PURPOSE. Although fundus photography is extensively used in ophthalmology, refraction prevents accurate distance measurement on fundus images, as the resulting scaling differs between subjects due... Show morePURPOSE. Although fundus photography is extensively used in ophthalmology, refraction prevents accurate distance measurement on fundus images, as the resulting scaling differs between subjects due to varying ocular anatomy. We propose a PARaxial Optical fundus Scaling (PAROS) method to correct for this variation using commonly available clinical data. METHODS. The complete optics of the eye and fundus camera were modeled using ray transfer matrix formalism to obtain fundus image magnification. The subject’s ocular geometry was personalized using biometry, spherical equivalent of refraction (RSE), keratometry, and/or corneal topography data. The PAROS method was validated using 41 different eye phantoms and subsequently evaluated in 44 healthy phakic subjects (of whom 11 had phakic intraocular lenses [pIOLs]), 29 pseudophakic subjects, and 21 patients with uveal melanoma. RESULTS. Validation of the PAROS method showed small differences between model and actual image magnification (maximum 3.3%). Relative to the average eye, large differences in fundus magnification were observed, ranging from 0.79 to 1.48. Magnification was strongly inversely related to RSE (R2 = 0.67). In phakic subjects, magnification was directly proportional to axial length (R2 = 0.34). The inverse relation was seen in pIOL (R2 = 0.79) and pseudophakic (R2 = 0.12) subjects. RSE was a strong contributor to magnification differences (1%–83%). As this effect is not considered in the commonly used Bennett–Littmann method, statistically significant differences up to 40% (mean absolute 9%) were observed compared to the PAROS method (P < 0.001). CONCLUSIONS. The significant differences in fundus image scaling observed among subjects can be accurately accounted for with the PAROS method, enabling more accurate quantitative assessment of fundus photography Show less
Background: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary... Show moreBackground: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary UM in the Netherlands between 1989 and 2019. Methods: A retrospective population-based cohort study based on patients with primary UM from the database of the Netherlands Cancer Registry (NCR), linked with the national population registry Statistics Netherlands on inhabitants' cause of death. Two time periods (1989-2004, 2005-2019) were compared with descriptive statistics. Kaplan-Meier and (multivariate) Cox proportional hazard models were used to assess changes over time for overall survival (OS) and cancer-specific survival (CSS). Results: In total, 5036 patients were analyzed with a median age of 64.0 years at the time of diagnosis. The number of patients increased over time. In the first (1989-2004) and second (2005-2019) period, 32% versus 54% of the patients received radiotherapy (p < 0.001). The median FU time was 13.4 years. The median OS of the first and second periods was 9.5 (95% CI 8.7-10.3) versus 11.3 years (95% CI 10.3-12.3; p < 0.001). The median CSS was 30.0 years (95% CI NA) in the first period and not reached in the second period (p = 0.008). In multivariate analysis (MVA), female gender (HR 0.85; 95% CI 0.79-0.92, p < 0.001) and radiotherapy treatment (HR 0.73; 95% CI 0.64-0.83, p < 0.001) were associated with better OS. Radiotherapy treatment (HR 0.74; 95% CI 0.61-0.90, p = 0.002) was also associated with better CSS. The period of diagnosis was not associated with OS or CSS. Conclusions: In this study of patients with primary UM, there was a shift to the diagnosis of smaller tumors, possibly due to stage migration. There was also an increase in eye-preserving treatments over time. OS and CSS were modestly improved in the second time period; however, the time period was not associated with OS or CSS in multivariate analyses. Show less
PurposeMRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical... Show morePurposeMRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound.MethodsTwenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline.ResultsPre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 x 10(-3)mm(2)/s increase 12 months after treatment (p = 0.15).ConclusionMR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound. Show less
Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. In cutaneous melanoma, MITF loss has been linked to an increased... Show moreMicrophthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. In cutaneous melanoma, MITF loss has been linked to an increased expression of stem cell markers, a shift in epithelial-to-mesenchymal transition (EMT)-related factors, and increased inflammation. We explored the role of MITF in Uveal Melanoma (UM) using a cohort of 64 patients enucleated at the Leiden University Medical Center. We analysed the relation between MITF expression and clinical, histopathological and genetic features of UM, as well as survival. We performed differential gene expression and gene set enrichment analysis using mRNA microarray data, comparing MITF-low with MITF-high UM. MITF expression was lower in heavily pigmented UM than in lightly pigmented UM (p = 0.003), which we confirmed by immunohistochemistry. Furthermore, MITF was significantly lower in UM with monosomy 3/BAP1 loss than in those with disomy 3/no BAP1 loss (p < 0.001) and with 8q gain/amplification 8q (p = 0.02). Spearman correlation analysis showed that a low MITF expression was associated with an increase in inflammatory markers, hallmark pathways involved in inflammation, and epithelial-mesenchymal transition. Similar to the situation in cutaneous melanoma, we propose that MITF loss in UM is related to de-differentiation to a less favourable EMT profile and inflammation. Show less
PurposeHeavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether... Show morePurposeHeavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether pigmentation should be included in prognostic tests.DesignRetrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation.ParticipantsA total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and 2021.MethodsCox regression and log-rank tests were used for survival analysis; the chi-square test and Mann–Whitney U test were used for correlation analysis.Main Outcome MeasuresUveal melanoma–related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors.ResultsThe 5-year UM-related mortality was 8% in patients with nonpigmented tumors (n = 54), 25% with lightly pigmented tumors (n = 489), 41% with moderately pigmented tumors (n = 333), and 33% with dark tumors (n = 178) (P < 0.001). The percentage of tumors with monosomy 3 (M3) or 8q gain increased with increasing pigmentation (31%, 46%, 62%, and 70% having M3 [P < 0.001], and 19%, 43%, 61%, and 63% having 8q gain [P < 0.001] in the 4 increasing pigment groups, respectively). BRCA-associated protein 1(BAP1) loss (known for 204 cases) was associated with increased tumor pigmentation (P = 0.001). Cox regression analysis on survival showed that when chromosome status and pigmentation were both included, pigmentation was not an independent prognostic indicator. Preferentially expressed antigen in melanoma (PRAME) expression was a significant prognostic marker in light tumors (P = 0.02) but not in dark tumors (P = 0.85).ConclusionsPatients with moderately and heavily pigmented tumors showed a significantly higher UM-related mortality than patients with unpigmented and light tumors (P < 0.001), supporting prior reports on the relation between increased tumor pigmentation and a worse prognosis. Although we previously showed that a dark eye color was associated with tumor pigmentation, we now show that the tumor’s genetic status (chromosome 3 and 8q/BAP1 status) is also related to tumor pigmentation. When pigmentation and chromosome 3 status are both included in a Cox regression analysis, pigmentation is not an independent prognostic factor. However, evidence from this and previous studies shows that chromosome changes and PRAME expression have a stronger association with survival when they occur in light tumors than in dark ones. Show less
Jaarsma-Coes, M.G.; Ferreira, T.A.; Marinkovic, M.; Vu, T.H.K.; Vught, L. van; Haren, G.R.V.; ... ; Beenakker, J.W.M. 2023
Objective: Conventionally, ocular proton therapy (PT) is planned using measurements obtained by an ophthalmologist using ultrasound, fundoscopy, biometry, and intraoperative assessments. Owing to... Show moreObjective: Conventionally, ocular proton therapy (PT) is planned using measurements obtained by an ophthalmologist using ultrasound, fundoscopy, biometry, and intraoperative assessments. Owing to the recent advances in magnetic resonance imaging (MRI) of uveal melanoma (UM), it is possible to acquire high-resolution 3-dimensional images of the eye, providing the opportunity to incorporate MRI in ocular PT planning. In this study, we described how these measurements can be obtained using MRI, compared the MRI-based measurements with conventional ophthalmic measurements, and identified potential pitfalls for both modalities. Design: Cross-sectional study. Subjects: Data from 23 consecutive patients with UM treated with PT were retrospectively evaluated. Methods: Magnetic resonance imaging-based measurements of axial length, tumor height and basal diameter, and marker-tumor distances were compared with the conventional ophthalmic measurements, and discrepancies were evaluated in a multidisciplinary setting. Main Outcome Measures: Tumor prominence and basal diameters on MRI and ultrasound, axial length on MRI and biometry, tumor-marker distances on MRI and measured intraoperatively. Results: The mean absolute differences of the tumor height and basal diameter measurements between ultrasound and MRI were 0.57 mm and 1.44 mm, respectively. Larger absolute differences in height and basal diameter were observed when the full tumor extent was not visible on ultrasound (0.92 mm and 1.67 mm, respectively) compared with when the full tumor extent was visible (0.44 mm and 1.15 mm, respectively). When the full tumor was not visible on ultrasound, MRI was considered more reliable. Tumor-marker distances measured using MRI and intraoperative techniques differed < 1 mm in 55% of the markers. For anteriorly located and mushroom-shaped tumors (25% of the markers), MRI provided more accurate measurements. In flat UM (15% of the markers), however, it was difficult to delineate the tumor on MRI. The mean absolute difference in axial length between optical biometry and MRI was 0.50 mm. The presence of the tumor was found to influence optical biometry in 15 of 22 patients; the remaining patients showed a better agreement (0.30 mm). Magnetic resonance imaging-based biometry was considered more reliable in patients with UM. Conclusions: Magnetic resonance imaging allowed for the 3-dimensional assessment of the tumor and surrounding tissue. In specific patients, it provided a more reliable measurement of axial length, tumor dimensions, and marker-tumor distances and could contribute to a more accurate treatment planning. Never-theless, a combined evaluation remains advised, especially for flat UM. Show less
Ravenstijn, M.; Bois, G. du; Jansen, R.C.; Liu, C.; Luyten, G.P.M.; Leeuwen, R. van; ... ; Klaver, C.C.W. 2023
PurposeTo understand and compare perspectives of patients and professionals on current ophthalmologic care for high myopia, and to identify challenges and future opportunities. MethodsSelf-reported... Show morePurposeTo understand and compare perspectives of patients and professionals on current ophthalmologic care for high myopia, and to identify challenges and future opportunities. MethodsSelf-reported data were collected through two online questionnaires. Patient perspective was obtained from highly myopic members of a patient organisation based in the Netherlands using a 17-item questionnaire consisting of open and multiple-choice questions regarding personal experience with myopia care. The ophthalmologist perspective was obtained from practising Dutch ophthalmologists with a 12-item questionnaire of multiple-choice questions on work-related demographics, myopia care in daily practice and need for improvement. The response rate for patients was 27% (n = 136/500) and for ophthalmologists, 24% (n = 169/716). ResultsPatients were highly concerned about personal progressive loss of vision (69%) and feared their psychological well-being (82%) in case this would happen. The quality of performance of care provided by ophthalmologists was rated as excellent or satisfactory by 64% of the patients. These ratings for multidisciplinary care and insurance reimbursement were as low as 28% and 18% respectively. The mean concern among ophthalmologists about the rise in high myopia was 6.9 (SEM 0.1) on a 10-point scale. Sixty-nine per cent of the ophthalmologists reported that asymptomatic myopic patients should not be examined regularly at outpatient clinics. Ophthalmologists urged the development of clinical guidelines (74%), but did report (95%) that they informed patients about risk factors and complications. This contrasted with the view of patients, of whom 42% were discontent with information provided by ophthalmologists. ConclusionsThese questionnaires demonstrated that the current clinical care delivered to highly myopic patients is in need of improvement. The expected higher demand for myopia care in the near future requires preferred practice patterns, professionals specifically trained to manage myopic pathology, accurate and comprehensive information exchange and collaboration of in- and out-of-hospital professionals across the full eye care chain. Show less
Vught, L. van; Que, I.; Luyten, G.P.M.; Beenakker, J.W.M. 2022
Purpose: To assess the effect of ocular anatomy and intraocular lens (IOL) design on negative dysphotopsia (ND).Setting: Department of Ophthalmology, Leiden University Medical Center, Leiden, the... Show morePurpose: To assess the effect of ocular anatomy and intraocular lens (IOL) design on negative dysphotopsia (ND).Setting: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.Design: Ray-tracing study based on clinical data.Methods: Ray-tracing simulations were performed to assess the effect of anatomical differences and differences in IOL design on the peripheral retinal illumination. To that end, eye models that incorporate clinically measured anatomical differences between eyes of patients with ND and eyes of pseudophakic controls were created. The anatomical differences included pupil size, pupil centration, and iris tilt. The simulations were performed with different IOL designs, including a simple biconvex IOL design and a more complex clinical IOL design with a convex-concave anterior surface. Both IOL designs were analyzed using a clear edge and a frosted edge. As ND is generally considered to be caused by a discontinuity in peripheral retinal illumination, this illumination profile was determined for each eye model and the severity of the discontinuity was compared between eye models.Results: The peripheral retinal illumination consistently showed a more severe discontinuity in illumination with ND-specific anatomy. This difference was the least pronounced, 8%, with the frosted edge clinical IOL and the most pronounced, 18%, with the clear edge biconvex IOL.Conclusions: These results show that small differences in the ocular anatomy or IOL design affect the peripheral retinal illumination. Therewith, they can increase the severity of ND by up to 18%. Copyright (c) 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS Show less
Background and Purpose: Three-dimensional (3D) Magnetic Resonance Imaging (MRI) is increasingly used to complement conventional two-dimensional ultrasound in the assessment of tumour dimension... Show moreBackground and Purpose: Three-dimensional (3D) Magnetic Resonance Imaging (MRI) is increasingly used to complement conventional two-dimensional ultrasound in the assessment of tumour dimension measurement of uveal melanoma. However, the lack of definitions of the 3D measurements of these tumour dimensions hinders further adaptation of MRI in ocular radiotherapy planning. In this study, we composed 3D MR-based definitions of tumour prominence and basal diameter and compared them to conventional ultrasound. Materials and methods: Tumours were delineated on 3DT2 and contrast-enhanced 3DT1 (T1gd) MRI for 25 pa-tients. 3D definitions of tumour prominence and diameter were composed and evaluated automatically on the T1gd and T2 contours. Automatic T1gd measurements were compared to manual MRI measurements, to auto-matic T2 measurements and to manual ultrasound measurements. Results: Prominence measurements were similar for all modalities (median absolute difference 0.3 mm). Auto-matic T1gd diameter measurements were generally larger than manual MRI, automatic T2 and manual ultra-sound measurements (median absolute differences of 0.5, 1.6 and 1.1 mm respectively), mainly due to difficulty defining the axis of the largest diameter. Largest differences between ultrasound and MRI for both prominence and diameter were found in anteriorly located tumours (up to 1.6 and 4.5 mm respectively), for which the tumour extent could not entirely be visualized with ultrasound. Conclusions: The proposed 3D definitions for tumour prominence and diameter agreed well with ultrasound measurements for tumours for which the extent was visible on ultrasound. 3D MRI measurements generally provided larger diameter measurements than ultrasound. In anteriorly located tumours, the MRI measurements were considered more accurate than conventional ultrasound. Show less
Rozendal, L.R.W.; Vught, L. van; Luyten, G.P.M.; Beenakker, J.W.M. 2022
SIGNIFICANCE There is a clinical need for a quantitative test to objectively diagnose negative dysphotopsia, especially because the diagnosis is generally assessed using patients' subjective... Show moreSIGNIFICANCE There is a clinical need for a quantitative test to objectively diagnose negative dysphotopsia, especially because the diagnosis is generally assessed using patients' subjective descriptions. In the search of a clinical test to objectify the shadow experienced in negative dysphotopsia, this study excludes static perimetry as suitable evaluation method. PURPOSE This study aimed to evaluate the value of static perimetry in the objective assessment and follow-up of negative dysphotopsia. METHODS Peripheral 60-4 full-threshold visual field tests were performed in 27 patients with negative dysphotopsia and 33 pseudophakic controls. In addition, 11 patients with negative dysphotopsia repeated the test after an intraocular lens exchange. Both the total peripheral visual field and the averaged peripheral visual field from 50 to 60 degrees eccentricity were compared between patients and controls, and pre-operatively and post-operatively in patients who had an intraocular lens exchange. RESULTS The peripheral visual fields from 30 to 60 degrees did not show significant differences between patients with negative dysphotopsia and pseudophakic controls. Analysis of the peripheral visual field from 50 to 60 degrees showed a median [Q1, Q3] of 20.0 [17.1, 22.5] dB in the negative dysphotopsia group compared with 20.1 [15.5, 21.3] dB in the control group (P = .43). Although 82% of patients treated with an intraocular lens exchange subjectively reported improvement of their negative dysphotopsia complaints post-operatively, there were no significant differences in their total peripheral visual field or averaged peripheral visual field from 50 to 60 degrees (P = .92). CONCLUSIONS Full-threshold static perimetry with a Goldmann size III stimulus up to 60 degrees eccentricity does not show significant differences between patients with negative dysphotopsia and pseudophakic controls or between measurements before and after intraocular lens exchange. Therefore, this type of static perimetry cannot be used as a quantitative objective test for diagnosis or follow-up of patients with negative dysphotopsia. Show less
Purpose: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not... Show morePurpose: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. Design: We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. Participants: A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). Methods: Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. Main Outcome Measures: Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. Results: Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. Conclusions: Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases. (C) 2021 by the American Academy of Ophthalmology. Show less
IMPORTANCE Highmyopia incidence and prevalence is increasing worldwide, and the visual burden caused bymyopia is expected to rise accordingly. Studies investigating the occurrence ofmyopic... Show moreIMPORTANCE Highmyopia incidence and prevalence is increasing worldwide, and the visual burden caused bymyopia is expected to rise accordingly. Studies investigating the occurrence ofmyopic complications in individuals of European ancestry with highmyopia are scarce, hampering insights into the frequency ofmyopic retinal complications in European individuals and their visual burden.OBJECTIVE To assess the frequency ofmyopic macular features in individuals of European ancestry with highmyopia.DESIGN, SETTING, AND PARTICIPANTS This cross-sectional analysis of the Dutch Myopia Study (MYST) and individuals with highmyopia from the Rotterdam Study (RS) included 626 patients with highmyopia (spherical equivalent of refractive error [SER] <=-6 diopters [D] or axial length [AL] >= 26 mm) who underwent an extensive ophthalmic examination including multimodal retinal imaging. In addition to this combination of a population-based cohort study and mix-based highmyopia study, a systematic literature review was also performed to compare findings with studies of individuals of Asian ancestry.EXPOSURES Highmyopia, age, and AL.MAIN OUTCOMES AND MEASURES Frequency ofmyopic macular and optic disc features: tessellated fundus, myopic macular degeneration (MMD), staphyloma, peripapillary intrachoroidal cavitation, peripapillary atrophy (PPA), and "plus" lesions (choroidal neovascularization, Fuchs spot, and lacquer cracks).RESULTS The mean (SD) SER of the combined study population (MYST and RS) was -9.9 (3.2) D; the mean (SD) age was 51.4 (15.1) years, and 387 (61.8%) were women. The prevalence of MMD was 25.9% and increased with older age (P for trend <.001), lower SER (odds ratio [OR], 0.70; 95% CI, 0.65-0.76; P <.001), and higher AL (OR, 2.53; 95% CI, 2.13-3.06; P <.001). Choroidal neovascularization or Fuchs spot was present in 2.7%(n = 17), both lesions in 0.3% (n = 2), and lacquer cracks in 1.4%(n = 9). Staphyloma, PPA, and MMD were highly prevalent in visual impaired and blind eyes (frequency was 73.9%[20 of 27], 90.5%[19 of 21], and 63.0%[17 of 27] of unilateral blind eyes for MMD, staphyloma, and PPA, respectively). Seven previous studies in Asian populations reported a variable MMD frequency ranging from 8.3% to 64%, but frequencies were similar for comparable risk profiles based on age and SER.CONCLUSIONS AND RELEVANCE In this cross-sectional study of a highlymyopic Dutch population of European ancestry, myopic retinal features were frequent; were associated with age, SER, and AL; and occurred in all visually severely impaired eyes. The absence of treatment options for most of these retinal complications emphasizes the need for effective strategies to prevent highmyopia. Show less
Marinkovic, M.; Pors, L.J.; Berg, V. van den; Peters, F.P.; Schalenbourg, A.; Zografos, L.; ... ; Horeweg, N. 2021
Simple Summary This study aims to assess cancer control and preservation of the eye and visual acuity after proton therapy abroad for eye melanoma. For this, medical files were reviewed of Dutch... Show moreSimple Summary This study aims to assess cancer control and preservation of the eye and visual acuity after proton therapy abroad for eye melanoma. For this, medical files were reviewed of Dutch uveal melanoma patients who were treated in Switzerland with proton therapy from 1987 to 2019. The tumours of these patients were too large and/or localised too close to the optic nerve to be treated with local plaque irradiation. There were 103 patients, of whom one had a uveal melanoma in both eyes. The tumours were relatively large and often localised around the central part of the retina. At five years after treatment, proton therapy had controlled the uveal melanomas of 94% of the patients and 81% had preserved their eye. Spread of the cancer beyond the eye was observed in 30% of the patients. Most patients (79%) became blind or had severe visual impairment after proton therapy; a small group of patients had mild or no visual impairment (17%). The size of the tumour, its localisation and the dose of proton therapy were important for the risk of decline in visual acuity. This study shows that proton therapy abroad for uveal melanoma is feasible and yields good results. Objective: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. Materials and Methods: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan-Meier's methodology and Cox proportional hazards models. Results: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6-26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. Conclusion: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy. Show less
Hassan, M.K.; Fleury, E.; Shamonin, D.; Fonk, L.G.; Marinkovic, M.; Jaarsma-Coes, M.G.; ... ; Stoel, B. 2021
Purpose: The optimal treatment strategy for uveal melanoma (UM) relies on many factors, the most important being tumor size and location. Building on recent developments in high-resolution 3D... Show morePurpose: The optimal treatment strategy for uveal melanoma (UM) relies on many factors, the most important being tumor size and location. Building on recent developments in high-resolution 3D ocular magnetic resonance imaging (MRI), we developed an automatic image-processing framework to create patient-specific eye models and to subsequently determine the full 3D tumor shape and size automatically.Methods and Materials: From 15 patients with UM, 3D inversion-recovery gradient-echo (T1-weighted) and 3D fat-suppressed spin-echo (T2-weighted) images were acquired with a 7T MRI scanner. First, the sclera and cornea were segmented from the T2 weighted image by mesh-fitting. The T1-and T2-weighted images were then coregistered. From the registered T1-weighted image, the lens, vitreous body, retinal detachment, and tumor were segmented. Fuzzy C-means clustering was used to differentiate the tumor from retinal detachments. The tumor model was verified and (if needed) edited by an ophthalmic MRI specialist. Subsequently, the prominence and largest basal diameter of the tumor were measured automatically based on the verified contours. These results were compared with manual assessments on the original images and with ultrasound measurements to show the errors in manual analysis.Results: The framework successfully created an eye model fully automatically in 12 cases. In these cases, a Dice similarity coefficient (mean surface distance) of 97.7%+/- 0.84% (0.17 +/- 0.11 mm) was achieved for the sclera, 96.8%+/- 1.05% (0.20 +/- 0.06 mm) for the vitreous body, 91.6%+/- 4.83% (0.15 +/- 0.06 mm) for the lens, and 86.0%+/- 7.4% (0.35 +/- 0.27 mm) for the tumor. The manual assessments deviated, on average, 0.39 +/- 0.31 mm in prominence and 1.7 +/- 1.22 mm in basal diameter from the automatic measurements.Conclusions: The described framework combined information from T1- and T2-weighted images to accurately determine tumor boundaries in 3D. The proposed process may have a direct effect on clinical workflow, as it enables an accurate 3D assessment of tumor dimensions, which directly influences therapy selection. (C) 2021 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. Show less
Objective To establish a good method to determine the retinal shape from MRI using three-dimensional (3D) ellipsoids as well as evaluate its reproducibility.Methods and analysis The left eyes of 31... Show moreObjective To establish a good method to determine the retinal shape from MRI using three-dimensional (3D) ellipsoids as well as evaluate its reproducibility.Methods and analysis The left eyes of 31 volunteers were imaged using high-resolution ocular MRI. The 3D MR-images were segmented and ellipsoids were fitted to the resulting contours. The dependency of the resulting ellipsoid parameters on the evaluated fraction of the retinal contour was assessed by fitting ellipsoids to 41 different fractions. Furthermore, the reproducibility of the complete procedure was evaluated in four subjects. Finally, a comparison with conventional two-dimensional (2D) methods was made.Results The mean distance between the fitted ellipsoids and the segmented retinal contour was 0.03 +/- 0.01 mm (mean +/- SD) for the central retina and 0.13 +/- 0.03 mm for the peripheral retina. For the central retina, the resulting ellipsoid radii were 12.9 +/- 0.9, 13.7 +/- 1.5 and 12.2 +/- 1.2 mm along the horizontal, vertical and central axes. For the peripheral retina, these radii decreased to 11.9 +/- 0.6, 11.6 +/- 0.4 and 10.4 +/- 0.7 mm, which was accompanied by a mean 1.8 mm posterior shift of the ellipsoid centre. The reproducibility of the ellipsoid fitting was 0.3 +/- 1.2 mm for the central retina and 0.0 +/- 0.1 mm for the peripheral retina. When 2D methods were used to fit the peripheral retina, the fitted radii differed a mean 0.1 +/- 0.1 mm from the 3D method.Conclusion An accurate and reproducible determination of the 3D retinal shape based on MRI is provided together with 2D alternatives, enabling wider use of this method in the field of ophthalmology. Show less
Purpose To evaluate the magnetic resonance imaging (MRI) characteristics of uveal melanoma (UM), to compare them with fundoscopy and ultrasound (US), and to validate them with histopathology.... Show morePurpose To evaluate the magnetic resonance imaging (MRI) characteristics of uveal melanoma (UM), to compare them with fundoscopy and ultrasound (US), and to validate them with histopathology. Methods MR images from 42 UM were compared with US and fundoscopy, and on 14 enucleated cases with histopathology. Results A significant relationship between the signal intensity on T1 and pigmentation on histopathology was found (p=0.024). T1 hyperintense UM were always moderately or strongly pigmented on histopathology, while T1-hypointense UM were either pigmented or non-pigmented. Mean apparent diffusion coefficient (ADC) of the UM was 1.16 +/- 0.26 x 10(-3) mm(2)/s. Two-thirds of the UM had a wash-out and the remaining a plateau perfusion time-intensity curve (TIC). MRI was limited in evaluating the basal diameter of flat tumors. US tends to show larger tumor prominence (0.5mm larger, p=0.008) and largest basal diameter (1.4mm larger, p<0.001). MRI was good in diagnosing ciliary body involvement, extrascleral extension, and optic nerve invasion, but limited on identifying scleral invasion. An increase of tumor prominence was associated with lower ADC values (p=0.030) and favored a wash-out TIC (p=0.028). An increase of tumor ADC correlated with a plateau TIC (p=0.011). Conclusions The anatomical and functional MRI characteristics of UM were comprehensively assessed. Knowing the MRI characteristics of UM is important in order to confirm the diagnosis and to differentiate UM from other intra-ocular lesions and because it has implications for treatment planning. MRI is a good technique to evaluate UM, being only limited in case of flat tumors or on identifying scleral invasion. Show less
Purpose To describe and present results after a technique for cataract surgery combined with explantation of an iris-fixated phakic intraocular lens (IF-pIOL).Methods The medical records of all... Show morePurpose To describe and present results after a technique for cataract surgery combined with explantation of an iris-fixated phakic intraocular lens (IF-pIOL).Methods The medical records of all patients, who had undergone cataract surgery combined with IF-pIOL explantation and subsequent implantation of a posterior chamber IOL by the Single Incision Technique (SIT), were reviewed. Data collection included preoperative and postoperative corrected distance visual acuity (CDVA), manifest refraction, and endothelial cell density (ECD) up to a follow-up time of 24 months.Results Fifty myopic eyes (34 patients) and 9 hyperopic eyes (6 patients) had undergone a SIT procedure mainly because of cataract (67%). Postoperative CDVA improved in both the myopic eyes to 0.16 +/- 0.37 logMAR, as in the hyperopic eyes to - 0.10 +/- 0.55 logMAR with no eyes having loss of Snellen lines. Mean postoperative spherical equivalent was - 0.34 +/- 0.72 D and - 0.10 +/- 0.55 D, respectively. ECD loss 6 months after surgery was 5% and remained stable thereafter.Conclusion SIT for combined phacoemulsification and IF-pIOL removal yields good visual and refractive results and is a safe procedure in regard to ECD loss. The technique has advantages over the conventional procedure and is easy to perform. Show less
Background Magnetic resonance imaging (MRI) is increasingly being used in the diagnosis and treatment planning of uveal melanoma (UM), the most common primary intraocular tumor. Initially, 7 T MRI... Show moreBackground Magnetic resonance imaging (MRI) is increasingly being used in the diagnosis and treatment planning of uveal melanoma (UM), the most common primary intraocular tumor. Initially, 7 T MRI was primarily used, but more recently these techniques have been translated to 3 T, as it is more commonly available. Purpose Compare the diagnostic performance of 3 T and 7 T MRI of UM. Study Type Prospective. Population Twenty-seven UM patients (19% female). Field Strength/Sequence 3 T: T1- and T2-weighted three-dimensional (3D) spin echo (SE) and multi-slice (MS) SE, 7 T: T1-weighted 3D gradient echo (GE), T2-weighted 3D SE and MS SE, 3 T and 7 T GE dynamic contrast-enhanced. T1 weighted images: acquired before and after Gadolinium (Gd) administration. Assessment For all sequences, scan and diagnostic quality was quantified using a 5-point Likert scale. Signal intensities on T1 and T2 relative to choroid and eye muscle respectively were assessed as well as the tumor prominence. Finally, the perfusion time-intensity curves (TICs) were classified as plateau, progressive, or wash-out. Statistical Tests Image quality scores were compared between both field strengths using Wilcoxon signed-rank and McNemar tests. Paired t-tests and Bland-Altman were used for comparing tumor prominences. P < 0.05 was considered statistically significant. Results Image quality was comparable between 3 T and 7 T, for 3DT1, 3DT2, 3DT1Gd (P = 0.86; P = 0.34; P = 0.78, respectively) and measuring tumor dimensions (P = 0.40). 2DT1 and 2DT2 image quality were rated better on 3 T compared to 7 T. Most UM had the same relative signal intensities at 3 T and 7 T on T1 (17/21) and T2 (13/17), and 16/18 diagnostic TICs received the same classification. Tumor prominence measurements were similar between field strengths (95% confidence interval: -0.37 mm to 0.03 mm, P = 0.097). Data Conclusion Diagnostic performance of the evaluated 3 T protocol proved to be as capable as 7 T, with the addition of 3 T being superior in assessing tumor growth into nearby anatomical structures compared to 7 T. Level of Evidence 2 Technical Efficacy Stage 3 Show less
Objective Dynamic contrast enhanced (DCE)-MRI is currently not generally used for intraocular masses as lesions are small, have an inhomogeneous T-1 and the eye is prone to motion. The aim of this... Show moreObjective Dynamic contrast enhanced (DCE)-MRI is currently not generally used for intraocular masses as lesions are small, have an inhomogeneous T-1 and the eye is prone to motion. The aim of this paper is to address these eye-specific challenges, enabling accurate ocular DCE-MRI. Materials & methods DCE-MRI of 19 uveal melanoma (UM) patients was acquired using a fat-suppressed 3D spoiled gradient echo sequence with TWIST (time-resolved angiography with stochastic trajectories sequence). The analysis consisted of a two-step registration method to correct for both head and eye motion. A T-1 map was calculated to convert signal intensities to concentrations. Subsequently, the Tofts model was fitted voxel wise to obtain K-trans and v(e). Results Registration significantly improved the concentration curve quality (p < 0.001). The T-1 of melanotic lesions was significantly lower than amelanotic lesions (888 ms vs 1350 ms, p = 0.03). The average achieved B-1(+) in the lesions was 91%. The average K-trans was 0.46 min(-1) (range 0.13-1.0) and the average v(e) was 0.22 (range 0.10-0.51). Conclusion Using this eye-specific analysis, DCE of intraocular masses is possible which might aid in the diagnosis, prognosis and follow-up of UM. Show less
Souri, Z.; Wierenga, A.P.A.; Kroes, W.G.M.; Velden, P.A. van der; Verdijk, R.M.; Eikmans, M.; ... ; Jager, M.J. 2021
Simple Summary Uveal melanoma (UM) is a rare type of intraocular malignancy, which often gives rise to metastases. While treatment with immune checkpoint inhibitors is often effective in the... Show moreSimple Summary Uveal melanoma (UM) is a rare type of intraocular malignancy, which often gives rise to metastases. While treatment with immune checkpoint inhibitors is often effective in the treatment of cutaneous melanoma metastases, it is hardly effective in the case of UM metastases. Lymphocyte-activation gene 3 (LAG3) is a recently recognized immune checkpoint; we determined the distribution of LAG3 expression and its ligands in three sets of primary UM. High-risk UM (epithelioid cell type, loss of chromosome 3/BAP1 staining) had a higher expression of LAG3 and its ligands, which correlated with the presence of infiltrating immune cells. We concluded that not only LAG3 but also its ligands Galectin-3 and HLA class II are especially expressed in high-risk UM and may be a target for adjuvant immunotherapy in UM. Uveal melanoma (UM) is a rare ocular malignancy which originates in the uveal tract, and often gives rise to metastases. Potential targets for immune checkpoint inhibition are lymphocyte-activation gene 3 (LAG3) and its ligands. We set out to analyse the distribution of these molecules in UM. The expression of mRNA was determined using an Illumina array in 64 primary UM from Leiden. The T lymphocyte fraction was determined by digital droplet PCR. In a second cohort of 15 cases from Leiden, mRNA expression was studied by Fluidigm qPCR, while a third cohort consisted of 80 UM from TCGA. In the first Leiden cohort, LAG3 expression was associated with the presence of epithelioid cells (p = 0.002), monosomy of chromosome 3 (p = 0.004), and loss of BAP1 staining (p = 0.001). In this Leiden cohort as well as in the TCGA cohort, LAG3 expression correlated positively with the expression of its ligands: LSECtin, Galectin-3, and the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP (all p < 0.001). Furthermore, ligands Galectin-3 and HLA class II were increased in monosomy 3 tumours and the expression of LAG3 correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, HLA-A and HLA-B expression: all p < 0.001). High expression levels of LAG3 (p = 0.01), Galectin-3 (p = 0.001), HLA-DRA1 (p = 0.002), HLA-DQA1 (p = 0.04), HLA-DQB2 (p = 0.03), and HLA-DPA1 (p = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands Galectin-3 and HLA class II strongly correlates with LAG3 expression and all are increased in UM with Monosomy 3/BAP1 loss. The distribution suggests a potential benefit of monoclonal antibodies against LAG3 or Galectin-3 as adjuvant treatment in patients with high-risk UM. Show less
