Therapy For Uveal Melanoma Research Articles

Programmed cell death ligand-1 expression in tumor and immune cells is associated with better patient outcome and decreased tumor-infiltrating lymphocytes in uveal melanoma

Programmed cell death-1/ligand (PD-1/PD-L1) interaction negatively regulates T cell activity. PD-L1 expression in tumor cells, antigen-presenting cells, and lymphocytes of the tumor microenvironment is associated with response to treatment with PD-1/PD-L1 inhibitors, but there is still debate on the cutoff value that correlates with responders. In uveal melanoma (UM), 40% of patients will develop liver metastases and, amongst them, 90% will succumb to their disease. The aim of this study was to analyze PD-L1 expression as a prognostic marker and as a possible therapeutic target for UM. Sixty-seven enucleated eyes from UM patients with relevant clinical information were analyzed. Univariate and multivariate analysis were used to evaluate association of PD-L1 with survival. PD-L1 expression was positive relatively to tumor cells, immune cells, and the tumor and tumor-infiltrating immune cell group scoring in 46, 34 and 55% of the cases, respectively. On univariate analysis, tumor cells and the tumor and tumor-infiltrating immune cell group PD-L1 expression was associated with a longer metastasis-free survival (P = 0.04 and P = 0.007). However, on multivariate analysis, only the tumor and tumor-infiltrating immune cell group positivity was associated with longer metastasis-free survival (P = 0.01). Furthermore, tumor cells and the tumor and tumor-infiltrating immune cell group PD-L1 expression was associated with decreased tumor-infiltrating lymphocytes (P = 0.02). PD-L1, when expressed in uveal melanoma, is associated with better patient outcome and decreased tumor-infiltrating lymphocytes. These results support the consideration of anti-PD-1/PD-L1 therapy in uveal melanoma. To determine the best cutoff value, further studies from patients enrolled in clinical trials treated with PD-1/PD-L1 inhibitors are necessary.

The Role of Histone Deacetylase Inhibitors in Uveal Melanoma: Current Evidence.

Uveal melanoma is the most common intraocular malignancy in adults, representing approximately 3% of all melanoma cases. Despite progress in chemotherapy, radiation and surgical treatment options, the prognosis and survival rates remain poor. Acetylation of histone proteins causes transcription of genes involved in cell growth, DNA replication and progression of cell cycle. Overexpression of histone deacetylases occurs in a wide spectrum of malignancies. Histone deacetylase inhibitors block the action of histone deacetylases, leading to inhibition of tumor cell proliferation. This article reviewed the potential therapeutic effects of histone deacetylase inhibitors on uveal melanoma. MEDLINE database was used under the key words/phrases: histone deacetylase, inhibitors, uveal melanoma and targeted therapies for uveal melanoma. A total of 47, English articles, not only referring to uveal melanoma, published up to February 2018 were used. Valproic acid, trichostatin A, tenovin-6, depsipeptide, panobinostat (LBH-589), vorinostat (suberanilohydroxamic acid) entinostat (MS-275), quisinostat, NaB, JSL-1, MC1568 and MC1575 are histone deacetylase inhibitors that have demonstrated promising antitumor effects against uveal melanoma. Histone deacetylase inhibitors represent a promising therapeutic approach for the treatment of uveal melanoma.

Somatostatin Receptors as Molecular Targets in Human Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 4–5 cases per million. The prognosis of UM is very poor. In the present study, our aim was to investigate the expression of mRNA and protein for somatostatin receptor types-1, -2, -3, -4, -5 (SSTR-1–5) in human UM tissue samples and in OCM-1 and OCM-3 human UM cell lines by qRT-PCR, western blot and ligand competition assay. The mRNA for SSTR-2 showed markedly higher expression in UM tissues than SSTR-5. The presence of SSTRs was demonstrated in 70% of UM specimens using ligand competition assay and both human UM models displayed specific high affinity SSTRs. Among the five SSTRs, the mRNA investigated for SSTR-2 and SSTR-5 receptors was strongly expressed in both human UM cell lines, SSTR-5 showing the highest expression. The presence of the SSTR-2 and SSTR-5 receptor proteins was confirmed in both cell lines by western blot. In summary, the expression of somatostatin receptors in human UM specimens and in OCM-1 and OCM-3 human UM cell lines suggests that they could serve as a potential molecular target for therapy of UM using modern powerful cytotoxic SST analogs targeting SSTR-2 and SSTR-5 receptors.

Plaque brachytherapy for posterior uveal melanoma in 2018: improved techniques and expanded indications.

Plaque brachytherapy remains the dominant globe-sparing therapy of uveal melanoma. This report highlights recent advances, which have expanded plaque brachytherapy's uses as well as improved the surgical technique. Plaque brachytherapy is effective for tumors that may previously have demanded enucleation. Plaque brachytherapy can be used to control large melanomas as well as melanomas touching the optic nerve. Improvements in planning and design have made plaque therapy simpler for the surgical operator and may reduce collateral radiation damage to normal ocular structures. The COMS implies a required dose of 85 Gy to the tumor apex for treatment of uveal melanoma. However, multiple reports indicate that lower doses may be equally effective for tumor control while reducing radiation dose to uninvolved structures. Vitreoretinal surgeons can be called upon safely to treat long-term side effects of radiation or tumor death such as intractable vitreous hemorrhage or inflammation. Further, vitreoretinal surgeons have employed tumor endoresection as primary local tumor control or in combination with plaque brachytherapy. Plaque brachytherapy for uveal melanoma remains highly effective for local tumor control and prevention of metastasis. Indications for plaque brachytherapy have expanded, and the technique has improved.

Antitumor efficacy of VP22-CD/5-FC suicide gene system mediated by lentivirus in a murine uveal melanoma model

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, which has high frequency of metastasis to the liver, typically causing a fatal outcome. Chemo-resistance remains a major obstacle in the therapeutic approach to UM, leaving limited choice for treating UM. Other possible treatments have been explored but the results are yet to be evident. To improve therapy for UM, transcriptional suicide genes were transfected into the OCM-1 cell line. In the current study, OCM-1 cells transfected with lentiviral-meditated EGFP, cytosine deaminase (CD)/EGFP, and VP22-CD/EGFP were established. Of the three groups, we examined the cell growth in vitro and in vivo by using the MTT method with cell culture media and MRI in murine UM models. According to our results, the cell proliferation in the transfected CD/EGFP group was slower than the non-suicide gene group. The VP22-CD/EGFP group manifested superior cell cytotoxicity than the CD/EGFP group. Further analysis of MRI and fluorescent imaging of the murine UM model identified significant differences in tumor volume among the three groups. Collectively, our study demonstrated that CD/5-FC is a potent therapeutic approach for UM. With the efficacy of VP22, suicide gene-induced cytotoxicity was superior to applying CD alone. Taken together, we concluded that novel therapy with the VP22-CD suicide gene may further contribute to treatment of UM.

Proton Beam Irradiation: A Safe Procedure in Postequatorial Extraocular Extension From Uveal Melanoma

This study was performed to show long-term outcomes concerning metastasis rates and local recurrence rates after primary proton beam therapy in uveal melanoma with posterior extraocular extension (EOE) with the main focus on optic nerve invasion. Retrospective case series. All patients treated with primary proton beam therapy for choroidal or ciliary body melanoma with posterior EOE between July 1998 and August 2010 were included. EOE was detected either upon sonography at primary examination or during the surgical application of tantalum clips onto the sclera. Ultrasound was performed in each patient before surgery, and if EOE was detected, a magnetic resonance imaging (MRI) scan was performed to confirm EOE. All patients with tumors exceeding 6mm in thickness or abutting the optic disc received a 1.5 Tesla MRI scan after clip surgery. To assess EOE during follow-up, either ultrasound examinations or-if initially detected only by MRI-MRI scans were performed during follow-up. A total of 27 patients underwent primary proton beam therapy. The EOE was separated into 3 growth types: optic nerve infiltration in 10 patients, vortex vein infiltration in 9 patients, and transscleral growth postequatorially in 8 patients. No local recurrences were found during the overall median follow-up of 80months (11-168months). Metastasis rates correlated with AJCC stages but not EOE volume. This study shows that posterior EOE can safely be treated by proton beam therapy, even if the optic nerve is infiltrated. MRI enables safe detection of optic nerve invasion.

Radiation Maculopathy After Proton Beam Therapy for Uveal Melanoma: Optical Coherence Tomography Angiography Alterations Influencing Visual Acuity.

To analyze microvascular and structural changes in radiation maculopathy and their influence on visual acuity (VA), using optical coherence tomography (OCT) and OCT angiography (OCTA). This was a retrospective analysis of consecutive patients with radiation maculopathy, 12 months or more after proton-beam irradiation for uveal melanoma, imaged with fluorescein angiography, OCT, and OCTA. Clinical parameters potentially affecting VA were recorded, including OCTA-derived metrics: foveal avascular zone (FAZ) area, vascular density, and local fractal dimension of the superficial (SCP) and deep capillary plexuses (DCP). Nonirradiated fellow eyes served as controls. Ninety-three patients were included. FAZ was larger, while SCP/DCP capillary density and local fractal dimension were lower in the 35 irradiated than in the 35 fellow eyes (P < 0.0001). Microvascular alterations graded on fluorescein angiography (minimally damaged/disrupted/disorganized) were correlated to FAZ area and SCP/DCP density on OCTA (P < 0.01). By univariate analysis, worse VA was associated to macular detachment at presentation (P = 0.024), total macular irradiation (P = 0.0008), higher central macular thickness (CMT) (P = 0.019), higher absolute CMT variation (P < 0.0001), cystoid edema (P = 0.030), ellipsoid zone disruption (P = 0.002), larger FAZ (P < 0.0001), lower SCP (P = 0.001) and DCP capillary density (P < 0.0001), and lower SCP (P = 0.009) and DCP local fractal dimension (P < 0.0001). Two multivariate models with either capillary density or fractal dimension as covariate showed that younger age (P = 0.014/0.017), ellipsoid zone disruption (P = 0.034/0.019), larger FAZ (P = 0.0006/0.002), and lower DCP density (P = 0.008) or DCP fractal dimension (P = 0.012), respectively, were associated with worse VA. VA of eyes with radiation maculopathy is influenced by structural and microvascular factors identified with OCTA, including FAZ area and DCP integrity.

Abstract 5198: Targeted alpha particle therapy for uveal melanoma

Abstract New effective therapies are greatly needed for uveal melanoma, the most common ocular malignancy, which has a very poor prognosis with a median survival of less than one year when metastatic disease develops. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanomas but is not expressed in normal tissues of concern for toxicity. Previously, we developed an MC1R specific ligand (MC1RL) with high affinity and selectivity for MC1R. We used the MC1RL as a targeting scaffold for development of a radiopharmaceutical by conjugation of 225Ac chelate to form 225Ac -MC1RL-DOTA. 225Ac is a therapeutic alpha-emitting radionuclide. 225Ac -MC1RL-DOTA was synthesized with high radiochemical yield and purity (&amp;gt;95 and &amp;gt;99 % respectively) with an excellent in vitro stability, i.e. 90% after 10 days in human serum at 37ºC. An MTT cytotoxicity study demonstrated MC1R specific antiproliferative effect in cutaneous, ocular and uveal melanoma cell lines. A maximum tolerated dose (MTD) study was completed, where a range of 0-148 kBq (0-4 µCi) of 225Ac -MC1RL-DOTA was administered to groups of BALB/c mice. The radiopharmaceutical was well tolerated at even the highest doses and animals did not reach any clinical endpoints, such as weight loss, loss of kidney function or abnormal pathology. Biodistribution studies on MC1R expressing tumor bearing mice revealed tumor selectivity and a combination of renal and hepatic clearance with minimal retention in other normal tissues. A blood PK study in rats showed rapid clearance of the agent from the blood in &amp;lt;60 min. To determine radiodosimetry, gamma spectra were acquired for tumors, blood and other tissues and organs over a 21-day time period and activity curves generated for each tissue for 225Ac and other gamma-emitting daughter products in the decay chain. An exponential line-fitting of these curves allowed the estimation of clearance kinetics, tissue biological half-life and total absorbed dose (Gy) for each tissue. Doses were highest in MC1R positive tumors and clearance organs (liver, kidney and spleen) and low in all other tissues. In vivo efficacy studies were performed in human A375/MC1R cutaneous and MEL20 uveal melanoma tumors in SCID mice, or syngeneic mouse B16 melanoma tumors in C57BL/6 mice (n=10/group) injected with either 225Ac -MC1RL-DOTA, 225Ac-scrambled-MC1RL-DOTA, La-MC1RL-DOTA (non-radioactive control agent) or saline. In every case a tumor growth delay was observed in treated mice relative to controls, and a percentage of mice bearing the human tumors had complete remission. In conclusion, we evaluated the in vitro and in vivo properties of 225Ac-MC1RL-DOTA in this study. This agent demonstrated a significant MC1R-specific in vivo therapeutic efficacy in a mouse model of uveal melanoma with low systemic toxicity. Citation Format: Narges K. Tafreshi, Nella C. Delva, Christopher J. Tichacek, Michael L. Doligalski, Darpan N. Pandya, Nikunj B. Bhatt, HyunJoo Kil, Mikalai M. Budzevich, Epifanio Ruiz, Thaddeus J. Wadas, Mark L. McLaughlin, David L. Morse. Targeted alpha particle therapy for uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5198. doi:10.1158/1538-7445.AM2017-5198

Chirurgische Methoden in der Behandlung des Aderhautmelanoms

Significant advancements have been made in the last decades in the treatment of uveal melanoma. Radiation therapy can achieve, depending on the method, local tumour control in up to 98% of cases. Surgical modalities have been implemented in the ocular therapy for uveal melanoma either to treat/prevent radiation complications, such as so-called toxic tumour syndrome, or to primarily treat the tumour with or without adjunctive radiotherapy. These include endoresection and transscleral resection for melanomas of the choroid/ciliary body or irido-trabeculo-cyclectomy for melanomas of the iris-ciliary body. Furthermore, tumour biopsy is playing a progressively more important role in the diagnosis, treatment and follow-up planning of melanoma cases. This paper focuses on the background, the surgical technique as well as the results and complications of tumour excisional and biopsy surgery.

Ocular melanoma-when you have seen one, you have not seen them all: a clinical outcome study from the Surveillance, Epidemiology and End Results (SEER) database (1973-2012).

BackgroundOcular melanoma (OM) comprises <5% of all melanomas. Uveal melanoma (UM) is the most common subtype of OM, while conjunctival melanoma (CM) is rare and differs significantly from UM. The purpose of this study is to evaluate a large cohort of OM patients to differentiate demographic, pathologic, and clinical factors between these two neoplasms, which may affect treatment and outcomes.MethodsThe Surveillance, Epidemiology, and End Results database (1973–2012) was used to extract demographic and clinical data on 8,165 OM patients (92.1% UM and 7.9% CM).ResultsBoth CM and UM were most prevalent among Caucasian males in the seventh decade of life. UM patients presented more often with localized disease (90.9% vs 81.2, P<0.01). Surgery (42.8%), radiation (43.0%), or combined surgery and radiation (7.0%) were used in the treatment of UM, while CM was treated almost exclusively with surgery (88.7%). Mean overall survival was longer (15.4 vs 14.6 years; P<0.01) and mortality rates were lower in patients (38.8% vs 46.1%; P<0.01) with CM.ConclusionDespite presenting with more advanced disease than UM, CM is associated with an increased overall survival. Surgery is the primary therapy for CM, whereas radiotherapy is the primary therapy for UM and is associated with prolonged survival.

Acute Side Effects of Proton Beam Therapy for Uveal Melanoma

Acute Side Effects of Proton Beam Therapy for Uveal Melanoma

Predictive risk factors for radiation retinopathy and optic neuropathy after proton beam therapy for uveal melanoma.

This study was performed in order to evaluate the incidence of radiation retinopathy and optic neuropathy occurring after proton beam therapy for uveal melanoma. Included in this study were all patients who had been treated with primary proton beam therapy for uveal melanoma at the oncology service between May 1998 and June 2014 with a minimum follow-up of 12months. Excluded were all patients who underwent re-irradiation, or vitrectomy due to exudative retinal detachment or for tumor-resection. During this period, 1127 patients matched the inclusion criteria, of whom 768 (68.1%) and 463 (41.0%) developed radiation retinopathy and optic neuropathy after a median time of 18.9months (2.0-99.84months) and 19.8months (0.2-170.4months), respectively. Mean follow-up was 53.4months (12-170.4months). Included were 558 men (49.5%) and 569 women (50.5%). Mean age was 61years (16-89 years). Visual acuity slightly decreased from initial levels of 0.3 logMAR-0.4 logMAR in patients without developing any radiation-induced complication but severely decreased to 1.0 logMAR or 1.5 logMAR in the case of developing radiation retinopathy only or optic neuropathy, respectively. Independent risk factors for radiation retinopathy were a centrally (<2.5mm from sensitive structures) located tumor or a thick tumor located more than 2.5mm from sensitive structures, while those for radiation optic neuropathy comprised a short distance and applied dose to the optic disk. The risk for radiation retinopathy is higher in central uveal melanoma. Mid-/peripheral tumors are at high risk for radiation retinopathy and maculopathy if presenting with increased thickness.

Antiangiogenic or Corticosteroid Treatment in Patients With Radiation Maculopathy After Proton Beam Therapy for Uveal Melanoma

To reveal differences or advantages in regard to different treatment options after proton beam therapy for uveal melanoma. Retrospective, comparative, interventional case series. All patients receiving intravitreal treatment between January 2011 and July 2014 for radiation maculopathy after proton beam therapy were included. Excluded were all patients who required re-irradiation, vitrectomies, or tumor resections; and those whose treatment was performed for potentially other reasons, such as radiation-induced optic neuropathy, or where visual outcome was influenced by tumor growth under the macula or macular ischemia. Minimum follow-up was 12months after last injection. Of 78 patients, 38 (48.7%) received bevacizumab injections, 35 (44.9%) triamcinolone acetonide injections, and 5 (6.4%) a dexamethasone implant. In the bevacizumab group visual acuity improved in 11 patients (28.9%) by 0.25 logMAR (0.1-0.4 logMAR) and remained stable in 24 patients (63.2%) 4weeks after injection. In the triamcinolone group visual acuity showed improved outcomes in 10 patients (28.6%) by 0.25 logMAR (0.1-0.4 logMAR) and stability in function in 20 patients (57.1%). Four weeks after dexamethasone implantation visual acuity remained stable in 4 patients (80%). No differences among the groups were detected regarding functional outcome or reduction in central foveal thickness. This study showed that antiangiogenic or corticosteroid intravitreal treatment led to reduced central foveal thickness and visual improvement in some patients without showing differences or advantages. Therefore a patient-specific treatment choice can be recommended.

Overexpression of Annexin II Receptor-Induced Autophagy Protects Against Apoptosis in Uveal Melanoma Cells.

Uveal melanoma is the most common primary malignant intraocular tumor in adults and still lacks effective systemic therapies. Annexin A2 receptor (AXIIR), a receptor for Annexin II, was demonstrated to play an important role in multiple cells, but its role in uveal melanoma cells remains exclusive. Herein, the authors reported that overexpression of AXIIR was able to reduce cell viability and activate apoptosis apparently in the Mum2C uveal melanoma cell line. Meanwhile, overexpression of AXIIR could induce autophagy and increase autophagy flux. After autophagy was inhibited by chloroquine, enhanced apoptosis and cytotoxicity could be detected. In summary, these data highlighted the crucial role of AXIIR in reducing Mum2C cell viability through inducing apoptosis, while autophagy played a protective role in this process. Interference of this gene may be a promising method for uveal melanoma therapy and combination with specific inhibitor of autophagy may serve as a supplementary.

Cataract development in patients treated with proton beam therapy for uveal melanoma.

To evaluate the incidence, risk factors, and dosages of proton beam therapy associated with cataract development, and long-term visual outcomes after treatment of uveal melanoma. All patients receiving primary proton beam therapy for uveal melanoma between 1998 and 2008 with no signs of cataract before irradiation were included. A minimum follow-up of 12months was determined. Exclusion criteria included all applied adjuvant therapies such as intravitreal injections, laser photocoagulation, tumor resections, or re-irradiation. For subgroup analysis, we included all patients who underwent brachytherapy between 1998 and 2008 for uveal melanoma, considering the above mentioned inclusion and exclusion criteria. Two hundred and fifty-eight patients matched our inclusion criteria. Median follow-up was 72.6months (12.0-167.4months). Of these 258 patients, 71 patients (66.3%) presented with cataract after 31.3months (0.7-142.4months), of whom 35 (20.4%) required surgery after 24.2 (0.7-111.1months) to ensure funduscopic tumor control. Kaplan-Meier estimates calculated a risk for cataract of 74.3% after 5years. There was no increase in metastasis or local recurrence in these patients. Patient's age was the sole independent statistically significant risk factor for cataract development. The probability of cataract occurrence significantly increased with doses to lens exceeding 15-20 CGE. Neither the appearance of cataract nor cataract surgery influenced long-term visual outcome. Cataract formation is the most frequent complication after irradiation. There is no benefit vis-a-vis brachytherapy with regard to cataract development. Data indicate a dose-effect threshold of 0.5 CGE for cataractogenesis, with significantly increasing risk above a dose of 15 CGE. Furthermore, cataract surgery can be performed without an increased risk for metastasis.

Trabeculectomy in patients with uveal melanoma after proton beam therapy.

Retrospective evaluation of intraocular pressure, use of topical and systemic anti-glaucoma medication, secondary complications, local tumor control and survival in patients treated with trabeculectomy for the regulation of the intraocular pressure (IOP) after proton beam therapy for uveal melanoma. In this retrospective clinical case series we evaluated the follow-up of 15 patients receiving a trabeculectomy as surgical treatment if the IOP could not be lowered adequately by medications or laser surgery. All patients had received proton beam therapy for uveal melanoma at the Helmholtz-Zentrum Berlin between 1998 and 2010. The median IOP decreased significantly from 35mmHg ± 8.8 before TE to 16mmHg ± 8.2 (=52.3%) six months after TE (Wilcoxon-Mann-Whitney-U Test, p<0.01). None of the patients needed any glaucoma medication six months after trabeculectomy. Two patients developed local recurrence during follow-up, which were independent of the trabeculectomy. One patient had to be enucleated due to intractable pain and suspected remaining tumor activity. One patient died due to metastasis. Trabeculectomy is an option in intractable glaucoma in patients with uveal melanoma after proton beam therapy in single cases. Secondary interventions are common. Inoculation metastases are possible. Secure local tumor control must be a prerequisite for filtrating operations.

Differential expression of TYRP1 in adult human retinal pigment epithelium and uveal melanoma cells

Uveal melanoma (UM) is the most frequently occurring primary intraocular malignancy in adults. Tyrosinase (TYR) is a copper-containing enzyme and a type I membrane protein that is involved in the generation of melanin, the main pigment in vertebrates. TYR-related protein 1 (TYRP1) is regarded to have a crucial role in the immunotherapy of melanoma. As biomarkers, the TYR-related proteins, TYRP1 and TYRP2, exhibit specific expression in melanocytes, while also contributing to melanin synthesis within melanosomes. In the present study, the differential expression of TYRP1 was investigated at the mRNA, protein and morphological levels in four human UM cell lines (SP6.5, OM431, OCM1 and OCM290) and the human retinal pigment epithelium (RPE) cell line, using polymerase chain reaction, western blotting, immunocytochemistry and immunofluorescence staining. It was found that SP6.5 cells expressed the highest level of TYRP1, in comparison to SP6.5 OCM1 and OM431 cells, which produced less TYRP1, and OCM290 cells, which produced almost no TYRP1. No TYRP1 protein expression was identified in the RPE cell line. These findings indicate the potential use of TYRP1 in the development of therapy for UM.

Ion therapy for uveal melanoma in new human eye phantom based on GEANT4 toolkit

Radiotherapy with ion beams like proton and carbon has been used for treatment of eye uveal melanoma for many years. In this research, we have developed a new phantom of human eye for Monte Carlo simulation of tumors treatment to use in GEANT4 toolkit. Total depth−dose profiles for the proton, alpha, and carbon incident beams with the same ranges have been calculated in the phantom. Moreover, the deposited energy of the secondary particles for each of the primary beams is calculated. The dose curves are compared for 47.8MeV proton, 190.1MeV alpha, and 1060MeV carbon ions that have the same range in the target region reaching to the center of tumor. The passively scattered spread-out Bragg peak (SOBP) for each incident beam as well as the flux curves of the secondary particles including neutron, gamma, and positron has been calculated and compared for the primary beams. The high sharpness of carbon beam׳s Bragg peak with low lateral broadening is the benefit of this beam in hadrontherapy but it has disadvantages of dose leakage in the tail after its Bragg peak and high intensity of neutron production. However, proton beam, which has a good conformation with tumor shape owing to the beam broadening caused by scattering, can be a good choice for the large-size tumors.

Patient, Tumor, and Dosimetric Predictors of Temporal Progression in Visual Acuity Following Proton Beam Radiation Therapy for Uveal Melanoma

Patient, Tumor, and Dosimetric Predictors of Temporal Progression in Visual Acuity Following Proton Beam Radiation Therapy for Uveal Melanoma

Serum adsorption, cellular internalization and consequent impact of cuprous oxide nanoparticles on uveal melanoma cells: implications for cancer therapy.

To investigate the biological fate of cuprous oxide nanoparticles (Cu2O-NPs) and to evaluate their potential in uveal melanoma therapy. The protein corona, cellular uptake mechanism and localization of Cu2O-NPs were investigated. Furthermore, the effect of Cu2O-NPs on uveal melanoma cell proliferation, migration and invasion, and possible mechanisms were studied in detail. Cu2O-NPs are able to adsorb serum proteins in cell culture medium, which are then internalized by uveal melanoma cells mainly through lipid raft-mediated endocytosis. Furthermore, Cu2O-NPs selectively inhibit cancer cell growth and impair the ability of uveal melanoma cell migration, invasion and the cytoskeleton assembly. The mechanism may be that Cu2O-NPs located in and damage mitochondria, autophagolysosomes and lysosomes, leading to elevated reactive oxygen species level and over-stimulated apoptosis and autophagy. The data provide detailed information of Cu2O-NPs for further application and indicate that Cu2O-NPs could be a potential agent for uveal melanoma therapy.