Dalvin, Lauren A

Purpose To investigate the clinical features, treatments, and outcomes of patients with secondary orbital lymphoma. Major Findings In this cohort of 31 patients, 15 (48.4%) were female and 27 (87.1%) were white. Follicular lymphoma was the most common subtype (n = 13, 41.9%) and was more associated with unilateral disease compared to other subtypes (p = 0.01). Common presenting symptoms included a palpable mass (n = 17, 54.8%), eyelid swelling (n = 16, 51.6%), and ptosis (n = 12, 38.7%). Patients were most often diagnosed with Ann Arbor Stage IV lymphoma (n = 17, 54.8%) via incisional biopsy (n = 13, 41.9%). Radiation therapy (n = 9, 29.0%) was the most common initial treatment, and most patients received radiation (n = 19, 61.3%) and/or chemotherapy (n = 21, 67.7%). A majority of patients had final best corrected visual acuity (BCVA) within 1 line of initial BCVA (n = 19, 82.6%) and had no local recurrences (n = 21, 67.7%). However, complete remission was rare (n = 3, 9.7%), and systemic recurrence occurred in over half of patients (n = 18, 58.1%). Conclusions Follicular lymphoma was the predominant subtype of secondary orbital lymphoma in this cohort. Most patients with secondary orbital lymphoma presented with advanced disease where few achieved complete remission and more than half of the patients developed systemic recurrence despite majority retaining visual acuity.

The objective of this study was to compare drug response of uveal melanoma patient-derived cell lines (PDLs) and patient-derived organoids (PDOs) with response of commercially available cell lines and contextualize laboratory outputs in terms of clinical trial results. Uveal melanoma commercial cell lines, PDLs, and PDOs were treated with drugs that were ultimately utilized in clinical trials. Four treatments were chosen for promising laboratory results that failed to yield clinical response, while darovasertib was a surrogate positive control given initial favorable clinical trial data in the neoadjuvant setting. Drug concentrations were matched to laboratory work that supported progression to clinical trials. Viability was measured using PrestoBlueHS Cell Viability Reagent. Commercial cell lines showed promising viability reduction similar to prior laboratory results with treatments, including 5-μM darovasertib, 700-nM selumetinib, 700-nM selumetinib + 1000-nM MK-2206, 500-nM sotrastaurin + 1000-nM alpelisib, and 100-nM trametinib, with overall viability reduced to 32.5% for all drugs. However, PDLs (viability 52.8%) and PDOs (viability 80.4%) showed more treatment resistance ( P < 0.05), better simulating ultimate lack of efficacy found in clinical trials. While uveal melanoma with BAP1 loss demonstrated greater treatment resistance under some conditions, other factors such as cell morphology or culture in a three-dimensional environment appeared to be more consistent drivers of therapeutic sensitivity. PDLs and PDOs may more accurately represent uveal melanoma clinical response. Demonstrating efficacy of novel therapeutics in these models could improve the likelihood of successful translation for future clinical trials, but future studies are needed to define clinically meaningful in-vitro response thresholds.

Purpose To explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma. Methods Single-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria. Results Initial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity ( p = 0.034), hypertension ( p = 0.017), and diabetes mellitus ( p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus ( p = 0.01) and obesity ( p = 0.04) remained significantly associated with earlier T category on initial presentation. Conclusion Among patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Radiation exposure to the eye during cancer treatment can lead to ocular radiation injury (ORI), a devastating condition that can have a profound and permanent impact on vision-related quality of life. Rodent models do not have adequate ocular anatomy to accurately simulate human ORI, and modeling in non-human primates is limited by logistical and ethical concerns. To improve future translational research investigating ways to treat or prevent ORI, we developed protocols for a tree shrew model of ORI. Northern tree shrews (Tupaia belangeri) were obtained by our laboratory. Custom housing and handling methods were developed, including custom body suits to maintain the tree shrew’s body temperature during procedures. Radiation delivery was optimized to accurately deliver radiation, and imaging was performed to observe fundus changes from ORI. Optimization of tree shrew handling, housing, anesthesia approaches, radiation delivery, and clinically-relevant ocular imaging permitted successful induction and assessment of ORI in tree shrews. With these protocols, tree shrews can be used as a highly relevant model organism with key anatomic features similar to humans to study ORI.

Purpose To evaluate the proportion of patients with choroidal nevus in an ocular oncology practice who would be suitable candidates for monitoring via a virtual photoscreening model, wherein imaging is asynchronously reviewed and longitudinally managed by an ocular oncologist. Methods Data were abstracted from the Prospective Ocular Tumor Study Database for all patients diagnosed with choroidal nevus from July 2019-October 2024. A stratification model for identification of virtual pathway candidates was defined and implemented as follows: good virtual pathway candidates included those with posteriorly located lesions for adequate photographic capture and no more than two high-risk features. Risk factors, outlined by the TFSOM-DIM acronym, included thickness >2 mm, presence of subretinal fluid, visual acuity 20/50 or worse, presence of orange pigment, low internal reflectivity, and basal diameter >5 mm. Of posteriorly located lesions, those with 0–2 risk factors were defined as good virtual pathway candidates, 3 risk factors as acceptable in select cases, and 4 or more as poor candidates. Results There were 614 choroidal nevi in 586 patients diagnosed during the study period. Mean patient age at initial visit was 63.5 years old (median 66.1, range 5.8–94.8), with 59.4% female and 98.8% white. Analysis identified 436 (71%) nevi in 408 (69.6%) patients as good virtual pathway candidates, 53 (8.6%) nevi in 53 (9%) patients as potential candidates in select cases, and 125 (20.4%) nevi in 125 (21.3%) patients as poor candidates. Conclusion Nearly 70% of patients with choroidal nevi followed by Mayo Clinic Ocular Oncology were identified as good candidates for follow-up via virtual photoscreening. This highlights the potential for improved clinical efficiency through virtual frameworks in ocular oncology.

Purpose To describe the clinical characteristics, histopathologic subtype distribution, treatment, and outcomes of patients with primary orbital lymphoma. Major Findings There were 126 biopsy-confirmed cases of primary orbital lymphoma, with 81 (64.3%) female and 110 (87.3%) white. The average age at diagnosis was 62.7 ± 13.9 years. There were 26 (20.6%) cases with bilateral involvement. The most frequent lymphoma subtype was MALT lymphoma (N = 76, 60.3%), followed by diffuse large B-cell lymphoma (N = 18, 14.3%) and follicular lymphoma (N = 12, 9.5%). Prognosis was generally favorable, as local recurrence occurred in only 14 (11.1%) patients and final best corrected visual acuity (BCVA) loss of >1 line was seen in 30 (28.0%) patients. Bilateral lymphoma and advanced stage (Ann Arbor Stage III or IV) at presentation were associated with increased risk of local recurrence ( p = 0.0025, p = 0.049). Improved disease-specific survival was associated with diagnosis at Stage I or II ( p = 0.013), MALT subtype ( p = 0.034), or lack of chemotherapy requirement as primary treatment ( p = 0.0073). Conclusions In this single center academic cohort, MALT lymphoma subtype was most common. Overall orbital recurrence frequency was low, and bilateral lymphoma and advanced stage were associated with increased risk of local recurrence. MALT lymphoma subtype was associated with improved disease-specific survival. Long-term follow-up showed that most patients retained good visual acuity in the affected eye(s).

Purpose: To identify demographic and clinical factors associated with delayed diagnosis in patients with primary vitreoretinal lymphoma (VRL). Methods: Retrospective, tertiary referral center-based cohort study of all patients at Mayo Clinic in Rochester, Minnesota, with a biopsy-proven diagnosis of VRL from January 1, 2000, to October 31, 2022. Results: There were 87 patients included during the 22-year study period with 73 patients (83.9%) diagnosed with VRL upon initial evaluation at the tertiary center, with the other 14 patients (16.1%) diagnosed later. The median referral time was 4.8 months (range: 0–113 months). Patients who received an initial diagnosis of inflammatory uveitis or another incorrect diagnosis elsewhere were referred slower than those initially diagnosed with VRL (P = 0.04). The most common incorrect initial diagnosis from an outside institution was inflammatory uveitis (n = 35, 40.2%). When patients were split into four groups based on referral time, prior use of corticosteroids was associated with a significant delay in referral (P = 0.03). Conclusion: Diagnosing VRL continues to be challenging, as months-long delays from initial evaluation to expert referral center evaluation are common. Prior use of corticosteroids was associated with delay in diagnosis and referral time, underscoring the need to increase awareness regarding differences between VRL and uveitis.

Angiogenesis has an essential role in the de novo evolution of choroidal melanoma as well as choroidal nevus transformation into melanoma. Differentiating early-stage melanoma from nevus is of high clinical importance; thus, imaging techniques that provide objective information regarding tumor microvasculature structures could aid accurate early detection. Herein, we investigated the feasibility of quantitative high-definition microvessel imaging (qHDMI) for differentiation of choroidal tumors in humans. This new ultrasound-based technique encompasses a series of morphological filtering and vessel enhancement techniques, enabling the visualization of tumor microvessels as small as 150 microns and extracting vessel morphological features as new tumor biomarkers. Distributional differences between the malignant melanomas and benign nevi were tested on 37 patients with choroidal tumors using a non-parametric Wilcoxon rank-sum test, and statistical significance was declared for biomarkers with p-values < 0.05. The ocular oncology diagnosis was choroidal melanoma (malignant) in 21 and choroidal nevus (benign) in 15 patients. The mean thickness of benign and malignant masses was 1.70 ± 0.40 mm and 3.81 ± 2.63 mm, respectively. Six HDMI biomarkers, including number of vessel segments (p = 0.003), number of branch points (p = 0.003), vessel density (p = 0.03), maximum tortuosity (p = 0.001), microvessel fractal dimension (p = 0.002), and maximum diameter (p = 0.003) exhibited significant distributional differences between the two groups. Contrast-free HDMI provided noninvasive imaging and quantification of microvessels of choroidal tumors. The results of this pilot study indicate the potential use of qHDMI as a complementary tool for characterization of small ocular tumors and early detection of choroidal melanoma.

To determine the frequency, characteristics, and clinical course of ophthalmic side effects associated with systemic BRAF inhibitor therapy. Medical records of patients taking BRAF inhibitors for the treatment of systemic malignances at Mayo Clinic, Rochester from 01/01/2010 to 08/30/2021, were retrospectively reviewed. Of 901 patients, 14 (1.6%) patients experienced an ophthalmic side effect. Mean age at presentation of the side effect was 60 years (median 59, range 50–80) and 11 (79%) were male. The most common side effect was uveitis in 7 (50%) patients, followed by dry eye in 4 (29%) patients, and central serous chorioretinopathy in 2 (14%) patients, with singular cases of cranial nerve VI palsy and conjunctival edema. A comparison between individual BRAF inhibitors (vemurafenib vs. dabrafenib vs. encorafenib) revealed that patients taking encorafenib had a shorter interval to any ophthalmic adverse event (mean 55.6 vs. 9.8 vs. 4.0 months, p = 0.03) and were the only patients to experience documented dry eye syndrome (DES) in this series. Outcomes were known in 13 (93%) patients, and ophthalmic adverse effects resolved or were controlled without discontinuing therapy in 10 (77%). Uveitis was successfully treated with topical corticosteroids in 4 patients, while 3 patients with refractory uveitis (2 with panuveitis and 1 with unspecified uveitis) required discontinuation of BRAF inhibitor therapy. Ophthalmic adverse events related to systemic BRAF inhibitor use are rare, with estimated frequency of 1.6%. Most events can be treated with local ophthalmic therapy. BRAF inhibitors provide life-saving therapy, and their discontinuation should be avoided.