Survival and Quality of Life after Isolated Hepatic Perfusion with Melphalan as a Treatment for Uveal Melanoma Liver Metastases - Final Results from the Phase III Randomized Controlled Trial SCANDIUM.

OBJECTIVE: To investigate overall survival (OS) and health-related quality of life (HRQOL) of first-line isolated hepatic perfusion (IHP) compared to best alternative care (BAC) for patients with uveal melanoma liver metastases. SUMMARY BACKGROUND DATA: Approximately half of patients with uveal melanoma develop metastatic disease, most commonly in the liver and systemic treatment options are limited. Isolated hepatic perfusion (IHP) is a locoregional therapy with high response rates but with unclear effect on overall survival (OS). METHODS: In this phase III randomized controlled multicenter trial (the SCANDIUM trial) patients with previously untreated isolated uveal melanoma liver metastases were included between 2013-2021, with at least 24 months of follow-up. The planned accrual was 90 patients randomized 1:1 to receive a one-time treatment with IHP or BAC. Crossover to IHP was not allowed. The primary endpoint was the 24-month OS rate, with the hypothesis of a treatment effect leading to a 50% OS rate in the IHP group compared to 20% in the control group. HRQOL was measured by the EuroQol 5-domains 3-levels (EQ-5D-3L) questionnaire over 12 months. RESULTS: The intention-to-treat (ITT) population included 87 patients randomized to the IHP group (43 patients; 41 [89%] received IHP) or the control group (44 patients). The control group received chemotherapy (49%), immunotherapy (39%), or localized interventions (9%). In the ITT population, the median PFS was 7.4 months in the IHP group compared with 3.3 months in the control group, with a hazard ratio of 0.21 (95% CI, 0.12-0.36). The 24-month OS rate was 46.5% in the IHP group versus 29.5% in the control group (P=0.12). The median OS was 21.7 months versus 17.6 months, with a hazard ratio of 0.64 (95% CI, 0.37-1.10). EQ-5D-3L showed a sustained high health status for the IHP group over 12 months, compared to a deteriorating trend in the control group. CONCLUSIONS: For patients with liver metastases from uveal melanoma, IHP offers high response rates translating to a benefit in PFS including a trend of better HRQOL compared to the control group. However, the primary endpoint of OS at 24 months was not met.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

Genetic Status Affects Disease-Specific Mortality But Not the Incidence of Local Recurrence in Patients with Uveal Melanoma.

PURPOSE: Increased disease-specific mortality has been observed among patients with local recurrence (LR) from uveal melanoma (UM), but the underlying mechanism is unknown. The purpose of this study was to determine if copy number alterations of chromosomes 3 and/or 8q, at the time of diagnosis, increase the incidence of LR and if disease-specific mortality among patients with LR depends on the chromosome status of the primary tumor. DESIGN: Retrospective cohort study. PARTICIPANTS: The study included 239 consecutive patients with primary UM (choroidal or ciliary body) treated with Ruthenium-106 (Ru-106) brachytherapy from January 2009 to December 2019 at a single national referral center. METHODS: Cox regression modeling and Kaplan-Meier analyses were used to assess the effect of the status of chromosomes 3 and 8q on the incidence of LR and disease-specific mortality after the event of LR. Multistate models were used to illustrate the probabilities over time of patients being alive and disease-free, alive with LR, dead from UM metastases, or dead from other causes split on the status of chromosomes 3 and 8q. MAIN OUTCOME MEASURES: Incidence of LR and disease-specific mortality. RESULTS: Local recurrence was observed in 42 patients (16%). Overall incidence of LR was not affected by aberrations of chromosomes 3 and/or 8q (P = 0.87). Although LR occurred earlier in patients with aberrations of chromosomes 3 and/or 8q compared with patients with a normal copy number of chromosomes 3 and 8q, the median time from primary diagnosis to LR was 1.6 years (interquartile range [IQR], 1.0-2.0) and 3.2 years (IQR, 2.1-5.0), respectively. Cox regression found LR to be an independent risk factor for disease-specific mortality (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-5.0) among all patients, but multistate models demonstrated a low risk of disease-specific death among patients with normal chromosomes 3 and 8q status, even after an LR. CONCLUSIONS: Copy number alterations of chromosome 3 and/or 8q in the primary UM did not increase the overall incidence of LR. However, the development of an LR enhanced the risk of disease-specific mortality among patients with copy number alterations of chromosomes 3 and/or 8q. Even after an LR, disease-specific mortality remained low among patients with normal copy numbers of chromosomes 3 and 8q. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Controlled Subretinal Injection Pressure Prevents Damage in Pigs.

INTRODUCTION: Administration of retinal gene and stem cell therapy in patients with retinal degenerative diseases is in many cases dependent on a subretinal approach. It has been indicated that manual subretinal injection is associated with outer retinal damage, which may be explained by a high flow rate in the injection cannula. In the present porcine study, we evaluated flow-related retinal damage after controlled subretinal injection at different flow rates. METHODS: The flow rate through a 41G cannula was estimated at different injection pressures (6-48 pounds per square inch [PSI]) in an in vitro setup. A linear correlation between the flow rate and injection pressure was found from 6 to 32 PSI. In full anesthesia, 12 pigs were vitrectomized and received a controlled subretinal injection of 300 µL balanced saline solution at injection pressures of 14, 24, and 32 PSI (four in each group). Prior to surgery and 2 and 4 weeks after surgery, the eyes were examined by multifocal electroretinogram (mfERG) and fundus photographs. At the end of follow-up, the eyes were enucleated for histology. RESULTS: The in vitro flow study determined that the flow in a 41G cannula shifts from laminar to turbulent at 32 PSI and that the manual injection flow is turbulent. In the porcine study, we showed a significant difference in retinal pigment epithelium (RPE) damage between the three pressure groups (p = 0.0096). There was no significant difference in damage to the outer retina (p = 0.1526), but the high-pressure group (32 PSI) had the most outer retinal damage. The middle-pressure group (24 PSI) showed minimum retinal damage. There was no significant change in the mfERG ratios during follow-up. DISCUSSION/CONCLUSION: This study indicates that an injection pressure at approximately 24 PSI might be safe for subretinal delivery. Retinal damage at low injection pressures may be explained by mechanical damage to the RPE due to prolonged needle time in the subretinal space, while retinal damage at high pressures can be related to high flow in the injection cannula. Controlled subretinal injection pressure of 24 PSI showed minimum mechanical- and flow-related damage to the porcine retina.

Outcome Measures of New Technologies in Uveal Melanoma: Review from the European Vision Institute Special Interest Focus Group Meeting.

Uveal Melanoma (UM) is the most common primary intra-ocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma", addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's wellbeing. This review highlights the meeting's presentations in the context of the published literature.

Dose-Response and Normal Tissue Complication Probabilities after Proton Therapy for Choroidal Melanoma.

PURPOSE: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT). DESIGN: Retrospective study from single, large referral center. PARTICIPANTS: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients. METHODS: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes. MAIN OUTCOME MEASURES: Dose-response relationship for VA deterioration and late complications. RESULTS: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland. CONCLUSIONS: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures.

COMPARATIVE EFFECTIVENESS OF PROTON BEAM VERSUS PHOTODYNAMIC THERAPY TO SPARE THE VISION IN CIRCUMSCRIBED CHOROIDAL HEMANGIOMA.

PURPOSE: The aim of this study was to compare the functional and anatomical effectiveness of photodynamic therapy (PDT) versus proton beam therapy (PBT) in a real-life setting for the treatment of circumscribed choroidal hemangioma. METHODS: A total of 191 patients with a diagnosis of circumscribed choroidal hemangioma and treated by PBT or PDT were included for analyses. RESULTS: The 119 patients (62.3%) treated by PDT were compared with the 72 patients treated by PBT. The final best-corrected visual acuity did not differ significantly between the two groups (P = 0.932) and final thickness was lower in the PBT compared with the PDT group (P = 0.001). None of the patients treated by PBT needed second-line therapy. In comparison, 53 patients (44.5%) initially treated by PDT required at least one other therapy and were associated with worse final best-corrected visual acuity (P = 0.037). In multivariate analysis, only an initial thickness greater than 3 mm remained significant (P = 0.01) to predict PDT failure with an estimated odds ratio of 2.72, 95% confidence interval (1.25-5.89). CONCLUSION: Photodynamic therapy and PBT provide similar anatomical and functional outcomes for circumscribed choroidal hemangioma ≤3 mm, although multiple sessions are sometimes required for PDT. For tumors >3 mm, PBT seems preferable because it can treat the tumor in only 1 session with better functional and anatomical outcomes.

Tumour control probability after Ruthenium-106 brachytherapy for choroidal melanomas.

Purpose: Ruthenium-106 (Ru-106) brachytherapy is a common eye-preserving treatment for choroidal melanomas. However, a dose-response model describing the relationship between the actual delivered tumour dose and tumour control has, to the best of our knowledge, not previously been quantified for Ru-106 brachytherapy; we aimed to rectify this.Material and methods: We considered consecutive patients with primary choroidal melanomas, treated with Ru-106 brachytherapy (2005-2014). Dosimetric plans were retrospectively recreated using 3D image-guided planning software. Pre-treatment fundus photographies were used to contour the tumour; post-treatment photographies to determine the accurate plaque position. Patient and tumour characteristics, treatment details, dose volume histograms, and clinical outcomes were extracted. Median follow-up was 5.0 years. The relationship between tumour dose and risk of local recurrence was examined using multivariate Cox regression modelling, with minimum physical tumour dose (D99%) as primary dose metric.Results: We included 227 patients with median tumour height and largest base dimension of 4 mm (range 1-12, IQR 3-6) and 11 mm (range 4-23, IQR 9-13). The estimated 3 year local control was 82% (95% CI 77-88). Median D99% was 105 Gy (range 6-783, IQR 65-138); this was the most significant factor associated with recurrence (p < .0001), although tumour height, combined TTT and Ru-106 brachytherapy, and sex were also significant. The hazard ratio (HR) for a 10 Gy increase in D99% was 0.87 (95% CI 0.82-0.93). Using biological effective dose in the model resulted in no substantial difference in dose dependence estimates. Robustness cheques with D1-99% showed D99% to be the most significant dose metric for local recurrence.Conclusion: The minimum tumour dose correlated strongly with risk of tumour recurrence, with 100 Gy needed to ensure at least 84% local control at 3 years.

Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know.

Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients.

Bruch's membrane allows unhindered passage of up to 2 µm latex beads in an in vivo porcine model.

PURPOSE: It has been proposed that changes in the permeability of Bruch's membrane play a role in the pathogenesis of age-related macular degeneration (AMD). This paper investigates, in an in vivo porcine model, the migration of fluorescent latex beads across the Bruch's membrane after subretinal injection. METHODS: Forty-one healthy eyes of 33 three-month-old domestic pigs received a subretinal injection of 0.5, 1.0, 2.0, or 4.0 µm fluorescent latex beads. Between three hours and five weeks after injection evaluations were performed with fundus photographs and histology. Fluorescent beads were identified in unstained histologic sections using the rhodamine filter with the light microscope. RESULTS: The fluorescent latex beads relocated from the subretinal space. Intact beads up to 2.0 µm were found in the choroid, sclera, and extrascleral space. The smaller beads were also found inside choroidal and extrascleral blood vessels. In contrast, the larger beads of 4.0 µm did not pass the Bruch's membrane. CONCLUSION: Subretinally implanted beads up to 2.0 µm pass the Bruch's membrane intact and cross the blood-ocular barrier. The intact beads are found in the choroid, sclera and inside blood vessels. The results give reason to consider the role of subretinal clearance and passage of Bruch's membrane in the development of AMD.

Adrenal Suppression in Infants Treated with Topical Ocular Glucocorticoids.

PURPOSE: To analyze the incidence of adrenal suppression and the glucocorticoid (GC) dose per kilogram body weight given in infants treated with standard protocol for topical ophthalmic GCs after congenital cataract surgery. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: All children younger than 2 years of age who underwent operation for congenital cataract between January 2011 and May 2015 in 1 center. METHODS: Patient charts were reviewed to collect data on results and timing of a standard corticotropin (adrenocorticotropic hormone [ACTH]) stimulation test and GC dose per kilogram body weight. MAIN OUTCOME MEASURES: Incidence of adrenal suppression in children tested on GC treatment. Glucocorticoid dose per kilogram body weight. RESULTS: Among 26 consecutive infants, 15 (58%) were tested while they were still on GC treatment. Ten of these 15 infants (67%) had adrenal suppression, 2 of whom had obvious clinical signs of Cushing's syndrome and 1 of whom had signs of Addisonian crises during general anesthesia. Eleven of the 26 infants (42%) were tested at a median time of 21 days (range, 6-89) after treatment cessation, and they all had normal test results. Children with suppressed adrenal function had received cumulative GC doses per body weight that were significantly higher the last 5 days before testing compared with children with normal test results. Infants with adrenal suppression were treated with hydrocortisone replacement therapy. Adrenal function recovered after a median of 3.1 months (range, 2.3 months to 2.3 years). CONCLUSIONS: Two thirds of the infants tested during treatment with a standard GC protocol after congenital cataract surgery showed adrenal suppression. There was a significant association between the cumulative daily dose of GCs and the test result. Because adrenal suppression is a serious but treatable condition, we recommend a systematic assessment of adrenal function in infants treated with doses of topical ocular GCs comparable to our regimen and careful evaluations of other treatment regimens.

Long-Term Metastatic Risk after Biopsy of Posterior Uveal Melanoma.

PURPOSE: Biopsy of posterior uveal melanoma continues to be intensely debated in terms of the clinical benefits and safety profile. Although several studies have reported a low frequency of ocular complications after tumor biopsy, the potential long-term risk of iatrogenic dissemination remains unresolved. The purpose of this study was to assess the risk of metastatic disease after biopsy of posterior uveal melanoma. DESIGN: Retrospective nationwide cohort study linking clinical and histopathologic records to pathology, cancer, and mortality registries. PARTICIPANTS: All patients with posterior uveal melanoma treated in Denmark between January 1985 and December 2016. METHODS: For each patient, we recorded detailed information on age, gender, tumor characteristics, and diagnostic and therapeutic measures, including tumor biopsy, if any, and the primary treating hospital. Absolute risk of melanoma-specific death was presented by cumulative incidence curves that accounted for competing risks. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and melanoma-specific mortality of patients who underwent biopsy during primary treatment compared with nonbiopsied patients through November 1, 2017. Fine and Gray risk regression was used as a sensitivity analysis to evaluate the impact of competing risks. MAIN OUTCOME MEASURES: All-cause and melanoma-specific mortality. RESULTS: Among 1637 patients, 567 (35%) underwent biopsy during primary treatment. At diagnosis, biopsied patients exhibited better prognostic characteristics, including smaller tumor size (P < 0.001) and younger age (P < 0.001), than nonbiopsied patients. In the adjusted analyses, we observed no apparent differences in all-cause mortality (HR, 1.07; 95% CI, 0.89-1.26; P = 0.47) or melanoma-specific mortality (HR, 1.11; 95% CI, 0.89-1.39; P = 0.35) among biopsied patients compared with nonbiopsied patients. CONCLUSIONS: All-cause and melanoma-specific mortality after primary treatment were similar among biopsied and nonbiopsied patients with posterior uveal melanoma. Our findings do not support an increased metastatic risk after intraocular tumor biopsy.

Repeated subretinal surgery and removal of subretinal decalin is well tolerated - evidence from a porcine model.

PURPOSE: Subretinal perfluorocarbon liquid (PFCL) is a serious complication that can occur after retinal detachment repair. It is possible to remove the PFCL surgically, but retinal damage related to the procedure is unknown. Also, increasing interest in subretinal treatment makes it relevant to examine the functional and morphological consequences of repeated subretinal manipulation. We hypothesized that PFCL in a porcine model can be injected in the subretinal space and removed with minimal effect on retinal structure and function. METHODS: The left eyes of ten healthy three-month-old female domestic pigs were included. Multifocal electroretinograms (mfERG) were recorded before surgery. Following vitrectomy, a PFCL bleb (decalin) was injected subretinally using a 41G cannula. After 14 days the decalin was removed through a 41G cannula in combination with a 2 ml syringe and an intermediate flexible tube. Two weeks after removal, a control mfERG was recorded, the pigs were enucleated and sacrificed and eyes were examined histologically. All statistics were carried out with a paired t-test in SAS Enterprise Guide 7.1® (SAS Institute Inc., Cary, NC, USA). RESULTS: There was no significant difference in mfERG amplitude ratio (left/right eye) between baseline and recordings two weeks after removal of decalin (P1 (M = 0.26, SD = 0.80, p = 0.39), second order kernel (M = -0.18, SD = 0.86, p = 0.57), Direct Response (M = 0.39, SD = 0.61, p = 0.12) or Induced Component (M = -0.03, SD = 0.40, p = 0.80)). Histologically, the photoreceptor outer segments were minimally affected. Otherwise the retina was normal 14 days after removal of decalin. In four pigs the subretinal decalin displaced inferiorly and was no longer accessible for removal. CONCLUSION: Subretinal decalin can be removed within 14 days without lasting retinal damage. Decalin is a heavy liquid where the risk of displacement is high. Future studies using PFCLs to control duration of an experimental retinal separation should focus on PFCLs that are isodense to the vitreus body.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN: Retrospective, multicenter observational study. PARTICIPANTS: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Update on simulation-based surgical training and assessment in ophthalmology: a systematic review.

TOPIC: This study reviews the evidence behind simulation-based surgical training of ophthalmologists to determine (1) the validity of the reported models and (2) the ability to transfer skills to the operating room. CLINICAL RELEVANCE: Simulation-based training is established widely within ophthalmology, although it often lacks a scientific basis for implementation. METHODS: We conducted a systematic review of trials involving simulation-based training or assessment of ophthalmic surgical skills among health professionals. The search included 5 databases (PubMed, EMBASE, PsycINFO, Cochrane Library, and Web of Science) and was completed on March 1, 2014. Overall, the included trials were divided into animal, cadaver, inanimate, and virtual-reality models. Risk of bias was assessed using the Cochrane Collaboration's tool. Validity evidence was evaluated using a modern validity framework (Messick's). RESULTS: We screened 1368 reports for eligibility and included 118 trials. The most common surgery simulated was cataract surgery. Most validity trials investigated only 1 or 2 of 5 sources of validity (87%). Only 2 trials (48 participants) investigated transfer of skills to the operating room; 4 trials (65 participants) evaluated the effect of simulation-based training on patient-related outcomes. Because of heterogeneity of the studies, it was not possible to conduct a quantitative analysis. CONCLUSIONS: The methodologic rigor of trials investigating simulation-based surgical training in ophthalmology is inadequate. To ensure effective implementation of training models, evidence-based knowledge of validity and efficacy is needed. We provide a useful tool for implementation and evaluation of research in simulation-based training.

Late surgical complications to endophthalmitis after cataract surgery in the post-EVS era.

BACKGROUND: To compare the risk of surgical complications after primary surgical intervention for postoperative endophthalmitis after cataract surgery (PE) in cases that underwent a pars plana vitrectomy (PPV) or a vitreous tap (VT) in Denmark in the calendar period 1 January 2000 to 30 June 2011. METHODS: Retrospective, register- and chart-based study. RESULTS: A total of 121 PE cases were identified and followed up to 12.8 years. The overall risk of surgical complications in PE cases that underwent a PPV and a VT was 24.2 and 36.7 %, respectively. This difference was non-statistically significant (p = 0.18). In all, 9.9 % of the PE cases had more than one surgical complication, and 97 % of the primary surgical complications occurred within the first 5 months. There was no statistically significant difference in the risk of retinal detachment (p = 0.45), surgery for PE (p = 0.22), intraocular lens removal (p = 0.19), or removal of the eye (p = 0.69) between the two groups. PE cases that underwent a VT had a statistically significantly higher risk of surgery for vitreous opacities (p = 0.047) compared to a PPV. CONCLUSIONS: In all, 27.3 % of all cases developed a surgical complication after primary surgical intervention for PE. If a PE case did not have a surgical complication within the first 5 months, it was highly unlikely that a new surgical complication would occur. A VT was not associated with a statistically significantly higher overall risk of surgical complications compared to a PPV.

A nationwide study on the incidence of rhegmatogenous retinal detachment in Denmark, with emphasis on the risk of the fellow eye.

PURPOSE: To estimate the risk of developing rhegmatogenous retinal detachment (RRD) in the fellow eye in patients with RRD in the first eye and to identify potential risk factors. METHODS: We used the Danish National Patient Registry to identify all surgeries performed for RRD in Denmark in the period from January 2000 to July 2011. RESULTS: In 11,451 cases of RRD in the study period, 8,553 cases in 8,081 patients were identified as primary RRD with an annual incidence of 13.7 per 100,000 citizens. There was a significant increase in the number of cases with RRD during the study period that was mainly explained by an increase of cataract surgeries. Four hundred and seventy-one of 7,941 patients with primary RRD on one eye and no other previous eye disease developed an additional RRD in the fellow eye with an overall incidence of 1% per year. Cox analysis revealed male gender, surgery on the lens, and young age as significant risk factors (P < 0.0001). CONCLUSION: Patients with RRD on the first eye have a 100 times greater risk of developing RRD on the second eye, and the risk increases with male gender and surgery on the lens but decreases with age.

Preoperative Positioning and Progression of Fovea-on Retinal Detachments.

PURPOSE: To study the relationship between positioning and rhegmatogenous retinal detachment (RRD) progression before surgery in patients with a fovea-on RRD. DESIGN: Prospective, single-cohort study. SUBJECTS: Patients with fovea-on RRD admitted to hospital for bedrest before surgical treatment were recruited. METHODS: Primary outcome was the shortest distance from the foveal center to the retinal detachment border on OCT. Secondary outcomes were measured with a head-mounted positioning sensor and included measures of head movement (linear acceleration and angular velocity) as well as measures of positioning regimen compliance. MAIN OUTCOME MEASURES: Distance from the fovea to the retinal detachment border. RESULTS: Overall, 50 patients with fovea-on positioned before RRD repair. One patient (1/50, 2%) progressed from fovea-on to fovea-off. Of the positioning measures, angular velocity demonstrated the strongest correlation with RRD border movement, whereas measures of positioning compliance showed nonsignificant correlation. After defining 3 movement groups: stable, intermediate, and mobile RRDs, we found that a doubling of head movement (angular velocity) correlated with a median RRD border progression of -6 µm/h, -75 µm/h, and -219 µm/h in the 3 groups, respectively. CONCLUSIONS: Rhegmatogenous retinal detachment border movement is correlated to angular velocity of the head, whereas compliance with our current positioning regimen does not have a significant impact on RRD border movement. Not all RRDs progress rapidly toward the fovea, but those that do seem to be highly influenced by head movement. For limiting RRD progression, a reduced movement positioning regimen may be superior to our current gravity-based approach. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Outcome of combined cataract surgery and iris prosthesis implantation in iris melanoma patients previously treated with iridocyclectomy: A national retrospective non-comparative case series.

PURPOSE: To examine complications, visual outcomes, photic patient-reported symptoms, corneal morphology, IOL tilt, and intraocular pressure after implantation of an intraocular lens (IOL) and iris prosthesis (IP) following iridocyclectomy. METHODS: Patients with previous iridocyclectomy treated with an IOL and IP at the Copenhagen University Hospital Rigshospitalet between 2007 and 2018 were included in this national retrospective non-comparative case series. The assessment encompassed BCVA, PRO questionnaire, corneal topography, and anterior segment OCT. RESULTS: 45 patients were included. Eight of 45 patients were previously treated with ruthenium-106 brachytherapy in conjunction with iridocyclectomy. Six of 45 patients developed endothelial dysfunction four of whom had received ruthenium-106 brachytherapy. Five of 45 patients had subluxation of the IOL/IP complex due to incomplete zonula apparatus. BCVA improved for all patients after lens surgery. 26 patients participated in the invited follow-up examination. 19 of 26 (73%) reported none or mild photic symptoms after IP instalment. Five (19%) reported ongoing severe photic symptoms. The corneal astigmatism significantly increased after iridocyclectomy but did not change after lens surgery. CONCLUSIONS: Implantation of an IOL and IP is a safe procedure, alleviating photic symptoms in most patients. It comes with higher risk of complications due to a more demanding procedure and larger surgical traumas from previous treatments. Ruthenium-106 brachytherapy increases the complication risk. Corneal astigmatism is induced by iridocyclectomy but does not change after lens surgery.

Wound Healing in a Porcine Model of Retinal Holes.

Purpose: To investigate retinal wound healing, we created a new porcine model of retinal hole and identified the cells involved in hole closure. Methods: Sixteen landrace pigs underwent vitrectomy, and a subretinal bleb was created before cutting a retinal hole using a 23G vitrector. No tamponade was used. Before surgery and one, two, and four weeks after surgery, the eyes were examined by optical coherence tomography and color fundus photos. At the end of follow-up, the eyes were enucleated for histology. Tissue sections of 5 µm were prepared for hematoxylin-eosin staining and immunohistochemical analysis with antibodies to retinal glial and epithelial cells. Results: Retinal holes below 1380 µm in diameter closed spontaneously within four weeks, whereas larger holes remained open. Hole closure was mediated by central movement of the edges of the hole and in most cases the formation of a gliotic plug. Fluorescence microscopy revealed that the plug consisted of cells positive for glial fibrillary acidic protein, indicating the presence of macroglial cell types. Specifically, the plug was positive for S100 calcium-binding protein B, mainly representing astrocytes, while it was negative for anti-glutamine syntethase, representing Müller glia. These findings suggest that astrocytes are the predominating cell type in the plug. Minimal glial reaction was seen in the retinal holes that did not close. Conclusions: We present a new porcine model for investigating large retinal holes. The retinal holes closed by approximation of hole edges, and the remnant retinal defect was closed with an astroglial plug.