Translational screening platform to evaluate chemotherapy in combination with focal therapy for retinoblastoma.

Retinoblastoma is the most common pediatric eye cancer. It is currently treated with a limited number of drugs, adapted from other pediatric cancer treatments. Drug toxicity and relapse of the disease warrant new therapeutic strategies for these young patients. In this study, we developed a robust tumoroid-based platform to test chemotherapeutic agents in combination with focal therapy (thermotherapy) - a treatment option widely used in clinical practice - in accordance with clinically relevant trial protocols. The model consists of matrix-embedded tumoroids that retain retinoblastoma features and respond to repeated chemotherapeutic drug exposure similarly to advanced clinical cases. Moreover, the screening platform includes a diode laser (810 nm, 0.3 W) to selectively heat the tumoroids, combined with an on-line system to monitor the intratumoral and surrounding temperatures. This allows the reproduction of the clinical settings of thermotherapy and combined chemothermotherapy treatments. When testing the two main drugs currently used in clinics to treat retinoblastoma in our model, we observed results similar to those clinically obtained, validating the utility of the model. This screening platform is the first system to accurately reproduce clinically relevant treatment methods and should lead to the identification of more efficient drugs to treat retinoblastoma.

The predictive capacity of in vitro preclinical models to evaluate drugs for the treatment of retinoblastoma.

Retinoblastoma is a rare childhood cancer of the eye. Of the small number of drugs are used to treat retinoblastoma, all have been repurposed from drugs developed for other conditions. In order to find drugs or drug combinations better suited to the improved treatment of retinoblastoma, reliable predictive models are required, which facilitate the challenging transition from in vitro studies to clinical trials. In this review, the research performed to date on the development of 2D and 3D in vitro models for retinoblastoma is presented. Most of this research was undertaken with a view to better biological understanding of retinoblastoma, and we discuss the potential for these models to be applied to drug screening. Future research directions for streamlined drug discovery are considered and evaluated, and many promising avenues identified.

Retinal and optic nerve relapse in retinoblastoma secondary to epiretinal and epipapillary vitreous seeds implantation documented by optical coherence tomography.

BACKGROUND: Retinal retinoblastoma growth phenotypes can be endophytic, exophytic, diffuse infiltrating or anterior diffuse. Herein, we describe a novel tumor growth pattern in two patients. MATERIAL AND METHODS: Imaging with spectral-domain optical coherence tomography (SD-OCT). RESULTS: Both cases were diagnosed with unilateral group D retinoblastoma treated with first-line or bridge intra-arterial chemotherapy (IAC). Case 1 had a new intravitreal/epiretinal relapse 3 months after brachytherapy and intravitreal chemotherapy. SD-OCT showed a disruption of the inner limiting membrane (INL) underneath a parapapillary epiretinal seed. The intravitreal/epiretinal disease completely regressed with intravitreal melphalan. Three months later, an isolated intraretinal growth was documented on SD-OCT at the site of previously INL disruption, which was treated by thermotherapy. He remained disease-free at 1-year follow-up with 0.6 visual acuity. Case 2 was seen 2 months after treatment interruption due to the COVID-19 pandemic. Fundus examination showed a massive intravitreal/epipapillary invasion completely obscuring the papilla. Salvage treatment of this seeing eye consisted of combined intra-arterial and intravitreal melphalan and topotecan injections. An infraclinical papillary regrowth 4 months later was treated with additional IAC. Six months later, enucleation was performed due to an infraclinical papillary relapse with suspicion of intralaminar invasion. Histopathology showed retrolaminar optic nerve invasion with tumor-free surgical section. The child received four cycles of adjuvant chemotherapy and remained disease-free at 1-year follow-up. CONCLUSION: Epiretinal/epipapillary vitreous seeding can be the source of a secondary intraretinal/optic nerve head relapse. SD-OCT is instrumental to follow such cases. Enucleation remains the safest option if secondary optic nerve invasion is suspected.

Conservative treatment of diffuse infiltrating retinoblastoma: optical coherence tomography-assisted diagnosis and follow-up in three consecutive cases.

BACKGROUND/AIMS: To report conservative therapy in diffuse infiltrating retinoblastoma (DIR) and describe specific optic coherence tomography (OCT) features of the tumour. METHODS: Retrospective review of all DIR cases treated conservatively between 1998 and 2012. RESULTS: Three patients (three eyes) were included, cases 1 and 3 with previous enucleation of the contralateral eye and case 2 with unilateral retinoblastoma referred after prior pars plana vitrectomy with silicone oil. Mean age at diagnosis was 7 years (range 14 months-14 years). Globe and vision preservation (Snellen visual acuity of 12.5/10) was achieved in case 3 with a recurrence-free follow-up of 33 months after first-line thermotherapy followed by salvage intra-arterial chemotherapy (IAC) plus focal treatments. Cases 1 and 2 were enucleated for progressive disease, case 1 after first-line intravenous chemotherapy (IVC) consolidated by focal therapies and salvage treatments given over 8 years of partial remission and case 2 after IAC, brachytherapy and intracameral chemotherapy. Neither showed any high-risk histopathological features, and no adjuvant chemotherapy was necessary. Both patients are alive without metastasis (mean follow-up of >10 years). Pathognomonic features of the tumour were revealed by OCT in all cases, showing infiltration of the ganglion cell layer and horizontal growth over the inner plexiform layer. Complete restoration of the retinal microanatomy was documented after retraction of the tumour following IVC in case 2 and IAC in case 3. CONCLUSION: This is the first report of successful conservative management in DIR. OCT enabled diagnosis, delimitation of the tumour margins and monitoring of the treatment response in this context.

Diagnosis and management of secondary epipapillary retinoblastoma.

BACKGROUND: Reports on retinoblastoma relapse at the optic nerve head (ONH) are anecdotal and include only treatments by external beam radiotherapy (EBRT) or enucleation. We aimed to describe such cases, termed secondary epipapillary retinoblastoma, diagnosed and monitored with the assistance of hand-held spectral domain optical coherence tomography (HHSD-OCT) and treated with intraophthalmic artery chemotherapy (IAC) and/or intravitreous chemotherapy (IViC). METHODS: A retrospective analysis of secondary epipapillary retinoblastoma cases treated conservatively. RESULTS: Four males and two females were included, diagnosed with secondary epipapillary retinoblastoma at a median time of 8.6 months (mean 24.0) from initial retinoblastoma diagnosis. HHSD-OCT was used in all cases for accurate diagnosis; in 2/6, the epipapillary relapse was detected only by means of HHSD-OCT. Treatments for secondary epipapillary retinoblastoma included IAC and IViC (n=4), IAC alone (n=1) and IViC alone (n=1). HHSD-OCT demonstrated complete epipapillary tumour regression in all cases, achieved in a median time of 1.6 months (mean 1.8). The median time from secondary epipapillary retinoblastoma resolution to last visit was 29.2 months (mean 27.5). At last visit, all eyes were tumour-free and no cases of metastasis recorded. CONCLUSIONS: Cases of retinoblastoma relapse at the ONH show common clinical features and represent specific diagnostic and therapeutic challenge; hence, we propose to consider this condition as a subset of retinoblastoma, termed secondary epipapillary retinoblastoma. HHSD-OCT is an invaluable diagnostic tool in the initial diagnosis as well as in monitoring these lesions, and IAC and IViC are efficient modalities for this clinical scenario, obviating the need for EBRT or enucleation.

Franceschetti hereditary recurrent corneal erosion.

PURPOSE: To describe new affected individuals of Franceschetti's original pedigree of hereditary recurrent erosion and to classify a unique entity called Franceschetti corneal dystrophy. DESIGN: Observational case series. METHODS: Slit-lamp examination of 10 affected individuals was conducted. Biomicroscopic examinations were supplemented by peripheral corneal biopsy in 1 affected patient with corneal haze. Tissue was processed for light and electron microscopy and immunohistochemistry was performed. DNA analysis was carried out in 12 affected and 3 nonaffected family members. RESULTS: All affected individuals suffered from severe ocular pain in the first decade of life, attributable to recurrent corneal erosions. Six adult patients developed bilateral diffuse subepithelial opacifications in the central and paracentral cornea. The remaining 4 affected individuals had clear corneas in the pain-free stage of the disorder. Histologic and immunohistochemical examination of the peripheral cornea in a single patient showed a subepithelial, avascular pannus. There was negative staining with Congo red. DNA analysis excluded mutations in the transforming growth factor beta-induced (TGFBI) gene and in the tumor-associated calcium signal transducer 2 (TACSTD2) gene. CONCLUSION: We have extended the pedigree of Franceschetti corneal dystrophy and elaborated its natural history on the basis of clinical examinations. A distinctive feature is the appearance of subepithelial opacities in adult life, accompanied by a decreased frequency of recurrent erosion attacks. Its clinical features appear to distinguish it from most other forms of dominantly inherited recurrent corneal erosion reported in the literature.

Chemotherapy for retinoblastoma.

Retinoblastoma is the most common eye cancer in children. Pilot studies of chemotherapy for intraocular retinoblastoma have been reported by several groups, using different combinations, dosages, schedules, and durations of carboplatin, etoposide, or teniposide, with or without vincristine, and with or without cyclosporine to counteract multidrug resistance. All studies of chemotherapy for intraocular retinoblastoma have included consolidation by focal therapy, with or without radiation. Chemotherapy alone reduces tumor size but does not cure retinoblastoma. Focal therapy, consisting of photocoagulation, thermotherapy, cryotherapy, or brachytherapy, is necessary to consolidate chemotherapy response.