Oncology Publications

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;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 to 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.
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.
Trofimov AV, Aronow ME, Gragoudas ES, Keane FK, Kim IK, Shih HA, Bhagwat MS. A systematic comparison of dose distributions delivered in iodine-125 plaque brachytherapy and proton radiation therapy for ocular melanoma. Int J Radiat Oncol Biol Phys 2022;Abstract
PURPOSE: To characterize dose distributions with iodine-125 plaque brachytherapy as compared to proton radiation therapy for ocular melanoma, for relevant clinical scenarios, based upon tumor base diameter (d), apical height (h), and location. METHOD: Plaque and proton treatment plans were created for four 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, 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 (i) fovea in large (d+h≥21 mm) NAS tumors; (ii) ON@3mm in REF cases located ≤4 dd (disc diameters) from disc, and in NAS overall. Protons achieved superior dose sparing of (i) fovea, optic disc in REF, SUP, TEMP; (ii) ON@3mm in REF >4 dd from disc, and in SUP, TEMP; (iii) the lens center overall, and lens periphery in REF ≤6 mm from the corneal limbus, and in TEMP, NAS with h≥5 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). CONCLUSION: Although comparison between plaque and proton therapy is not straightforward, due to 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.
McCoskey M, Reshef ER, Wolkow N, Yoon MK. Bilateral enlargement of all extraocular muscles: a presenting ophthalmic sign of hematologic malignancy. Orbit 2022;:1-4.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.
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.
Neerukonda VK, Kim IK, Stagner AM. Primary vitreoretinal involvement and immunopositivity for BRAFV600E help distinguish metastatic from primary intraocular melanoma: a detailed histopathologic study of metastatic cutaneous melanoma to the eye. Histopathology 2022;80(7):1061-1070.Abstract
OBJECTIVE: To evaluate the clinicopathologic characteristics of metastatic cutaneous melanoma to the eye and identify potential distinguishing characteristics from the more common primary uveal melanoma; particularly, tumour location within the eye, cytomorphology and immunohistochemical/specific molecular genetic features. METHODS: A retrospective observational case series using surgical enucleation and diagnostic vitrectomy cytologic specimens from seven patients with suspected intraocular melanoma, eventually diagnosed as metastatic melanoma, was conducted. Haematoxylin and eosin-stained sections of tumour and immunohistochemical (IHC) stains for BRAFV600E and Ki-67 were critically reviewed; BAP1 IHC was also evaluated in cases where additional tissue was available. Clinical imaging studies and medical records were reviewed. RESULTS: The majority of patients (86%) with metastatic melanoma have primary vitreoretinal (not uveal) involvement and epithelioid, highly malignant cytomorphology (100%); many (50%) harbour BRAFV600E mutations, a finding not seen in large cohorts of primary uveal melanoma. CONCLUSIONS: Characteristics favouring or defining metastatic intraocular melanoma over primary uveal melanoma include high-grade epithelioid cytology, predominant involvement of the vitreous cavity and/or retina, and presence of positive immunostaining for BRAFV600E.
Barrantes PC, Zhou P, MacDonald SM, Ioakeim-Ioannidou M, Lee NG. Granular Cell Tumor of the Orbit: Review of the Literature and a Proposed Treatment Modality. Ophthalmic Plast Reconstr Surg 2022;38(2):122-131.Abstract
PURPOSE: To document a unique case of granular cell tumor of the orbit, located lateral to and abutting the optic nerve, that benefited from treatment with proton beam irradiation, with a comprehensive review of the literature on granular cell tumor of the orbit. METHODS: Clinicopathologic case report with detailed imaging features and histopathologic and immunohistochemical evaluation for cytoplasmic tumor biomarkers differentiating granular cell tumor (GCT) from it mimicking lesions with relevant literature citations. The authors reviewed 20 cases of orbital GCT from 2011 to 2020 in addition to 40 cases from 1948 to 2011 and included a summary of imaging and clinical features, outcomes, and recommended treatment modalities. RESULTS: A 32-year-old man with 1-year history of left retrobulbar pain and diplopia on lateral gaze, intermittent left eyelid swelling, and a tonic left pupil was found to have a fusiform intraconal mass extending toward the orbital apex and abutting the optic nerve. Histopathologic and immunohistochemical investigations collectively supplied data diagnostic of a GCT with an initial low proliferation rate. GCT is a soft tissue neoplasm that originates in the nervous system and can occur anywhere in the body. This enhancing tumor is isointense to gray matter on T1-weighted MRI, hypointense on T2. After an incisional biopsy, the patient's symptoms persisted, and follow-up imaging several months later revealed further growth of the mass. The impossibility of complete surgical removal prompted the decision to treat with proton beam radiation therapy, which resulted in substantial regression in the size of the residual tumor. Most frequently involving the inferior rectus muscle (42%), orbital GCT is usually benign with only 4 reported cases of malignant orbital GCT (7%). Wide surgical resection with complete removal is usually curative for benign orbital GCT, and proton beam radiation therapy can aid in tumor shrinkage. CONCLUSIONS: GCT should be considered in the differential diagnosis when encountering patients with mass lesions involving the extraocular muscles, peripheral nerves, or less frequently, the optic nerve or orbital apex. Immunohistochemical analysis of biopsied tissue is required for the definitive diagnosis of GCT. Consideration of adjuvant therapies such as proton beam radiation therapy may be appropriate in cases of incomplete surgical resection of benign GCT. Proton beam radiation therapy can be an excellent therapeutic option for symptomatic relief and residual tumor size reduction with an acceptable toxicity profile.
Neerukonda VK, Stagner AM, Wolkow N. Lymphoma of the Lacrimal Sac: The Massachusetts Eye and Ear Experience With a Comparison to the Previously Reported Literature. Ophthalmic Plast Reconstr Surg 2022;38(1):79-86.Abstract
PURPOSE: To describe the frequency, clinical features, and histologic subtypes of biopsy proven lacrimal sac lymphomas, and to compare these results to the previously published literature. METHODS: A retrospective chart review was performed at a single institution from 2004 to 2017. Pathology reports, operative notes, and patients' medical charts were reviewed. RESULTS: Of 566 lacrimal sacs submitted for routine histopathologic evaluation, 16 cases of lymphoma were identified. All were low-grade, non-Hodgkin B-cell lymphomas, biopsied at an average age of 71 years. Thirteen patients (81.25%) had a pre-existing lymphoma diagnosis; the average interval between the diagnosis of systemic or nonocular adnexal lymphoma and lacrimal sac lymphoma was 7.9 years (range 2-26 years; median 5.5 years). Three cases of primary lacrimal sac lymphoma were identified. Histopathology showed 3 cases (18.75%) of follicular lymphoma, 3 (18.75%) of extranodal marginal zone lymphoma, and 10 (62.5%) of chronic lymphocytic leukemia/small lymphocytic lymphoma. Primary cases presented with epiphora and nasolacrimal duct obstruction, while secondary cases predominantly manifested as dacryocystitis. All lacrimal sac neoplasms were locally responsive (without local recurrence) to chemotherapy, radiation, or both. CONCLUSIONS: Lacrimal sac lymphoma is uncommon but should be suspected among patients with known lymphoma who develop dacryocystitis. In this series, primary lacrimal sac lymphoma most often presented as a mass or nasolacrimal duct obstruction. Chronic lymphocytic leukemia/small lymphocytic lymphoma was the most commonly identified cause of secondary lacrimal sac lymphoma. Distinguishing primary from secondary lacrimal sac lymphomas is important, as the extent of disease and histopathologic subtypes differ, which may affect patient management.
Papageorgiou GI, Symeonidis DG, Tsakatikas SA, Liatsos AD, Douglas KA, Douglas VP, Moschos MM, Kosmas C. Central neurotoxicity induced by trastuzumab emtansine (T-DM1): a case report. Anticancer Drugs 2021;32(10):1146-1149.Abstract
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (Her2) - targeted antibody-drug conjugate that is approved for patients previously treated with trastuzumab and a taxane for Her2-positive advanced breast cancer and those who have progressed within 6 months of completion of adjuvant chemotherapy, as well as for patients with residual invasive Her2-positive disease after the completion of adjuvant chemotherapy. Peripheral neuropathy is a common adverse event; however, ocular events have also been described. With the current report we present the case of a 67-year old woman who developed transient grade 2-3 blurred vision after the first T-DM1 infusion, which was complicated with grade 2 diplopia causing vertigo after the second infusion. After extended investigation, this symptomatology was attributed to central neurotoxicity, and gradually resolved after T-DM1 discontinuation.