Juan P. Velazquez-Martin

Ocular Toxicity of Targeted Therapies

Molecularly targeted agents are commonly used in oncology practice, and many new targeted agents are currently being tested in clinical trials. Although these agents are thought to be more specific and less toxic then traditional cytotoxic chemotherapy, they are associated with a variety of toxicities, including ocular toxicity. Many of the molecules targeted by anticancer agents are also expressed in ocular tissues. We reviewed the literature for described ocular toxicities associated with both approved and investigational molecularly targeted agents. Ocular toxicity has been described with numerous approved targeted agents and also seems to be associated with several classes of agents currently being tested in early-phase clinical trials. We discuss the proposed pathogenesis, monitoring guidelines, and management recommendations. It is important for oncologists to be aware of the potential for ocular toxicity, with prompt recognition of symptoms that require referral to an ophthalmologist. Ongoing collaboration between oncologists and ocular disease specialists is critical as the use of molecularly targeted agents continues to expand and novel targeted drug combinations are developed.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group

PURPOSE To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN Retrospective, multicenter observational study. PARTICIPANTS Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Association Between Uveal Melanoma and Myotonic Dystrophy: A Series of 3 Cases

Myotonic dystrophy is the most common type of adult muscular dystrophy. It is an autosomal dominant multisystem neuromuscular disorder. Type 1 myotonic dystrophy is caused by unstable trinucleotide (CTG) expansion in the dystrophia myotonica-protein kinase (DMPK) gene. Type 2 myotonic dystrophy is caused by unstable tetranucleotide (CCTG) expansion in the zinc finger protein 9 (ZNF9) gene. Both subtypes are characterized by progressive skeletal muscle weakness and myotonia. Other clinical features include insulin resistance, cardiac conduction defects, testicular atrophy, respiratory insufficiency, early-onset cataracts, and varying degrees of cognitive impairment. Patients with myotonic dystrophy have been recognized as having an increased risk of various malignancies. Uveal melanoma is the most common primary intraocular malignant tumor in adults, and it is not until recently that patients with myotonic dystrophy have been encountered with an increased risk of developing uveal melanoma. In our study, we report 3 cases with the association between uveal melanoma and myotonic dystrophy. Patients were evaluated at the Ocular Oncology Clinic of the Princess Margaret Hospital in Toronto, Canada, between April 1997 and April 2012. Patients underwent a comprehensive ophthalmologic evaluation, and the clinical appearance and ancillary testing of the intraocular tumor were compatible with choroidal melanoma. All cases had diagnosis of type 1 myotonic dystrophy confirmed by genetic testing and a positive family history of myotonic dystrophy.

Bilateral Multifocal Choroidal Melanosis: A Report of Two Cases

Flat choroidal pigmented lesions have few differential diagnoses but encompass a wide range of clinical presentations. The authors report two cases of bilateral multifocal choroidal hyper-pigmented patches discovered in asymptomatic patients. Fluorescein angiography showed a normal pattern without blockage in the hyperpigmented areas with an otherwise normal choroidal vascular architecture. Optical coherence tomography with enhanced depth imaging demonstrated normal choroidal thickness and structure in the hyperpigmented areas. These cases may represent an atypical presentation of previously described bilateral isolated choroidal melanocytosis or a different clinical entity. Histopathological evidence and longer follow-up of these patients and patients with isolated choroidal melanocytosis may elucidate the best descriptive term for this unusual condition.

Ocular melanoma in a patient successfully treated for diffuse malignant peritoneal mesothelioma: a case report.

BackgroundDiffuse malignant peritoneal mesothelioma and ocular melanoma are both rare tumors. To the best of our knowledge there is only one previous report of three cases in a family with known susceptibility to malignancies associating diffuse malignant peritoneal mesothelioma and ocular melanoma, with no sporadic cases previously reported.Case presentationWe describe the case of a 59-year-old man with a history of diffuse malignant peritoneal mesothelioma, who presented with ocular melanoma 41 months after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. We also briefly review the literature.ConclusionsDiffuse malignant peritoneal mesothelioma is an uncommon but aggressive disease. As diffuse malignant peritoneal mesothelioma characteristically remains confined to the abdominal cavity, any new extra-abdominal symptom should eventually raise suspicion of another primary tumor. Few cases of diffuse malignant peritoneal mesothelioma associated with other primary tumors have been reported. As ocular melanoma is also infrequent, we suspect a genetic predisposition to these tumors. There is emerging evidence supporting the role of BAP1 mutations in the pathogenesis of these two neoplasias.

Presumed Idiopathic Central Serous Chorioretinopathy in a 12-Year-Old Girl

Idiopathic central serous chorioretinopathy (CSC) typically affects middle-aged males. To date, only one case of idiopathic CSC in a prepubertal subject has been reported. Atypical idiopathic CSC presentation may be challenging to diagnose. Exclusion of secondary causes of serous retinal detachment (SRD) is warranted. We describe the atypical case of a 12-year-old female with a circumscribed SRD that resolved spontaneously and with fluorescein angiography (FA) findings that were compatible with idiopathic CSC. Optical coherence tomography (OCT) and systemic assessment were performed to exclude other etiologies. FA demonstrated multiple focal leaks in early phases, with subretinal leakage and pooling in late phases. OCT showed a localized circumscribed retinal detachment. Complete blood count was within normal limits. Serum cortisol was normal (22.1 µg/dl) and mean arterial blood pressure was 100/60 mm Hg, thereby excluding secondary causes of CSC. This is the second reported case of idiopathic CSC in a prepubertal female and the first one documented by FA and OCT, as well as other studies to exclude secondary causes. Albeit rare, idiopathic CSC should be considered in the differential diagnosis of SRD in this (prepubertal) age group, after excluding secondary ocular or systemic etiologies.

Outcomes of hypofractionated palliative radiotherapy for choroidal metastases.

194 Background: External beam radiotherapy (RT) is an effective palliative treatment for choroidal metastases aimed at preserving vision and obtaining local tumor control. Delivery of 30-40 Gy in 2 Gy daily fractions is a standard approach in many centers. At our center, a shorter, more convenient schedule of 20 Gy in 5 fractions has been used in this palliative setting. This study reports the efficacy and toxicity of this hypofractionated RT approach. METHODS We conducted a retrospective review of patients treated in the Ocular Oncology clinic at Princess Margaret Cancer Center who received RT (20 Gy in 5 fractions) for choroidal metastases between January 1, 1999 and November 30, 2012. Primary outcome measures were change in visual acuity and tumor response. Secondary outcomes included toxicities of RT, tumor control, and overall survival from the date of choroidal metastases diagnosis. RESULTS A total of 55 patients with 71 involved eyes were included. Decreased vision was the presenting symptom in 43 eyes (61%). Visual acuity improved from a median of 20/70 to 20/40 between baseline assessment and last follow-up, and remained stable or improved in 56 eyes (80%). On ultrasound, tumor regression was observed in 64 eyes (91%) with complete response in 47 eyes (67%). Metastases progressed in 4 eyes (6%) despite RT with 1 eye requiring enucleation. Median survival after diagnosis of choroidal metastases was 13 months with estimated overall survival at 1, 2, and 3 years to be 50% (36-62), 23% (12-35), and 8% (3-18), respectively. Forty-nine patients (89%) did not experience any acute complications. Mild acute toxicities included transitory dryness in 5 patients and episcleritis in 1 patient. Cataracts developed in 4 eyes (6%), retinopathy in 1 eye, optic neuropathy in 7 eyes (10%), pigmentary maculopathy in 5 eyes (7%), and neovascular glaucoma in 1 eye. CONCLUSIONS A short fractionation schedule of 20 Gy in 5 fractions is a well-tolerated treatment that effectively preserves vision and gains local tumor control for many patients with choroidal metastases. This hypofractionated approach would help reduce the burden of a longer treatment course in this palliative patient population.