9510 Background: Darovasertib is a protein kinase C (PKC) inhibitor with meaningful activity in metastatic uveal melanoma (UM) due to its effect on PKC delta downstream of canonical GNAQ/GNA11 mutations. To date, its clinical activity in patients with localized primary disease has not been assessed in either neoadjuvant or adjuvant settings. Methods: Patients planned for enucleation with localized UM were treated in an initial safety cohort with darovasertib 300mg BID for 1 month (n=3 patients), and then following DSMB agreement in an expansion cohort for up to 6 months (n=12 patients) as neoadjuvant treatment prior to definitive management (enucleation, plaque brachytherapy or EBRT) across 3 Australian centers. All patients were eligible to receive up to 6 months of adjuvant treatment with darovasertib at investigator discretion after definitive management of their primary tumour. Tumour volume was calculated by the rotational ellipsoid method. Results: 15 patients (male n=7, female n=8; median age 62 years (range, 33-76 years)) were enrolled. At baseline, AJCC tumor stages were T3a (n=5), T3b (n=4), T4a (n=4), T4b (n=2), and the median tumor size (maximum thickness/diameter/volume) was 9.7mm/ 15.6 mm/ 2463 mm 3 . At datalock; 11/15 patients had completed primary treatment, 4/15 remained on neoadjuvant treatment, 6 patients received adjuvant darovasertib after primary treatment of their UM with 3 patients completing the planned 6-months . Median tumor shrinkage (maximum height/base/volume change) was 11.2%/ 7.6%/ 22.7% after 1 month of treatment and 31.7%/ 11.9% /45.3% after 6 months. At datalock, 6/9 (66%) currently completed neoadjuvant patients were converted to plaque brachytherapy (n=5) or EBRT (n=1) with 3 ongoing. One patient with high-risk cytogenetic features had relapsed with metastatic disease despite receiving 6-months of neoadjuvant darovasertib and another 6-months of adjuvant treatment. Treatment emergent adverse events included postural hypotension (Gr1/2 – 13/13%), syncope (Gr3 – 13%), rash (Gr1/2 – 33/5%), pruritis (Grr1 – 13%), dizziness (Gr1 – 27%), fatigue (Gr1/2 – 30/5%), nausea (Gr1/2 – 73/6%), vomiting (Gr1 – 40%), and diarrhea (Gr1 – 60%). Updated results, histopathological and genomic outcomes will be presented. Conclusions: NADOM provides the first evidence that a globe-salvage neoadjuvant treatment strategy in UM is feasible, safe, and efficacious. The results suggest that PKC inhibition with darovasertib can induce clinically meaningful tumor shrinkage in patients with primary UM patients who otherwise require enucleation. Larger trials are in now progress (NCT05907954) to further quantify visual and oncological outcomes. Clinical trial information: 05187884.
To determine the expression of histone deacetylase enzymes in uveal melanoma tumour cells.This is an observational immunohistochemical study of 16 formalin-fixed, paraffin-embedded eyes enucleated for uveal melanoma between January 2001 and March 2002. Haematoxylin and eosin paraffin sections were reviewed for histopathological parameters according to the American Joint Committee on Cancer 7th edition. Sections were then immunohistochemically stained for histone deacetylases 1, 2, 3, 4 and 6 and sirtuin 2 using an automated Leica Bond II platform and Fast Red chromogen, then digitally scanned using Aperio software before assessment of staining.Nuclear expression of histone deacetylases 1, 2, 3, 4 and 6 and of sirtuin 2 was confirmed in uveal melanoma tumour cells. In addition, the tumour cells showed cytoplasmic expression of histone deacetylases 4 and 6 and sirtuin 2. Nuclear and cytoplasmic immunostaining was also seen in intraocular tissues uninvolved by the tumour.Uveal melanoma tumour cells express histone deacetylases 1, 2, 3, 4 and 6 and sirtuin 2, confirming potential tissue targets for histone deacetylase inhibitors.
Uveal melanoma (UM) is the principal type of intraocular malignancy in adults.Up to 50% of UM patients develop metastatic disease with very poor survival.There are few drugs available to treat the primary or metastatic UM.This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM.The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays.Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling.The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model.Lapatinib decreased the viability of four UM cell lines (IC50: 3.67-6.53µM).The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors.In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth.Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines.Importantly, lapatinib suppressed tumourigenesis in mice carrying UM cell xenografts.Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM.Lapatinib is active in primary and metastatic UM as a clinically approved HER2 inhibitor.The activity of lapatinib in UM patients could be evaluated in future clinical trials.
PURPOSE: To report successful stromal lenticule extraction, 18 weeks after an aborted small incision lenticule extraction (SMILE) procedure. METHODS: Case report. RESULTS: SMILE was planned in both eyes in another center to correct high myopia. The right eye was treated uneventfully with immediate lenticule extraction and normal postoperative corneal and topographic appearance. Femtosecond laser treatment was applied to the left eye, but the lenticule could not be removed and the procedure was aborted. Eighteen weeks later, lenticule extraction was attempted again with success. Uncorrected distance visual acuity improved from counting fingers to 20/15, with a successful refractive outcome as planned. CONCLUSIONS: Delayed lenticule extraction was successful in achieving the target refractive outcome. To the authors' knowledge, this is the first case of successful delayed lenticule extraction following an incomplete SMILE procedure. Target refractive outcomes were achieved and there were no postoperative complications. [ J Refract Surg. 2017;33(3):199–202.]
Abstract Objectives Uveal melanoma (UM) is the most common primary intraocular tumour in adults. UM has a poor overall prognosis and ~50% of patients progress to metastatic disease that has a median survival of 5.2 months. There are currently no proven pharmacological treatments for primary or metastatic UM. Research efforts continue to seek new agents. Many natural compounds have shown promising anti-UM activity in in-vitro and/or in-vivo studies. This review summarises the current findings for natural compounds that may be potentially useful in treating UM. Key findings Literature suggests that natural compounds, such as pristimerin, picropodophyllin, oridonin, zeaxanthin, withaferin and FR-900359, may be promising candidate compounds to treat UM. Most of these compounds have demonstrated satisfactory efficacy in inhibiting in-vitro UM cell growth. Summary The evidence regarding the anti-UM effects of natural compounds is mainly limited to in-vitro studies; to date, only a small number of these agents have been evaluated in vivo. The molecular mechanisms underpinning the anti-UM properties of these compounds remain largely undefined. Further studies are required to evaluate the in-vivo anticancer activity, appropriate dosage regimen and safety of natural compounds that could be developed for use in UM.
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