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.

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.

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.

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.

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.

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.

Managing vitreoretinal complications in uveal melanoma: Surgical treatment and practical considerations.

BACKGROUND: In the past few decades, the primary management for uveal melanoma has evolved from enucleation to eye-preserving treatments. However, despite achieving a high rate of local tumour control, complications following eye-preserving treatments still occur and are partly responsible for functional loss and secondary enucleation. METHODS: A literature review by a broad international panel. RESULTS: We summarised the current literature on utilizing vitreoretinal (VR) surgery for managing the complications of uveal melanoma. We also provided insights from the authors' personal experience and practical recommendations for clinical care. CONCLUSIONS: With the advancement of VR instruments and surgical techniques and the combination of VR and ocular oncology knowledge ("Onco-VR"), it is now possible to manage or even prevent complications such as vitreous haemorrhage, retinal detachment, and toxic tumour syndrome.

A distorted pupil could be caused by an iris melanoma.

Melanoma isolated to the iris is rare and can present with a distorted pupil. This is a case report of an 81-year-old asymptomatic man, who had a large pigmented element in his left iris through 30 years. Because of involvement of the angle the tumour was excised with the ciliary body, and histopathologic examination revealed an iris melanoma. The aim of this report is to underscore the clinical signs of an iris melanoma and when surgery is needed.

Ocular tumours.

Ocular tumours may arise from various tissues and therefore present as a heterogeneous group of diseases with unspecific symptoms. Some of the tumours carry a high mortality with a life expectancy less than 50% after ten years. Early diagnosis and treatment are essential for a good outcome, and centralization has led to a decreased morbidity and increased survival in Denmark. Tumour-specific somatic mutations can be used for personalized follow-up programmes and may lead to new treatment modalities, as argued in this review.

Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial).

PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

Risk of New Primary Cancer in Patients with Posterior Uveal Melanoma: A National Cohort Study.

BACKGROUND: Studies on the risk of new primary cancer in patients with posterior uveal melanoma (UM) have produced conflicting results, and the role of socioeconomic status (SES) is unknown. The purpose of this population-based matched cohort study was to determine the risk of new primary cancer following the diagnosis of posterior UM. METHODS: 2179 patients with posterior UM 1968-2016 and 22,717 matched controls without cancer were included. Incidence and time-dependent hazard ratio (HR) of new primary cancer were described, and the effect of SES was emphasized in a sub-cohort. RESULTS: The incidence of new primary cancer was increased in patients with posterior UM, rate ratio (RR) 1.21 (95% CI: 1.08; 1.35), but the specific cancer types did not differ compared to the controls. The rate of new primary cancer following the diagnosis of posterior UM was significantly increased 2-5 years (HR 1.49 (95% CI: 1.23; 1.80)) and 11-15 years (HR: 1.49 (95% CI: 1.12; 1.99)), and adjusting for SES did not change the rate (HR 1.35 (95% CI:1.20; 1.55)). CONCLUSIONS: Patients with posterior UM have an increased risk of new primary cancer independent of SES. No difference in incidence of specific cancer type was observed compared to the control group.

von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Measuring aniseikonia tolerance range for stereoacuity - a tool for the refractive surgeon.

OBJECTIVE: No method exists to measure aniseikonia tolerance in stereoacuity. The brain can compensate for 2%-3% aniseikonia (i.e. 2-3 dioptres of anisometropia) without impairing stereoacuity; however, a substantial proportion of anisometropic patients experience problems caused by disruptions of sensory fusion due to surgically induced aniseikonia. We hypothesized that individual differences in tolerance to aniseikonia exist and sought to develop a method to measure aniseikonia tolerance. METHODS: A total of 21 eye-healthy phakic individuals older than 50 years of age and 11 patients awaiting clear lens extraction were included. Patients were tested with best corrected near and distance visual acuity, cover/uncover test, eye dominance test, stereoacuity threshold (TNO test), slit lamp examination and ocular coherence tomography. The stereoacuity threshold was determined with aniseikonia induced by different size lenses ranging from 1% to 9% magnification of both eyes in increments of 1%. The aniseikonia tolerance range (ATR) was defined as the percentage aniseikonia in which the stereoacuity threshold was maintained. RESULTS: We examined 32 patients with a median age of 65 (95% CI: 62-66 years), CDVA better than 6/7.5 (0.1 logMAR), and median near visual acuity better than 6/6 (0.0 logMAR). The median stereoacuity threshold was 60 arcsec (maximum 30, minimum 120). We observed large inter-individual differences in ATR: 6/31 (19%) participants had an ATR of ≤1%, 1/31 (3%) had an ATR of 1-5%, 7/31 (22%) had an ATR of 5-10%, and 17/31 (54%) had an ATR of >10%. CONCLUSION: We present a reliable method for measuring the amount of aniseikonia that a person can tolerate without impairing stereopsis. We report large inter-individual differences in tolerance of aniseikonia.