- Email: [email protected]
Distinct Cytokine and Chemokine Profiles in the Aqueous of Patients With Uveitis and Cystoid Macular Edema
Distinct Cytokine and Chemokine Profiles in the Aqueous of Patients With Uveitis and Cystoid Macular Edema
sion molecules in uveitis, 31 diagnostic aqueous humor samples from patients with uveitis, which were stored at ⫺80°C in sterile screw-cap tubes within five hours of collection, were analyzed for 16 mediators (Table) in a multiplex immunoassay as described previously.1 Controls consisted of 11 aqueous humor samples from patients with age-related cataract without uveitis or other associated ocular disease. This study was performed according to the tenets of the Declaration of Helsinki. Approval of the institutional review board has been obtained. The findings were related to several clinical features, such as intraocular infection, activity of inflammation, and cystoid macular edema (CME). Only patients with a laboratory confirmed intraocular infection were considered to have infectious uveitis. The activity of uveitis at the time of sampling was registered, and the presence of CME was evaluated on fluorescein angiograms. Concentrations above or below the detection limit were given as the highest or lowest detectable value. Data analysis was performed using SPSS (version 12.0; SPSS Inc, Chicago, Illinois, USA). Results are presented as the geometric mean concentration and the range of detectable samples (Table). The mediator levels were compared between all groups with the Mann-Whitney U test. A P-value of ⬍.05 was considered to be significant. Patients with uveitis had higher levels of interleukin-6 (IL; P ⬍ .001), IL-8 (P ⫽ .002), soluble intercellular adhesion molecule (sICAM; P ⫽ .002), soluble vascular cell adhesion molecule (sVCAM; P ⫽ .003), and interferon-inducible protein-10 (IP-10; P ⬍ .001) compared with nonuveitic controls (Table). During active uveitis, higher levels of IL-6 (P ⫽ .020), IL -10 (P ⫽ .028), interferon-␥ (IFN-␥; P ⫽ .030), sVCAM (P ⫽ .009), regulated on activation, normal T cell expressed and secreted (RANTES) (P ⫽ .016), and IP-10 (P ⬍ .001) were found than during quiescent uveitis. Patients with infectious uveitis had higher levels of IL-10 (P ⫽ .034) than patients with noninfectious uveitis. No significant differences were found between uveitis patients with or without CME. Our findings confirm and extend previous findings of elevated levels of IL-6, IL-8, and IFN-␥ in patients with uveitis.2,3 Elevated IL-10 levels in intraocular infections were also noted by others,4 but in contrast to our study, these levels were compared with nonuveitis controls. Our data show that IL-10 may be an indicator for an active or infectious uveitis, or both. Within these subgroups there is variation in the IL-10 levels, which warrants more in-depth analysis of the microbiologic causes of the infection. Elevated IL-6 and sICAM levels previously were reported in patients with CME associated with diabetic retinopathy and branch retinal vein occlusion.5,6 In contrast, in our patients with uveitis-associated CME, we
Bram van Kooij, MD, Aniki Rothova, MD, PhD, Ger T. Rijkers, PhD, and Jolanda D. F. de Groot-Mijnes, PhD To investigate the global cytokine and chemokine expression pattern in the aqueous humor of uveitis patients and relate them to clinical features. DESIGN: Cross-sectional study. METHODS: In 31 aqueous humor samples from uveitis patients, the concentration of mediators was measured by a multiplex immunoassay. Eleven control samples were included. RESULTS: Uveitis samples had higher levels of interleukin-6, interleukin-8, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule (sVCAM), and interferon-inducible protein-10 (IP-10) than nonuveitis controls. Active uveitis samples had higher levels of interleukin-6, interleukin-10, interferon-␥, sVCAM, regulated on activation, normal T cell expressed and secreted (RANTES), and IP-10 than quiescent uveitis samples. Infectious uveitis was associated with higher levels of interleukin-10 than noninfectious uveitis (P < .03 for all subgroups). No significant differences were found between cystoid macular edema (CME) and nonCME samples. CONCLUSIONS: Elevated levels of specific mediators were found in active and in infectious uveitis, but not in CME. Mediator profiles might lead to a better understanding of the pathogenesis of uveitis (Am J Ophthalmol 2006; 142:192–194. © 2006 by Elsevier Inc. All rights reserved.) PURPOSE:
C
YTOKINES, CHEMOKINES, AND SOLUBLE ADHESION
molecules modulate immune reactions; they influence the communication between various cell types and can alter the properties of the vascular endothelium. To investigate the role of cytokines, chemokines, and adhe-
Accepted for publication Feb 15, 2006. From the F. C. Donders Institute of Ophthalmology, Utrecht, The Netherlands (B.v.K., A.R., J.D.F.d.G.-M.), Department of Pediatric Immunology, Wilhelmina Children’s Hospital, Utrecht, The Netherlands (G.T.R.), and Department of Virology, Eijkman-Winkler Center (J.D.F.d.G.-M.), University Medical Center Utrecht, Utrecht, The Netherlands. This study was supported in part by the Dr F. P. Fischer Foundation, Utrecht, The Netherlands. Inquiries to Bram van Kooij, MD, F. C. Donders Institute, Department of Ophthalmology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands; e-mail: b.vankooij@ oogh.azu.nl
192
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JULY 2006
VOL. 142, NO. 1
TABLE. Mediator Concentrations in the Aqueous Humor of Patients With Uveitis and Controls Uveitis n ⫽ 31
BRIEF REPORTS
Mean age (years) 50 Geometric mean concentration Range of detectable samples (number IL-6 637 39–⬎13821 (0) IL-8 43 11–⬎4544 (10) IL-10 17 25–⬎4975 (23) IFN-␥ 5.0 6.4–52 (26) sICAM 440 34–3806 (0) sVCAM 813 156–⬎6531 (0) RANTES 95 40–1016 (11) IP-10 836 40–⬎7384 (0)
Controls n ⫽ 11
66
P Value
CME n ⫽ 12*
Non CME n ⫽ 17*
57
43
of samples in the undetectable range) 38 ⬍.001 338 693 32–240 70–⬎13822 39–⬎13821.81 (2) (0) (0) 12 .002 21 42 79 13–94 11–1693 (10) (4) (6) 8.1 .066 9.9 14 ⬍8.1 82 25–503 (11) (11) (12) 4.1 .162 4.1 5.2 ⬍4.1 ⬍4.1 6.4–25 (11) (12) (14) 106 .002 373 428 30–665 136–1566 34–3806 (0) (0) (0) 269 .003 598 942 60–697 189–2472 156–⬎6531 (0) (0) (0) 73 .674 55 120 49–248 49–343 40–1016 (3) (6) (5) 83 ⬍.001 585 978 30–448 40–5183 62–⬎7384 (0) (0) (0)
P Value
.756
.498
.211
.076
.507
.199
.067
.268
Active Disease n ⫽ 17
Quiescent Disease, n ⫽ 14
44
56
1413 78–⬎13822 (0) 73 11–⬎4544 (3) 27 25–⬎4975 (10) 6.0 6.4–52 (12) 625 98–3806 (0) 1285 249–⬎6531 (0) 148 49–1016 (3) 1955 324–⬎7384 (0)
242 39–⬎13822 (0) 23 13–362 (7) 9.0 32 (13) 4.1 ⬍4.1 (14) 287 34–1133 (0) 466 156–1553 (0) 55 40–331 (8) 298 40–⬎7384 (0)
P Value
.020
.076
.028
.030
.104
.009
.016
⬍.001
Infectious Uveitis, n ⫽ 11
Non Infectious Uveitis, n ⫽ 20
52
49
676 39–⬎13822 (0) 75 11–⬎4544 (4) 42 33–⬎4975 (6) 5.4 6.4 and 52 (9) 379 34–3045 (0) 802 156–4312 (0) 103 49–745 (3) 1487 62–⬎7384 (0)
615 62–⬎13822 (0) 32 13–1693 (6) 10 25–39 (17) 4.9 9.7–25 (17) 478 98–3806 (0) 819 189–⬎6531 (0) 90 40–1016 (8) 609 40–⬎7384 (0)
P Value
.708
.488
.034
.821
.869
.967
.659
.076
CME ⫽ cystoid macular edema; IL ⫽ interleukin; INF ⫽ interferon; sICAM ⫽ soluble intercellular adhesion molecule; sVCAM ⫽ soluble vascular cell adhesion molecule; IP-10 ⫽ interferon-inducible protein 10. *CME could not be evaluated in two patients. The levels of IL-1, IL-2, IL-4, IL-12, IL-13, IL-18, TNF-␣, Eotaxin were mainly below the detection limit and did not vary statistically in any of the comparison groups.
193
Systemic Absorption of 5-Fluorouracil During Vitrectomy
found no differences in the levels of these mediators, nor in the other cytokines and chemokines analyzed. We did not observe clear Th1 (IFN-␥, IL-2, and tumor necrosis factor-␣) or Th2 cytokine profiles (IL-4) in patients with uveitis. In contrast, we found a strong correlation of active uveitis with sVCAM and IP-10, both of which are important mediators for leukocyte recruitment.7 The differences with previous findings might in part be explained by the complex biologic function of the mediators, transient production during the course of the inflammatory process, with specific uveitis entities and medications at the time of sampling.4 Clearly, future research of cytokines and other mediators involved in specific types of uveitis is needed to elucidate the role of these proteins in the inflammation process. As different mediators possess biologic overlapping functions and often influence the production of each other, the ability to simultaneously monitor changes in multiple cytokines would hold a greater discriminatory as well as instructive power than single cytokine analysis. Knowledge of these local cytokine and adhesion molecule biosignatures, which can nowadays easily be obtained even in small samples using the multiplex immunoassay, might lead to a better understanding of the pathogenesis of uveitis and CME and help to design new therapies.
Onne Creten, MD, Werner Spileers, MD, PhD, and Peter Stalmans, MD, PhD The aim of this study is to determine if systemic absorption is present after 5-fluorouracil (5FU) is used in the vitrectomy infusion. DESIGN: A two-case clinical study. METHODS: A catabolite of 5FU, ␣-fluoro--alanine (FBAL), was measured in urine samples of two patients who underwent vitrectomy using 5FU in the infusion fluid. RESULTS: In both patients, FBAL was found in the urine samples collected up to 48 hours after the surgery, although in significantly different concentrations. CONCLUSIONS: The use of 5FU in the vitrectomy infusion fluid to prevent the formation of proliferative vitreoretinopathy may lead to significant general absorption and may be avoided in children and young adults. (Am J Ophthalmol 2006;142:194 –196. © 2006 by Elsevier Inc. All rights reserved.) PURPOSE:
D
retinal surgical techniques, proliferative vitreoretinopathy (PVR) remains the leading cause of surgery failure.1 Studies have evaluated the efficacy of different drugs in the control of PVR. However, 5-fluorouracil (5FU), a synthetic pyrimidine analog, is the most extensively studied agent for inhibition of retinal pigment epithelium proliferation. It has been shown that 5FU reduces the rate of PVR by more than 50%,1 without corneal or retinal toxicity.2 Nevertheless, no positive effect on the success rate of surgery for established PVR has been proven. Although the side effects of 5FU are well established, no data are available on the systemic absorption and the influence of intravitreal 5FU on procreation. Because 60% to 90% of the administered dose is excreted in urine as ␣-fluoro-alanine (FBAL)3 (Figure), we measured the amount of FBAL during the first 72 hours postoperatively to determine whether intravitreally administered 5FU is systemically absorbed. Two patients underwent a three-port pars plana vitrectomy, using intravitreal infusion with 5FU (200 g/ml) and low-molecular-weight heparin (8 IU/ml). The local ethics committee approved the study. All patients gave informed consent according to institutional guidelines. The first patient underwent a vitrectomy to remove silicone oil, used in previous surgery. The infusion lasted
REFERENCES
1. de Jager W, Prakken BJ, Bijlsma JW, Kuis W, Rijkers GT. Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J Immunol Methods 2005;300:124 –135. 2. Curnow SJ, Falciani F, Durrani OM, et al. Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis. Invest Ophthalmol Vis Sci 2005;46: 4251– 4259. 3. Wallace GR, John CS, Wloka K, Salmon M, Murray PI. The role of chemokines and their receptors in ocular disease. Prog Retin Eye Res 2004;23:435– 448. 4. Ongkosuwito JV, Feron EJ, van Doornik CE, et al. Analysis of immunoregulatory cytokines in ocular fluid samples from patients with uveitis. Invest Ophthalmol Vis Sci 1998;39: 2659 –2665. 5. Funatsu H, Yamashita H, Sakata K, et al. Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule one are related to diabetic macular edema. Ophthalmology 2005;112:806 – 816. 6. Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2006;244: 309 –315. 7. Sorensen TL. Targeting the chemokine receptor CXCR3 and its ligand CXCL10 in the central nervous system: potential therapy for inflammatory demyelinating disease? Curr Neurovasc Res 2004;1:183–190.
194
AMERICAN JOURNAL
ESPITE IMPROVED RESULTS WITH ADVANCED VITREO-
Accepted for publication Feb 15, 2006. From the Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium. Inquiries to Peter Stalmans, MD, PhD, Department of Ophthalmology UZLeuven, Capucijnenvoer 33, B3000 Leuven, Belgium; e-mail: peter. [email protected] OF
OPHTHALMOLOGY
JULY 2006
sion molecules in uveitis, 31 diagnostic aqueous humor samples from patients with uveitis, which were stored at ⫺80°C in sterile screw-cap tubes within five hours of collection, were analyzed for 16 mediators (Table) in a multiplex immunoassay as described previously.1 Controls consisted of 11 aqueous humor samples from patients with age-related cataract without uveitis or other associated ocular disease. This study was performed according to the tenets of the Declaration of Helsinki. Approval of the institutional review board has been obtained. The findings were related to several clinical features, such as intraocular infection, activity of inflammation, and cystoid macular edema (CME). Only patients with a laboratory confirmed intraocular infection were considered to have infectious uveitis. The activity of uveitis at the time of sampling was registered, and the presence of CME was evaluated on fluorescein angiograms. Concentrations above or below the detection limit were given as the highest or lowest detectable value. Data analysis was performed using SPSS (version 12.0; SPSS Inc, Chicago, Illinois, USA). Results are presented as the geometric mean concentration and the range of detectable samples (Table). The mediator levels were compared between all groups with the Mann-Whitney U test. A P-value of ⬍.05 was considered to be significant. Patients with uveitis had higher levels of interleukin-6 (IL; P ⬍ .001), IL-8 (P ⫽ .002), soluble intercellular adhesion molecule (sICAM; P ⫽ .002), soluble vascular cell adhesion molecule (sVCAM; P ⫽ .003), and interferon-inducible protein-10 (IP-10; P ⬍ .001) compared with nonuveitic controls (Table). During active uveitis, higher levels of IL-6 (P ⫽ .020), IL -10 (P ⫽ .028), interferon-␥ (IFN-␥; P ⫽ .030), sVCAM (P ⫽ .009), regulated on activation, normal T cell expressed and secreted (RANTES) (P ⫽ .016), and IP-10 (P ⬍ .001) were found than during quiescent uveitis. Patients with infectious uveitis had higher levels of IL-10 (P ⫽ .034) than patients with noninfectious uveitis. No significant differences were found between uveitis patients with or without CME. Our findings confirm and extend previous findings of elevated levels of IL-6, IL-8, and IFN-␥ in patients with uveitis.2,3 Elevated IL-10 levels in intraocular infections were also noted by others,4 but in contrast to our study, these levels were compared with nonuveitis controls. Our data show that IL-10 may be an indicator for an active or infectious uveitis, or both. Within these subgroups there is variation in the IL-10 levels, which warrants more in-depth analysis of the microbiologic causes of the infection. Elevated IL-6 and sICAM levels previously were reported in patients with CME associated with diabetic retinopathy and branch retinal vein occlusion.5,6 In contrast, in our patients with uveitis-associated CME, we
Bram van Kooij, MD, Aniki Rothova, MD, PhD, Ger T. Rijkers, PhD, and Jolanda D. F. de Groot-Mijnes, PhD To investigate the global cytokine and chemokine expression pattern in the aqueous humor of uveitis patients and relate them to clinical features. DESIGN: Cross-sectional study. METHODS: In 31 aqueous humor samples from uveitis patients, the concentration of mediators was measured by a multiplex immunoassay. Eleven control samples were included. RESULTS: Uveitis samples had higher levels of interleukin-6, interleukin-8, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule (sVCAM), and interferon-inducible protein-10 (IP-10) than nonuveitis controls. Active uveitis samples had higher levels of interleukin-6, interleukin-10, interferon-␥, sVCAM, regulated on activation, normal T cell expressed and secreted (RANTES), and IP-10 than quiescent uveitis samples. Infectious uveitis was associated with higher levels of interleukin-10 than noninfectious uveitis (P < .03 for all subgroups). No significant differences were found between cystoid macular edema (CME) and nonCME samples. CONCLUSIONS: Elevated levels of specific mediators were found in active and in infectious uveitis, but not in CME. Mediator profiles might lead to a better understanding of the pathogenesis of uveitis (Am J Ophthalmol 2006; 142:192–194. © 2006 by Elsevier Inc. All rights reserved.) PURPOSE:
C
YTOKINES, CHEMOKINES, AND SOLUBLE ADHESION
molecules modulate immune reactions; they influence the communication between various cell types and can alter the properties of the vascular endothelium. To investigate the role of cytokines, chemokines, and adhe-
Accepted for publication Feb 15, 2006. From the F. C. Donders Institute of Ophthalmology, Utrecht, The Netherlands (B.v.K., A.R., J.D.F.d.G.-M.), Department of Pediatric Immunology, Wilhelmina Children’s Hospital, Utrecht, The Netherlands (G.T.R.), and Department of Virology, Eijkman-Winkler Center (J.D.F.d.G.-M.), University Medical Center Utrecht, Utrecht, The Netherlands. This study was supported in part by the Dr F. P. Fischer Foundation, Utrecht, The Netherlands. Inquiries to Bram van Kooij, MD, F. C. Donders Institute, Department of Ophthalmology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands; e-mail: b.vankooij@ oogh.azu.nl
192
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JULY 2006
VOL. 142, NO. 1
TABLE. Mediator Concentrations in the Aqueous Humor of Patients With Uveitis and Controls Uveitis n ⫽ 31
BRIEF REPORTS
Mean age (years) 50 Geometric mean concentration Range of detectable samples (number IL-6 637 39–⬎13821 (0) IL-8 43 11–⬎4544 (10) IL-10 17 25–⬎4975 (23) IFN-␥ 5.0 6.4–52 (26) sICAM 440 34–3806 (0) sVCAM 813 156–⬎6531 (0) RANTES 95 40–1016 (11) IP-10 836 40–⬎7384 (0)
Controls n ⫽ 11
66
P Value
CME n ⫽ 12*
Non CME n ⫽ 17*
57
43
of samples in the undetectable range) 38 ⬍.001 338 693 32–240 70–⬎13822 39–⬎13821.81 (2) (0) (0) 12 .002 21 42 79 13–94 11–1693 (10) (4) (6) 8.1 .066 9.9 14 ⬍8.1 82 25–503 (11) (11) (12) 4.1 .162 4.1 5.2 ⬍4.1 ⬍4.1 6.4–25 (11) (12) (14) 106 .002 373 428 30–665 136–1566 34–3806 (0) (0) (0) 269 .003 598 942 60–697 189–2472 156–⬎6531 (0) (0) (0) 73 .674 55 120 49–248 49–343 40–1016 (3) (6) (5) 83 ⬍.001 585 978 30–448 40–5183 62–⬎7384 (0) (0) (0)
P Value
.756
.498
.211
.076
.507
.199
.067
.268
Active Disease n ⫽ 17
Quiescent Disease, n ⫽ 14
44
56
1413 78–⬎13822 (0) 73 11–⬎4544 (3) 27 25–⬎4975 (10) 6.0 6.4–52 (12) 625 98–3806 (0) 1285 249–⬎6531 (0) 148 49–1016 (3) 1955 324–⬎7384 (0)
242 39–⬎13822 (0) 23 13–362 (7) 9.0 32 (13) 4.1 ⬍4.1 (14) 287 34–1133 (0) 466 156–1553 (0) 55 40–331 (8) 298 40–⬎7384 (0)
P Value
.020
.076
.028
.030
.104
.009
.016
⬍.001
Infectious Uveitis, n ⫽ 11
Non Infectious Uveitis, n ⫽ 20
52
49
676 39–⬎13822 (0) 75 11–⬎4544 (4) 42 33–⬎4975 (6) 5.4 6.4 and 52 (9) 379 34–3045 (0) 802 156–4312 (0) 103 49–745 (3) 1487 62–⬎7384 (0)
615 62–⬎13822 (0) 32 13–1693 (6) 10 25–39 (17) 4.9 9.7–25 (17) 478 98–3806 (0) 819 189–⬎6531 (0) 90 40–1016 (8) 609 40–⬎7384 (0)
P Value
.708
.488
.034
.821
.869
.967
.659
.076
CME ⫽ cystoid macular edema; IL ⫽ interleukin; INF ⫽ interferon; sICAM ⫽ soluble intercellular adhesion molecule; sVCAM ⫽ soluble vascular cell adhesion molecule; IP-10 ⫽ interferon-inducible protein 10. *CME could not be evaluated in two patients. The levels of IL-1, IL-2, IL-4, IL-12, IL-13, IL-18, TNF-␣, Eotaxin were mainly below the detection limit and did not vary statistically in any of the comparison groups.
193
Systemic Absorption of 5-Fluorouracil During Vitrectomy
found no differences in the levels of these mediators, nor in the other cytokines and chemokines analyzed. We did not observe clear Th1 (IFN-␥, IL-2, and tumor necrosis factor-␣) or Th2 cytokine profiles (IL-4) in patients with uveitis. In contrast, we found a strong correlation of active uveitis with sVCAM and IP-10, both of which are important mediators for leukocyte recruitment.7 The differences with previous findings might in part be explained by the complex biologic function of the mediators, transient production during the course of the inflammatory process, with specific uveitis entities and medications at the time of sampling.4 Clearly, future research of cytokines and other mediators involved in specific types of uveitis is needed to elucidate the role of these proteins in the inflammation process. As different mediators possess biologic overlapping functions and often influence the production of each other, the ability to simultaneously monitor changes in multiple cytokines would hold a greater discriminatory as well as instructive power than single cytokine analysis. Knowledge of these local cytokine and adhesion molecule biosignatures, which can nowadays easily be obtained even in small samples using the multiplex immunoassay, might lead to a better understanding of the pathogenesis of uveitis and CME and help to design new therapies.
Onne Creten, MD, Werner Spileers, MD, PhD, and Peter Stalmans, MD, PhD The aim of this study is to determine if systemic absorption is present after 5-fluorouracil (5FU) is used in the vitrectomy infusion. DESIGN: A two-case clinical study. METHODS: A catabolite of 5FU, ␣-fluoro--alanine (FBAL), was measured in urine samples of two patients who underwent vitrectomy using 5FU in the infusion fluid. RESULTS: In both patients, FBAL was found in the urine samples collected up to 48 hours after the surgery, although in significantly different concentrations. CONCLUSIONS: The use of 5FU in the vitrectomy infusion fluid to prevent the formation of proliferative vitreoretinopathy may lead to significant general absorption and may be avoided in children and young adults. (Am J Ophthalmol 2006;142:194 –196. © 2006 by Elsevier Inc. All rights reserved.) PURPOSE:
D
retinal surgical techniques, proliferative vitreoretinopathy (PVR) remains the leading cause of surgery failure.1 Studies have evaluated the efficacy of different drugs in the control of PVR. However, 5-fluorouracil (5FU), a synthetic pyrimidine analog, is the most extensively studied agent for inhibition of retinal pigment epithelium proliferation. It has been shown that 5FU reduces the rate of PVR by more than 50%,1 without corneal or retinal toxicity.2 Nevertheless, no positive effect on the success rate of surgery for established PVR has been proven. Although the side effects of 5FU are well established, no data are available on the systemic absorption and the influence of intravitreal 5FU on procreation. Because 60% to 90% of the administered dose is excreted in urine as ␣-fluoro-alanine (FBAL)3 (Figure), we measured the amount of FBAL during the first 72 hours postoperatively to determine whether intravitreally administered 5FU is systemically absorbed. Two patients underwent a three-port pars plana vitrectomy, using intravitreal infusion with 5FU (200 g/ml) and low-molecular-weight heparin (8 IU/ml). The local ethics committee approved the study. All patients gave informed consent according to institutional guidelines. The first patient underwent a vitrectomy to remove silicone oil, used in previous surgery. The infusion lasted
REFERENCES
1. de Jager W, Prakken BJ, Bijlsma JW, Kuis W, Rijkers GT. Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J Immunol Methods 2005;300:124 –135. 2. Curnow SJ, Falciani F, Durrani OM, et al. Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis. Invest Ophthalmol Vis Sci 2005;46: 4251– 4259. 3. Wallace GR, John CS, Wloka K, Salmon M, Murray PI. The role of chemokines and their receptors in ocular disease. Prog Retin Eye Res 2004;23:435– 448. 4. Ongkosuwito JV, Feron EJ, van Doornik CE, et al. Analysis of immunoregulatory cytokines in ocular fluid samples from patients with uveitis. Invest Ophthalmol Vis Sci 1998;39: 2659 –2665. 5. Funatsu H, Yamashita H, Sakata K, et al. Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule one are related to diabetic macular edema. Ophthalmology 2005;112:806 – 816. 6. Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2006;244: 309 –315. 7. Sorensen TL. Targeting the chemokine receptor CXCR3 and its ligand CXCL10 in the central nervous system: potential therapy for inflammatory demyelinating disease? Curr Neurovasc Res 2004;1:183–190.
194
AMERICAN JOURNAL
ESPITE IMPROVED RESULTS WITH ADVANCED VITREO-
Accepted for publication Feb 15, 2006. From the Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium. Inquiries to Peter Stalmans, MD, PhD, Department of Ophthalmology UZLeuven, Capucijnenvoer 33, B3000 Leuven, Belgium; e-mail: peter. [email protected] OF
OPHTHALMOLOGY
JULY 2006