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Purpose: To emphasize the differences between angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura’s disease (KD), two entities often confused in the ophthalmic literature. Methods: Case report of a subcutaneous mass in the periocular region of a 45-year old woman and a MEDLINE review of the ophthalmic and non-ophthalmic literature on ALHE and KD. Results: The clinical and histopathological findings of the present case were consistent with ALHE, but not with KD. A survey of the current ophthalmic literature indicates that these two designations are still often used synonymously, despite that non-ophthalmic papers now separate ALHE from KD. Conclusion: The clinical and histopathological features of ALHE are most often distinctly different from KD and these entities should be clearly separated in the ophthalmic literature.

Purpose To outline clinical features and diagnostic techniques available for ocular adnexal tumours Methods Review of pertinent literature and personal unpublished data. Results Ocular adnexal tumours include a wide range of beningn and malignant neoplasms, some of which may be systemic. A correct pre-operative diagnosis is imperative for appropriate management of these tumours. In most cases a combination of distinct clinical features, pertinent review of the patient's history and the judicial use of salient diagnostic techniques, like exfolitaion cytology and punch biopsies will provide the clinician with an approach to manage these lesions. Conclusion The wide range of ocular adnexal tumours may cause significant clinical confusion. Recognition of distinct clinical features and judicial use of auxiliary diagnostic techniques will in most cases provide the clinician with a correct pre-operative diagnosis.

Purpose To outline recent development and future research avenues for molecular mechanisms in uveal melanoma Methods Review of pertinent literature and unpublished personal data Results While most eyes with uveal melanoma now can be treated with one or more of a range of sight-conserving options, overall patient survival has not improved during recent years. It remains clear that overall survival for patients with uveal melanoma can only be improved if effective treatment for disseminated disease can be offered and that such treatment need to be provided early in the disease progression. The molecular mechanisms involved in uveal melanoma appear to be distinctly different from those identified in cutaneous melanoma. Although much progress has been made in mapping the pathways likely to play a role in uveal melanoma initiation, progression and dissemination has been made in recent years, much remains to be unravelled. Targeted therapy combined with early detection of disseminated disease or the identification of patients at high risk of tumour spread is likely to impact prognosis in the next decade to come. Conclusion Recent progress in identifying molecular mechanisms involved in uveal melanoma initiation, progression and dissemination has been significant. The next decade is likely to see the translation of this knowledge to effective treatment which may result in improved patient survival.

Purpose: To compare the 4-year outcome of primary pterygium excision using intraoperative mitomycin C (MMC) with suturing a free conjunctival autograft (CA). Methods: A total of 115 eyes with nasal primary pterygium of 115 patients were included in the study. After randomization into two groups, the eyes were operated on by a single surgeon (GK). After excision of the pterygium, 56 eyes received 0.04% MMC intraoperatively on the bare sclera for 3 min and 59 eyes received a free CA sutured using 7-0 Vicryl. Postoperative follow-up was 4 years. Main outcome measures were recurrences, re-operations, surgery time, complications, visual acuity and astigmatism. Statistical evaluation was performed with the chi-squared test. Results: The recurrence rate was 38% in the MMC group and 15% in the CA group (p

BACKGROUND: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E2 (PGE2) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies. The objective of the current study was to investigate whether Tregs infiltrate uveal melanomas (UMs) and whether their prevalence is linked to COX-2 expression and the prediction of overall survival (OS). METHODS: One hundred patients who underwent enucleation after they were diagnosed with UM were included in the study. Immunohistochemical staining with monoclonal anti-FOXP3, anti-CD4, and anti-COX-2 antibodies was performed, and immunoreactivity was assessed. Correlations of COX-2 expression with the presence of Tregs, established clinicopathologic parameters, and OS were evaluated in univariate and multivariate analyses. RESULTS: High expression of COX-2 was predictive of shortened OS. FOXP3-positive Tregs were detectable in 24% of UMs and were restricted to malignant tissue. The extent of COX-2 expression was associated significantly with Treg prevalence (P = .004) and Treg intratumoral localization (P = .005). Intratumoral Tregs (but not the prevalence of Tregs) were independent marker for worse OS with a hazard ratio of 5.36 in patients with COX-2–positive tumors. CONCLUSIONS: The current results demonstrated that high COX-2 expression is associated with OS and Treg prevalence in UM. These findings are in line with the observations that COX-2/PGE2 induces Tregs and that Tregs may alter antitumor responses, resulting in a negative effect on the clinical disease course. Intratumoral Tregs are an independent prognostic marker for COX-2–positive UM, and these results put COX-2 inhibitors and Treg depletion into the spotlight of potential novel treatment modalities for patients with UM. Cancer 2010. © 2010 American Cancer Society.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin-embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p = 0.04; hazard ratio (HR) = 2.3) predict disease-specific survival (DSS) as assessed by Kaplan-Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p = 0.02) predicted a shortened survival as assessed by Kaplan-Meier analysis. However, iNOS did not appear to be a significant (p = 0.16; HR = 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.

Purpose To review the role of European Society of Ophthalmology (SOE) and its role in the integration of Europan Ophthalmology and the Concordia initiative Methods Review of records and SOE Congress Programmes combined with interviews of key leaders. Results The European Society of Ophthalmology currently have 42 member societies (national ophthalmic socities). The SOE is largely confined to geographical Europe but notably also includes three associate member societies of Jordan, Egypt andIisrael. The SOE strongly supports the Concordia initiative. Current work includes the revision of statutes to be able to work more closly with membership societies and subspeciality socities. Also, the biennual Congress has now been transformed to a "platform" for subspeciality, educational and research socities to further integrate European ophthalmology. The SOE strongly believe that for European integration to be lasting it should be designed "bottom-up" based on common goals. Conclusion The SOE support the Concordia intiative and further integration of European ophthalmology.

The aim of this study was to describe morphological changes in Dystrophia Smolandiensis, a corneal disease that is characterized by recurrent corneal erosive episodes and the formation of central corneal keloid-like opacities in approximately half of those affected.The corneas of seven affected individuals were examined using in-vivo confocal microscopy. Specimens of one primary corneal graft, one regraft and one biopsied keloid-like region--all obtained from members of a large family with the disease--were re-examined with a light microscope. Sections were stained with Congo red and analysed immunohistochemically for fibronectin and S100A4.Light microscopic examination revealed epithelial hyperplasia, absence of Bowman's layer and subepithelial fibrosis. Fibronectin was expressed in the area of subepithelial fibrosis, and the keratocytes in this area generally expressed S100A4. The biopsy specimen stained positive for Congo red, suggesting an amyloid deposit. In-vivo confocal microscopy confirmed epithelial abnormalities, loss of Bowman's layer and significant alterations of the subbasal nerve plexus in affected individuals.The morphological picture in Dystrophia Smolandiensis is novel for a condition dominated by recurrent corneal erosions at the clinical level. Although no single morphological feature unique to the disease could be found, the general morphological pattern of pathology (true keloid formation, absence of Bowman's layer, subepithelial fibrosis and abnormal subbasal nerves) probably reflects a novel phenotypic expression of the healing response to recurrent erosion of the corneal epithelium. However, the pathogenesis of Dystrophia Smolandiensis remains to be elucidated fully.

Purpose: To study time trends in the incidence of conjunctival melanoma in Sweden. Methods: All patients with conjunctival melanoma 1960 to 2005 in Sweden were identified through the Swedish Cancer Registry, cross-checked against hospital files and validated by histopathologic review (97.5%) or detailed hospital records (2.5%). The crude and age-standardized incidences were estimated separately for each gender and the annual change in incidence over time was estimated using a regression model with logarithmic incidence numbers. Time trends of the largest diameter, thickness and location of the tumor when diagnosed were analyzed. Results: The age-standardized incidence of conjunctival melanoma increased significantly in males (n = 89) from 0.10 cases/million to 0.74 cases/million (P = 0.001) and in females (n = 81) from 0.06 cases/million to 0.45 cases/million (P = 0.007). The annual relative change in age-standardized incidence was 16.9 % (95 % CI, 12.2 % - 21.6 %) in males and 19.5 % (95% CI, 9.3 % - 29.7 %) in females. The age-specific incidence was higher in men and women 65 years and older (1.48 and 1.39 cases/million, respectively) than in younger men and women (0.3 and 0.2 cases/million, respectively). During the period of study, tumors became smaller (P = 0.005) and thinner (P = 0.002) at the time of diagnosis and increasingly arose from parts of the conjunctiva exposed to ultraviolet radiation (P = 0.001). Conclusions: The incidence of conjunctival melanoma increased in Sweden during the period 1960 through 2005.

PURPOSE: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%), which preferentially occurs in the liver. Conventional chemotherapy, being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. EXPERIMENTAL DESIGN: We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. RESULTS: We showed that PPP efficiently blocks growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanisms involved in metastasis, including tumor cell adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layers. Furthermore, PPP significantly delayed establishment of uveal melanoma tumors and drastically reduced the incidence of liver metastasis in mice. CONCLUSIONS: Our data suggest that IGF-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.

Transpupillary thermotherapy (TTT) of choroidal melanoma, initially described to be used primarily in combination with plaque radiotherapy in 1995,1 2 has been subsequently used by several investigators, particularly in the United States as primary or sole therapy for “small” choroidal melanocytic lesions (melanomas or high-risk nevi with or without documented growth) (table 1). While the technique of TTT used by the investigators is similar (2–3 mm spot size, inclusion of 1 mm margin, overlapping spots, one to three applications 3–4 months apart), the inclusion criteria for selecting the patients to be treated with TTT has varied between series, although most investigators excluded tumours that were more than 4 mm in height.3 4 View this table: Table 1 Primary transpupillary thermotherapy of “small” choroidal melanoma: summary of data Following the initial encouraging results as primary therapy without brachytherapy,5 TTT rapidly increased in popularity because of …

To compare the efficacy of low-dose transpupillary thermotherapy (TTT) and verteporfin photodynamic therapy (PDT) in patients with occult neovascular age-related macular degeneration (AMD).Patients were randomised to receive either low-dose TTT (136 mW/mm) (and sham PDT) (n = 52) or PDT (and sham TTT) (n = 46) with retreatment if leakage was documented by fluorescein angiography. At baseline and at every follow-up, best corrected visual acuity (BCVA) was measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, lesion size on fluorescein angiography and foveal thickness with optical coherence tomography. The primary outcome measure was the proportion of patients who lost15 letters at 12 months' follow-up. Secondary outcome measures included the proportion of patients who gained/=0 letters, the change in mean lesion size and the change in foveal thickness at 12 months' follow-up.The percent of patients losing fewer than 15 letters at 12 months was 75.0% in the TTT group and 73.9% in the PDT group (p0.05). The percent of patients with preserved or improved BCVA was 36.5% in the TTT group versus 23.9% in the PDT group (p0.05). The mean decrease in foveal thickness was 15% for TTT and 24% (p0.05) for PDT-treated patients, and the mean increase in total lesion area was -0.7% and -1.1% (p0.05), respectively.In this prospective, randomised trial low-dose TTT and PDT appeared to be equally efficient at stabilising visual acuity in patients with occult neovascular AMD. Low-dose TTT may be considered as an alternative to PDT in this set of patients and also as an adjuvant to pharmacotherapy.

Purpose: Choroidal neovascularization (CNV) accounts for 85–90% of severe visual impairment in age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a major factor mediating angiogenesis, and VEGF inhibitors have become a new treatment modality. In this prospective study, we used bevacizumab (Avastin®), a recombinant monoclonal antibody to VEGF, to treat neovascular AMD. Methods: The case material comprised 36 subjects (26 females, 10 males) aged 65–88 years with subfoveal neovascular AMD with all subtypes of CNV. There were two categories of patients: category I, long-standing CNV (12 months or more), preoperative visual acuity (VA) 0.16 (mean); category II, CNV (duration

Visual perception occurs when radiation with a wavelength between 400 and 760 nm reaches the retina. The retina has evolved to capture photons efficiently and initiate visual transduction. The retina, however, is vulnerable to damage by light, a vulnerability that has long been recognized. Photochemical damage has been widely studied, because it can cause retinal damage within the intensity range of natural light. Photochemical lesions are primarily located in the outer layers at the central region of the retina. Two classes of photochemical damage have been recognized: Class I damage, which is characterized by the rhodopsin action spectrum, is believed to be mediated by visual pigments, with the primary lesions located in the photoreceptors; whereas Class II damage is generally confined to the retinal pigment epithelium. The action spectrum peaks in the short wavelength region, providing the basis for the concept of blue light hazard. Several factors can modify the susceptibility of the retina to photochemical damage. Photochemical mechanisms, in particular mechanisms that arise from illumination with blue light, are responsible for solar retinitis and for iatrogenic retinal insult from ophthalmological instruments. Further, blue light may play a role in the pathogenesis of age-related macular degeneration. Laboratory studies have suggested that photochemical damage includes oxidative events. Retinal cells die by apoptosis in response to photic injury, and the process of cell death is operated by diverse damaging mechanisms. Modern molecular biology techniques help to study in-depth the basic mechanism of photochemical damage of the retina and to develop strategies of neuroprotection.

Objective To evaluate the effects of preoperative sub–Tenon's capsule injection of ropivacaine on intraoperative hemodynamics, postoperative pain, nausea, and recovery in patients undergoing scleral buckling surgery under general anesthesia (GA). Design Randomized double-masked controlled clinical trial. Participants Ninety-eight patients with primary rhegmatogenous retinal detachment undergoing scleral buckling surgery under GA. Methods Random allocation to either preoperative sub–Tenon's capsule injection of 3 ml of 0.75% ropivacaine or sub–Tenon's capsule injection of 3 ml of saline (controls) immediately before a scleral buckling procedure under GA. Intraoperative monitoring of hemodynamic parameters, need of analgesia with sevoflurane and alfentanil, time in the recovery unit, measurements of pain and nausea on the visual analog scale (VAS) up to 12 hours postoperatively, and consumption of analgesics and antiemetics was recorded. Main Outcome Measures Intraoperative systolic blood pressure (BP); bradycardia; minimum alveolar concentration (MAC) of sevoflurane; maximum postoperative VAS scores of pain and nausea; time in recovery unit; and total need of alfentanil, ketobemidone, dextropropoxyphene, and dixyrazine. Results Ninety-seven patients were analyzed (48 in the ropivacaine group and 49 controls). A significantly lower intraoperative systolic BP (104±6 vs. 112±7 mmHg; P = 0.004), less need of sevoflurane (1.33±0.19 vs. 1.56±0.23; P = 0.03), and shorter time in the recovery unit (67±9 vs. 76±16 minutes; P = 0.01) were observed in the ropivacaine group. Maximum VAS pain scores were 50±21 in the control group and 36±25 in the ropivacaine group ( P = 0.05), with a significantly lower consumption of opioids (ketobemidone) in the ropivacaine group (3.6±3.5 vs. 1.3±2.0 mg). No significant difference was observed regarding nausea or need of dixyrazine or dextropropoxyphene postoperatively. Conclusions Preoperative sub–Tenon's capsule injection of ropivacaine in scleral buckling surgery under GA lowers the intraoperative systolic BP, reduces the amount of inhalable sevoflurane needed, and enhances postoperative vigilance through reduction of pain and need of opioids.

Ciftci, Ergin/0000-0002-4955-160X; Klebe, Sonja/0000-0002-8976-4714; Hugle, Boris/0000-0003-1145-6719; Klammt, Jurgen/0000-0003-2293-9193 WOS: 000241586100028 PubMed: 16849641 Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (116%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.

A series of 85 fine-needle aspiration (FNA) biopsies from orbital space occupying lesions of 82 patients are reviewed. A total of 32 benign lesions and 49 malignant lesions were conclusively diagnosed. In two cases the aspirates were insufficient for diagnosis. Of two cases, which were cytologically suspicious for lymphoma, a repeat FNA resulted in a conclusive diagnosis of lymphoma in one case, while the second case proved to be a pseudotumor on an open biopsy material. Of the 32 benign lesions seven were fibrosis, six pseudotumors, four epidermal cysts, four meningiomas, and three pleomorphic adenomas. The remaining cases included two hematomas, one granuloma, three inflammations, and one malformation. In 43 of 49 malignant tumors cytomorphology was corroborated with immunocytochemistry. Thirty five of these were low- or high-grade lymphomas, nine metastases, two sarcomas, two plasmacytomas, and one chloroma. All lymphomas were of B phenotype with monoclonal light chain expression. The rate of cell proliferation as measured by Ki-67 immunostaining varied between 4–25% and 30–80% for low- and high-grade lymphomas, respectively. These results confirm previous reports on the usefulness of FNA biopsy in diagnosing orbital masses and emphasize the value of immunocytochemistry in tumor characterization. Diagn. Cytopathol. 2006; 34:1–5. © 2005 Wiley-Liss, Inc.

To evaluate the recurrence rate, reoperation rate and side-effects of a novel technique for pterygium surgery.Retrospective study.The study included 461 eyes of 381 patients operated for primary nasal pterygium by the same surgeon between 1994 and 2003 and followed for 23 +/- 20 months (range 6-112 months).Autologous conjunctival grafts harvested at the superotemporal limbus were used to cover the sclera after pterygium excision. Using a retrospective chart review, the outcome after attaching the transplant to the sclera with a fibrin tissue adhesive (n = 325) was compared to the outcome after graft attachment using absorbable sutures (n = 136).Recurrence rate, reoperation rate and complications.The recurrence rate was 5.3% in the glue group and 13.5% in the suture group (p = 0.01). The reoperation rates were 1.2% and 3.3%, respectively (p = 0.31). Complications, such as transient transplant oedema and persistent corneal epithelial defects, occurred equally in both groups.Using a fibrin tissue adhesive instead of sutures when attaching the conjunctival transplant in primary pterygium surgery results in a significantly lower recurrence rate.

Melanomas of the ocular and adnexal structures comprise approximately 5% of all melanomas. The majority (85%) of ocular melanomas are uveal in origin; primary conjunctival and orbital melanomas are rare. The diagnosis of uveal melanoma is made by clinical examination including indirect ophthalmoscopy and by ancillary studies such as fluorescein angiography and ultrasonography. Metastases to the liver develop within 15 years after the initial diagnosis and treatment in approximately 50% of patients with posterior uveal melanoma; however, clinically evident metastatic disease at the time of initial presentation is uncommon, indicating that there is early subclinical metastasis in most cases.

SummaryPlasmin(ogen) plays an important role in fibrinolysis and wound healing. Severe hypoplasminogenemia has recently been linked to ligneous conjunctivitis. Plasminogen (plg) is known as a polymorphic protein and most of these variants have been identified using isoelectric focusing (IEF) gel electrophoresis. Here, we studied common plg variants from healthy subjects and plg mutants from three patients with hypoplasminogenemia and three subjects with dysplasminogenemia by molecular genetic analysis and IEF. Analysis of 24 healthy subjects showed that subjects with the most common IEF plg phenotype A (n = 12) were homozygous for aspartate at position 453 (453D), while both subjects with IEF plg phenotype B were homozygous for asparagine at this position (453N). Subjects with IEF plg phenotype AB (n = 10) were compound-heterozygous for 453D/453N. Three patients with severe hypoplasminogenemia and different plg gene mutations exhibited characteristic “abnormal” IEF band patterns when compared with IEF plg phenotypes A and B. In all heterozygous family members the observed IEF plg phenotype was derived from the wild type plg molecule only, probably due to low concentration of the mutant plg molecule in plasma. In contrast, in three unrelated subjects with heterozygous dysplasminogenemia an equal “mixture” of wild type and mutant plg was found by IEF analysis. In conclusion, plg phenotyping by IEF in combination with molecular analysis of the plg gene seems to be a useful method for characterization of plg variants and mutants.

Aim: Evaluation of the benefits of a new technique for pterygium surgery with respect to postoperative pain and surgery time. Methods: A prospective randomised clinical trial was carried out in 43 patients. 43 eyes were operated for primary nasal pterygium. Autologous conjunctival graft taken at the superotemporal limbus was used to cover the sclera after pterygium excision. After randomisation, in 20 patients the transplant was attached to the sclera with a fibrin tissue adhesive (Tisseel Duo Quick) and in 23 patients with absorbable sutures (7–0 Vicryl Rapid). The Mann-Whitney test was used as statistical analysis. Postoperative pain was graded according to the visual analogue scale (VAS) twice daily during the first week after surgery. Surgery time was noted from the first incision until the lid speculum was removed. Results: The average pain was significantly lower when glue had been used, p

It is now 25 years since the publication of the landmark article by Zimmerman, McLean, and Foster, in which they cast doubts on the benefit of enucleation, which was the prevailing management of choroidal melanoma at that time. Over the past 25 years several advances have been made in the management of uveal melanoma. Research in the pathobiology of cancer metastasis in general and uveal melanoma in particular has also provided new insights. In this review, the Zimmerman-McLean-Foster hypothesis is explored in the light of current clinical, epidemiological, statistical, and experimental evidence.

The aim of this study was to compare how diabetic retinopathy was detected from red-free digital images and colour transparencies.Two ophthalmologists graded two-field, nonstereoscopic, 60 degrees red-free digital images and colour transparencies utilizing an ETDRS-based grading scale, from 107 mainly type 2 diabetic patients. The discordantly scored eyes were graded by the graders together to obtain a consensus level of retinopathy for each method. The eyes with discordant consensus grading results were further graded using all available photographic material to reach a final consensus level of diabetic retinopathy. Intermethod variations were presented as percentages and using kappa (k) and weighted kappa (wk) statistics. The errors of the two consensus gradings with respect to the final consensus grading were compared using McNemar's test.For the colour transparencies there was an agreement between the individual and the consensus grading results in 93% (k=0.90, wk=0.97) and 86% (k=0.79, wk 0.88) for grader 1 and grader 2. Corresponding figures for red-free digital images were 88% (k=0.83, wk=0.96) and 84% (k=0.78, wk 0.91). Agreement between methods was obtained in 76/107 eyes (71%; k=0.58 and wk=0.79). In the 31 discordantly graded eyes the level of retinopathy was underestimated in 20/31 (64%) vs 7/31 eyes (23%) and overestimated in 1/31 (3%) vs 3/31 eyes (10%) from colour transparencies and red-free digital images, respectively. The error tendencies were significantly lower when using red-free digital images (p0.008).Red-free digital images are comparable with two-field colour transparencies in the identification of mild to moderate nonproliferative diabetic retinopathy.

Purpose To assess the expression of MMP (matrix metalloproteinase)-2 and -9 and TIMP (tissue inhibitors of metalloproteinases)-1, -2, and -3 in Sorsby fundus dystrophy. Design Cliniciopathological report Methods A donor eye with a confirmed S181C mutation in the TIMP-3 gene and an age-matched normal donor eye were studied using in situ hybridization technique with MMP -2 and -9 and TIMP -1, -2, and -3 probes. Results There is a reduction of mRNA expression of MMP-2 and TIMP-3 in the Sorsby retinal pigment epithelium cells. Conclusion Increased expression of TIMP-3 mRNA does not cause accumulation of TIMP-3 in the Bruch membrane of Sorsby fundus dystrophy nor is it likely to cause age-related macular degeneration.

Corneal neovascularization is a significant, sight-threatening, complication of many ocular surface disorders, but its underlying molecular background is still not fully understood. In the present study, we analysed the expression and role of matrix metalloproteinase-2 (MMP-2), a proteolytic enzyme suggested to regulate angiogenesis, in a mouse model of inflammation-related corneal neovascularization. A silk suture was placed centrally in pigmented mice corneas causing limbal vasculature to sprout, forming new vessels. Neovascularization progressed centrally involving the entire cornea after about 12 days. Histological analysis revealed vascularization of the corneal stroma accompanied by a marked inflammatory response. The neovascularization correlated with an increased expression of MMP-2 mRNA and protein that was mainly found in cells that stained positively for S100A4, a marker for activated keratocytes. MMP-2-deficient mice and wild-type mice were compared in a kinetic study, showing a statistically significant delay of neovascularization in MMP-2-deficient mice. These results implicate a role for MMP-2 in experimental inflammation-associated corneal neovascularization.

PURPOSE. To investigate the crude and relative survival rates in patients with uveal melanoma in Sweden during the period from 1960 to 1998. METHODS. A population-based national survey revealed 2997 cases of uveal melanoma in the Swedish Cancer Registry. The survival rates were calculated by the Hakulinen life-table method, using relative survival as an estimate for deaths due to uveal melanoma. The excess mortality rates were calculated with confidence intervals for the first 15 years after diagnosis. Multivariate regression analysis was undertaken to evaluate the influence of gender, age, and calendar period on relative survival the first 5 years after diagnosis. The underlying causes of deaths in the patients with uveal melanoma, as found in the Cause of Death Registry were also investigated. RESULTS. Up to December 31, 1998, 2003 patients had died. The 5-year crude survival rate was 60.3% and the relative survival 70.1%. After 10 years, the rates were 42.5% and 59.4%, respectively. Significant excess mortality existed up to 5.5 years after diagnosis. In the multivariate model, younger age (P < 0.001) and later calendar period (P = 0.002), but not gender (P = 0.117), were associated with better relative survival. Deaths due to uveal melanoma were misclassified in the Cause of Death Registry in more than half of the cases. CONCLUSIONS. This study, covering more than 95% of the uveal melanoma cases in the Swedish population revealed an improvement in relative survival rates for patients with uveal melanoma over time and a significant excess mortality up to 5.5 years after diagnosis.

To perform a phase I/II safety and efficacy study in order to assess the outcome following transpupillary thermotherapy (TTT) for occult choroidal neovascularization (CNV) with no or minimally classic CNV in age-related macular degeneration.The study comprised 113 referred patients (79 females, 34 males) aged 59-89 years (mean 77.7 years) with predominantly occult CNV. There were 49 cases of occult with no classic CNV and 64 of occult with minimally classic CNV. According to their greatest linear dimension, lesions were classified as being3.0 mm or3.0 mm. Transpupillary thermotherapy was delivered with a diode laser, emission at 810 nm, duration 60 seconds, laser power 500-800 mW. Clinical examination, ETDRS logMAR visual acuity and fluorescein angiography were carried out at baseline, and at 3, 6 and 12 months in all cases.The average baseline visual acuity was 0.20 (50.6 letters). Following TTT, it was 0.12 (42.0 letters) at 6 months and 0.12 (38.0 letters) at 12 months. Visual acuity improved in 9/113 eyes (8.0%), remained unchanged in 46 (40.7%) eyes, and deteriorated in 58 (51.3%) eyes. There was no significant difference in the proportion of eyes that had lost at least 15 letters at 12 months in the subgroup of occult with no classic CNV (18/49; 36.7%) versus those with minimally classic lesions3.0 mm (15/39; 38.5%). However, 13/25 (52.0%) of cases with minimally classic lesions3.0 mm had lost at least 15 letters at 12 months (p = 0.31). The most common complications in the 46 eyes that suffered visual loss comprised subretinal progressive fibrosis (18 eyes) and atrophy of the retinal pigment epithelium (13 eyes).This study shows that TTT generally prevents moderate and severe visual loss at 12 months follow-up in occult CNV with no classic CNV. Eyes with minimally classic lesions with a greatest linear dimension of3.0 mm also show the same positive outcome. These results compare favourably with published data on the natural course of the disease. However, minimally classic lesions of3.0 mm responded poorly in this treatment setting.

To assess change in incidence of retinoblastoma in Northern Europe and to compare commonly used methods for calculating its incidence against birth cohort analysis.Retrospective cohort study.Individual and pooled data of 291 Swedish and 174 Finnish children diagnosed with retinoblastoma between 1958 and 1998.Incidence per 1 million children younger than 5 years of age (37 812 035 person- years at risk) and per 100 000 live births (7 152 265 live-born children at risk).Data were from Swedish and Finnish Cancer Registries and corresponding national referral centers for retinoblastoma. Incidence was calculated both by standard analysis per children younger than 5 years of age and per live births, and by birth cohort analysis. Curves were smoothed with robust, locally weighted regression. Linear regression was used to fit pooled data.The number of new retinoblastoma cases per year ranged from 0 to 13 (1-13 per birth cohort) in Sweden and from 0 to 10 in Finland (1-9 per birth cohort). The mean incidence was 11.8 (95% confidence interval [CI], 10.5-13.1) and 11.2 (95% CI, 9.4-13.0) per 1 million children younger than 5 years of age in Sweden and Finland, respectively, and 6.7 (95% CI, 5.9-7.5) and 6.2 (95% CI, 5.3-7.2) per 100 000 live births, respectively. Analysis based on year of diagnosis suggested moderate increase in incidence since 1990, but by birth cohort analysis, incidence rates were stable for both countries. The pooled incidence by birth cohort was 6.0 (95% CI, 5.4-6.6) per 100 000 live births, corresponding to 1 in 16 642 (95% CI, 15 105-18 528) live births.The data suggest that the incidence of retinoblastoma is stable in Northern Europe. Analysis based on birth cohort is recommended for future epidemiologic studies, because it minimizes the effect of variable age at diagnosis of this developmental cancer and results in less variable incidence rates than standard analysis based on year of diagnosis.

To assess the efficacy of photodynamic therapy (PDT) as a new treatment for circumscribed choroidal haemangioma (CCH).Eight patients with CCH were treated with PDT using a protocol similar to that used in the standard treatment of neovascular age-related macular degeneration.Visual acuity improved in six of eight eyes, remained unchanged in one eye and deteriorated in one eye after 3-15 months (median 7 months) follow-up. Pre-treatment metamorphopsia disappeared in all but two cases. The thickness of the CCH measured with standardized echography showed marked regression within 1 month after PDT. In six eyes there was no remaining protrusion after PDT and one lesion was barely detectable. One patient experienced a transient choroidal effusion and perifoveal haemorrhage.Photodynamic therapy is a promising new treatment for CCH as it restores visual function in most cases without causing apparent ocular or systemic side-effects.

To investigate the incidence of uveal melanoma in Sweden during the period from 1960 to 1998, with respect to age distribution, gender, and changes in incidence over time.The Swedish Cancer Registry was searched for patients with uveal melanoma and cross-checked against hospital files over patients where an eye-sparing treatment had been applied, to ensure inclusion in the Registry even when no histologic specimen was available. The crude and age-standardized incidence was estimated separately for each gender. The Swedish population of 1970 to 1974 was used as a standard, and the annual change in incidence was calculated by using a regression model with logarithmic incidence numbers.In total, 2997 patients met the criteria, of whom 1542 were males and 1455 females. During the 39-year period, the age-standardized incidence of uveal melanoma declined significantly in the male population, from 11.7 cases/million to 8.4 cases/million (P = 0.002). The trend toward reduced incidence in females, from 10.3 to 8.7 cases/million did not reach statistical significance (P = 0.108). The annual relative change in incidence was 1% (95% CI, 0.8%-1.2%) in males and 0.7% (95% CI, 0%-1.3%) in females. The age-specific incidence revealed a significantly higher incidence among men older than 45 years (23.5 cases/million) compared with the incidence in women of the same age group (19.2 cases/million; P0.001).A Swedish national survey performed to establish the incidence of uveal melanoma during the period from 1960 to 1998 revealed a decreasing incidence in the male and a stable incidence in the female population.

To assess cognitive and visual outcomes in children treated for retinoblastoma.A population-based group of 22 children treated for retinoblastoma were followed in a longitudinal, prospective study. Eleven children had unilateral tumours, all of which had been enucleated. The remaining 11 had bilateral tumours. Seven of these had undergone unilateral enucleation and local or external beam radiation to the other eye. Four children had been treated with local or external beam radiation only. Cognitive outcome and visual function was assessed at 4 and 6 years of age.We found no general delay in cognitive or motor development at 4 or 6 years of age. Better cognitive capacities were found in the bilateral/irradiated retinoblastoma patients than in unilateral/non-irradiated patients. However, two of the irradiated children, both of whom had been treated at 1 month of age, performed below group mean. None of the children was totally blind. Three children were visually impaired due to tumours affecting the macular area in the remaining eye; another three had subnormal visual acuity but no macular pathology. A total of 14 children had been enucleated and had normal vision in the remaining eye. Visual fields and dark adaptation were adversely affected in a few cases, but colour vision was normal in all.Bilateral retinoblastoma seems to be associated with superior cognitive capacities. Few children were visually impaired according to WHO criteria. We speculate that children treated during the first months of life may be at risk of adverse cognitive and visual outcomes. The immature brain may be affected by radiation treatment, causing both cognitive and visual deviations.

To identify in human retinoblastoma and normal retinal tissue the type of cadherin, its relationship with cytoplasmic catenins, and its participation in invasion.The cadherin/catenin complex was characterized in surgical retinoblastoma specimens from five patients and human retinas from four donor eyes by immunocytochemistry, flow cytometry, and coimmunoprecipitation with antibodies against N-cadherin, alpha-catenin, and beta-catenin, followed by Western blot analysis or autoradiography. Y79 and WERI-Rb-1 retinoblastoma cell lines serve the evaluation of the cadherin/catenin complex in aggregation and collagen type I invasion in vitro. The association of the cadherin/catenin complex with the cytoskeleton was examined by an antibody-capping assay.In retinoblastoma and normal retina N-cadherin associated with alpha-catenin and beta-catenin but not E- or P-cadherin. The N-cadherin/catenin complex formed a regular, linear, and continuous honeycomb pattern in normal retina that was irregular, clustered, and interrupted in retinoblastoma. The N-cadherin/catenin complex was found also in the retinoblastoma cell lines WERI-Rb and Y79, in which it also showed an irregular pattern. Both cell lines were invasive in collagen type I, and invasion was inhibited by the GC-4 antibody, which functionally neutralizes N-cadherin. Less GC-4 antibody was needed to inhibit invasion of Y79 cells, which expressed N-cadherin at a lower level, than to inhibit invasion of WERI-Rb-1 cells. In both cell lines, antibody capping of the N-cadherin/catenin complex indicated that its linkage with the cytoskeleton were weak or absent.Retinoblastoma cells, in contrast with normal retina, express an N-cadherin/catenin complex that is irregularly distributed and weakly linked to the cytoskeleton. In retinoblastoma, this complex acts as an invasion promoter.

Purpose: To compare the visual outcome after surgical removal of subfoveal choroidal neovascularization (CNV) in patients younger and older than 50 years of age. Methods: Patient records from all Swedish centers performing submacular CNV surgery were reviewed and 90 patients treated between 1992–1999 with a follow-up of 6 months or more were included. The results obtained in 49 patients aged 51–89 years (median=72 years) with neovascular disease caused by age-related macular degeneration (AMD) were compared with the outcome of 41 patients aged 6–49 years (median=36 years) with CNV secondary to non-AMD causes. The main outcome measure was the improvement or deterioration in visual acuity (standardized in logMAR units) at 6 months following surgery. Secondary endpoints were recurrent CNV and surgical complications. Results: The level of preoperative visual acuity was not significantly different between younger patients with CNV associated with non-AMD and older patients with visual loss due to AMD (p=0.069). However, visual acuity at 6 months after surgery was better (p=0.0042) in younger patients (median improvement=0.19 logMAR) than in older patients (median improvement=0.0 log MAR). Marked visual improvement (>1 log MAR unit) was seen in 29% of non-AMD patients 50 years. Conclusion: Surgical removal of submacular CNV does not appear to improve visual acuity in patients > 50 years of age. However, it may be beneficial for younger patients where a substantial improvement of visual acuity is seen in a subset of these patients. Further studies are required to assess the long-term outcome.

To investigate the expression of the insulin-like growth factor-1 receptor (IGF-1R) with special focus on its role in cell growth in uveal melanoma.Paraffin material from 36 clinicopathologically well characterized cases of primary uveal melanomas (18 of which had metastasized to the liver) with more than 15 years' follow-up was used for immunohistochemical analysis. In the experimental studies, three uveal melanoma cell lines (OCM-1, OCM-3, and 92-1) were used. The expression level of IGF-1R in the cell lines was modulated by glycosylation inhibitors, and the IGF-1R was neutralized with the antibody alphaIR-3. Expression of IGF-1R was assayed by Western blot analysis and immunohistochemistry. Cell growth and survival were analyzed by cell counting, thymidine incorporation, and viability assays.Western blot analysis and immunohistochemistry confirmed that IGF-1R is expressed in uveal melanoma. Although 10 of 18 patients who died of metastasizing disease showed high IGF-1R expression, only 5 of 18 tumors from patients who survived for 15 years or more after enucleation exhibited a high IGF-1R expression. Kaplan-Meier analysis showed a significant association (P = 0.035) between a high IGF-1R expression and death due to metastatic uveal melanoma. Using in vitro experimental models, we found that inhibition of the IGF-1R activity (tyrosine phosphorylation) was associated with a drastic decrease in uveal melanoma cell viability.These data suggest an important role of IGF-1R in uveal melanoma. The significant association between high IGF-1R expression and death due to metastatic disease may be explained by the fact that IGF-1 is mainly produced in the liver, which is the preferential site for uveal melanoma metastases. These data also point to the possibility of therapeutically interfering with IGF-1R, which appears to be expressed preferentially in uveal melanomas that appear to follow an aggressive clinical course.

Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade basement membrane and extracellular matrix proteins. To gain information on the possible role of MMPs in choroidal neovascularization (CNV), we have analyzed the mRNA expression of MMP-2 and MMP-9, two forms of MMPs implicated in ocular neovascularization, in a rat model.Choroidal neovascularization was induced in pigmented rats by krypton laser photocoagulation of the fundus whereafter eyes were enucleated at 1, 3, 5, 7, 10 and 60 days. Antisense and sense riboprobes were generated using DNA complementary to MMP-2 and MMP-9, and mRNA expression was analyzed using in situ hybridization.In the untreated eyes MMP-2 mRNA expression was weakly detected in cells within the choroid. In laser-treated eyes MMP-2 mRNA expression was markedly increased and mainly localized to macrophage-like and retinal pigment epithelial (RPE)-like cells invading the choroid, subretinal space and inner retina. This increase in MMP-2 mRNA expression peaked at day 10 whereafter a decline was detected. MMP-9 mRNA expression was low in untreated eyes and did not increase following laser treatment.The results show that MMP-2 mRNA expression is increased in experimental CNV, and support of a role for MMP-2 in the development of CNV in age-related macular degeneration.

Background: In some retinal diseases and following transplantation of retinal pigment epithelium (RPE), melanin granules are liberated to the subretinal space. Our aim was to investigate the cellular response to implanted extracellular melanin. Methods: After pars plana vitrectomy, 17 albino rabbits received a suspension of melanin granules in the subretinal space. Postoperative examination included ophthalmoscopy, color fundus photography, histology using monoclonal antibodies identifying RPE cells (AE1/3), macrophages (RAM 11), B-lymphocytes (CD20) and T-lymphocytes (CD45), and electron microscopy. The follow-up time was 2 weeks, 4 weeks and 6 months. Results: On fundus photographs, the layer of melanin showed focal attenuation with lighter areas at 6 months. Melanin granules were phagocytosed by RPE cells and macrophages at 2 weeks, as identified by monoclonal antibodies. In areas where an abundance of melanin was present, multilayers of macrophages were seen associated with considerable photoreceptor damage. Pigment-laden cells invaded the neural retina. The cellular infiltration of the retina was focal, and when it involved the outer nuclear layer the photoreceptor damage was severe. Electron microscopy demonstrated the presence of melanosomes intracellularly in Muller glia. The process of phagocytosis and removal of melanin granules from the subretinal space was slow and not completed at 6 months. Conclusion: Our experiments show that implantation of melanin granules in the subretinal space of albino rabbits may induce a considerable phagocytic cellular response featuring the host’s RPE, macrophages and glial cells. The migration of pigment-laden cells into the neural retina was associated with focal photoreceptor damage.

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) are all implicated in the development of neovascularization. To investigate the possible role of these factors in corneal neovascularization we have analysed the expression of MMP-2, MMP-9 and VEGF in a rat model of inflammation-associated corneal neovascularization. In this model, corneal neovascularization was induced in Long-Evans rats by krypton laser photocoagulation whereafter eyes were enucleated at 1, 4, 7, 10 and 20 days. Slit-lamp biomicroscopy and histologic analysis revealed a gradual development of corneal neovascularization that peaked 7-10 days after treatment when newly formed vessels could be seen throughout the corneal surface reaching deep into the stroma. Antisense and sense riboprobes were generated using DNA complementary to MMP-2, MMP-9 and VEGF, and mRNA expression was analysed using in situ hybridization. The expression of MMP-2 and MMP-9 in untreated corneas was low or absent whereas VEGF was weakly expressed in the corneal epithelium. MMP-2 expression was increased during corneal neovascularization and was mainly localized to the cells infiltrating areas of new vessel formation. Many of these cells appeared to be inflammatory cells. VEGF expression had a similar overall distribution to MMP-2 during neovascularization with the exception that its expression in the corneal epithelium remained and even increased slightly. MMP-9 was prominently expressed at the border of regenerating corneal epithelium in areas with epithelial wounding but was not detected in the vascularized stroma. Together, the results of the present study support a role for MMP-2 and VEGF in inflammation-associated corneal neovascularization whereas MMP-9 instead appears to be involved in corneal epithelial wound-healing.

Purpose: This study aimed to present the clinical and histopathological features of a pigmented spindle cell naevus (PSCN) appearing in the conjunctiva. Methods: Histopathological examination of the lesion following excision and review of the pertinent literature. Results: The features were consistent with those previously recognized in the skin as the PSCN of Reed. Conclusion: The PSCN can appear in the conjunctiva and should not be confused with conjunctival melanoma.

Loss of nm23 gene expression is believed to enhance metastatic spread in diverse human tumors, including skin melanoma. The purpose of this work was to determine the pattern and prognostic relevance of nm23 protein immunoexpression in conjunctival melanoma and potential precursor lesion. Formaldehyde-fixed, paraffin-embedded conjunctival specimens comprising 85 melanocytic lesions (nevi, primary aquired melanosis with and without atypia and primary and locally recurrent malignant melanomas) from 73 patients were used. Sections from all specimens were examined by light microscopy to assess diverse prognostic parameters. Additional sections were then immunostained for nm23 H-1 protein and the immunoreactivity was assessed semi-quantitatively. Survival data for all patients were retrieved from the National Causes of Death Registry of Sweden. Nm23 H-1 protein was differentially expressed in conjunctival melanocytic lesions, however loss of immunoexpression was not more common in melanocytic lesions asociated with a high risk of malignant transformation. Also, primary and recurrent conjunctival melanomas showed an essentially similar nm23 expression pattern and we could not associate the pattern of nm23 immunoexpression with an increased risk for malignant transformation or locally recurrent disease. While there was a tentative separation between cause-specific survival curves after excision for low and high nm23 expression conjunctival melanoma, there was no statistically significant association with metastatic death of patients. However, loss of nm23 protein immunoexpression may still be of some importance as a marker for prognosis in conjunctival melanoma because the present study could only detect large differences in survival. Our results suggest that any potential prognostic value of nm23 immunoexpression would be independent of other markers, underlining the importance of further studies.