Metastatic uveal melanoma: The final frontier Rantala, Elina S.; Hernberg, Micaela M.; Piperno-Neumann, Sophie ...
Progress in retinal and eye research,
09/2022, Letnik:
90
Journal Article
Recenzirano
Odprti dostop
Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an ...international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10–13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95–100% and 83–100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.
Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. ...Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a “state of metastatic grace” never to be violated.
Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy.
Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the “state of metastatic grace”, with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.
The aim of this study was to define, following the IC3D template format, the clinical and histopathologic phenotype of the p.(His626Arg) missense variant lattice corneal dystrophy (LCDV-H626R), the ...most common variant lattice dystrophy, and to record long-term outcome of corneal transplantation in this dystrophy.
A database search and a meta-analysis of published data on LCDV-H626R were conducted. A patient diagnosed with LCDV-H626R who underwent bilateral lamellar keratoplasty followed by rekeratoplasty of 1 eye is described, including histopathologic examination of the 3 keratoplasty specimens.
One hundred forty-five patients from at least 61 families and 11 countries diagnosed with LCDV-H626R were found. This dystrophy is characterized by recurrent erosions, asymmetric progression, and thick lattice lines that extend to corneal periphery. The median age is 37 (range, 25-59) years at the onset of symptoms, 45 (range, 26-62) years at the time of diagnosis, and 50 (range, 41-78) years at the time of the first keratoplasty, suggesting a median interval from the first symptoms to diagnosis and to keratoplasty of 7 and 12 years, respectively. Clinically unaffected carriers have been of age 6 to 45 years. Central anterior stromal haze and centrally thick, peripherally thinner branching lattice lines in the anterior to midstroma of the cornea were noted preoperatively. Histopathology of the host anterior corneal lamella showed a subepithelial fibrous pannus, a destroyed Bowman layer, and amyloid deposits extending to the deep stroma. In the rekeratoplasty specimen, amyloid localized to scarring along the Bowman membrane and to the margins of the graft.
The IC3D-type template for LCDV-H626R should help diagnose and manage variant carriers. The histopathologic spectrum of findings is broader and more nuanced than what has been reported.
To determine the incidence of retinoblastoma (Rb) and subsequent survival in the Finnish population during five decades.
This retrospective observational cohort study comprised all patients with Rb ...born in Finland during 1964
2014 and diagnosed in 2018 (birth cohort analysis) or diagnosed in 1964
2014 (standard annual analysis), identified from the Finnish Cancer Registry and the national referral centre. We report age-adjusted incidences and survival according to cause of death.
Of children born in 1964
2014, 205 developed Rb, whereas 204 Rbs were diagnosed during these years; 196 belonged to both cohorts. Altogether 80 (38%) of the 213 children had heritable Rb and 19 (9%) had familial disease. The sex ratio was 1.34, suggesting male preponderance. Birth cohort analysis showed a median incidence of 6.2 per 100 000 live births (1:16 130) and less variability as compared with standard annual analysis (12.1, 6.5 and 4.4 per million children 0
4, 0
9 and 0
14 years of age, respectively). The incidence of heritable Rb increased with time, reflecting the increase in familial tumours. Five-year mortality rates from Rb were 6.2% and 7.6% for non-heritable and heritable diseases, respectively, and 35-year mortality rates from second malignancies were 0% and 14.3%, respectively. Family history predicted improved survival, whereas the period of diagnosis did not.
The incidence of familial Rb has increased, along with improvement in survival in Finland in 1964-2014, whereas the overall incidence of Rb was stable. Long-term risk of dying of second malignancies after heritable Rb was in line with other countries.
Purpose
To report the indications and the outcomes of keratoplasties in children over four decades.
Methods
A retrospective cohort study of patients aged 16 years or younger who underwent ...keratoplasty in the Helsinki University Eye Hospital during 1968–2011. Diagnosis, preoperative status, age at the time of surgery, surgical technique, complications and follow‐up time were registered. Main outcome measures were visual acuity and graft survival as assessed by Kaplan–Meier analysis. The independent role of risk factors on outcomes was evaluated by Cox multivariate regression analysis.
Results
Forty‐eight keratoplasties, 42 penetrating and six lamellar, were performed in 44 eyes of 39 children at the age of 4.5 months to 16 years (median, 12 years). Five patients had bilateral grafts, and five grafts were regrafts. The indication for keratoplasty was injury for 13 grafts, non‐traumatic acquired corneal opacities for 11, keratoconus for eight, corneal dystrophy for seven, congenital corneal opacities for six and aniridia for three grafts. The cumulative proportion of clear grafts was 46% at 5 years postoperatively, and the median follow‐up time of clear grafts was 5.1 years (range, 0.4–29 years) for 41 penetrating allografts (PKP). Simultaneous intraocular surgery at the time of grafting hazard ratio (HR) 9.7, corneal vascularization (HR 8.1) and regrafting (HR 5.4) were the main independent risk factors for graft failure in this PKP cohort. The cumulative proportion of clear grafts was 84% at 5 years in the absence of any of these risk factors. PKP for keratoconus and corneal dystrophy yielded clear grafts in 83% of the eyes, and a visual acuity ≥0.3 (Snellen) in 75% of the eyes. Seventeen of the 20 graft failures were due to rejection.
Conclusions
Favourable graft survival was obtained in primary keratoplasties for non‐vascularized corneal opacities performed without any other simultaneous intraocular surgery. Visual outcome was favourable in keratoconus and corneal dystrophies and poor in most eyes with injury.
Germline mutations of the BRCA1-associated protein-1 gene (BAP1) predispose carriers to uveal melanoma. We report the population-based frequency of germline pathogenic variants of BAP1 in Finnish ...patients with uveal melanoma who live in a high-risk region for this cancer.
Cohort study.
In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 148 of 188 consecutive patients diagnosed from January 2010 through December 2012. Seven of these patients from 6 families had a history of uveal melanoma in 1 relative, and 2 patients from 2 additional families had such a history in 2 relatives.
Sequencing BAP1.
Pathogenic variants in BAP1.
We found 2 different pathogenic variants in BAP1 in 3 patients. Two patients had a single nucleotide insertion in exon 14 resulting in a shift of reading frame. Both had a family history of uveal melanoma in at least 1 relative. One patient without a family history of uveal melanoma had a single nucleotide substitution in the conserved splice donor site of intron 2. BAP1 cancer predisposition syndrome-related cancers were present in all 3 families. The overall frequency of BAP1 pathogenic variants was 2.0% (3/148; 95% confidence interval, 0.4-5.8), the frequency among patients 50 years of age or younger was 3.6% (1/28; 95% confidence interval, 0.1-18), and a pathogenic variant was detected in 2 of 8 families with a history of uveal melanoma.
The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations.
Abstract
Background
Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous ...melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS.
Methods
We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system.
Results
In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c.1780_1781insT, and a likely pathogenic missense variant c.281A>G reduced adhesion (all p ≤ 0.015) and proliferation by 74%–83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G>A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT.
Conclusions
BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.
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