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The management of retinoblastoma is complex. With increasing treatment modalities and increasing experience with each treatment modality, the globe salvage rates have drastically improved with time. Aqueous seeding in an eye with retinoblastoma is classified as group E based on International Classification of Intraocular Retinoblastoma, and most group E eyes were enucleated a decade earlier. Newer modalities of treatment have improved the globe salvage rates in group E eyes including those with aqueous seeding. Various globe salvage treatment modalities attempted for the management of aqueous seeds include external beam radiotherapy, plaque radiotherapy, intra-arterial chemotherapy, periocular chemotherapy, intravitreal chemotherapy and intracameral chemotherapy. Of all treatment modalities, intracameral chemotherapy holds promise for the management of aqueous seeds in selected patients, but it should be done with the utmost care by a trained ocular oncologist. Enucleation is still the preferred modality of treatment for eyes with advanced retinoblastoma and anterior segment invasion. This review focuses on the current evidence on aqueous seeding, highlighting the pathogenesis, classification, clinical presentation, treatment and outcomes.

Background Retinoblastoma (RB) outcomes in Thailand are unfavorable compared to those of developed countries. This study aims to determine whether the clinical outcomes of patients with RB significantly improved after the implementation of new therapeutic approaches and which clinical factors affect survival and globe-saving outcomes. Methods The medical records of patients newly diagnosed with RB and treated at Siriraj Hospital between January 2005 and December 2018 were reviewed retrospectively. Clinical data, treatments, and outcomes were collected and analyzed. Results In 194 eyes (144 patients), leukocoria was the most common presenting feature (76.8%); 129 (66.5%) eyes were staged in group E of the International Classification of Intraocular Retinoblastoma. Of the 149 enucleated eyes, 35 had high-risk histopathological features, mostly choroidal invasion; 45 eyes (23.2%) could be salvaged. The 5-year overall survival rate was 90.3%, an improvement compared to the previous study. The 5-year enucleation-free survival rates of Groups A and B, C, D and E were 100%, 83.1%, 36.7% and 16.6% respectively. Factors associated with a lower survival rate were interval from symptom onset to diagnosis >3 months (hazard ratio (HR): 5.8: 95% confidence interval (CI): 1.637, 20.579) and buphthalmos (HR: 12.57: 95% CI: 3.936, 40.153). Factors associated with high-risk features were secondary glaucoma (HR: 11.016: 95% CI: 1.24, 98.10) and pseudohypopyon (HR: 14.110: 95% CI: 2.16, 92.05). Conclusions Survival rates and globe-saving rates appear to have improved; however, advanced-stage presentation remains the major hindrance. Further studies with a larger cohort and longer follow-up are warranted.

Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia Introduction Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Results Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers. Open access funding enabled and organized by Projekt DEAL.

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.

Importance: Retinoblastoma (Rb) is the most common primary malignant intraocular cancer in children. Systemic chemotherapy combined with local therapy is safe and effective for intraocular Rb. Objective: To summarize the short-term outcomes of patients with Rb to provide evidence for optimizing treatment protocols and improving therapeutic safety and efficacy. Methods: The clinical data of 356 patients (486 eyes) with intraocular Rb admitted to our center from December 2009 to April 2017 were retrospectively analyzed. The measures included drug toxicity, eye-preservation rate, and survival rate, with an emphasis on safety and short-term efficacy. The date of last follow-up was 30 November, 2017. Results: The patients comprised 226 unilateral Rb and 130 bilateral Rb. Enucleation before chemotherapy was performed in 72 patients. Among the 174 patients with unilateral Rb, enucleation after chemotherapy was performed in 80 patients (46.0%), and the eye was not enucleated in 89 (51.1%); 68 eyes were preserved (68/114, 59.6%) in Group D and 20 eyes (20/59, 33.8%) in Group E. Among the 220 eyes in patients with bilateral Rb, enucleation after chemotherapy was performed for 35 eyes; the eye-preservation rate was 91.7% in Group C, 79.1% in Group D, and 52.1% in Group E. All patients developed grade II to IV myelosuppression after chemotherapy, among whom 18 patients (5%) requiring transfusion. Fourteen patients (3.9%) died of intracranial metastasis following self-elected discontinuation of treatment (n = 7). Patients were followed up for a median of 47 (range, 1–96) months. The expected 5-year overall survival rate was 95.3% (96.7% for unilateral Rb and 92.9% for bilateral Rb, P = 0.074). Interpretation: The VEC (vincristine, etoposide, and carboplatin) regimen with local treatment was safe for intraocular Rb. Intracranial metastasis remains the most common cause of Rb-related death. Key words: Chemotherapy; Enucleation; Intraocular retinoblastoma; Local therapy

Background Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. Purpose To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. Study type Prospective case series. Population Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). Field strength/sequence In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. Assessment After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). Results Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 μm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 μm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. Data conclusion Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. Level of evidence 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.

PURPOSE: To determine the significance of large tumour size as a criteria for classifying advanced intraocular retinoblastoma, analysing rates of globe survival and high-risk (HE) histopathologic features. METHODS: Retrospective chart review of 212 eyes diagnosed with Group D (111 eyes) or Group E (101 eyes) retinoblastoma in at least one eye from January 1, 2006 to December 31, 2016 using the Los Angeles (LA) Classification System (no tumour size criteria for Group E). The 111 Group D tumours were then reclassified to Group E using 10, 12, 14, 16, 18 mm tumour size criteria, as determined by ultrasound or magnetic resonance imaging dimensions. RESULTS: For eyes in the original LA classification, 66.7% of Group D and 10.5% of Group E eyes undergoing globe preservation therapy avoided enucleation or radiotherapy (p < 0.0001; median follow-up of 33.0 months). In the LA classification, 8.5% of Group D and 26.3% of Group E enucleated globes had HE histopathologic features (p = 0.0065). When Group D eyes with tumours meeting the size criteria were reclassified to Group E, 65.7–74.4% of Group D and 16.1–36.7% of Group E eyes avoided enucleation or radiotherapy. Applying the tumour size criteria, 0–10.9% of Group D and 20.7–23.8% of Group E eyes had HE histopathologic features. CONCLUSION: Our retrospective analysis suggests that a large tumour size criteria for Group E retinoblastoma have no clinical basis, given that the LA classification system provided the greatest separation in globe salvage rates between Group D and E eyes. The LA classification system was also able to show a statistically significant difference in the rates of HE histopathologic features between Group D and E eyes. To avoid discrepancies in the literature, we recommend that centres use one uniform system for classifying advanced intraocular retinoblastoma.

Purpose To report the efficacy of combined intravitreal chemotherapy (IViC) and intra-arterial chemotherapy (IAC) for the treatment of advanced stage retinoblastoma. Methods The medical records of twenty patients affected by unilateral advanced retinoblastoma (Reese-Ellsworth stage Vb/D of ABC classification). After clinical and ophthalmoscopic evaluation, they underwent MRI to exclude local and CNS dissemination. The IAC was given to treat retinal masses and intravitreal injections to treat vitreous seeding. Patients had received two cycles (six infusions) of IAC, and from six up to ten melphalan injections into the vitreous, with an interval of 7–10 days between them. Results All patients underwent to bimonthly MRI examination, during treatment and every 3 months for 1 year after last injection, to exclude orbital dissemination. Successful control (57.8%) of tumor masses and vitreous seeds was achieved in all cases at 12 up to 60 months follow-up. No permanent complications have been reported. Transient omplications disappeared throughout the months. No intraocular or orbital tumor recurrence or retinoblastoma metastases were observed. Conclusions Sequential IAC and intravitreal melphalan for advanced retinoblastoma is a good tool to provide retinal and vitreous seed control.

Background Retinoblastoma is the most common primary intraocular malignancy of childhood. Systemic chemotherapy is a common treatment for intraocular retinoblastoma, and laser treatment is used as adjuvant therapy during or immediately after chemotherapy courses in selected cases. Objectives To compare the effectiveness and safety of adding focal laser therapy to systemically-delivered chemotherapy in treating intraocular retinoblastoma. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 9), MEDLINE Ovid (1946 to 20 October 2016), Embase Ovid (1980 to 20 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 20 October 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 20 October 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 20 October 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 20 October 2016. We did not use any date or language restrictions in the electronic searches for trials. Selection criteria We searched for randomised controlled trials (RCTs) of systemic chemotherapy with versus without adjuvant laser therapy for postequatorial retinoblastoma. Data collection and analysis We planned to use standard methodological procedures expected by Cochrane. We planned to meta-analyse the primary outcome, that is the proportion of eyes with recurrence of tumours within three years from treatment Main results No studies met the inclusion criteria for this review. Authors' conclusions No evidence from randomised controlled trials was found to support or refute laser therapy in addition to systemic chemotherapy for postequatorial retinoblastoma.

The delivery route of chemotherapy for intraocular retinoblastoma has become controversial. One objection to systemic delivery is the need for central venous access. We cross-referenced a hospital vascular access database with our tumor registry to determine the incidence of chemotherapy infiltrates. Sixty-five patients received 270 cycles of chemotherapy via peripheral intravenous access. Vincristine infiltration was 0% (95% confidence interval [CI] 0–0.16%) while that of non-vesicant chemotherapy was 0.7% (95%CI 0.1–2.6%). Giving chemotherapy via peripheral access to patients with retinoblastoma is safe. It can decrease therapy costs and prevent central line associated blood stream infections. Pediatr Blood Cancer 2015;62:1859–1861. © 2015 Wiley Periodicals, Inc.

In the US, approximately 2,000 children are diagnosed with rare cancers each year, with 5-year survival ranging from 95% for children with intraocular retinoblastoma or localized germ cell tumors. During the last years, 12 clinical studies have been successfully completed in children with retinoblastoma, liver tumors, germ cell tumors, and infrequent malignancies, including therapeutic, epidemiologic, and biologic studies. Current efforts are centered in the development of large international collaborations to consolidate evidence-based definitions and risk stratifications that will support international Phase 3 clinical trials in germ cell tumors, hepatoblastoma, and other rare cancers.

BACKGROUND: New, effective chemotherapeutic agents are needed for intraocular retinoblastoma. METHODS: This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m2/day for 5 days and was adjusted to target a systemic exposure of 140 ± 20 ng/mL · hour. The vincristine dose was 0.05 mg/kg for patients 12 months of age at diagnosis. RESULTS: From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7-22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%-96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony-stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life. CONCLUSIONS: The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony-stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0-3, 3-6, 6-9, 9-12, and >12 months of age are specified. Cancer 2012. © 2012 American Cancer Society.

Background: To determine the predictors of long-term visual outcome after chemoreduction for management of intraocular retinoblastoma. Design: Retrospective case series. Participants: One hundred and forty eyes of 96 new retinoblastoma patients. Methods: The clinical records were reviewed for demographical profile, tumour characteristics, treatment methods, treatment side effects and final visual outcome. Multivariate analysis was used to evaluate factors predictive of final visual acuity. Main Outcome Measure: The clinical data were analysed for main outcome measures of good vision (visual acuity ≥6/12) or ambulatory vision (visual acuity ≥6/60). The correlation among predictor variables was determined using Pearson's product moment correlation for continuous variables, and t-test and analysis of variance test for categorical baseline variables. Results: Follow-up ranged from 2 years to 14 years (median 75 months). The final mean logarithm of minimum angle of resolution visual acuity was 0.79. Ambulatory vision (≥6/60) was achieved in 100 of 140 (71%) eyes, and vision of ≥6/12 was seen in 52 eyes (37%). Extrafoveolar tumour and greater number of tumours in the eye were the only predictors of visual acuity ≥20/40. Greater number of tumours correlated with smaller mean basal tumour diameter. The mean basal tumour diameter was 9.8 mm in eyes with multiple tumours and 12.2 mm in eyes with single tumours (P = 0.03). Conclusion: Long-term ambulatory vision (≥6/60) was achieved in the majority (71%) of retinoblastoma containing eyes not requiring enucleation after treatment with chemoreduction and adjunctive therapy. Absence of foveolar involvement and greater number of tumours were the predictor of long- term visual outcome of 6/12 or better.

Purpose: To report our experience in superselective ophthalmic artery infusion of melphalan (SOAIM) for intraocular retinoblastoma. Methods: From June 2008 to October 2010, 38 patients (18 women, 20 men; age range at first treatment, 7 months to 22 years) with 41 eyes with retinoblastoma were scheduled for SOAIM, for 17 newly diagnosed retinoblastomas Tumour, Node and Metastasis (TNM) 7th Edition 1a (n = 1), 1b (n = 1), 2a (n = 7), 2b (n = 4) and 3a (n = 4) and 24 retinoblastomas with partial remission/relapse TNM 7th Edition 1b (n = 13), 2a (n = 1) and 2b (n = 10). Eight patients (ten eyes) have been treated by SOAIM alone. Follow-up was 6–27 months in 28 patients (30 eyes). Results: Ophthalmic artery cannulation failed in two patients. Thirty-six patients underwent 140 treatments by internal (n = 112) or external (n = 28) carotid arteries. No major procedural complications occurred. Two patients have been lost to follow-up. Remaining 34 patients (37 eyes) had no metastatic disease. Four patients suffered permanent ocular complications: chorioretinal dystrophy (n = 2), ptosis (n = 1) and strabismus/exotropia (n = 1). Eight (22%) eyes in eight (24%) patients underwent enucleation: 7/16 (43%) newly diagnosed retinoblastomas and 1/22 (4.5%) retinoblastomas undergoing partial remission/relapse. For all treated eyes, Kaplan–Meier eye enucleation-free rates (K-M) were 85.4% (95% CI, 73.3–97.5%), 74.4% (95% CI, 57–91.8%) and still stable at 6, 12 months and 2 years, respectively. For eyes with partial remission/relapse, and eyes at presentation, K–M at 2 years were 95.5% (95% CI, 86.9–100%) and 45.6% (95% CI, 16.6–74.6%), respectively. Conclusion: Superselective ophthalmic artery infusion of melphalan was safe and powerful, especially following other therapies. Superselective ophthalmic artery infusion of melphalan should be added to focal therapies spectrum. In selected cases, melphalan should be combined with other chemotherapeutic agents.

Background To evaluate the occurrence of second malignant neoplasms (SMN) following chemoreduction (CRD) with carboplatin, vincristine, and etoposide (CEV) as frontline therapy in patients with retinoblastoma (RB). Prodecure We conducted a two-institution retrospective chart review of 245 patients with intraocular RB treated with six cycles of vincristine, carboplatin, and etoposide for treatment of intraocular retinoblastoma. Cumulative incidence of SMN was calculated with adjustment for the competing risk of death. Results There were 187 patients with germline retinoblastoma and 58 with non-germline disease. External beam radiotherapy was subsequently utilized in 46 (24%) of germline cases and six (10%) of non-germline cases. Mean follow-up of germline and non-germline patients was 80 and 70 months, respectively. Seven subsequent cancers were found in six patients for an overall incidence of 3% at a mean of 11 years. For germline cases, following CEV alone (n = 156), SMN were found in 4% following the RB diagnosis. We found no SMN in patients with non-germline RB. One patient developed pineoblastoma. SMN included osteosarcoma (n = 3), rhabdomyosarcoma (n = 1), orbital and conjunctival melanoma (n = 1), low-grade glioma (n = 1), and acute promyeloctic leukemia (n = 1). Five of the six patients with a second malignancy survive at mean of 46 months (range 15–71 months). Conclusions At a mean of 11 years, 4% of children with germline RB treated with CEV as frontline therapy developed SMN's. No SMN was found in non-germline patients. Concerns regarding CEV-induced second cancers should not deter clinicians from using life and vision preserving therapy in patients with retinoblastoma. Pediatr Blood Cancer 2012; 59: 121–125. © 2011 Wiley Periodicals, Inc.

Background To present the characteristics and treatment outcome of patients with intraocular retinoblastoma in a Chinese cooperative group. Procedure Between January 2005 and March 2009, 159 eyes of 133 patients with retinoblastoma were included in this retrospective study. The International Classification of Retinoblastoma (ICRB) staging system was noted for each patient. Cases with visible extraocular extension at diagnosis were excluded. The patient data were reviewed for demographic information, clinical findings, and managements. Results Of 133 cases, there were 83 (62%) male and 50 (38%) female, ranging in age from 2 months to 134 months (median, 23 months; mean, 26 months). There were 26 bilateral cases (20%). One hundred and twenty-four cases (93%) were deemed sporadic and nine cases (7%) were deemed familial. Leukocoria was the most common presenting symptom. One hundred and twenty-three eyes (77%) of 123 patients (92%) had no visual potential. Only 36 eyes (23%) of 30 patients (23%) utilized vision-preserving treatments. The ocular salvage rate was 83% (30/36) for this group. The cumulative probability of survival was 98% (Kaplan–Meier method) at 60 months follow up. Conclusions The overall survival rate of this study is in agreement with data from developed countries. In appropriate patients, systemic chemotherapy, and focal ophthalmic therapy are effective and carry little morbidity. Compared with more medically developed countries, there are still many challenges in the management of retinoblastoma in China. Early detection and doctor education should be an important future goal. Pediatr Blood Cancer 2011; 57: 1113–1116. © 2011 Wiley Periodicals, Inc.

A transplantable intraocular retinoblastoma-like tumour growing in F 344 rat eyes and tissue cultures suitable for therapeutic experiments is characterized. The tumours grew in the vitreous and infiltrated the internal layers of the retina. Feeder vessels from the retina supplied the tumours. Few and often incomplete rosettes were seen, and calcification was sparse in areas of necrosis. Stainings for glial fibrillary acidic protein, S-100 protein, neuron-specific enolase and desmin were negative. Ultrastructural analysis brought out a close correspondence between the tumour cell and the human retinoblastoma and other virus-induced retinoblastoma-like tumours. The experimental tumour cells lacked cilia, but had neurosecretory granules. Chromosome analysis showed a modal chromosome number in the triploid range, and 6 marker chromosomes were demonstrated. Flow-cytometric analysis showed a S-phase cell fraction of 42%, and chromosome stability was suggested by a tumour-cell DNA index which remained stable for more than 3 months.

The histopathological effect of photodynamic therapy (PDT) was investigated in an intraocular retinoblastoma-like tumour in vivo. Eighty-two tumours were studied by light microscopy and 8 by electron microscopy. Damage of the vascular endothelium with dilation of the organelles was evident 1 h after treatment, followed by leakage of the blood vessels, tissue hemorrhages, and vascular collapse. Histopathological examination showed an overall pattern of shrinkage of the cytoplasm and pycnosis of the nuclei in most of the tumour cells 3–5 days after treatment. The tumour recurrence often developed from the periphery of the tumours and in a few cases from small islets of viable tissue. Use of high doses of Photofrin II or light energy was associated with damage in the light irradiated area both to the conjunctiva or cornea in the form of leucocyte infiltration or ulcers, and to the retina, which often developed edema and appeared severely disorganized, with damage of the photoreceptors.

Retinoblastoma-like cells grew in colonies on the bottom of tissue culture flasks. The population doubling time was 19 h. Tumour cells from cell cultures had a 39% plating efficiency, and fresh tumour cells from intraocular tumours had a 32% plating efficiency in colony forming assays. Inoculation of 1.5 times 104 tumour cells in the vitreous of F-344 rats resulted in a 100% tumour take and regularly growing tumours with a doubling time of 3 days. The tumour take-rate was not changed in wholebody immunosuppressed animals. The tumour volume was assessed under a stereo microscope, and it was possible to divide the tumours into 4 groups according to the number of intraocular tumour cells. Tumour growth caused eye perforation in 89% of the inoculated eyes. Spontaneous tumour regression was not seen in non-perforation groups. Immunosuppression with whole-body irradiation and dense traumatic cataract had no significant effect on the growth. It is concluded that this animal retinoblastoma-like tumour is suitable for quantitative therapy studies in vivo and in vitro.

Objective: Parents must rapidly assimilate complex information when a child is diagnosed with cancer. Education correlates with the ability to process and use medical information. Graphic tools aid reasoning and communicate complex ideas with precision and efficiency. Methods: We developed a graphic tool, DePICT (Disease-specific electronic Patient Illustrated Clinical Timeline), to visually display entire retinoblastoma treatment courses from real-time clinical data. We report retrospective evaluation of the effectiveness of DePICT to communicate risk and complexity of treatment to parents. We assembled DePICT graphics from multiple children on cards representing each stage of intraocular retinoblastoma. Forty-four parents completed a 14-item questionnaire to evaluate the understanding of retinoblastoma treatment and outcomes acquired from DePICT. Results: As a proposed tool for informed consent, DePICT effectively communicated knowledge of complex medical treatment and risks, regardless of the education level. We identified multiple potential factors affecting parent comprehension of treatment complexity and risk. These include language proficiency (p=0.005) and age-related experience, as younger parents had higher education (p=0.021) but lower comprehension scores (p=0.011), regardless of first language. Conclusion: Provision of information at diagnosis concerning long-term treatment complexity helps parents of children with cancer. DePICT effectively transfers knowledge of treatments, risks, and prognosis in a manner that offsets parental educational disadvantages. Copyright © 2008 John Wiley & Sons, Ltd.

Background Retinoblastoma is the most common intraocular tumor of childhood. Vision salvage rates in advanced cases are less than ideal, and the optimal treatment for intraocular retinoblastoma has not been established. We report the results of an institutional retinoblastoma treatment trial to determine the vision salvage rates and toxicity of a regimen combining carboplatin and etoposide with focal retinal therapy. Procedure Twenty-nine patients diagnosed with retinoblastoma in 48 eyes were treated between 1992 and 2004 with at least six cycles of carboplatin and etoposide combined with focal retinal therapy. Results The response rate of eyes after six cycles of chemotherapy was 85.4%. Twenty-two eyes were enucleated, but only seven eyes received EBRT. The vision salvage rate without EBRT was 82.6% for eyes with Reese-Ellsworth (R-E) groups I–IV tumors and 20% for eyes with R-E group V tumors. The vision salvage rate without EBRT for eyes with Murphree groups A and B tumors was 77.3% but was only 26.9% for eyes with groups C and D tumors. Acute side effects were minimal. Conclusions The combination of carboplatin and etoposide with focal therapy is a well-tolerated regimen that has acceptable vision salvage rates for R-E groups I–IV and Murphree groups A and B retinoblastoma. This combination avoids the use of EBRT and the toxicity of additional chemotherapy agents. However, patients with R-E group V and Murphree groups C and D retinoblastoma have poorer outcomes and require more intensive therapy. Pediatr Blood Cancer 2008;50:567–572. © 2007 Wiley-Liss, Inc.

Background Retinoblastoma patients with RB1 germline mutations are at risk of developing second malignancies and external beam radiation therapy increases the risk. Carboplatin-containing chemotherapy regimens in conjunction with local therapies have been investigated for intraocular retinoblastoma, but the lack of data regarding the efficacy of single agent intravenous carboplatin prompted this phase II study. Procedure Twenty-five patients (43 eyes) were treated with intravenous carboplatin (18.7 mg/kg for patients

Background Chemoreduction is used for the treatment of retinoblastoma in industrialized nations; however, there are fewer data from developing countries. Before the implementation of this program, radiotherapy was used in almost all preserved eyes. Methods Retrospective evaluation from 1995 to 2001 at the Hospital Garrahan (Argentina). Carboplatin 18.7 mg/kg/day 1 and vincristine (0.05 mg/kg/day 1) were offered to patients with Reese–Ellsworth (RE) groups I–III and all unilateral cases. Etoposide (3.3 mg/kg/day 1 and 2) was added for groups IV and V. The number of cycles was tailored according to response. Results Fifty-eight patients (78 eyes) were evaluated (39 bilateral, 19 unilateral). With a median follow-up of 47 months, 40 patients had unilateral enucleation, 14 were not enucleated, and 4 had bilateral enucleation. Nineteen patients had unilateral initial enucleation. Eye preservation at 5 years was: RE groups I–III (n = 24 eyes), 0.9 (SE: 0.095) IV–V (n = 54), 0.45 (SE 0.07). Patients received a median of four cycles of chemotherapy. Acute toxicity was mild. External beam radiotherapy was avoided in 41% of eyes with groups I–III. Etoposide was avoided in 24 patients. Two patients died of metastasis. No secondary malignancy occurred. Conclusions Compared to our previous experience, eye preservation was better and even though less radiotherapy was used, it was prescribed more often than currently recommended in eyes with less advanced disease because of limited availability of sophisticated local therapy. © 2004 Wiley-Liss, Inc.

BACKGROUND: To assess the efficacy of chemotherapy (chemoreduction) plus local treatments as an alternative to external beam and enucleation for intraocular retinoblastoma. MATERIALS AND METHODS: A prospective study was performed on 21 patients with retinoblastoma treated in our institution from September 1997 to December 2000 to study the ocular outcome of those 33 eyes. RESULTS: There were 9 unilateral and 12 bilateral retinoblastoma cases. There were 12 eyes with Reese-Ellsworth group I-IV and 21 eyes with group V. Among 33 eyes, nine eyes (27%) were initially managed by enucleation. The remaining 24 eyes (73%) were initially treated with chemoreduction (maximum of six cycles of carboplatin, vincristine, etoposide) or chemothermotherapy. Among those 24 eyes, 20 were successfully treated with local treatments (thermotherapy plus cryotherapy in 16 eyes and thermotherapy plus cryotherapy plus (125)I plaque radiotherapy in 4 eyes), enucleation eventually underwent in two eyes and was proposed but refused in one child with bilateral group V retinoblastoma. With a median follow-up of 21 months, conservative management without external beam radiation was successful in all 12 eyes with group I-IV and in a total of 20/33 eyes (60%). Among the nine cases of unilateral retinoblastoma, eight were enucleated but among the 24 eyes with bilateral retinoblastoma, 19 (79%) were successfully treated with conservative therapy. CONCLUSIONS: It may be possible to eradicate viable tumor in all eyes with Reese-Ellsworth group I-IV retinoblastoma by chemoreduction followed by local treatments. Although 8 out of 21 eyes (38%) with group V retinoblastoma may be salvaged after chemoreduction and local therapies, enucleation remained the treatment of choice in those eyes with total retinal detachment and diffuse vitreous seeding.

BACKGROUND. Trilateral retinoblastoma refers to bilateral retinoblastoma associated with an intracranial primitive neuroectodermal tumor in the pineal or suprasellar region. The purpose of this study was to review patient and tumor characteristics and treatment outcome in patients with trilateral retinoblastoma and to determine whether there is a difference in presentation or outcome according to the location of the intracranial tumor. METHODS. A MEDLINE search of all English language articles pertaining to trilateral retinoblastoma published between 1977-1997 was performed. A total of 94 different cases were identified and analyzed. RESULTS. The gender was male in 39 patients (41.5%), female in 50 patients (53.2%), and unknown in 5 patients (5.3%). Family history for retinoblastoma was positive in 44 patients (46.8%), negative in 39 patients (41.5%), and unknown in 11 patients (11.7%). The median age at the time of diagnosis of retinoblastoma was 6 months. The median time interval to the development of an intracranial tumor from the time of diagnosis of retinoblastoma was 21 months. In 78 patients (83.0%) the intracranial tumor was in the pineal region and in 16 patients (17.0%) it was in the suprasellar region. The median time interval from the time of diagnosis of retinoblastoma to the development of a pineal region tumor was 24 months whereas the median time interval for the development of a suprasellar region tumor was 1 month. At 6 months after the diagnosis of intraocular tumors, 6 of 61 children with pineal region tumors and 10 of 14 patients with suprasellar region tumors had developed intracranial disease (P = 0.005). Unilateral intraocular retinoblastoma associated with intracranial tumor was more likely to occur in patients with suprasellar region tumors than pineal region tumors (P < 0.015). The median survival after the diagnosis of an intracranial tumor was 6 months regardless of the location of the intracranial tumor. For patients who received no treatment for the intracranial tumor the median survival was 1 month whereas it was 8 months for those who received treatment. Children who were asymptomatic at the time of diagnosis of the intracranial tumor had a better overall survival than those who were symptomatic (P = 0.002). CONCLUSIONS. The prognosis of children who develop trilateral retinoblastoma is dismal with current treatment strategies. Tumors of the suprasellar region present earlier than tumors of the pineal region after the diagnosis of intraocular tumors. Because patients who were asymptomatic at the time of diagnosis of intracranial disease had a better overall survival than those who were symptomatic, screening for intracranial tumors may be a valuable strategy in the management of patients with bilateral and/or hereditary retinoblastoma. [See editorial on pages 3-5, this issue].

Only a few cases of retinoblastomas in older children have been reported and the clinical diagnosis may be difficult. In case, fine-needle aspiration from an atypical retinal mass of an 11-yr-old boy was performed. The vitreous fluid was stained with Diff-Quik for an immediate cytological examination and the diagnosis of retinoblastoma was suggested. The rest of the specimen was separated into two parts. One was stained with May-Grunwald-Giemsa and the other was centrifuged, embedded in paraffin, and finally stained with hematoxylin -eosin-safran. The undifferentiated blue cells were associated with abundant necrotic debris and portions of capillaries with perivascular tumor cells around. The cytoplasm of the tumor cells was strongly stained with neuron-specific enolase antibody. The diagnosis of retinoblastoma was confirmed. The specimen of enucleation confirmed the diagnosis. In conclusion, cytological aspiration can categorically diagnose suspected intraocular tumors of older children in whom clinical and noninvasive investigations have failed to establish the diagnosis.

Purpose To report five years of conservative treatment for advanced retinoblastoma with the direct intra-arterial-ophthalmic artery infusion of Melphalan alone or Melphalan and Topotecan. Methods 75 children (82 eyes) with advanced retinoblastoma (Stage D-E/VA –VB) were entered in phase two of one center open study-approved protocol of ophthalmic artery infusion (Italian intra-arterial protocol, approved by the Ethic Commettee – University Hospital of Siena). Seven cases have been treated bilaterally. 40 eyes were first diagnosis (naive) and 42 were relapses following chemotherapy and focal therapy and/or radiotherapy. Results Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters (magic 1.5) while the children were under general anesthesia and anticoagulated. Chemotherapy (Melphalan alone or Melphalan and Topotecan) was infused into the artery over a 30-minute period (dose of 3-7 mg of Melphalan and 0.3-0.4 mg of Topotecan, according to the age and size of the globe). Local and systemic toxicity have been evaluated and documented. Conclusion 75 children (82 eyes) with advanced retinoblastoma were eligible for the intra-arterial Italian Protocol. The 65.8% of all treated eyes is in complete remission. Superselective chemotherapy delivered through the ophthalmic artery can avoid enucleation, primary radiation or abuse of systemic chemotherapy.

The presence of active vitreous seeding following state-of-the-art conservative treatment of intraocular retinoblastoma leads in the vast majority of cases to either external beam irradiation (EBR) and/or enucleation. Intravitreal chemotherapy (IVC) is theoretically the best route for delivering the highest vitreous concentration of a chemotherapeutic drug, over intravenous, periocular and ophthalmic artery chemotherapy. This makes IVC the best candidate for treatment of diffuse vitreous disease in eyes with retinoblastoma, but it has remained highly controversial, as considered an invasive procedure associated with the risk of tumor exteriorization. We retrospectively reviewed all consecutive patients with vitreous disease found eligible and then treated by intravitreal injections of melphalan. IVC was performed every 7 to 10 days up to 8 injections of Melphalan (20-30 g) per event, using a novel injection technique characterized by the prevention of vitreous reflux and sterilization of the needle track. The results appear promising in terms of safety (with no evidence of exteriorization), and efficacy with unprecedented salvage rate over 85%. Control of vitreous seeding was achieved without EBR in all cases.

Purpose To report the preliminary results of the conservative treatment of advanced retinoblastoma (Stage Va e Vb) obtained with the melphalan protocol (direct intraarterial-ophthalmic artery infusion ). Methods 33 children (35 eyes) with advanced retinoblastoma who were eligible for enucleation were entered in phase two of one center open study-approved protocol of ophthalmic artery infusion of Melphalan to avoid enucleation (Italian Melphalan protocol, approved by the Ethic Commettee – University Hospital of Siena). Two cases have been treated bilaterally. 15 eyes were first diagnosis and 18 were relapses following chemo and/or radiotherapy. In two cases has not been possible to conclude the procedure due to haemodynamic problems. Results The ophthalmic artery was successfully cannulated in 35 eyes (total, 121 procedures). In 2 attempts was impossible to successfully conclude the procedure due to hemodynamic problems. Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters (magic 1.5) while the children were under general anesthesia and anticoagulated. Melphalan was infused into the artery over a 30-minute period (dose of 3-7 mg according to the age and size of the globe). Local and systemic toxicity have been evaluated and documented. Conclusion 33 children (35 eyes) with advanced retinoblastoma (Stage Va and Vb Reese classification) were eligible for the Melphalan Italian Protocol. The 78.7% of treated eyes is in complete remission. Superselective chemotherapy delivered through the ophthalmic artery can avoid enucleation, primary radiation or abuse of systemic chemotherapy.

A retrospective analysis of 50 patients with retinoblastoma was undertaken to determine the appearance of intraocular retinoblastoma that had received external beam radiation a minimum of 10 years previously. Of the 91 tumors found in 59 eyes, 76 (84%) continued to be ophthalmoscopically visible after 10 years. The most common ophthalmoscopic appearance was a Type III regression pattern. The type of radiation regression pattern correlated with the pretreatment volume of the tumor. The largest tumors (mean, 10.0 disc diameter [dd]) became Type I regression patterns, whereas the smallest tumors (mean, 1.0 dd) completely disappeared. This represents the first long-term follow-up of the intraocular status of radiated retinoblastoma.