Risk factors for endophthalmitis following cataract surgery: a retrospective case-control study.

To gain further knowledge of possible risk factors for the development of postoperative endophthalmitis (POE) following cataract surgery, a single-centre retrospective case-control study was conducted for 1994-2000. In total, 46292 cataract procedures were performed during the study period. Sixty cases of POE were noted and 240 control cases were selected at random. Parameters pertaining to patient history and to peri-operative technique and complications were analysed. The relative risk of POE was calculated using univariate analyses and multi-variate forward stepwise logistic regression. In the logistic regression analyses, three statistically significant parameters were found. The use of intracameral prophylaxis with cefuroxime as opposed to topical treatment alone, and performing phaco-emulsification instead of extra- or intracapsular cataract extraction appeared to be protective against POE. Silicone intra-ocular lenses carried a higher risk than heparin surface modified poly (methyl methacrylate) implants. In summary, the important finding of this study was the protective effect against POE of intracameral prophylaxis with cefuroxime compared with topical anti-infectives alone.

BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patient with AIDS.

BACKGROUND: The two widely spread human polyomaviruses, BK virus (BKV) and JC virus (JCV) establish latency in the urinary tract, and can be reactivated in AIDS. JCV might cause progressive multifocal leucoencephalopathy, but although up to 60% of AIDS patients excrete BKV in the urine there have been few reports of BKV-related renal and/or neurological disease in AIDS. OBJECTIVE: To report on an AIDS patient with progressive renal and neurological symptoms involving the retina. DESIGN: Case report. SETTING: Venhälsan, Söder Hospital, Stockholm, Sweden. METHODS: The brain, eye tissue, cerebrospinal fluid, urine and peripheral blood mononuclear cells were analysed by nested PCR for polyoma-virus DNA. Macroscopical and microscopical examination were performed of the kidney and brain post mortem. Immunohistochemical stainings for the two BKV proteins, the VP1 and the agnoprotein, were performed on autopsy material and virus infected tissue culture cells. RESULTS: BKV could be demonstrated in the brain, cerebrospinal fluid, eye tissues, kidneys and peripheral blood mononuclear cells. CONCLUSION: During 6 years, approximately 400 cerebrospinal fluid samples from immunosuppressed individuals with neurological symptoms have been investigated by PCR for the presence of polyomaviruses. BKV DNA has, so far, only been found in the case reported here. Although reports of BKV infections in the nervous system are rare, there is now evidence for its occurrence in immunocompromised patients and the diagnosis should be considered in such patients with neurological symptoms and signs of renal disease. The diagnosis is simple to verify and is important to establish.

Giant cell angiofibroma. A distinctive orbital tumor in adults.

A series of seven cases of a previously unrecognized potentially recurrent tumor occurring in the orbit of adult patients is reported. This lesion shows histologic appearances intermediate between, but distinct from, solitary fibrous tumor and giant cell fibroblastoma of soft tissue. Morphologically it is characterised by a richly vascularized, patternless spindle-cell proliferation containing pseudovascular spaces. Multinucleate giant cells (often of floret type) and cells with large, rounded nuclei are present both in the cellular areas and also lining the pseudovascular spaces. The stroma is variably collagenized or sometimes myxoid. Immunohistochemically, the tumor cells exhibit positivity for vimentin and CD34. Follow-up in five cases (median duration 24 months) revealed local recurrence in one patient and persistent tumor in another. The clinical and morphologic features enable distinction of this lesion from both solitary fibrous tumor and giant cell fibroblastoma, and we suggest the designation "giant cell angiofibroma of the orbit".

PC-10 as a predictor of prognosis after antigen retrieval in posterior uveal melanoma.

PURPOSE: The immunoexpression of the PC-10 monoclonal antibody for the proliferating cell nuclear antigen is claimed to have prognostic value in diverse tumors, but previous data on posterior uveal melanoma are conflicting. The aim of the current study was to investigate further the potential value of the PC-10 antibody in predicting tumor-related death after enucleation for posterior uveal melanoma. METHODS: One observer calculated the number of cells after antigen retrieval that showed immunoreactivity for PC-10 in the high expression areas of 212 specimens containing posterior uveal melanomas. Survival data for all patients were entered into stepwise multivariate Cox regressions that included other potential prognostic covariates. The prognostic accuracy was assessed by receiver operating characteristic curve analysis. RESULTS: The only covariates of statistically significant prognostic value were the number of cells featuring immunoreactivity for PC-10 and the largest tumor diameter. When using the median PC-10 count as the cutoff, the cumulative 10-year survival proportion was 84% for the low PC-10 count group and 40% for patients harboring tumors with high PC-10 counts. Those with tumors featuring high PC-10 counts had a 5.8 times greater risk to die of metastatic melanoma. However, the prognostic accuracy of the PC-10 count was not significantly better than that of the largest tumor diameter, presumably because of insufficient statistical power. CONCLUSIONS: The number of cells showing immunoreactivity for the PC-10 antibody may be used to assess prognosis in posterior uveal melanoma, provided that antigen retrieval is performed. Additional work using a larger sample size is warranted for better comparison of the predictive accuracy with that of other prognostic markers.

Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent and specific angiogenic growth factor, in vitro and in vivo, that may be associated with the development of intraocular neovascularization. In the current study, the authors analyze the expression of VEGF in subfoveal fibrovascular membranes from patients with age-related macular degeneration. METHODS: Surgically removed subfoveal fibrovascular membranes from 18 eyes were analyzed for the expression of VEGF mRNA and protein using in situ hybridization and immunohistochemistry, respectively. RESULTS: Most specimens expressed both VEGF mRNA and protein. The VEGF mRNA expression was particularly high in areas with a marked inflammatory response, in which the expression was concentrated to cells resembling fibroblasts and to surrounding inflammatory cells. VEGF protein expression was seen in fibrovascular parts of the membranes and was predominantly localized to the cytoplasm of fibroblastlike cells. In some of these membranes, strong VEGF protein immunoreactivity also was concentrated to extracellular matrix foci within the fibrovascular stroma. CONCLUSIONS: Results indicate that VEGF may be of pathogenetic importance for the development of the choroidal neovascularization (age-related macular degeneration) and also may implicate a role of fibroblasts of presumable choroidal origin in this process.

Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes.

PURPOSE: Matrix metalloproteinases (MMP) are a family of extracellular matrix degrading enzymes associated with the development of neovascularization. To investigate the possible role of these enzymes in choroidal neovascularization, the mRNA expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) were analyzed in subfoveal fibrovascular membranes from patients with age-related macular degeneration (AMD). METHODS: Surgically removed subfoveal fibrovascular membranes from five eyes were analyzed for the expression of MMP and TIMP mRNA. In situ hybridization anti-sense and sense riboprobes were generated using DNA complementary to human collagenase (MMP-1), 72 kDa gelatinase (MMP-2), stromelysin (MMP-3), 92-kDa gelatinase (MMP-9), TIMP-1, TIMP-2, and TIMP-3. Vascular endothelial cells were detected using immunostaining for von Willebrand factor. RESULTS: MMP-2 and MMP-9 mRNA were detected in all specimens. Most of the membranes also expressed TIMP-1 and TIMP-3 mRNA, and two of the membranes expressed TIMP-2 mRNA. MMP-2, TIMP-1, and TIMP-2 mRNA had a similar overall distribution that was relatively uniform within the vascularized membrane stroma. MMP-2 expression appeared to be localized mainly to the vascular endothelial cells, whereas TIMP-1 and TIMP-3 were detected in other cell types such as fibroblastlike cells. MMP-9 expression was distinctly expressed by cells at the margins of the membranes and often in proximity to a thickened Bruch's membrane-like layer under the retinal pigment epithelial cells. TIMP-3 mRNA was strongly expressed within the retinal pigment epithelial cell layer and also in the stroma of one membrane. None of the membranes showed detectable MMP-1 or MMP-3 expression. CONCLUSIONS: The results support a role for MMPs in the development of choroidal neovascularization in AMD. The localization of MMP-2 and MMP-9 to the areas of new vessel formation and to the enveloping Bruch's-like membrane, respectively, suggests that MMP-2 and MMP-9 may be cooperatively involved in the progressive growth of choroidal neovascular membranes in AMD.

Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma.

PURPOSE: To elucidate the genetic differences between metastasizing and nonmetastasizing primary tumors, uveal melanoma samples were screened for DNA copy number alterations by comparative genomic hybridization (CGH). METHODS: DNA copy number changes were studied on 14 primary uveal melanomas that had not metastasized, 15 primary uveal melanomas that had metastasized, and on 6 metastases that were available from 6 primary uveal melanomas. CGH is based on quantitation of the fluorescence intensity of differentially labeled DNAs. Tumor DNA labeled with FITC dCTP and dUTP and normal DNA labeled with Texas red dCTP and dUTP were hybridized to normal metaphase chromosomes. The hybridizations were analyzed using an Olympus fluorescence microscope and the ISIS digital image analysis system to identify gain or loss of genetic material. RESULTS: Primary uveal melanomas that had metastasized and metastases had significantly more changes than primary uveal melanomas that had not metastasized. Comparison between primary nonmetastasizing tumors, metastasizing tumors, and metastases showed that the most common DNA copy number changes were -3 (21%, 73%, 67%, respectively), -6q (7%, 40%, 83%), -1p (0, 33%, 33%), -13q (14%, 13%, 50%), -8p (14%, 27%, 0), -18 (7%, 13%, 33%), +8q (14%, 53%, 100%), +6p (29%, 20%, 17%), +1q (0, 7%, 33%), and +16p (0, 7%, 33%). CONCLUSIONS: Loss of chromosome 3, loss of 6q, and gain of 8q were significantly associated with poor overall survival. In addition, losses of 1p were only found in primary uveal melanomas that had metastasized and in metastases, which suggests that this region may harbor a tumor suppressor gene important in the tumor progression. Finally, loss of chromosome 3 may be associated with isochromosome formation of 1q, 6p, 8q, 16p, 20q, and 22q.

Association of HLA class I and class II antigen expression and mortality in uveal melanoma.

PURPOSE: Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLA antigens mediate interactions of tumor cells with T cells and NK cells. Uveal melanoma is a highly malignant tumor of the eye and is characterized by a hematogenic spread to the liver. Little is known about the role of HLA expression in progression of this malignant disease. METHODS: In the present study HLA class I antigen, beta(2)-microglobulin (beta(2)-m), and HLA class II antigen expression was analyzed in primary uveal melanoma lesions by immunoperoxidase staining with monoclonal antibodies of 65 archival clinical samples. The results were correlated with the clinical course of the disease. RESULTS: HLA class I antigen expression and beta(2)-m expression were downregulated in 40 and 35 lesions, respectively. HLA class II antigens were expressed in 30 lesions. Patients with high HLA class I, including beta(2)-m, and HLA class II antigen expression in their primary melanoma lesions had a significantly decreased survival (P = 0.009, P < 0.001, and P = 0.006, respectively). CONCLUSIONS: The findings argue against a major role of cytotoxic T-lymphocyte (CTL)-mediated control of tumor growth in the clinical course of uveal melanoma and are compatible with a potential role of NK-cell-mediated control of hematogenic metastatic spread.

Homozygous and compound-heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.

Severe type I plasminogen deficiency has been recently linked to ligneous conjunctivitis, a rare and uncommon form of chronic conjunctivitis. In this study, eight unrelated ligneous conjunctivitis patients living in different parts of the world were examined. All affected subjects from which plasma was available displayed absent or markedly reduced plasminogen antigen and plasminogen functional activity. Molecular genetic studies of seven patients identified a Lys19-->Glu mutation in two boys in a homozygous state, and in two girls in a compound-heterozygous state in which the second plasminogen gene carried a missense (Arg134-->Lys) and a nonsense mutation (Cys133--> Stop), respectively. A fifth patient was shown to be homozygous for a frameshift mutation in plasminogen exon 14 (Gly565ins-G). In two unrelated subjects with ligneous conjunctivitis no mutations in the plasminogen gene were identified. Our results suggest that the Lys19-->Glu mutation is the most prevalent mutation in the plasminogen gene of patients with ligneous conjunctivitis.

Cell growth and p53 expression in primary acquired melanosis and conjunctival melanoma.

AIMS: To evaluate cell growth and the pattern of p53 suppressor gene expression in atypical primary acquired melanosis (PAM) and in recurrent conjunctival melanoma. METHODS: Eighteen specimens of PAM with atypia and 24 specimens, comprising early and late lesions, from 12 patients with conjunctival melanoma were stained for the proliferating cell nuclear antigen using the PC10 antibody, and for the p53 gene product using the BP53-12-1, 1801 and DO7 clones. The immunoreactive cells were counted manually and the data evaluated statistically. RESULTS: Seven of nine PAM specimens progressing to melanoma expressed PC10. None of these lesions expressed the p53 gene product. The number of proliferating cells was higher in the late than in the early lesions of conjunctival melanoma. Four of the 12 recurrent melanomas displayed focal, but minimal, p53 expression. The proliferating cell count in the p53 positive tumours was very similar to that of the p53 negative conjunctival melanomas. CONCLUSION: Examination of the expression of proliferating cells in atypical PAM may be used as an adjunct to predict which lesions will progress to melanoma. The increase in the number of proliferating cells over time in recurrent conjunctival melanomas probably reflects more aggressive behaviour and may be used to monitor recurrence. The absence of p53 expression in PAM and minimal staining of conjunctival melanomas did not correlate with cell growth, suggesting that alterations in the p53 tumour suppressor gene are uncommon and late events in conjunctival melanoma, and that p53 expression is unlikely to be a useful prognostic indicator.

Conjunctival melanoma.

Conjunctival melanoma is an uncommon tumor that is likely to recur and carries an overall mortality rate of approximately 30%. The seemingly unpredictable and enigmatic character of this entity has initiated much debate over the past decades regarding the etiology, histogenesis, prognosis, and preferred management. This review outlines the historical perspective; incidence and demographics; etiologic factors; histogenesis; cytogenetic findings; clinical characteristics; histopathologic and ultrastructural features; differential diagnoses; classifications; management of primary, recurrent, and systemic disease; survival after conjunctival melanoma; and diverse factors of potential prognostic significance. Finally, a brief outlook on present and future research objectives is provided.

Cell proliferation as a prognostic indicator in conjunctival malignant melanoma.

Expression of proliferating cell nuclear antigen, a DNA polymerase delta auxiliary protein, was studied in 20 specimens from 20 patients with conjunctival malignant melanoma by means of the total number of cells that showed immunoreactivity per square millimeter. The countings were shown to be reproducible with minimal intraobserver variability. In a multifactor analysis of variance (ANOVA) that adjusted for possible confounders, patients who subsequently died of metastatic disease had significantly higher counts of cells that were positive for proliferating cell nuclear antigen per square millimeter (P = .0011) than patients with a minimum survival of five years without clinical signs of metastatic disease. A multivariate Cox regression model confirmed the independent prognostic value (P = .048) of the cell counts. Individual hazard ratios were estimated in a final Cox model and two groups of patients with low and high hazard ratios were formed. Five-year cumulated survival proportions of the two groups were 90% and 60%, respectively. The total count of cells displaying immunoreactivity for proliferating cell nuclear antigen per square millimeter may be used as a prognostic indicator in patients with conjunctival melanoma.

Epiphora as a side effect of topical mitomycin C.

AIM: To report symptoms and findings of lacrimal duct malfunction after topical mitomycin C (MMC) for conjunctival neoplasia. METHODS: 14 consecutive patients treated with 1-6 cycles of topical 0.04% MMC four times daily for periods of 2 weeks were interviewed about symptoms of lacrimal duct malfunction. Patients who complained of tearing had examination of the puncta and canaliculi including probing and lacrimal duct irrigation. RESULTS: Nine patients complained of epiphora after topical MMC. Three of these patients had normal puncta and canaliculi, patent to irrigation. In these patients epiphora ceased spontaneously after probing and irrigation. The additional six patients had stenosis of the punctum (n = 3), the common canaliculus (n = 1), both puncta and both canaliculi (n = 1) and complete occlusion of the lower canaliculus (n = 1). CONCLUSION: Obstruction of the puncta or canaliculi is not an infrequent event after topical 0.04% MMC.

Two cases of primary bilateral malignant melanoma of the choroid.

The first two Swedish cases of primary bilateral malignant melanoma of the choroid are presented. In one case bilateral histological confirmation was obtained as both eyes were enucleated. In the other case one eye was enucleated and the other irradiated with an episcleral ruthenium plaque. Sweden has a population of 8.38 millions, so that bilateral choroidal melanomas may be less rare than previously thought.

Cut and paste: a no suture, small incision approach to pterygium surgery.

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<0.05. Average surgery time was 9.7 minutes (range 6-13) for glue and 18.5 minutes (range 12-30) for sutures, p<0.001. No complications occurred. CONCLUSION: Using glue instead of sutures when attaching the conjunctival transplant in pterygium surgery causes significantly less postoperative pain and shortens surgery time significantly.

AgNOR counts in conjunctival malignant melanoma lack prognostic value.

Using a silver staining technique, argyrophilic nucleolar organiser region-associated proteins (AgNORs) have been studied in routinely processed paraffin sections of 46 invasive malignant melanomas (MM) of the conjunctiva. The aim of this retrospective study was to assess the value of the AgNOR method as a prognostic indicator for this neoplasm. The 46 cases were divided into two groups: (A) 14 cases of MM that metastasised and caused death of the patient within 5 years of (histological) diagnosis, and (B) 32 cases of MM that did not metastasise and in which patients survived beyond 5 years. The mean of the AgNOR counts per nucleus was 7.03 (95% CI: 5.81-8.24) in group A, and 7.15 (95% CI: 6.53-7.77) in group B. A comparison using a multifactor analysis of variance (ANOVA) model, which corrected for possible confounding effect of tumour thickness, site, and cell type showed no significant difference in AgNOR counts between groups A and B (p = 0.8). Analysis by the Cox proportional hazards regression model showed that survival was not influenced significantly by the mean AgNOR number (hazard ratio: 0.92). Whereas the AgNOR technique may be used to distinguish benign from malignant melanocytic lesions of the conjunctiva, we conclude it has no value in predicting the outcome for patients with conjunctival MM.

The Zimmerman-McLean-Foster hypothesis: 25 years later.

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.

Cell proliferation activity in posterior uveal melanoma after Ru-106 brachytherapy: an EORTC ocular oncology group study.

AIM: To evaluate the cell proliferation activity in posterior uveal melanomas after Ru-106 brachytherapy. METHODS: Eyes containing choroidal or ciliary body melanoma from seven ocular oncology centres, which were enucleated after first being treated by Ru-106 brachytherapy and which had enough melanoma tissue to enable histological assessment, were included. The 57 eligible specimens were divided into a group of 44 eyes that were enucleated because of tumour regrowth, and a non-recurrent group of 13 eyes that were enucleated because of complications such as neovascular glaucoma. 46 non-irradiated eyes harbouring uveal melanoma served as a control group. All specimens underwent routine processing. They were cut into 5 microm sections, and were stained with two main cell proliferation markers: PC-10 for PCNA and MIB-1 for Ki-67. The stained sections were assessed, and the cells that were positive in the immunostaining were counted in each section. The results were evaluated by various statistical methods. RESULTS: The PC-10 score showed a statistically significant difference across the three groups (p = 0.002). The control group showed the highest PC-10 score (median 31.0 PCC/HPF) followed by the tumour regrowth group (median 4.9 PCC/HPF). The lowest PC-10 scores were found in the non-recurrent tumours (median 0.05 PCC/HPF). The MIB-1 score in the control group (median 5.77 PCC/HPF) was similar to the regrowth group (median 5.4 PCC/HPF). In contrast, the MIB-1 score in the non-recurrent tumours was statistically significantly lower (median 0.42 PCC/HPF). The PC-10 and MIB-1 scores were similar in tumours composed of either spindle cells or epithelioid cells in all groups. CONCLUSIONS: The non-recurrent melanomas demonstrate significantly lower cellular proliferation activity than melanomas that showed regrowth or that were not irradiated at all. In our hands, PCNA gave more meaningful information than Ki-67. Our findings strongly support the need for treating regrowing posterior uveal melanoma either by enucleation or re-treatment by brachytherapy. On the other hand, also in the non-recurrent uveal melanomas there are viable cells with potential for proliferation, although fewer in number, with unknown capacity for metastatic spread. Therefore, the irradiated tumours should be followed for many years, probably for life.

Risk of acute suprachoroidal hemorrhage with phacoemulsification.

PURPOSE: To establish whether small incision cataract surgery with phacoemulsification decreases the risk of acute suprachoroidal hemorrhage (ASCH) compared with traditional nucleus expression by extracapsular cataract extraction (ECCE). SETTING: St. Erik Eye Hospital, Stockholm, Sweden. METHODS: A retrospective study was done on the incidence of ASCH in cataract surgery between July 1990 and July 1996. During this period, 37,565 cataract extractions (phacoemulsification and ECCE) were performed at St. Erik Eye Hospital, combined procedures excluded. The criteria for diagnosis were the suspicion of ASCH during surgery and a verified diagnosis via an expulsive hemorrhage into the wound (4 cases), postoperative ultrasonic examination (20 cases), or a choroidal mass on performing ophthalmoscopy together with a postoperative history alluding to the diagnosis (2 cases). RESULTS: Twenty-six eyes were identified with ASCH, including 7 during phacoemulsification and 19 during ECCE. The incidence of ASCH was 0.03% in the 23,213 phacoemulsification cases and 0.13% in the 14,352 ECCE cases. The difference was statistically significant (P = .0003; chi-square test). CONCLUSION: Small incision surgery with phacoemulsification decreased the risk of ASCH in cataract surgery compared with the traditional nucleus expression technique.

Improvement of the recurrence-free interval using biological adjuvant therapy in uveal melanoma.

This study was an attempt to compensate for an alleged aetiological deficiency in melanoma by the prophylactic oral administration of the essential biological components missing. Nine random patients suffering from high-risk uveal melanoma (T3) were, in this preliminary study, treated secondarily with biological dietary adjuvants after primary standard therapy, enucleation or brachytherapy. Secondary treatment consisted of certain natural amino-acids, trace-element salts, folic acid and a diet containing neurogenic lipid components. It entailed no side-effects, no toxicity and was inexpensive. None of these nine patients has suffered recurrent disease. The mean follow-up time was over 80 months (median 69, range 58-140 months). Local tumour control was 100%. This clinical result is significantly better (p = 0.018) as compared to similar T3 uveal melanoma patients in standard care who did not receive adjuvant dietary remedies after primary treatment. The control patients consisted of similar adjusted T3 cases selected from the Swedish official registries, and T2 patients from Germany. Based on the previous positive clinical results obtained with cutaneous malignant melanoma in bioimmunotherapy this additional positive result supports the notion that biological components administered orally may compensate for the etiological deficiency leading to malignant melanoma.