Lacrimal sac adenocarcinoma managed with androgen deprivation.

PURPOSE: To describe a case of primary lacrimal sac adenocarcinoma treated primarily with androgen deprivation therapy (ADT) with good clinic response. OBSERVATIONS: An 82-year-old male presented with a painless right orbital mass. Pathology following partial resection was consistent with primary lacrimal sac adenocarcinoma positive for androgen receptors (AR). Magnetic resonance imaging (MRI) scan showed an orbital mass with extension into the nasolacrimal apparatus and intraconally between the medial and inferior recti. Staging positron emission tomography/computed tomography (PET/CT) showed one hypermetabolic right sided lymph node in addition to the known orbital mass. Orbital exenteration and external beam radiation therapy were offered as the primary treatment modality however the patient refused. He subsequently received four years of androgen deprivation monotherapy, before stopping due to sexual side effects, with no progression of local or metastatic disease and some local regression documented on MRI at 5 years. CONCLUSIONS AND IMPORTANCE: Lacrimal sac adenocarcinoma is commonly found to be AR positive on pathology. Our case shows that ADT can serve as an effective treatment modality for those patients that defer primary surgical management.

Progressive choroidal thinning (leptochoroid) and fundus depigmentation associated with checkpoint inhibitors.

PURPOSE: To report asymptomatic progressive fundus depigmentation and choroidal thinning in the absence of intraocular inflammation in a patient treated with checkpoint inhibitors. OBSERVATIONS: A 69-year-old woman with metastatic cutaneous melanoma, treated with checkpoint inhibition (nivolumab, ipilimumab and pembrolizumab), developed asymptomatic progressive fundus depigmentation associated with choroidal thinning in both eyes over 26 months. Serial multimodal imaging was obtained over the study period including fundus photography, fundus autofluorescence and optical coherence tomography (OCT). Over 26 months, the central choroidal thickness decreased by 34% (from 270µm to 92µm, mean between both eyes). Concurrently, central retinal thickness remained stable (206µm to 214µm, mean between both eyes). There were no findings of intraocular inflammation, subretinal fluid or retinal pigment epithelium disturbance. The patient reported no visual symptoms and maintained a visual acuity of 20/25+ in the right eye and 20/30 in the left eye throughout the observation period. Concurrently, cutaneous vitiligo and poliosis, inclusive of her periorbital dermis and eyelashes also developed. CONCLUSIONS AND IMPORTANCE: Progressive fundus depigmentation and choroidal thinning can be observed with checkpoint inhibition in the absence of intraocular inflammation.

MEK Inhibitor-Associated Central Retinal Vein Occlusion Associated with Hyperhomocysteinemia and MTHFR Variants.

BACKGROUND: Central retinal vein occlusion (CRVO) is a visually threatening event that has rarely been observed in patients taking MEK1/2 inhibitors and that may necessitate permanent discontinuation of a potentially efficacious therapy. We investigated the clinical characteristics of CRVO in patients on mitogen-activated protein kinase kinase (MEK) inhibition to better understand their predisposing factors and clinical course. CASE SERIES: This was a single-center, retrospective cohort study (between December 2006 and September 2018). Three of 546 patients enrolled in 46 prospective trials involving treatment with MEK inhibitors at Memorial Sloan Kettering Cancer Center were identified as having CRVO. Clinical examination and course, multimodal ophthalmic imaging, and serum laboratory results (including homocysteine levels and genetic variants of methylene tetrahydrofolate reductase [MTHFR]) were reviewed for the 3 affected patients. All 3 patients with MEK inhibitor-associated CRVO had elevated serum homocysteine and gene variants of MTHFR (1 homozygous for A1298C, 1 heterozygous for A1298C, and 1 homozygous for C677T). Following intravitreous injections of anti-VEGF and discontinuation of drug, all patients regained vision to their baseline. DISCUSSION: MEK inhibitor-associated CRVO is a rare event which can exhibit visual recovery after drug cessation and intravitreous anti-VEGF injections. In this cohort, it was associated with hyperhomocysteinemia and genetic mutations in MTHFR, suggesting a potential role for hyperhomocysteinemia screening prior to initiation of MEK inhibitor therapy.

Isolated Abducens Nerve Palsy Following Pembrolizumab.

Pembrolizumab is a checkpoint inhibitor targeting the programmed cell death 1 receptor of lymphocytes and is used in the treatment of solid tumours including melanoma. The authors report a 64-year-old man treated with pembrolizumab for stage IV cutaneous melanoma (primary cutaneous melanoma of the right lower back) with liver metastases. The patient developed a horizontal binocular diplopia due to an isolated unilateral cranial nerve VI palsy. Following 1 week of high dose oral steroid therapy and cessation of the drug, the patient's nerve palsy and associated diplopic symptoms improved dramatically, and after 6 weeks of oral steroid taper and drug cessation, the palsy resolved completely. Few reports of checkpoint inhibitor autoimmune-induced isolated cranial nerve palsies have been described, and this is the first report of drug-induced isolated cranial nerve VI palsy.

Intravitreous Cutaneous Metastatic Melanoma in the Era of Checkpoint Inhibition: Unmasking and Masquerading.

PURPOSE: Cutaneous melanoma metastatic to the vitreous is very rare. This study investigated the clinical findings, treatment, and outcome of patients with metastatic cutaneous melanoma to the vitreous. Most patients received checkpoint inhibition for the treatment of systemic disease, and the significance of this was explored. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Fourteen eyes of 11 patients with metastatic cutaneous melanoma to the vitreous. METHODS: Clinical records, including fundus photography and ultrasound results, were reviewed retrospectively, and relevant data were recorded for each patient eye. MAIN OUTCOME MEASURES: Clinical features at presentation, ophthalmic and systemic treatments, and outcomes. RESULTS: The median age at presentation of ophthalmic disease was 66 years (range, 23-88 years), and the median follow-up from diagnosis of ophthalmic disease was 23 months. Ten of 11 patients were treated with immune checkpoint inhibition at some point in the treatment course. The median time from starting immunotherapy to ocular symptoms was 17 months (range, 4.5-38 months). Half of eyes demonstrated amelanotic vitreous debris. Five eyes demonstrated elevated intraocular pressure, and 4 eyes demonstrated a retinal detachment. Six patients showed metastatic disease in the central nervous system. Ophthalmic treatment included external beam radiation (30-40 Gy) in 6 eyes, intravitreous melphalan (10-20 µg) in 4 eyes, enucleation of 1 eye, and local observation while receiving systemic treatment in 2 eyes. Three eyes received intravitreous bevacizumab for neovascularization. The final Snellen visual acuity ranged from 20/20 to no light perception. CONCLUSIONS: The differential diagnosis of vitreous debris in the context of metastatic cutaneous melanoma includes intravitreal metastasis, and this seems to be particularly apparent during this era of treatment with checkpoint inhibition. External beam radiation, intravitreous melphalan, and systemic checkpoint inhibition can be used in the treatment of ophthalmic disease. Neovascular glaucoma and retinal detachments may occur, and most eyes show poor visual potential. Approximately one quarter of patients demonstrated ocular disease that preceded central nervous system metastasis. Patients with visual symptoms or vitreous debris in the context of metastatic cutaneous melanoma would benefit from evaluation by an ophthalmic oncologist.

Dexamethasone and methylprednisolone do not inhibit neuritic outgrowth while inhibiting outgrowth of fibroblasts from spiral ganglion explants.

CONCLUSION: Dexamethasone and methylprednisolone do not inhibit neuritic outgrowth while inhibiting fibroblastic outgrowth from spiral ganglion micro-explants. OBJECTIVES: To demonstrate reduced fibroblastic outgrowth while maintaining neurite outgrowth for several corticosteroids using an in vitro test system of neonatal rat spiral ganglion micro-explants. MATERIALS AND METHODS: The in vitro test system comprised 3-day-old rat spiral ganglion micro-explants. Dexamethasone, methylprednisolone, triamcinolone acetonide, and human recombinant brain-derived neurotrophic factor (hrBDNF) were tested in vitro. The control was ganglion micro-explants in supplemented Dulbecco's modified Eagle's medium. Areas of the ganglion explant, neurite and fibroblast outgrowth of ganglion explants after 10 days in vitro were imaged, digitized, and analyzed using Image Tool 3.00 on a PC workstation. Areas of neurite and fibroblast outgrowth from the experimental explants were compared against values obtained from control explants. RESULTS: Dexamethasone gave the best result of the three corticosteroids tested for inhibiting fibroblast outgrowth while not inhibiting neurite outgrowth from the ganglion micro-explants. Media containing hrBDNF (10 ng/ml) stimulated significantly greater neurite outgrowth than outgrowth from control explants (p < 0.001). Ganglion micro-explants treated with dexamethasone (0.02 mg/ml) and methylprednisolone (0.5 mg/ml) provided the greatest inhibition of fibroblast outgrowth compared with control explants (p < 0.001).