Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Uveal melanoma: clinical management of ocular complications after tumor biopsy

Sampling of uveal tumors using fine-needle aspiration biopsy (FNAB) or vitrectomy cutter choroidal biopsy (VCCB) has become part of the standard of care in diagnosis and prognosis of uveal melanomas and borderline melanocytic uveal tumors. For early adopters, the use of FNAB (or VCCB) has shown that benefits of tumor sampling far outweigh the risks, particularly with respect to the ability to confirm tumor diagnostic and prognostic testing. This manuscript will review the different techniques used to obtain small samples of uveal tumors with minimal disruption of the ocular tissues, briefly discuss clinical applications and complications of FNAB and VCCB, and ways in which to improve specimen yield and patient outcomes. The published literature shows a lack of uniformity in indication and surgical techniques among ocular oncologists performing FNAB and VCCB. This fact can potentially lead to discrepant results that include variable rates of success in obtaining a sufficient specimen and a wide range of complications, from intraocular hemorrhage, retinal detachment to anecdotal cases of seeding of the biopsy needle track and extraocular tumor extension. Uniform indications and surgical techniques would allow comparison among different centers and protocols to minimize and manage complications

Assessing Prognosis in Uveal Melanoma

Because uveal melanoma is the most common primary malignant intraocular tumor in adults and carries a significant risk of metastases, which are mostly unresponsive to available systemic therapy, researchers have been searching for prognostic indicators to identify patients at increased risk for developing such metastasis. The purpose of this study is to describe recent advances in prognostic testing of patients with uveal melanoma and the impact of these advances on the management of uveal melanoma. The relevant, peerreviewed literature as extracted and then further reviewed for scientific content. Demographic characteristics, clinical, and histopathological features alone are inadequate for predicting metastatic risk in individual patients with uveal melanoma. Some research has shown that cytogenetic abnormalities and principally transcriptomic features of tumor cells can independently predict high risk for uveal melanoma metastatic spread. Gene expression profiling of uveal melanoma cells may be accurate and biologically informative for molecular prognostication. Methods for detecting chromosomal gains and losses have predictive value but require additional clinical and cytological information. The latest step in the evolution of molecular testing has been the discovery of major driver mutations for possible use in targeted therapy. Assay validation, quality control, and interpretation of results are essential for the reliability and reproducibility of these tests. Although these prognostic tests have improved the ability to identify patients at increased risk for developing metastasis, their use has not changed the management of uveal melanoma. However, genomic, analytical, and sequencing technologies will provide a critical step toward useful targeted therapies for patients with high-risk uveal melanoma

Sufficiency of FNAB aspirates of posterior uveal melanoma for cytologic versus GEP classification in 159 patients, and relative prognostic significance of these classifications

To determine the relative sufficiency of paired aspirates of posterior uveal melanomas obtained by FNAB for cytopathology and GEP, and their prognostic significance for predicting death from metastasis. Prospective non-randomized IRB-approved single-center longitudinal clinical study of 159 patients with posterior uveal melanoma sampled by FNAB in at least two tumor sites between 09/2007 and 12/2010. Cases were analyzed with regard to sufficiency of the obtained aspirates for cytopathologic classification and GEP classification. Statistical strength of associations between variables and GEP class was computed using Chi-square test. Cumulative actuarial survival curves of subgroups of these patients based on their cytopathologic versus GEP-assigned categories were computed by the Kaplan-Meier method. The endpoint for this survival analysis was death from metastatic uveal melanoma. FNAB aspirates were insufficient for cytopathologic classification in 34 of 159 cases (21.9 %). In contrast, FNAB aspirates were insufficient for GEP classification in only one of 159 cases (0.6 %). This difference is statistically significant (P < 0.001). Six of 34 tumors (17.6 %) that yielded an insufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2, while 43 of 125 tumors (34.7 %) that yielded a sufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2. To date, 14 of the 49 patients with a GEP class 2 tumor (28.6 %) but only five of the 109 patients with a GEP class 1 tumor (5.6 %) have developed metastasis. Fifteen of 125 patients (12 %) whose tumors yielded sufficient aspirates for cytopathologic classification but only four of 34 patients (11.8 %) whose tumors yielded insufficient aspirates for cytopathologic classification developed metastasis. The median post-biopsy follow-up time for surviving patients in this series was 32.5 months. Cumulative actuarial 5-year probability of death from metastasis 14.1 % for those with an insufficient aspirate for cytopathologic classification versus 22.4 % for those with a sufficient aspirate for cytopathologic classification (log rank P = 0.68). In contrast, the cumulative actuarial 5-year probability of metastatic death was 8.0 % for those with an insufficient/unsatisfactory aspirate for GEP classification or GEP class 1 tumor, versus 45.0 % for those with a GEP class 2 tumor (log rank P = 0.005). This study confirmed that GEP classification of posterior uveal melanoma cells obtained by FNAB is feasible in almost all cases, including most in which FNAB yields an insufficient aspirate for cytodiagnosis. The study also confirmed that GEP classification is substantially better than cytologic classification for predicting subsequent metastasis and metastatic death

Relationship Between Rate of Posterior Uveal Melanoma Flattening Following Plaque Radiotherapy and Gene Expression Profile Class of Tumor Cells

PURPOSE. To evaluate the relationship between rate of flattening of posterior uveal melanomas (PUMs) over the first 6 months following I-125 plaque radiotherapy and gene expression profile (GEP) class of tumor cells obtained by fine needle aspiration biopsy (FNAB) prior to treatment. METHODS. Retrospective analysis of relationship between GEP of PUM cells obtained by FNAB at or prior to treatment and rate of tumor flattening following I-125 plaque radiotherapy. Impact of initial tumor thickness was minimized by pairing cases so baseline tumor thickness in subgroups was matched to within +/- 0.5 mm. Paired t-testing compared mean tumor thickness in GEP subgroups at 3- and 6-months post treatment assessments. RESULTS. Our initial group consisted of 269 patients. Seventy-seven tumors (28.6%) were GEP class 2. Twenty-seven of these were treated by I-125 plaque radiotherapy post-FNAB and returned for post treatment evaluations at 3 and 6 months. A matched GEP class 1 tumor was identified for 25 class 2 cases. Matched tumor pairs ranged in thickness from 2.5 to 11.5 mm at baseline. Mean tumor thickness at baseline in the GEP 1 subgroup was 5.8 and 5.9 mm in the GEP 2 subgroup. Three-months post plaque, mean tumor thickness was 4.5 mm in class 1 cases and 4.6 mm in class 2 cases (paired t = 0.31, P = 0.76). The 6-month post-plaque, mean tumor thickness was 4.0 mm in each subgroup (paired t = 0.25, P = 0.81). CONCLUSIONS. Our study showed a lack of association between the GEP class and the rate of flattening of posterior uveal melanomas following I-125 plaque radiotherapy of PUMs

Deep Learning Applications in Ocular Oncology

This chapter highlights deep learning applications in uveal melanoma, the most common primary intraocular malignancy in adults. Future directions of machine learning applications in ocular oncology are discussed as well