Training in cataract surgery in Spain: analysis of the results of a survey of the European Board of Ophthalmology in a Spanish cohort.

INTRODUCTION: A survey conducted by the European Board of Ophthalmology (EBO) revealed significant differences in the surgical training of the ophthalmology residents in Europe, including a disparity between the sexes and a variation in the experience on cataract surgery (CC) between them. This study is about the Spanish sub-cohort of the survey, and its objective is to present and analyse the peculiarities of ophthalmology training in Spain within the European context, as well as discussing ways to harmonise and improve that training throughout the EU. METHODS: We analyse data of the Spanish participants in the EBO exams, defining subgroups by the Autonomous Communities existing in Spain. RESULTS: 93 of 135 requested participants (68.9%) responded. A 60.2% passed the EBO exam between 2021 and 2022, being mostly women (65.59%) aged 31 years old on average. The 91.4% were right-handed, coming from 13 of the 17 Spanish autonomous communities, although mostly from the Community of Valencia, Madrid and Catalonia. Respectively, 16.1%, 3.2% and 8.7% of the respondents said they have completed 10 or more training sessions on animal eyes, synthetic eyes and through the virtual reality simulator. This training was correlated with greater self-confidence in the management of a posterior capsular tear during surgery (p .025). All respondents manifested to have already performed stages of the CC. The average number of operations reported was 181.6 with regional disparities. A significant difference is observed between the sexes against women (-28.3%, p 0.03). DISCUSSION: Ophthalmologists in Spain, much more than other European countries, have greater opportunities for surgical training, with surgical procedures during the residency, that nearly triples those made by the others. Spanish women refer, like their European colleagues, to be in disadvantage in learning opportunities about cataract surgery. The Simulation Based Medical Education (SBME) allows to respond to the training deficit and complements the training on the patient. Although we demonstrate a significant correlation between the number of procedures carried out and self-confidence to operate simple cases, the SBME would be a complementary tool in self-confidence in front of a complication like capsular rupture. CONCLUSION: Spain massively adopts the model named by us "surgery for all", despite the underrepresentation of women in this area, emphasising a need for cultural change that the SBME could facilitate.

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond.

The tumour, node, metastasis (TNM) classification is a universal cancer staging system, which has been used for five decades. The current seventh edition became effective in 2010 and covers six ophthalmic sites: eyelids, conjunctiva, uvea, retina, orbit, and lacrimal gland; and five cancer types: carcinoma, sarcoma, melanoma, retinoblastoma, and lymphoma. The TNM categories are based on the anatomic extent of the primary tumour (T), regional lymph node metastases (N), and systemic metastases (M). The T categories of ophthalmic cancers are based on the size of the primary tumour and any invasion of periocular structures. The anatomic category is used to determine the TNM stage that correlates with survival. Such staging is currently implemented only for carcinoma of the eyelid and melanoma of the uvea. The classification of ciliary body and choroidal melanoma is the only one based on clinical evidence so far: a database of 7369 patients analysed by the European Ophthalmic Oncology Group. It spans a prognosis from 96% 5-year survival for stage I to 97% 5-year mortality for stage IV. The most accurate criterion for prognostication in uveal melanoma is, however, analysis of chromosomal alterations and gene expression. When such data are available, the TNM stage may be used for further stratification. Prognosis in retinoblastoma is frequently assigned by using an international classification, which predicts conservation of the eye and vision, and an international staging separate from the TNM system, which predicts survival. The TNM cancer staging manual is a useful tool for all ophthalmologists managing eye cancer.

Reduction of intra-ocular pressure by ocular compression before combined peri- and retrobulbar block.

The intra-ocular pressure immediately before glaucoma surgery can be raised. We wished to investigate if ocular compression for 20 min before a combined peri- and retrobulbar injection would result in a lower pressure after the block. Sixty consecutive patients scheduled for filtration surgery were randomly assigned to receive ocular compression using an external pressure device for 20 min before combined peri- and retrobulbar injection (intervention group, who also received compression after the block) or to a control group in whom pressure was applied only after the block was completed. The intra-ocular pressure was measured at baseline, after the 20-min pre-injection compression (intervention group), after injecting the block, and after the 10-min post-injection compression. The pressure did not differ between groups at baseline, after the block or after the post-injection compression. In the intervention group, the compression before the block reduced the median (IQR [range]) pressure from 21.0 (17.0-25.0 [12.0-40.0]) mmHg to 16.8 (12.5-22.5 [7.5-33.5]) mmHg (p<0.001). We conclude that external ocular compression reduces the intra-ocular pressure, but applying an additional compression for 20 min before injecting the block is not beneficial.

Cerebroretinal microangiopathy with calcifications and cysts.

BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation. METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively. RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen. CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.

Primary lymphoma of the lacrimal sac: an EORTC ophthalmic oncology task force study.

AIM: To define the clinical and histopathological characteristics of primary lacrimal sac lymphoma in a predominantly white population. METHODS: Specimens of lacrimal sac lymphoma and follow up data were solicited from members of the Ophthalmic Oncology Task Force of the European Organization for Research and Treatment of Cancer (EORTC) and the European Ophthalmic Pathology Society (EOPS). Specimens were stained with haematoxylin and eosin and an immunohistochemical panel against leucocyte antigens was applied. Diagnosis was reached by consensus of five experienced pathologists according to the World Health Organization classification system. The histopathological findings were correlated with the clinical data. RESULTS: Of 15 primary lacrimal sac lymphomas, five (33%) were diffuse large B cell lymphoma (DLBCL), five (33%) were extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma), three were classified as "transitional MALT lymphoma," being in transition from MALT lymphoma to DLBCL, and two were unclassified B cell lymphomas. Nine of the patients were female, and the median age at the time of diagnosis was 71 years (range 45-95 years). The most frequent presenting symptoms were epiphora (85%), swelling in the region of the lacrimal sac (79%), and dacryocystitis (21%). All but one patient presented in stage I. Systemic spread occurred in three of nine patients (33%). The 5 year overall survival was 65%. CONCLUSIONS: DLBCL and MALT lymphoma are equally common in the lacrimal sac in contrast with the remaining periorbital and/or orbital region where MALT lymphoma predominates.

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.

Bleomycin, vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma.

This EORTC multicentre study analysed the efficacy and tolerability in patients with metastatic uveal melanoma of BOLD chemotherapy in combination with recombinant interferon alpha-2b. The dose of bleomycin was 15 mg on days 2 and 5, of vincristine 1 mg/m(2) on days 1 and 4, of lomustine 80 mg on day 1, and of dacarbazine (DTIC) 200 mg/m(2) on days 1-5, given every 4 weeks for a minimum of two cycles. Subcutaneous (s.c.) interferon alpha-2b at a dose of 3 x 10(6) IU was initiated on day 8 of the first cycle, and continued at a dose of 6 x 10(6) IU three times per week after 6 weeks. A median of two cycles were administered to 24 patients (median age 60.5 years). None achieved an objective response (0%; 95% Confidence Interval (CI): 0-14), 2 (8.3%) remained stable, 20 showed progression, and 2 (8.3%) were invaluable. The median progression-free survival was 1.9 months (95% CI: 1.8-3.4) and overall survival 10.6 months (95% CI: 6.9-16.4). Overall survival improved with increasingly favourable pretreatment characteristics (median, 14.7 versus 6.9 versus 6.0 months for Helsinki University Central Hospital (HUCH) Working Formulation stages IVBa, IVBb and IVBc, respectively; P=0.018). Grade 3 alopecia and neurotoxicity occurred in 13% of the patients. This multicentre study did not confirm earlier reports that BOLD with human leucocyte or recombinant interferon would induce at least 15% objective responses in metastatic uveal melanoma.

Mode of presentation and time to treatment of uveal melanoma in Finland.

AIMS: To investigate the current referral pattern and delays in treatment of patients with primary uveal melanoma. METHODS: 184 consecutive Finnish patients with uveal melanoma diagnosed between July 1994 and June 1999 were eligible, and 159 were enrolled (inclusion rate, 86%). Their mean age was 60 years (range 14-87). The dates of visits to dispensing optician, physician, ophthalmologist and ocular oncologist, the presence of symptoms, and reason for consultation were determined by structured telephone interview. Time intervals to treatment planning and treatment were calculated. RESULTS: 139 patients (87%) had symptoms at presentation and 44 patients (28%) had been seen by an ophthalmologist less than 2 years previously. The median height of the tumour was 6 mm (range, 1.0-17.0) and its largest basal diameter 11 mm (range 2.5-22.0) at diagnosis. Melanoma developed from a previously detected presumed naevus in 13 patients (8%). When the first contact was a dispensing optician (15%) the median time to treatment planning was 22 days (range 1-1156). When a physician other than an ophthalmologist (19%) was contacted the delay was 68 days (range 0-1283) and when an ophthalmologist (65%) was seen it was 34 days (range 1-1426). These differences were not significant (p=0.32). The chance of being referred at first visit was 89%. Median time to treatment was not associated with symptoms (p=0.16) and tumour volume (p=0.29), but it was significantly different between patients who were and were not referred at first visit (140 days v 34 days; p<0.001) and between those treated by ruthenium and iodine brachytherapy (59 days v 33 days; p=0.009). CONCLUSIONS: Analysis of delays in management indicates that earlier treatment could be achieved if dilated fundus examinations were performed without exceptions, all suspicious naevi were referred for a second opinion, and if the patients with melanoma were referred to the ocular oncology service concurrently with staging examinations done at the regional hospital.

Ezrin as a prognostic indicator and its relationship to tumor characteristics in uveal malignant melanoma.

PURPOSE: Immunohistochemistry was used to investigate whether uveal malignant melanoma expresses ezrin, a protein involved in cell migration and cell recognition by acting as a linker between the plasma membrane and actin cytoskeleton. Also investigated was whether ezrin immunoreactivity correlates with survival prognosis. METHODS: A monoclonal antibody, 3C12, that reacts with the carboxyl-terminal part of ezrin was used in retrospective analysis of a population-based cohort of 167 consecutive choroidal and ciliary body melanomas in eyes enucleated from 1972 through 1981, with a median follow-up of 22 years. RESULTS: Ezrin immunoreactivity in tumor cells was graded negative in 47 (36%) melanomas, positive in 74 (57%), and strongly positive in 9 (7%). The immunoreactivity tended to be homogenous throughout the tumor, with focal concentrations along the cell surface. Positive reaction was significantly associated with high microvascular density (P < 0.001) and presence of macrophages (P < 0.001), but not with tumor size, cell type, or microvascular loops and networks. The 10-year melanoma-specific survival was significantly associated with ezrin immunoreactivity (P = 0.018). After adjustment by Cox regression for tumor size, cell type, microvascular loops and networks, and microvascular density, a clinically meaningful 0.15 difference in 10-year melanoma-specific survival persisted. CONCLUSIONS: The presence of ezrin immunoreactivity in uveal malignant melanoma is associated with higher mortality and with two independent high-risk characteristics: microvascular density and number of infiltrating macrophages. Further experimental studies on the interrelationship of these three factors may shed light on the progression of uveal melanoma and perhaps that of other cancers.

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.

Exudative retinal detachment from malignant uveal melanoma: predictors and prognostic significance.

PURPOSE: To determine independent predictors of exudative retinal detachment (RD) in eyes with uveal melanoma and the significance of RD in melanoma-specific survival. METHODS: The extent of exudative RD was recorded retrospectively in a population-based cohort of 167 consecutive patients with eyes enucleated from 1972 through 1981 because of choroidal and ciliary body melanoma, representing all melanomas treated during that period. Histopathologic features including microvascular loops and networks, microvascular density (MVD), and tumor-infiltrating macrophages were determined. Clinical and histologic predictors of RD were modeled by multiple logistic regression with a split-sample, cross-validation design. Survival was assessed by Kaplan-Meier analysis and adjusted for the effect of competing predictors by Cox proportional hazards regression. RESULTS: Of 142 (85%) eyes with adequate data, 25% had no RD, 16% had subretinal fluid around the tumor, 43% had clinical RD in one to two quadrants, and 16% had RD in three to four quadrants. The RD was more extensive if the tumor was large (P < 0.0001) and had microvascular loops and networks (P = 0.0094) and less extensive if it involved ciliary body (P = 0.011). High MVD (P = 0.054) and ruptured Bruch's membrane (P = 0.065) tended to be associated with RD. Multiple logistic regression showed largest basal diameter (odds ratio [OR] 1.43 for each 1-mm change, P < 0.0001), microvascular loops and networks (OR 1.95 for each category change, P = 0.0095), and ciliary body involvement (OR 0.20, P = 0.0039) to be independently associated with RD; ruptured Bruch's membrane (P = 0.96) and MVD (P = 0.87) were not associated. Clinical RD predicted poor survival (0.59 vs. 0.37 at 20 years; P = 0.029) by Kaplan-Meier analysis, but not after adjusting for other prognostic factors by Cox regression (hazard ratio [HR] 1.00, P = 1.0). CONCLUSIONS: Tumor size, which may be a surrogate measure for total vascular content and decompensation of choriocapillaris and retinal pigment epithelium, is a strong predictor of exudative RD. Microvascular loops and networks are likewise associated with exudative RD. Exudative RD is not associated with survival after adjusting for tumor size and microvascular loops and networks.

Sebaceous carcinoma of the eyelid associated with retinoblastoma.

OBJECTIVE: To analyze the association between retinoblastoma (Rb) and sebaceous carcinoma (SC) of the eyelid to improve surveillance of survivors of RB: DESIGN: Case report and systematic literature review. METHODS: Ten patients who had SC develop after Rb were identified by systematic literature review, and a child who died with lymph node, lung, and liver metastases 7 years after irradiation for Rb is described. The data were analyzed by univariate statistics, including cumulative frequency distribution plots and Kaplan-Meier analysis. RESULTS: Of 11 children with SC of the eyelid who all had hereditary RB, 9 (82%; 95% confidence interval, 48-98) received a median of 46 Gy (range, 21-89) of radiotherapy at a median age of 16 months (range, 0.5-15 years) and had SC develop within the field of radiation. Their median age at diagnosis of SC was 14 years (range, 8-30 years), median diagnostic delay 12 months (range, 6 months-3 years), and median interval from irradiation 11 years (range, 5-26 years); 7 of them (78%; 95% confidence interval, 40-97) were diagnosed between 5 and 15 years after radiotherapy. SC also developed at the age of 32 and 54 years in two nonirradiated Rb patients. Five patients had regional lymph node metastases after a median time of 12 months (range, 1 month-24 years). The 5-year cumulative probability of survival was 87%. CONCLUSIONS: SC of the eyelid may occur in patients with hereditary Rb regardless of primary treatment, especially within the field 5 to 15 years after radiotherapy.

Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma.

PURPOSE: To investigate the hypothesis that tumor-infiltrating macrophages contribute to prognosis of uveal melanoma and to study their association with tumor characteristics, especially microvessels. METHODS: This was a retrospective, population-based cohort study of 167 consecutive patients who had had an eye with choroidal and ciliary body melanoma removed between 1972 and 1981. Macrophages were identified with mAb PG-M1 to the CD68 epitope, and their number and morphologic type were recorded. Kaplan-Meier and Cox regression analyses of melanoma-specific survival were performed. RESULTS: CD68-positive macrophages could be assessed in 139 (83%) of the 167 melanomas. Their number was moderate to high in 115 (83%) of the 139 tumors, and their morphology ranged from dendritic to round. A high number of macrophages was associated with presence of epithelioid cells (P = 0.025), heavy pigmentation (P = 0.001), and high microvascular density (P = 0.001). The 10-year melanoma-specific mortality rate increased with higher numbers of macrophages (0.10 for low versus 0.57 for high numbers, P = 0.0012). The morphologic type of infiltrating macrophages was not associated with mortality. The number of macrophages was modeled by stratification, which significantly improved a Cox regression model (P < 0.001). Adjusting for the other independent indicators of metastatic death 10-year melanoma-specific mortality was 0.17 for low versus 0.45 for high numbers of macrophages. CONCLUSIONS: The number of tumor-infiltrating CD68-positive macrophages contributes to prognosis and associates with cell type and microvascular density, which merits a further analysis of the biological role of these cells in uveal melanoma.