The role of c-kit and imatinib mesylate in uveal melanoma

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, leading to metastasis in 40% of the cases and ultimately to death in 10 years, despite local and/or systemic treatment. The c-kit protein (CD117) is a membrane-bound tyrosine kinase receptor and its overexpression has been observed in several neoplasms. Imatinib mesylate is a FDA approved compound that inhibits tyrosine quinase receptors, as well as c-kit. Imatinib mesylate controls tumor growth in up to 85% of advanced gastrointestinal stromal tumors, a neoplasia resistant to conventional therapy. METHODS: Fifty-five specimens of primary UM selected from the archives of the Ocular Pathology Laboratory, McGill University, Montreal, Canada, were immunostained for c-kit. All cells displaying distinct immunoreactivity were considered positive. Four human UM cell lines and 1 human uveal transformed melanocyte cell line were tested for in vitro proliferation Assays (TOX-6) and invasion assay with imatinib mesylate (concentration of 10 μM). RESULTS: The c-kit expression was positive in 78.2% of the UM. There was a statistical significant decrease in the proliferation and invasion rates of all 5 cell lines. CONCLUSION: The majority of UM expressed c-kit, and imatinib mesylate does decrease the proliferation and invasion rates of human UM cell lines. These results justify the need for a clinical trial to investigate in vivo the response of UM to imatinib mesylate

The correlation between ultrasound biomicroscopy of filtering blebs, with or without mitomycin C, and intraocular pressure

Purpose: To evaluate the presence or absence of filtering blebs, its cavities, differences in diameter, height, wall thickness, seen on ultrasound biomicroscopy (UBM) of eyes submited to trabeculectomy, with or without using mitomicyn C (MMC), and to evaluate the effect of these caracteristics on the intraocular pressure (IOP). Methods: In a nonrandomized fashion, a six-month cohort study of 61 eyes of 44 glaucoma patients examined by UBM, all of which underwent trabeculectomy. Of these, 38 received MMC and 23 did not. All eyes were examined and evaluated post-operatively by UBM, with a 50 mHz probe, using the technique described by Pavlin in 1991 (Pavlin et al., 1991). Results: Bleb height was 1.80 ± 0.74 mm in eyes with MMC and 1.40 ± 0.53 mm in the ones without MMC. The thickness of the bleb wall was 0.91 ± 0.59 mm in eyes with MMC and 0.51 ± 0.45 mm in the ones without MMC. IOP measured was 12.37 ± 5.45 mmHg in eyes with MMC and 14.91 ± 5.48 mm in the ones without MMC. Conclusions: UBM study showed that bleb height was the main influencing factor in lowering IOP. The bleb wall was significantly thicker in eyes with MMC than in the ones without MMC. Decrease of IOP was significantly higher in eyes with MMC, with an average difference of 2.54 mmHg.Objetivo: Avaliar, pela biomicroscopia ultra-sônica (UBM), a presença ou não de bolhas filtrantes antiglaucomatosas, observando sua cavidade, e suas diferenças no diâmetro, altura e espessura da parede, em olhos submetidos à cirurgia de trabeculectomia, com ou sem o uso de mitomicina C (MMC), e avaliar o efeito destas características sobre a pressão intra-ocular (Po). Métodos: De forma aleatória, em um estudo de coorte com duração de seis meses, foram examinados pela UBM 61 olhos de 44 pacientes portadores de glaucoma, submetidos à cirurgia de trabeculectomia, tendo 38 recebido a mitomicina C (MMC) e 23 não. Todos os olhos foram examinados e avaliados no pós-operatório pelo UBM, com sonda de 50 MHz, utilizando a técnica descrita por Pavlin em 1991 (Pavlin et al., 1991). Resultados: A altura da bolha filtrante foi de 1,80 ± 0,74 mm nos olhos com MMC e de 1,40 ± 0,53 mm naqueles sem MMC. A espessura da parede da bolha foi de 0,91 ± 0,59 mm nos olhos que receberam a MMC e 0,51 ± 0,45 mm naqueles que não receberam. A Po foi de 12,37 ± 5,45 mmHg nos olhos com MMC e de 14,91 ± 5,48 mmHg nos que não receberam. Conclusões: O estudo pelo UBM demonstrou que foi a altura da bolha o elemento que mais influenciou na diminuição da Po. A espessura da parede foi significativamente maior nos olhos com MMC do que nos sem MMC. A diminuição da Po foi maior nos olhos em que foi utilizada a MMC, com uma diferença média de 2,54 mmHg.Fundação Faculdade Federal de Ciências Médicas de Porto AlegreISCMPA Santa Casa de Porto Alegre serviço de oftalmologiaFFFCMPA ISCMPAUniversidade Federal de São Paulo (UNIFESP) EPM departamento de oftalmologiaFaculdade de Ciências Médicas de SantosISCMPA serviço de oftalmologia setor de retina, oncologia oftalmológica e ultra-sonografia ocularISCMPA FFFCMPAUNIFESP, EPM, Depto. de oftalmologiaSciEL

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

The Role of Ultrasound Biomicroscopy in Surgical Planning for Limbal Dermoids

PURPOSELimbal dermoids usually involve corneal stroma and more rarely might extend into the anterior chamber. Depending on the size and amount of penetration of the lesion, different therapeutic approaches are indicated. Depth information is difficult to obtain by slit-lamp examination because the structure is opaque. We investigated the use of ultrasound biomicroscopic (UBM) examination for surgical planning in limbal dermoids. METHODSThe UBM (Zeiss Humphrey) with its 50-MHz probe was used for preoperative evaluation of the depth of penetration in two cases of infantile limbal dermoid. Histology specimens of the lesion corresponding to the UBM images were obtained. RESULTSUBM was able to distinguish normal cornea from the more sonolucent lesion. Presence or absence of Descemetʼs membrane could be identified. Depth of involvement of limbal dermoids could be assessed. CONCLUSIONUBM is able to assess depth involvement of opaque corneal lesions such as limbal dermoids. Because planning of the surgical approach in these cases is facilitated by preoperative knowledge about the depth of penetration of these opaque lesions, UBM can be regarded as a helpful tool in the clinical management

Indications for Fine Needle Aspiration Biopsy of Posterior Segment Intraocular Tumors

PURPOSE: To define 4 indication categories of fine needle aspiration biopsies (FNABs) of solid intraocular tumors and describe the differences among the patients, tumors, and results of biopsy in these 4 indication categories. METHODS: Retrospective descriptive analysis of 880 FNABs of a solid intraocular tumor of the posterior ocular segment performed by in the authors' ocular oncology practice during the period July 1980 through July 2014. RESULTS: FNABs were performed as a separate procedure in 372 cases (42.3%), at plaque implantation in 279 (31.7%), post-enucleation in 225 (25.6%), and postresection/pre-laser in 4 (0.4%). FNABs were categorized as diagnostic in 292 (33.2%), confirmatory in 121 (13.8%), investigational in 187 (21.3%), and prognostic in 280 (31.8%). Prior to the biopsy, all patients who underwent diagnostic FNAB had a tumor of uncertain pathologic type, while all patients who underwent confirmatory FNAB had a clinically diagnosed malignant intraocular neoplasm. In contrast, all patients who underwent a prognostic FNAB had an unequivocal primary posterior uveal melanoma clinically, while patients who underwent an investigational biopsy all had an unequivocal or probable malignant intraocular tumor of a specific type. Most diagnostic FNABs were performed transvitreously (n = 255, 87.3%) compared to prognostic FNABs (n = 143, 51.1%) (P < .001). Overall, 733 FNABs (83.3%) yielded a sufficient specimen for cytologic diagnosis. Diagnostic and confirmatory FNABs were the most likely to yield an insufficient aspirate (28.4% and 20.7%, respectively), while investigational and prognostic FNABs were most likely to yield sufficient specimens (94.7% and 90.0%, respectively) (P < .001). Mean post-FNAB follow-up of the entire group was 62.7 months (standard deviation [SD] = 59.8, 95% confidence interval [CI] = 58.7-66.6). Mean posttreat ment follow-up or total follow-up of untreated patients was 53.7 months (SD = 58.7, 95% CI = 49.8-57.6). CONCLUSIONS: Because of the substantial differences shown among FNAB cases performed for different indications, it seems appropriate to report results of FNAB or other biopsy methods according to the category (indication) of the biopsy. (C) 2019 Elsevier Inc. All rights reserved