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Atypical choroid plexus papilloma (APP) represents a novel intermediate-grade subtype of choroid plexus tumor (CPT), the clinical outcome of which has not been described yet. We present the first analysis of a group of APP patients enrolled in the ongoing CPT-SIOP-2000 study of CPTs. A worldwide registration and a randomized trial for those patients who require chemotherapy started in 2000. For APP, maximal surgical resection was recommended. After surgery, patients who had undergone complete resection were observed, whereas patients with incompletely resected or metastasized APP were treated with six chemotherapy courses (etoposide and vincristine, combined with either carboplatin or cyclophosphamide). Risk-adapted radiotherapy was given only to patients older than 3 years of age. Of the 106 patients with a centrally confirmed CPT histology, 30 had APP, 42 CPP and 34 CPC. APP patients were significantly younger (median = 0.7 years) than patients with CPP or CPC (both medians = 2.3 years). Complete resection was achieved in 68 (64%) patients (79% in CPP, 63% in APP, and 47% in CPC). Metastases were present at diagnosis in 17% of APP patients, 5% of CPP patients, and 21% of CPC patients. All nine APP patients who received postoperative chemotherapy showed an early response after two cycles: two had complete remission, four had partial response, and three had stable disease. In the observation group of 15 patients, one event was seen, and all patients were alive. In the treatment group, one patient with a metastasized tumor and incompletely resected APP died. While APP was defined histologically, median percentages of both the Ki-67/MIB-1 proliferation marker and the p53 tumor suppressor protein increased across the three histological subtypes (from CPP to APP and then CPC), suggesting that the subtypes comprise an ordinal categorization of increasingly severe CPT tumors. This ordering was reiterated by clinical outcome in the 92 patients treated per the study protocol, with 5-year EFS rates of 92% in 39 CPP patients, 83% in 24 APP patients, and 28% in 29 CPC patients. A similar ordering was seen when all 106 patients were evaluated for EFS. APP responded favorably to chemotherapy. The intermediate position of APP between CPP and CPC was supported by the clinical data.

The aim of this study was to review and describe therapeutic approaches in children with choroid plexus tumor (CPT) based on a nationwide series. The World Health Organization classification subdivides these rare tumors into three histological subtypes corresponding to three grades of malignancy: low grade (grade I) choroid plexus papilloma (CPP), intermediate grade (grade II) atypical choroid plexus papilloma (aCPP) and high grade (grade III) choroid plexus carcinoma (CPC). This retrospective study included 102 French children younger than 18 years, treated from 2000 to 2012: 54 CPP, 26 aCPP and 22 CPC. The 5 year overall survival was 100% in CPP, 96.2% in aCPP and 64.7% in CPC. In patients with localized disease, complete surgical resection was achieved in 48/52 CPP, 20/26 aCPP and 7/14 CPC. In this group, patients with complete surgical resection had better event free survival than patients with partial resection (88.9 vs. 41.6%). 28 patients (1 CPP, 6 aCPP and 22 CPC) had adjuvant chemotherapy. 2 aCPP and 9 CPC had radiotherapy. We underlined the need for a central histological review to accurately analyze clinical data; we reported a much higher overall survival for CPC than in most previous CPT series probably including atypical teratoid rhabdoid tumors. In our series, the 5 years overall survival in CPC (64.7%) was higher than event free survival (25.2%) and could be interpreted as a clue for the efficiency of adjuvant/salvage therapy even if the heterogeneity of applied treatments in this retrospective series does not allow for meaningful statistical comparisons.

Purpose To investigate fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy (PCV). Methods This phase IV, prospective, single-arm, interventional case series was conducted in eight centers. Forty treatment-naïve PCV patients were administered three monthly doses of intravitreal aflibercept (2.0 mg) and an injection every 2 months thereafter. Best-corrected visual acuity (BCVA) and central subfield macular thickness (CSMT) were measured at each visit. Fluorescein and indocyanine green angiography (ICGA) were performed at baseline, 3 and 12 months. The primary outcome measure was the proportion of patients who maintained BCVA (<15 letters loss) at 12 months. Changes in BCVA, macular appearance, and polypoidal lesion appearance were also examined. Results Thirty-five eyes (87.5 %) had maintained BCVA at 12 months. Average BCVA was significantly higher at 12 months (20/53, 64.2 letters) than at baseline (20/80, 55.1 letters, 9-letter gain; P  < .001). Mean CSMT was significantly lower at 12 months (253.6 μm) than at baseline (365.2 μm, P  < .001). The macula was dry in 32 (76.2 %), 27 (64.3 %), and 24 eyes (60.0 %) at 3, 6, and 12 months respectively. Fourteen eyes (33.3 %) had a fluid recurrence or increase at 6 months, and they had a significantly lower vision gain ( P  = .005) than other patients at 12 months. Complete polyp regression occurred in 26 eyes (66.7 %) at 12 months. Conclusions Fixed-dosing aflibercept showed favorable outcomes in PCV patients at 12 months. However, some patients had worse outcomes because of fluid recurrence during maintenance dosing, and these patients would require additional treatments.

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms 1 – 3 . However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease 4 – 6 . Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans 7 and linked to cognitive function 8 —is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date. Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.

BackgroundChoroid plexus tumors are rare entities. Resection is the mainstay of treatment in grade I and grade II tumors and adjuvant treatment is usually reserved for the less frequent choroid plexus carcinoma (CPC). Outcome is not only related to their histological grade but also dependent on their size, location, and presence of often multifactorial disturbances of cerebrospinal fluid (CSF) circulation.MethodsRetrospective analysis of 36 consecutive patients operated on a choroid plexus tumor at our institution in a mixed pediatric and adult population between 1991 and 2016.ResultsTwenty-one CPP, 11 atypical choroid plexus papillomas (aCPP), and four CPC were encountered in 17 children and 19 adults. Regardless of histological grading, gross-total resection (GTR) could be achieved in 91.7% of patients. Tumor recurrence (25.0%) was significantly associated with histological grading (p = 0.004), subtotal resection (p = 0.002), and intraoperatively evident zones of tumor infiltration (p = 0.001). Adjuvant therapy was performed in 19.4% of patients, mainly diagnosed with CPC. The 5-year overall survival rate was 95.2% for CPP and 100.0% for both aCPP and CPC. Survival was related to the extent of resection (p = 0.001), tumor progression (p = 0.04), and the presence of leptomeningeal metastases (p = 0.002). Even after resection, either ventricular or subdural shunting was required in 25.0% of patients.ConclusionsWe could confirm that GTR is crucial for treatment of choroid plexus tumors. Parenchymal tumor infiltration as detected intraoperatively was associated with the extent of resection and not limited to CPC. CSF disturbances mandating treatment may persist after resection.

Background/aimThe study's aim was to compare chromosome 3 aberrations of choroidal melanoma (CM) as determined by multiplex ligation dependent probe amplification (MLPA) or microsatellite analysis (MSA) in intraocular tumour biopsies with those results obtained from subsequent endoresection/enucleation of the same CM.MethodsA retrospective cohort of 28 patients with CM seen between 2007 and 2014 at the Liverpool Ocular Oncology Centre was analysed. Prognostic genetic testing, for chromosome 3 status, was performed on all tumour specimens, either by MLPA or MSA, depending on DNA yield. In nine cases genetic testing was performed on a sample taken after radiotherapy; four of these had genetic information pre- and post-radiotherapy.ResultsFourteen biopsy specimens were analysed by MLPA and 14 by MSA. Twenty-seven endoresection or enucleation specimens were analysed by MLPA, and a single enucleation specimen by MSA. Chromosome 3 data showed prognostic concordance for the patient-matched samples in all 28 cases including 4 cases where samples were taken pre pre- and post radiotherapy. Thirteen cases were classified as monosomy 3 and 12 as disomy 3. Two cases had a loss of chromosome arm 3q in both samples and a single case showed loss of 3p in the biopsy sample with complete monosomy 3 in the subsequent enucleation sample taken 5 months later.ConclusionsIntraocular biopsy of CM yields similar prognostic information to larger surgical specimens. Initial evidence, that genetic testing can be successfully conducted post radiotherapy, is also provided.Trial registration numberNITRO trial, ISRCTN35236442.

Choroid plexus tumors (CPT) are rare neoplasms accounting for 1–4% of all pediatric brain tumors. They are divided into choroid plexus papilloma (CPP), atypical choroid plexus papilloma (APP) and choroid plexus carcinoma (CPC). CPTs are known to primarily affect children less than 2 years of age. Gross total resection is the most important predictor of survival especially in CPC. Although small case series have been published, limited clinical data are available to describe treatment and outcome of CPTs. More clinical data would be necessary to complete the picture, particularly in populations that are not age limited. Here we share data from the two major hospitals in Cleveland to describe treatment and outcome of adult and pediatric patients. We performed a retrospective analysis of patients with CPT seen in Cleveland Clinic from 1990 to 2015 and at University Hospitals from 1994 to 2015. Results were compared to previously published historical controls. We identified 30 cases with CPT, including 22 pediatric and eight adult cases; 11 females and 19 males. The mean age at presentation was 12.4 years with a median age of 4.5 years (range 2 months–51 years). Gross total surgical resection was achieved in 22, subtotal resection in four, partial resection in two and unknown in two. The histology was CPP in 23 patients, two of whom developed recurrence requiring repeat resection and adjuvant therapy. Median event free survival (EFS) for CPP patients was 7.6 years. The histology was CPC in seven patients. All CPC patients were treated with adjuvant therapy. Median EFS of CPC patients was 4.4 years. Overall survival of all CPT patients was 100% with a median follow up of 7 years. A systematic literature review identified 1012 CPT patients treated from 1989 to 2013. The mean and median age of CPT patients was 13 and 3 years respectively. The median survival of 541 CPP patients was undefined vs. 2.7 years for the 452 CPC patients. The difference between the two populations was highly significant (p < 0.001). Kaplan–Meier survival curves comparing CPTs at Cleveland Clinic and University Hospitals versus a systematic literature review showed a statistically significant advancement in overall survival among the patients treated at Cleveland Clinic and University Hospitals. Our data are consistent with the literature review regarding epidemiology, clinical presentation, and treatment modalities but differed in regards to survival. Differences in survival may be related to different methods of data collection or details in patient care.

Purpose To investigate the effect of nicotine on choroidal thickness using optical coherence tomography (OCT). Design Prospective, case–control study. Methods Sixteen young, healthy subjects and 16 age and gender matched control cases were included in this study; 4 mg nicotine gum was given to the study group and placebo gum to the control group. All participants underwent OCT scanning with a high-speed and resolution spectral-domain OCT device (3D OCT 2000, Topcon, Japan) at baseline, and 1 h following nicotine or placebo administration. The measurements were taken in the morning (10:00–12:00 hours) to avoid diurnal fluctuation. Results The median foveal choroidal thickness at baseline was 337.00 μm (IQR 84.50), which decreased to 311.00 μm (IQR 78.00) at 1 h following oral nicotine intake (p=0.001). The median choroidal thickness was also significantly decreased at five other extrafoveal points (p<0.05 for all). In the control group, the median baseline choroidal thickness at the fovea was 330.50 μm (IQR 104.25), and was 332.00 μm (IQR 103.75) at 1 h (p=0.271). Conclusions Nicotine causes a significant decrease in choroidal thickness following oral intake. This acute decrease might be a result of reduced ocular blood flow due to the vasoconstrictive effect of nicotine.

The human retinal pigment epithelium (RPE) and choroid are complex tissues that provide crucial support to the retina. Disease affecting either of these supportive tissues can lead to irreversible blindness in the setting of age-related macular degeneration. In this study, single-cell RNA sequencing was performed on macular and peripheral regions of RPE-choroid from 7 human donor eyes in 2 independent experiments. In the first experiment, total RPE/choroid preparations were evaluated and expression profiles specific to RPE and major choroidal cell populations were identified. As choroidal endothelial cells represent a minority of the total RPE/choroidal cell population but are strongly implicated in age-related macular degeneration (AMD) pathogenesis, a second single-cell RNA-sequencing experiment was performed using endothelial cells enriched by magnetic separation. In this second study, we identified gene expression signatures along the choroidal vascular tree, classifying the transcriptome of human choriocapillaris, arterial, and venous endothelial cells. We found that the choriocapillaris highly and specifically expresses the regulator of cell cycle gene (RGCC), a gene that responds to complement activation and induces apoptosis in endothelial cells. In addition, RGCC was the most up-regulated choriocapillaris gene in a donor diagnosed with AMD. These results provide a characterization of the human RPE and choriocapillaris transcriptome, offering potential insight into the mechanisms of choriocapillaris response to complement injury and choroidal vascular disease in age-related macular degeneration.

Pachychoroid is a relatively novel concept describing a phenotype characterized by attenuation of the choriocapillaris overlying dilated choroidal veins, and associated with progressive retinal pigment epithelium dysfunction and neovascularization. The emphasis in defining pachychoroid-related disorders has shifted away from simply an abnormally thick choroid (pachychoroid) toward a detailed morphological definition of a pathologic state (pachychoroid disease) with functional implications, which will be discussed in this review. Several clinical manifestations have been described to reside within the pachychoroid disease spectrum, including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, focal choroidal excavation, peripapillary pachychoroid syndrome. These conditions all exhibit the characteristic choroidal alterations and are believed to represent different manifestations of a common pathogenic process. This review is based on both the current literature and the clinical experience of our individual authors, with an emphasis on the clinical and imaging features, management considerations, as well as current understanding of pathogenesis of these disorders within the context of the recent findings related to pachychoroid disease.