Hidden in the Eyes-Recurrence of Systemic Hemopathies Reportedly "In Remission": Six Cases and Review of Literature.

Background and Objectives: Secondary ocular localizations of hematological malignancies are blinding conditions with a poor prognosis, and often result in a delay in the diagnosis. Materials and Methods: We describe a series of rare cases of ocular involvement in six patients with hematological malignancies, reportedly in remission, who presented secondary ocular localizations, challenging to diagnose. Two patients had an acute lymphoblastic leukemia (ALL) and developed either a posterior scleritis or a pseudo-panuveitis with ciliary process infiltration. One patient had iris plasmacytoma and developed an anterior uveitis as a secondary presentation. Two patients had a current systemic diffuse large B-cell lymphoma (DLBCL) and were referred either for intermediate uveitis or for papilledema and vitritis with secondary retinitis. Finally, one patient with an acute myeloid leukemia (AML) presented a conjunctival localization of a myeloid sarcoma. We herein summarize the current knowledge of ophthalmologic manifestations of extramedullary hematopathies. Results: Inflammatory signs were associated with symptomatic infiltrative lesions well displayed in either the iris, the retina, the choroid, or the cavernous sinus, from the admission of the patients in the ophthalmological department. These findings suggest that patients with ALL, AML, systemic DLBCL, and myeloma can present with ophthalmic involvement, even after having been reported as in remission following an effective systemic treatment and/or allograft. Conclusions: Early detection of hidden recurrence in the eyes may permit effective treatment. Furthermore, oncologists and ophthalmologists should be aware of those rare ocular malignant locations when monitoring patient's progression after initial treatment, and close ophthalmologic examinations should be recommended when detecting patient's ocular symptoms after treatment.

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.

Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy.

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic retinal disorder usually occurring in the context of metastatic melanoma. Patients present with night blindness, photopsias and a constriction of the visual field. MAR is an auto-immune disorder characterized by the production of autoantibodies targeting retinal proteins, especially autoantibodies reacting to the cation channel TRPM1 produced in melanocytes and ON-bipolar cells. TRPM1 has at least three different isoforms which vary in the N-terminal region of the protein. In this study, we report the case of three new MAR patients presenting different anti-TRPM1 autoantibodies reacting to the three isoforms of TRPM1 with variable binding affinity. Two sera recognized all isoforms of TRPM1, while one recognized only the two longest isoforms upon immunolocalization studies on overexpressing cells. Similarly, the former two sera reacted with all TRPM1 isoforms on western blot, but an immunoprecipitation enrichment step was necessary to detect all isoforms with the latter serum. In contrast, all sera labelled ON-bipolar cells on Tprm1+/+ but not on Trpm1-/- mouse retina as shown by co-immunolocalization. This confirms that the MAR sera specifically detect TRPM1. Most likely, the anti-TRPM1 autoantibodies of different patients vary in affinity and concentration. In addition, the binding of autoantibodies to TRPM1 may be conformation-dependent, with epitopes being inaccessible in some constructs (truncated polypeptides versus full-length TRPM1) or applications (western blotting versus immunohistochemistry). Therefore, we propose that a combination of different methods should be used to test for the presence of anti-TRPM1 autoantibodies in the sera of MAR patients.

Comparative Cytogenetic Abnormalities in Paired Choroidal Melanoma Samples Obtained Before and After Proton Beam Irradiation by Transscleral Fine-Needle Aspiration Biopsy and Endoresection.

This study compared the cytogenetic profiles of choroidal melanoma samples retrieved before and after proton beam irradiation. Twenty-four consecutive patients who underwent both fine-needle aspiration biopsy (FNAB) during tantalum clip positioning, and endoresection within three months of irradiation, were retrospectively included. Chromosome alterations were explored by array comparative genomic hybridization. Age at diagnosis was 50 ± 14 years, tumor thickness was 8.6 ± 1.7 mm and tumor diameter was 12.4 ± 2.3 mm. Six FNAB samples were non-contributive (25%), versus one endoresection sample (4%) (p = 0.049). Among 17 cases with paired contributive samples, the profiles of chromosomes 3 and 8 were identical in all cases, except one with partial chromosome 3 loss on the FNAB sample only. Three cases presented additional discordant aberrations on chromosomes other than 3 or 8q. Overall, we identified monosomy 3 in two cases, 8q gain in six cases, and both alterations in three cases. All cases presented GNAQ or GNA11 mutations assessed by a custom next-generation sequencing panel. Among the six cases with non-contributive initial FNAB, three cases presented abnormal 3 or 8q chromosomes detected on the endoresection material. These results demonstrate the higher rentability of endoresection material for cytogenetic analysis compared to FNAB, and provide clinical evidence of tumor heterogeneity in choroidal melanoma.

Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations.

PURPOSE: Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas.Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing. RESULTS: MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse. CONCLUSIONS: MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.

[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.

Morphological Predictive Features on Spectral-Domain Optical Coherence Tomography for Visual Outcomes in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab.

PURPOSE: To identify spectral-domain optical coherence tomography (SD-OCT) predictive morphological features for the outcome of Ranibizumab therapy for neovascular age-related macular degeneration (AMD). METHODS: This is a retrospective multicentric study that involved 64 eyes with naïve AMD. Patients who received three monthly intravitreal injections of Ranibizumab were stratified into (1) "responders" [≥ 5 letters gain on Early Treatment Diabetic Retinopathy Study (ETDRS) scale] and (2) "nonresponders" (< 5 letters gain). Best-corrected visual acuity (BCVA) and SD-OCT morphological features were compared at baseline and one month after three consecutive injections of Ranibizumab. Univariate and multivariate analyses were carried out to correlate these morphological features with the change in BCVA. RESULTS: Among the 64 patients enrolled, 40 (62.5%) were "responders" and 24 (37.5%) "nonresponders". Age, sex, and BCVA were comparable between both groups. A multivariate correlational analysis found that subfoveal choroidal thickness (SFCT) and the presence of pigment epithelial detachment (PED) > 250 µm at baseline were two independent prognostic indicators of final BCVA. No other SD-OCT morphological studied features seem to affect final BCVA after Ranibizumab treatment. CONCLUSION: SFCT and the presence of PED > 250 µm are two significant biomarkers that may predict improvement after Ranibizumab therapy for AMD. These markers may guide ophthalmologists' treatment decision under financial constraints and limited time.

Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

Photocoagulation therapy of leaking archer's type 2 retinal arteriovenous communication.

PURPOSE: Type 2 retinal arteriovenous communication is characterized by direct arteriovenous communication without an intervening arteriolar or capillary segment. It may be complicated by extravascular exudation. The successful results of low-intensity argon laser photocoagulation in two cases are reported. METHODS: Case report of two patients. RESULTS: Both cases were associated with a serous macular detachment, showing evidence of vascular leakage. Argon laser photocoagulation was performed. Visual improvement was observed in both cases, with disappearance of vascular leakage. CONCLUSION: Type 2 arteriovenous communications lead to increased arterial flow through a low-resistance vein. The resulting high intraluminal pressure may explain the observed vascular ectasia and consequent fluid leakage. Spontaneous regression may occur. Nevertheless, direct argon laser photocoagulation may be considered a therapeutic option and lead to visual improvement.

Foveal shape and structure in a normal population.

PURPOSE: The shape of the human fovea presents important but still poorly characterized variations. In this study, the variability of the shape and structure of normal foveae were examined. METHODS: In a group of 110 eyes of 57 healthy adults, the shape and structure of the fovea were analyzed by automated segmentation of retinal layer on high-resolution optical coherence tomography scans. In an additional group of 10 normal eyes of 10 patients undergoing fluorescein angiography, the size of the foveal avascular zone (FAZ) was correlated to foveal shape. RESULTS: From the thickest to the thinnest fovea, there was a structural continuum ranging from a shallow pit with continuity of the inner nuclear layer (INL) over the center (seven eyes; 6.7%), to a complete separation of inner layers overlying a flat and thinner central outer nuclear layer (ONL; eight eyes; 7.3%). Central foveal thickness correlated inversely to the degree of inner layer separation and to the surface of the FAZ. CONCLUSIONS: Foveal structure strongly correlates with its neurovascular organization. The findings support a developmental model in which the size of the FAZ determines the extent of centrifugal migration of inner retinal layers, which counteracts in some way the centripetal packing of cone photoreceptors.

Optical coherence tomography identification of occult choroidal neovascularization in age-related macular degeneration.

PURPOSE: To evaluate and describe the various optical coherence tomography (OCT) features of occult choroidal neovascularization (CNV) in age-related macular degeneration (AMD) at the time of diagnosis. DESIGN: Prospective, consecutive, observational case series. METHODS: One hundred and fifty-three eyes of 130 consecutive patients with subfoveal occult CNV diagnosed on scanning laser ophthalmoscope (SLO) fluorescein angiography (FA) and SLO indocyanine green angiography (ICGA) were evaluated with OCT. The diagnostic criteria for occult CNV on angiography were heterogeneous hyperfluorescence with late leakage in the macular region associated with pigment epithelial detachment (PED), stippled hyperfluorescent dots, and signs of deterioration. OCT findings were evaluated and described. RESULTS: A PED was observed on OCT in 98% (150 eyes) either as a limited retinal pigment epithelium (RPE) elevation (54 eyes [35.3%]) or a complete detachment (96 eyes [62.7%]). Occult CNV corresponded to zones of hyperreflectivity in contact with the RPE band and was detected in 62.7% of eyes. In fibrovascular PED (63 eyes [65.5%]), the elevated RPE was highlighted posteriorly by a moderately reflective band overlying a hyporeflective cavity. In serous PED, the cavity remained optically empty. The RPE in the detached zone showed changes such as fragmentation (137 eyes [89.5%]). OCT also showed intraretinal (122 eyes [79.7%]) and subretinal (64 eyes [41.8%]) fluid. CONCLUSIONS: Analysis of the various OCT features observed in this study confirms the polymorphic nature of occult CNV in AMD, their exudative reactions, the almost constant presence of PED, and the different changes in the RPE band. OCT examination, therefore, provides valuable data to confirm the features of subepithelial occult CNV.