High dose rate and low dose rate ruthenium brachytherapy for uveal melanoma. No association with ocular outcome.

BACKGROUND: Episcleral brachytherapy is the most common eye-preserving option for treating uveal melanoma, with ruthenium-106 widely used in Europe. Case series have reported on ocular outcome, but there are very little data on the impact of dose rate. Therefore, we studied the association of dose rate with secondary enucleation. METHODS: Data for all patients in Sweden managed with brachytherapy from 1979 to 2012 were retrieved (962 patients) and divided in quartiles based on dose rates at the tumour apex and at the scleral surface. Kaplan-Meier curves for secondary enucleation were generated independent of dose rate and for each dose rate quartile. Cox regression univariate and multivariate modelling included clinical parameters and dose rates at the tumour apex and the scleral surface. RESULTS: Baseline clinical characteristics were not significantly different across the quartiles except that thinner tumours had higher dose rates at the tumour apex. Dose rates ranged widely, with a near normal distribution at the scleral surface but skewed at the tumour apex. For all quartiles, secondary enucleation was more often caused by tumour progression than by ocular side effects. Univariate and multivariate modelling including clinical parameters showed no association between dose rate and secondary enucleation. CONCLUSIONS: Although dose rates ranged widely, there was no apparent association with secondary enucleation, suggesting that based on ocular survival, current practice of annual replacement of applicators is acceptable, irrespective of the significant reduction in each applicator's dose rate. Nevertheless, patients treated with higher dose rates have shorter plaque exposure and presumably less ocular irritation.

Diagnostic incisional biopsies in clinically indeterminate choroidal tumours.

Most intraocular tumours are reliably diagnosed by a careful clinical examination combined with one or more non-invasive diagnostic techniques. However, in a small percentage of tumours, typically small and clinically amelanotic, the features are insufficiently distinct for a confident clinical diagnosis and tissue is required for diagnosis. We used a 23-G vitreous cutter to access the biopsy site in 43 patients with clinically indeterminate tumours. After retinotomy, an incisional choroidal biopsy yielded a specimen of ∼1 mm(3). Obtained tissue was routinely processed for light microscopy including an immunohistochemical panel of monoclonal antibodies. Adequate tissue for diagnosis was provided in 41/43 (95%) patients. The sensitivity and specificity to detect malignant disease were 0.97 and 1.00, respectively. The positive predictive value was 1.00. Complications included progression of pre-existing retinal detachment in 5/43 (12%) patients and transient rise in intraocular pressure to >40 mm Hg in 6/43 (14%) patients; 4 of these 6 patients had a pre-existing retinal detachment. No patient with a pre-operatively attached retina had a retinal detachment. We conclude that an incisional transretinal choroidal biopsy yields abundant material and may adequately confirm or exclude malignancy in patients with clinically indeterminate tumours. The complication rate can be minimised when patients with pre-existing retinal detachment are excluded from biopsy.

Time trends in the incidence of conjunctival melanoma in Sweden.

AIM: To study time trends in the incidence of conjunctival melanoma in Sweden. METHODS: All patients with conjunctival melanoma from 1960 to 2005 in Sweden were identified through the Swedish Cancer Registry, cross-checked against hospital files, and validated by histopathological review (97.5%) or detailed hospital records (2.5%). The crude and age-standardised incidences were estimated separately for each sex and the annual change in incidence over time was estimated using a regression model with logarithmic incidence numbers. Time trends for the largest diameter, thickness and location of the tumour when diagnosed were analysed. RESULTS: The age-standardised incidence of conjunctival melanoma increased significantly in men (n = 89) from 0.10 cases/million to 0.74 cases/million (p = 0.001) and in women (n = 81) from 0.06 cases/million to 0.45 cases/million (p = 0.007). The annual relative change in age-standardised incidence was 16.9% (95% confidence interval (CI) 12.2 to 21.6) in men and 19.5% (95% CI 9.3 to 29.7) in women. The age-specific incidence was higher in men and women > or = 65 years (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, tumours 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). CONCLUSION: The incidence of conjunctival melanoma increased in Sweden during the period 1960 to 2005.

A prospective randomised study on low-dose transpupillary thermotherapy versus photodynamic therapy for neovascular age-related macular degeneration.

AIM: 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). METHODS: 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 lost <15 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. RESULTS: 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 (p>0.05). The percent of patients with preserved or improved BCVA was 36.5% in the TTT group versus 23.9% in the PDT group (p>0.05). The mean decrease in foveal thickness was 15% for TTT and 24% (p>0.05) for PDT-treated patients, and the mean increase in total lesion area was -0.7% and -1.1% (p>0.05), respectively. CONCLUSION: 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.

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.

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.

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.

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.

The EORTC ophthalmic oncology quality of life questionnaire module (EORTC QLQ-OPT30). Development and pre-testing (Phase I-III).

AIMS: The research objective was to develop a questionnaire module to be used, in addition to the European Organisation into Research and Treatment of Cancer (EORTC) QLQ-C30, for measurement of quality of life (QL) among patients with uveal melanoma treated with methods such as transpupillary thermotherapy, plaque radiotherapy, proton beam radiotherapy, local resection, and enucleation. The present paper describes the development through Phases I-III. METHODS: Relevant QL issues were generated from literature search and from interviews with ophthalmologists, nurses, and patients with uveal melanoma representing three major treatment options: enucleation, plaque brachytherapy, and proton beam therapy. RESULTS: The provisional module was pretested in 61 patients from Finland, Sweden, and UK. The EORTC QLQ-OPT30 module consists of 26 items for all patients, and four additional items for patients receiving treatments other than enucleation. It measures ocular irritation, vision impairment, headache, worry about recurrent disease, problems with driving, problems with appearance functional problems due to vision impairment, and problems reading. CONCLUSIONS: Several treatment modalities are available for uveal melanoma. There is limited knowledge of the impact of these treatments on QL in the long and short term. We hope that the OPT30 module together with the EORTC QLQ-C30 core questionnaire can be a useful tool in research.

Experimental transplantation of autologous iris pigment epithelial cells to the subretinal space.

PURPOSE: To investigate the cellular morphology in the subretinal space following transplantation of iris pigment epithelial (IPE) cells from the same eye. METHODS: Following an iridectomy, fresh IPE cells were prepared and no culturing performed. After pars plana vitrectomy, a suspension of autologous IPE cells was injected into the subretinal space in 37 rabbits. The grafts were monitored by ophthalmoscopy and colour fundus photography. Rabbits were sacrificed at 1, 2, 3 and 6 months, respectively, and the eyes examined with light and electron microscopy. RESULTS: The grafted area retained the same configuration over 6 months but then appeared less pigmented. At 1-3 months, the IPE formed one or more contiguous layers on top of native RPE. At 6 months, cells compatible with grafted IPE were present in the subretinal space, often forming monolayer-like chains integrating with the native RPE. Depigmented cells of presumed IPE origin were seen and frequently in association with abundant melanin granules located in the apical portion of adjacent RPE cells. In such areas, large macrophage-like cells were observed. CONCLUSION: Transplanted IPE cells survived for up to 6 months in the subretinal space. Our observations suggest a scenario of remodelling of the cellular layers in the subretinal space over time where grafted IPE cells formed a compound layer with the native RPE. Transplantation of autologous IPE cells may have a potential as a treatment modality in selected cases of age-related macular degeneration.

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.

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.

Transpupillary thermotherapy as an adjunct to ruthenium plaque radiotherapy for choroidal melanoma.

PURPOSE: To review the Swedish experience using transpupillary thermotherapy (TTT) as an adjunct to ruthenium plaque radiotherapy for choroidal melanoma. METHODS: A retrospective chart review of 27 patients receiving TTT for juxtapapillary or juxtafoveal growth present at the time of diagnosis, or recurrent growth at the tumour margin, or significant exudation following ruthenium brachytherapy for choroidal melanoma. RESULTS: Follow-up ranged from 6 to 29 months (median=20 months). Tumour growth regressed completely (n=8), regressed partially (n=11), remain unchanged (n=6) or progressed (n=2). Complications included focal lens opacity with or without associated posterior synechiae (n=3), retinal haemorrhage (n=2) and retinal vein occlusion (n=1). Seventeen patients (63%) maintained or improved visual acuity and 2 eyes were enucleated following combined treatment. CONCLUSION: Many of the treated eyes would have been enucleated in the past, suggesting that TTT used in combination with ruthenium brachytherapy improves the short term globe salvage rate. Ocular side effects do occur but are usually not significant.

Angiolymphoid hyperplasia with eosinophilia should not be confused with Kimura's disease.

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.

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.

Transpupillary thermotherapy of occult CNV with no or minimally classic CNV in age-related macular degeneration.

Transpupillary thermotherapy (TTT) has been suggested as a putative treatment for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). This prospective study comprised 66 consecutive patients referred for exudative AMD with predominantly occult subfoveal CNV. Based on fluorescein angiography, there were 38 cases with occult CNV only, and 28 eyes with minimally classic CNV as well. Visual acuity was determined using the logarithmic ETDRS chart. For TTT a diode laser (810nm) with a power of 800 mW or 500-600 mW for a 3.0 mm spot was used (duration 60 sec.). Follow-up included clinical examination with biomicroscopy and fluorescein angiography at 2-3 months and 6 months in all cases. In the entire case material (n = 66), the mean visual acuity was preoperatively 20/125 (47.4 letters) and postoperatively 20/160 (41.8 letters) yielding a decay of 5.6 letters ("one line"). Visual acuity improved in 8 cases (12.1%), deteriorated in 17 (25.8%), and remained stable in 74.2%. In purely occult CNV visual acuity remained stable in 81.6% as compared to 64.3% in occult & minimally classic CNV; the former subgroup lost on the average 3.6 letters, the latter 8.3 letters (close to "two lines") over 6 months. The proportion of eyes losing at least 15 letters was 13.2% in purely occult CNV versus 35.7% in the occult & minimally classic subgroup. In 39 of 66 cases (59.1%) fluorescein leakage regressed to staining only concomitant with absorption of subretinal fluid. Complications associated with deterioration of visual acuity (17 cases) included postoperative hemorrhage, increase of exudation on angiography, and progressive fibrosis. The results indicate that TTT stabilizes visual acuity concomitant with regression of exudation and resorption of subretinal fluid in the majority of cases with predominantly occult CNV Cases with occult CNV only seem to do better than those with minimally classic CNV as well. The safety and complication rate appear to be acceptable. A randomized controlled trial is in progress.

The Swedish national survey of surgical excision for submacular choroidal neovascularization (CNV).

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 compared to 0% in the AMD group >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.

Direct puncture and sclerotherapy with sotradecol ((r)) . Orbital lymphatic malformations.

SUMMARY: We evaluated sclerotherapy in the treatment of orbital lymphatic malformations. Six consecutive patients with unilateral orbital cystic masses and recurrent episodes of orbital swelling were included in this retrospective study. All have been treated with percutaneous puncture and injection of Sotradecol (sodium tetredecyl sulphate) under radiographic guidance, on one or more occasions. Reduction of orbital mass volume was documented clinically and radiologically within a few weeks in all cases. There was total regression of proptosis in three instances. There were no immediate complications. One subject suffered a presumably coincidental orbital hemorrhage two weeks after treatment. Follow-up times ranged between six months and four years. Sotradecol sclerotherapy appears to be a useful adjunct to the therapeutic arsenal for orbitallymphatic malformations.