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.
Purpose
The purpose of this study is to report our experience with the use of artificial dermis grafts for orbital socket reconstruction following orbital exenteration (OE).
Method
A retrospective ...study was conducted in our ocular oncology centre from May 2018 to June 2020 in patients undergoing OE for orbital malignancies in whom an artificial dermis device (Integra® template, 2 layers) was used for reconstruction. Data recorded included demographics, previous and adjuvant treatments, aetiologies, surgical procedure, surgical reconstruction, complications and follow-up. The main outcome measure was the time between OE and the full granulation of the cavity.
Results
Ten patients (mean age, 71.3 years 43–92) were included. Tumours originated from the conjunctiva (
n
= 5, 50%), eyelid (
n
= 3, 30%) and orbit (
n
= 2, 20%). Nine patients underwent total OE, and one required enlarged OE. Orbital reconstruction was performed using an artificial dermis alone (
n
= 9, 90%) or combined with regional flaps (
n
= 1, 10%). The mean granulation time was 3.3 weeks (2–4). Three (30%) patients received adjuvant radiotherapy 1 month post-surgery. The mean time to spontaneous epithelialization was 9.4 weeks (6–12). Preoperative and postoperative radiotherapy was not associated with a delayed epithelialization of the socket (
p
= 0.463 and
p
= 0.236, respectively). One (10%) and 2 (20%) patients experienced postoperative socket infection and an ethmoidal fistula, respectively. The mean follow-up was 11.6 months (6–16).
Conclusion
Using artificial dermis grafts alone or with regional flaps appears to be a viable surgical procedure for orbital socket reconstruction. They reduce surgical morbidity and hospital stay. Preoperative and postoperative radiotherapy does not seem to delay socket healing.
Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which ...develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.
Liquid biopsy and circulating tumor cell (CTC) screening has gained interest over the last two decades for detecting almost all solid malignancies. To date, the major limitation in terms of the ...applicability of CTC screening in daily clinical practice is the lack of reproducibility due to the high number of platforms available that use various technologies (e.g., label-dependent versus label-free detection). Only a few studies have compared different CTC platforms. The aim of this study was to compare the efficiency of four commercially available CTC platforms (Vortex (VTX-1), ClearCell FX, ISET, and Cellsearch) for the detection and identification of uveal melanoma cells (OMM 2.3 cell line). Tumor cells were seeded in RPMI medium and venous blood from healthy donors, and then processed similarly using these four platforms. Melan-A immunochemistry was performed to identify tumor cells, except when the Cellsearch device was used (automated identification). The mean overall recovery rates (with mean recovered cells) were 39.2% (19.92), 22.2% (11.31), 8.9% (4.85), and 1.1% (0.20) for the ISET, Vortex (VTX-1), ClearCell FX, and CellSearch platforms, respectively. Although paramount, the recovery rate is not sufficient to assess a CTC platform. Other parameters, such as the purpose for using a platform (diagnosis, genetics, drug sensitivity, or patient-derived xenograft models), reproducibility, purity, user-friendliness, cost-effectiveness, and ergonomics, should also be considered before they can be used in daily clinical practice and are discussed in this article.
Tissue biopsy is considered the gold standard when establishing a diagnosis of cancer. However, tissue biopsies of intraocular ophthalmic malignancies are hard to collect and are thought to be ...associated with a non-negligible risk of extraocular dissemination. Recently, the liquid biopsy (LB) has emerged as a viable, non-invasive, repeatable, and promising way of obtaining a diagnosis, prognosis, and theragnosis of patients with solid tumors. LB refers to blood, as well as any human liquid. The natural history of uveal melanoma (UM) and retinoblastoma (RB) are radically opposed. On the one hand, UM is known to disseminate through the bloodstream, and is, therefore, more accessible to systemic venous liquid biopsy. On the other hand, RB rarely disseminates hematogenous, and is, therefore, more accessible to local liquid biopsy by performing an anterior chamber puncture. In this review, we summarize the current knowledge concerning LB in UM, RB, conjunctival tumors, and choroidal metastases. We also develop the current limitations encountered, as well as the perspectives.
Cystic lymphatic malformations (LMs) are rare chronic conditions which management differs according to the type (macrocystic LMs, microcystic LMs or both). Studies are lacking due to rarity of the ...pathology. We aimed to establish a French National Diagnosis and Care Protocol (PNDS: Protocole National de Diagnostic et de Soins), to provide health professionals with free open access synthesis on optimal management and care of patients with LMs ( https://www.has-sante.fr/upload/docs/application/pdf/2021-03/malformations_lymphatiques_kystiques_-_pnds.pdf ). The process included a critical review of the literature and multidisciplinary expert consensus. LMs are congenital but are not always discovered at birth. Nearly 75% of them are located in the head and neck because of the highly dense lymphatic system in this region. Physical examination (showing painless masses with normal skin color and depressible consistency, or cutaneous/mucosal lymphangiectasia) and color Doppler ultrasonography, usually allow for diagnosis. MRI (involving T2 sequences with fat saturation in at least two spatial planes) is the tool of choice for evaluating anatomical extension, characterizing lesions (microcystic and macrocystic), and before considering therapeutic management. A biopsy, coupled to a blood sample, can also be used for molecular biology analyses, to search for activating mutations of the PIK3CA gene, particularly with LM integrating in a syndromic form (CLOVES or Klippel-Trenaunay syndrome) but also in certain isolated (or common) LMs. The spontaneous evolution of LMs, in particular microcystic forms, is often toward progressive aggravation, with an increase in the number of vesicles, thickening, increased oozing and bleeding, while pure macrocystic LMs may regress due to "natural sclerosis", i.e. fibrosis secondary to an inflammatory reorganization after common infantile infections. In case of voluminous LMs or syndromic forms, functional and psychological repercussions can be major, deteriorating the patient's quality of life. LMs must be treated by physicians integrated in multidisciplinary teams, and be personalized. Management is a life-long process that involves one or several of these therapies: conservative management, physical therapy (compression), sclerotherapy, surgery, drugs such as mTOR inhibitors (sirolimus), that has shown efficacy in decreasing the volume of LMs, and, more recently, PI3K-inhibitors in syndromic forms. Psychological and social support is necessary, taking into account the patient and his family.
Purpose. To determine the course and outcomes of cataract surgery in one-eyed patients. Methods. This retrospective cohort study was conducted at the University Hospital of Nice, France. All one-eyed ...patients who underwent cataract surgery in their functional eye between January 2014 and December 2018 were included. A one-eyed patient was defined as having a visual acuity (VA) ≤20/200 in the other eye. Data were collected from the medical records and included the sociodemographic factors, the past medical history, data from the preoperative and postoperative clinical examinations, the surgical course, and the visual outcomes. Results. One hundred one-eyed patients with a mean age of 74.01 years were included (48 men/52 women). The mean preoperative VA was 20/100 (+0.74 logMAR). The VA ranged between 20/200 and 20/40 in 75 (75%) patients, was >20/40 in 8 (8%), and was <20/200 in 17 (17%) patients. Fifty-eight (58%) patients were operated on an outpatient basis. General or locoregional anesthesia was used in 29 (29%) and 9 (9%) patients, respectively. All cataract surgery procedures were performed by phacoemulsification. Five (5%) patients experienced intraoperative complications. Seventy-three (73%) one-eyed patients achieved a final VA ≥20/40. The mean final VA was 20/50 (+0.37 logMAR) (p<0.001). Conclusion. A low rate of intraoperative complications was observed in one-eyed patients during cataract surgery. In most cases, a good visual recovery was achieved after cataract surgery, even in patients who experienced a surgical complication.
In this paper, a new access to several chiral 3-aminoglycals as potential precursors for glycosylated natural products is reported from a common starting material, (-)-methyl-L-lactate. The ...stereodivergent strategy is based on the implementation of a ring-closing metathesis of vinyl ethers as key step of reaction sequences developed.
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