previous studies to 1.9 per 1 million population in more recent studies.1 This increase in reported incidence is probably due to advances in neuroimaging modalities, particularly magnetic resonance imaging (MRI).2,3 Once diagnosed of VS, the treatment options include observation with the use of serial MRIs, microsurgical resection to fractionated radiotherapy. Factors that influence the choice of treatment include patient age, severity of symptoms, and tumor size. Advances in neuroanesthesia and microsurgery contribute toward minimal morbidity and mortality after complete removal of the schwannoma.4 Though long-term outcomes are favorable, recurrence rates range from 0.5% to 9.2%.5,6 Roche et al,7 in a long-term retrospective analysis after translabyrinthine approach of resection of VS, reported a recurrence rate of 9.2%. The authors attributed it to microfragments of VS that had been left along the course of the facial nerve or at the surface of the pons. Furthermore, the authors suggest that management of the recurrent VS depends on the tumor size and patient’s condition. This inconsistency in reported incidence of recurrence of VS suggests that it is poorly evaluated and hence probably underestimated. Understanding factors associated with recurrence is more important because Steinhart et al,8 in a prospective long-term follow-up study using serial MRI after resection of VS, reported tumor doubling time from residual fragments was 22 months. Furthermore, Tysome et al9 suggest that tumor recurrence happens despite gross total resection (GTR) and often occurs late, even decades after treatment. Furthermore, Nakatomi et al6 report that in patients undergoing subtotal resection of the VS, recurrence can happen as early as 2.7 years post surgical resection. The authors further suggest that it would be optimal to detect any recurrence or treatment failure early so that additional surgery, if
From the Departments of 1Neurosurgery, 2Neurology, and 3Pathology, Krishna Institute of Medical Sciences, Secunderabad, Telangana, India To whom correspondence should be addressed: Manas Panigrahi, M.Ch. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.09.039 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
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ORIGINAL ARTICLE MANAS PANIGRAHI ET AL.
MIB INDEX IN VESTIBULAR SCHWANNOMAS
required, carries a lower risk. In the context of these reports, identifying predictors of recurrence in these patients is important. Literature on factors regulating cell death and cell proliferation in VS is sparse. Marwin et al10 have previously reported that VS expressing proapoptotic factor Bax showed a higher proliferative index as measured by MIB-1 labeling index. Similarly, Antinheimo et al,11 have reported that VS due to neurofibromatosis 2, which are more invasive than sporadic VS, have higher MIB-1 indices, irrespective of age. The authors attribute the findings to probable differences in molecular biology of both tumors. In the current study, we evaluate the association of role of cell proliferative markers like MIB with recurrence of sporadic VS after surgical resection. METHODS Retrospective analysis of data collected prospectively in 144 consecutive patients who have undergone surgical excision for sporadic VS between January 2010 and July 2015 at a tertiary referral center was done. The inclusion criteria included 1) patients with VS undergoing surgical excision through retromastoid approach and 2) provisional diagnosis and histologically confirmation of vestibular schwannoma after surgery by senior neuropathologist according to the World Health Organization 2007 classification. Patients not available for follow-up and those with neurofibromatosis formed the exclusion criteria. The study was approved by institutional ethics committee; an informed consent was obtained from all the participants. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines have been implemented in our manuscript.
was excised in piecemeal using bipolar cautery and ultrasonic aspirator. Resection was guided by continuous electromyography of the facial nerve. Gross total resection was attempted in all cases; however, total excision was not achieved when the tumor was tightly adherent to the nerve complex or brainstem, if patients had excessive hemorrhage, and cerebellar edema. Mastoid air cells were packed with the fat tissue harvested from the periumbilical abdominal wall. Dura closed tightly with overlay fat-grafting, like a bath-plug technique. We perform the Valsalva maneuver to confirm the absence of cerebrospinal fluid leak from the dura. The musculopericranial flap was sutured back using 2e0 Vicryl sutures, followed by subcutaneous tissue and skin (Figure 1). MIB-1 (Ki-67) Labeling Index Sections of 5-micron thickness collected on poly-L-lysinecoated slides were subjected to immunohistochemistry immunoperoxidase technique. Briefly, the sections were dewaxed in 2 changes each in xylene and alcohol and stabilized in 0.1 M phosphate buffer saline (PBS) solution. Antigen retrieval was performed by high-temperature unmasking using a pressure cooker (125 C for 30 seconds at 25-lb pressure). Sections were then cooled to room temperature and immersed in 3% methanol hydrogen peroxide for blocking endogenous peroxidase activity. Following blockage of nonspecific binding sites using 3% casein, sections were incubated with primary antibody (Ki-67, monoclonal antibody, DAKO, Santa Clara, USA) for 1 hour, followed by incubation in secondary antibody for 30 minutes (polymer detection kit, Biogenix, Memphis, USA). The antigen-antibody complex was visualized by using diaminobenzidine as chromogen. Sections were counterstained with Harris hematoxylin, dehydrated, and mounted in DPX. At
Data Collection The variables collected included demographic profile, preoperative neurologic assessment, duration of symptoms, neurologic status, imaging features, and size of the tumor. Intraoperative tumor characteristics and immediate postoperative complications such as lower cranial nerve palsy, cerebrospinal fluid fistulas, and meningitis were noted. MIB-1 (Ki-67) labeling indices of tumors were recorded. Follow-up assessment and evaluation was done at 3 months, 12 months, and 24 months after the surgery or when the patient’s condition warranted an evaluation, such as a new-onset symptom in the postoperative period. Surgical Technique After the anesthesia and placement of electrodes, patients were positioned in supine position, with the neck extended and head turned to the opposite side so that the ipsilateral mastoid bone was at the highest point. The head was fixed to the Sugita frame system. A C-shaped curvilinear incision was made 21/2 inches from the external auditory meatus, parallel to the tragus and behind the hairline. A vascularized musculopericranial flap was raised based on the occipital artery. Retromastoid suboccipital craniotomy was done inferomedial to the transverse and sigmoid sinus junction, with a diameter of 4 cm. The dura was opened in a cruciate fashion from the center to the periphery of craniotomy. The cerebellum was retracted inferiorly, and the cerebellomedullary cistern was punctured to let out the cerebrospinal fluid and achieve laxity of the brain. The tumor
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Figure 1. Receiver operating characteristic curve for calculating specificity and sensitivity of MIB index to detect recurrence of vestibular schwannoma after surgical resection.
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least 1000 nuclei were 33 counted at high magnification (40 objectives) without recounting the same areas, and the average was expressed as a percentage. Foci of necrosis were excluded. Definitions Clinical hydrocephalus—subjective symptoms of hydrocephalus along with presence of papilledema. Radiologic hydrocephalus—compression of the fourth ventricle with dilatation of third and lateral ventricles or dilated ventricles with periventricular lucency on T2-fluid-attenuated inversion recovery sequence. GTR—total macroscopic tumor excision of the tumor. Near-total resection GT—>95% macroscopic tumor excised, leaving behind a small intracanalicular part or a thin strip of tumor adherent to the nerve complex or brainstem. Subtotal resection (STR) —<95% tumor excision. Outcome Measure Regrowth/recurrence of tumor occurs when there is a >5 mm increase in the residual tumor size in the latest follow-up MRI, as compared with previous postoperative imaging. STATISTICAL ANALYSIS After confirming the homogeneity of the data, all continuous variables are expressed as mean standard deviation. Categorical
variables are expressed as percentages. The study population was divided into 2 groups on the basis of the recurrence of VS. Differences between groups for continuous variables were evaluated using the independent Student’s t-test. The chi-squared test was employed to evaluate differences between groups for categorical variables. Logistic regression analysis was done to evaluate predictors of recurrence. Receiver operating characteristic (ROC) curves were undertaken to evaluate the role of MIB index. All statistical analysis was done using SPSS version 17.0 for windows (IBM Computers, Armonk, New York, USA). P 0.05 was considered to be significant. RESULTS The average age of the study population was 43.95 12.86 (11e78) years with 77 (53.5%) men. The tumor was located on the left side in 77 (53.5%) patients and on right side in 66 (45.8%). One patient had bilateral VS, with the tumor larger on the right side. The average duration of symptoms was 11.3 11.8 (0.2e48) months. On neurologic examination, hydrocephalous was observed in 61 (42.4%) patients. Involvement of the fifth cranial nerve was observed in 55 (38.2%) patients. While signs of involvement of seventh cranial nerve were observed in 80 (55.6%) patients, 1 (0.7%) patient elicited signs involving the sixth cranial nerve. Furthermore, clinical signs of involvement of the eighth cranial nerve were observed in 136 (94.4%) patients. Involvement of the
Table 1. Comparison for Clinical Variables Between Recurrence Groups (n ¼ 144) Serial Number 1
Variable
Nonrecurrence (n [ 126)
Recurrence (n [ 18)
P Value
Age (years)
44.19 13.03
42.28 11.76
0.557
2
Women (%)
70 (55.6%)
7 (38.9%)
0.213
3
Duration of symptoms (months)
12.01 12.05
7.06 9.92
0.090
4
Maximum diameter of tumor (mm)
39.64 7.00
42.22 8.04
0.191
5
Hydrocephalus (%)
55 (63.2%)
6 (54.5%)
0.743
6
Fifth cranial nerve involved (%)
44 (34.9%)
11 (61.1%)
0.040
7
Sixth cranial nerve involved (%)
1 (0.8%)
0 (0.0%)
1.000
8
Seventh cranial nerve involved (%)
66 (52.4%)
14 (77.8%)
0.047
9
Eighth cranial nerve involved (%)
118 (93.7%)
18 (100.0%)
0.596
10
Lower cranial nerves involved (%)
12 (9.5%)
1 (5.6%)
1.000
11
Cerebellum involved (%)
63 (50.0%)
108 (55.6%)
0.802
12
Mean MIB value (%)
1.89 1.48
4.78 5.77
<0.001
13
Extent of resection Gross total (%)
48 (38.1%)
4 (22.2%)
0.293
Near total (%)
69 (54.8%)
12 (66.7%)
0.448
Subtotal (%)
9 (7.1%)
2 (11.1%)
0.629
14
Postoperative Cerebrospinal fluid leak (%)
3 (2.4%)
0 (0.0%)
1.000
Reservoir placed (%)
28 (22.3%)
2 (11.1%)
0.365
Ventriculoperitoneal shunt (%)
15 (11.9%)
2 (11.1%)
1.000
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Table 2. Sensitivity and Specificity of MIB (n ¼ 131) MIB Index Cutoff Value
On evaluating specificity of MIB versus recurrence of VS on receiver operating characteristic curves (Figure 1), the area under the curve was 0.735. At a cutoff value of 2.5, the sensitivity and specificity of MIB index were 55.6% and 80.5% respectively. At a cutoff value of 3.5, the sensitivity and specificity were 44.4% and 84.1%, respectively. At a cutoff value of 4.5 for MIB index, the specificity rose up to 87.6%, and at a cutoff value of 5.5 for MIB, the specificity was 96.5% (Table 2).
Sensitivity (%)
Specificity (%)
1.5 (%)
77.8%
61.9%
2.5 (%)
55.6%
80.5%
3.5 (%)
44.4%
84.1%
4.5 (%)
33.3%
87.6%
5.5 (%)
16.7%
96.5%
DISCUSSION
7.0 (%)
16.7%
100.0%
In the current study, we evaluate the association of MIB, a cell proliferative index, with recurrence of VS in patients undergoing surgical resection. We report that a higher maximal diameter of the tumor at the initial surgery is associated with recurrence in VS. Moreover, patients with recurrence have a higher mean MIB index at initial surgery. Importantly, a cutoff value of 3% for MIB index could probably predict recurrence of VS. On the contrary, EOR of the tumor is perhaps not associated with recurrence of VS.
lower cranial nerves and cerebellum was observed in 13 (9.0%) and 73 (50.7%) patients. The average maximal diameter of the tumor was 40.25 7.23 mm (20e57). During the surgery, GTR was done in 52 (36.1%) patients. While near total resection was performed in 81 (56.3%) patients, the remaining 11 (7.6%) patients underwent a sub total resection. Post-operatively, cerebrospinal fluid leak was seen in three (2.1%) patients. While, 30 (20.9%) patients required a reservoir, ventriculoperitoneal shunt was placed in 17 (11.8%) patients. The mean follow-up period was 37.99 10.09 months (24e60). Recurrence of VS was observed in 18 (12.5%) patients. On analysis of factors affecting recurrence of VS, there was no difference between the groups for diameter of the tumor (42.22 8.04 vs. 39.64 7.00 mm; P ¼ 0.191). More number of patients with recurrence had clinical signs of involvement of fifth (61.1% vs. 34.9%; P ¼ 0.040) and seventh cranial nerve (77.8% vs. 52.4%; P ¼ 0.047) at presentation. The average MIB index value was higher in patients with recurrence of tumor at follow-up (4.78 5.77 vs. 1.89 1.48 mm; P < 0.001). There was no difference between the groups for extent of resection (EOR) or postoperative complications (Table 1). On logistic regression analysis for factors predicting recurrence, the model included variables that were significantly between the groups: involvement of fifth cranial nerve, involvement of seventh cranial nerve, maximal diameter of the VS, mean MIB value, and whether GTR was done. The model assumed statistical significance (P ¼ 0.033) with MIB as the only significant predictor for recurrence (b ¼ 1.355 [1.07e1.78; CI 95%]; P ¼ 0.031). Factors like GTR (b ¼ 0.619 [0.153e2.503; CI 95%]; P ¼ 0.501) maximal diameter of the VS (b ¼ 1.023 [0.94 to 1.11; CI 95%]; P ¼ 0.578) did not predict recurrence.
Patient and Tumor Characteristics The mean age of patients with VS in the current study was 43 years, marginally lower than that reported by Babu et al12 from a larger cohort of patients from the United States of America. This variance could be because the upper limit of range of age in the current population was 78 years, whereas that reported by Babu et al12 is 103 years. The fraction of women in the current study at 46.5% is similar to 51.98% previously reported.12 Similarly, there was no difference in the occurrence of VS due to tumor location (left or right). Importantly, the rate of recurrence of VS at 12.5% in the current study, though higher than the reported 0.5%e9.2% from the literature,13 is similar to the recurrence reported by Steinhart et al8 (Table 3). In the existing literature, the source of recurrence was usually attributed to microscopic tumor deposits left on the facial nerve, in the fundus of the internal auditory canal, or on the preserved cochlear or vestibular nerves. Furthermore, partial resection of VS is reportedly associated with regrowth in up to 44% of cases after a mean follow-up of 6.2 years.16,17 However, in the current study, we did not find a significant difference for the EOR between patients with recurrence of VS in comparison with those without recurrence. The reason for our findings could be that we analyzed EOR as 3 categories (gross total, near total, and subtotal resections), whereas all the previous studies have analyzed EOR either as gross total or subtotal groups only. Similarly, we did not find differences between groups of recurrence for the mean maximal diameter of
Table 3. Rate of Recurrence in Vestibular Schwannomas After Surgical Resection Author (Number)
Approach to Resection
Rate of Recurrence
Translabyrinthine
9.2%
Retrosigmoid-transmeatal
5.9%
Ansari et al., 2012 (n ¼ 5064)
Retrosigmoid, midcranial, translabyrinthine
7.3%
Steinhart et al., 20038 (n ¼ 50)
Transtemporal
12%
Retromastoid suboccipital
12.5%
Roche et al., 2008 (n ¼ 20) 7
14
Ramina et al., 2007
(n ¼ 252)
15
Current study (n ¼ 162)
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MIB INDEX IN VESTIBULAR SCHWANNOMAS
the tumor. We also reported that patients with recurrent VS also have a higher proliferative index measured by MIB index. The association between a higher maximal diameter of VS and its proliferative index should be evaluated in more robust studies. Yanamandala et al,18 in 2013, reported the case report of a 46year-old woman with right-sided VS. The initial MRI scan showed a benign VS with a MIB of 5.7%. At 43 months after Gamma Knife surgery, the patient had a recurrent VS with an MIB of 7.4% and subsequently underwent a subtotal resection. However, a third resection was required when the VS showed frank transformation to malignancy with an MIB of 33.8%. Similarly, Steinhart et al,8 in a study of 50 patients with VS, observed for association between cellular proliferative index MIB and tumor doubling time. The authors reported 3 patients with clinical tumor growth where 1 patient had a MIB of 3.3% at presentation and the other 2 patients had a MIB of 0% at follow-up, suggesting a dip in the proliferative index just before the planned resection. Furthermore, Marwin et al10 have previously suggested that MIB is elevated in patients with sporadic VS expressing proapoptotic factor Bax. The findings of the current study that a
Strengths and Limitations The current study, a single-center experience, helped us collect data specific and more pertinent to the research hypothesis. Results of the current study reflect findings from a consistent environment and patient care protocols, with little scope for variability that is often attributed to different models of care at different institutions in multicenter studies. We included univariate comparisons; therefore the findings of our study must be interpreted with caution, but the findings seem to be clinically plausible. CONCLUSION Vestibular schwannomas with a MIB index 3.5% at initial presentation are associated with recurrence. On the contrary, maximal diameter of the tumor and EOR of the tumor are perhaps not associated with recurrence of VS. Determining proliferation through MIB index can help in decision making for future follow-up and further management in these patients.
Gamma Knife radiosurgery]. Neurochirurgie. 2004; 50:383-393.
of large and giant residual and recurrent vestibular schwannomas. Skull Base. 2007;17:109-117.
8. Steinhart H, Triebswetter F, Wolf S, Gress H, Bohlender J, Iro H. [Growth of sporadic vestibular schwannomas correlates with Ki-67 proliferation index]. Laryngorhinootologie. 2003;82:318-321.
15. Ansari SF, Terry C, Cohen-Gadol AA. Surgery for vestibular schwannomas: a systematic review of complications by approach. Neurosurg Focus. 2012; 33:E14.
REFERENCES 1. Propp JM, McCarthy BJ, Davis FG, PrestonMartin S. Descriptive epidemiology of vestibular schwannomas. Neuro Oncol. 2006;8:1-11.
cutoff value of 3.5% is associated with recurrence in VS materialize the observations made by Steinhart et al.8
2. Modan B, Wagener DK, Feldman JJ, Rosenberg HM, Feinleib M. Increased mortality from brain tumors: a combined outcome of diagnostic technology and change of attitude toward the elderly. Am J Epidemiol. 1992;135: 1349-1357.
9. Tysome JR, Moffat DA. Magnetic resonance imaging after translabyrinthine complete excision of vestibular schwannomas. J Neurol Surg B Skull Base. 73:121-124.
3. Stangerup SE, Tos M, Caye-Thomasen P, Tos T, Klokker M, Thomsen J. Increasing annual incidence of vestibular schwannoma and age at diagnosis. J Laryngol Otol. 2004;118:622-627.
10. Mawrin C, Kirches E, Dietzmann K, Roessner A, Boltze C. Expression pattern of apoptotic markers in vestibular schwannomas. Pathol Res Pract. 2002; 198:813-819.
4. Whitmore RG, Urban C, Church E, Ruckenstein M, Stein SC, Lee JY. Decision analysis of treatment options for vestibular schwannoma. J Neurosurg. 2011;114:400-413.
11. Antinheimo J, Sallinen SL, Sallinen P, Haapasalo H, Helin H, Horelli-Kuitunen N, et al. Genetic aberrations in sporadic and neurofibromatosis 2 (NF2)associated schwannomas studied by comparative genomic hybridization (CGH). Acta Neurochir (Wien). 2000;142:1099-1104.
5. Ahmad RA, Sivalingam S, Topsakal V, Russo A, Taibah A, Sanna M. Rate of recurrent vestibular schwannoma after total removal via different surgical approaches. Ann Otol Rhinol Laryngol. 2012; 121:156-161. 6. Nakatomi H, Jacob JT, Carlson ML, Tanaka S, Tanaka M, Saito N, et al. Long-term risk of recurrence and regrowth after gross-total and subtotal resection of sporadic vestibular schwannoma. J Neurosurg. 2017;19:1-7. 7. Roche PH, Regis J, Deveze A, Delsanti C, Thomassin JM, Pellet W. [Surgical removal of unilateral vestibular schwannomas after failed
16. El-Kashlan HK, Zeitoun H, Arts HA, Hoff JT, Telian SA. Recurrence of acoustic neuroma after incomplete resection. Am J Otol. 2000;21:389-392. 17. Matthies C, Samii M. Management of 1000 vestibular schwannomas (acoustic neuromas): clinical presentation. Neurosurgery. 1997;40:1-9. 18. Yanamadala V, Williamson RW, Fusco DJ, Eschbacher J, Weisskopf P, Porter RW. Malignant transformation of a vestibular schwannoma after gamma knife radiosurgery. World Neurosurg. 2013; 79:e591-e598.
12. Babu R, Sharma R, Bagley JH, Hatef J, Friedman AH, Adamson C. Vestibular schwannomas in the modern era: epidemiology, treatment trends, and disparities in management. J Neurosurg. 2013;119:121-130.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
13. Samii M, Metwali H, Gerganov V. Microsurgical management of vestibular schwannoma after failed previous surgery. J Neurosurg. 2016;125: 1198-1203.
Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.09.039
14. Ramina R, Coelho Neto M, Bordignon KC, Mattei T, Clemente R, Pires Aguiar PH. Treatment
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