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MeSH term: Melanoma
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BRAF V600E-dependent role of autophagy in uveal melanoma.
J Cancer Res Clin Oncol. 2017; 143(3):447-455 [PubMed] Related Publications
METHODS: Two human uveal melanoma cell lines, OCM1A, which harbors the BRAF mutation V600E and Mel 290, which is BRAF wild type, were studied. Autophagy levels were determined by Western blot assay with/without the addition of autophagic flux inhibitor (bafilomycin A1). Cell proliferation was assessed by an MTT assay.
RESULTS: Starvation triggered autophagy in BRAF V600E-mutant OCM1A cells but not in BRAF wild-type Mel 290 cells. Enhanced autophagy helped the OCM1A cells survive under stressed conditions. The BRAF inhibitor vemurafenib upregulated autophagy through suppression of the PI3K/Akt/mTOR/p70S6 K pathway in BRAF V600E-mutant uveal melanoma cells. Autophagy inhibition impaired the treatment efficacy of vemurafenib in BRAF V600E-mutant uveal melanoma cells.
CONCLUSIONS: Our data demonstrate that starvation-trigged autophagy, which is BRAF V600E dependent, promotes cancer cell survival in uveal melanoma. Vemurafenib induces autophagic cell death rather than adaptive cell survival in BRAF V600E-mutant melanoma.
Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma.
J Cancer Res Clin Oncol. 2017; 143(3):439-445 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications.
RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores.
CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.
Elucidating the role of the FoxO3a transcription factor in the IGF-1-induced migration and invasion of uveal melanoma cancer cells.
Biomed Pharmacother. 2016; 84:1538-1550 [PubMed] Related Publications
HIC1 modulates uveal melanoma progression by activating lncRNA-numb.
Tumour Biol. 2016; 37(9):12779-12789 [PubMed] Related Publications
Choroidal melanoma and pregnancy.
Acta Ophthalmol. 2016; 94(7):e652-e660 [PubMed] Related Publications
METHODS: We conducted a single-centre retrospective study at the Institut Curie on the population of women of childbearing age who were diagnosed with choroidal melanoma between June 1980 and October 2013. We took a particular interest in the prognosis of those who were pregnant at the time of diagnosis and in the prognosis of those who chose to get pregnant after the treatment.
RESULTS: We found 27 pregnant patients at the time of diagnosis and 13 patients who became pregnant after the treatment. There was no difference in the survival between these two groups of patients and the group of other women of childbearing age diagnosed with choroidal melanoma (p = 0.52). There was also no difference in metastasis-free survival (p = 0.91). Most women were able to carry their pregnancies to term (67% had a term pregnancy, and only 7% had an abortion). For women who were pregnant when they were diagnosed with choroidal melanoma, a conservative treatment was chosen in 85% of cases, and proton beam therapy was the most widely used treatment.
CONCLUSIONS: Survival in women of childbearing age does not appear to be influenced by pregnancy. We show that proton beam therapy can be used to treat women who are pregnant at the time of choroidal melanoma diagnosis.
Update on Ophthalmic Oncology 2014: Retinoblastoma and Uveal Melanoma.
Asia Pac J Ophthalmol (Phila). 2016 Sep-Oct; 5(5):368-82 [PubMed] Related Publications
DESIGN: This study is a literature review.
METHODS: The terms retinoblastoma and uveal melanoma were used in a MEDLINE literature search. Abstracts were studied, and the most relevant articles were selected for inclusion and further in-depth review.
RESULTS: In retinoblastoma, more eyes are being salvaged due to intravitreal melphalan. The year 2014 marks a deepening in our understanding of the biological basis of the disease and the cell of origin. Knowledge on the genetic underpinnings of uveal melanoma has broadened to include other pathways, interactions, and potential therapeutic targets.
CONCLUSIONS: In 2014, there were valuable advancements in our knowledge of retinoblastoma and uveal melanoma. Some of these resulted in improved patient management.
Is it sufficient to repeat LINEAR accelerator stereotactic radiosurgery in choroidal melanoma?
Bratisl Lek Listy. 2016; 117(8):456-62 [PubMed] Related Publications
METHODS: We used model Clinac 600 C/D Varian (system Aria, planning system Corvus version 6.2 verification IMRT OmniPro) with 6 MeV X by rigid immobilization of the eye to the Leibinger frame. The stereotactic treatment planning after fusion of CT and MRI was optimized according to the critical structures (lens, optic nerve, also lens and optic nerve at the contralateral side, chiasm). The first plan was compared and the best plan was applied for therapy at C LINAC accelerator. The planned therapeutic dose was 35.0 Gy by 99 % of DVH (dose volume histogram).
RESULTS: In our clinical study in the group of 125 patients with posterior uveal melanoma treated with SRS, in 2 patients (1.6 %) was repeated SRS indicated. Patient age of the whole group ranged from 25 to 81 years with a median of 54 TD was 35.0 Gy. In 2 patients after 5 year interval after stereotactic radiosurgery for uveal melanoma stage T1, the tumor volume increased to 50 % of the primary tumor volume and repeated SRS was necessary.
CONCLUSION: To find out the changes in melanoma characteristics after SRS in long term interval after irradiation is necessary to follow up the patient by an ophthalmologist regularly. One step LINAC based stereotactic radiosurgery with a single dose 35.0 Gy is one of treatment options to treat T1 to T3 stage posterior uveal melanoma and to preserve the eye globe. In some cases it is possible to repeat the SRS after more than 5 year interval (Fig. 8, Ref. 23).
P2RX7-V3 is a novel oncogene that promotes tumorigenesis in uveal melanoma.
Tumour Biol. 2016; 37(10):13533-13543 [PubMed] Related Publications
Choroidal malignant melanoma with no extraocular extension presenting as orbital cellulitis.
Orbit. 2016; 35(5):285-7 [PubMed] Related Publications
Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma.
Clin Epigenetics. 2016; 8:80 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
RESULTS: miR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without. None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without tumor infiltrating lymphocytes. Tumors manifesting monosomy-3 were also characterized by higher levels of TARBP2 and DDX17 and by lower levels of XPO5 and HIWI, miR biogenesis factors. miR profiling of plasma by a quantitative nuclease protection assay found elevated levels of 11 miRs and reduction in four in patients with tumor monosomy-3. Only three miRs differentially expressed in the tumor arrays were detectable in plasma. miRs implicated in uveal melanoma development were not differentially expressed. Elevated plasma levels in patients with tumor monosomy-3 of miR-92b, identified in the tumor array, and of miR-199-5p and miR-223, identified in the plasma array, were confirmed by quantitative real-time polymerase chain reaction. Levels were also higher in patients compared to normal controls.
CONCLUSIONS: These results support a role for epigenetic mechanisms in the development of metastasis in patients with uveal melanoma and the analysis of miRs as biomarkers of metastatic risk. They also suggest that potentially useful blood miRs may be derived from the host response as well as the tumor.
Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations.
Biomed Res Int. 2016; 2016:4521807 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Vascularized solid iris lesion in a 3 year old child: 5 years of follow up.
BMC Ophthalmol. 2016; 16:89 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
CASE PRESENTATION: We report on an unusual case of a vascularized iris lesion in a three year old Caucasian patient, with no symptoms and no visual impairment. We evaluated in a 50-month follow up with non-invasive diagnostic tools in order to avoid eye biopsy.
CONCLUSION: We focused attention on the differential diagnoses and underlined the role of non-invasive diagnostic tools in a child to avoid or postpone the eye biopsy. We performed a review of the literature to identify the best medical practice in pediatric iris lesions with atypical characteristics.
CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas.
BMC Ophthalmol. 2016; 16:74 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
METHODS: The expression of CD147 and MMP-2 was analyzed in 49 samples of uveal melanomas. Triple immunofluorescence stainings using markers against glial cells (GFAP), endothelial cells (CD34) and macrophages (CD68) were performed to further analyse the exact localisation of CD147 and MMP-2 positivity. In 28 cases clinical metastatic disease were found. The remaining 21 cases showed no signs of metastatic disease for an average follow-up of 10 years. Correlation analysis (Pearson correlation) was performed to analyse the association of CD147 and MMP-2 expression with known prognostic factors, vasculogenic mimicry (VM), the mature vasculature (von Willebrand Factor) and tumor induced angiogenesis (by means of Endoglin expression).
RESULTS: CD147 and MMP-2 were expressed in 47 (96.0 %) of the uveal melanomas. CD147 up-regulation was significantly correlated with a higher MMP-2 expression. The overall expression analysis revealed no significant difference in the metastatic (p = 0.777) and non-metastatic subgroup (p = 0.585). No correlation of CD147 expression and any system of blood supply was evident. In the non-metastatic sub-group a significant correlation of clustered CD147 positive cells with largest basal diameter (p = 0.039), height (p = 0.047) and TNM-stage (p = 0.013) was evident.
CONCLUSIONS: These data may indicate that CD147 regulates MMP-2 expression in uveal melanoma cells.
Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile.
Acta Ophthalmol. 2016; 94 Thesis 1:1-27 [PubMed] Related Publications
Overexpression of Annexin II Receptor-Induced Autophagy Protects Against Apoptosis in Uveal Melanoma Cells.
Cancer Biother Radiopharm. 2016; 31(4):145-51 [PubMed] Related Publications
Imaging of ocular melanoma metastasis.
Br J Radiol. 2016; 89(1065):20160092 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
Tumor Characteristics, Genetics, Management, and the Risk of Metastasis in Uveal Melanoma.
Semin Ophthalmol. 2016; 31(4):304-9 [PubMed] Related Publications
Disparities in Uveal Melanoma: Patient Characteristics.
Semin Ophthalmol. 2016; 31(4):296-303 [PubMed] Related Publications
Metastatic Disease in Polyploid Uveal Melanoma Patients Is Associated With BAP1 Mutations.
Invest Ophthalmol Vis Sci. 2016; 57(4):2232-9 [PubMed] Related Publications
METHODS: In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ-hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing.
RESULTS: Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P = 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16-fold increased hazard ratio (HR 15.90, P = 0.009).
CONCLUSIONS: The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM.
Protein Tyrosine Phosphatase 4A3 (PTP4A3) Promotes Human Uveal Melanoma Aggressiveness Through Membrane Accumulation of Matrix Metalloproteinase 14 (MMP14).
Invest Ophthalmol Vis Sci. 2016; 57(4):1982-90 [PubMed] Related Publications
METHODS: Cell membrane localization of matrix metalloprotease 14 (MMP14) in uveal melanoma cells expressing protein tyrosine phosphatase A3 (PTP4A3) was assessed by flow cytometry or immunohistochemistry. The vesicular trafficking of MMP14 in the presence of PTP4A3 was evaluated in OCM-1 cells expressing either the wild-type or mutated phosphatase. Finally, MMP14 localization at the cell membrane of OCM-1 cells was impaired using RNA interference, and the PTP4A3-related migration in vitro and invasiveness in vivo of the treated cells were evaluated.
RESULTS: We found that the membrane-anchored MMP14 is enriched at the cell surface of OCM-1 cells, patient-derived xenograft cells, and human primary uveal melanoma tumors expressing PTP4A3. Moreover, we show that PTP4A3 and MMP14 colocalize and that the vesicular trafficking of MMP14 is faster in the presence of active PTP4A3. Finally, we demonstrate that inhibition of MMP14 expression in uveal melanoma cells expressing PTP4A3 impairs their migration in vitro and invasiveness in vivo.
CONCLUSIONS: Our observations indicate that PTP4A3 increases cell membrane accumulation of MMP14 as a result of increased cellular trafficking of the metalloprotease. We also show that downregulation of MMP14 expression reduced PTP4A3-induced cell migration and invasiveness. Taken together, our findings suggest that PTP4A3-related subcellular localization of MMP14 is an important event in metastasis induction.
Feasibility of Proton Beam Therapy for Ocular Melanoma Using a Novel 3D Treatment Planning Technique.
Int J Radiat Oncol Biol Phys. 2016; 95(1):353-9 [PubMed] Related Publications
METHODS AND MATERIALS: We evaluated 26 consecutive patients with choroidal melanomas on a prospective registry. Ophthalmologic work-up included fundoscopic photographs, fluorescein angiography, ultrasonographic evaluation of tumor dimensions, and magnetic resonance imaging of orbits. Three tantalum clips were placed as fiducial markers to confirm eye position for treatment. Macula, fovea, optic disc, optic nerve, ciliary body, lacrimal gland, lens, and gross tumor volume were contoured on treatment planning compute tomography scans. 3D treatment planning was performed using noncoplanar field arrangements. Patients were typically treated with 3 fields, with at least 95% of planning target volume receiving 50 GyRBE in 5 fractions.
RESULTS: Tumor stage was T1a in 10 patients, T2a in 10 patients, T2b in 1 patient, T3a in 2 patients, T3b in 1 patient, and T4a in 2 patients. Acute toxicity was mild. All patients completed treatment as planned. Mean optic nerve dose was 10.1 Gy relative biological effectiveness (RBE). Ciliary body doses were higher for nasal (mean: 11.4 GyRBE) than temporal tumors (5.8 GyRBE). Median follow-up was 31 months (range: 18-40 months). Six patients developed changes which required intraocular bevacizumab or corticosteroid therapy, but only 1 patient developed neovascular glaucoma. Five patients have since died: 1 from metastatic disease and 4 from other causes. Two patients have since required enucleation: 1 due to tumor and 1 due to neovascular glaucoma.
CONCLUSIONS: 3D treatment planning can be used to obtain appropriate coverage of choroidal melanomas. This technique is feasible with relatively low doses to anterior structures, and appears to have acceptable rates of local control with low risk of enucleation. Further evaluation and follow-up is needed to determine optimal dose-volume relationships for organs at risk to decrease complications rates.
Practice Patterns Analysis of Ocular Proton Therapy Centers: The International OPTIC Survey.
Int J Radiat Oncol Biol Phys. 2016; 95(1):336-43 [PubMed] Related Publications
METHODS AND MATERIALS: Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow.
RESULTS: Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers (P=.0161). Generally, ophthalmologists followed up the post-radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers.
CONCLUSIONS: The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients.
Visual Outcomes of Parapapillary Uveal Melanomas Following Proton Beam Therapy.
Int J Radiat Oncol Biol Phys. 2016; 95(1):328-35 [PubMed] Related Publications
METHODS AND MATERIALS: Of 5205 patients treated between 1991 and 2014, those treated using computed tomography (CT)-based planning to 52 Gy (prescribed dose, not accounting for relative biologic effectiveness correction of 1.1) in 4 fractions, with minimal 6-month follow-up and documented initial and last visual acuity, were included. Deterioration of ≥0.3 logMAR between initial and last visual acuity results was reported.
RESULTS: A total of 865 consecutive patients were included. Median follow-up was 69 months, mean age was 61.7 years, tumor abutted the papilla in 35.1% of patients, and tumor-to-fovea distance was ≤3 mm in 74.2% of patients. Five-year relapse-free survival rate was 92.7%. Visual acuity was ≥20/200 in 72.6% of patients initially and 47.2% at last follow-up. A wedge filter was used in 47.8% of the patients, with a positive impact on vision and no impact on relapse. Glaucoma, radiation-induced optic neuropathy, maculopathy were reported in 17.9%, 47.5%, and 33.6% of patients, respectively. On multivariate analysis, age, diabetes, thickness, initial visual acuity and percentage of macula receiving 26 Gy were predictive of visual acuity. Furthermore, patients irradiated to ≥80% of their papilla had better visual acuity when limiting the 50% (30-Gy) and 20% (12-Gy) isodoses to ≤2 mm and 6 mm of optic nerve length, respectively.
CONCLUSIONS: A personalized proton therapy plan with optic nerve and macular sparing can be used efficiently with good oncological and functional results in parapapillary melanoma patients.
Multiple simultaneous choroidal melanomas arising in the same eye: globe salvage by radiotherapy.
Acta Ophthalmol. 2016; 94(8):e799-e802 [PubMed] Related Publications
OBSERVATIONS: Both patients presented with two simultaneous choroidal melanomas in one eye. The first patient was only 30 years old and presented with two largely amelanotic tumours with large exudative retinal detachment. Cytology from fine needle aspiration biopsies from both tumours with immunohistochemistry confirmed two separate melanomas. Sequential radioactive iodine plaque brachytherapy led to regression of both tumours. The second, older patient's two tumours both had the typical appearance of choroidal melanoma and he underwent proton beam irradiation to the entire field leading to tumour regression.
CONCLUSIONS: Multiple choroidal melanomas can rarely arise simultaneously in the same eye, and despite their variable appearance, a definitive diagnosis can be aided by cytology and immunohistochemistry in atypical-appearing cases. While all other previously reported cases have necessitated enucleation, we demonstrate that globe salvage is possible using either proton beam irradiation to the entire tumour field, or with sequential radioactive plaque brachytherapy.
Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.
Am J Hum Genet. 2016; 98(4):789-95 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
Epithelial, non-melanocytic and melanocytic proliferations of the ocular surface.
Semin Diagn Pathol. 2016; 33(3):122-32 [PubMed] Related Publications
BRAF mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions.
Acta Ophthalmol. 2016; 94(5):463-70 [PubMed] Related Publications
METHODS: Data from 139 patients with conjunctival melanoma (1960-2012) were collected. Archived conjunctival melanoma samples and premalignant lesions were analysed for BRAF mutations using droplet digital polymerase chain reaction (PCR). Results were associated with clinicopathological features and compared with BRAF V600E oncoprotein stainings.
RESULTS: The overall incidence of conjunctival melanoma (0.5 cases/1 000 000/year) increased during the study period with 0.13 cases/1 000 000/10 years. The increase comprised a higher proportion of patients aged >65 years, epibulbar tumours and tumours developed from a primary acquired melanosis with atypia. BRAF mutations were identified in 39 of 111 (35%) cases. The rate ratio of BRAF-mutated versus BRAF-wild-type melanoma did not change over time. BRAF mutations were associated with T1 stage (p = 0.007), young age (p = 0.001), male gender (p = 0.02), sun-exposed location (p = 0.01), mixed/non-pigmented tumour colour (p = 0.02) and nevus origin (p = 0.005), but did not associate with prognosis. BRAF status in conjunctival melanoma and paired premalignant lesions corresponded in 19 of 20 cases. Immunohistochemistry detected BRAF V600E mutations with a sensitivity of 0.94 and a specificity of 1.00 in newer conjunctival melanoma samples (2000-2012, n = 47).
CONCLUSION: The incidence of conjunctival melanoma increased in Denmark over 50 years. The proportion of BRAF-mutated conjunctival melanoma was constant. BRAF mutations were identified as early events in conjunctival melanoma, associated with a distinct clinicopathological profile, similar to BRAF-mutated cutaneous melanoma. Immunohistochemical detection of BRAF can be used to assess BRAF V600E mutations.
Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey.
APMIS. 2016; 124(6):475-86 [PubMed] Related Publications
Update on Metastatic Uveal Melanoma: Progress and Challenges.
BioDrugs. 2016; 30(3):161-72 [PubMed] Related Publications
The influence of physical wedges on penumbra and in-field dose uniformity in ocular proton beams.
Phys Med. 2016; 32(4):612-7 [PubMed] Related Publications