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Current Progress and Research Trends in Ocular Oncology

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 15043

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Special Issue Editors

Prof. Dr. Utta Berchner-Pfannschmidt

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Guest Editor

Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Interests: ocular oncology; primary tumor and metastasis; genetic and cellular heterogeneity; oncogenic pathways; cancer biology and immunology; molecular biomarkers; drug screening; 3D cell culture models; novel treatment options
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Dr. Miltiadis Fiorentzis

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Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Interests: ocular oncology; primary tumor; uveal melanoma; conjunctival melanoma; metastatic risk; diagnostic strategies; innovative therapeutic options; electrochemotherapy; patient-derived xenograft models; vitreoretinal surgery
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nikolaos E. Bechrakis

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Guest Editor

Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Interests: ocular oncology; uveal melanoma; conjunctival melanoma; retinoblastoma; primary tumor; metastatic risk; clinic–pathologic analysis; diagnostic strategies; prognostic factors; therapeutic options; vitreoretinal surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue with an original article or review in the field of ocular oncology with a focus on uveal melanoma, conjunctival melanoma or retinoblastoma. Uveal melanoma and retinoblastoma, which cause blindness and even death, are the most common primary intraocular malignancies in adults and children, respectively. Conjunctival melanoma shares genetic and pathophysiological features with cutaneous melanomas and is distinct from uveal melanoma. Although our understanding of these ocular cancers has advanced over the last decade and local tumor control is mostly achievable, they remain malignancies with recurrence and no treatment for metastatic disease.

This Special Issue aims to highlight current progress and research trends in all aspects of ocular oncology, including oncogenic pathways and genetic and cellular heterogeneity, and cancer immunity that underlie the initiation, progression, recurrence and metastasis of ocular tumors. Basic science studies with translational aspects as well as clinical trials are strongly encouraged. Experts in the field are invited to contribute with articles reviewing the latest perspectives in ocular cancer biology or diagnosis and therapy. This Special Issue reflects the wide range of efforts to advance the understanding and treatment of eye cancers.

Prof. Dr. Utta Berchner-Pfannschmidt
Dr. Miltiadis Fiorentzis
Prof. Dr. Nikolaos E. Bechrakis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ocular oncology
uveal melanoma
conjunctival melanoma
retinoblastoma
primary tumor
recurrence
metastasis
oncogenic pathways
genetic and cellular heterogeneity
cancer immunity
diagnostic strategies
therapeutic options

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Published Papers (9 papers)

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14 pages, 1434 KiB

Open AccessArticle

Long-Term Outcomes After Multidisciplinary Treatment for Pediatric Orbital Rhabdomyosarcoma

by Nur Khatib, Johannes H. M. Merks, Jeroen E. Markenstein, Brian V. Balgobind, Cemile. D. Savci-Heijink, Michele Morfouace, Bradley R. Pieters and Peerooz Saeed

Cancers 2025, 17(4), 615; https://doi.org/10.3390/cancers17040615 - 11 Feb 2025

Viewed by 779

Abstract

(1) Background: Orbital rhabdomyosarcoma is a rare and aggressive soft tissue tumor that primarily occurs in the eye socket (orbit) of children. Treatment usually involves a combination of surgery, chemotherapy, and radiation therapy, aiming to remove the tumor and prevent metastasis. (2) Methods: An institutional retrospective study was conducted with data from 39 patients with primary orbital RMS treated between 1995 and 2016 at the Amsterdam University Medical Centers/Emma Children Hospital. (3) Results: The median age at presentation was 7 years (range, 9 months to 16 years). The median follow-up period was 9.4 years (range, 3 to 25 years). Ten underwent chemotherapy and excision without additional radiotherapy. A total of 29 patients received additional local treatment: Ablative surgery MOld technique with after loading brachytherapy and surgical REconstruction (AMORE) (N = 21), proton (N = 4) or external beam radiation treatment (EBRT; N = 4). We found 14 cases with recurrences, 9 of which underwent exenteration and two of which died. The 10-year overall survival rate was 95% and the EFS was 63%. (4) Conclusions: long-term follow-up with 10-year survival rate of orbital RMS in this series was 95% achieved by local tumor control and eye preservation in 77% of our study population. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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9 pages, 1648 KiB

Open AccessArticle

Silicone Fiducial Markers Improve Precision in Uveal Melanoma Radiation Therapy

by Svenja Rebecca Sonntag, Olaf Wittenstein, Oliver Blanck, Jürgen Dunst, Stefan Huttenlocher, Melanie Grehn, Maximilian Busch, Dirk Rades, Ayseguel Tura and Salvatore Grisanti

Cancers 2025, 17(2), 189; https://doi.org/10.3390/cancers17020189 - 8 Jan 2025

Viewed by 857

Abstract

Objectives: Accurate target definition, treatment planning and delivery increases local tumor control for radiotherapy by minimizing collateral damage. To achieve this goal for uveal melanoma (UM), tantalum fiducial markers (TFMs) were previously introduced in proton and photon beam radiotherapy. However, TFMs cause pronounced scattering effects in imaging that make the delineation of small tumors difficult. The aim of this study was to evaluate silicone fiducial markers (SFMs) for the guiding of stereotactic radiosurgery (SRS) for UM. Methods: In this retrospective interventional pilot case series, three patients with small UMs 3 mm or less in tumor thickness and ≤10 mm in largest basal diameter received silicone fiducial markers. The fiducial markers were punched out (3 mm) from conventional silicone encircling bands for buckle surgery. The markers were sutured onto the sclera at the tumor margins according to the use of TFMs. MRI and CT images were used for the localization of the tumor and the markers before robotic-guided SRS. Results: The silicone fiducial markers were punched out easily from the original band, better to handle than TFMs and easy to suture onto the sclera. They could be visualized in both MRI and CT, but were more visible in CT. In the absence of scattering effects, both the markers and thus the tumor boundaries could be clearly delineated. Conclusions: This is the first report that introduces fiducial markers intraoperatively shaped from conventional silicone encircling bands usually used for retinal detachment surgery. The SFMs allow more accurate tumor delineation, resulting in the more precise planning and administration of SRS when compared to TFMs. This simple modification has a major impact on a well-known treatment approach. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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14 pages, 1650 KiB

Open AccessArticle

Impact of Metastatic Pattern on Survival in Patients with Posterior Uveal Melanoma: A Retrospective Cohort Study

by Tine G. Hindso, Peter S. Jensen, Mette B. Sjøl, Kristoffer Nissen, Camilla W. Bjerrum, Eric von Benzon, Carsten Faber, Steen F. Urbak, Marco Donia, Inge M. Svane, Eva Ellebaek, Steffen Heegaard, Karine Madsen and Jens F. Kiilgaard

Cancers 2024, 16(19), 3346; https://doi.org/10.3390/cancers16193346 - 30 Sep 2024

Cited by 1 | Viewed by 1205

Abstract

Background/Objectives: Metastatic posterior uveal melanoma (PUM) is one of the deadliest types of melanomas. Though the median survival is short, some patients with metastatic disease live for a long time. In this study, we investigated whether the anatomical location of the metastatic lesions is associated with differences in survival. Methods: One hundred and seventy-eight patients with metastatic PUM with baseline whole-body imaging were retrospectively included. The patients were divided into three groups based on the anatomical location of metastases: (1) exclusive liver metastases (hepatic pattern), (2) both hepatic and extrahepatic metastatic lesions (hepatic–extrahepatic pattern), and (3) exclusive extrahepatic lesions (extrahepatic pattern). Survival was investigated using Kaplan–Meier plots, log-rank test, and the Cox proportional hazard model. Results: In total, 95 patients (53%) presented with hepatic pattern, 66 patients (37%) presented with hepatic–extrahepatic pattern, and 17 patients (10%) presented with extrahepatic pattern. Overall survival was significantly longer in patients with extrahepatic pattern (median 17.0 months) compared to those with hepatic pattern (median 11.0 months) and hepatic–extrahepatic pattern (median 7.0 months) (p < 0.001, log-rank test). Multivariate Cox regression analysis showed increased hazard ratios (HR) for hepatic pattern (HR 2.37, 95% CI 1.08–5.17, p = 0.031) and hepatic–extrahepatic pattern (3.25, 95% CI 1.42–7.41, p = 0.005) compared to extrahepatic pattern. Most patients with hepatic (95%) and hepatic–extrahepatic patterns (82%) were diagnosed with metastases by liver ultrasonography screening, whereas 81% of patients with extrahepatic pattern developed symptoms that led to the diagnosis. Conclusions: Extrahepatic pattern was associated with prolonged survival in patients with metastatic PUM, despite there being a larger proportion of symptomatic patients. It is therefore important to consider the anatomical location of the metastatic lesions when stratifying patients into clinical trials. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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17 pages, 5589 KiB

Open AccessArticle

Genome-Wide Methylation Patterns in Primary Uveal Melanoma: Development of MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification

by Emilie Lalonde, Dong Li, Kathryn Ewens, Carol L. Shields and Arupa Ganguly

Cancers 2024, 16(15), 2650; https://doi.org/10.3390/cancers16152650 - 25 Jul 2024

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Abstract

Despite studies highlighting the prognostic utility of DNA methylation in primary uveal melanoma (pUM), it has not been translated into a clinically useful tool. We sought to define a methylation signature to identify newly diagnosed individuals at high risk for developing metastasis. Methylation profiling was performed on 41 patients with pUM with stage T2–T4 and at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (N = 24) and the EPIC BeadChip (N = 17). Findings were validated in the TCGA cohort with known metastatic outcome (N = 69). Differentially methylated probes were identified in patients who developed metastasis. Unsupervised consensus clustering revealed three epigenomic subtypes associated with metastasis. To identify a prognostic signature, recursive feature elimination and random forest models were utilized within repeated cross-validation iterations. The 250 most commonly selected probes comprised the final signature, named MethylSig-UM. MethylSig-UM could distinguish individuals with pUM at diagnosis who develop future metastasis with an area under the curve of ~81% in the independent validation cohort, and remained significant in Cox proportional hazard models when combined with clinical features and established genomic biomarkers. Altered expression of immune-modulating genes were detected in MethylSig-UM positive tumors, providing clues for pUM resistance to immunotherapy. The MethylSig-UM model is available to enable additional validation in larger cohort sizes including T1 tumors. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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18 pages, 6181 KiB

Open AccessArticle

MR Imaging of Adverse Effects and Ocular Growth Decline after Selective Intra-Arterial Chemotherapy for Retinoblastoma

by Christiaan M. de Bloeme, Sabien van Elst, Paolo Galluzzi, Robin W. Jansen, Joeka de Haan, Sophia Göricke, Annette C. Moll, Joseph C. J. Bot, Francis L. Munier, Maja Beck-Popovic, Francesco Puccinelli, Isabelle Aerts, Theodora Hadjistilianou, Selma Sirin, Mériam Koob, Hervé J. Brisse, Liesbeth Cardoen, Philippe Maeder, Marcus C. de Jong and Pim de Graaf

Cancers 2024, 16(10), 1899; https://doi.org/10.3390/cancers16101899 - 16 May 2024

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Abstract

This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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22 pages, 4249 KiB

Open AccessArticle

Gastric Inhibitory Polypeptide Receptor (GIPR) Overexpression Reduces the Tumorigenic Potential of Retinoblastoma Cells

by André Haase, Emily Alefeld, Fatma Yalinci, Dario Van Meenen, Maike Anna Busch and Nicole Dünker

Cancers 2024, 16(9), 1656; https://doi.org/10.3390/cancers16091656 - 25 Apr 2024

Viewed by 1554

Abstract

Retinoblastoma (RB) is the most common malignant intraocular tumor in early childhood. Gene expression profiling revealed that the gastric inhibitory polypeptide receptor (GIPR) is upregulated following trefoil factor family peptide 1 (TFF1) overexpression in RB cells. In the study presented, we found this G protein-coupled transmembrane receptor to be co-expressed with TFF1, a new diagnostic and prognostic RB biomarker for advanced subtype 2 RBs. Functional analyses in two RB cell lines revealed a significant reduction in cell viability and growth and a concomitant increase in apoptosis following stable, lentiviral GIPR overexpression, matching the effects seen after TFF1 overexpression. In chicken chorioallantoic membrane (CAM) assays, GIPR-overexpressing RB cells developed significantly smaller CAM tumors. The effect of GIPR overexpression in RB cells was reversed by the GIPR inhibitor MK0893. The administration of recombinant TFF1 did not augment GIPR overexpression effects, suggesting that GIPR does not serve as a TFF1 receptor. Investigations of potential GIPR up- and downstream mediators suggest the involvement of miR-542-5p and p53 in GIPR signaling. Our results indicate a tumor suppressor role of GIPR in RB, suggesting its pathway as a new potential target for future retinoblastoma therapy. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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12 pages, 2688 KiB

Open AccessArticle

CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells

by Keita Togashi, Shuhei Suzuki, Yuta Mitobe, Yurika Nakagawa-Saito, Asuka Sugai, Senri Takenouchi, Masahiko Sugimoto, Chifumi Kitanaka and Masashi Okada

Cancers 2024, 16(1), 118; https://doi.org/10.3390/cancers16010118 - 25 Dec 2023

Cited by 2 | Viewed by 1516

Abstract

Uveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investigate in this study the effects on UM cells of CEP-1347, a novel MDM4 inhibitor with a known safety profile in humans. We also examined the impact of CEP-1347 on the protein kinase C (PKC) pathway, known to play a pivotal role in UM cell growth. High-grade UM cell lines were used to analyze the effects of genetic and pharmacological inhibition of MDM4 and PKC, respectively, as well as those of CEP-1347 treatment, on p53 expression and cell viability. The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth. These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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14 pages, 2545 KiB

Open AccessArticle

Trefoil Family Factor Peptide 1—A New Biomarker in Liquid Biopsies of Retinoblastoma under Therapy

by Maike Anna Busch, André Haase, Emily Alefeld, Eva Biewald, Leyla Jabbarli and Nicole Dünker

Cancers 2023, 15(19), 4828; https://doi.org/10.3390/cancers15194828 - 2 Oct 2023

Cited by 5 | Viewed by 1839

Abstract

Effective management of retinoblastoma (RB), the most prevalent childhood eye cancer, depends on reliable monitoring and diagnosis. A promising candidate in this context is the secreted trefoil family factor peptide 1 (TFF1), recently discovered as a promising new biomarker in patients with a more advanced subtype of retinoblastoma. The present study investigated TFF1 expression within aqueous humor (AH) of enucleated eyes and compared TFF1 levels in AH and corresponding blood serum samples from RB patients undergoing intravitreal chemotherapy (IVC). TFF1 was consistently detectable in AH, confirming its potential as a biomarker. Crucially, our data confirmed that TFF1-secreting cells within the tumor mass originate from RB tumor cells, not from surrounding stromal cells. IVC-therapy-responsive patients exhibited remarkably reduced TFF1 levels post-therapy. By contrast, RB patients’ blood serum displayed low-to-undetectable levels of TFF1 even after sample concentration and no therapy-dependent changes were observed. Our findings suggest that compared with blood serum, AH represents the more reliable source of TFF1 if used for liquid biopsy RB marker analysis in RB patients. Thus, analysis of TFF1 in AH of RB patients potentially provides a minimally invasive tool for monitoring RB therapy efficacy, suggesting its importance for effective treatment regimens. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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17 pages, 2274 KiB

Open AccessReview

Conjunctival Melanoma: A Clinical Review and Update

by Karam Butt, Rumana Hussain, Sarah E. Coupland and Yamini Krishna

Cancers 2024, 16(18), 3121; https://doi.org/10.3390/cancers16183121 - 10 Sep 2024

Cited by 2 | Viewed by 3455 | Correction

Abstract

Conjunctival melanoma (Co-M) is an aggressive, invasive eye and eyelid cancer. Its global incidence of ~1 in a million is increasing at a rate ratio of ~1.4, but this rises sharply in over 65-year-olds. Although rare, Co-M has a devastating impact on the lives of those who develop it. Co-M is often misdiagnosed or overlooked, leading to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases. Due to its rarity, there is limited evidence for diagnosis and management; hence, there is no standardised treatment and not all cases are referred to a specialised ocular oncology centre. Recent progress in cancer immunology and genetics have revolutionised the treatment of cutaneous melanomas, which share some similarities to Co-M. Importantly, a better understanding of Co-M and its precursor lesions is urgently needed to lead to the development of novel targeted and immunotherapies both for local tumour control and disseminated disease. This review aims to provide a comprehensive clinical overview of the current knowledge regarding Co-M, its epidemiology, pathogenesis, presentation, diagnosis and recent changes in the classification of its precursor lesions, management, and recent advances in novel biological therapies for personalised treatment of this disease. Full article

(This article belongs to the Special Issue Current Progress and Research Trends in Ocular Oncology)

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