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Clinical Sciences |

Vascular Endothelial Growth Factor in Aqueous Humor Before and After Intravitreal Injection of Bevacizumab in Eyes With Diabetic Retinopathy FREE

Osamu Sawada, MD; Hajime Kawamura, MD; Masashi Kakinoki, MD; Tomoko Sawada, MD; Masahito Ohji, MD
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan.


Arch Ophthalmol. 2007;125(10):1363-1366. doi:10.1001/archopht.125.10.1363.
Text Size: A A A
Published online

Objective  To study the concentration of vascular endothelial growth factor in the aqueous humor before and after intravitreal injection of bevacizumab in eyes with proliferative diabetic retinopathy.

Methods  In this prospective, interventional case series, 1.25 mg of bevacizumab was injected into the vitreous cavity as preoperative adjunctive therapy 1 week before pars plana vitrectomy to treat proliferative diabetic retinopathy in 18 eyes in 18 patients. Aqueous humor samples were obtained just before intravitreal injection of bevacizumab and just before vitrectomy 1 week after the injection. Aqueous humor samples also were obtained in patients with cataract without diabetes mellitus (control group). The vascular endothelial growth factor concentration in the aqueous humor was measured using an enzyme-linked immunosorbent assay.

Results  Vascular endothelial growth factor concentration in the aqueous humor ranged from 146 to 676 pg/mL (mean ± SD, 326 ± 125 pg/mL) before intravitreal injection of bevacizumab and decreased to less than 31 pg/mL (P < .001) in all eyes 1 week after injection. Intravitreal bevacizumab therapy caused no adverse events. The concentrations in the control group ranged from 80 to 218 pg/mL (mean ± SD, 146 ± 40 pg/mL).

Conclusion  Intravitreal injections of bevacizumab resulted in a substantial decrease in vascular endothelial growth factor in the aqueous humor.

Figures in this Article

Proliferative diabetic retinopathy (PDR) is a serious complication secondary to diabetes mellitus and a leading cause of blindness.1 Diabetes causes microvascular occlusion resulting in retinal ischemia. The ischemic retina secretes vascular endothelial growth factor (VEGF), an endothelial cell mitogen and an angiogenic inducer, into the vitreous cavity.24 Vascular endothelial growth factor increases vascular permeability and causes the formation of new vessels arising from the plane of the retina, resulting in PDR.3 Inhibiting VEGF concentration can decrease vascular permeability and prevent iris and retinal neovascularization in PDR. Photocoagulation applied in eyes with PDR reduces the VEGF concentration in the eyes3 and results in regression of the iris and retinal neovascularization, reduced leakage, and better visual outcomes.57

Bevacizumab (Avastin; Genentech Inc, South San Francisco, California) is a full-length humanized monoclonal antibody to all isoforms of VEGF8 and has been approved by the Food and Drug Administration for intravenous treatment of metastatic colorectal cancer.9 Recently, intravenous injection of bevacizumab was reported effective in treating age-related macular degeneration.10,11 Systemically administered bevacizumab carries a substantial risk of thromboembolic events such as stroke or myocardial infarction in patients with cancer.9,12 The intravitreal dose of 1.25 mg of bevacizumab is about 300- to 400-fold lower than the systemic dose,13 and a lower risk of systemic adverse effects would be expected. Intravitreal injections of bevacizumab then began to be used, and its efficacy without serious adverse events has been reported in neovascular age-related macular degeneration,1417 central retinal vein occlusion,18,19 and PDR with retinal and iris neovascularization.13,2023

Intravitreally injected bevacizumab is expected to decrease the intraocular VEGF level, cause regression of the retinal and iris neovascularization, and reduce leakage. However, to our knowledge no report has been published on measurement of intraocular VEGF levels before and after intravitreal injection of bevacizumab in human beings. We measured VEGF concentrations in the aqueous humor before and after intravitreal injection of bevacizumab, which was used as a preoperative adjunctive therapy before vitrectomy to treat PDR.

This study of the off-label use of bevacizumab and collection of aqueous humor before and after intravitreal injection was approved by the Institutional Review Board of Shiga University of Medical Science Hospital, Shiga, Japan. Informed consent was obtained from all participants, including patients with PDR and a control group of patients with cataract.

SUBJECTS

Aqueous humor samples were obtained from 18 eyes in 18 patients (11 men and 7 women) with PDR. Of the 18 study eyes, 7 had a vitreous hemorrhage, 8 had a tractional retinal detachment, and 3 had diabetic macular edema. Mean patient age was 55.6 years (age range, 31-73 years). The mean ± SD hemoglobin A1C value was 8.0% ± 2.7% (range, 4.9%-17.4%). Laser photocoagulation had been performed in 16 of 18 patients; no patients underwent surgery before the study. Aqueous humor also was sampled from 7 eyes in 7 patients (3 men and 4 women) with cataract who did not have diabetes mellitus or ocular disease other than cataract. Mean patient age in this control group was 77.6 years (age range, 70-86 years).

OPHTHALMOLOGIC EXAMINATION

Patients underwent a comprehensive ophthalmologic examination that included measurement of the best-corrected visual acuity and biomicroscopic examination. Fluorescein angiography was performed, and color photographs were obtained using a fundus camera (Topcon TRC-50IA; Tokyo Optical Co Ltd, Tokyo, Japan). The eyes were classified as having diabetic retinopathy, vitreous hemorrhage, tractional retinal detachment, or diabetic macular edema.

SAMPLE COLLECTION

Bevacizumab, 1.25 mg/0.05 mL, was injected into the vitreous cavity in the 18 study eyes with PDR 1 week before vitrectomy. A 0.2-mL sample of undiluted aqueous humor was obtained using a 29-gauge needle immediately before injection of bevacizumab and immediately before vitrectomy 1 week after the intravitreal bevacizumab injection. Undiluted aqueous humor also was obtained as a control sample from 7 eyes in 7 patients without other ocular disorders immediately before cataract surgery. All injections and sample collections were performed using a standard sterilization procedure that included the use of topical povidone-iodine and levofloxacin drops. The samples were stored in a deep freezer at −80°C until analysis.

MEASUREMENT OF VEGF

The VEGF concentration in the aqueous humor was measured using an enzyme-linked immunosorbent assay for human VEGF (R&D Systems Inc, Minneapolis, Minnesota). The primary antibody against VEGF detected 2 isoforms (VEGF121 and VEGF165) of the 4 VEGF isoforms.24 The limit of the detectable VEGF concentration was 31 pg/mL.

STATISTICAL ANALYSIS

Data were analyzed using commercially available software (SigmaStat version 3.1; Systat Software Inc, Richmond, California). Data are presented as mean ± SD. The differences between the groups were evaluated using the t test in a comparison between results in patients with diabetes mellitus and control patients. The Wilcoxon signed rank test was used to compare VEGF concentrations before and after injection. P < .05 was considered statistically significant.

The VEGF concentrations in the aqueous humor in eyes with PDR ranged from 146 to 676 pg/mL (326 ± 125 pg/mL) before intravitreal injection of bevacizumab (Figure 1). The VEGF concentrations in the aqueous humor in the control eyes with cataract ranged from 80 to 218 pg/mL (146 ± 40 pg/mL). The mean concentration in eyes with PDR was higher than that in control eyes (P = .002, t test). The VEGF concentration in eyes with PDR dramatically decreased to less than 31 pg/mL, the limit of detection, in all cases 1 week after injection of bevacizumab (P < .001, Wilcoxon signed rank test) (Figure 2).

Place holder to copy figure label and caption
Figure 1.

Vascular endothelial growth factor (VEGF) concentration in the aqueous humor in eyes with proliferative diabetic retinopathy and control eyes. The VEGF levels are shown for eyes with vitreous hemorrhage (VH), tractional retinal detachment (TRD), diabetic macular edema (DME), and control eyes.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Vascular endothelial growth factor (VEGF) concentration in the aqueous humor in eyes with proliferative diabetic retinopathy before and 1 week after intravitreal injection of bevacizumab. The VEGF levels are shown for eyes with diabetic macular edema (DME), tractional retinal detachment (TRD), and vitreous hemorrhage (VH).

Graphic Jump Location

Of the 18 study eyes, 7 eyes had a vitreous hemorrhage, 8 had tractional retinal detachment, and 3 had diabetic macular edema. The VEGF concentration in the aqueous humor before intravitreal injection of bevacizumab ranged from 146 to 393 pg/mL (339 ± 106) in the group with vitreous hemorrhage, from 159 to 676 pg/mL (335 ± 149) in the group with tractional retinal detachment, and from 196 to 368 pg/mL (271 ± 72) in the group with diabetic macular edema (Figure 1). There were no substantial differences among the groups.

After injection of bevacizumab, no complications developed, such as uveitis, endophthalmitis, effects of ocular toxic effects, or any obvious systemic adverse events. High-quality fundus photographs and fluorescein angiographs were obtained before and after intravitreal bevacizumab injection in 10 eyes. One week after the injection of bevacizumab, substantial regression of neovascularization or fluorescein leakage was seen in 6 of the 10 eyes (60%) (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Tractional retinal detachment from proliferative diabetic retinopathy in a 43-year-old woman. Fluorescein angiograph before intravitreal injection of bevacizumab (A) and 1 week after the injection (B). Fluorescein leakage decreased substantially after intravitreal bevacizumab injection.

Graphic Jump Location

The mean VEGF concentration in the aqueous humor in eyes with PDR in the present study was similar to that found by Funatsu et al,25 who reported that the concentrations in the aqueous humor and vitreous fluid in eyes with PDR were substantially higher than in eyes with quiescent PDR. Our results showed that the VEGF concentration in the aqueous humor was also higher than in control eyes. We did not measure the protein level in the aqueous humor, and the concentration of proteins other than VEGF also may increase as a result of increased vascular permeability or disruption of the blood-aqueous barrier. However, the VEGF concentration has a key role in the pathogenesis of diabetic retinopathy.3

As expected, intravitreal injection of bevacizumab substantially decreased the VEGF concentration in the aqueous humor in eyes with PDR by at least 10-fold, although the exact concentration 1 week after intravitreal injection of bevacizumab was not determined because the limit of measurement of the enzyme-linked immunosorbent assay was 31 pg/mL. The VEGF concentration in the vitreous seems to be more important than that in the aqueous humor. However, it was reported that the VEGF level in the aqueous humor was substantially correlated with the VEGF level in the vitreous and the aqueous level of VEGF was correlated with the severity of diabetic retinopathy and the activity of PDR.3,25 The purpose of this study was to evaluate the changes in the intraocular VEGF concentration before and after intravitreal injection of bevacizumab. However, because it is difficult to obtain vitreous samples before and after intravitreal injection of bevacizumab, we measured the VEGF concentration in the aqueous humor before and after intravitreal injection of bevacizumab. Because we clearly showed that VEGF in the aqueous humor decreased substantially after intravitreal injection of bevacizumab, the VEGF concentration in the vitreous also might decrease substantially after intravitreal injection of bevacizumab. In addition, fluorescein leakage from the retinal neovascularization decreased substantially after intravitreal injection of bevacizumab, as reported previously.21 Furthermore, bleeding from retinal vessels or new vessels during vitrectomy was reported to be much less than during standard vitrectomy in which bevacizumab therapy was not used,22 resulting in a higher level of safety during surgery. It is reasonable to think that decreased VEGF concentrations in the vitreous cavity caused decreased fluorescein leakage and minimal bleeding during vitrectomy.

Funatsu et al25 reported that the VEGF level in the aqueous was correlated with the severity of diabetic retinopathy according to the modified Early Treatment Diabetic Retinopathy Study retinopathy severity scale. However, there was no substantial difference in the VEGF concentrations in the aqueous humor among the subgroups with vitreous hemorrhage, tractional retinal detachment, or diabetic macular edema. There may be no differences among the types of PDR or we may not have been able to reach a definitive conclusion in the present study because of the small number of eyes in each group.

We showed that intravitreal injection of bevacizumab decreased the VEGF level in the aqueous humor and probably the vitreous cavity. We could not measure the exact VEGF concentration 1 week after the intravitreal injection of bevacizumab because of the limits of the enzyme-linked immunosorbent assay used. We found a decrease in the VEGF concentration only 1 week after intravitreal injection of bevacizumab. We do not know how long the reduced level of VEGF is maintained. Further study is warranted to elucidate these issues.

Correspondence: Osamu Sawada, MD, Department of Ophthalmology, Shiga University of Medical Science, Seta-Tukinowacho, Otsu, Shiga 520-2192, Japan.

Submitted for Publication: January 16, 2007; final revision received May 13, 2007; accepted May 17, 2007.

Financial Disclosure: None reported.

Support/Funding: This study was supported by grant 18591915 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and a grant from the Ministry of Health, Labour, and Welfare.

Rosenblatt  BJBenson  WE Diabetic retinopathy. Yanoff  MDuker  JSAugsburger  JJ  et al. edsOphthalmology.2nd St Louis, MO Mosby2004;877
Adamis  APMiller  JWBernal  MT  et al.  Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118 (4) 445- 450
PubMed
Aiello  LPAvery  RLArrigg  PG  et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331 (22) 1480- 1487
PubMed
Pe’er  JShweiki  DItin  AHemo  IGnessin  HKeshet  E Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest 1995;72 (6) 638- 645
PubMed
Wand  MDueker  DKAiello  LMGrant  WM Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma. Am J Ophthalmol 1978;86 (3) 332- 339
PubMed
Diabetic Retinopathy Study Research Group, Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81 (4) 383- 396
PubMed
Early Treatment Diabetic Retinopathy Study Research Group, Early photocoagulation for diabetic retinopathy. ETDRS report No. 9. Ophthalmology 1991;98 (5) ((suppl)) 766- 785
PubMed
Ferrara  N Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25 (4) 581- 611
PubMed
Hurwitz  HFehrenbacher  LNovotny  W  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350 (23) 2335- 2342
PubMed
Michels  SRosenfeld  PJPuliafito  CAMarcus  ENVemlatraman  AS Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112 (6) 1035- 1047
PubMed
Moshfeghi  AARosenfeld  PJPuliafito  CA  et al.  Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study [published online ahead of print October 5, 2006]. Ophthalmology 2006;113 (11) 2002.e1- e1210.1016/j.ophtha.2006.05.070
PubMed
 Important drug warning. FDA MedWatch.http://www.fda.gov/medwatch/SAFETY/2005/Avastin_dearhcp.pdfOctober 10, 2005.
Avery  RLPearlman  JPieramici  D  et al.  Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113 (10) 1695- 1705
PubMed
Rosenfeld  PJMoshfeghi  AAPuliafito  CA Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36 (4) 331- 335
PubMed
Avery  RLPieramici  DJRabena  MDCastellarin  AANasir  MARabena  M Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration [published online ahead of print February 3, 2006]. Ophthalmology 2006;113 (3) 363- 37210.1016/j.ophtha.2005.11.019
PubMed
Spaide  RFLaud  KFine  HF  et al.  Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26 (4) 383- 390
PubMed
Rich  RMRosenfeld  PJPuliafito  CA  et al.  Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26 (5) 495- 511
PubMed
Schwartz  SGHickey  MPuliafito  CA Bilateral CRAO and CRVO from thrombotic thrombocytopenic purpura: OCT findings and treatment with triamcinolone acetonide and bevacizumab. Ophthalmic Surg Lasers Imaging 2006;37 (5) 420- 422
PubMed
Iturralde  DSpaide  RFMeyerle  CB  et al.  Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26 (3) 279- 284
PubMed
Oshima  YSakaguchi  HGomi  FTano  Y Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy. Am J Ophthalmol 2006;142 (1) 155- 157
PubMed
Spaide  RFFisher  YL Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26 (3) 275- 278
PubMed
Mason  JONixon  PAWhite  MF Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142 (4) 685- 688
PubMed
Chen  EPark  CH Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina 2006;26 (6) 699- 700
PubMed
Hyodo  IDoi  TEndo  H  et al.  Clinical significance plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 1998;34 (13) 2041- 2045
PubMed
Funatsu  HYamashita  HNoma  H  et al.  Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients [published online ahead of print July 17, 2004]. Graefes Arch Clin Exp Ophthalmol 2005;243 (1) 3- 810.1007/s00417-004-0950-7
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Vascular endothelial growth factor (VEGF) concentration in the aqueous humor in eyes with proliferative diabetic retinopathy and control eyes. The VEGF levels are shown for eyes with vitreous hemorrhage (VH), tractional retinal detachment (TRD), diabetic macular edema (DME), and control eyes.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Vascular endothelial growth factor (VEGF) concentration in the aqueous humor in eyes with proliferative diabetic retinopathy before and 1 week after intravitreal injection of bevacizumab. The VEGF levels are shown for eyes with diabetic macular edema (DME), tractional retinal detachment (TRD), and vitreous hemorrhage (VH).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Tractional retinal detachment from proliferative diabetic retinopathy in a 43-year-old woman. Fluorescein angiograph before intravitreal injection of bevacizumab (A) and 1 week after the injection (B). Fluorescein leakage decreased substantially after intravitreal bevacizumab injection.

Graphic Jump Location

Tables

References

Rosenblatt  BJBenson  WE Diabetic retinopathy. Yanoff  MDuker  JSAugsburger  JJ  et al. edsOphthalmology.2nd St Louis, MO Mosby2004;877
Adamis  APMiller  JWBernal  MT  et al.  Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118 (4) 445- 450
PubMed
Aiello  LPAvery  RLArrigg  PG  et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331 (22) 1480- 1487
PubMed
Pe’er  JShweiki  DItin  AHemo  IGnessin  HKeshet  E Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest 1995;72 (6) 638- 645
PubMed
Wand  MDueker  DKAiello  LMGrant  WM Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma. Am J Ophthalmol 1978;86 (3) 332- 339
PubMed
Diabetic Retinopathy Study Research Group, Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81 (4) 383- 396
PubMed
Early Treatment Diabetic Retinopathy Study Research Group, Early photocoagulation for diabetic retinopathy. ETDRS report No. 9. Ophthalmology 1991;98 (5) ((suppl)) 766- 785
PubMed
Ferrara  N Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25 (4) 581- 611
PubMed
Hurwitz  HFehrenbacher  LNovotny  W  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350 (23) 2335- 2342
PubMed
Michels  SRosenfeld  PJPuliafito  CAMarcus  ENVemlatraman  AS Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112 (6) 1035- 1047
PubMed
Moshfeghi  AARosenfeld  PJPuliafito  CA  et al.  Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study [published online ahead of print October 5, 2006]. Ophthalmology 2006;113 (11) 2002.e1- e1210.1016/j.ophtha.2006.05.070
PubMed
 Important drug warning. FDA MedWatch.http://www.fda.gov/medwatch/SAFETY/2005/Avastin_dearhcp.pdfOctober 10, 2005.
Avery  RLPearlman  JPieramici  D  et al.  Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113 (10) 1695- 1705
PubMed
Rosenfeld  PJMoshfeghi  AAPuliafito  CA Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36 (4) 331- 335
PubMed
Avery  RLPieramici  DJRabena  MDCastellarin  AANasir  MARabena  M Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration [published online ahead of print February 3, 2006]. Ophthalmology 2006;113 (3) 363- 37210.1016/j.ophtha.2005.11.019
PubMed
Spaide  RFLaud  KFine  HF  et al.  Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26 (4) 383- 390
PubMed
Rich  RMRosenfeld  PJPuliafito  CA  et al.  Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26 (5) 495- 511
PubMed
Schwartz  SGHickey  MPuliafito  CA Bilateral CRAO and CRVO from thrombotic thrombocytopenic purpura: OCT findings and treatment with triamcinolone acetonide and bevacizumab. Ophthalmic Surg Lasers Imaging 2006;37 (5) 420- 422
PubMed
Iturralde  DSpaide  RFMeyerle  CB  et al.  Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26 (3) 279- 284
PubMed
Oshima  YSakaguchi  HGomi  FTano  Y Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy. Am J Ophthalmol 2006;142 (1) 155- 157
PubMed
Spaide  RFFisher  YL Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26 (3) 275- 278
PubMed
Mason  JONixon  PAWhite  MF Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142 (4) 685- 688
PubMed
Chen  EPark  CH Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina 2006;26 (6) 699- 700
PubMed
Hyodo  IDoi  TEndo  H  et al.  Clinical significance plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 1998;34 (13) 2041- 2045
PubMed
Funatsu  HYamashita  HNoma  H  et al.  Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients [published online ahead of print July 17, 2004]. Graefes Arch Clin Exp Ophthalmol 2005;243 (1) 3- 810.1007/s00417-004-0950-7
PubMed

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