Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Choroidal Neovascularization Associated With Birdshot Chorioretinopathy

Jessica G. Shantha, MD; Vincent Y. Ho, MD; Purnima Patel, MD; Farzin Forooghian, MD, MSc, FRCSC; Steven Yeh, MD

Abstract

BACKGROUND AND OBJECTIVE:

Patients with birdshot chorioretinopathy (BCR) may develop visual compromise due to choroidal neovascularization (CNV), and few series address management strategies in the anti-vascular endothelial growth factor (VEGF) era. The purpose of this study was to describe the clinical outcomes of combination anti-VEGF and immunosuppressive therapy for CNV associated with BCR.

PATIENTS AND METHODS:

Retrospective, interventional case series. Patients with BCR from two tertiary uveitis and retina practices were reviewed. Patients with CNV in association with BCR were identified and reviewed in detail. Clinical features, treatments utilized (ie, anti-VEGF injections, immunosuppressive therapy), and functional and structural outcomes over long-term follow-up were recorded. Outcomes measured included Snellen visual acuity, spectral-domain optical coherence tomography macular thickness during treatment, number and type of anti-VEGF injections, the need for initiation or escalation of immunosuppression, and incidence of CNV in macula-involved versus macula-sparing BCR.

RESULTS:

Four of 36 BCR patients were diagnosed with choroidal neovascularization (11%). Identification of CNV in all patients prompted treatment with intravitreal anti-VEGF injections and an increase or initiation of local or systemic immunosuppression. Mean Snellen visual acuity improved from 20/60 to 20/30 at final follow-up (P = .02). Mean central subfield thickness improved from 443 μ to 254 μ (P = .04). CNV in association with BCR occurred at a rate of 0.11 events per patient-year (95% CI, 0.02–0.31) in macula-involved BCR versus zero events/patient-year in macula-spared BCR (95% CI, 0–0.058; P = .009).

CONCLUSION:

Anti-VEGF therapy was effective for the treatment of CNV in BCR patients. A combination of systemic or local immunosuppression and anti-VEGF therapy may be useful in the management of CNV associated with BCR.

[Ophthalmic Surg Lasers Imaging Retina. 2016;47:450–457.]

Abstract

BACKGROUND AND OBJECTIVE:

Patients with birdshot chorioretinopathy (BCR) may develop visual compromise due to choroidal neovascularization (CNV), and few series address management strategies in the anti-vascular endothelial growth factor (VEGF) era. The purpose of this study was to describe the clinical outcomes of combination anti-VEGF and immunosuppressive therapy for CNV associated with BCR.

PATIENTS AND METHODS:

Retrospective, interventional case series. Patients with BCR from two tertiary uveitis and retina practices were reviewed. Patients with CNV in association with BCR were identified and reviewed in detail. Clinical features, treatments utilized (ie, anti-VEGF injections, immunosuppressive therapy), and functional and structural outcomes over long-term follow-up were recorded. Outcomes measured included Snellen visual acuity, spectral-domain optical coherence tomography macular thickness during treatment, number and type of anti-VEGF injections, the need for initiation or escalation of immunosuppression, and incidence of CNV in macula-involved versus macula-sparing BCR.

RESULTS:

Four of 36 BCR patients were diagnosed with choroidal neovascularization (11%). Identification of CNV in all patients prompted treatment with intravitreal anti-VEGF injections and an increase or initiation of local or systemic immunosuppression. Mean Snellen visual acuity improved from 20/60 to 20/30 at final follow-up (P = .02). Mean central subfield thickness improved from 443 μ to 254 μ (P = .04). CNV in association with BCR occurred at a rate of 0.11 events per patient-year (95% CI, 0.02–0.31) in macula-involved BCR versus zero events/patient-year in macula-spared BCR (95% CI, 0–0.058; P = .009).

CONCLUSION:

Anti-VEGF therapy was effective for the treatment of CNV in BCR patients. A combination of systemic or local immunosuppression and anti-VEGF therapy may be useful in the management of CNV associated with BCR.

[Ophthalmic Surg Lasers Imaging Retina. 2016;47:450–457.]

Introduction

Birdshot chorioretinopathy (BCR) is a rare HLA-A29-associated bilateral posterior uveitis with distinctive cream-colored choroidal lesions. This disease represents less than 7% of posterior uveitis cases referred to tertiary care centers. The distribution of lesions has been described in four different patterns, including macular predominance, diffuse, macular-sparing, and asymmetric.1 BCR is characterized by “exacerbations and remissions,” which leads to retinal and optic nerve dysfunction. Complications of BCR leading to visual loss include macular edema, optic disk edema, epiretinal membrane, retinal neovascularization, progressive retinal degeneration, and choroidal neovascular membrane formation.2

Choroidal neovascularization (CNV) in BCR was first reported in a small case series in 1983.3 Since this time there have been few reports of BCR and CNV. In a literature review regarding outcomes in BCR by Shah et al., 5% of the patients developed CNV.1 CNV leads to vision loss from the growth of new vessels causing leakage with subretinal fluid and eventual subretinal fibrosis.2

Risk factors reported in the literature for CNV formation in inflammatory uveitis are active inflammation, retinal neovascularization, CNV in the contralateral eye, and posterior uveitis. Specifically, diseases that affect the outer retina and retinal pigment epithelium (RPE) junction give rise to ruptures in Bruch's membrane, leading to an increased risk of CNV formation. The RPE also has an infiltration of inflammatory cells that secrete angiogenic factors contributing to CNV development.4,5 BCR is characterized by focal choroidal lesions with inflammatory cells that could lead to weakness in Bruch's membrane/RPE, predisposing BCR to CNV.

Immunohistological evaluation of CNV associated with multifocal choroiditis with panuveitis and punctate inner choroidopathy (PIC) showed vascular endothelial growth factor (VEGF) in the RPE, fibroblasts, and endothelial cells of the CNV.6 VEGF contributes to angiogenesis and increased vascular permeability in CNV. It is of particular importance because therapeutic options have been developed to inhibit VEGF. Bevacizumab (Avastin; Genentech, South San Francisco, CA) and ranibizumab (Lucentis; Genentech, South San Francisco, CA) and are a murine antibody and murine antibody fragment that bind to all VEGF isoforms.7 Many case series of inflammatory posterior uveitis show success in resolution of the CNV and improvement in visual acuity with the use of anti-VEGF therapy.8 Alternative treatment modalities have been described in the literature for inflammatory CNV, which include observation, laser photocoagulation,9 surgical removal of the CNV,10 photodynamic therapy (PDT),11 local12 and systemic corticosteroids,13 and immunosuppression.14

Patients and Methods

An institutional review board-approved, retrospective review of 36 BCR patients from the Emory Eye Center (Atlanta, GA) and St. Paul's Hospital (Vancouver, BC) was performed from January 1999 to October 2013. Patients with CNV were identified for analysis of their clinical course, systemic and local immunosuppression therapy requirement, anti-VEGF injections, Snellen visual acuity (VA), and spectral-domain optical coherence tomography (SD-OCT) macular thickness. The Spectralis HRA-OCT (Heidelberg Engineering, Heidelberg, Germany) was utilized at St. Paul's Hospital, and the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) was used at the Emory Eye Center.

Descriptive data collected consisted of demographic data, ophthalmic exam findings (slit lamp exam, dilated fundus exam), and complications of BCR. Diagnosis of CNV was made based on patient symptoms, clinical exam, SD-OCT, and fluorescein angiography (FA) findings. The criteria for treatment included persistence of subretinal/intraretinal fluid on exam and OCT and/or active leakage on FA as determined by the treating physician. Follow-up initially was every 4 weeks until resolution of the CNV. Informed consent was obtained for intravitreal injections and treatment was initiated with intravitreal bevacizumab (1.25 mg/0.05 mL) or ranibizumab (0.5 mg/0.05 mL) at the individual physician's discretion.

Main outcomes measured included Snellen VA, number of anti-VEGF injections, need for immunosuppression, and SD-OCT central subfield thickness (CST). Data analysis was performed using a paired t test comparing the logarithm of the minimal angle of resolution equivalent VA (LogMAR units) and SD-OCT CST at diagnosis and after resolution of the CNV. CNV event rates per patient-year and 95% confidence intervals were calculated in the entire cohort of patients to account for variable follow-up. Incidence rates of CNV were compared between macula-involved and macula-spared BCR patients from the Emory Eye Center.

Results

Four patients were identified to have choroidal neovascularization (11%). Three were women and one was a man, with an average age of 57 years (range: 47 years to 63 years) at the time of CNV diagnosis. Demographic data and baseline characteristics are reported in Table 1. Presenting symptoms included blurry vision, metamorphopsia, and eye pain with Snellen VA ranging from 20/25 to 20/200 (mean VA: 20/60).


Summary of Patients and Baseline Characteristics

Table 1:

Summary of Patients and Baseline Characteristics

Identification of the CNV in all patients prompted treatment with intravitreal anti-VEGF injections. Three patients received bevacizumab and one patient received ranibizumab. An average of four injections were given to treat the CNV with a final Snellen VA ranging from 20/20 to 20/80 (mean VA: 20/30). A mean VA improvement was observed during the follow-up period, which was statistically significant (P = .02). Follow-up ranged from 8 months to 27 months (mean: 25 months) from the initial diagnosis of CNV.

SD-OCT findings at the time of diagnosis included pigment epithelial detachment, disruption of the ellipsoid junction, increase in retinal thickness, and intraretinal and subretinal fluid. Mean initial SD-OCT CST was 443 μ and improved to final average CST of 254 μ (P = .04). Findings for individual patients are summarized in Table 2 and representative images are summarized in Figures 1, 2, 3, and 4.


Summary of Data: Visual Acuity, SD-OCT Outcomes, and Treatments

Table 2:

Summary of Data: Visual Acuity, SD-OCT Outcomes, and Treatments


Fundus photographs and optical coherence tomography (OCT) scans of Patient 1. Fundus photograph (A) at the onset of choroidal neovascularization (CNV) shows subretinal hemorrhage to an area of cystoid macular edema (CME). Fundus photograph 2 months after treatment of CNV (B) with bevacizumab shows few residual pinpoint hemorrhages. OCT scan of the left eye at onset of CNV (C) shows density consistent with subretinal hemorrhage (yellow arrows) and adjacent cystoid spaces. Following treatment with bevacizumab, the subretinal heme has resolved but CME persists (D). Following fluocinolone acetonide implantation, the edema has completely resolved (E).

Figure 1.

Fundus photographs and optical coherence tomography (OCT) scans of Patient 1. Fundus photograph (A) at the onset of choroidal neovascularization (CNV) shows subretinal hemorrhage to an area of cystoid macular edema (CME). Fundus photograph 2 months after treatment of CNV (B) with bevacizumab shows few residual pinpoint hemorrhages. OCT scan of the left eye at onset of CNV (C) shows density consistent with subretinal hemorrhage (yellow arrows) and adjacent cystoid spaces. Following treatment with bevacizumab, the subretinal heme has resolved but CME persists (D). Following fluocinolone acetonide implantation, the edema has completely resolved (E).


Fundus photograph, fluorescein angiogram, and optical coherence tomography (OCT) scan of Patient 2. Fundus photograph (A) shows a focal choroidal neovascularization (CNV) with heme in the right eye with leakage by fluorescein angiography (B). OCT shows subretinal hyperreflectivity and subretinal fluid (C). Following treatment with bevacizumab and immunosuppression with adalimumab, a follow-up fundus photograph (D) shows resolution of the edema and heme. Corresponding fluorescein angiogram (E) shows a window defect in the area of atrophy. OCT scan (F) shows a small subretinal pigment epithelium scar with no overlying subretinal fluid.

Figure 2.

Fundus photograph, fluorescein angiogram, and optical coherence tomography (OCT) scan of Patient 2. Fundus photograph (A) shows a focal choroidal neovascularization (CNV) with heme in the right eye with leakage by fluorescein angiography (B). OCT shows subretinal hyperreflectivity and subretinal fluid (C). Following treatment with bevacizumab and immunosuppression with adalimumab, a follow-up fundus photograph (D) shows resolution of the edema and heme. Corresponding fluorescein angiogram (E) shows a window defect in the area of atrophy. OCT scan (F) shows a small subretinal pigment epithelium scar with no overlying subretinal fluid.


Fundus photography, fluorescein angiography (FA), indocyanine green (ICG) angiography, and spectral-domain optical coherence tomography (SD-OCT) imaging for Patient 3. Fundus photography (A) FA with late phase leakage consistent with choroidal neovascularization (B). ICG confirmed the presence of active choroidal lesions consistent with birdshot (C). SD-OCT showed subretinal fluid and ellipsoid layer disruption (D). Following five injections of bevacizumab and initiation of methotrexate with an oral prednisone taper, complete resolution of the subretinal fluid and only a residual pigment epithelial detachment is seen by SD-OCT (E).

Figure 3.

Fundus photography, fluorescein angiography (FA), indocyanine green (ICG) angiography, and spectral-domain optical coherence tomography (SD-OCT) imaging for Patient 3. Fundus photography (A) FA with late phase leakage consistent with choroidal neovascularization (B). ICG confirmed the presence of active choroidal lesions consistent with birdshot (C). SD-OCT showed subretinal fluid and ellipsoid layer disruption (D). Following five injections of bevacizumab and initiation of methotrexate with an oral prednisone taper, complete resolution of the subretinal fluid and only a residual pigment epithelial detachment is seen by SD-OCT (E).


Fundus photography, fluorescein angiography (FA), and spectral-domain optical coherence tomography (SD-OCT) imaging for Patient 4. Fundus photograph (A) shows a macular pucker with choroidal neovascularization (CNV) and diffuse pattern of birdshot chorioretinopathy lesions. (B) SD-OCT displays a subretinal hyperreflectivity and intraretinal fluid with resolution of the intraretinal fluid and pigment epithelial detachment after treatment (C). (D-F) FA shows leaking at the fovea consistent with the location of the CNV on fundus photography.

Figure 4.

Fundus photography, fluorescein angiography (FA), and spectral-domain optical coherence tomography (SD-OCT) imaging for Patient 4. Fundus photograph (A) shows a macular pucker with choroidal neovascularization (CNV) and diffuse pattern of birdshot chorioretinopathy lesions. (B) SD-OCT displays a subretinal hyperreflectivity and intraretinal fluid with resolution of the intraretinal fluid and pigment epithelial detachment after treatment (C). (D-F) FA shows leaking at the fovea consistent with the location of the CNV on fundus photography.

There were no observed ophthalmic or medical complications from the intravitreal anti-VEGF injections. Two of the patients were initiated on systemic immunosuppressive therapy once the CNV was diagnosed. One patient required a fluocinolone acetonide intravitreal implant to treat concurrent cystoid macular edema (CME).

The event rate of CNV in the cohort of BCR patients from the Emory Eye Center was three events per 91.5 patient-years. For macula-involved BCR, the event rate was three events per 28 patient-years, for an incidence of 0.107 (95% CI; 0.022–0.31). For macula-spared BCR, the event rate was zero events per 63.5 patient-years (95% CI; 0–0.058) yielding an incidence rate difference of 0.107 (95% CI 0.027–0.188; P = .0091).

Discussion

Choroidal neovascular membrane formation is a rare complication of BCR, although in our series, this finding was identified in 11% of patients in our BCR cohort with an event rate of approximately 0.11 events per patient-year in macula-involved BCR. Given that BCR patients characteristically demonstrate choroidal lesions with inflammatory cells capable of secreting angiogenic factors that may promote CNV formation, CNVs may form over areas adjacent to or directly overlying choroidal lesions. In addition, the location of the BCR lesion within the choroid my cause structural changes to Bruch's membrane and the RPE further contributing to CNV development. In this series, all patients had inflammatory lesions within the macula, which further supports this hypothesis.4–6 Although we did not specifically classify birdshot patients into diffuse, macular predominance, asymmetric, and macular sparing variants, we hypothesized that the presence or absence of macular lesions (ie, macula-involved vs. macula-spared) was the salient feature to analyze statistically. Further classification of BCR into diffuse and asymmetric variants would be helpful to determine if these eyes would have any influence on the incidence of CNV development.

The CNV membrane comprises vascular and inflammatory components, which allows for multiple targets for therapy.15 Prior therapies that have been described in case reports or small case series for CNV and BCR have included observation, laser photocoagulation,3 PDT,29 intravitreal bevacizumab,29 intravitreal ranibizumab27 and intravitreal kenalog23 with or without systemic immunosuppression. The different treatment modalities reflect the available therapies in the given time period since these limited reports have described the treatment outcomes of 13 eyes from 11 patients spanning the course of three decades (Table 3).


Summary of Prior Series of Birdshot Chorioretinopathy and Choroidal Neovascularization

Table 3:

Summary of Prior Series of Birdshot Chorioretinopathy and Choroidal Neovascularization

Laser photocoagulation has been used with success for juxtafoveal and extrafoveal CNV but is limited in clinical practice given the atrophy and enlargement of scars that leads to further vision loss.9 In a case report of BCR and juxtafoveal CNV, laser photocoagulation was shown to mildly improve VA.16 Photodynamic therapy improves VA in subfoveal CNV associated with inflammation in multiple case series with stabilization and minimal visual recovery in other reports.11,17,18 Improvement of the results with PDT was shown with the use of corticosteroids or systemic immunosuppression with better visual outcomes and fewer PDT treatments.13,18–20 Corticosteroids act by decreasing vascular permeability, inhibiting angiogenesis, and diminishing the migration of inflammatory cells.21,22 They have been used as monotherapy delivered orally, via intravitreal injection, or through sub-Tenon's injection. The results of cases series using corticosteroids in inflammatory CNV associated with ocular histoplasmosis, PIC, and multifocal inner choroiditis (MIC) have shown variable success both anatomically and functionally.11,12,21,24

The use of anti-VEGF therapy has emerged as the preferred treatment for inflammation-associated CNV given that thermal laser photocoagulation and PDT may be associated with atrophy and scarring at long-term follow-up. Anti-VEGF therapy also avoids the possibility of local destructive tissue inflammation that may be observed with laser therapy. Several case series have demonstrated the benefit of anti-VEGF therapy in improving vision, decreasing macular edema, and resolution of active CNV, supporting the notion that VEGF plays a role in inflammatory CNV formation.23–29 Mansour et al. published a case series of 99 eyes, including one BCR case, and showed that an average of 3.6 intravitreal bevacizumab injections significantly improved CST and Snellen VA by at least 2.2 lines at 24 months.8,24 In 2009, Doctor et al. reported five cases of inflammatory CNV, with one case of BCR in their series. Their results support the previously mentioned report with 60% of the cases showing improved Snellen VA and all cases having a decrease in size of the CNV.23 Besides bevacizumab, ranibizumab has also demonstrated efficacy for the treatment of inflammatory CNV.28–31 Two case series using a combination of bevacizumab and ranibizumab intravitreal injections in MIC and PIC with associated inflammatory CNV have shown beneficial effects.29,30

Although local targeted anti-VEGF therapy has proven to be a useful treatment for inflammatory CNV, long term treatment with systemic immunosuppression is often required to control chronic inflammatory diseases such as BCR.2 Dees et al. described the use of corticosteroids with or without cyclosporine and azathioprine to treat 17 eyes with inflammatory CNV. Thirteen eyes (76%) had angiographic resolution of the CNV, and VA improved in nine eyes (53%).31

In the four patients identified in our study, VA was improved in four eyes and stabilized in one eye, and anatomic improvement was observed by SD-OCT measures in all eyes. These cases support that anti-VEGF therapy is effective in treating inflammatory CNV in BCR and preventing further visual decline. Importantly, all patients were treated concomitantly with local or systemic immunosuppression. Given that BCR is a chronic disease and may lead to progressive visual dysfunction, immunosuppression therapy is often used to stabilize and prevent visual decline.32 Although anti-VEGF agents target angiogenesis and vascular permeability, they may not impact inflammation associated with posterior uveitis. Appropriately targeting active, ongoing inflammation has been suggested for patients with choroidal neovascularization associated with posterior uveitis.33 For example, in Patient 1, anti-VEGF therapy was helpful in the CNV treatment; however, persistent macular edema due to ongoing inflammation required local immunosuppressive therapy with the fluocinolone acetonide implant. In Patient 2, several anti-VEGF agents were administered while the patient was on immunosuppressive therapy. After the immunosuppressive therapy was switched to an agent that demonstrated improved efficacy, the number of anti-VEGF agent injections decreased and eventually, no further anti-VEGF agents were needed. Anti-VEGF agents are preferred to escalation of immunosuppressive therapy if the findings are predominantly related to structural change and the inflammation is under control (eg, Patient 3); however, a combination of agents may be needed to ensure adequate treatment of both aspects of CNV pathology in BCR.

Limitations of this study included its retrospective nature, small sample size, the differences in imaging devices between institutions, and a lack of a standardized protocol for treatment. However, these patients represent a small cohort of patients treated successfully in the anti-VEGF era. Interestingly, the proportion of patients with BCR who developed CNV was greater than that reported in the literature, which could be reflective of selection bias versus improved detection with SD-OCT methods, which were unavailable in the majority of patients reported previously. All patients responded to anti-VEGF therapy and immunosuppression with a mean improvement in VA and anatomic outcomes by SD-OCT metrics. A combination strategy employing anti-VEGF therapy with local or systemic immunosuppression may be useful in the management of CNV associated with BCR.

References

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Summary of Patients and Baseline Characteristics

PatientAffected EyeAge (Years)GenderBCR Lesion DistributionHLA-A29 PositivityPrevious Treatment
1OS66FemaleDiffusePositiveFluocinolone acetonide implants (2) for CME
2OU62FemaleMacularPositiveCellcept 1 gram BID, Ciclosporin 150 mg daily, Retroseptal Kenalog OD (2), OS (3) for CME
3OD58MaleMacularPositive
4OD50FemaleDiffusePositive

Summary of Data: Visual Acuity, SD-OCT Outcomes, and Treatments

PatientInitial VA SnellenFinal VA SnellenInitial CST, μFinal CST, μTreatmentInjectionsImmunosuppression After CNV
120/20020/80638177bevacizumab4Fluocinolone acetonide implant Intravitreal Kenalog (2) Retroseptal Kenalog
2, OD20/2520/25285268bevacizumab5Retroseptal Kenalog (2) Adalimumab 40mg/2 weeks
2, OS20/4020/25269268bevacizumab4Retroseptal Kenalog (1)
320/6020/20497252bevacizumab5Methotrexate 15mg/week Prednisone taper
420/5020/30526304ranibizumab2Cellcept 1 gram BID Tacrolimus 3 grams daily
Average20/6020/304432544

Summary of Prior Series of Birdshot Chorioretinopathy and Choroidal Neovascularization

Case ReportCasesAgeSexTreatmentInitial VAFinal VAImmunosuppression
1983, Soubrane3Case 141FLaser photocoagulation6/9Unknown
Case 243FNone/unknown6/9Unknown
Case 358FNone/unknown1/20UnknownYes

1985, Brucker16Case 1 right eye57FNone/unknown20/8020/80
Case 1 left eyeNone/unknown20/10020/300
Case 2 right eye54MLaser photocoagulation20/5020/25
Case 2 left eyeLaser photocoagulation20/30Unknown

1989, Godel35Case 142MNone/unknownUnknownUnknown

2007, Nguyen29Case 150FPDT, pegaptanib, intravenous bevacizumab, IVT bevacizumab20/6320/40

2008, Doctor23Case 146FIVT Kenalog, 2 IVT bevacizumab20/20020/125

2010, Oueghlani27Case 140MIVT bevacizumab, IVT ranibizumab6/186/9Yes

2012, Iannetti28Case 172F3 IVT bevacizumab0.40.6Yes
Case 267M6 IVT bevacizumab0.20.1Yes
Authors

From the Department of Ophthalmology, Emory Eye Center, Emory University School of Medicine, Atlanta (JGS, VYH, PP, SY); and the University of British Columbia, Vancouver, BC, Canada (FF).

Presented previously at the American Uveitis Society Annual Meeting at the American Academy of Ophthalmology in Chicago on October 19, 2014.

Supported in part by an unrestricted departmental grant from Research to Prevent Blindness (New York, NY) to the Emory Eye Center, an NEI Core Grant for Vision Research (P30 EY 006360), and the Knights Templar Educational Foundation of Georgia (SY).

The authors report no relevant financial disclosures.

Address correspondence to Steven Yeh, MD, Associate Professor of Ophthalmology, Uveitis, Vitreoretinal Surgery and Disease, 1365B Clifton Road NE, Atlanta, GA 30322; 404-778-5070; fax: 404-778-4380; email: steven.yeh@emory.edu.

Received: September 07, 2015
Accepted: March 15, 2016

10.3928/23258160-20160419-08

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