Publications by authors named "Francis L Munier"

142 Publications

Secondary enucleated retinoblastoma with MYCN amplification.

Ophthalmic Genet 2021 Apr 19:1-6. Epub 2021 Apr 19.

Jules-Gonin Eye Hospital, Lausanne University, Lausanne, Switzerland.

: Absence of mutation is rare in retinoblastoma and MYCN amplifications were recently identified in a subset of aggressive retinoblastomas occurring in infants. Here we describe not only the clinical phenotype of MYCN retinoblastoma at presentation, but also the tumor response to the first attempt of conservative management in this context.: Interventional retrospective case report: A 6-month-old boy was referred with right leukocoria. Examination under anesthesia revealed a group D unilateral retinoblastoma with an extensive whitish mass and total retinal detachment. Despite partial response following combined sequential intravenous and intra-arterial chemotherapy, tumor relapse in the aqueous humor occurred with posterior chamber involvement over 360°, this transiently controlled by intracameral and intravitreal melphalan injections. Eleven months post-diagnosis the eye was enucleated due to diffuse retinal recurrence invading the ciliary body and obscuring the optic nerve, associated with neovascular glaucoma. Histopathology revealed a poorly differentiated retinoblastoma with diffuse retinal invasion, extending from the superior ciliary body to the inferior equatorial choroid. There was post laminar optic nerve extension without involvement of the surgical margin. RB1 and diffuse MYCN nuclear expression were identified. FISH and SNP-array confirmed MYCN amplification. At 65 months follow-up the patient remained in good health without local recurrence or metastasis.: To the best of our knowledge, this study is the first to attempt conservative management of an MYCN retinoblastoma, although secondary enucleation could not be avoided due to highly aggressive recurrence resisting all targeted modalities of chemotherapy.
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http://dx.doi.org/10.1080/13816810.2021.1897847DOI Listing
April 2021

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

Pediatr Blood Cancer 2021 Jun 15;68(6):e28963. Epub 2021 Mar 15.

The Goldschleger eye institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1002/pbc.28963DOI Listing
June 2021

Response criteria for intraocular retinoblastoma: RB-RECIST.

Pediatr Blood Cancer 2021 May 23;68(5):e28964. Epub 2021 Feb 23.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, California, USA.

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.
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http://dx.doi.org/10.1002/pbc.28964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049511PMC
May 2021

Incidence of Retinoblastoma Has Increased: Results from 40 European Countries.

Ophthalmology 2021 Jan 26. Epub 2021 Jan 26.

International Centre for Eye Health, London School of Hygiene & Tropical Medicine, London, United Kingdom; Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel-Aviv University, Tel-Aviv, Israel.

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http://dx.doi.org/10.1016/j.ophtha.2021.01.024DOI Listing
January 2021

MR Imaging Features to Differentiate Retinoblastoma from Coats' Disease and Persistent Fetal Vasculature.

Cancers (Basel) 2020 Nov 30;12(12). Epub 2020 Nov 30.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, 1081HV Amsterdam, The Netherlands.

Retinoblastoma mimickers, or pseudoretinoblastoma, are conditions that show similarities with the pediatric cancer retinoblastoma. However, false-positive retinoblastoma diagnosis can cause mistreatment, while false-negative diagnosis can cause life-threatening treatment delay. The purpose of this study is to identify the MR imaging features that best differentiate between retinoblastoma and the most common pseudoretinoblastoma diagnoses: Coats' disease and persistent fetal vasculature (PFV). Here, six expert radiologists performed retrospective assessments (blinded for diagnosis) of MR images of patients with a final diagnosis based on histopathology or clinical follow-up. Associations between 20 predefined imaging features and diagnosis were assessed with exact tests corrected for multiple hypothesis testing. Sixty-six patients were included, of which 33 (50%) were retinoblastoma and 33 (50%) pseudoretinoblastoma patients. A larger eye size, vitreous seeding, and sharp-V-shaped retinal detachment were almost exclusively found in retinoblastoma ( < 0.001-0.022, specificity 93-97%). Features that were almost exclusively found in pseudoretinoblastoma included smaller eye size, ciliary/lens deformations, optic nerve atrophy, a central stalk between optic disc and lens, Y-shaped retinal detachment, and absence of calcifications ( < 0.001-0.022, specificity 91-100%). Additionally, three newly identified imaging features were exclusively present in pseudoretinoblastoma: intraretinal macrocysts ( < 0.001, 38% [9/24] in Coats' disease and 20% [2/10] in PFV), contrast enhancement outside the solid lesion ( < 0.001, 30% [7/23] in Coats' disease and 57% [4/7] in PFV), and enhancing subfoveal nodules (38% [9/24] in Coats' disease). An assessment strategy was proposed for MR imaging differentiation between retinoblastoma and pseudoretinoblastoma, including three newly identified differentiating MR imaging features.
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http://dx.doi.org/10.3390/cancers12123592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760210PMC
November 2020

Risk Factors for Acute Choroidal Ischemia after Intra-arterial Melphalan for Retinoblastoma: The Role of the Catheterization Approach.

Ophthalmology 2021 May 19;128(5):754-764. Epub 2020 Sep 19.

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.

Purpose: To identify risk factors for acute choroidal ischemia (ACI) after intra-arterial chemotherapy (IAC) for retinoblastoma.

Design: Retrospective cohort study.

Participants: Two hundred twenty patients (248 eyes) treated with IAC in Lausanne between November 2008 and September 2019 (665 procedures). All patients were evaluated on a monthly basis with fundus photography and fluorescein angiography before and after each IAC injection.

Methods: Acute choroidal ischemia, defined as any new choroidal ischemia clinically diagnosed within 35 days after an IAC injection, were noted. Eyes with choroidal complications diagnosed later than 35 days after the last IAC injection (n = 7) or those for which the status of the choroid was not assessable (n = 35) were excluded. Specific procedure parameters and treatment regimens were compared between the group of eyes with and without ACI.

Main Outcome Measures: Procedure-related risk factors for ACI after IAC injection and visual acuity assessment in the group of eyes with ACI.

Results: Acute choroidal ischemia developed in 35 of 206 included eyes after a mean of 2 injections. No differences were found between the two study groups regarding age at first IAC injection, disease grouping at diagnosis, previously administered treatments, number of IAC injections, drug dose, mean injection time, injection method (pulsatile vs. continuous), or concomitant intravitreal melphalan use. Treatment regimen (melphalan vs. combined melphalan plus topotecan; P < 0.05), catheterization route (internal carotid artery vs. external carotid or posterior communicating artery; P < 0.001), and catheterization type (occlusive into the ophthalmic artery [OA] vs. nonocclusive; P < 0.001) were included in multivariate analysis, and occlusive catheterization was identified as an independent risk factor for ACI (P < 0.001). In the subgroup undergoing an occlusive procedure, placement of the catheter tip into the OA distal third versus medial and proximal thirds (P = 0.04) and a mean catheter diameter-to-OA lumen ratio of 0.6 or more (P < 0.001) were correlated significantly with ACI. Complete vision loss was noted in 27% of the eyes with ACI that were old enough for visual assessment (n = 9/33), whereas 33% maintained a useful vision ranging between 0.1 and 0.8 (n = 11/33).

Conclusions: Catheterization of the OA should be attempted from an ostial position or an external carotid approach to minimize the risk of potentially vision-threatening choroidal complications.
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http://dx.doi.org/10.1016/j.ophtha.2020.09.021DOI Listing
May 2021

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries.

Br J Ophthalmol 2020 Sep 15. Epub 2020 Sep 15.

Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.

Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.

Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease.

Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316613DOI Listing
September 2020

Successful treatment of ciliary body medulloepithelioma with intraocular melphalan chemotherapy: a case report.

BMC Ophthalmol 2020 Jun 18;20(1):239. Epub 2020 Jun 18.

Department of Ophthalmology, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Avenue de France 15, 1000, Lausanne 7, Vaud, Switzerland.

Background: Intraocular medulloepithelioma is commonly treated with primary enucleation. Conservative treatment options include brachytherapy, local resection and/or cryotherapy in selected cases. We report for the first time the use of targeted chemotherapy to treat a ciliary body medulloepithelioma with aqueous and vitreous seeding.

Case Presentation: A 17-month-old boy with a diagnosis of ciliary body medulloepithelioma with concomitant seeding and neovascular glaucoma in the right eye was seen for a second opinion after parental refusal of enucleation. Examination under anesthesia showed multiple free-floating cysts in the pupillary area associated with iris neovascularization and a subluxated and notched lens. Ultrasound biomicroscopy revealed a partially cystic mass adjacent to the ciliary body between the 5 and 9 o'clock meridians as well as multiple nodules in the posterior chamber invading the anterior vitreous inferiorly. Fluorescein angiography demonstrated peripheral retinal ischemia. Left eye was unremarkable. Diagnosis of intraocular medulloepithelioma with no extraocular invasion was confirmed and conservative treatment initiated with combined intracameral and intravitreal melphalan injections given according to the previously described safety-enhanced technique. Ciliary tumor and seeding totally regressed after a total of 3 combined intracameral (total dose 8.1 μg) and intravitreal (total dose 70 μg) melphalan injections given every 7-10 days. Ischemic retina was treated with cryoablation as necessary. Three years later, ab interno trabeculotomy followed by 360° gonioscopy-assisted transluminal trabeculotomy 6 months later was performed for uncontrolled intraocular pressure despite antihypertensive drugs combined to cyclophotocoagulation and 7 intravitreal anti-VEGF injections for recurrent iris neovascularization. Cataract was removed at the same operative time. The child has remained disease- and metastasis-free at a 5-year follow-up since the last melphalan injection (25-month follow-up after the combined lensectomy-trabeculotomy) with a controlled intraocular pressure under topical quadritherapy and a best corrected Snellen visual acuity of 0.08.

Conclusions: We report for the first time complete regression of a non-infiltrating ciliary body medulloepithelioma with seeding achieved with only a small number of intracameral and intravitreal melphalan injections. Concomitant secondary neovascular glaucoma and cataract needed appropriate management to allow long-term eye and vision preservation.
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http://dx.doi.org/10.1186/s12886-020-01512-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302148PMC
June 2020

Retinal Structure in RPE65-Associated Retinal Dystrophy.

Invest Ophthalmol Vis Sci 2020 04;61(4):47

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Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals.

Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated.

Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30.

Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).
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http://dx.doi.org/10.1167/iovs.61.4.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401957PMC
April 2020

Global Retinoblastoma Presentation and Analysis by National Income Level.

JAMA Oncol 2020 05;6(5):685-695

Imam Hussein Cancer Center, Karbala, Iraq.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.

Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.

Design, Setting, And Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.

Main Outcomes And Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.

Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).

Conclusions And Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
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http://dx.doi.org/10.1001/jamaoncol.2019.6716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047856PMC
May 2020

Pars plana vitrectomy under melphalan irrigation for recurrent retinal detachment in eyes treated for retinoblastoma: a case report.

BMC Ophthalmol 2020 Jan 28;20(1):34. Epub 2020 Jan 28.

Department of ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.

Background: Tractional retinal detachment with or without secondary tear is a rare complication reported in less than 0.5% of in eyes treated for retinoblastoma. Pars plana vitrectomy (PPV) in eyes with history of retinoblastoma has been associated with a significant risk for recurrence, extraocular spread, and systemic metastases. We report here the successful management by PPV under melphalan irrigation of 2 children presenting with tractional retinal detachment after retinoblastoma therapy and scleral buckle surgery.

Case Presentation: A 7-year-old girl with a history of bilateral retinoblastoma (group D) presented with light perception best-corrected visual acuity (BCVA) and tractional retinal detachment (RD) in her left eye, 3 years after the last intra-arterial chemotherapy (IAC) injection. Moreover, she had history of left eye rhegmatogenous RD treated by scleral buckle 1 month after the last IAC and cataract surgery 12 months later. PPV associated with retinectomy, laser photocoagulation and silicone oil tamponade was performed. Silicone oil was removed 4 months later. Fifteen months after PPV, BCVA had increased to 20/32 without recurrence of RD and no evidence of tumor activity. A 7-year-old boy with a history of unilateral retinoblastoma (group D) in his left eye presented with rhegmatogenous RD 21 months after the last treatment for retinoblastoma. Scleral buckle surgery was performed, but 3 weeks later the patient presented with tractional RD associated with proliferative vitreo-retinopathy. BCVA was counting fingers. PPV associated with membrane peel, laser photocoagulation and silicone oil tamponade was performed. Silicone oil was removed after 5 months followed by cataract surgery 5 months later. Twenty months after PPV, BCVA was 20/20 and there was no sign of tumor recurrence.

Conclusions: PPV under melphalan irrigation, with retinectomy, if necessary, and silicone oil tamponade, allows anatomical and functional improvement in eyes with history of retinoblastoma and scleral buckling developing tractional RD.
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http://dx.doi.org/10.1186/s12886-020-1315-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986012PMC
January 2020

Optical coherence tomography (OCT) to image active and inactive retinoblastomas as well as retinomas.

Acta Ophthalmol 2020 Mar 26;98(2):158-165. Epub 2019 Aug 26.

Department of Ophthalmology, Amsterdam UMC, location VUMC, HV Amsterdam, The Netherlands.

Purpose: To illustrate Optical Coherence Tomography (OCT) images of active and inactive retinoblastoma (Rb) tumours.

Methods: Current observational study included patients diagnosed with retinoblastoma and retinoma who were presented at Amsterdam UMC and Jules-Gonin Eye Hospital, between November 2010 and October 2017. Patients aged between 0 and 4 years were imaged under general anaesthesia with handheld OCT in supine position. Patients older than 4 years were imaged with the conventional OCT (Heidelberg Engineering, Heidelberg Spectralis, Germany). All patients included were divided into two groups: active and inactive tumours (retinoma and regression patterns). Patients' medical records and OCT images were analysed during meetings via discussions by ophthalmologists and physicists.

Results: Twelve Dutch and 8 Swiss patients were divided into two groups: 2 patients with active tumour versus 18 patients with inactive tumour. Subsequently, inactive group could be divided in two groups, which consisted of 10 patients with retinoma and 8 patients with different regression pattern types. Of all included patients, 15 were male (75%). Median age at diagnosis was 18.0 months (range 0.19-715.2 months). A total of 12 retinoblastoma (active and inactive) and 8 retinoma foci were investigated by OCT. No distinction could be made between active and inactive tumours using only OCT.

Conclusion: Optical coherence tomography alone cannot distinguish between active and inactive Rbs. However, handheld OCT adds useful information to the established imaging techniques in the monitoring and follow-up of retinoblastoma patients. With this study, we provide an overview of OCT images of active and inactive Rbs.
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http://dx.doi.org/10.1111/aos.14214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078953PMC
March 2020

Granular type I corneal dystrophy in a large consanguineous Tunisian family with homozygous p.R124S mutation in the gene.

Ophthalmic Genet 2019 08 19;40(4):329-337. Epub 2019 Jul 19.

Department of Ophthalmology, Habib Thameur Hospital , Tunis , Tunisia.

: We report the clinical features and the mutational analysis in a large Tunisian family with granular corneal dystrophy type I (GCD1). : Thirty-three members of the Tunisian family underwent a complete ophthalmologic examination. DNA extraction and direct Sanger sequencing of the exons 4 and 12 of transforming growth factor β Induced (TGFBI) gene was performed for 42 members. For the molecular modeling of TGFBI protein, we used pGenTHREADER method to identify templates, 3D-EXPRESSO program to align sequences, MODELLER to get a homology model for the FAS1 (fasciclin-like) domains and finally NOMAD-ref web server for the energy minimization. : The diagnosis of GCD1 was clinically and genetically confirmed. Sequencing of exon 4 of TGFBI gene revealed the p.[R124S] mutation at heterozygous and homozygous states in patients with different clinical severities. Visual acuity was severely affected in the homozygous patients leading to a first penetrating keratoplasty. Recurrence occurred rapidly, began in the seat of the corneal stitches and remained superficial up to 40 years after the graft. For heterozygous cases, visual acuity ranged from 6/10 to 10/10. Corneal opacities were deeper and predominating in the stromal center. According to bioinformatic analysis, this mutation likely perturbs the protein physicochemical properties and reduces its solubility without structural modification. : Our study describes for the first time phenotype-genotype correlation in a large Tunisian family with GCDI and illustrates for the first time clinical and histopathological presentation of homozygous p.[R124S] mutation. These results help to understand pathophysiology of the disease.
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http://dx.doi.org/10.1080/13816810.2019.1639202DOI Listing
August 2019

Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans.

Front Physiol 2019 4;10:688. Epub 2019 Jun 4.

Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland.

Cataract, the loss of ocular lens transparency, accounts for ∼50% of worldwide blindness and has been associated with water and solute transport dysfunction across lens cellular barriers. We show that neutral amino acid antiporter LAT2 ) and uniporter TAT1 () are expressed on mouse ciliary epithelium and LAT2 also in lens epithelium. Correspondingly, deletion of LAT2 induced a dramatic decrease in lens essential amino acid levels that was modulated by TAT1 defect. Interestingly, the absence of LAT2 led to increased incidence of cataract in mice, in particular in older females, and a synergistic effect was observed with simultaneous lack of TAT1. Screening in patients diagnosed with congenital or age-related cataract yielded one homozygous single nucleotide deletion segregating in a family with congenital cataract. Expressed in HeLa cells, this LAT2 mutation did not support amino acid uptake. Heterozygous LAT2 variants were also found in patients with cataract some of which showed a reduced transport function when expressed in HeLa cells. Whether heterozygous LAT2 variants may contribute to the pathology of cataract needs to be further investigated. Overall, our results suggest that defects of amino acid transporter LAT2 are implicated in cataract formation, a situation that may be aggravated by TAT1 defects.
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http://dx.doi.org/10.3389/fphys.2019.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558864PMC
June 2019

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity".

Prog Retin Eye Res 2019 11 5;73:100764. Epub 2019 Jun 5.

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.
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http://dx.doi.org/10.1016/j.preteyeres.2019.05.005DOI Listing
November 2019

The utility of massively parallel sequencing for posterior polymorphous corneal dystrophy type 3 molecular diagnosis.

Exp Eye Res 2019 05 7;182:160-166. Epub 2019 Mar 7.

Research Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 128 08, Prague 2, Czech Republic; UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL, London, United Kingdom; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08, Prague, Czech Republic. Electronic address:

The aim of this study was to identify the molecular genetic cause of disease in posterior polymorphous corneal dystrophy (PPCD) probands of diverse origin and to assess the utility of massively parallel sequencing in the detection of ZEB1 mutations. We investigated a total of 12 families (five British, four Czech, one Slovak and two Swiss). Ten novel and two recurrent disease-causing mutations in ZEB1, were identified in probands by Sanger (n = 5), exome (n = 4) and genome (n = 3) sequencing. Sanger sequencing was used to confirm the mutations detected by massively parallel sequencing, and to perform segregation analysis. Genome sequencing revealed that one proband harboured a novel ∼0.34 Mb heterozygous de novo deletion spanning exons 1-7 and part of exon 8. Transcript analysis confirmed that the ZEB1 transcript is detectable in blood-derived RNA samples and that the disease-associated variant c.482-2A>G leads to aberrant pre-mRNA splicing. De novo mutations, which are a feature of PPCD3, were found in the current study with an incidence rate of at least 16.6%. In general, massively parallel sequencing is a time-efficient way to detect PPCD3-associated mutations and, importantly, genome sequencing enables the identification of full or partial heterozygous ZEB1 deletions that can evade detection by both Sanger and exome sequencing. These findings contribute to our understanding of PPCD3, for which currently, 49 pathogenic variants have been identified, all of which are predicted to be null alleles.
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http://dx.doi.org/10.1016/j.exer.2019.03.002DOI Listing
May 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

Macular Hole Complicating Familial Exudative Vitreoretinopathy Due to LRP5 Mutation in an Adolescent.

Ophthalmic Surg Lasers Imaging Retina 2019 02;50(2):e49-e51

A 17-year-old boy, previously diagnosed with familial exudative vitreoretinopathy (FEVR) due to LRP5 mutation, complained of left eye decreased vision. Serial imaging by optical coherence tomography showed vitreomacular traction that progressed to lamellar macular hole (MH), and further evolved to full-thickness MH 3 weeks later. Visual acuity (VA) was 20/200. Pars plana vitrectomy with encircling buckle, internal limiting membrane peeling, and gas tamponade were performed. Three months postoperatively, VA had increased to 20/25 and the MH remained closed. This case illustrates how vitreomacular interface disorders may complicate FEVR, as exemplified for the first time in a case with LRP5 mutation. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e49-e51.].
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http://dx.doi.org/10.3928/23258160-20190129-19DOI Listing
February 2019

Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01.

Sci Transl Med 2019 01;11(476)

Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain.

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.
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http://dx.doi.org/10.1126/scitranslmed.aat9321DOI Listing
January 2019

Middle meningeal artery occlusion for intra-arterial chemotherapy of retinoblastoma.

Interv Neuroradiol 2019 Jun 28;25(3):335-337. Epub 2018 Nov 28.

1 Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland.

We report the intentional occlusion of the middle meningeal artery arising from the lacrimal artery, a novel technique to improve drug delivery in a 14-month-old boy with a history of right sporadic unilateral cavitary retinoblastoma group D. The patient was referred to our institution for intra-arterial chemotherapy after two systemic chemotherapy treatments. The digital subtraction angiography showed a large middle meningeal artery arising from the right lacrimal artery and decrease choroidal enhancement thus decreased flow to the tumor. The ophthalmological examination after the first intra-arterial chemotherapy observed no tumor regression. Assuming a vascular steal, in the second intra-arterial chemotherapy session, the origin of the middle meningeal artery was occluded. Following this treatment, a significant response was observed at ophthalmological follow up. In the presented case, the efficacy of intra-arterial chemotherapy was improved after occlusion of a meningeal branch arising from the lacrimal artery, which was responsible for the vascular steal.
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http://dx.doi.org/10.1177/1591019918815286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547214PMC
June 2019

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR THE MANAGEMENT OF NEOVASCULARIZATION IN RETINOBLASTOMA AFTER INTRAVENOUS AND/OR INTRAARTERIAL CHEMOTHERAPY: Long-Term Outcomes in a Series of 35 Eyes.

Retina 2019 Dec;39(12):2273-2282

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.

Purpose: To report the use of anti-vascular endothelial growth factor in the management of retinoblastoma.

Methods: Retrospective review of 35 eyes (33 patients) treated with at least one intravitreal anti-vascular endothelial growth factor (ranibizumab and/or aflibercept) for new iris (n = 26) and/or retinal neovascularization (n = 21) after intravenous chemotherapy and/or intraarterial chemotherapy.

Results: Most eyes (n = 31/35, 89%) were Group D or E. Previous treatments were salvage intraarterial chemotherapy after intravenous chemotherapy (n = 21/35, 60%), first-line intraarterial chemotherapy (n = 7/35, 20%), and first-line intravenous chemotherapy (n = 7/35, 20%). Associated clinical features were retinal ischemia (94%), retinal detachment (51%), active tumor (34%), intravitreal hemorrhage (43%), and/or glaucoma (17%). Mean 1.6 anti-vascular endothelial growth factor injections/eye were given; 28 eyes received ranibizumab, 2 aflibercept, and 5 both agents. Eight eyes underwent complementary treatments of ischemic retina. Resolution of neovascularization was observed in 28 eyes (n = 28/35, 80%). Globe salvage was achieved in 51% (n = 18/35), including 25% of those with active tumor (n = 3/12). One eye became phthisic. Sixteen eyes were enucleated, nine for tumor relapse/progression. Five eyes had high-risk histopathologic risk factors and received adjuvant intravenous chemotherapy. All patients are alive with no extraocular extension nor metastases (mean follow-up 3.7 years, range 1.1-7.6).

Conclusion: Intravitreal anti-vascular endothelial growth factor contributed to a globe salvage rate of 51% by providing conditions to continue conservative treatment.
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http://dx.doi.org/10.1097/IAE.0000000000002339DOI Listing
December 2019

CRX-linked macular dystrophy with intrafamilial variable expressivity.

Ophthalmic Genet 2018 10 1;39(5):637-641. Epub 2018 Aug 1.

a Jules-Gonin Eye Hospital, Department of Ophthalmology , University of Lausanne , Lausanne , Switzerland.

Background: We present a macular dystrophy of differing severity in a single kindred caused by a heterozygous nonsense mutation in CRX.

Case Report: A 21-year-old Caucasian male from a Swiss family was investigated for decreasing central visual acuity associated with dischromatopsia. Clinical examination revealed posterior pole atrophy, including the maculopapillary bundle. Multimodal imaging, including autofluorescence, showed a hyperautofluorescent paramacular ring in both eyes. Genetic analysis identified a c.313C>T, p.Q105* nonsense mutation in CRX. The same mutation was identified in his father and uncle. Both of them showed signs of the disease, however with different severity.

Conclusion: We describe an intrafamilial variable expressivity of a CRX mutation causing an isolated macular dystrophy.
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http://dx.doi.org/10.1080/13816810.2018.1502789DOI Listing
October 2018

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

Br J Ophthalmol 2019 06 26;103(6):826-830. Epub 2018 Jul 26.

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland

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.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312546DOI Listing
June 2019

Anterior Chamber Chemotherapy in Retinoblastoma-Necessary but Not Sufficient for Aqueous Seeding Control.

JAMA Ophthalmol 2018 05;136(5):596-597

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1001/jamaophthalmol.2018.0630DOI Listing
May 2018

OCT-guided management of subclinical recurrent retinoblastoma.

Ophthalmic Genet 2018 06 9;39(3):338-343. Epub 2018 Feb 9.

a Department of Ophthalmology, University of Lausanne , Jules-Gonin Eye Hospital, Fondation Asile des Aveugles , Lausanne , Switzerland.

Purpose: Retinoblastoma (Rb) tumor recurrence in the papillary or macular region is a threat to life and visual prognosis respectively, making early detection indispensable. This study demonstrates the value of optical coherence tomography (OCT) in the early detection of subclinical tumor recurrence.

Methods: Since June 2012, hand-held SD-OCT (spectral domain Optical Coherence Tomography) of retro-equatorial foci, the optic head nerve and macula, is systematically performed under anesthesia in children treated and followed for Rb.

Results: Between June 2012 and January 2017, 16 subclinical recurrent tumors in 14 children were detected only by OCT in flat pigmented scars (n = 9), in type 2 regression (n = 3), on the optic nerve head (n = 3), and as secondary retinal seeding (n = 1).

Conclusion: OCT has become invaluable in the modern management of Rb. It allows not only early detection of a lesion before any tumor extension towards the macula or optic nerve head, but also the monitoring of the therapeutic response.
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http://dx.doi.org/10.1080/13816810.2018.1436183DOI Listing
June 2018

Cataract development in children with Coats disease: risk factors and outcome.

J AAPOS 2018 02 29;22(1):44-49. Epub 2017 Dec 29.

Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland. Electronic address:

Purpose: To describe the clinical features of cataract during the course of Coats disease and to determine its risk factors and effects on the long-term visual outcome.

Methods: The medical records of consecutive patients with Coats disease followed for at least 2 years were analyzed retrospectively. Ophthalmological examination, ancillary tests, and treatment modalities were reviewed. The time of cataract diagnosis and its management were recorded. Parameters influencing cataract development and final visual outcome were investigated using uni- and multivariate analysis.

Results: A total of 57 patients (mean age, 5.0 ± 4.0 years; 51 males) were included; cataract formation was observed in 16 (28%) during a mean follow-up of 7.1 ± 3.7 years. The mean time from diagnosis of Coats disease to cataract detection was 25 ± 22 months. Total white cataract developed in 12 patients (75%); posterior subcapsular cataract, in 4 (25%). Cataracts were surgically removed in 10 patients to improve fundus visualization and clinical follow-up. Presence of exudative retinal detachment at diagnosis was an independent risk factor for cataract formation (P = 0.031). Cataract development was associated with more advanced disease stages (P < 0.001). History of cataract was a significant predictor for worse final visual outcome (P < 0.001), independent of disease stage (P = 0.003) and presence of macular complication, such as atrophy, fibrosis, or tractional retinal detachment (P < 0.001, adjusted R = 0.83).

Conclusions: Cataract development is frequent in children with Coats disease and aggravates the visual prognosis. Exudative retinal detachment at diagnosis, present in more advanced disease stages, is an independent risk factor for cataract formation.
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http://dx.doi.org/10.1016/j.jaapos.2017.09.009DOI Listing
February 2018

Intracameral Chemotherapy for Globe Salvage in Retinoblastoma with Secondary Anterior Chamber Invasion.

Ophthalmology 2018 04 6;125(4):615-617. Epub 2017 Dec 6.

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1016/j.ophtha.2017.11.010DOI Listing
April 2018

Successful conservative treatment of massive choroidal relapse in 2 retinoblastoma patients monitored by ultrasound biomicroscopy and/or spectral domain optic coherence tomography.

Ophthalmic Genet 2018 04 3;39(2):242-246. Epub 2017 Nov 3.

a Department of Ophthalmology , University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des aveugles , Lausanne, Switzerland.

Purpose: To report the occurrence and management of secondary choroidal infiltration in two retinoblastoma (rb) patients.

Methods: Fundus examination and imaging with spectral domain optical coherence tomography (SD-OCT), B-scan ultrasonography (B-scan), and ultrasound biomicroscopy (UBM).

Results: Case 1: A 19-month-old girl with multifocal unilateral group B rb pretreated with intravenous chemotherapy (IVC) was referred for further management. At 3.5 years of age, routine 3-Tesla magnetic resonance imaging (3T-MRI) revealed an asymptomatic pinealoblastoma that underwent resection and adjuvant intensive IVC. Concomitant ophthalmic follow-up revealed a recurrence 8.3 × 2.8 mm at the posterior pole nasally to the optic disc on B-scan, localized within the choroid on SD-OCT and 3T-MRI. With high dose IVC ongoing, total regression of the choroidal mass was confirmed on SD-OCT already after 3 weeks. At 6-month follow-up, choroidal and pineal tumors were in complete remission. Sadly, the child died of intravascular disseminated coagulation-like disease after the 5th IVC. Case 2: A heavily pretreated 20-month-old girl with bilateral rb was referred for persistent vitreous seeding in her remaining eye (OD). Three months after intravitreal chemotherapy and chemothermotherapy, a hemorrhagic mass was observed inferior to the primary tumor. Two weeks later, an underlying peripheral choroidal mass 16 × 6 mm was documented by UBM and confirmed by 3T-MRI. Complete resolution was achieved 3 weeks after combined intra-arterial chemotherapy (IAC) of melphalan-topotecan. No recurrence or metastasis was observed at 34-month follow-up.

Conclusion: Isolated massive choroidal invasion can be treated conservatively with IVC or IAC in selected cases. SD-OCT, UBM, and B-scan ultrasonography are instrumental in the detection and follow-up of choroidal lesions.
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http://dx.doi.org/10.1080/13816810.2017.1393826DOI Listing
April 2018

Risk of Extraocular Extension in Eyes With Retinoblastoma Receiving Intravitreous Chemotherapy.

JAMA Ophthalmol 2017 12;135(12):1426-1429

Department of Ophthalmology, Jules-Gonin Eye Hospital, Lausanne, Switzerland

Importance: The risk of extraocular extension from injecting chemotherapy into eyes with retinoblastoma is minimally understood; however, understanding this risk is important because of the increasing use of intravitreous chemotherapy.

Objective: To evaluate the risk of extraocular extension in eyes with retinoblastoma that have received intravitreous chemotherapy injections.

Design, Setting, And Participants: This retrospective cohort study was performed in 655 patients at 10 retinoblastoma centers in North and South American, European, Israeli, and Chinese centers. Physicians at the retinoblastoma centers administered more than 120 intravitreous chemotherapy injections in eyes with retinoblastoma from February 1, 1999, through February 28, 2017.

Main Outcomes And Measures: Risk of extraocular extension with secondary observational variables, including injection and precautionary techniques.

Results: A total of 3553 intravitreous chemotherapy injections (3201 melphalan hydrochloride, 335 topotecan hydrochloride, and 17 methotrexate sodium) were administered to 704 eyes in 655 patients with retinoblastoma (mean [SD] age of patients at the time of the initial injections, 31.6 [11.6] months; 348 male [53.1%]). There were no extraocular tumor events related to prior intravitreous injections. This finding resulted in a calculated proportion of zero extraocular events per eye. According to the rule of 3, the risk is no greater than 0.08% injections. All 10 centers included in this study used at least 2 presumed precautionary injection methods (lowering of intraocular pressure, cryotherapy, ocular surface irrigation, ultrasonic biomicroscopy surveillance of the injection site, and subconjunctival chemotherapy deposition).

Conclusions And Relevance: With use of at least 2 presumed precautionary safety methods, no extraocular extension of tumor events occurred. According to the rule of 3, this finding suggests that the risk is no greater than 0.08% injections.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.4600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583521PMC
December 2017