To determine if serum amyloid A (A-SAA) could be detected in human osteoarthritic (OA) joints and further clarify if high A-SAA level in joints result from a local production or from a diffusion ...process from abnormally elevated plasma concentration. Regulatory mechanism of A-SAA expression and its pro-inflammatory properties were also investigated.
A-SAA levels in serum and synovial fluid of OA (n = 29) and rheumatoid arthritis (RA) (n = 27) patients were measured and compared to matched-healthy volunteers (HV) (n = 35). In vitro cell cultures were performed on primary joint cells provided from osteoarthritis patients. Regulatory mechanisms were studied using Western-blotting, ELISA and lentiviral transfections.
A-SAA was statistically increased in OA plasma patients compared to HV. Moreover, A-SAA level in OA plasma and synovial fluid increased with the Kellgren & Lauwrence grade. For all OA and RA patients, A-SAA plasma level was higher and highly correlated with its corresponding level in the synovial fluid, therefore supporting that A-SAA was mainly due to the passive diffusion process from blood into the joint cavity. However, A-SAA expression was also observed in vitro under corticosteroid treatment and/or under IL-1beta stimuli. A-SAA expression was down-regulated by PPAR-γ agonists (genistein and rosiglitazone) and up-regulated by TGF-β1 through Alk1 (Smad1/5) pathway. RhSAA induced proinflammatory cytokines (IL-6, IL-8, GRO-α and MCP-1) and metalloproteinases (MMP-1, MMP-3 and MMP-13) expression in FLS and chondrocytes, which expression was downregulated by TAK242, a specific TLR4 inhibitor.
Systemic or local A-SAA expression inside OA joint cavity may play a key role in inflammatory process seen in osteoarthritis, which could be counteracted by TLR4 inhibition.
Osteoarthritis (OA) is associated with a local inflammatory process. Dyslipidemia is known to be an underlying cause for the development of OA. Therefore, lipid and inflammatory levels were ...quantified ex vivo in blood and synovial fluid of OA patients (n=29) and compared to those of rheumatoid arthritis (RA) patients (n=27) or healthy volunteers (HV) (n=35). The role of apolipoprotein A-I (ApoA1) was investigated in vitro on inflammatory parameters using human joint cells isolated from cartilage and synovial membrane obtained from OA patients after joint replacement. Cells were stimulated with ApoA1 in the presence or not of serum amyloid A (SAA) protein and/or lipoproteins (LDL and HDL) at physiological concentration observed in OA synovial fluid. In our ex vivo study, ApoA1, LDL-C and total cholesterol levels were strongly correlated to each other inside the OA joint cavity whereas same levels were not or weakly correlated to their corresponding serum levels. In OA synovial fluid, ApoA1 was not as strongly correlated to HDL as observed in OA serum or in RA synovial fluid, suggesting a dissociative level between ApoA1 and HDL in OA synovial fluid. In vitro, ApoA1 induced IL-6, MMP-1 and MMP-3 expression by primary chondrocytes and fibroblast-like synoviocytes through TLR4 receptor. HDL and LDL attenuated joint inflammatory response induced by ApoA1 and SAA in a ratio dependent manner. In conclusion, a dysregulated lipidic profile in the synovial fluid of OA patients was observed and was correlated with inflammatory parameters in the OA joint cavity. Pro-inflammatory properties of ApoA1 were confirmed in vitro.
(1) Background: Radiotherapeutic treatments of ocular tumors are often challenging because of nearby radiosensitive structures and the high doses required to treat radioresistant cancers such as ...uveal melanomas. Although increased local control rates can be obtained with advanced techniques such as proton therapy and stereotactic radiosurgery, these modalities are not always accessible to patients (due to high costs or low availability) and side effects in structures such as the lens, eyelids or anterior chamber remain an issue. Minibeam radiation therapy (MBRT) could represent a promising alternative in this regard. MBRT is an innovative new treatment approach where the irradiation field is composed of multiple sub-millimetric beamlets, spaced apart by a few millimetres. This creates a so-called spatial fractionation of the dose which, in small animal experiments, has been shown to increase normal tissue sparing while simultaneously providing high tumour control rates. Moreover, MBRT with orthovoltage X-rays could be easily implemented in widely available and comparably inexpensive irradiation platforms. (2) Methods: Monte Carlo simulations were performed using the TOPAS toolkit to evaluate orthovoltage X-ray MBRT as a potential alternative for treating ocular tumours. Dose distributions were simulated in CT images of a human head, considering six different irradiation configurations. (3) Results: The mean, peak and valley doses were assessed in a generic target region and in different organs at risk. The obtained doses were comparable to those reported in previous X-ray MBRT animal studies where good normal tissue sparing and tumour control (rat glioma models) were found. (4) Conclusions: A proof-of-concept study for the application of orthovoltage X-ray MBRT to ocular tumours was performed. The simulation results encourage the realisation of dedicated animal studies considering minibeam irradiations of the eye to specifically assess ocular and orbital toxicities as well as tumour response. If proven successful, orthovoltage X-ray minibeams could become a cost-effective treatment alternative, in particular for developing countries.
Abstract Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive microvasculopathy, ...ischemia and macular edema, ultimately leading to vision loss, neovascular glaucoma, and, in extreme cases, secondary enucleation. Intravitreal anti-VEGF agents, steroids and laser photocoagulation have limited effects on RR. The role of retinal inflammation and its contribution to the microvascular damage occurring in RR remain incompletely understood. To explore cellular and vascular events after irradiation, we analyzed their time course at 1 week, 1 month and 6 months after rat eyes received 45 Gy X-beam photons. Müller glial cells, astrocytes and microglia were rapidly activated, and these markers of retinal inflammation persisted for 6 months after irradiation. This was accompanied by early cell death in the outer retina, which persisted at later time points, leading to retinal thinning. A delayed loss of small retinal capillaries and retinal hypoxia were observed after 6 months, indicating inner blood‒retinal barrier (BRB) alteration but without cell death in the inner retina. Moreover, activated microglial cells invaded the entire retina and surrounded retinal vessels, suggesting the role of inflammation in vascular alteration and in retinal cell death. Radiation also triggered early and persistent invasion of the retinal pigment epithelium by microglia and macrophages, contributing to outer BRB disruption. This study highlights the role of progressive and long-lasting inflammatory mechanisms in RR development and demonstrates the relevance of this rat model to investigate human pathology.
The aim of this study was to highlight the diagnostic and management challenges of primary vitreoretinal lymphoma (PVRL) through a review of the literature and a European survey on real-life ...practices for PVRL.
The care of PVRL patients is heterogeneous between specialists and countries. Upfront systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce or delay the risk of brain relapse.Ibrutinib, lenalidomide with or without rituximab, and temozolomide are effective for patients with relapsed/refractory PVRL and should be tested as first-line treatments.
The prognosis of PVRL remains dismal. No firm conclusion regarding optimal treatment can yet be drawn. The risk of brain relapse remains high. Diagnostic procedures and assessment of therapeutic responses need to be homogenized. Collaboration between specialists involved in PVRL and multicentric prospective therapeutic studies are strongly needed. The recommendations of the French group for primary oculocerebral lymphoma (LOC network) are provided, as a basis for further European collaborative work.
Highlights
This EHA‐ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.
The guideline covers clinical, imaging and pathological diagnosis, staging and ...risk assessment, treatment and follow‐up.
Algorithms for first‐line and salvage treatments are provided.
The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.
Recommendations are based on available scientific data and the authors' collective expert opinion.
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%) (
= 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
or
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.
PurposeThe purpose of this study was to determine whether optical density ratio (ODR) of subretinal fluid (SRF) on optical coherence tomography (OCT) differs between choroidal naevi and ...melanomas.MethodsOne hundred ninety-nine patients (one eye per patient) presenting choroidal melanoma or choroidal naevus with SRF on OCT, evaluated between February and June 2019, were retrospectively included. Other retinal conditions, opaque media, and low-quality OCT were excluded. Mean pixel intensity of SRF (range = 0-255) was quantified using a semi-automated procedure by a masked observer on standard horizontal OCT sections. Mean vitreous intensity served as the reference for ODR.ResultsOne hundred twenty-eight patients with choroidal melanoma and 71 patients with choroidal naevus were included in this study. ODR (mean ± SD) was higher in melanomas (181 ± 64) than in naevi (78 ± 48, P < 0.0001). ODR was correlated to lesion thickness (P < 0.0001, r = 0.27), largest basal diameter (P = 0.028, r = 0.16) and, among naevi, to the number of risk factors for growth into melanoma (P = 0.032, r = 0.22). Among 110 patients with naevi or melanoma who underwent fluorescein angiography, ODR was 120.7 ± 550.1 in eyes presenting angiographic pinpoints versus 14.19 ± 26.0 in eyes that did not (P = 0.06). Fourteen eyes with naevi that transformed into melanoma over 3 years had a mean baseline ODR of 94.7 ± 243.5 compared to 4.01 ± 9.74 in 28 matched naevi eyes of similar size that did not transform (P = 0.027).ConclusionsSRF ODR is higher in choroidal melanoma compared to choroidal naevi. This OCT-derived imaging marker is also higher in choroidal naevi with the potential to transform into melanoma, compared to stationary naevi.
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