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Background Wilson's disease (WD) is an autosomal recessive genetic disorder due to a mutation of the ATP7B gene, resulting in impaired hepatic copper excretion and accumulation in various tissues. Lifelong decoppering treatments are the keystone of the treatment. These treatments can prevent, stabilize, or reverse the symptoms making WD a chronic disease. Quality of life (QoL) is one of the best outcome measures of any therapeutic intervention in chronic diseases but has not been evaluated in large cohorts of WD patients.Method To better evaluate the QoL in WD and the correlation with different clinical or demographic factors we have performed a prospective cross-sectional study.Results Two hundred fifty-seven patients (53.3% men, mean age of 39.3 years and median disease duration of 18.8 years) were included between 1st January 2021 and 31st December 2021. Hepatoneurological form of the disease and depression were significantly correlated with low QoL (p Conclusions Neurological patients should be closely monitored to prevent and treat symptoms of depression that impact their quality of life.

This study was undertaken to determine the role of optical coherence tomography (OCT) in predicting the final visual and structural outcome, and to evaluate the correlation between functional eye outcome and retinal changes, in patients with a first episode of optic neuritis (ON).In this prospective study, consecutive adult patients with acute ON underwent ophthalmological evaluation at baseline and at 1 and 12 months, including OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell and inner plexiform layer, and inner nuclear layer thicknesses; high- and low-contrast visual acuity; visual field assessment; and baseline brain magnetic resonance imaging. Univariate and multivariate linear regressions were used to assess predictive factors of outcome. Correlations between 12-month visual function and retinal structure were estimated by Spearman coefficients. Two groups of patients were analyzed, with or without multiple sclerosis (MS).Among 116 patients, 79 (68.1%) had MS, and 37 (31.9%) had ON not related to MS (including 19 idiopathic [i.e., isolated] ON, and 13 and five with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies, respectively). We found no independent predictive factor of visual and retinal outcome. Analysis of the relationship between the visual field test (mean deviation) and pRNFL thickness demonstrated a threshold of 75.4 μm and 66.4 μm, below which the mean deviation was worse, for patients with MS (p = 0.007) and without MS (p lt; 0.001), respectively.We found that inner retinal layer measurements during the first month are not predictive of final outcome. The critical threshold of axonal integrity, below which visual function is damaged, is different between patients with and without MS.

This section contains details of all mixed models utilized in the statistical analyses. The inferential tests performed in this paper necessitates a multiple comparisons adjustment, and details of the adjustment procedure is included in this section as well.

Purpose: Bone marrow–derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II–III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

The top panel shows the reaction chemistry of established lysyl oxidase (LOX) activity assay. The bottom panel shows the Amplex Red/HRP-based LOX activity assay that detects LOX activity in vitro.

This is the demographics table containing brief summary of baseline patient characteristics of patients enrolled on trial.

This is the demographics table containing detailed baseline patient characteristics listed for each of the 75 patients. The data is de-identified.

Purpose: To determine the prevalence and characteristics of foveal hypoplasia (also called fovea plana) in patients with Best disease using spectral-domain (SD) optical coherence tomography (OCT) and OCT-angiography (OCT-A). Design: A retrospective observational study including patients diagnosed with Best disease. Subjects and Participants: Fifty-nine eyes of thirty-two patients (fifteen females (46.9%) and seventeen males (53.1%), p = 0.9) diagnosed with Best disease were included. Patients’ eyes were categorized into two groups: Eyes with a fovea plana appearance (‘FP group’) and eyes without fovea plana appearance (‘no FP group’), based on the foveal appearance on B-scan SD-OCT. Methods and Main Outcome Measures: Cross-sectional OCT images were assessed for the persistence of inner retinal layers (IRL) and OCT-A was analyzed for the presence of a foveal avascular zone (FAZ), the size of which was determined when applicable. Results: Overall, 16 eyes (27.1%) of 9 patients had a fovea plana appearance (‘FP group’) with the persistence of IRL, and 43 eyes (72.9%) of 23 patients did not have fovea plana appearance (‘no FP group’). Among FP eyes, OCT-A performed in 13 eyes showed bridging vessels through the FAZ in 100% of eyes with OCT-A. Using Thomas classification, 14 out of the 16 eyes with fovea plana (87.5%) had atypical foveal hypoplasia, and the 2 others (12.5%) had a grade 1b fovea plana. Conclusion: In our series, foveal hypoplasia was present in 27.1% of patients with Best disease. OCT-A showed bridging vessels through the FAZ in all eyes. These findings highlight the microvascular changes associated with Best disease, which can be an early sign of the disease in patients with a family history.

Introduction: The performance of “en-face” optical coherence tomography (OCT) in screening for chloroquine (CQ) or hydroxychloroquine (HCQ) retinopathy has not been largely explored. The aim of this study was to determine the concordance of “en-face” OCT with multifocal electroretinography (mfERG) in screening for CQ/HCQ retinopathy. Methods: This is a prospective cohort study conducted at the Rothschild Foundation Hospital – Paris between August 2016 and February 2021. Patients taking hydroxychloroquine were followed up over 2 consecutive years and received an “en-face” OCT and a mfERG on each visit. Results: A total of 91 patients (182 eyes) were analyzed. mfERG and “en-face” OCT were concordant in 147 eyes (86.3%). Cohen’s Kappa coefficient for concordance between mfERG and “en-face” OCT was considered weak with a value 0.61 (95% CI: 0.50-0.72). The sensitivity and specificity of “en-face” OCT are 70% (95% CI: 59-79%) and 91% (95% CI: 83-96%) respectively, relatively to mfERG. Proportion of abnormal R2/R5 and R3/R5 ratios did not differ between patients with normal and abnormal “en-face” OCT (p=0.2). Discussion/Conclusion: “En-face” OCT and mfERG have low concordance and cannot be used interchangeably as each investigation evaluates a different facet of CQ/HCQ retinopathy. “En-face” OCT could be used as a complement in screening for CQ/HCQ retinal toxicity if the anomalies detected on “en-face” OCT are confirmed by B-scan OCT sections.

To differentiate OCVM from other orbital lesions using structural MRI.This IRB-approved a historical-prospective cohort single-center analysis of a prospective cohort that included consecutive adult patients presenting with an orbital lesion undergoing a 3T MRI before surgery from December 2015 to May 2021. Two readers blinded to all data read all MRIs assessing structural MRI characteristics. A univariate analysis followed by a stepwise multivariate analysis identified structural MRI features showing the highest sensitivity and specificity when diagnosing OCVM.One hundred ninety-one patients with 30/191 (16%) OCVM and 161/191 (84%) other orbital lesions were included. OCVM were significantly more likely to present with a higher signal intensity than that of the cortex on T2WI: 26/29 (89.7%) versus 28/160 (17.5%), p0.001, or with a chemical shift artifact (CSA): 26/29 (89.7%) versus 16/155 (10.3%), p0.001, or to present with a single starting point of enhancement, as compared to other orbital lesions: 18/29 (62.1%) versus 4/159 (2.5%), p = 0.001. The step-wise analysis identified 2 signatures increasing performances. Signature 1 combined a higher signal intensity than that of the cortex on T2WI and a CSA. Signature 2 included these two features and the presence of a single starting point of enhancement. Sensitivity, specificity, and accuracy were 0.83, 0.94, and 0.92 for signature 1 and 0.97, 0.93, and 0.93 for signature 2, respectively.Structural MRI yields high sensitivity and specificity when diagnosing OCVM.• Structural MRI shows high sensitivity and specificity when diagnosing orbital cavernous venous malformation. • We identified two signatures combining structural MRI features which might be used easily in routine clinical practice. • The combination of higher signal intensity of the lesion as compared to the cortex on T2WI and of a chemical shift artifact yields a sensitivity and specificity of 0.83 and 0.94 for the diagnosis of orbital cavernous venous malformation, respectively.

OBJECTIVES To assess the impact of timing from visual symptoms' onset to diffusion-weighted (DW) 3 T MRI completion to detect ischemic changes of the optic disc and optic nerve in AION patients. METHODS This IRB-approved retrospective single-center study included 3 T MRI data from 126 patients with AION and 111 controls with optic neuritis treated between January 2015 and May 2020. Two radiologists blinded to all data individually analyzed imaging. A senior neuroradiologist resolved any discrepancies by consensus. The primary judgment criterion was the restricted diffusion of the optic disc and/or the optic nerve assessed subjectively on the ADC maps. ADC values were also measured. Spearman rank correlations were used to examine the relationships between timing from visual symptoms' onset to MRI completion and both the restricted diffusion and the ADC values. RESULTS One hundred twenty-six patients (47/126 [37.3%] women and 79/126 [62.7%] men, mean age 69.1 ± 13.7 years) with AION were included. Restricted diffusion of the optic disc in AION eyes was more frequent in the early MRI group than in the late MRI group: 35/49 (71.4%) eyes versus 3/83 (3.6%) eyes, p

Purpose: Bone marrow–derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II–III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

Background: The pre-metastatic niche mobilizes copper to assist in conditioning the tumor microenvironment facilitating tumor progression. This includes bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX). We hypothesized that TM-associated CD would reduce EPCs and other copper dependent processes in the pre-metastatic niche in BC pts. Methods: Stage 2 triple negative BC, Stage 3 and stage 4 without any evidence of disease, (NED) BC pts, received oral TM to maintain ceruloplasmin (Cp) between 8-17mg/dL for 2 years or until relapse. Endpoints included change in EPCs, safety, disease-free (DFS) and overall survival (OS) and effect on biomarkers. Laboratory studies: MDA-LM2-luciferase cells were implanted into CB17-SCID mice, and treated with TM or water. Tumor progression was quantified by bioluminescence imaging (BLI), CD status by Cp oxidase levels, lysyl oxidase (LOXL2) activity by ELISA, and collagen deposition by Picrosirius Red staining and Second Harmonic Generation (SHG) imaging analysis. Results: 75 pts (45 stage 2/3 BC, 30 stage 4 NED) received over 2400 cycles of TM on the primary and extension studies. Median age: 51 yrs (range 29-66). Of the 75 pts, 48% had TNBC, 40% were stage 4 NED. Median Cp level decreased from 28 at baseline to 15.5 (p Conclusions: TM is safe, well tolerated and appears to affect multiple copper dependent biologic processes in the tumor microenvironment known to be important for tumor progression, most striking in TNBC. Randomized trials in a high risk for relapse population are warranted. Citation Format: Eleni Nackos, Sharrell Lee, Amy Willis, Naomi Kornhauser, Maureen Ward, Marta Cobham, Tessa Cigler, Anne Moore, Veronica Fitzpatrick, Sarah Schneider, Alysia Wiener, Jessica Guillaume-Abraham, Bo Ri Seo, J David Warren, Anna Rubinchik, Claudia Fischbach, Vivek Mittal, Linda Vahdat. Copper depletion as a strategy to affect the tumor microenvironment in breast cancer patients at high risk of relapse and in triple negative preclinical models of breast cancer: Updated results of a phase II study of tetrathiomolybdate (TM) in breast cancer (BC) patients (pts) at high risk for recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-349.