A Review of Pediatric Ophthalmic Tumors.

Tumors of the eye, orbit, and ocular adnexa can arise in the pediatric population. These entities can be both vision- and life-threatening and may be associated with systemic disease. Given their relative rarity, pediatricians must be aware of these conditions and understand what findings warrant immediate referral to an ophthalmologist for initiation of further testing. We aimed to review these conditions and highlight clinical features to promote awareness and expedite diagnosis. Tumors are subdivided into the following categories for review: anterior tumors of the eyelid and ocular surface, orbital tumors, and intraocular tumors.

Ophthalmologic Findings in Pediatric Erdheim-Chester Disease: A Literature Review With a Novel Case Report.

PURPOSE: The authors aim to describe the ophthalmologic manifestations of pediatric Erdheim-Chester disease (ECD). METHODS: The authors describe a novel case of ECD presenting as isolated bilateral proptosis in a child and provide a comprehensive review of the documented pediatric cases to observe overall trends and ophthalmic manifestations of disease. Twenty pediatric cases were identified in the literature. RESULTS: The mean age at presentation was 9.6 years (1.8-17 years) with a mean time of symptom presentation to diagnosis of 1.6 years (0-6 years). Nine patients (45%) had ophthalmic involvement at diagnosis, 4 who presented with ophthalmic complaints: 3 with observable proptosis and 1 with diplopia. Other ophthalmic abnormalities included eyelid findings of a maculopapular rash with central atrophy on the eyelids and bilateral xanthelasmas, neuro-ophthalmologic findings of a right hemifacial palsy accompanied by bilateral optic atrophy and diplopia, and imaging findings of orbital bone and enhancing chiasmal lesions. No intraocular involvement was described, and visual acuity was not reported in most cases. CONCLUSIONS: Ophthalmic involvement occurs in almost half of documented pediatric cases. Typically presenting with other symptoms, the case highlights that isolated exophthalmos may be the only clinical sign, and ECD should be included in the differential diagnosis of bilateral exophthalmos in children. Ophthalmologists may be the first to evaluate these patients, and a high index of suspicion and an understanding of the varied clinical, radiographic, pathologic, and molecular findings are critical for prompt diagnosis and treatment of this unusual disease.

Targeted Neoadjuvant Intra-arterial Chemotherapy in Lacrimal Gland Adenoid Cystic Carcinoma: A Histological Correlation Using Apoptotic Tumor Markers.

Neoadjuvant intra-arterial cytoreductive chemotherapy is used for the treatment of lacrimal gland adenoid cystic carcinomas (ACC) to improve outcomes in this condition with an otherwise dismal prognosis. We share our experience in the management of an advanced case of ACC using a novel, highly targeted intra-arterial cytoreductive chemotherapy delivery technique involving both the internal and external carotid circulation, with an attempt to correlate the effect histologically. Refinement of the chemotherapy delivery using the tumor's vascular anatomy and appropriate blood vessel selection may lead to future globe sparing procedures without compromising survival.

Response criteria for intraocular retinoblastoma: RB-RECIST.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

A Potential Role For Apparent Diffusion Coefficient in the Diagnosis of Trilateral Retinoblastoma.

We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (>1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.

A case of bilateral acute depigmentation of the Iris in one of two identical twins.

BACKGROUND: Bilateral Acute Depigmentation of the Iris (BADI) is a condition which was first described in a case series from Turkey by Tugal-Tutkin and Urgancioglu in (Graefes Arch Clin Exp Ophthalmol 244:742-6, 2006). The condition is characterized by bilateral acute depigmentation and discoloration of the iris stroma, pigment dispersion, and deposition of pigment in the angle. In our case we report a patient who developed BADI after receiving pitcher plant extract injections for chronic migraine, while her identical twin sister has normal iris architecture and pigmentation and never received any pitcher plant injections. CASE PRESENTATION: Patient is a 41-year-old female with history of pitcher plant extract injections to her face for chronic migraine, who later developed bilateral depigmentation of the iris. She did not have any signs of anterior segment uveitis or iridocyclitis. She has an identical twin sister who maintained normal iris pigmentation during the entire course. CONCLUSIONS: Bilateral Acute depigmentation of the is a recently discovered condition described in the literature in Turkish patients (Tugal-Tutkun and Urgancioglu, Graefes Arch Clin Exp Ophthalmol 244:742-6, 2006; Tugal-Tutkun et al., Ophthalmology 116(8):1552-7, 2009). This condition affects mainly young females and is characterized by acute bilateral stromal depigmentation, without other pathologic ocular findings. These patients usually maintain normal vision and do not develop significant glaucoma from pigment collecting in the anterior chamber angle. This condition can be mistaken for Fuchs' heterochromic iridocyclitis, pigment dispersion syndrome, pseudoexfoliation syndrome, and viral iridocyclitis. This is the first reported case in North America and is important for differentiation from the above pathologies. Our patient had a history of pitcher plant extract injections to the face but it is unclear if this is associated with our patient's development of BADI. As awareness of this condition progresses, a possible etiology may be elucidated.

Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists.

PURPOSE: To provide a set of surveillance guidelines for children at risk for development of retinoblastoma. DESIGN: Consensus panel. PARTICIPANTS: Expert panel of ophthalmic oncologists, pathologists, and geneticists. METHODS: A group of members of the American Association of Ophthalmic Oncologists and Pathologists (AAOOP) with support of the American Association for Pediatric Ophthalmology and Strabismus and the American Academy of Pediatrics (AAP) was convened. The panel included representative ophthalmic oncologists, pathologists, and geneticists from retinoblastoma referral centers located in various geographic regions who met and discussed screening approaches for retinoblastoma. A patient "at risk" was defined as a person with a family history of retinoblastoma in a parent, sibling, or first- or second-degree relative. MAIN OUTCOME MEASURES: Screening recommendations for children at risk for retinoblastoma. RESULTS: Consensus statement from the panel: (1) Dedicated ophthalmic screening is recommended for all children at risk for retinoblastoma above the population risk. (2) Frequency of examinations is adjusted on the basis of expected risk for RB1 mutation. (3) Genetic counseling and testing clarify the risk for retinoblastoma in children with a family history of the disease. (4) Examination schedules are stratified on the basis of high-, intermediate-, and low-risk children. (5) Children at high risk for retinoblastoma require more frequent screening, which may preferentially be examinations under anesthesia. CONCLUSIONS: Risk stratification including genetic testing and counseling serves as the basis for screening of children at elevated risk for development of retinoblastoma.

Efficacy and Toxicity of Intravitreous Chemotherapy for Retinoblastoma: Four-Year Experience.

PURPOSE: To investigate the efficacy and toxicity of intravitreous melphalan for treatment of retinoblastoma, as a single agent or with concomitant topotecan. PARTICIPANTS: A total of 130 eyes of 120 patients with retinoblastoma receiving 630 intravitreous (melphalan, topotecan) or topotecan periocular injections. A total of 83 (64%) of these eyes were treated with concomitant ophthalmic artery chemosurgery (OAC). DESIGN: Retrospective cohort study. METHODS: Indirect ophthalmoscopy and clinical imaging were used to evaluate clinical response. Ocular survival and disease-free survival were estimated using Kaplan-Meier methods in 130 eyes. Ocular toxicity was evaluated by clinical findings and electroretinography (ERG) on 244 evaluable injections in 63 patients using 30-Hz flicker responses. Analysis was performed using linear mixed effects models with a random intercept and slope for each patient and a fixed effect for number of injections, in addition to any other fixed effect of interest. MAIN OUTCOME MEASURES: Ocular survival, disease-free survival, ERG: peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation. RESULTS: There were no disease- or treatment-related deaths, and no patient developed externalization of tumor or metastatic disease. Two-year Kaplan-Meier estimates of ocular survival and disease-free survival were 94.2% (95% confidence interval, 89.2-99.4) and 86.2% (95% confidence interval, 78.7-94.5), respectively. There was a significant association between the number of injections and diminished ERG responses, such that on average each intravitreous melphalan injection was associated with a 5.3-µV decrease in ERG amplitude (P < 0.001). Concomitant intra-arterial chemotherapy (P = 0.01) and greater inherent ocular pigment also were significantly associated with a reduction in ERG (P = 0.045). Patient age and weight, new injection site location, addition of topotecan, concomitant focal treatment, and time interval between injections were not significantly associated with toxicity. CONCLUSIONS: Intravitreous melphalan is an effective treatment for vitreous seeding in retinoblastoma, resulting in high rates of ocular survival and disease-free survival. However, in this study, each injection of melphalan was associated, on average, with a decrement in ERG response. The findings suggest increased toxicity (1) when OAC is given within 1 week of the intravitreous injection and (2) in more deeply pigmented eyes.

Primary Extradural Ectopic Orbital Meningioma.

The authors describe a rare case of a primary extradural ectopic meningioma occurring in a 9-year-old female. A review of the literature with respect to clinical presentation, radiographic findings, management, and outcome among similar cases is discussed. Common features that may assist with diagnosing this unusual tumor include absence of bone or optic nerve sheath involvement, presentation at a young age, occurrence in the medial orbit, and sinus asymmetry on radiographic imaging. Preferred method of treatment is complete surgical excision.

Chronic medical conditions in adult survivors of retinoblastoma: Results of the Retinoblastoma Survivor Study.

BACKGROUND: Limited data are available regarding long-term morbidity in adult survivors of retinoblastoma (Rb). METHODS: The Retinoblastoma Survivor Study is a retrospective cohort of adult survivors of Rb diagnosed between 1932 and 1994. Participants completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study surveys. Chronic conditions were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03). Multivariate Poisson regression was used to compare survivors of Rb with 2377 non-Rb controls, consisting of the Childhood Cancer Survivor Study sibling cohort and survivors with bilateral versus unilateral disease. RESULTS: Survivors of Rb (53.6% with bilateral disease) and non-Rb controls had a mean age of 43.3 years (standard deviation, 11 years) and 37.6 years (SD, 8.6 years), respectively, at the time of study enrollment. At a median follow-up of 42 years (range, 15-75 years), 86.6% of survivors of Rb had at least 1 condition and 71.1% had a severe/life-threatening (grade 3-4) condition. The adjusted relative risk (RR) of a chronic condition in survivors compared with non-Rb controls was 1.4 (95% confidence interval [95% CI], 1.3-1.4; P<.01); for a grade 3 to 4 condition, the RR was 7.6 (95% CI, 6.4-8.9; P<.01). Survivors were at an excess risk regardless of laterality. After stratifying by laterality and excluding ocular conditions and second malignant neoplasms (SMNs), only those with bilateral disease were found to be at an increased risk of any nonocular, non-SMN condition (RR, 1.2; 95% CI, 1.1-1.2) and for grade 3 to 4 nonocular, non-SMN conditions (RR, 1.7; 95% CI, 1.2-2.5). CONCLUSIONS: Survivors of Rb have an increased risk of chronic conditions compared with non-Rb controls. After excluding ocular conditions and SMNs, this excess risk was found to persist only for those with bilateral disease. Cancer 2016;122:773-781. © 2016 American Cancer Society.

Classification of Vitreous Seeds in Retinoblastoma: Correlations with Patient, Tumor, and Treatment Characteristics.

PURPOSE: To evaluate the patient, disease, and tumor characteristics of the 3 morphologically distinct groups of vitreous seeds in retinoblastoma presenting for treatment with ophthalmic artery chemosurgery (OAC): dust (class 1), spheres (class 2), and clouds (class 3) in primary and recurrent vitreous seeds. DESIGN: Retrospective cohort study of patients treated for vitreous seeds at Memorial Sloan Kettering Cancer Center between May 2006 and March 2015. PARTICIPANTS: A total of 135 eyes with active vitreous seeds, presenting for primary treatment with OAC or with recurrent vitreous disease. METHODS: Vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to locate and evaluate the extent of retinal and vitreous disease. Patient and disease characteristics (age, laterality of disease, treatment status) were compared among classification groups. A 2-tailed Fisher exact test and paired Student t test were used for statistical analysis. MAIN OUTCOME MEASURES: Age of patient, laterality of disease, location of retinal disease, extent of vitreous disease, and treatment status. RESULTS: Primary treated disease: Patients with eyes containing class 3 (cloud) vitreous seeds were significantly older than patients with class 1 or 2 seeds (P < 0.05). The median age of patients with class 1, 2, and 3 seeds was 11, 15.5, and 32 months, respectively. Eyes containing class 3 seeds were significantly more likely to occur in the equator-ora region of the fundus (P < 0.0001), in a diffuse pattern (P < 0.0001), and in patients with unilateral disease (P < 0.05), compared with class 1 and 2 seeds. Recurrent disease: Recurrent vitreous seeds were significantly more common to class 2 (P < 0.05), occurring in a diffuse pattern (P = 0.01) and in patients with bilateral disease (P < 0.001). CONCLUSIONS: The 3 classes of vitreous seeds have distinct clinical characteristics associated with the age of patient, laterality of disease, and extent and location of tumor-producing seeds. Furthermore, recurrent vitreous seeds appear to have a unique clinical profile compared with seeds receiving primary treatment.

The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan.

PURPOSE: To evaluate the clinical characteristics of the 3 classifications of vitreous seeds in retinoblastoma-dust (class 1), spheres (class 2), and clouds (class 3)-and their responses to intravitreal melphalan. DESIGN: Retrospective, bi-institutional cohort study. PARTICIPANTS: A total of 87 patient eyes received 475 intravitreal injections of melphalan (median dose, 30 µg) given weekly, a median of 5 times (range, 1-12 times). METHODS: At presentation, the vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response to weekly intravitreal melphalan injections and time to regression of vitreous seeds. Kaplan-Meier estimates of time to regression and ocular survival, patient survival, and event-free survival (EFS) were calculated and then compared using the Mantel-Cox test of curve. MAIN OUTCOME MEASURES: Time to regression of vitreous seeds, patient survival, ocular survival, and EFS. RESULTS: The difference in time to regression was significantly different for the 3 seed classes (P < 0.0001): the median time to regression was 0.6, 1.7, and 7.7 months for dust, spheres, and clouds, respectively. Eyes with dust received significantly fewer injections and a lower median and cumulative dose of melphalan, whereas eyes with clouds received significantly more injections and a higher median and cumulative dose of melphalan. Overall, the 2-year Kaplan-Meier estimates for ocular survival, patient survival, and EFS (related to target seeds) were 90.4% (95% confidence interval [CI], 79.7-95.6), 100%, and 98.5% (95% CI, 90-99.7), respectively. CONCLUSIONS: The regression and response of vitreous seeds to intravitreal melphalan are different for each seed classification. The vitreous seed classification can be predictive of time to regression, number, median dose, and cumulative dose of intravitreal melphalan injections required.

Efficacy and toxicity of second-course ophthalmic artery chemosurgery for retinoblastoma.

OBJECTIVE: Assess the usefulness of second-course ophthalmic artery chemosurgery (OAC) for patients with intraocular retinoblastoma that recurred after prior OAC. This study evaluated the efficacy and toxicity of second-course OAC. DESIGN: Single-arm retrospective study of 29 eyes of 30 patients treated with second-course OAC at Memorial Sloan Kettering Cancer Center between May 2006 and July 2013, with a median follow-up of 25.9 months. PARTICIPANTS: Retinoblastoma patients who underwent a course of OAC, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently received additional OAC for recurrent tumor. METHODS: To determine efficacy, Kaplan-Meier survival estimates were generated and the Mantel-Cox test was used to compare curves. To determine toxicity, electroretinography (ERG) amplitudes were measured in response to 30-Hz photopic flicker stimulation before and after OAC treatment; systemic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). MAIN OUTCOME MEASURES: For efficacy, ocular progression-free survival, ocular event-free survival (e.g., enucleation, external-beam radiation, or intravitreal melphalan), and ocular survival. For toxicity, peak-to-peak comparisons between ERG studies before and after OAC treatment and CTCAE 4.0-graded systemic adverse events. RESULTS: Fifty percent of all recurrences were within 4.4 months and 90% were within 16 months of completion of the first course of OAC. The 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after second-course OAC were 82.8% (95% confidence interval [CI], 60.1%-93.2%), 57.3% (95% CI, 36.1%-73.7%), and 26.5% (95% CI, 11.0%-45.0%), respectively. All eyes without vitreous seeding were progression free, whereas eyes with vitreous seeding were associated significantly with worse ocular survival after second-course OAC (P = 0.03). After second-course OAC, 90% of eyes had stable or improved ERG responses. Of all evaluable cases, there was no increased risk of systemic toxicity during the second course compared with the initial course of OAC. CONCLUSIONS: Retinoblastoma eyes requiring second-course OAC after initial OAC treatment have good salvage rates, and the treatment has an acceptable ocular and systemic toxicity profile. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods because of progression of disease after second-line OAC, particularly if vitreous seeds are present at the time of initial OAC failure.

Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study.

PURPOSE: Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model. DESIGN: Clinical and preclinical, prospective, cohort study. PARTICIPANTS: In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 µg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 µg of intravitreal melphalan or vehicle to the right eye. METHODS: Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated. MAIN OUTCOME MEASURES: For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings. RESULTS: By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 µV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina. CONCLUSIONS: Weekly injections of 30 µg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.

Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study.

BACKGROUND: Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMNs) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage. PROCEDURE: Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 to August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs. RESULTS: Twenty-five patients had at least one WB-MRI performed (range: 1-5). First WB-MRI was performed at a median age of 16 years (range: 8-25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in five patients: two were diagnosed with localized high-grade OS of the extremity and three were found to have benign osseous abnormalities after dedicated imaging (n = 5/5) and/or biopsy (n = 3/5). One patient was diagnosed with secondary OS 3 months after a normal screening WB-MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%. CONCLUSIONS: Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors.

Non-selectivity of ERG reductions in eyes treated for retinoblastoma.

PURPOSE: We have monitored retinal function in patients treated for retinoblastoma (primarily, but not exclusively by intra-arterial chemotherapy infusion) by electroretinography (ERG) recordings for the past 7 years. We here present data from 599 ERG studies of 108 patients, in which a complete ERG protocol including both photopic and scotopic recordings was performed, in justification of our frequent practice of reporting primarily 30-Hz photopic flicker amplitude data. METHODS: Patients referred for treatment of retinoblastoma underwent ERG recordings during examination under anesthesia whenever possible: at baseline and following most treatment sessions. Correlations were calculated for the complete datasets between the four primary amplitude response parameters: photopic single flash b-wave, photopic 30-Hz flicker peak-to-trough, scotopic rod-isolating b-wave, and scotopic maximal flash b-wave. RESULTS: Using our adaptation of the International Society for Clinical Electrophysiology of Vision-recommended standard ERG protocol, ERG responses of eyes of patients with untreated retinoblastoma or following traditional or intra-arterial treatment for retinoblastoma show very high correlations between 30-Hz flicker amplitude responses and three other standard photopic and scotopic ERG response amplitudes. Reductions in ERG amplitudes seen in these eyes following treatment show no significant difference between retinal dysfunction estimated using rod- or cone-dominated responses. CONCLUSION: These observations support the use of photopic response amplitudes (especially in response to 30-Hz flicker) as the primary ERG outcome measure in studies of treated and untreated eyes with retinoblastoma when more complete ERG protocols may be impractical.

Retinal toxicities of cancer therapy drugs: biologics, small molecule inhibitors, and chemotherapies.

PURPOSE: To review reported retinal side effects from current cancer therapy drugs. METHODS: Retinal toxicities from ophthalmologic or oncologic case reports, case series, and clinical trials were identified by a systematic literature search using Lexicomp and PubMed. RESULTS: Four biologics, 8 small molecule inhibitors, and 17 traditional chemotherapy agents had reported retinal side effects. For biologics, interferon alpha 2b was associated with retinopathy, denileukin diftitiox with pigmentary retinopathy, ipilimumab with a Vogt-Koyanagi-Harada-like syndrome, and trastuzumab with retinal ischemia. For small molecule inhibitors, v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors were associated with uveitis, mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitors with pigment epithelium detachments, and tyrosine kinase inhibitors with macular edema. Steroid antagonists were associated with crystalline retinopathy and macular edema. Nitrosoureas, platinum analogs, and cytosine arabinoside were associated with retinal vascular occlusions. Antimicrotubular agents were associated with cystoid macular edema but without fluorescein leakage. Retinoic acid derivatives were associated with impaired night vision, and mitotane was associated with a pigmentary retinopathy and papilledema. CONCLUSION: Certain agents used in the treatment of systemic cancer are associated with ocular complications. Awareness of these complications will allow early detections and maybe reversal of some of the ocular problems.

Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.

IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.

Ophthalmic artery chemosurgery for retinoblastoma prevents new intraocular tumors.

OBJECTIVE: To determine the incidence and timing of new intraocular tumor foci in genetic retinoblastoma cases after treatment with ophthalmic artery chemosurgery (OAC). DESIGN: Single-center retrospective review of all genetic retinoblastoma cases managed at Memorial Sloan-Kettering Cancer Center/Weil-Cornell Medical School since May 2006. PARTICIPANTS: Eighty-one patients (80 with bilateral disease and 1 with unilateral disease with a family history) with genetic retinoblastoma, with a total of 116 eyes treated with OAC since May 2006. METHODS: Retrospective, single-institution review of patients with bilateral retinoblastoma and unilateral retinoblastoma with a positive family history. New tumors were assessed by clinical notes, retinal drawings, and RetCam digital imaging (Clarity Medical Systems, Pleasanton, CA). MAIN OUTCOME MEASURES: New intraocular retinoblastoma tumors after treatment with OAC. RESULTS: Forty-one eyes were treated primarily with OAC (treatment-naïve group) and 75 eyes were treated with OAC after prior treatment with systemic chemotherapy, external beam radiation, or both and focal techniques. Of the 41 treatment-naïve eyes, a new intraocular tumor (one focus) subsequently developed in 1 eye. Of the 75 previously treated eyes, new tumors (single focus in each eye) subsequently developed in 6 eyes. CONCLUSIONS: Eyes receiving OAC demonstrate fewer new intraocular retinoblastomas after radiation or systemic chemotherapy than has been reported in the literature. This suggests that ophthalmoscopically undetectable tumors are present at the initial diagnosis and effectively are eliminated as a result of OAC.