The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.

Retinoblastoma is a non-hereditary as well as an inherited pediatric tumor of the developing retina resulting from the inactivation of both copies of the RB1 tumor suppressor gene. Familial retinoblastoma is a highly penetrant genetic disease that usually develops by carrying germline mutations that inactivate one allele of the RB1 gene, leading to multiple retinoblastomas. However, large and complete germline RB1 deletions are associated with low or no tumor risk for reasons that remain unknown. In this study, we define a minimal genomic region associated with this low penetrance. This region encompasses few genes including MED4 a subunit of the mediator complex. We further show that retinoblastoma RB1 -/- cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, therefore identifying MED4 as a survival gene in retinoblastoma. We propose that the contiguous loss of the adjacent retinoblastoma gene, MED4, explains the low penetrance in patients with large deletions that include both RB1 and MED4. Our findings also point to another synthetic lethal target in tumors with inactivated RB1 and highlight the importance of collateral damage in carcinogenesis.

Intraocular Invasion by Conjunctival Squamous Cell Carcinoma: Clinical Presentation, Histopathological Findings, and Outcome.

Introduction: Intraocular localization of conjunctival squamous cell carcinoma (SCC) is due to scleral or corneal invasion. Herein, we describe the clinical and histopathological findings in four cases of SCC complicated by intraocular invasion, and we review cases reported in the literature and their management. We retrospectively collected and analyzed clinical characteristics, histopathology, management, and follow-up data from 4 patients with conjunctival SCC complicated by intraocular invasion. We reviewed the literature and summarized cases of intraocular invasion by conjunctival SCC reported over the last 30 years. Case Presentations: Two patients presented with intraocular invasion by conjunctival SCC at diagnosis. The two others developed intraocular invasion as recurrence of conjunctival SCC, previously treated with excisional biopsy and adjuvant radiotherapy. All 4 cases had a previous history of conjunctival surgery, but no history of intraocular surgery. Three patients were managed with modified enucleation, including one that required adjuvant orbital radiotherapy. One patient required orbital exenteration. Histopathology analysis showed a well-differentiated conjunctival SCC in all cases. None developed distant localization after at least 2.5-year follow-up. Discussion/Conclusion: Intraocular invasion is a rare complication of conjunctival SCC. Appropriate treatment in a tertiary center and long-term follow-up are highly recommended.

Molecular diagnosis of retinoblastoma by circulating tumor DNA analysis.

PURPOSE: The analysis of circulating tumor DNA (ctDNA), a fraction of total cell-free DNA (cfDNA), might be of special interest in retinoblastoma patients. Because the accessibility to tumor tissue is very limited in these patients, either for histopathological diagnosis of suspicious intraocular masses (biopsies are proscribed) or for somatic RB1 studies and genetic counseling (due to current successful conservative approaches), we aim to validate the detection of ctDNA in plasma of non-hereditary retinoblastoma patients by molecular analysis of RB1 gene. EXPERIMENTAL DESIGN: In a cohort of 19 intraocular unilateral non-hereditary retinoblastoma patients for whom a plasma sample was available at diagnosis, we performed high-deep next-generation sequencing (NGS) of RB1 in cfDNA. Two different bioinformatics/statistics approaches were applied depending on whether the somatic RB1 status was available or not. RESULTS: Median plasma sample volume was 600 µL [100-1000]; median cfDNA plasma concentration was 119 [38-1980] and 27 [11-653] ng/mL at diagnosis and after complete remission, respectively. In the subgroup of patients with known somatic RB1 alterations (n = 11), seven of nine somatic mutations were detected (median allele fraction: 6.7%). In patients without identified somatic RB1 alterations (n = 8), six candidate variants were identified for seven patients. CONCLUSIONS: Despite small tumor size, blood-ocular barrier, poor ctDNA blood release and limited plasma sample volumes, we confirm that it is possible to detect ctDNA with high-deep NGS in plasma from patients with intraocular non-hereditary retinoblastoma. This may aid in diagnosis of suspicious cases, family genetic counseling or follow-up of residual intraocular disease.

Results of external beam radiotherapy for diffuse choroidal hemangiomas in Sturge-Weber syndrome.

PURPOSE: The Sturge-Weber Syndrome (SWS) is a phacomatosis which include facial nevus flammeus, glaucoma, diffuse choroidal hemangioma, and leptomeningeal hemangiomatosis. External beam radiotherapy (EBRT) using photons was used to treat retinal detachment. We investigate the anatomical and functional results in a long-term basis. METHODS: Retrospective review of SWS patients treated by EBRT (20 Gy in 10 fractions) for an exudative diffuse choroidal hemangioma. Visual acuity, B-scan tumor thickness, size of retinal detachment, intra-ocular pressure, and hypotonic treatment were collected before EBRT, 1 year after, and at the latest news. RESULTS: Twenty-five patients (26 eyes) were treated between 2001 and 2014. Retinal detachment including the macula was found among twenty-six eyes before treatment. The average follow-up time was 47 months. The mean tumor thickness was initially 4.5 mm, 2.8 mm at first year, and 2.7 mm at the last visit. The retina was reattached at the last visit for all eyes except two. The visual acuity was stable or better for 20 eyes (p = 0.02). Four patients developed mild cataract during the follow-up. CONCLUSION: EBRT using 20 Gy in 10 fractions is efficient, decreases tumor thickness, reattaches the retina, and stabilizes visual acuity. In the long term, retinal reattachment allows ocular conservation by preventing phthisis bulbi.

Retinoblastoma: Update on Current Management.

Retinoblastoma is a rare cancer in children, where in less than a century of dire mortality there has been a cure in industrialized countries. Unfortunately, mortality remains high in emerging countries. The evolution of treatment makes it possible to go further by preserving the eyeball but this must not be done at the cost of the reappearance of metastases. Herein we outline the evolution of treatment from the beginning of the 20th century until the last recent evolutions, trying to imagine what could be the future treatments. In this pathology, the ophthalmologist is a doctor who must cure his patient and enucleation is considered a failure. This situation should not lead to shizophrenic situations where to keep an eye one would take risks with the life of the child. New international classifications, international prospective multicentric studies, and the search for blood biomarkers that can predict the risk of micrometastases could allow for better stratification of patients.

Functional results after treatment of retinoblastoma.

PURPOSE: Because of the long-term complications associated with external beam radiation in retinoblastoma, alternative treatment methods have been investigated. We conducted a retrospective study to evaluate the functional results of new treatment modalities. METHODS: Thirty-seven eyes were treated without external beam irradiation in 31 patients. The median diameter of the largest tumor in each eye was 6 mm. Primary chemotherapy was used in 25 cases, chemothermotherapy was used in 32 cases, cryotherapy was used in 28 cases, iodine 125 Plaques were used in 15 cases, diode laser thermotherapy was used alone in 11 cases, and photocoagulation was performed in 5 cases. The median follow-up after diagnosis of retinoblastoma was 41 months. The visual results were evaluated at a median age of 54 months. RESULTS: The median visual acuity of the treated eyes was 20/33. Twenty-four eyes presented a visual acuity better than 20/40, 4 eyes had a visual acuity between 20/200 and 20/40, and 9 eyes had a visual acuity less than 20/200. Maculopathy was observed in 16 cases, associated with papillopathy in 1 case. A cataract was observed in 1 case and a vitreous hemorrhage was observed in another case. Twenty-one eyes did not develop any complications. No corneal dryness and very few lens changes were observed. CONCLUSION: The functional results after local treatments for retinoblastoma are very good. The most frequent complication is maculopathy, particularly when the tumor involves or is situated close to the macula.

Specific TP53 mutation pattern in radiation-induced sarcomas.

The mutagenic properties of ionizing radiation are well known, but the presence of specific mutations in human radiation-induced tumours is not established. We have studied a series of 36 secondary sarcomas arising in the irradiation field of a primary tumour following radiotherapy. The allelic status and the presence of mutations of the TP53 gene were investigated. The mutation pattern was compared with data from sporadic sarcomas recorded in the IARC TP53 somatic mutations database. A high proportion (58%) of the radiation-induced sarcomas exhibited a somatic inactivating mutation for one allele of TP53, systematically associated with a loss of the other allele. The high frequency (52%) of short deletions observed in the mutation pattern of radiation-induced sarcomas may be related to the induction of DNA breaks by ionizing radiation. The lack of hyper-reactivity of CpG dinucleotides and the presence of recurrent sites of mutation at codons 135 and 237 seem also to be specific for radiation tumorigenesis.

Chemothermotherapy in the management of retinoblastoma.

OBJECTIVE: To evaluate the results of chemothermotherapy for the treatment of retinoblastoma. DESIGN: Non-comparative interventional case series. PATIENTS: Fifty-one children (65 eyes and 103 tumors) were treated with chemothermotherapy in a single institution from January 1995 to May 1998. METHODS: Chemothermotherapy consists of a combination of transpupillary thermotherapy delivered shortly after intravenous (IV) injection of carboplatin (560 mg/m(2)). Each tumor is treated separately with a diode laser using a microscope. Laser intensity, spot size, and duration are adapted to the size of each tumor and to the clinical response. After 8 days, thermotherapy alone is repeated. This cycle is performed from one to six times, every 28 days. The treatment data and outcome are analyzed separately. MAIN OUTCOME MEASURES: Assessment of local tumor control. RESULTS: One hundred three tumors were treated in 65 eyes of 51 children. Age at diagnosis was 0 to 60 months (median, 7 months). Median tumor diameter at the time of treatment was 3.5 mm (range, 1.5-12 mm). Laser modalities were as follows: median intensity, 450 mW (range, 150-1000 mW); median spot size, 1.2 mm (range, 0.3-2.0 mm); and median number of cycles required to obtain tumor control, three. Tumor regression was obtained for 99 tumors (96.1%) after a median follow-up of 30 months (17-61 months). Seven tumors relapsed after initial control (6.8%). Salvage treatment (external beam radiation, iodine plaques, or enucleation) was necessary for a total of 11 tumors (10.7%). The only risk factor for relapse was the initial diameter of the lesion greater than 3.5 mm, whereas the other tumor characteristics or treatment variables were not significantly correlated with relapse. Ninety-seven percent of treated eyes were able to be preserved, and 92% of cases were treated without external beam radiation. CONCLUSIONS: Chemothermotherapy is an effective technique to treat small- to medium-sized retinoblastomas in children, avoiding external beam irradiation.

Familial uveal melanoma: a report on two families and a review of the literature.

PURPOSE: A total of 69 families affected by uveal melanoma have been reported in the literature. This report describes two additional families. In addition to presenting these cases, which constitute exceptions, the paper reviews the literature. MATERIAL AND METHODS: Two families, each with two affected members, were analysed in this retrospective study. The pedigree of each family has been pieced together. RESULTS: Considering the low incidence of familial uveal melanoma in the general population, it seems unlikely that inherited genetic factors are responsible for the condition; this question remains difficult to resolve. DISCUSSION: The characteristics of each family history are described and compared with the literature data. The mode of possible inheritance is discussed. Both the histopathology and anatomical location are studied, after which we discuss the body of evidence to establish whether there is an inherited cancer predisposition syndrome in patients with familial uveal melanoma. CONCLUSION: The statistical likelihood of such an uncommon tumour occurring independently in two or more family members leads us to believe that some cases of familial uveal melanoma may go unrecognized, and that reports on too few families have been published worldwide to prove the existence of a single mendelien gene. However, appropriate tissue samples, such as blood and tumour samples, should be obtained and conserved for present or future cytogenetic and molecular genetic studies.