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The management of retinoblastoma is complex and involves strategically chosen methods of enucleation, radiotherapy, chemotherapy, laser photocoagulation, thermotherapy, and cryotherapy. Chemotherapy has become the most common eye-sparing modality. There are four routes of delivery of chemotherapy for retinoblastoma, including intravenous, intra-arterial, periocular, and intravitreal techniques. The purpose of this review is to discuss the current rationale for each method and the anticipated outcomes.The diagnosis of retinoblastoma should be clinically established prior to embarking on a chemotherapy protocol. There are over 25 conditions that can closely simulate retinoblastoma in a young child. In addition, enucleation is an acceptable method for management, particularly with advanced retinoblastoma. Intravenous chemotherapy is generally used for germline mutation (bilateral, familial) retinoblastoma with excellent tumor control for groups A, B, and C and intermediate control for group D eyes. Intra-arterial chemotherapy is used as primary therapy in selected cases for nongermline mutation (unilateral) retinoblastoma with excellent control, and also used as secondary therapy for recurrent solid retinoblastoma, subretinal seeds, and vitreous seeds. Periocular chemotherapy is employed to boost local chemotherapy dose in advanced bilateral groups D and E eyes or for localized recurrences. Intravitreal chemotherapy is used for recurrent vitreous seeds from retinoblastoma. Patients at high risk for metastases should receive intravenous chemotherapy.Chemotherapy is effective for retinoblastoma and the targeted treatment route depends on the clinical features and anticipated outcomes.

Purpose Retinoblastoma is a childhood cancer of the retina. Clinical trials have shown that local delivery of broad spectrum chemotherapeutic agents is efficacious. Recent studies characterizing the genomic and epigenomic landscape of retinoblastoma identified spleen tyrosine kinase (SYK) as a promising candidate for targeted therapy. The purpose of this study was to conduct preclinical testing of the SYK antagonist R406 to evaluate it as a candidate for retinoblastoma treatment. Methods The efficacy of the SYK antagonist R406 delivered locally in a human orthotopic xenograft mouse model of retinoblastoma was tested. Intraocular exposure of R406 was determined for various routes and formulations. Results There was no evidence of efficacy for subconjunctival. R406. Maximal vitreal concentration was 10-fold lower than the minimal concentration required to kill retinoblastoma cells in vitro. Dosage of R406 subconjunctivally from emulsion or suspension formulations, direct intravitreal injection of the soluble prodrug of R406 (R788), and repeated topical administration of R406 all increased vitreal exposure, but failed to reach the exposure required for retinoblastoma cell death in culture. Conclusion Taken together, these data suggest that R406 is not a viable clinical candidate for the treatment of retinoblastoma. This study highlights the importance of pharmacokinetic testing of molecular targeted retinoblastoma therapeutics. Electronic supplementary material The online version of this article (doi:10.1007/s11095-014-1399-y) contains supplementary material, which is available to authorized users.

To delineate and discuss a not yet described possible ocular complication of selective intra-arterial chemotherapy (SIAC) for treatment of retinoblastoma.A 23-month-old girl with a large unilateral retinoblastoma was treated with repeated SIAC using 5 mg melphalan between July 2010 and January 2012. Clinical course of tumor and further ocular changes after therapy and histopathologic findings are described.In total, 5 SIAC were performed over a time period of 18 months. After the last SIAC, diffuse dense cataract prevented further funduscopy. In addition, anterior chamber seeding was obvious, leading to the decision to enucleate the eye. Histopathologically, nearly complete regression of the main tumor mass with prominent calcifications, but vital tumor seeding in the vitreous, on the lens surface, on the ciliary body, and in the anterior chamber, was observed. Peculiar vacuolation of the lens epithelial cells, liquefaction of the subepithelial lens fibers, and diffuse small vacuoles within the lens were striking.Repeated SIAC with melphalan may induce cataract formation, possibly as a toxic effect of the chemotherapeutic to the lens, maybe combined with radiation exposure during fluoroscopy. This ocular complication should be taken into consideration as a limitation of the number of feasible repeated treatments.

Purpose To use micro–ribonucleic acid (microRNA) profiles in the vitreous for differential diagnosis of primary vitreoretinal lymphoma and uveitis. Design Prospective cross-sectional study. Methods This prospective cross-sectional study included 17 diffuse large B-cell primary vitreoretinal lymphoma and 12 uveitis patients. The supernatant of ocular fluid was subjected to total RNA extraction, followed by complementary deoxyribonucleic acid (cDNA) synthesis. Selected samples (primary vitreoretinal lymphoma, n = 3; uveitis, n = 3) were arrayed by a real-time polymerase chain reaction (RT-PCR)-based microRNA panel that detects 168 human mature microRNAs. The markers promising in distinct levels between uveitis and lymphoma were further tested for in all the other 23 samples by individual RT-PCR analysis. Results Of 168 microRNAs in the array, 66.5% were detectable with consistent higher microRNA-484, microRNA-197, and microRNA-132 in the primary vitreoretinal lymphoma vitreous and higher microRNA-155, microRNA-200c, and microRNA-22* in the uveitic ocular fluids. The results were normalized by different combinations of 7 control microRNAs (microRNA-103, microRNA-191, microRNA-42-5p, microRNA-16, microRNA-425, microRNA-93, and microRNA-451). After optimization, normalization against microRNA-16 was equally as reliable as the average of the 7 control microRNAs. Individual assays of all samples supported the pattern yielded from the array analysis. But only microRNA-155 was significantly higher in the uveitic vitreous compared to that with lymphoma. Conclusions Mature microRNAs are detectable in ocular fluid samples. Primary vitreoretinal B-cell lymphoma and uveitis might be characterized by distinct microRNA signatures. Quantification of ocular microRNA-155 might be helpful in the differential diagnosis of these 2 diseases.

Retinal hemangioblastomas are highly vascular benign tumors that can be encountered either sporadically or within the von Hippel-Lindau (VHL) syndrome. We report a case of a VHL patient with retinal hemangioblastoma who underwent PET/CT scans using F-FDG and Ga-DOTATATE. The tumor showed low-level F-FDG and increased Ga-DOTATATE activity, suggesting cell-surface overexpression of somatostatin receptors. The presented case indicates the clinical applications of somatostatin receptor imaging with Ga-DOTA-conjugated peptides in detection and follow-up of VHL manifestations, screening of asymptomatic gene carriers, and in diagnosis of sporadic retinal hemangioblastomas, which may have similar features on MRI with other retinal tumors.

Intraocular lymphoma is considered a uveitis masquerade syndrome and may rarely present with features resembling a necrotizing viral retinitis. The authors report a secondary vitreoretinal lymphoma presenting in this fashion, which was treated with a unique combination of intravitreal methotrexate and rituximab. [ Ophthalmic Surg Lasers Imaging Retina. 2015;46:1048–1050.]

We present a case of a child with unilateral group E retinoblastoma (according to the International Classification of Retinoblastoma) who received superselective intra-arterial chemotherapy as primary therapy. Although the tumor showed signs of regression, the patient developed orbital metastases requiring surgical excision and chemotherapy. Eventually the affected eye progressed to total retinal detachment and required enucleation.

The purpose of the study is to report the clinical case of a 53-year-old woman whose presenting manifestation of primary intraocular lymphoma (PIOL) was unilateral retinal degeneration.A case report was created with review of clinical, imaging, electrophysiologic, and pathological investigations.A 53-year-old woman with a distant history of ocular herpes simplex developed progressive central visual loss and intermittent photopsia over 4 years in her right eye. Ophthalmic examination revealed reduced visual acuity OD, central scotoma, and minimal ocular findings. Autofluorescence and infrared imaging revealed mild reflectance changes in the temporal macula, and spectral-domain optical coherence tomography identified mild disruptions of inner segment/outer segment junctions in the subfoveal region of the right eye. A mild window defect was seen on fluorescein angiography. Electrophysiology with multifocal electroretinogram (ERG) revealed evidence of unilateral macular dysfunction. Full-field ERGs revealed progressive global retinal dysfunction over 6 months, with unilateral decreases in amplitude and implicit time shifts, as seen in cases of autoimmune retinopathies. The eye eventually exhibited mild vitreous cellular infiltration on ophthalmoscopic examination, and vitrectomy diagnosed B cell non-Hodgkin's lymphoma. Further evaluation revealed no evidence of central nervous system or systemic disease, consistent with occult PIOL.This case illustrates an atypical presentation of PIOL characterized by unilateral retinal disease presenting with symptoms and signs of macular dysfunction. Clinical and ERG features evolved into an acute zonal occult outer retinopathy (AZOOR)-like phenotype. PIOL should be considered in atypical cases of AZOOR with vitreal reactions, and some cases of AZOOR may be related to B cell lymphocyte disorders.

Background: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. Methods: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. Results: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. Conclusion: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.

Background Intravitreal injection therapy (IViT) for retinoblastoma has shown promise in the treatment of vitreous seeds; however, the potential for tumour dissemination following intravitreal penetration has limited its use. This review evaluates the risk of extraocular tumour spread in patients receiving therapeutic intravitreal injections for retinoblastoma. Methods PUBMED (1946–present), SCOPUS (all years), Science Citation Index (1900–present) and Conference Proceedings Citation Index—Science (1990–present) electronic databases were searched to identify all published reports of IViT for retinoblastoma in humans. Results 14 studies with original IViT data were included in this review. A total of 1304 intravitreal injections were given in 315 eyes of 304 patients, with one report of extraocular tumour spread and one patient in whom intravitreal treatment could not be excluded as a contributor to metastatic disease. The proportion of subjects with extraocular tumour spread potentially due to IViT in these combined reports was 0.007 (95% CI 0.0008 to 0.0236), with a mean follow-up of 72.1 months. In a subset of 61 patients receiving IViT via safety enhancing injection techniques (347 injections, 19.6 months mean follow-up), there were no reports of tumour spread. Conclusions Local and systemic tumour spread following IViT in cases of retinoblastoma is rare, and this risk is potentially reduced by the use of safety enhancing injection techniques. These results suggest that the risk of tumour spread should not preclude IViT use for carefully selected patients as part of multi-modal globe salvaging therapy.

Retinoblastoma remains incurable in many regions of the world. The major obstacles to cure are delayed diagnosis, poor treatment compliance, and lack of evidence-based recommendations for clinical management. Although enucleation is curative for intraocular disease, in developing countries retinoblastoma is often diagnosed after the disease has disseminated beyond the eye. A SIOP-PODC committee generated guidelines for the clinical management of retinoblastoma in developing countries and developed a classification system based on the resources available in those settings. Recommendations are provided for staging and treatment of unilateral and bilateral retinoblastoma and counseling of families for whom compliance is an issue.

Management of retinoblastoma (Rb), the most common intraocular malignant tumor in childhood, is tailored to each individual case and based on the overall situation. We present a case of bilateral Rbs in a 4-month-old girl, referred to our center for bilateral leukocoria. In the right eye, the optic disc was partially visible, and three large foci of retinoblastoma were noted adjective in the vitreous cavity with satellite retinal detachment. The macula was obscured by the tumors. The tumor was therefore classified as group D (International classification of retinoblastoma), and thus underwent intravenous chemotherapy with the standard three-agent protocol of ifosfamide, carboplatin and etoposide (ICE protocol) delivered monthly for six cycles, regressing with a type I calcified pattern. The left eye presented three multifocal yellow-white retinal masses, with a total retinal detachment, and secondary glaucoma. The lesions were classified as group E and, therefore, taking the results obtained by Shields et al. in group E tumors into consideration, underwent enucleation. This case clearly shows that this cancer is curable if detected at a stage in which it is still contained within the retina, subretinal space or vitreous, and that the management of Rb relies on an experienced team of ocular oncologists, pediatricians and pediatric ophthalmologists working together for the single goal of saving the child's life.

Translational research in retinoblastoma – a pediatric tumor that originates during the development of the retina – would be improved by the creation of new patient-derived models. Using tumor samples from enucleated eyes we established a new battery of preclinical models that grow in vitro in serum-free medium and in vivo in immunodeficient mice. To examine whether the new xenografts recapitulate human disease and disseminate from the retina to the central nervous system, we evaluated their histology and the presence of molecular markers of dissemination that are used in the clinical setting to detect extraocular metastases. We evaluated GD2 synthase and CRX as such markers and generated a Taqman real-time quantitative PCR method to measure CRX mRNA for rapid, sensitive and specific quantification of local and metastatic tumor burden. This approach was able to detect 1 human retinoblastoma cell in 100.000 mouse brain cells. Our research adds novel preclinical tools for the discovery of new retinoblastoma treatments for clinical translation. Fil: Pascual Pasto, Guillem. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Olaciregui, Nagore G.. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Vila Ubach, Monica. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Paco, Sonia. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Monterrubio, Carles. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Rodriguez, Eva. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Winter, Ursula Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Sant Joan de Deu Barcelona; España. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Batalla Vilacis, Mireia. Fundacio Sant Joan de Deu; España Fil: Catala, Jaume. Hospital Sant Joan de Deu Barcelona; España Fil: Salvador, Hector. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Parareda, Andreu. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; España Fil: Mora, Jaume. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Lavarino, Cinzia. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: de Torres, Carmen. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Carcaboso, Angel M.. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España

To report spectral-domain optical coherence tomography, en face optical coherence tomography (OCT), and optical coherence tomography angiography findings in retinal astrocytic hamartomas. Four cases of retinal astrocytic hamartomas, with small white or yellowish typical retinal mass, were imaged with fundus photography, intravenous fluorescein angiography, fundus autofluorescence, spectral-domain OCT, en face OCT, and OCT angiography. The tumor was solitary in all cases and involved the posterior pole. It was idiopathic in three cases and was related to tuberous sclerosis complex in one case. The OCT findings included intralesional lucencies in two cases with no exudation. The tumor was within the retinal nerve fiber layer or deeper, usually overlying the inner plexiform layer providing a protusion in the vitreous cavity. Vitreous changes were present in all cases, corresponding to thickening and adhesion of the vitreous facing the lesion (two cases), apparent interdigitation with vitreous (one case), and marked condensation of the vitreous with interdigitations (one case). En face OCT imaging at the level of the retinal pigment epithelial zone showed a hyporeflective, round, well-delineated mass. A peripheral poorly defined hyperreflectivity with a central hyporeflectivity was observed at the level of mid-retina, likely because of shadowing effect. The OCT-A reveals a dense vascular network within the tumor. Retinal astrocytic hamartomas may be well characterized by non-invasive imaging using spectral-domain OCT, en face OCT, and OCT angiography. The OCT angiography seemed to show tumor vascularity, which may represent dilated disorganized and anastomotic superficial and deep plexus capillaries. The tumor is often unique, peripapillary, small in diameter, and dome-shaped on spectral-domain OCT protruding into the vitreous cavity, responsible for vitreous changes facing the lesion.

To identify predictors of treatment response by evaluating long-term outcomes of vasoproliferative retinal tumors after ruthenium-106 brachytherapy.In a retrospective case series, 39 eyes of 38 patients with vasoproliferative retinal tumors received ruthenium-106 brachytherapy between 2001 and 2013. Baseline clinical and morphologic parameters were analyzed regarding posttreatment tumor activity status.Within a median follow-up period of 2.9 ± 2.9 years, overall, a tumor inactivation was achieved in 72% of cases and visual acuity remained stable in 69%. The mean apex dose was 90 ± 23 Gy (range, 51-140 Gy). Mean tumor thickness decreased significantly, from 2.9 ± 0.9 mm to 1.5 ± 1.0 mm (P0.001; paired t-test). Persistence or recurrence of tumor activity occurred in 28% of cases, requiring secondary intervention with intravitreal drug injections, vitrectomy, cryotherapy, or repeated brachytherapy. Comparison of inactive and active vasoproliferative retinal tumors revealed significant correlation between both initial basal tumour diameter and area and subsequent tumour activity status. In particular, a diameter7.5 mm was associated with an 8-fold risk of persistent or recurrent activity, whereas basal area40 mm demonstrated a 6-fold risk (P = 0.009 and 0.021, respectively; Fisher's exact-test). In contrast, tumor thickness was not found to be of prognostic relevance.Ruthenium-106 brachytherapy is an effective and safe therapeutic option for vasoproliferative retinal tumors. Additionally, tumor diameter and area are efficient predictors of persistence or recurrence of tumor activity.

BACKGROUND AND OBJECTIVE: The introduction of optical coherence tomography angiography (OCTA) provides new insights into the retinal vasculature. The aim of this study was to explore the value of OCTA in imaging retinal hemangioblastomas and monitoring laser treatment in patients with von Hippel-Lindau (VHL) disease. PATIENTS AND METHODS: Ten eyes of 10 patients with VHL disease were included in this retrospective case series. All patients underwent complete ophthalmological work-up including OCTA for retinal and optic nerve head hemangioblastoma. RESULTS: Two patients showed retinal scars and no recurrence of hemangioblastoma in OCTA. Three patients revealed recurrent hemangioblastomas. Two patients demonstrated a new hemangioblastoma. Three patients showed hemangioblastomas of the optic nerve head. Successful laser photocoagulation could be monitored with OCTA. CONCLUSIONS: Screening for retinal hemangioblastomas with OCTA alone is not possible. OCTA may help to distinguish hemangioblastomas and other lesions in VHL disease, especially after treatment and allows the differentiation from harmless non-vascular lesions in questionable cases. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:935–946.]

The eye is a rare site for the development of malignant lymphoma. Based on cell type and involved intraocular structures, which as a whole represent an immune-privileged site, several subtypes of primary intraocular lymphoma need to be discerned. Primary vitreoretinal lymphoma (PVRL), the most common form, is an aggressive B-cell malignancy and considered a subtype of primary central nervous system (CNS) lymphoma. Ocular symptoms are non-specific and often mimic uveitis, frequently resulting in delayed diagnosis. Bilateral ocular involvement and dissemination/relapse in the CNS are common. Diagnosis of PVRL is usually based on the analysis of vitreous biopsy material. In addition to cytological and immunocytochemical examination, measurements of cytokine levels and molecular determination of B-cell clonality and recurrent mutations increase the diagnostic yield. Both systemic chemotherapy and exclusively local treatment, including ocular radiotherapy and intravitreal chemotherapy, are successful approaches for the management of PVRL, although it is currently not predictable which patients require systemic treatment in order to avoid cerebral dissemination, a complication associated with a considerably worse prognosis.

Purpose of review Retinoblastoma is the most common primary ocular malignancy in children. Although currently retinoblastoma has an excellent survival rate in developed countries, hereditary retinoblastoma survivors as well as those with a history of radiation therapy as children are at an increased risk for second primary tumors (SPTs), and specifically, for orbital sarcomas. Despite the known increased risk for SPTs in retinoblastoma survivors and the associated morbidity and mortality, no screening or treatment guidelines exist. Recent findings Understanding of retinoblastoma tumorigenesis and genomic expression has expanded significantly, and treatment has evolved with a shift away from radiotherapy. Until the last two decades, however, radiation was the therapy of choice for patients with bilateral disease. Because both hereditary retinoblastoma and radiation are independent risk factors for the development of SPTs such as sarcomas and these SPTs are often fatal, appropriate surveillance for retinoblastoma survivors is crucial. Summary As a result of the excellent survival rates for retinoblastoma patients, it is important to: recognize the risk of sarcoma, particularly in patients with hereditary retinoblastoma and/or prior radiation therapy; establish a screening protocol, such as the one proposed, to maximize early detection; and discuss and develop treatment guidelines for high-risk patients. Future directions of research for these patients will involve the development of molecularly targeted agents and the use of proton radiotherapy.

Purpose: Systemic metastatic retinal lymphoma (SMRL) originates in systemic organs. It has been reported to exhibit clinical features similar to those of primary vitreoretinal lymphoma (PVRL). We report six cases of SMRL in a single-center survey in Japan.Methods: The clinical and pathologic features in SMRL at the Kyushu University Hospital were retrospectively studied.Results: The mean patient age at the onset of ocular involvement was 75.3 years. Four patients had brain involvement. The primary sites were: breast (2); chest (1); testis (1); intestinal tract (1); and nasal sinus (1). In all patients, the cytology of vitreous samples indicated diffuse large B-cell lymphoma (DLBCL).Conclusions: DLBCL is the most common subtype in our study. The prevalence of CNS involvement in patients with SMRL is similar to that with PVRL. The testis and breast may be common sites of origin for SMRL.

The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, allele-specific (AS)-PCR for a somatic nonsense mutation confirmed that a temple mass was metastatic retinoblastoma. In a second patient, a rib mass shared somatic copy number gains and losses with the primary tumor. For definitive diagnosis, however, an RB1 mutation was needed, but heterozygous promoter→exon 11 deletion was the only RB1 mutation detected in the primary tumor. We used a novel application of inverse PCR to identify the deletion breakpoint. Subsequently, AS-PCR designed for the breakpoint confirmed that the rib mass was metastatic retinoblastoma. These cases demonstrate that personalized molecular testing can confirm retinoblastoma metastases and rule out a second primary cancer, thereby helping to direct the clinical management.

Anterior chamber cholesterolosis is a rare phenomenon typically associated with non-neoplastic conditions such as hyphema or Coats disease; it has never been reported to be associated with intraocular malignancy. We report a case of anterior chamber cholesterolosis presenting in the setting of retinoblastoma and discuss clinical features relevant for its differentiation from Coats disease.

We report the case of a 23-month-old girl with bilateral retinoblastoma that demonstrated absence of retinal lesions in one eye but had an isolated white tumor in the posterior chamber. Genetic testing confirmed a novel and de novo RB1 germline mutation in the proband that was not carried by her parents. After intravenous chemotherapy and brachytherapy to the eye with apparently disease-free retina, anatomic and functional preservation of the eye was achieved. The patient has been in remission for 18 months.

To report novel observations of previously described solitary circumscribed retinal astrocytic proliferation using spectral domain optical coherence tomography that suggests this tumor does not arise in the nerve fiber layer as initially believed, but arises within deep retinal or retinal pigment epithelial structures.Retrospective review of four cases.Patient age ranged from 46 to 75 years. The tumor was pearl white or yellow-white (n = 4, 100%), located in the macula (n = 1, 25%) or macula to equator (n = 3, 75%) regions, and with mean tumor base of 1.2 mm and thickness of 0.8 mm. There were no feeding vessels, intrinsic vessels, subretinal fluid, or vitreoretinal traction. Mild surrounding retinal pigment epithelial hyperplasia and atrophy rimmed each tumor (n = 4, 100%). Fluorescein angiography depicted the mass with early hypofluorescence (n = 3/3, 100%) and late hypofluorescence (n = 2/3, 67%). Spectral domain optical coherence tomography demonstrated the mass with an abruptly elevated "snowball" configuration (n = 4, 100%), with smooth or slightly irregular surface (n = 4, 100%), and originating from deep retina or retinal pigment epithelial (n = 4, 100%), with overlying compression and draping of retinal tissue (n = 4, 100%).This previously described small yellow-white retinal tumor appears to arise in the outer retinal layers and not from the inner retinal layers as formerly believed. This tumor may not be astrocytic as initially believed since it arises deep within the retina, but it could represent a deep glial or pigment epithelial fibrous mass. The pathogenesis and pathology of this rare lesion remain unknown.

Purpose Retinoblastoma is the most common primary malignant intra-ocular tumor in children. Although intra-arterial chemotherapy (IAC) by selectively infusing chemotherapy through the ophthalmic artery has become an essential technique in the treatment of advanced intra-ocular retinoblastoma in children, the outcome of IAC as primary therapy for infants less than 3 months of age remains unknown. In this retrospective study, we reviewed the outcome of IAC as primary therapy for retinoblastoma in infants less than 3 months of age. Methods We retrospectively reviewed ten retinoblastoma patients attending our center from January 2009 to September 2015 and beginning primary IAC before the age of 3 months. The patient characteristics, overall outcomes and therapy-related complications were assessed. Results The mean patient age at the first IAC treatment was 10.4 weeks (range 4.9–12.9 weeks). These eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group A (n = 0), B (n = 2), C (n = 0), D (n = 9), or E (n = 2). A total of 28 catheterizations were performed, and the procedure was stopped in one patient because of internal carotid artery spasm. Each eye received a mean of 2.6 cycles of IAC (range 2–4 cycles). After IAC with a mean follow-up of 28.3 months (range 9–65 months), tumor regression was observed in 12 of 13 eyes. One eye was enucleated due to tumor progression. All patients are alive and no patient has developed metastatic disease or other malignancies. Conclusions Our experience suggests IAC as primary therapy is a feasible and promising treatment for retinoblastoma in infants less than 3 months of age.

Masquerade syndromes are disorders occurring with intraocular inflammation misdiagnosed as uveitis. The underlying causes may be benign or malignant conditions, and one of the most important diagnoses to take into consideration in children is retinoblastoma. We present two cases with uncertain early misdiagnosis whose definite diagnosis eventually was retinoblastoma.

Our aim was to evaluate the potential effect of imatinib mesylate (IM), a small molecule that specifically inhibits the tyrosine quinase receptors, on the proliferation and invasive abilities of two human retinoblastoma (Rb) cell lines. Furthermore, the ability of IM to radiosensitize Rb cells was evaluated. The potential targets of IM (C-kit, PDGRF-α and -β, and c-Abl) were also investigated in these cell lines.Two human Rb cell lines (WERI-RB-1 and Y79) were cultured under normal growth conditions. An MTT-based proliferation assay and a Matrigel invasion assay were performed with and without exposure to 10 μM of IM. The cells were also irradiated with graded dosages of 0, 2, 4, 6, 8, and 10 Gy with and without IM and their proliferations rates were analyzed. Western blot and immunocytochemical analysis of cytospins were performed to evaluate the expression of C-kit, PDGRF-α and -β, and c-Abl.When IM was added to both cell lines a statistically significant (P0.05) reduction in proliferation and invasive ability were observed. Exposure to IM also significantly increased the radiosensitivity of both Rb cell lines. The c-Abl expression was strongly positive, PDGRF-α and -β expression were also positive but the C-kit expression was negative in both cell lines.These results indicate that Gleevec may be useful as an adjuvant treatment in Rb patients, specially those considered for radiation therapy.

Case report The case of five members of a family who suffer from Von Hippel–Lindau disease (VHL) is presented. It is shown that retinal capillary hemangioma was the main ophthalmic symptom, with hemovitreous and tractional retinal detachment as the main complications. Discussion VHL disease is rare, but very serious, even fatal, and thus it is important to obtain an early diagnosis by ophthalmoscopy, in order to change the visual prognosis and life expectancy, not only for the patient, but also for the family.

Retinitis pigmentosa (RP) is a retinal dystrophy characterised by progressive loss of photoreceptors (particularly rods) and retinal pigment epithelium (RPE) resulting in night blindness and visual...

Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%–90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of IgH or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.

We review the role of MRI in retinoblastoma and simulating lesions. Retinoblastoma is the most common paediatric intra-ocular tumour. It may be endophytic, exophytic or a diffuse infiltrating tumour. MRI can detect intra-ocular, extra-ocular and intracranial extension of the tumour. MRI is essential for monitoring patients after treatment and detection of associated second malignancies. It helps to differentiating the tumour from simulating lesions with leukocoria.

Second malignancies, mostly in the form of bone sarcomas, are known to occur in hereditary retinoblastomas, which usually present with bilateral disease. Only 2 cases of Ewing's sarcoma have been reported in the literature following sporadic unilateral retinoblastoma. A 5-year-old boy presented to our hospital with Ewing's sarcoma of the right humerus (proven by biopsy and immunohistochemistry) following successful treatment of retinoblastoma of the left eye with enucleation and chemotherapy 2 years previously. He was treated with 2 cycles of chemotherapy followed by radiation therapy. At 15 months follow-up, the tumor had reduced in size and the child had a good functional outcome. The cumulative risk of second malignancies in retinoblastoma survivors is 32%. Ninety-eight percent of second malignancies occur in patients with bilateral retinoblastoma. Germ line mutations have been considered in sporadic tumors occurring bilaterally and multifocal unilateral sporadic tumors. Bone and soft tissue sarcomas are the most common second malignancies. Radiation therapy increases the risk of developing a second malignancy in the irradiated field. Unilateral retinoblastomas, which comprise the majority of retinoblastomas, are not immune from the development of second malignancies. Close follow-up of all retinoblastomas--even in the early period--can improve the outcome by facilitating the early detection and aggressive treatment of second malignancies.

Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short- and long-term side effects without risking mortality because of tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, Nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, Nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood–ocular barrier. Therefore, we developed an ocular formulation of Nutlin-3a, Nutlin-3aOC, and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here, we show that Nutlin-3aOC specifically and efficiently targets the p53 pathway and that the combination of Nutlin-3aOC with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma. Cancer Res; 71(12); 4205–13. ©2011 AACR.

Purpose: Systemic metastatic retinal lymphoma (SMRL) is exceptionally rare, as systemic lymphomas most often metastasize to the uvea. We have evaluated a series of SMRL cases to elucidate the clinical and pathological features of SMRL. Methods: The pathological specimens of intraocular lymphomas (IOLs) at the National Eye Institute from 1991 to 2009 were retrospectively reviewed. These cases were diagnosed by cytology, cytokine measurement (ELISA for interleukin (IL)-10 and IL-6 levels) and Immunoglobulin-Heavy (IgH) and T-cellreceptor (TCR) gene analyses. Results: There were nine B-cell SMRLs (B-SMRL) among 96 B-cell retinal lymphomas (9.4%) and three T-cell SMRLs (T-SMRL) among five T-cell retinal lymphomas (60%) from a total of 116 IOLs, in which 101 were retinal lymphoma. The original sites were nasopharynx (3), testis (2), skin (2), breast (1), blood (1), retroperitoneum (1), ileo-caecum (1) and stomach (1). Cytology of vitreous samples illustrated atypical lymphoma cells with either B- or T-monoclonality. More B-SMRLs had a high ratio of vitreal IL-10 to IL-6 than T-SMRLs. Molecular pathology demonstrated lymphoma cells with gene rearrangements of IgH in all B-SMRLs and TCR in all T-SMRLs. Conclusions: SMRL and primary retinal lymphoma present with similar clinical manifestations. Systemic T-cell lymphoma invades the retina and vitreous more aggressively than systemic B-cell lymphoma. A diagnosis of SMRL is made when there is a clinical history of systemic lymphoma (particularly from nasopharynx, testis and skin), and lymphoma cells are identified in the vitreous or retina. Molecular analysis is more useful than vitreal cytokine measurement for SMRL diagnosis.

Objective: Little is known about the incidence of secondary neoplasms among survivors of retinoblastoma in Japan. The objective of our study was to analyze the cumulative incidence rate of secondary neoplasms following retinoblastoma and to investigate the risk factors of developing secondary neoplasms. Methods: We conducted a retrospective cohort study of 754 retinoblastoma patients who visited the National Cancer Center Hospital in Tokyo between 1964 and 2007. The cumulative incidence rate curves were drawn using the competing risk method and compared with the Gray’s test. Using competing risk regression analysis, multivariate analysis estimated the subdistribution hazard ratio of factors related to the development of secondary neoplasms. Results: The median length of follow-up was 108 months (0 –5 94 months). Twenty-one (2.8%) patients developed 23 secondary neoplasms in total. The cumulative incidence rates of secondary neoplasms after retinoblastoma treatment were 2.4% at 10 years after diagnosis, 4.3% at 20 years, 6.4% at 30 years and 19.1% at 40 years. Ten patients (1.3%) died and 723 (95.9%) were alive without developing secondary neoplasms. The subdistribution hazard ratios of hereditary retinoblastoma and external beam irradiation were 4.85 (95% confidence interval ¼ 0.74–31.85) and 4.76 (95% confidence interval ¼ 0.69–33.09), respectively. Conclusions: We demonstrated the cumulative incidence rate of secondary neoplasms following retinoblastoma in Japan. The subdistribution hazards ratios of hereditary retinoblastoma and external beam irradiation were high but not significant because of statistical power. The long-term follow-up of retinoblastoma survivors is warranted to understand secondary neoplasm risk.

Purpose To present a unique case of an 8.5-year-old child with unilateral, anterior, pseudouveitis. He was found to have unilateral, invasive, small blue cell tumor of the anterior segment that was diagnosed as diffuse infiltrating retinoblastoma despite lack of retinal involvement on fundus examination or histopathologic analysis. Design Interventional case report. Participants One patient. Intervention The patient was treated with topical prednisolone acetate 1% and oral prednisone with no improvement in anterior chamber reaction. The patient underwent fine-needle aspiration biopsy (FNAB) of anterior chamber fluid, the results of which were consistent with a primitive neuroectodermal neoplasm, either retinoblastoma or medulloepithelioma. Retinoblastoma was favored strongly, and the patient underwent enucleation followed by chemotherapy with vincristine, carboplatin, and etoposide, and radiation to the eye socket of 4140 cGy total was performed. Main Outcome Measures The patient is alive and tumor free with follow-up of 5 years. Results Microscopic examination demonstrated cells similar to those seen on the FNAB infiltrating the iris stroma, trabecular meshwork, Schlemm's canal, and the inner portion of sclera in the region of the angle. No calcifications were identified. Serial sections of the entire globe were performed to determine the origin of the tumor. No retinal involvement was identified, and tumor was not seen to arise from the ciliary epithelium. Immunohistochemistry demonstrated positive staining with synaptophysin and negative staining with leukocyte common antigen and CD34. Conclusions This patient represents a case of diffuse anterior retinoblastoma with lack of obvious retinal involvement. Morphologic features typical of medulloepithelioma were not found on pathologic analysis. Although the patient lacked a retinal focus, he is alive at 5 years without evidence of recurrence of tumor. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Hereditary patients with a history of treated retinoblastoma (RB) have a greatly increased risk of a broad spectrum of secondary malignancies appearing many years later, with a high incidence in the head and neck region. Leiomyosarcomas (LMS) account for up to 58% of these tumors. LMS in the sinonasal region generally are uncommon and are associated with a locally aggressive course and have a poor prognosis. RB may occur in two forms. The hereditary form is generally bilateral but can present unilaterally with a positive family history and typically exhibits a germline mutation in the RB1 gene on chromosome 13. The non-hereditary form is usually unilateral but can show the same germline mutation in up to 10% of cases. Patients with hereditary RB have been shown to have a significantly higher cumulative risk of developing secondary malignancies than those with the non-hereditary form (28 vs. 1.44% respectively). Most reported cases of sinonasal LMS are in patients with a history of the bilateral hereditary form of treated RB. We report a case of LMS of the nasal sinus area in a 35-year-old African American male with a history of non-hereditary unilateral RB and radiation therapy. To the best of our knowledge, this is the first reported case of sinonasal LMS arising in a patient with a history of non-hereditary unilateral RB. The clinical history, radiology, and pathology are presented along with a brief discussion of the literature.