PERSEUS 24-month analysis: a prospective non-interventional study to assess the effectiveness of intravitreal aflibercept in routine clinical practice in Germany in patients with neovascular age-related macular degeneration.

PURPOSE: To evaluate the real-world effectiveness of intravitreal aflibercept injections in Germany in patients with neovascular age-related macular degeneration over 24 months. METHODS: PERSEUS was a prospective, non-interventional cohort study. The primary endpoint was the mean change in visual acuity (VA) from baseline. Secondary endpoints included the proportion of patients with a VA gain or loss of ≥ 15 letters and the frequency of injections and examinations. Patients with regular (bimonthly after 3 monthly injections during year 1 and ≥ 4 injections in year 2) and irregular (any other) treatment were analyzed. The last observation carried forward (LOCF) and the observed cases (OC) approach was applied for primary endpoint analysis to account for missing data. RESULTS: 803 patients were considered for effectivity analysis. At month 24, only 38% of the patients were still under observation. The LOCF population included 727, the OC population 279 patients. Treatment-naïve patients improved by 6.3 (LOCF)/8.1 (OC) letters with regular treatment over 24 months but only by 3.3 (LOCF)/3.1 (OC) letters with irregular treatment. The proportion of treatment-naïve patients achieving a VA improvement of ≥ 15 letters was similar between regularly and irregularly treated cohorts. However, considerably more patients in the irregular cohorts experienced a VA worsening of ≥ 15 letters than in the regular cohorts (LOCF: 18.7% vs. 7.4%). CONCLUSIONS: Regular IVT-AFL treatment resulted in better VA outcomes than irregular treatment at month 24. However, only a minority of patients received regular treatment over a 2-year period.

Importance of continuous treatment with intravitreal aflibercept injections in patients with neovascular age-related macular degeneration-12-month post hoc analysis of the PERSEUS real-world evidence study.

PURPOSE: To investigate the influence of treatment regularity with intravitreal aflibercept injections (IVT-AFL injections) on visual acuity (VA) outcomes in patients with neovascular age-related macular degeneration (nAMD) enrolled in the PERSEUS trial who received at least 7 IVT-AFL injections during the first year. METHODS: This was a post hoc analysis of the PERSEUS trial, a prospective, non-interventional, multicenter cohort study, and included 370 patients with nAMD who had received ≥ 7 IVT-AFL injections during year 1. In addition to the prespecified subgroups of treatment-naïve and previously treated patients, results were compared between patients with regular (n = 209) and irregular (n = 161) treatment. Regular treatment was defined as initial dosing with monthly IVT-AFL injections for 3 months, then bimonthly IVT-AFL injections until month 12. Irregular treatment was defined as any deviation from regular treatment (provided ≥ 7 injections were received). The outcome of primary interest was the mean change in VA from baseline after 12 months. Further outcomes of interest included VA gain or loss, proportion of patients achieving reading vision, and percentage of patients with fluid. RESULTS: At month 12, the mean (± standard deviation, SD) VA improvement from baseline was 6.1 ± 15.6 Early Treatment Diabetic Retinopathy Study letters in the regular cohort and 2.5 ± 16.7 letters in the irregular cohort with ≥ 7 IVT-AFL injections (P = 0.0514). Best results were obtained in the treatment-naïve regular sub-cohort with a mean ± SD VA improvement of 8.0 ± 17.7 letters, whereas treatment-naïve patients with irregular treatment experienced a considerably lower VA gain (2.8 ± 20.0 letters). Irregular treatment consistently correlated with inferior results in treatment-naïve patients. At month 12, the proportion of treatment-naïve patients who had experienced a worsening of ≥ 5 letters was 29.6% in the irregular sub-cohort versus 13.6% in the regular sub-cohort (P = 0.0049). However, among the treatment-naïve patients, the mean number of injections was significantly higher in the irregular than in the regular sub-cohort (8.0 ± 1.2 vs. 7.4 ± 0.6; P = 0.0001). Furthermore, compared with the treatment-naïve, regular sub-cohort, patients in the irregular sub-cohort had more visits (19.1 ± 8.6 vs. 16.1 ± 5.7), VA tests (14.2 ± 6.9 vs. 12.0 ± 4.6), and optical coherence tomography examinations (5.1 ± 3.7 vs. 3.4.0 ± 3.0). CONCLUSIONS: Although irregularly treated patients received more injections and more monitoring visits during the first year of IVT-AFL treatment, they experienced worse VA outcomes than regularly treated patients.

Aflibercept for Patients with Neovascular Age-Related Macular Degeneration in Routine Clinical Practice in Germany: Twelve-Month Outcomes of PERSEUS.

PURPOSE: To explore real-world effectiveness of intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration (nAMD) in Germany. DESIGN: A 24-month, prospective, noninterventional, noncontrolled, multicenter observational cohort study. PARTICIPANTS: Patients (n = 848) with nAMD treated with IAI. METHODS: Patients (n = 988) were screened at 67 study sites. Therapeutic decisions were made by the treating physician. Primary end point analysis was performed after 12 months for the entire study cohort and for predetermined subgroups of treatment-naïve and previously treated patients. Additionally, outcomes with regular injection intervals (bimonthly after 3 monthly injections) were compared with those of patients with irregularities in their treatment regimen. MAIN OUTCOME MEASURES: The primary end point was the mean change in visual acuity (VA) from baseline after 12 months. Other key end points included the proportions of patients gaining 15 letters or more and patients with reading vision (≥70 letters). Furthermore, the number of injections, anatomic measurements, and safety data were recorded. RESULTS: Mean ± standard deviation VA improvement was 5.3±17.4 letters in treatment-naïve patients and -0.1±15.6 letters in previously treated patients (P ≤ 0.0001), and that of the total study group was 2.9±16.8 letters. Baseline VA was 53.4±17.9 letters for treatment-naïve patients, 52.9±18.4 letters for previously treated patients, and 53.2±18.1 letters for the total patient population. Treatment pattern was associated with VA outcome: best outcomes-an average VA gain of 8.0±17.7 letters-were seen in treatment-naïve patients in the regularly treated population, whereas irregularly treated, treatment-naïve patients achieved a mean VA gain of only 4.0±17.1 letters. Among previously treated patients, regular treatment also was associated with better outcomes (+3.1±10.7 vs. -1.1±16.8 letters). For the total study group, the mean VA gain was the following: regularly treated population, 6.1±15.6 letters; irregularly treated population, 1.5±17.1 letters (P = 0.008). No cases of endophthalmitis were observed during the first 12 months of the study. Adverse events were in line with the known safety profile of IAI. CONCLUSIONS: After 12 months of treatment with IAI, treatment-naïve patients showed substantial functional benefit, whereas previously treated patients maintained their VA. With regular IAI treatment, it seems that similar results as those in pivotal IAI studies can be achieved in routine clinical practice.

Beta-ray brachytherapy with 106Ru plaques for retinoblastoma.

PURPOSE: A retrospective analysis of 134 patients who received (106)Ru brachytherapy for retinoblastomas (175 tumors in 140 eyes). Treatment and follow-up were analyzed with special emphasis on tumor control organ, preservation, and late complications. RESULTS: Treated tumors had a mean height and diameter of 3.7+/-1.4 mm and 5.0+/-2.8 disk diameters, respectively. The radiation dose values were recalculated according to the calibration standard recently introduced by the National Institute of Standards and Technology. The recalculation revealed a mean applied dose of 419 Gy at the sclera (SD, 207 Gy) and 138 Gy (SD, 67 Gy) at the tumor apex. The 5-year tumor control rate was 94.4%. Tumor recurrence was more frequent in eyes with vitreous tumor cell seeding or fish-flesh regression. The estimated 5-year eye preservation rate was 86.5%. Previous treatment by brachytherapy or external beam radiotherapy, as well as a large tumor diameter, were significant factors for enucleation. The radiotherapy-induced complications after 5 years of follow-up were retinopathy (22%), optic neuropathy (21%), and cataract (17%). These complications were significantly more frequent after prior brachytherapy or external beam radiotherapy. CONCLUSION: Brachytherapy using (106)Ru plaques is a highly efficient therapy with excellent local tumor control and an acceptable incidence of side effects.

Photodynamic therapy using verteporfin for choroidal neovascularization associated with angioid streaks--long-term effects.

AIM: To investigate the safety and efficacy of photodynamic therapy with verteporfin (PDT) in patients with choroidal neovascularization associated with angioid streaks (CNVAS). METHODS: A nonrandomized, prospective clinical investigation of 12 patients with CNVAS was performed. PDT was based on the criteria concerning the treatment of age-related macular degeneration. RESULTS: The mean follow-up was 41.75 months (range 24-60). The mean number of (re)treatments was 3.3 (range 2-7). Visual acuity improved by at least 1 line in 42%, was stable within +/-2 lines in 33%, decreased by at least 1 line in 58% and by >3 lines in 25% of the patients. The mean visual acuity was 0.30 (range 0.2-0.5) prior to and 0.17 (range 0.03-0.6) after the final PDT. The mean visual acuity of the contralateral eye was 0.1. 75% of contralateral eyes and 25% of the treated eyes had a final visual acuity of < or =0.1 (20/200). At the final follow-up, a significant enlargement of the lesion size was noted in 92% of the cases. CONCLUSION: Using the current (re)treatment criteria, PDT does not appear to limit the growth of CNVAS. Compared to the aggressive natural course and to the limited treatment options, PDT may at least in part help to stabilize macular function over a limited period of time.

Long-term effect of acetazolamide treatment of patients with uveitic chronic cystoid macular edema is limited by persisting inflammation.

PURPOSE: To assess the long-term effect of acetazolamide treatment on patients with cystoid macular edema (CME) in the course of intermediate or posterior chronic uveitis and to define those patients who may particularly benefit from the drug. METHODS: Fifty-two eyes (45 patients) with chronic uveitic CME were treated with acetazolamide at an initial dosage of 500 mg/d. The effect of treatment was assessed by fluorescein angiography, ophthalmoscopy, visual acuity, and Amsler testing. Therapy was withdrawn when CME did not improve at 3 weeks. In cases with CME improvement, the dosage was gradually tapered. RESULTS: The mean follow-up was 3.1 years (minimum, 1.5 years). Two subgroups were identified: group 1, quiescence of uveitis with acetazolamide as the single therapeutic agent (33 eyes); and group 2, chronically active uveitis requiring additional systemic antiinflammatory drugs (19 eyes). In both groups, visual acuity improvement was statistically significant (group 1, P = 0.012; group 2, P = 0.025). In 12 patients with a stable visual acuity gain, the medication dose could be tapered off completely without any recurrent edema shown by fluorescein angiography after a minimum follow-up of 1 year. Sixteen patients required a maintenance dosage, ranging from 125 to 500 mg daily. No major adverse effects of the medication were observed. CONCLUSIONS: During long-term follow-up, low-dose acetazolamide can be a useful therapeutic option for chronic CME in uveitis. The effect was better in patients with quiescence of uveitis than in those with chronically active uveitis. Permanent therapy is not imperative in every case.

Differential expression of tissue inhibitor of matrix metalloproteinases 3 in uveal melanoma.

Based on gene profiling, two entities of uveal melanomas exist. So far, these two entities can be distinguished by the chromosome 3 status which strongly associates with the metastatic potential of the tumours. Reorganization of the extracellular matrix is one of the steps towards dissemination of tumour cells. In the present study, we examined the tissue inhibitor of matrix metalloproteinases (TIMP) 3 expression in 19 uveal melanomas and compared the results with histopathological and genetic features. The expression level of TIMP-3 mRNA as determined by microarray analysis was associated with the chromosome 3 status of the tumour (p = 0.003). All tumours with disomy 3 showed moderate to high expression of TIMP-3 mRNA, whereas TIMP-3 was highly expressed in one tumour, less expressed in 3 tumours and absent in the remaining 6 tumours with monosomy 3. Immunohistochemistry for TIMP-3 was positive in 9/19 tumours, but only in 3 tumours were more than 5% of the tumour cells stained positive. There was no association between immunohistochemical detection of TIMP-3 and chromosome 3 status. In tumours with disomy 3, we found none or very few TIMP-3-positive cells though the mRNA level was high which indirectly postulates posttranscriptional problems in protein biosynthesis in this entity of uveal melanomas. There was a trend between TIMP-3 protein expression and both cell type (p = 0.11) and presence of loops and/or networks (p = 0.06) in tumour which may indicate a role of TIMP-3 in the biology of uveal melanoma.

Optical energy transfer for intraocular microsystems studied in rabbits.

BACKGROUND: The development of a visual prosthesis aims to restore partial vision in patients with diseases which lead to total photoreceptor loss. The wireless power supply for a retinal implant may be realized with electromagnetic induction or with optical energy transfer. The present study investigates the feasibility of a photovoltaic power generation in the intraocular lens (IOL) part of an epiretinal implant for long-term tests in rabbits. METHODS: IOLs containing an array of photovoltaic cells (PVC) and a light-emitting diode (LED) were implanted into the capsular bag after phacoemulsification in three chinchilla rabbits. Optical energy transfer was established with an infrared laser beam at 850 nm wavelength. Lighting up of the LED proved the functioning of the PVC array. The maximum duration of in vivo functioning of the implant was determined by regular tests involving laser beam application. The explanted microsystems were technically analyzed. Tissues of both eyes underwent routine histological examinations. RESULTS: The lifespan of the microsystems ranged from 14 days to more than 7 months. Final malfunction was caused by PVC defects or by defective contacts between PVC and LED that may originate from the low adhesive strength between the silicone cover and the underlying electronic components. The histological examination showed no alterations of the retinal structure in the treated eyes. CONCLUSIONS: The power supply for intraocular microsystems by an array of photovoltaic cells was proven to be feasible in long-term tests in rabbits. An essential prerequisite for a future device is hermetic coating of the electronics.

[Endogenous bacterial endophthalmitis: a retrospective study on 22 consecutive cases]. / Endogene bakterielle Endophthalmitis: eine retrospektive Studie an 22 konsekutiven Fällen.

BACKGROUND: Cases of endogenous bacterial endophthalmitis were analysed regarding predisposing factors, timing of diagnosis, sources of infection, causative organisms, and visual outcome. The value of an immediate vitrectomy compared to exclusively injected intravitreal antibiotics was evaluated reviewing the literature. METHODS: Records of 22 consecutive cases of the last 9 years with endogenous bacterial endophthalmitis were reviewed. The identified source of infection was treated with systemic antibiotics. All affected eyes were treated with intraocular injection of antibiotics, whenever possible combined with vitrectomy. RESULTS: 90% of the patients had severe predisposing diseases, primarily diabetes mellitus combined with renal insufficiency and urinary tract infection (70%). Diagnoses were made 3.5 days after beginning of symptoms. An average of 75% of the patients had gram-positive and 25% gram-negative bacteria as causative organisms. Most common gram-positive bacteria were Staphylococcus aureus and S. epidermidis. In 73% of all eyes vitrectomy was used as primary treatment. In 57% of the cases the visual outcome was light perception or better (excluding primary enucleations and deceased patients). 7% of the eyes had no light perception, 36% underwent secondary enucleation. Especially in cases of early diagnoses (less than or equal to 2 days) therapy was successful (60% of the patients); in contrast to delayed diagnoses (33%). The literature review suggests that immediate vitrectomy is superior to exclusive intravitreal injection of antibiotics concerning bulb conservation and remaining function. CONCLUSIONS: Immediate diagnosis and therapy are crucial for a positive outcome in this ophthalmological emergency. Immediate pars plana vitrectomy with intraocular antibiotic instillation seems to improve the prognosis of the affected eyes.

Higher vessel densities in retinoblastoma with local invasive growth and metastasis.

In this study, the importance of angiogenesis (the growth of new blood vessels from existing ones) for the growth of retinoblastoma was investigated by a retrospective immunohistochemical analysis. An individual vessel index for each tumor was determined using the endothelial-specific antibody CD 31 for vessel staining. The obtained data were correlated with clinical features, pathohistological characteristics, and the presence of metastasis. In 107 retinoblastomas collected between 1980 and 1990, we found no difference in the vessel densities between uni- and bilateral retinoblastomas (P = 0.41). However, tumors that had invaded the chorioid and/or the optic nerve statistically showed higher vessel densities than tumors without local invasive growth (P = 0.05 and P = 0.024). A tendency of higher vessel densities in retinoblastomas presenting with metastasis at the time of diagnosis was observed (P = 0.11). Based on this observation, we proceeded to examine all retinoblastomas presenting with metastasis at the time of diagnosis. These included patients that were treated between 1968 and 1993. The 18 investigated retinoblastomas had significantly higher vessel densities than all other retinoblastomas presenting without metastasis (P = 0.025). Our data indicate that in retinoblastoma, blood vessels are essential for local and systemic invasive growth. Therefore, an anti-angiogenic therapy could be considered in the multimodal therapy concept for retinoblastomas with invasive growth, both locally and systemically.

[Brivudine as an alternative systemic therapy to aciclovir and ganciclovir in acute retinal necrosis syndrome due to varicella-zoster virus]. / Brivudin als alternative systemische Therapie zu Aciclovir und Ganciclovir bei akutem retinalen Nekrosesyndrom durch Varizella-Zoster-Virus.

BACKGROUND: Two cases of acute retinal necrosis (ARN-) syndrome caused by an infection with varicella zoster virus (VZV) are demonstrated. VZV-DNA was detected in vitreous biopsies by polymerase-chain-reaction (PCR). The course of retinal necrosis was decisively improved by changing antiviral therapy from aciclovir and/or ganciclovir to brivudine. MATERIAL AND METHODS: Patient 1: 51 years, male, initial visual acuity 20/40; patient 2: 17 years, female, initial visual acuity 20/30. Both patients were immunocompetent and presented with an unilateral acute retinal necrosis syndrome with peripheral chorioretinitis, retinal vasculitis, vitreous inflammation and optic disc swelling, which resulted in progressive visual loss in a few days. RESULTS: In both patients VZV-DNA was detected in vitreous biopsies with PCR. A regression of intraocular inflammation and necrotic retinal foci was only observed after changing the initial systemic therapy from aciclovir (Zovirax) intravenously 1500 mg/day) and/or ganciclovir (Cymeven) intravenously 250 mg/day) to brivudine (Zostex) per os 500 mg/day). Vitreoretinal surgery was necessary in both patients because of rhegmatogenous retinal detachment. Visual acuity stabilised in patient 1 to 20/200 and in patient 2 to 20/25 during a follow-up of 16 or 32 months, respectively. CONCLUSION: Brivudine represents an alternative therapy, if standard treatment with aciclovir and/or ganciclovir failed in cases of ARN-syndrome due to presumed drug-resistant varicella zoster virus-subtypes. Complete remission and preservation of a satisfactory function can be achieved.

Combined phacoemulsification and pars plana vitrectomy: clear corneal versus scleral incisions: prospective randomized multicenter study.

PURPOSE: To compare the complications and outcomes of implantation of a foldable intraocular lens (IOL) through a clear corneal incision and implantation of a poly(methyl methacrylate) (PMMA) IOL through a scleral incision in combined phacoemulsification and pars plana vitrectomy. SETTING: Departments of Ophthalmology, St. Franziskus Hospital, Muenster, Eye Hospital, Muelheim, and University of Essen, Essen, Germany. METHODS: This prospective randomized study included 62 eyes having implantation of a PMMA IOL (811B, Pharmacia) through a scleral incision and 61 eyes having implantation of a polyacrylic (AcrySof, Alcon) IOL through a clear corneal incision. The preoperative visual acuity, underlying retinal disease, and vitreoretinal surgical maneuvers did not differ between groups. The surgical methods and intraoperative complications were noted. Examinations 2 days and 3 months after surgery included visual acuity, refractive error, keratometry, slitlamp evaluation, tonometry, and ophthalmoscopy. RESULTS: Intraoperatively, both incisions were stable and no serious complications occurred. Two days after surgery, the incidence and quantity of cells and fibrin in the anterior chamber were lower in the clear corneal incision group than in the scleral incision group (P<.05). Corneal endothelial dysfunction was more common in the clear corneal group than in the scleral group (P<.05). Three months after surgery, the astigmatic changes did not differ significantly between groups and the incidence of posterior capsule opacification (PCO) was lower in the clear corneal group (P<.05). Postoperative visual acuity improved significantly in 63% of eyes and 61% of eyes in the scleral group and clear corneal group, respectively. Visual acuity was limited by macular pathology. CONCLUSIONS: Both clear corneal and scleral incisions were safe in combined phacoemulsification and vitrectomy. Eyes with smaller clear corneal incisions and foldable IOLs had less postoperative inflammation and PCO.

Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities.

Uveal melanoma is the most common intraocular malignancy. About 50% of patients die of metastases, which almost exclusively originate from primary tumors that have lost one chromosome 3 (monosomy 3). To gain insight into the biological mechanisms that underlie the various metastasizing potential of uveal melanoma, we have determined gene expression levels in 20 primary tumors using oligonucleotide microarrays containing 12500 probe sets. The expression measurements of those 7902 genes that were expressed in more than 10% of tumors were analyzed using two different statistical approaches. We used a modified Wilcoxon rank-sum test to identify genes differentially expressed between tumors with and without monosomy 3. Seven genes showed complete loss of expression in tumors with monosomy 3 but were expressed in tumors with disomy 3. Two of them, CHL1 and fls485, are located within or close to the uveal melanoma susceptibility locus UVM2 at 3p25. However, mutation analysis of both genes in eight tumors with monosomy 3 did not reveal structural or epigenetic alteration. To identify tumor classes, we performed unsupervised hierarchical cluster analysis; this approach separated uveal melanomas into two groups. We found that this classification is strikingly robust because, when tested by "resampling," the same grouping is obtained from 47 of 50 subsamples of genes. In clusterings of the three remaining subsamples, the grouping of only one tumor does not conform with the original classification. Excluding this tumor, cluster analyses of subsamples containing as few as 300 randomly chosen genes consistently result in the same classification, thus indicating that the difference between the two tumor classes is pervasive. Interestingly, all of the tumors in one of the groups have disomy 3, whereas all of the others have monosomy 3. Our findings suggest that there are two distinct entities of uveal melanoma that were previously unrecognized because they are not obviously distinguishable by clinicopathological features.