Oncology

Oncology Publications

McCoskey M, Reshef ER, Wolkow N, Yoon MK. Bilateral enlargement of all extraocular muscles: a presenting ophthalmic sign of hematologic malignancy. Orbit 2024;43(1):160-163.Abstract
Hematologic malignancies such as leukemia and lymphoma can frequently present in the orbit; however, involvement of the extraocular muscles is rare. The authors report two cases of systemic hematologic malignancy presenting with bilateral extraocular muscle enlargement and associated compressive optic neuropathy (CON). Both patients experienced clinical and radiographic improvement of ocular and systemic manifestations of disease with prompt initiation of targeted chemotherapy. These cases highlight the importance of including hematologic malignancy in the differential diagnosis of atypical bilateral extraocular muscle enlargement.
Kim EJ, Lee JY, Ganga A, Barton A, Rana V, Araia E, Adriance W, Wang R, Somsasundar P, Kim LA. Analysis of Uveal Melanoma 5-Year Survival Rates by Medicaid Status: A Nationwide Analysis. Ophthalmic Epidemiol 2023;:1-7.Abstract
PURPOSE: The survival outcomes of patients with primary uveal melanomas based on Medicaid status have not been previously discussed in the literature. METHODS: The Surveillance, Epidemiology, and End Results Medicaid database were utilized to identify patients with primary uveal melanomas diagnosed between 2006 and 2013. The Kaplan-Meier method was utilized to construct 5-year survival curves in adult, non-elderly patients. Log-rank testing was used to determine differences in survival rates, and multivariate Cox proportional hazards modeling was utilized to perform adjusted survival analysis. RESULTS: A total of 1,765 patients were included (Medicaid: 81, non-Medicaid: 1684). A total of 1683 (95.4%) were White. The average age was 51.75 years (SD = 9.5 years). Medicaid patients were more likely to be unmarried, live in a high poverty neighborhood, and live in a rural area (all p < .001). We observed no significant difference in 5-year survival rates between those enrolled in Medicaid (86.6%, 95% CI: 79.1%1-94.7%) and those not enrolled in Medicaid (85.5, 95% CI: 83.8%-87.2%) (p = .80). After controlling for socioeconomic and clinical factors, Medicaid enrollment was not associated with an increased risk of mortality compared to non-Medicaid enrollment. Age (aHR: 1.04, 95% CI: 1.02-1.06, p < .001) and tumor size >10 mm (aHR: 3.04, 95% CI: 1.49-6.21, p = .002) were associated with an increased risk of mortality. CONCLUSION: Medicaid enrollment was not associated with worse cancer-specific 5-year survival. Further research needs to be elicited to better understand the role of Medicaid enrollment in patients with primary uveal melanoma.
Philip AM, Anesi SD, Foster SC, Chang P. Ocular Inflammatory Complications of Treatment for Metastatic Melanoma. Ocul Immunol Inflamm 2023;31(8):1669-1673.Abstract
PURPOSE: To characterize various ocular inflammatory complications arising from metastatic cutaneous melanoma therapies and their management. METHODS: Retrospective case series of patients who were referred to a tertiary uveitis practice for ophthalmic exam All patients received targeted metastatic cutaneous melanoma treatment, including BRAF/MEK inhibitors and various immunotherapies. RESULTS: 109 patients were identified, with 43 (39.4%) having 65 definitive instances of OIAE. Sixteen different OIAE were identified. Ipilimumab monotherapy and ipilimumab/nivolumab combination therapy were most commonly associated. Anterior uveitis was the most common OIAE (18/65, 27.7%). Thirty patients (69.8%) were managed with observation or topical steroid therapy. Only 4 patients required further therapies for OIAE, with one patient not attaining resolution. CONCLUSIONS AND RELEVANCE: While a broad range of OIAE was identified, most were not vision-threatening and did not require discontinuation of the associated therapy.
Goenka A, Khan F, Verma B, Sinha P, Dmello CC, Jogalekar MP, Gangadaran P, Ahn B-C. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun (Lond) 2023;43(5):525-561.Abstract
Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
Trofimov AV, Aronow ME, Bussière MR, Gragoudas ES, Keane FK, Kim IK, Shih HA, Bhagwat MS. In Reply to Elmali and Yazici. Int J Radiat Oncol Biol Phys 2023;115(3):810-811.
Correa VSMC, Efstathiou NE, Ntentakis DP, Yu Z, Narimatsu T, Gragoudas E, Kim IK, Vavvas DG. The NLRP3 inflammasome - interleukin 1β axis in uveal melanoma. FEBS Open Bio 2023;13(3):545-555.Abstract
Uveal melanoma (UM) is the most common primary intraocular cancer in the adult population. Recent studies suggested that the NLRP3 inflammasome could be a therapeutic target for cutaneous melanoma (CM), but the role of NLRP3 in UM remains unknown. Here, we analyzed the NLRP3-IL-1β axis in 5 UM and 4 CM cell lines. Expression of NLRP3 mRNA in UM and CM was low, and expression in UM was lower than in CM (P < 0.001). NLRP3 protein levels were below detection limit for all cell lines. UM exhibited lower baseline IL-1β secretion than CM, especially when compared to the Hs294t cell line (P < 0.05). Bioinformatic analysis of human tumor samples showed that UM has significantly lower expression of NLRP3 and IL-1β compared with CM. In conclusion, our work shows evidence of extremely low NLRP3 expression and IL-1β secretion by melanoma cells and highlight differences between CM and UM.
Trofimov AV, Aronow ME, Gragoudas ES, Keane FK, Kim IK, Shih HA, Bhagwat MS. A Systematic Comparison of Dose Distributions Delivered in 125I Plaque Brachytherapy and Proton Radiation Therapy for Ocular Melanoma. Int J Radiat Oncol Biol Phys 2023;115(2):501-510.Abstract
PURPOSE: To characterize dose distributions with 125I plaque brachytherapy compared with proton radiation therapy for ocular melanoma for relevant clinical scenarios, based on tumor base diameter (d), apical height (h), and location. METHODS AND MATERIALS: Plaque and proton treatment plans were created for 4 groups of cases: (1) REF: 39 instances of reference midsize circular-base tumor (d = 12 mm, h = 5 mm), in locations varying by retinal clock hours and distance to fovea, optic disc, and corneal limbus; (2) SUP: 25 superiorly located; (3) TEMP: 25 temporal; and (4) NAS: 25 nasally located tumors that were a fixed distance from the fovea but varying in d (6-18 mm) and h (3-11 mm). For both modalities, 111 unique scenarios were characterized in terms of the distance to points of interest, doses delivered to fovea, optic disc, optic nerve at 3 mm posterior to the disc (ON@3mm), lens, and retina. Comparative statistical evaluation was performed with the Mann-Whitney U test. RESULTS: Superior dose distributions favored plaque for sparing of (1) fovea in large (d + h ≥ 21 mm) NAS tumors; (2) ON@3mm in REF cases located ≤4 disc diameters from disc, and in NAS overall. Protons achieved superior dose sparing of (1) fovea and optic disc in REF, SUP, and TEMP; (2) ON@3mm in REF >4 disc diameters from disc, and in SUP and TEMP; and (3) the lens center overall and lens periphery in REF ≤6 mm from the corneal limbus, and in TEMP with h = 3 mm. Although protons could completely spare sections of the retina, plaque dose was more target conformal in the high-dose range (50% and 90% of prescription dose). CONCLUSIONS: Although comparison between plaque and proton therapy is not straightforward because of the disparity in dose rate, prescriptions, applicators, and delivery techniques, it is possible to identify distinctions between dose distributions, which could help inform decisions by providers and patients.
Farhat W, Yeung V, Ross A, Kahale F, Boychev N, Kuang L, Chen L, Ciolino JB. Advances in biomaterials for the treatment of retinoblastoma. Biomater Sci 2022;10(19):5391-5429.Abstract
Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.
Karg MM, John L, Refaian N, Buettner C, Rottmar T, Sommer J, Bock B, Resheq YJ, Ksander BR, Heindl LM, Mackensen A, Bosch JJ. Midkine promotes metastasis and therapeutic resistance via mTOR/RPS6 in uveal melanoma. Mol Cancer Res 2022;Abstract
Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance and displays an inherent propensity for hepatic metastases. Since metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma. Midkine expression in primary uveal melanoma significantly correlates with poor survival and is elevated in patients that develop metastatic disease. Monosomy 3 and histopathological staging parameters are associated with midkine expression. In addition, we demonstrate that midkine promotes survival, migration across a barrier of hepatic sinusoid endothelial cells and resistance to AKT/mTOR inhibition. Furthermore, midkine is secreted and mediates mTOR activation by maintaining phosphorylation of the mTOR target RPS6 in uveal melanoma cells. Therefore, midkine is identified as a uveal melanoma cell survival factor that drives metastasis and therapeutic resistance, and could be exploited as a biomarker as well as a new therapeutic target. Implications: Midkine is identified as a survival factor that drives liver metastasis and therapeutic resistance in melanoma of the eye.
Bloom JR, Castillejos AG, Jones B, Patel N, Rosenstein BS, Stock RG. Ocular complications with the use of radium-223: a case series. Radiat Oncol 2022;17(1):97.Abstract
BACKGROUND: Radium-223 is used for the treatment of osseous metastases in castrate-resistant prostate cancer, and has been shown to increase time to the first skeletal-related event, reduce the rate of hospitalization, and improve quality of life. It is well tolerated, with hematologic toxicity as the main adverse event. Thus far, no ocular complication has been reported in the literature after initial administration of radium-223 with a single case reported of ocular complications after a patient's second course of radium-223. CASE PRESENTATIONS: We present three cases of ocular complications after the use of radium-223 in patients with metastatic prostatic adenocarcinoma. Ocular complications presented as blurry vision, and formal diagnosis included uveitis and hyphema. CONCLUSIONS: Documentation of adverse events is exceedingly important due to the high incidence of metastatic prostate cancer and increasing interest for the use of radium-223 in other osteoblastic disease. The authors postulate that these ocular complications may be a result of radiation's potential effect on neovascularization, polypharmacy, or the biomolecular effects of radium-223 on integral signaling proteins, potentially coupled with poor underlying ocular health.
Rhee JY, Torun N, Neilan TG, Guidon AC. Consider Myocarditis When Patients Treated with Immune Checkpoint Inhibitors Present with Ocular Symptoms. Oncologist 2022;Abstract
Immune checkpoint inhibitors (ICIs) have been associated with neurological immune related adverse events (irAE-N) and patients with ICI toxicity may present with neurological or ocular symptoms. Furthermore, patients on ICI may initially present to oncology or neurology. We report a case series of 3 patients treated with ICIs presenting with diplopia or ptosis, found to have concurrent myocarditis in addition to immune-related myopathy (irMyopathy) or myasthenia gravis (irMG). None of the patients described cardiac symptoms, underscoring the importance of screening for myocarditis in patients presenting with diplopia and/or other neuromuscular symptoms which may suggest either irMyopathy or irMG.

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