Single-Masked Randomized Phase 2 Study Assessing 2 Forms of Hypofractionated Proton Therapy in Patients With Large Choroidal Melanomas.

PURPOSE: Patients with large uveal melanomas are at major risk of liver metastases. Some patients are reluctant to undergo the standard treatment (ie, immediate enucleation). Proton therapy yields 5-year local control rates and eyeball retention of >85% and ≈20% in large uveal melanomas. Patients with T3/T4 uveal melanomas refusing enucleation were randomized between standard 4 to 13 Gy-fraction or moderately hypofractionated 8 to 6.5 Gy-fraction proton therapy. The main endpoint was the 2-year local recurrence-free survival without enucleation. METHODS AND MATERIALS: A single-masked 1:2 randomized phase 2 trial was conducted between 2015 and 2017 with planned endoresection and distance to the posterior pole as strata. Local events were defined as local relapse, or enucleation due to complications or relapse. RESULTS: The 32 patients, with a mean age of 64 years, had T3/4 (N = 17/15), M1 (N = 2) uveal melanomas, of mean tumor diameter and thickness of 16.5 mm and 9.1 mm, and of posterior location in 56.5%. Median follow-up was 56.7 months. The 2-year local recurrence-free survival rate without enucleation was 79% (95% confidence interval, 65%-96%), similar in both arms. There were 9 enucleations, 3 at relapse and 6 for toxicities. Twelve patients had distant metastases. The 2-year-overall survival was 72% (95% confidence interval, 58%-89%). At baseline, visual acuity by average logarithm value of the minimum angle of resolution was 0.68 and 0.70 in the standard and experimental arms, and at last follow-up 2 and 1.7, with mean differences of 1.44 and 1.01, respectively (P = .39). CONCLUSION: An 8-times 6.5 Gy scheme is feasible without deteriorating local control and with similar toxicity rates in patients with large uveal melanomas. Larger studies incorporating adjuvant treatments are warranted.

OCT-angiography for the diagnosis of radiation maculopathy in patients treated with proton beam therapy: A 2-year prospective study.

PURPOSE: Radiation maculopathy (RM) is the leading cause of visual acuity (VA) loss after proton beam therapy (PBT) of choroidal melanoma. The aim of this study was to assess the value of optical coherence tomography-angiography (OCT-A) for the diagnosis of RM in patients with choroidal melanoma treated with PBT. MATERIALS & METHODS: This 2-year prospective, descriptive, single-center study included patients treated with PBT for choroidal melanoma. VA measurement, retinography, OCT and OCT-A were performed. Vascular density (VD) in the superficial capillary plexus (SCP), peri-foveal anastomotic ring changes and foveal avascular zone (FAZ) enlargement were studied. RESULTS: Nineteen patients were included in the study. The median baseline melanoma thickness was 5.7 [3.6-8.1] mm. The median melanoma-to-macula distance was 3.5 [2.6-4.6] mm. The earliest signs of RM identified on retinography were hard exudates developing at 12 [12-24] months, followed by retinal hemorrhages at 18 [12-30] months, found in 88.9% and 77.8% of patients respectively. On OCT, the earliest sign was the onset/progression of cystoid macular edema (CME) at 12 [6-12] months, found in 10 patients (52.6%). On OCT-A, 100% of patients presented with a discontinuity of the perifoveal anastomotic ring and a FAZ enlargement after 12 [6-24] months. After 12 months, a VD loss in the SCP by 11.7% and 10.8% compared to baseline, was found in the macular and foveal areas respectively. A significant negative correlation was found between the VA and the VD in the macular SCP (R = -0.43; p = 0.029). CONCLUSION: OCT-A is a reliable and effective diagnostic tool for RM in patients with choroidal melanoma treated with PBT.

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives.

Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, "no-touch" surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with "medical" eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.

Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease.

Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.

Conjunctival melanoma treatment outcomes in 288 patients: a multicentre international data-sharing study.

BACKGROUND: To relate conjunctival melanoma characteristics to local control. METHODS: Retrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. RESULTS: 288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2-8.9%), 19.3% (14.4-25.5%) and 36.9% (26.5-49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence. CONCLUSION: This multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.

COMPARATIVE EFFECTIVENESS OF PROTON BEAM VERSUS PHOTODYNAMIC THERAPY TO SPARE THE VISION IN CIRCUMSCRIBED CHOROIDAL HEMANGIOMA.

PURPOSE: The aim of this study was to compare the functional and anatomical effectiveness of photodynamic therapy (PDT) versus proton beam therapy (PBT) in a real-life setting for the treatment of circumscribed choroidal hemangioma. METHODS: A total of 191 patients with a diagnosis of circumscribed choroidal hemangioma and treated by PBT or PDT were included for analyses. RESULTS: The 119 patients (62.3%) treated by PDT were compared with the 72 patients treated by PBT. The final best-corrected visual acuity did not differ significantly between the two groups (P = 0.932) and final thickness was lower in the PBT compared with the PDT group (P = 0.001). None of the patients treated by PBT needed second-line therapy. In comparison, 53 patients (44.5%) initially treated by PDT required at least one other therapy and were associated with worse final best-corrected visual acuity (P = 0.037). In multivariate analysis, only an initial thickness greater than 3 mm remained significant (P = 0.01) to predict PDT failure with an estimated odds ratio of 2.72, 95% confidence interval (1.25-5.89). CONCLUSION: Photodynamic therapy and PBT provide similar anatomical and functional outcomes for circumscribed choroidal hemangioma ≤3 mm, although multiple sessions are sometimes required for PDT. For tumors >3 mm, PBT seems preferable because it can treat the tumor in only 1 session with better functional and anatomical outcomes.

Uveitis associated with latent tuberculosis: A comparative study of the impact of antitubercular therapy combined or not with systemic corticosteroids.

PURPOSE: To study the outcome of latent tubercular uveitis (LTBU) treated with antitubercular therapy (ATT) combined or not with adjuvant systemic corticosteroids. METHODS: Twenty patients (27 eyes) with LTBU were included in a monocentric retrospective study and evaluated for the absence of active disease after treatment. Data on the clinical outcomes (active inflammation), vision (best-corrected visual acuity, BCVA) and treatment were collected retrospectively. RESULTS: Fourteen patients received ATT alone and six patients received ATT combined with systemic corticosteroids. The two groups were not comparable in terms of proportion of tubercular panuveitis cases and initial BCVA (59.3 ± 8.2 letters vs 44.2 ± 15.2 letters). There was no significant difference in remission rate and in BCVA between both groups 3 months after ATT discontinuation. CONCLUSION: Patients with LTBU treated with ATT alone had visual and inflammatory outcomes at least comparable to those of patients treated with ATT combined with systemic corticosteroids.

Dose-Response and Normal Tissue Complication Probabilities after Proton Therapy for Choroidal Melanoma.

PURPOSE: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT). DESIGN: Retrospective study from single, large referral center. PARTICIPANTS: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients. METHODS: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes. MAIN OUTCOME MEASURES: Dose-response relationship for VA deterioration and late complications. RESULTS: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland. CONCLUSIONS: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures.

Psychometric properties of the revised symptoms inventory scl-90 r: Remote administration during confinement by COVID-19 in Mendoza / COMPORTAMIENTO PSICOMÉTRICO DEL INVENTARIO DE SÍNTOMAS REVISADO SCL-90 R: Administración remota durante confinamiento por COVID-19 en el Gran Mendoza

The SCL-90-R test is used to evaluate and describe various psychopathological symptoms; Therefore, it is necessary to have a normative basis for clinical practice and research in a pandemic context. In the present investigation, this technique was administered remotely using an online form made on the SurveyHeart platform. The compilation of current data occurs in the context of social, preventive and compulsory isolation by COVID-19 in a general population made up of both sexes in Greater Mendoza, in order to provide an scale assessment for a more approximate orientation in the evaluation of clinical practice, research and inventory administration in this remote modality in a pandemic context or in any other situation in which its application be appropriate. The nine main dimensions of the SCL-90-R showed high levels of internal consistency, confirming the reliability of this statistical analysis.

El test SCL-90-R es utilizado para evaluar y describir diversos síntomas psicopatológicos; es por tanto necesario contar con una base normativa para la práctica clínica e investigación en contexto pandémico. En la presente investigación, dicha técnica fue administrada a distancia mediante un formulario online realizado en la plataforma SurveyHeart. La recolección de los presentes datos se da en contexto de aislamiento social, preventivo y obligatorio por COVID-19 en una población general compuesta por ambos géneros en el Gran Mendoza. Se realiza, además, el baremo de valoración, cuyo objetivo es brindar una base de datos referencial para una orientación más aproximada en la evaluación de la práctica clínica, la investigación y la administración del inventario en esta modalidad remota en contexto pandémico o en cualquier otra situación en donde su aplicación pueda resultar procedente. Las nueve dimensiones principales del SCL-90-R mostraron elevados niveles de consistencia interna, lo que confirma la confiabilidad de la que fue objeto este análisis estadístico.

Perceived relaxation and its role as a protective factor against phobic anxiety during the course of preventive and compulsory social isolation due to COVID-19 in population of Mendoza. / LA RELAJACIÓN PERCIBIDA Y SU ROL COMO FACTOR PROTECTOR FRENTE A LA ANSIEDAD FÓBICA DURANTE EL TRANSCURSO DEL AISLAMIENTO SOCIAL, PREVENTIVO Y OBLIGATORIO POR COVID-19 EN EL GRAN MENDOZA

A crisis situation arises when an unprecedented event breaks into our reality, and the ways of coping that were used to solve similar problems are insufficient. This study is situated within the framework of "social, preventive and compulsory isolation", imposed by decree in the face of the COVID-19 pandemic, declared by the WHO. It was found that the perceived relaxation would have an incidence in favor of the reduction of phobic anxiety when comparing groups that perceive or not relaxation during the preventive and compulsory social isolation by COVID-19 in Greater Mendoza, thus behaving as a possible protective factor. Currently, very little is known about the psychological consequences that this type of measures, or this context, could produce, for which reason it is pertinent to analyze the factors that could be determining factors in the mental health and well-being of the population of Greater Mendoza.

Una situación de crisis surge cuando irrumpe en nuestra realidad un evento sin precedentes, y los modos de afrontamiento que se utilizaban para solucionar problemas similares, resultan insuficientes. El presente estudio se sitúa en el marco de "aislamiento social, preventivo y obligatorio", impuesto por decreto ante la pandemia de COVID-19, declarada por la OMS. Se encontró que la relajación percibida tendría una incidencia a favor de la reducción de la ansiedad fóbica al comparar grupos que perciben o no relajación durante el aislamiento social preventivo y obligatorio por COVID-19 en el Gran Mendoza, comportándose así, como un posible factor protector. Actualmente se conoce muy poco acerca de las consecuencias psicológicas que este tipo de medidas, o este contexto, podría producir, por lo cual resulta pertinente analizar los factores que podrían ser determinantes en la salud mental y el bienestar de la población del Gran Mendoza.

Ultra-widefield fundus photography for radiation therapy planning of ocular tumours.

PURPOSE: The use of planar ultra-widefield fundus photography (UWF) may result in distortions and inaccurate measurement. The aim of the study was to evaluate the accuracy of UWF instead of the standard narrow field (SF) for the treatment planning phase of ocular tumours. METHODS: Distortions between conformal SF and UWF were assessed in 43 patients with choroidal melanoma treated with either proton therapy or brachytherapy. imagej software was used to measure distortion. RESULTS: The median interquartile range ([IQR]) distortion for all cases was 3.7% [1.7-10.8]. For cases with tumours within 6 mm of the optic disc, distortions appeared clinically nonsignificant. For peripheral and/or large tumours, significantly larger distortions were observed on UWF (median 4.4% [2.7-22.6] for tumours ≥6 mm from the optic disc versus 3.3% [1.6-9.9] for those <6 mm, p = 0.04). Images can be subdivided into three groups: minimal distortion (79.1% of eyes), similar level of major distortion for both measured distances (11.6%) and distortion with unequal level of distortion between the measured distances (9.3%). CONCLUSION: Distortions with UWF appeared minimal in posterior regions of the fundus and increased with the distance from the posterior pole. UWF could therefore be used for treatment planning of ocular tumours as the planned radiation dose to the macula and optic disc are not impacted.

Diagnosis and treatment of peripheral exudative haemorrhagic chorioretinopathy.

PURPOSE: Peripheral exudative haemorrhagic chorioretinopathy (PEHCR) is a rare disorder that is often misdiagnosed. The aim of this study was to better characterise PEHCR and to assess treatment options. MATERIAL AND METHODS: Retrospective multicentric chart review. RESULTS: Of 84 eyes (69 patients) with PEHCR referred between 2005 and 2017, the most common referral diagnosis was choroidal melanoma (41.3%). Bilateral involvement was found in 21.7% of cases. Haemorrhagic retinal pigment epithelium detachment was the most common peripheral lesion (53.6%). Maculopathy was associated with peripheral lesions in 65.8% of cases. PEHCR lesions were mostly heterogeneous (58.8%) on B-scan ultrasonography. Choroidal neovascularisation was found in 10 eyes (26.3%) out of 38 eyes that underwent fluorescein angiography. Polyps were observed in 14 eyes (58.3%) out of 24 eyes that underwent indocyanine green angiography. Fifty-one eyes were treated (62.2%). Intravitreal injections (IVTI) of antivascular endothelial growth factor (VEGF) were the most used treatment (36.6%) before laser photocoagulation, photodynamic therapy, vitrectomy and cryotherapy. Only vitrectomy improved visual acuity. Most lesions (65.6%) regressed at the last follow-up visit. CONCLUSION: In case of PEHCR, multimodal imaging is useful to avoid misdiagnosis, to characterise PEHCR lesions and to guide treatment strategies. Regression of PEHCR lesions was observed in two-thirds of the patients. Vitrectomy improved visual acuity. More than a third of patients underwent anti-VEGF IVTI. Further studies are needed to assess IVTI's efficacy.

Oncologic and visual outcomes after postoperative proton therapy of localized conjunctival melanomas.

INTRODUCTION: conjunctival melanomas have high local relapse rates. Oncologic and visual outcomes can be improved with proton therapy and no-touch surgery. MATERIAL AND METHODS: a monocentric retrospective study of consecutive patients treated with surgery and proton therapy for conjunctival melanoma was conducted. Proton therapy was performed to a total dose of 45 Grays physical dose delivered in eight fractions over two weeks. RESULTS: Ninety-two patients were included. The mean age was 63-year-old. 65.2% of patients had primary acquired melanosis. The mean tumor thickness and diameter was 2.5 mm and 7.0 mm respectively. The clinical stage was T1 in 71.6% of cases, with a quadrangular involvement of more than 90° in 69% of cases. Conjunctival melanomas were of epithelioid cell-type in 40% of cases. Mean follow-up was 4.7 years. Five-year local failure rate was 33.2%. Of 25 local recurrences, 14 were marginal/out-of-field, 4 in-field, others were undetermined. First surgery at expert center resulted in 24.3% of local failure at 5 years versus 38.7% if performed elsewhere (p = 0.41). Salvage exenteration was performed in 13 patients. Tumor stage and quadrangular involvement were significant factors for local failure. Five-year progression-free survival and cause-specific death rates were 61.5 and 3.6%. Stage and epithelioid type were associated with poorer progression-free survival. Trophic toxicity occurred in 22.9% of patients and was treated locally, with grafts in 7 patients. Glaucoma and cataract occurred in 13 and 22 patients respectively. Prognostic factors for visual deterioration were age, tumor extent (multifocality, quadrangular involvement > 180°) and cryotherapy. CONCLUSIONS: 5-year local failure rate after postoperative proton therapy for conjunctival melanoma was of 33.2%. Radiation-induced complications were overall manageable.

The Molecular Pathology of Eye Tumors: A 2019 Update Main Interests for Routine Clinical Practice.

Over the last few years, we have seen constant development of molecular pathology for the care of patients with cancer. The information obtained from molecular data has transformed our thinking about the biological diversity of cancers, particularly in the field of ophthalmic oncology. It has reoriented the way in which therapeutic decisions and decisions concerning patient surveillance are made, both in the area of pediatric cancers, including rhabdomyosarcoma and retinoblastoma, and adult cancers, such as uveal melanoma and lymphomas. A better definition of the molecular classification of these cancers and of the different biological pathways involved is essential to the understanding of both the pathologist and the onco-ophthalmologist. Molecular tests based on targeted or expanded analysis of gene panels are now available. These tests can be performed with tumor tissue or biofluids (especially blood) to predict the prognosis of tumors and, above all, the benefit of targeted therapies, immunotherapy or even chemotherapy. Looking for the BAP1 mutation in uveal melanoma is essential because of the associated metastatic risk. When treating retinoblastoma, it is mandatory to assess the heritable status of RB1. Conjunctival melanoma requires investigation into the BRAF mutation in the case of a locally advanced tumor. The understanding of genomic alterations, the results of molecular tests and/or other biological tests predictive of a therapeutic response, but also of the limits of these tests with respect to the available biological resources, represents a major challenge for optimal patient management in ophthalmic oncology. In this review, we present the current state of knowledge concerning the different molecular alterations and therapeutic targets of interest in ophthalmic oncology.

Multicenter, International Assessment of the Eighth Edition of the American Joint Committee on Cancer Cancer Staging Manual for Conjunctival Melanoma.

IMPORTANCE: Eye cancer staging systems used for standardizing patient care and research need to be validated. OBJECTIVE: To evaluate the accuracy of the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual in estimating metastatis and mortality rates of conjunctival melanoma. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, registry-based case series pooled data from 10 ophthalmic oncology centers from 9 countries on 4 continents. A total of 288 patients diagnosed with conjunctival melanoma from January 1, 2001, to December 31, 2013, were studied. Data analysis was performed from July 7, 2018, to September 11, 2018. INTERVENTIONS: Treatments included excision biopsy, cryotherapy, topical chemotherapy, radiation therapy, enucleation, and exenteration. MAIN OUTCOMES AND MEASURES: Metastasis rates and 5-year and 10-year Kaplan-Meier mortality rates according to the clinical T categories and subcategories of the eighth edition of the AJCC Cancer Staging Manual. RESULTS: A total of 288 eyes from 288 patients (mean [SD] age, 59.7 [16.8] years; 147 [51.0%] male) with conjunctival melanoma were studied. Clinical primary tumors (cT) were staged at presentation as cT1 in 218 patients (75.7%), cT2 in 34 (11.8%), cT3 in 15 (5.2%), and cTx in 21 (7.3%). There were no T4 tumors. Pathological T categories (pT) were pTis in 43 patients (14.9%), pT1 in 169 (58.7%), pT2 in 33 (11.5%), pT3 in 12 (4.2%), and pTx in 31 (10.8%). Metastasis at presentation was seen in 5 patients (1.7%). Metastasis during follow-up developed in 24 patients (8.5%) after a median time of 4.3 years (interquartile range, 2.9-6.0 years). Of the 288 patients, 29 died (melanoma-related mortality, 10.1%) at a median time of 5.3 years (interquartile range, 1.8-7.0 years). The cumulative rates of mortality among patients with cT1 tumors were 0% at 1 year, 2.5% (95% CI, 0.7%-7.7%) at 5 years, and 15.2% (95% CI, 8.1%-27.4%) at 10 years of follow-up; among patients with cT2 tumors, 0% at 1 year, 28.6% (95% CI, 12.9%-58.4%) at 5 years, and 43.6% (95% CI, 19.6%-77.9%) at 10 years of follow-up; and among patients with cT3 tumors, 21.1% (95% CI, 8.1%-52.7%) at 1 year of follow-up and 31.6% (95% CI, 13.5%-64.9%) at 5 years of follow-up. Patients with cT2 and cT3 tumors had a significantly higher cumulative mortality rate compared with those presenting with cT1 tumors (log-rank P < .001). Patients with ulcerated melanomas had significantly higher risk of mortality (hazard ratio, 7.58; 95% CI, 1.02-56.32; P = .04). CONCLUSIONS AND RELEVANCE: This multicenter, international, collaborative study yielded evidence that the conjunctival melanoma staging system in the eighth edition of the AJCC Cancer Staging Manual can be used to accurately estimate metastasis and mortality rates. These findings appear to support the use of AJCC staging as a tool for patient care and research.

The Lens Opacities Classification System III Grading in Irradiated Uveal Melanomas to Characterize Proton Therapy-Induced Cataracts.

PURPOSE: To evaluate the use of the Lens Opacities Classification System III grading (LOCS III) for the characterization of radiation-induced cataract, and to correlate the proton beam projection onto the lens with cataract location and grade as defined by the LOCS III. DESIGN: Prospective, interventional case series. METHODS: Fifty-two consecutive patients with cataract following proton therapy were included. All cataracts were graded using LOCS III. Relationships between proton beam and cataract subtypes, as well as between dose, proportion of lens irradiated, and extent of cataracts, were assessed. RESULTS: Tumor diameter, volume, stage, and equatorial tumor location were associated with extent of posterior subcapsular cataracts (PSC) that were diagnosed at a median (interquartile range) 36 months (22;83) after treatment. In multivariate analysis, the tumor volume (P < .01) and an equatorial tumor location (P = .01) were risk factors for extensive PSC. Lens irradiation was avoided in 10 patients. In the remaining 42 patients (81%), the extent of PSC significantly correlated with the dose to the lens receiving 10, 26, and 47 Gy (P = .03, P = .03, and P = .04, respectively), the dose to the lens periphery receiving 10 and 26 Gy (P = .02 and P = .02, respectively), and the dose to the ciliary body receiving 10 and 26 Gy (P = .03 and P = .02, respectively). Nuclear color significantly correlated with the dose to the ciliary body receiving 10 Gy (P = .03) and 26 Gy (P = .02). After adjustment of the results on tumor volume and tumor location, the volume of lens receiving 10 Gy (P = .04) and 26 Gy (P = .03) remained significantly associated with the extent of PSC. CONCLUSIONS: Proton dose correlated with the occurrence of PSC and nuclear color cataracts as defined by LOCS III grading. Better characterization of cataracts with the LOCS III after irradiation may help to further fill gaps in the current understanding of the mechanisms of radiation-induced cataracts.

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome.

Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

Management of Invasive Squamous Cell Carcinomas of the Conjunctiva.

PURPOSE: Ocular surface squamous neoplasia includes a spectrum of diseases from dysplasia to invasive squamous cell carcinoma (SCC) of the conjunctiva. Whether the degree of invasion influences outcomes is debated. We evaluated the outcomes and management of conjunctival carcinomas defined as ≤0.2 mm invasion of the chorion (microinvasive; miSCC) or over (SCC). DESIGN: Retrospective case series. METHODS: Clinical, tumor, and therapeutic characteristics and outcomes were collected for consecutive patients with histology-proven invasive conjunctival miSCC/SCC treated between 2002 and 2017. RESULTS: Patients were 70% men, ≥70 years old (56%), with carcinomas of the bulbar conjunctiva (83.0%). Limbal, corneal, and/or scleral involvement were present in 70.4%, 42.6%, and 27.8%, respectively. Patient characteristics, tumor characteristics, and no-touch surgery rates were similar between the 39 SCC and 15 miSCC. However, mitomycin was performed in 93.3% and 20.5% of miSCC and SCC, respectively (P < .001). Proton therapy was performed in 0% and 92.0% of miSCC and SCC, respectively (P < .001). SCC received mitomycin in case of tumoral resection margins, respectively (P = .018). The 24-month incidence of local relapse was 14.8%, including 20% and 12% for miSCC and SCC, respectively (P = .079). Irradiation was the only prognostic factor associated with a lower risk for local relapse (hazard ratio [0.25]; P = .045). There were 2 cancer-related deaths (2%). Mild/moderate anterior segment complications occurred in one third of the patients. CONCLUSIONS: miSCC had slightly worse relapse rates compared with SCC. Postoperative proton therapy, performed in SCC only, was associated with a lower risk for relapse.

[Management of uveal melanomas, guidelines for oncologists]. / Prise en charge des mélanomes oculaires, le minimum pour les oncologues.

Uveal melanomas are the most frequent primary malignant eye tumor. Enucleation was historically the gold standard. Since then, several studies showed that conservative treatments did not increase the risk of metastasis or survival. Choroidal melanomas are both radioresistant and located close to visual structures (the optic nerve and macula) of the eye, which may be preserved in some settings without compromising tumor control, as this is the first priority. Different types of radiation therapy may be used for such tumors: brachytherapy and charged particles, including proton beam therapy. If visual prognosis is dependent to the local treatment, the vital prognosis is dependent on the metastatic risk, with a risk of liver involvement in 20 to 50% of patients, depending on tumor size and genomics. Median survival after the discovery of liver metastases is about 15 months. The management of these patients is often complex. Systemic therapies (chemotherapy, targeted therapies, immunotherapy, etc.) yield limited response rates and although local treatments of liver metastases are promising, they are only feasible in selected patients. The mission of the MELACHONAT national network is to improve the management of patients regardless of the stage of the disease. The patient association ANPACO is dedicated to help uveal melanoma patients in their health care path and to promote knowledge dissemination within the patient community. The aim of this review is to focus on the local treatments of uveal melanomas as well as the management of their metastatic evolution.