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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.

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.

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.

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.