Vitreous metastasis from cutaneous melanoma: diagnosis and management / Metástase vítrea de melanoma cutâneo: diagnóstico e tratamento

ABSTRACT Purpose: To report the clinical findings, treatments, and outcomes in a series of patients with vitreous metastasis from cutaneous melanoma. Methods: This single-center, retrospective, interventional case series included patients with biopsy-confirmed vitreous metastasis from cutaneous melanoma diagnosed between 1997 and 2020. Standard 23- or 25-gauge pars plana vitrectomy was performed for diagnostic sampling. Sclerotomies were treated with double or triple freeze-thaw cryotherapy. Perioperative intravitreal injections of melphalan (32 µg/0.075 mL) were administered, when indicated. Visual acuity, intraocular pressure, and systemic and ocular treatment responses were reported. Results: Five eyes of five patients with unilateral vitreous metastasis from cutaneous melanoma were identified. The median age at diagnosis was 84 (range, 37-88) years. The median follow-up after ophthalmic diagnosis was 28 (8.5-36) months; one patient did not have a follow-up. The initial visual acuity ranged from 20/30 to hand motions. Baseline clinical findings included pigmented or non-pigmented cellular infiltration of the vitreous (5/5), anterior segment (4/5), and retina (3/5). Four patients had secondary glaucoma. Systemic therapy included checkpoint inhibitor immunotherapy (n=3, all with partial/complete response), systemic chemotherapy (n=2), surgical resection (n=3), and radiation (n=2). The median time from primary diagnosis to vitreous metastasis was 2 (2-15) years. One patient had an active systemic disease at the time of vitreous metastasis. The final visual acuity ranged from 20/40 to no light perception. Ophthalmic treatment included vitrectomy in all five patients, intravitreal administration of melphalan in three, and intravitreal administration of methotrexate in one. One patient required enucleation, and histopathology revealed extensive invasion by melanoma cells. Conclusions: Vitreous metastasis from cutaneous melanoma can present as a diffuse infiltration of pigmented or non-pigmented cells into the vitreous and may be misdiagnosed as uveitis. Diagnostic pars plana vitrectomy and periodic intravitreal chemotherapy may be indicated.

RESUMO Objetivo: Descrever os achados clínicos, tratamentos, e desfechos em uma série de pacientes com me tástases vítreas de melanoma cutâneo. Métodos: Série retrospectiva de casos de único centro com intervenção. Pacientes incluídos tiveram seu diagnóstico de MVMC confirmado por biópsia entre 1997 e 2020. Vitrectomia via pars plana com 23 ou 25 gauge foram realizadas para obter espécimens. Esclerotomias foram tratadas com crioterapia em duplo ou triplo congelamento. Injeção intravítrea perioperatória de melfalano (32 ug/0,075 mL) foi administrada quando necessário. Foram relatados acuidade visual, pressão intraocular, resposta terapêutica sistêmica e ocular. Resultados: Cinco olhos de 5 pacientes com metástases vítreas de melanoma cutâneo unilateral foram identificados. Idade média de diagnóstico foi 84 anos (variando de 37-88). Seguimento médio após diagnóstico oftalmológico foi 28 (8,5-36) meses; 1 paciente não teve acompanhamento. Acuidade visual inicial variou de 20/30 a movimentos de mão. Achados clínicos iniciais incluíram infiltração de células pigmentadas e não-pigmentadas no vítreo (5/5), segmento anterior (4/5), e retina (3/5). Quatro pacientes tiveram glaucoma secundário. Tratamento sistêmico incluiu imunoterapia com inibidores da via de sinalização (3 - todos com resposta parcial/completa), quimioterapia sistêmica (2), ressecção cirúrgica (3), e irradiação (2). Intervalo médio entre diagnóstico primário e metástases vítreas foi 2 (2-15) anos. Um paciente teve doença sistêmica ativa simultânea as metástases vítreas. Acuidade visual final variou entre 20/40 e SPL. Tratamento oftalmológico incluiu vitrectomia nos 5 pacientes, melfalano intravítreo em 3 e metotrexato intravítreo em 1. Um paciente precisou de enucleação. A histopatologia revelou invasão celular extensa de melanoma. Conclusões: Metástases vítreas de melanoma cutâneo pode se manifestar como uma infiltração difusa de células pigmentadas e não-pigmentadas no vítreo e erroneamente diagnosticada como uveites. Vitrectomia diagnóstica e quimioterapia intravítrea periódica podem estar indicadas.

Outcomes and complications of primary rhegmatogenous retinal detachment repair with pars plana vitrectomy in young adults.

BACKGROUND: Scleral buckling has been the standard for rhegmatogenous retinal detachment repair in young patients given the typical lack of posterior vitreous detachment, phakic status, and lower risk of proliferative vitreoretinopathy. In older patients, pars plana vitrectomy alone is typically used for rhegmatogenous retinal detachment repair. We report the outcomes and complications of pars plana vitrectomy for rhegmatogenous retinal detachment in young eyes. METHODS: Retrospective, single-center cohort study. Medical records of patients between 15 to 45 years of age undergoing primary pars plana vitrectomy for rhegmatogenous retinal detachment repair between 2010 and 2020 were carefully reviewed. All analyses were performed using the Kruskal-Wallis tests for numeric covariates between age groups. RESULTS: Eyes were stratified by age: 15-24 (group 1, n = 10), 25-34 (group 2, n = 14), and 35-45 (group 3, n = 38). The average number of surgeries were 1.9, 1.4, and 1.1 in groups 1, 2, and 3, respectively (p = 0.004). Single surgery success rates were 50%, 64%, and 92% in groups 1, 2 and 3, respectively (p = 0.005). Final reattachment rates were 80%, 93%, 100% in groups 1, 2, and 3, respectively (p = 0.568). Proliferative vitreoretinopathy developed in 50%, 7%, and 8% of eyes in groups 1, 2, and 3, respectively (p < 0.001). CONCLUSION: While the final reattachment rates were excellent in all groups, the higher rates of proliferative vitreoretinopathy and lower single surgery success rate in younger patients may suggest that primary pars plana vitrectomy may not be the optimal repair method in these age groups.

CHRONIC PEDIATRIC RETINAL DETACHMENT WITH MULTIPLE MACROCYSTS.

PURPOSE: To describe a case of chronic pediatric retinal detachment with multiple macrocysts, its surgical management, and a review of the literature. METHODS: Case report with fundus photography and optical coherence tomography. RESULTS: We describe a case of an asymptomatic, 11-year-old boy with a chronic rhegmatogenous retinal detachment with multiple peripheral macrocysts. The patient had counting fingers visual acuity on presentation. The detachment was successfully surgically repaired with scleral buckling, subretinal fluid drainage, cryotherapy, and a SF6 tamponade. At the 12-month follow-up, the retina remained attached with improvement of visual acuity to 20/100 with resolution of the cysts. Optical coherence tomography revealed loss of macular ellipsoid zone. Genetic testing revealed a heterozygous dominant COL11A1 mutation. CONCLUSION: To the authors' knowledge, this is the first reported case of chronic retinal detachment presenting with multiple peripheral macrocysts in a pediatric patient with Stickler syndrome. More research is needed into the cause and significance of retinal macrocysts, particularly in the pediatric population.

Visual barcodes for clonal-multiplexing of live microscopy-based assays.

While multiplexing samples using DNA barcoding revolutionized the pace of biomedical discovery, multiplexing of live imaging-based applications has been limited by the number of fluorescent proteins that can be deconvoluted using common microscopy equipment. To address this limitation, we develop visual barcodes that discriminate the clonal identity of single cells by different fluorescent proteins that are targeted to specific subcellular locations. We demonstrate that deconvolution of these barcodes is highly accurate and robust to many cellular perturbations. We then use visual barcodes to generate 'Signalome' cell-lines by mixing 12 clones of different live reporters into a single population, allowing simultaneous monitoring of the activity in 12 branches of signaling, at clonal resolution, over time. Using the 'Signalome' we identify two distinct clusters of signaling pathways that balance growth and proliferation, emphasizing the importance of growth homeostasis as a central organizing principle in cancer signaling. The ability to multiplex samples in live imaging applications, both in vitro and in vivo may allow better high-content characterization of complex biological systems.

Squamoid Eccrine Ductal Carcinoma of the Eyelid: Clinicopathologic Correlation of a Case.

Squamoid eccrine ductal carcinoma (SEDC) is a rare cutaneous neoplasm that often manifests as a plaque or nodule in sun-exposed areas of older patients. Herein, the authors report the first case of SEDC in the eyelid. A 76-year-old man presented with a 2.5 × 1.5 mm area of left upper eyelid erythema, thickening, ulceration, and scaling with madarosis superotemporally just above the lash line. Full-thickness wedge biopsy demonstrated irregular epithelial tubules with nuclear atypia and focal squamous differentiation, consistent with SEDC. The patient underwent Mohs resection and has had no recurrence approximately 27 months after surgical removal. The authors present this case to raise awareness of SEDC to ophthalmologists as all previous cases have been described in the nonophthalmic literature. A full-thickness biopsy is recommended to avoid misdiagnosing SEDC as squamous cell carcinoma (SCC), a less aggressive tumor. With greater awareness, there may be increased recognition of this likely underreported, more malignant entity.

Metastatic Uterine Carcinosarcoma to the Orbit.

Metastases of solid tumors to the eye and ocular adnexa are rare. Herein, the authors describe the clinical, histologic, and immunohistochemical findings of a patient with a history of adenocarcinoma of the colon and a uterine carcinosarcoma (malignant mixed Müllerian tumor) who presented with proptosis and decreased vision. Positive staining with PAX-8, p16 and negative reaction for CK20 and CDX2 helped to establish the uterine origin of the metastasis. This rare case demonstrates the utility of immunohistochemical probes, especially in patients with a complex oncological history, where multiple primary sources of the metastasis are in the differential diagnosis.

Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.

While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints-mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size. In this study, we show that the specific target size required for inactivation of p38 and transition through the cell cycle is determined by CDK4 activity. Our data suggest a model whereby p38 and CDK4 cooperate analogously to the function of a thermostat: while p38 senses irregularities in size, CDK4 corresponds to the thermostat dial that sets the target size.

Brolucizumab-related retinal vasculitis with exacerbation following ranibizumab retreatment: A clinicopathologic case study.

PURPOSE: To describe the clinical and pathologic characteristics of a case of retinal vasculitis and vitritis following brolucizumab administration and subsequent ranibizumab treatment. OBSERVATIONS: A 76-year old Caucasian woman experienced pain, decreased vision and floaters one week after receiving her third monthly intravitreal brolucizumab injection in the right eye for exudative age-related macular degeneration. Examination was significant for 0.5+ anterior chamber cells, vitritis, mild peripheral vascular sheathing, and decreased vision from 20/70 to 20/200. She was started on topical 1% prednisolone acetate with improvement in her examination. She was switched to ranibizumab one month after her last brolucizumab injection of the right eye. Three weeks after her ranibizumab injection, she noticed photophobia, pain and decreased vision. Examination revealed worsening uveitis, vitritis, vascular sheathing, and decreased vision to count fingers. Despite starting on 0.05% difluprednate drops every 2 hours and oral high-dose methylprednisolone, the patient did not have any significant improvement in her symptoms or examination. She underwent pars plana vitrectomy and vitreous biopsy with intravitreal triamcinolone injection to the right eye. Vitreous biopsy and culture ruled out infectious endophthalmitis, and further cytopathologic analysis revealed chronic inflammatory infiltrate. CONCLUSION AND IMPORTANCE: Treatment with brolucizumab can result in intraocular inflammation and retinal vasculitis likely due to a delayed hypersensitivity reaction to the drug, supported by cytopathologic analysis of a vitreous sample. We demonstrate a case where retreatment with an alternative anti-VEGF agent resulted in worsening vision and vasculitis.

Clinical Diagnosis and Histopathologic Features of a Synthetic Fiber Granuloma.

The authors report a case of a synthetic fiber granuloma to demonstrate the challenges in diagnosing these lesions and to highlight their histopathologic features. This is the first report in the literature to use histopatho-logic and immunofluorescence studies to characterize the subtype and distribution of macrophages in synthetic fiber granuloma. [J Pediatr Ophthalmol Strabismus. 2020;57:e92-e95.].

A phage-displayed single-chain Fab library optimized for rapid production of single-chain IgGs.

Phage-displayed synthetic antibody (Ab) repertoires have become a major source of affinity reagents for basic and clinical research. Specific Abs identified from such libraries are often screened as fragments antigen binding (Fabs) produced in bacteria, and those with desired biochemical characteristics are reformatted for production as full-length immunoglobulin G (IgG) in mammalian cells. The conversion of Fabs to IgGs is a cumbersome and often rate-limiting step in the development of Abs. Moreover, biochemical properties required for lead IgG development are not always shared by the Fabs, and these issues are not uncovered until a significant effort has been spent on Abs that ultimately will not be useful. Thus, there is a need for simple and rapid techniques to convert phage-displayed Fabs to IgGs at an early stage of the Ab screening process. We report the generation of a highly diverse phage-displayed synthetic single-chain Fab (scFab) library, in which the light and heavy chains were tethered with an optimized linker. Following selection, pools of scFabs were converted to single-chain IgGs (scIgGs) en masse, enabling facile screening of hundreds of phage-derived scIgGs. We show that this approach can be used to rapidly screen for and select scIgGs that target cell-surface receptors, and scIgGs behave the same as conventional IgGs.

Association of Co-occurring Dementia and Self-reported Visual Impairment With Activity Limitations in Older Adults.

Importance: The number of older adults with visual impairment (VI) and dementia is projected to increase in the US because of the aging of the population. Dementia and VI commonly co-occur and are each independently associated with disability. To care for an aging population, it may be important to characterize the association of coexisting dementia and self-reported VI on daily functioning. Objective: To evaluate the association of co-occurring dementia and self-reported VI on daily functioning. Design, Setting, and Participants: This cross-sectional analysis of a nationally representative cohort study used data from the National Health and Aging Trends Study (NHATS), an annual study of US adults 65 years and older. Participants in the 2015 survey with complete data on outcomes, associated factors, and covariates were included in this study. Data analysis took place from January 2019 to November 2019. Main Outcomes and Measures: Multivariable Poisson regression was used to model the independent associations and interaction of dementia and self-reported VI status on 3 functional activity scales (self-care, mobility, and household activities). Marginal predicted proportions were calculated. Analyses were adjusted for sociodemographic and medical factors and accounted for the complex survey design. Results: A total of 7124 participants were included. The weighted proportion of female respondents was 55.3% (95% CI, 54.0%-56.6%), and 56.1% (95% CI, 54.1%-58.1%) were between 65 and 74 years old. Self-reported VI was present in 8.6% (95% CI, 7.8%-9.3%) of participants, while 8.3% (95% CI, 7.8%-8.9%) had possible dementia and 6.3% (95% CI, 5.7%-6.9%) had probable dementia. Self-reported VI was associated with an expected decrease in mobility score of 14.7% (functional scale scores: no VI, 10.82 vs VI, 9.23), self-care score of 9.5% (no VI, 14.54 vs VI, 13.16), and household activity score of 15.2% (no VI, 18.23 vs VI, 15.45), while probable dementia was associated with expected decreases of 27.8% (no dementia, 10.82 vs probable dementia, 7.81), 22.9% (no dementia, 14.54 vs probable dementia, 11.20), and 34.7% (no dementia, 18.23 vs probable dementia, 11.90), respectively. Among those with probable dementia and self-reported VI, there was an expected decrease in mobility score of 50.1% (functional ability scores: no VI and no dementia, 10.82 vs VI and probable dementia, 5.40), self-care score of 42.4% (no VI and no dementia, 14.54 vs VI and probable dementia, 8.38), and household activity score of 52.4% (no VI and no dementia, 18.23 vs VI and probable dementia, 8.68), suggesting that respondents with co-occurring dementia and self-reported VI had lower functional activity scores than would be associated with the independent contributions of these conditions. Conclusions and Relevance: Older adults with both dementia and self-reported VI may be at high risk for disability, and their co-occurrence may potentiate this risk. These findings suggest that the growing population of older adults with both visual impairment and dementia may benefit from interventions to maximize vision and cognition and promote functioning and independence.

Novel Anatomic Predictors of New Persistent Left Bundle Branch Block After Evolut Transcatheter Aortic Valve Implantation.

New persistent left bundle branch block (NP-LBBB) has been associated with adverse outcomes after TAVI but few predictors thus far reported. We sought to identify predictors of NP-LBBB after TAVI with EvolutR/PRO (ER/EP). From 1/2016 to 4/2019, 544 patients from 2 centers underwent TAVI with Evolut (54% ER, 46% EP) for severe native aortic stenosis. Patients with previous LBBB and pacemaker were excluded. Aortic root analysis was performed using 3Mensio Valves Software and membranous septal length (MSL) was determined using the standard coronal view. Clinical, anatomic and procedural characteristics of 396 Evolut were analyzed and predictors of NP-LBBB were identified. Valve Academic Research Consortium-2 outcomes were reported. At discharge, NP-LBBB was seen in 76(19.2%) patients. NP-LBBB in Evolut was associated with implant depth at left coronary cusp (p = 0.004) and 34 mm ER (p = 0.026). Independent predictors of NP-LBBB in Evolut were shorter MSL (odds ratio [OR] = 0.82 per mm septum, 95% confidence interval [CI] = 0.68 to 0.98,p = 0.030), left ventricular outflow tract (LVOT) eccentricity (OR = 1.04 per %, 95% CI = 1.01 to 1.06,p = 0.002), implant depth at noncoronary cusp (NCC) (OR = 1.28 per mm ventricular, 95% CI = 1.11 to 1.48,p = 0.001) and annular perimeter oversizing ≥20% (OR = 2.38, 95% CI = 1.20 to 4.72, p = 0.013). On ROC curve analysis, MSL ≤6.5 mm, NCC depth ≥3 mm and LVOT eccentricity ≥35% were optimal threshold values to predict NP-LBBB. In Conclusion, shorter MSL, LVOT eccentricity, annular oversizing and deeper implant depth are novel predictors of NP-LBBB in Evolut TAVI. Preprocedural CT assessment of aortic root anatomy may help identify patients at risk for NP-LBBB. In such patients, modifying procedural factors such as higher implant and less annular oversizing may reduce the risk of NP-LBBB. Further evaluation of our hypothesis is warranted.

Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

Trends and Outcomes of Intravascular Imaging-guided Percutaneous Coronary Intervention in the United States.

INTRODUCTION: Intravascular imaging-guided percutaneous coronary intervention (PCI) has shown to improve outcomes in randomized controlled trials. However, there are little real-world data about intravascular imaging utilization during PCI and its outcomes in the United States. METHODS: We conducted an observational analysis on the use of intravascular imaging (Intravascular Ultrasound or Optical Coherence Tomography)-guided PCI in 2,425,036 patients undergoing PCI between January 2010 and December 2014 from the Nationwide Inpatient Sample database. Utilizing propensity score matching, 83,988 matched pairs were identified. The primary outcome was in-hospital mortality. The secondary outcomes included cardiogenic shock and acute kidney injury. RESULTS: Among the 2,425,036 patients, 161,808 (6.7%) underwent imaging-guided PCI. Use of imaging-guidance increased from 6% in 2010 to 6.6% in 2014 (Ptrend < 0.001). The in-hospital mortality was significantly different between imaging-guided PCI and angiography-guided PCI [1.0% vs. 1.5%; adjusted OR: 0.67; 95% confidence interval (CI): 0.54-0.83, P < 0.001]. The rates of cardiogenic shock (2.5% vs. 3.1%; adjusted OR: 0.78; 95% CI: 0.66-0.93; P = 0.005) were significantly lower in imaging-guided PCI group and acute kidney injury rates (7.0% vs. 7.1%; adjusted OR: 0.99; 95% CI: 0.89-1.12; P = 0.919) were not significantly different. CONCLUSIONS: Imaging-guided PCI is associated with lower in-hospital mortality. Yet, a small proportion of patients undergoing PCI have imaging-guidance.

Survey of Intravitreal Injection Practice Patterns Among Retina Specialists.

Purpose: Intravitreal injection therapy (IVT) is the most performed procedure in ophthalmology. This study was conducted to determine current trends in IVT delivery. Methods: An online, 31-question, multiple-choice survey was sent to 1677 retina specialists. The survey consisted of 3 sections: general questions, procedure technique, and postprocedure technique. Results: A total of 264 (16%) retina specialists completed the survey. The use of povidone-iodine (100%) and small-gauge needles (97%) was common, whereas ocular anesthesia was split among lidocaine gel (31%), lidocaine drops (25%), subconjunctival lidocaine (28%), and lidocaine-soaked pledgets (15%). More than 85% indicated povidone-iodine contributes to post-IVT corneal toxicity, and 12% reported that a needlestick injury to physician or staff occurred during IVT. Conclusions: Key areas for IVT improvement include optimized ocular anesthesia, development of a guarded needle for ocular drug delivery, and formulation of a less toxic ocular antiseptic.

Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice.

Secreted Wnt proteins regulate development and adult tissue homeostasis by binding and activating cell-surface Frizzled receptors and co-receptors including LRP5/6. The hydrophobicity of Wnt proteins has complicated their purification and limited their use in basic research and as therapeutics. We describe modular tetravalent antibodies that can recruit Frizzled and LRP5/6 in a manner that phenocopies the activities of Wnts both in vitro and in vivo. The modular nature of these synthetic Frizzled and LRP5/6 Agonists, called FLAgs, enables tailored engineering of specificity for one, two or multiple members of the Frizzled family. We show that FLAgs underlie differentiation of pluripotent stem cells, sustain organoid growth, and activate stem cells in vivo. Activation of Wnt signaling circuits with tailored FLAgs will enable precise delineation of functional outcomes directed by distinct receptor combinations and could provide a new class of therapeutics to unlock the promise of regenerative medicine.