Background To report eye salvaging rate, visual acuity (VA), local recurrences, complications and the potential benefit of adjuvant brachytherapy after endoresection of large uveal melanomas. Methods 200 patients were included in this retrospective study. They were treated from March 1999 to December 2010 with preoperative stereotactic gamma knife radiosurgery followed by endoresection and adjuvant brachytherapy in most cases. Results A total of 200 patients were included in this study (113 male, 87 female). Mean tumour height was 9.4 mm and the largest basal diameter ranged from 6.3 to 20 mm. The median follow-up time was 32.3 months. In 13.4% the eye was retained with a VA of 20/50 or better, in 33.6% VA was ranging from 20/400 to 20/50 and 53% had a VA of less than 20/400. In almost 90% of the cases the eye was preserved at the final visit. In 15.5% additional major surgery was required. In terms of survival 15.5% of our patients developed liver metastases during follow-up and died. Local tumour recurrence was observed in 10 out of 200 patients (5%) and was mainly treated with enucleation. The use of an adjuvant ruthenium-106 plaque did not lower the recurrence or enucleation rate significantly. Conclusions Eyes with a large uveal melanoma can be preserved by stereotactic radiotherapy followed by endoresection with the chance to obtain useful vision in approximately half of the cases. Adjuvant brachytherapy has no beneficial effect except a reduction of the frequency for major revision surgery.

Retinoblastoma (RB) is the most common childhood eye cancer. The expression of trefoil factor family peptide 1 (TFF1), a small secreted peptide, has been correlated with more advanced RB stages and it might be a promising new candidate as a RB biomarker. The study presented addressed the question of if TFF1 is detectable in aqueous humor (AH) of RB patients’ eyes, providing easy accessibility as a diagnostic and/or therapy accompanying predictive biomarker. The TFF1 expression status of 15 retinoblastoma AH samples was investigated by ELISA and Western blot analyses. The results were correlated with the TFF1 expression status in the tumor of origin and compared to TFF1 expression in established corresponding primary tumor cell cultures and supernatants. Nine out of fifteen AH patient samples exhibited TFF1 expression, which correlated well with TFF1 levels of the original tumor. TFF1 expression in most of the corresponding primary cell cultures reflects the levels of the original tumor, although not all TFF1-expressing tumor cells seem to secret into the AH. Together, our findings strongly suggest TFF1 as a reliable new RB biomarker.

Background To demonstrate histopathological findings in retinoblastoma eyes enucleated after intra-arterial chemotherapy (IAC) with special emphasis on vascular toxicity and local tumour control. Methods Retrospective study with a consecutive series of 23 retinoblastoma eyes enucleated after IAC where histopathological work-up was available. Results From November 2010 to June 2019 23 eyes were enucleated after the attempt of eye salvaging therapy with IAC using melphalan. IAC was the first line treatment in nine and salvage treatment in 14 eyes. Doses of melphalan ranged from 3 to 7.5 mg, whereby a strict protocol with age-appropriate dosage was not used until 2015. The mean number of treatment cycles was 1.8. The main indications for enucleation were poor treatment response or tumour progression in 14 eyes, severe vascular complications in five eyes and a total exudative retinal detachment with amaurosis in the remaining four eyes. We found active disease in 15 eyes with an indication for adjuvant chemotherapy due to high risk factors for metastases in four eyes. To date none of these patients developed metastatic disease. Concerning vascular toxicity, we detected a central retinal artery occlusion in three eyes, severe vasculitis in another three, ischaemic outer retina atrophy and choroidal ischaemia in seven eyes with one eye developing a severe proliferative retinopathy. Conclusion IAC is a highly effective treatment option for advanced retinoblastoma, but the described potential risks should be kept in mind. These include severe vascular complications, as well as the possibility of persisting vital tumour cells fulfilling high-risk criteria for adjuvant chemotherapy.

Despite the increased risk of subsequent primary tumors (SPTs) external beam radiation (EBRT) may be the only therapeutic option to preserve a retinoblastoma eye. Due to their physical properties, proton beam therapy (PBT) offers the possibility to use the effectiveness of EBRT in tumor treatment and to decisively reduce the treatment-related morbidity. We report our experiences of PBT as rescue therapy in a retrospectively studied cohort of 15 advanced retinoblastoma eyes as final option for eye-preserving therapy. The average age at the initiation of PBT was 35 (14–97) months, mean follow-up was 22 (2–46) months. Prior to PBT, all eyes were treated with systemic chemotherapy and a mean number of 7.1 additional treatments. Indication for PBT was non-feasibility of intra-arterial chemotherapy (IAC) in 10 eyes, tumor recurrence after IAC in another 3 eyes and diffuse infiltrating retinoblastoma in 2 eyes. Six eyes (40%) were enucleated after a mean time interval of 4.8 (1–8) months. Cataract formation was the most common complication affecting 44.4% of the preserved eyes, yet 77.8% achieved a visual acuity of >20/200. Two of the 15 children treated developed metastatic disease during follow-up, resulting in a 13.3% metastasis rate. PBT is a useful treatment modality as a rescue therapy in retinoblastoma eyes with an eye-preserving rate of 60%. As patients are at lifetime risk of SPTs consistent monitoring is mandatory.

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013–2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in DICER1 was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.

Constitutional haploinsufficiency of the RB1 gene causes heritable retinoblastoma, a tumor predisposition syndrome. Patients with heritable retinoblastoma develop multiple retinoblastomas early in childhood and other extraocular tumors later in life. Constitutional pathogenic variants in RB1 are heterogeneous, and a few genotype-phenotype correlations have been described. To identify further genotype-phenotype relationships, we developed the retinoblastoma variant effect classification (REC), which considers each variant’s predicted effects on the common causal mediator, RB1 protein pRB. For validation, the RB1 variants of 287 patients were grouped according to REC. Multiple aspects of phenotypic expression were analyzed, known genotype-phenotype associations were revised, and new relationships were explored. Phenotypic expression of patients with REC-I, -II, and -III was distinct. Remarkably, the phenotype of patients with variants causing residual amounts of truncated pRB (REC-I) was more severe than patients with complete loss of RB1 (REC-II). The age of diagnosis of REC-I variants appeared to be distinct depending on truncation’s localization relative to pRB structure domains. REC classes identify genotype-phenotype relationships and, therefore, this classification framework may serve as a tool to develop tailored tumor screening programs depending on the type of RB1 variant.