Presumed incipient choroidal melanoma: proposed diagnostic criteria and management.

AIMS: To propose diagnostic criteria for a presumed incipient choroidal melanoma based on tumour growth rate and tumour doubling time (TDT) and to describe management of such tumours with transpupillary thermotherapy (TTT). METHODS: Retrospective interventional case series of nine consecutive presumed incipient uveal melanomas diagnosed and treated with TTT in 2010-2017. Growth rate in mm/year and per cent/year in largest basal diameter (LBD) and TDT were compared with published data for uveal melanomas and growing naevi that did not transform to melanoma under long-term follow-up. RESULTS: The median LBD and thickness were 1.6 mm (range 0.9-2.3) and 0.20 mm (range 0.15-0.29), respectively. The median age was 57 years (range 47-78). Seven tumours were classified as de novo melanomas and two as transformed naevi. The median time from first observation to diagnosis was 3.3 years (range 2.2-7.3), LBD growth rate 0.25 mm/year (range 0.11-0.72) and 34 per cent/year (range 10-1437), and TDT 609 days (range 97-1612). The estimates matched those reported for uveal melanoma (median TDT 521 days, 90th percentile 2192) and exceeded those for growing naevi (median growth rate 0.04 mm/year, 90th percentile 0.12; 1.1 per cent/year, 90th percentile 2.6). The predicted median age at de novo appearance was 51 years (range 32-63). No tumour grew after TTT during a median follow-up of 2.1 years (range 0.6-8.7). CONCLUSIONS: In this series, relative growth rate and TDT best qualified as diagnostic criteria for an incipient choroidal melanoma. Too small for brachytherapy, they could be managed with TTT.

Brachytherapy of Choroidal Melanomas Less Than 10 mm in Largest Basal Diameter: Comparison of 10-mm and 15-mm Ruthenium Plaques.

PURPOSE: To compare tumor control, vision, and complications between patients with a choroidal melanoma of <10 mm in largest basal diameter (LBD) irradiated with 10-mm or 15-mm ruthenium plaques. DESIGN: Retrospective, comparative case series. PARTICIPANTS: One hundred sixty-four consecutive patients with a choroidal melanoma of <10 mm in LBD, 76 and 88 treated with the 10-mm and 15-mm plaque, respectively, from 1998-2014 in a national ocular oncology service. METHODS: Diagnosis was based on growth or high-risk characteristics. The apical dose was 100 to 120 Gy aiming to deliver ≥250 Gy to the sclera. Plaque positioning was modeled retrospectively. An increase of ≥0.3 mm in thickness and ≥0.5 mm in LBD indicated local recurrence. Outcomes were compared with cumulative incidence analysis and Cox regression. Median follow-up time for patients still alive was 8.4 years. MAIN OUTCOME MEASURES: Recurrence rate, low vision, blindness, radiation maculopathy, and optic neuropathy. RESULTS: Melanomas treated with the 10-mm plaque were smaller (median thickness, 1.9 mm vs. 2.6 mm; LBD, 7.1 mm vs. 8.6 mm) and located closer to foveola (median, 2.0 mm vs. 2.8 mm) than those treated with the 15-mm plaque (P < 0.001). The 2 plaques provided a safety margin in 43% versus 40% eyes, provided no safety margin to guard foveola in 17% versus 33%, and did not entirely cover tumor mainly close to the disc in 32% versus 18% of eyes, respectively (P = 0.052). The incidence of a local recurrence was comparable (13% vs. 15% at 10 years; P = 0.31) and associated with plaque positioning (hazard ratio [HR], 2.81 for no safety margin; P = 0.041). At 5 years, the incidence of low vision was 14% versus 24%, and that of blindness was 3% versus 6%. Distance to the foveola was associated with loss of both levels of vision (HR, 0.65 per 1 mm vs. 0.68 per 1 mm; P ≤ 0.001 vs. P = 0.004). The incidence of radiation maculopathy was comparable (19% vs. 18% at 5 years), whereas that of optic neuropathy tended to be higher with the 15-mm plaque (2% vs. 9%; P = 0.054). CONCLUSIONS: The 10-mm ruthenium plaque contributes to better visual preservation, particularly with tumors close to fovea, without increase in local recurrence rate, and may therefore be preferable to the 15-mm plaque.

Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma.

Uveal melanoma (UM) is a rare intraocular cancer with the highest incidence in northern latitudes. Metastases develop in approximately 50% of patients, whereafter the median survival is 13 months. Generally, the mutation burden of these tumors is low. Germline variants predisposing to UM have been previously described in BRCA1-associated protein 1 (BAP1). Recently, germline and somatic loss-of-function (LOF) variants in the methyl-CpG-binding domain 4 (MBD4) gene have been found to cause a hypermutated UM, and MBD4 also has been put forward as a gene predisposing to UM. We sequenced for MBD4 germline variants in 440 Finnish patients with UM and identified seven rare exonic missense variants in 16 (3.6%) patients, of which one likely alters MBD4 function. The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01-1.28). We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.

Population-based analysis of BAP1 germline variations in patients with uveal melanoma.

Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish-Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3' UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G>T) and exon 14 (c.1780_1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A>G) and 9 (c.680G>A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9/433 (2%) and 4/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS.

Variations in the functional visual field for detection of lung nodules on chest computed tomography: Impact of nodule size, distance, and local lung complexity.

PURPOSE: To explore the characteristics that impact lung nodule detection by peripheral vision when searching for lung nodules on chest CT-scans. METHODS: This study was approved by the local IRB and is HIPAA compliant. A simulated primary (1°) target mass (2 × 2 × 5 cm) was embedded into 5 cm thick subvolumes (SV) extracted from three unenhanced lung MDCT scans (64 row, 1.25 mm thickness, 0.7 mm increment). One of 30 solid, secondary nodules with either 3-4 mm and 5-8 mm diameters were embedded into 192 of 207 SVs. The secondary nodule was placed at a random depth within each SV, a transverse distance of 2.5, 5, 7.5, or 10 mm, and along one of eight rays cast every 45° from the center of the 1° mass. Video recordings of transverse paging in cranio-caudal direction were created for each SV (frame rate three sections/sec). Six radiologists observed each cine-loop once while gaze-tracking hardware assured that gaze was centered on the 1° mass. Each radiologist assigned a confidence rating (0-5) to the detection of a secondary nodule and indicated its location. Detection sensitivity was analyzed relative to secondary nodule size, transverse distance, radial orientation, and lung complexity. Lung complexity was characterized by the number of particles (connected pixels) and the sum of the area of all particles above a -500 HU threshold within regions of interest around the 1° mass and secondary nodule. RESULTS: Using a proportional odds logistic regression model and eliminating redundant predictors, models fit individually to each reader resulted in the following decreasing order of association based on greatest reduction in Akaike Information Criterion: secondary nodule diameter (6/6 readers, P < 0.001), distance from central mass (6/6 readers, P < 0.001), lung complexity particle count (5/6 readers, P = 0.05), and lung complexity particle area (3/6 readers, P = 0.03). Substantial inter-reader differences in sensitivity to decreasing nodule diameter, distance, and complexity characteristics were observed. CONCLUSIONS: Of the investigated parameters, secondary nodule size, distance from the gaze center and lung complexity (particle number and area) significantly impact nodule detection with peripheral vision.

BAP1 Germline Mutations in Finnish Patients with Uveal Melanoma.

PURPOSE: Germline mutations of the BRCA1-associated protein-1 gene (BAP1) predispose carriers to uveal melanoma. We report the population-based frequency of germline pathogenic variants of BAP1 in Finnish patients with uveal melanoma who live in a high-risk region for this cancer. DESIGN: Cohort study. PARTICIPANTS: In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 148 of 188 consecutive patients diagnosed from January 2010 through December 2012. Seven of these patients from 6 families had a history of uveal melanoma in 1 relative, and 2 patients from 2 additional families had such a history in 2 relatives. METHODS: Sequencing BAP1. MAIN OUTCOME MEASURES: Pathogenic variants in BAP1. RESULTS: We found 2 different pathogenic variants in BAP1 in 3 patients. Two patients had a single nucleotide insertion in exon 14 resulting in a shift of reading frame. Both had a family history of uveal melanoma in at least 1 relative. One patient without a family history of uveal melanoma had a single nucleotide substitution in the conserved splice donor site of intron 2. BAP1 cancer predisposition syndrome-related cancers were present in all 3 families. The overall frequency of BAP1 pathogenic variants was 2.0% (3/148; 95% confidence interval, 0.4-5.8), the frequency among patients 50 years of age or younger was 3.6% (1/28; 95% confidence interval, 0.1-18), and a pathogenic variant was detected in 2 of 8 families with a history of uveal melanoma. CONCLUSIONS: The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations.

Characterizing search, recognition, and decision in the detection of lung nodules on CT scans: elucidation with eye tracking.

PURPOSE: To determine the effectiveness of radiologists' search, recognition, and acceptance of lung nodules on computed tomographic (CT) images by using eye tracking. MATERIALS AND METHODS: This study was performed with a protocol approved by the institutional review board. All study subjects provided informed consent, and all private health information was protected in accordance with HIPAA. A remote eye tracker was used to record time-varying gaze paths while 13 radiologists interpreted 40 lung CT images with an average of 3.9 synthetic nodules (5-mm diameter) embedded randomly in the lung parenchyma. The radiologists' gaze volumes ( GV gaze volume s) were defined as the portion of the lung parenchyma within 50 pixels (approximately 3 cm) of all gaze points. The fraction of the total lung volume encompassed within the GV gaze volume s, the fraction of lung nodules encompassed within each GV gaze volume (search effectiveness), the fraction of lung nodules within the GV gaze volume detected by the reader (recognition-acceptance effectiveness), and overall sensitivity of lung nodule detection were measured. RESULTS: Detected nodules were within 50 pixels of the nearest gaze point for 990 of 992 correct detections. On average, radiologists searched 26.7% of the lung parenchyma in 3 minutes and 16 seconds and encompassed between 86 and 143 of 157 nodules within their GV gaze volume s. Once encompassed within their GV gaze volume , the average sensitivity of nodule recognition and acceptance ranged from 47 of 100 nodules to 103 of 124 nodules (sensitivity, 0.47-0.82). Overall sensitivity ranged from 47 to 114 of 157 nodules (sensitivity, 0.30-0.73) and showed moderate correlation (r = 0.62, P = .02) with the fraction of lung volume searched. CONCLUSION: Relationships between reader search, recognition and acceptance, and overall lung nodule detection rate can be studied with eye tracking. Radiologists appear to actively search less than half of the lung parenchyma, with substantial interreader variation in volume searched, fraction of nodules included within the search volume, sensitivity for nodules within the search volume, and overall detection rate.

Accuracy of a remote eye tracker for radiologic observer studies: effects of calibration and recording environment.

RATIONALE AND OBJECTIVES: To determine the accuracy and reproducibility of a remote eye-tracking system for studies of observer gaze while displaying volumetric chest computed tomography (CT) images. MATERIALS AND METHODS: Four participants performed calibrations using three different gray-scale backgrounds (black, gray, and white). Each participant then observed a three-dimensional 10-point test pattern embedded in five Digital Imaging and Communications in Medicine (DICOM) datasets (test backgrounds): a full 190-section chest CT scan, 190 copies of a single chest CT section, and three 190-section datasets of homogeneous intensity (black, gray, and white). RESULTS: Significant variances between participants, calibration backgrounds, and test backgrounds were observed. The least mean systematic error (deviation of recorded gaze position from target) was obtained when the calibration background and test background were black (27 pixels). Systematic error increased when displaying a test background that deviated from the calibration background intensity. Hence, the largest mean systematic error occurred when calibrating to a black background and displaying a white background (67 pixels). For complex chest CT volumes the white calibration background performed best (38 pixels). An angular analysis of the systematic error was performed and demonstrated that the systemic error primarily affects the vertical position of the estimated gaze position. CONCLUSION: Our findings indicate a potential source of systematic error during gaze recording in a dynamic environment and highlight the importance of configuring the calibration procedure according to the brightness of the display. We recommend that investigators develop routines for postcalibration accuracy measurement and report the effective accuracy for the display environment in which the data are collected.