Publications by authors named "Jonathan W Kim"

86 Publications

Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy.

Cancers (Basel) 2021 Mar 13;13(6). Epub 2021 Mar 13.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

Because direct tumor biopsy is prohibited for retinoblastoma (RB), eye-specific molecular biomarkers are not used in clinical practice for RB. Recently, we demonstrated that the aqueous humor (AH) is a rich liquid biopsy source of cell-free tumor DNA. Herein, we detail clinically-relevant molecular biomarkers from the first year of prospective validation data. Seven eyes from 6 RB patients who had AH sampled at diagnosis and throughout therapy with ≥12 months of follow-up were included. Cell-free DNA (cfDNA) from each sample was isolated and sequenced to assess genome-wide somatic copy number alterations (SCNAs), followed by targeted resequencing for pathogenic variants using a and custom hybridization panel. Tumoral genomic information was detected in 100% of diagnostic AH samples. Of the seven diagnostic AH samples, 5/7 were positive for RB SCNAs. Mutational analysis identified variants in 5/7 AH samples, including the 2 samples in which no SCNAs were detected. Two eyes failed therapy and required enucleation; both had poor prognostic biomarkers (chromosome 6p gain or amplification) present in the AH at the time of diagnosis. In the context of previously established pre-analytical, analytical, and clinical validity, this provides evidence for larger, prospective studies to further establish the clinical utility of the AH liquid biopsy and its applications to precision oncology for RB.
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http://dx.doi.org/10.3390/cancers13061282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001323PMC
March 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
May 2021

Feasibility of asynchronous video-based telemedicine in the diagnosis and management of paediatric blepharoptosis.

J Telemed Telecare 2021 Jan 20:1357633X20985394. Epub 2021 Jan 20.

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

Introduction: The purpose of this study was to assess the validity of using video glasses as part of an asynchronous telemedicine screening protocol for paediatric blepharoptosis.

Methods: A physician assistant wearing Pivothead SMART Series glasses recorded videos of paediatric patients referred for blepharoptosis in primary, down and upgaze while holding a ruler next to the eyes. An oculoplastic surgeon viewed the stored videos and recorded margin-reflex distance 1 and levator function. Using these measurements, the surgeon determined whether surgical intervention was recommended and, if so, which procedure was recommended. The surgeon recorded the same parameters for each patient based on an in-person examination performed later that day. Videos were reviewed eight months later and the same parameters were recorded.

Results: Twenty-nine children ( = 58 eyes) were enrolled. Margin-reflex distance 1 and levator function measurements based on same-day video review agreed with in-person examination 94.8% (intraclass correlation coefficient = 0.82) and 98.3% (intraclass correlation coefficient = 0.96) of the time, respectively. Margin-reflex distance 1 and levator function measurements based on later video review agreed with in-person examination 93.1% (intraclass correlation coefficient = 0.85) and 94.8% (intraclass correlation coefficient = 0.93) of the time, respectively. Agreement in identifying surgical candidates was almost perfect (= = 0.93) for same-day video review and substantial (= = 0.73) for later video review. Sensitivity of identifying surgical patients was 100% for both same-day video review and later video review; though specificity was lower at 94.1% for same-day video review and 76.5% for later video review.

Discussion: Asynchronous telemedicine encounters employing video glasses are a useful screening modality for identifying surgical paediatric blepharoptosis patients.
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http://dx.doi.org/10.1177/1357633X20985394DOI Listing
January 2021

Intravitreal Melphalan for Retinoblastoma: The Impact of Toxicity on Recurrence and Ultimate Globe Salvage.

Ocul Oncol Pathol 2020 Dec 25;6(6):388-394. Epub 2020 Aug 25.

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

Introduction: Intravitreal melphalan (IVM) has emerged as an efficacious treatment for vitreous seeding in retinoblastoma. Although rarely severe, IVM-related toxicity may be treatment limiting. There is paucity of data on the impact of IVM toxicity on new tumor formation and ultimate globe salvage.

Objectives: To investigate whether the grade of retinal toxicity post-IVM impacts retinal and seeding tumor recurrence, as well as the overall ability to salvage the eye.

Methods: A single-institution retrospective chart review was performed on 47 eyes of 42 patients who received systemic intravenous chemotherapy followed by IVM as salvage treatment for persistent or recurrent vitreous seeding. Chorioretinal toxicity was graded from 0 to 5.

Results: Toxicity grade was inversely associated with the risk of recurrence, where a one-unit increase in toxicity grade correlated with nearly a 54% reduction in the odds of tumor recurrence (OR 0.46 [0.25-0.84], = 0.01). Similarly, toxicity grade was related to enucleation, where a one-unit increase in toxicity grade was associated with a 31% reduction in the odds of undergoing enucleation (OR 0.69 [0.40-1.18], = 0.17).

Conclusions: While retinoblastoma therapy aims to limit toxicity, especially visually significant toxicity, eyes with higher grades of post-IVM toxicity are less likely to have retinal and seeding tumor recurrence.
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http://dx.doi.org/10.1159/000509080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772881PMC
December 2020

Cell-Free DNA Tumor Fraction in the Aqueous Humor Is Associated With Therapeutic Response in Retinoblastoma Patients.

Transl Vis Sci Technol 2020 09 30;9(10):30. Epub 2020 Sep 30.

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

Purpose: The aqueous humor (AH) liquid biopsy enables in vivo evaluation of tumor-derived cell-free DNA (cfDNA) from retinoblastoma (RB) eyes. Herein, we test our hypothesis that longitudinal dynamics of AH cfDNA-including tumor fraction (TFx) and somatic copy number alteration (SCNA) amplitude-correspond to therapeutic response.

Methods: Eyes with ≥3 AH extractions during intravitreal chemotherapy (IVM) or at secondary enucleation between 2015 to 2019 were included. AH cfDNA was sequenced to assess RB SCNA amplitude; ichorCNA software was used to estimate TFx. Eyes without SCNAs or with TFx < 0.10 across all samples were excluded. Therapeutic responses for each eye were determined from clinical records. Statistical analyses included Mann-Whitney U and Pearson correlation tests.

Results: Twenty eyes of 20 patients underwent ≥3 AH extractions; 6 eyes lacked SCNAs or had TFx < 0.10 throughout sampling and were excluded. Clinical progression was associated with significantly higher SCNA amplitudes and TFx values than regression ( ≤ 0.04). Relative increases in TFx (ΔTFx 1.86 ± 2.22) were associated with disease progression, whereas relative decreases in TFx (ΔTFx 0.53 ± 0.36) were associated with disease regression ( < 0.00001). A ≥15% increase in TFx relative to baseline during treatment was associated with an over 90-fold increased likelihood of clinical progression (odds ratio = 90.67, 95% confidence interval = 8.30-990.16, = 0.0002). TFx and SCNA amplitude were significantly positively correlated throughout sampling ( ≤ 0.002).

Conclusions: Longitudinal changes in AH-derived cfDNA TFx and SCNA amplitude are concordant with clinical responses of intraocular RB during active therapy.

Translational Relevance: Longitudinal evaluation of AH cfDNA may provide an objective, quantitative way to monitor therapeutic response and disease burden in RB patients.
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http://dx.doi.org/10.1167/tvst.9.10.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533735PMC
September 2020

Simultaneous identification of clinically relevant mutations and copy number alterations in aqueous humor of retinoblastoma eyes.

Ophthalmic Genet 2020 12 17;41(6):526-532. Epub 2020 Aug 17.

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

Background: Detection of germline mutations is critical for risk assessment of retinoblastoma (RB) patients. Assessment of somatic copy number alterations (SCNAs) is also critically important because of their prognostic significance. Herein we present a refined approach for the simultaneous identification of variants and SCNAs in the aqueous humor (AH) of RB eyes.

Materials And Methods: Subjects included 7 eyes of 6 RB patients that underwent AH extraction, and 4 matched tumor samples. Cell-free DNA (cfDNA) was isolated and sequenced to assess genome-wide SCNAs. The same sequencing libraries then underwent targeted resequencing and mutation detection using a custom hybridization panel that targets and . Illumina paired-end 2x150bp sequencing was used to characterize single-nucleotide variants (SNVs) and loss of heterozygosity (LOH). Results were compared to peripheral blood testing. Tumor fraction (TFx) was calculated using ichorCNA.

Results: Four of 7 AH samples contained clinically significant SCNAs. Of the 3 other samples, 1 showed focal amplification and 1 showed focal deletion. All 4 enucleated tumors contained SCNAs. Mutational analysis of tumor DNA identified all first hits (2 germline SNVs, 2 germline CNAs) and second hits (4 SNVs). variants in AH were concordant with those obtained from corresponding tumor tissue and blood. In AH samples without paired tumor, both hits were identified with high variant allele frequency, even in the absence of SCNAs.

Conclusions: AH liquid biopsy is a minimally invasive, alternative to tissue analysis for the simultaneous identification of variants and SCNAs in RB eyes.
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http://dx.doi.org/10.1080/13816810.2020.1799417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806277PMC
December 2020

Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival.

Mol Cancer Res 2020 08 20;18(8):1166-1175. Epub 2020 May 20.

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

Aqueous humor contains tumor-derived cell-free DNA (cfDNA) and can serve as a liquid biopsy for retinoblastoma. We previously associated somatic copy-number alteration (SCNA) 6p gain with a 10-fold increased risk of enucleation. Here we provide a 2-year update to further explore 6p gain as a prognostic biomarker for ocular survival. Patients diagnosed with retinoblastoma from December 2014 to July 2019 from whom aqueous humor was sampled were included. cfDNA was extracted and shallow whole-genome sequencing performed to identify highly recurrent retinoblastoma SCNAs (gain of 1q, 2p, 6p, loss of 13q, 16q). 116 aqueous humor samples from 50 eyes of 46 patients were included: 27 eyes were salvaged, 23 were enucleated. Highly recurrent retinoblastoma SCNAs were found in 66% eyes. 6p gain was the most prevalent SCNA (50% eyes). It was particularly more prevalent in enucleated eyes (73.9%) than in salvaged eyes (29.6%; = 0.004). 6p gain in aqueous humor cfDNA portended nearly 10-fold increased odds of enucleation (OR = 9.87; 95% confidence interval = 1.75-55.65; = 0.009). In the enucleated eyes, 6p gain was associated with aggressive histopathologic features, including necrosis, higher degrees of anaplasia, and focal invasion of ocular structures. With extended follow-up and nearly double the aqueous humor samples, we continue to demonstrate 6p gain as a potential prognostic biomarker for retinoblastoma. IMPLICATIONS: Aqueous humor is a high-yield source of tumor-derived DNA in retinoblastoma eyes. Detection of 6p gain in the aqueous humor allows for targeted, patient-centered therapies based on this molecular prognostic marker. Prospective, multicenter studies with aqueous humor sampled from all eyes at diagnosis are warranted to validate these findings.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415535PMC
August 2020

Variability in retinoblastoma genome stability is driven by age and not heritability.

Genes Chromosomes Cancer 2020 Oct 9;59(10):584-590. Epub 2020 Jun 9.

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

Retinoblastoma (RB) is a childhood intraocular cancer initiated by biallelic inactivation of the RB tumor suppressor gene (RB1 ). RB can be hereditary (germline RB1 pathogenic allele is present) or non-hereditary. Somatic copy number alterations (SCNAs) contribute to subsequent tumorigenesis. Previous studies of only enucleated RB eyes have reported associations between heritability status and the prevalence of SCNAs. Herein, we use an aqueous humor (AH) liquid biopsy to investigate RB genomic profiles in the context of germline RB1 status, age, and International Intraocular Retinoblastoma Classification (IIRC) clinical grouping for both enucleated and salvaged eyes. Between 2014 and 2019, AH was sampled from a total of 54 eyes of 50 patients. Germline RB1 status was determined from clinical blood testing, and cell-free DNA from AH was analyzed for SCNAs. Of the 50 patients, 23 (46.0%; 27 eyes) had hereditary RB, and 27 (54.0%, 27 eyes) had non-hereditary RB. Median age at diagnosis was comparable between hereditary (13 ± 10 months) and non-hereditary (13 ± 8 months) eyes (P = 0.818). There was no significant difference in the prevalence or number of SCNAs based on (1) hereditary status (P > 0.56) or (2) IIRC grouping (P > 0.47). There was, however, a significant correlation between patient age at diagnosis, and (1) number of total SCNAs (r[52] = 0.672, P < 0.00001) and (2) number of highly-recurrent RB SCNAs (r[52] = 0.616, P < 0.00001). This evidence does not support the theory that specific molecular or genomic subtypes exist between hereditary and non-hereditary RB; rather, the prevalence of genomic alterations in RB eyes is strongly related to patient age at diagnosis.
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http://dx.doi.org/10.1002/gcc.22859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441809PMC
October 2020

Global Retinoblastoma Presentation and Analysis by National Income Level.

Authors:
Ido Didi Fabian Elhassan Abdallah Shehu U Abdullahi Rula A Abdulqader Sahadatou Adamou Boubacar Dupe S Ademola-Popoola Adedayo Adio Armin R Afshar Priyanka Aggarwal Ada E Aghaji Alia Ahmad Marliyanti N R Akib Lamis Al Harby Mouroge H Al Ani Aygun Alakbarova Silvia Alarcón Portabella Safaa A F Al-Badri Ana Patricia A Alcasabas Saad A Al-Dahmash Amanda Alejos Ernesto Alemany-Rubio Amadou I Alfa Bio Yvania Alfonso Carreras Christiane Al-Haddad Hamoud H Y Al-Hussaini Amany M Ali Donjeta B Alia Mazin F Al-Jadiry Usama Al-Jumaily Hind M Alkatan Charlotta All-Eriksson Ali A R M Al-Mafrachi Argentino A Almeida Khalifa M Alsawidi Athar A S M Al-Shaheen Entissar H Al-Shammary Primawita O Amiruddin Romanzo Antonino Nicholas J Astbury Hatice T Atalay La-Ongsri Atchaneeyasakul Rose Atsiaya Taweevat Attaseth Than H Aung Silvia Ayala Baglan Baizakova Julia Balaguer Ruhengiz Balayeva Walentyna Balwierz Honorio Barranco Covadonga Bascaran Maja Beck Popovic Raquel Benavides Sarra Benmiloud Nissrine Bennani Guebessi Rokia C Berete Jesse L Berry Anirban Bhaduri Sunil Bhat Shelley J Biddulph Eva M Biewald Nadia Bobrova Marianna Boehme H C Boldt Maria Teresa B C Bonanomi Norbert Bornfeld Gabrielle C Bouda Hédi Bouguila Amaria Boumedane Rachel C Brennan Bénédicte G Brichard Jassada Buaboonnam Patricia Calderón-Sotelo Doris A Calle Jara Jayne E Camuglia Miriam R Cano Michael Capra Nathalie Cassoux Guilherme Castela Luis Castillo Jaume Català-Mora Guillermo L Chantada Shabana Chaudhry Sonal S Chaugule Argudit Chauhan Bhavna Chawla Violeta S Chernodrinska Faraja S Chiwanga Tsengelmaa Chuluunbat Krzysztof Cieslik Ruellyn L Cockcroft Codruta Comsa Zelia M Correa Maria G Correa Llano Timothy W Corson Kristin E Cowan-Lyn Monika Csóka Xuehao Cui Isac V Da Gama Wantanee Dangboon Anirban Das Sima Das Jacquelyn M Davanzo Alan Davidson Patrick De Potter Karina Q Delgado Hakan Demirci Laurence Desjardins Rosdali Y Diaz Coronado Helen Dimaras Andrew J Dodgshun Craig Donaldson Carla R Donato Macedo Monica D Dragomir Yi Du Magritha Du Bruyn Kemala S Edison I Wayan Eka Sutyawan Asmaa El Kettani Amal M Elbahi James E Elder Dina Elgalaly Alaa M Elhaddad Moawia M Ali Elhassan Mahmoud M Elzembely Vera A Essuman Ted Grimbert A Evina Zehra Fadoo Adriana C Fandiño Mohammad Faranoush Oluyemi Fasina Delia D P G Fernández Ana Fernández-Teijeiro Allen Foster Shahar Frenkel Ligia D Fu Soad L Fuentes-Alabi Brenda L Gallie Moira Gandiwa Juan L Garcia David García Aldana Pascale Y Gassant Jennifer A Geel Fariba Ghassemi Ana V Girón Zelalem Gizachew Marco A Goenz Aaron S Gold Maya Goldberg-Lavid Glen A Gole Nir Gomel Efren Gonzalez Graciela Gonzalez Perez Liudmira González-Rodríguez Henry N Garcia Pacheco Jaime Graells Liz Green Pernille A Gregersen Nathalia D A K Grigorovski Koffi M Guedenon D Sanjeeva Gunasekera Ahmet K Gündüz Himika Gupta Sanjiv Gupta Theodora Hadjistilianou Patrick Hamel Syed A Hamid Norhafizah Hamzah Eric D Hansen J William Harbour M Elizabeth Hartnett Murat Hasanreisoglu Sadiq Hassan Shadab Hassan Stanislava Hederova Jose Hernandez Lorelay Marie Carcamo Hernandez Laila Hessissen Diriba F Hordofa Laura C Huang G B Hubbard Marlies Hummlen Kristina Husakova Allawi N Hussein Al-Janabi Russo Ida Vesna R Ilic Vivekaraj Jairaj Irfan Jeeva Helen Jenkinson Xunda Ji Dong Hyun Jo Kenneth P Johnson William J Johnson Michael M Jones Theophile B Amani Kabesha Rolande L Kabore Swathi Kaliki Abubakar Kalinaki Mehmet Kantar Ling-Yuh Kao Tamar Kardava Rejin Kebudi Tomas Kepak Naama Keren-Froim Zohora J Khan Hussain A Khaqan Phara Khauv Wajiha J Kheir Vikas Khetan Alireza Khodabande Zaza Khotenashvili Jonathan W Kim Jeong Hun Kim Hayyam Kiratli Tero T Kivelä Artur Klett Jess Elio Kosh Komba Palet Dalia Krivaitiene Mariana Kruger Kittisak Kulvichit Mayasari W Kuntorini Alice Kyara Eva S Lachmann Carol P S Lam Geoffrey C Lam Scott A Larson Slobodanka Latinovic Kelly D Laurenti Bao Han A Le Karin Lecuona Amy A Leverant Cairui Li Ben Limbu Quah Boon Long Juan P López Robert M Lukamba Livia Lumbroso Sandra Luna-Fineman Delfitri Lutfi Lesia Lysytsia George N Magrath Amita Mahajan Abdul Rahim Majeed Erika Maka Mayuri Makan Emil K Makimbetov Chatonda Manda Nieves Martín Begue Lauren Mason John O Mason Ibrahim O Matende Miguel Materin Clarissa C D S Mattosinho Marchelo Matua Ismail Mayet Freddy B Mbumba John D McKenzie Aurora Medina-Sanson Azim Mehrvar Aemero A Mengesha Vikas Menon Gary John V D Mercado Marilyn B Mets Edoardo Midena Divyansh K C Mishra Furahini G Mndeme Ahmed A Mohamedani Mona T Mohammad Annette C Moll Margarita M Montero Rosa A Morales Claude Moreira Prithvi Mruthyunjaya Mchikirwa S Msina Gerald Msukwa Sangeeta S Mudaliar Kangwa I Muma Francis L Munier Gabriela Murgoi Timothy G Murray Kareem O Musa Asma Mushtaq Hamzah Mustak Okwen M Muyen Gita Naidu Akshay Gopinathan Nair Larisa Naumenko Paule Aïda Ndoye Roth Yetty M Nency Vladimir Neroev Hang Ngo Rosa M Nieves Marina Nikitovic Elizabeth D Nkanga Henry Nkumbe Murtuza Nuruddin Mutale Nyaywa Ghislaine Obono-Obiang Ngozi C Oguego Andrzej Olechowski Scott C N Oliver Peter Osei-Bonsu Diego Ossandon Manuel A Paez-Escamilla Halimah Pagarra Sally L Painter Vivian Paintsil Luisa Paiva Bikramjit P Pal Mahesh Shanmugam Palanivelu Ruzanna Papyan Raffaele Parrozzani Manoj Parulekar Claudia R Pascual Morales Katherine E Paton Katarzyna Pawinska-Wasikowska Jacob Pe'er Armando Peña Sanja Peric Chau T M Pham Remezo Philbert David A Plager Pavel Pochop Rodrigo A Polania Vladimir G Polyakov Manca T Pompe Jonathan J Pons Daphna Prat Vireak Prom Ignatius Purwanto Ali O Qadir Seema Qayyum Jiang Qian Ardizal Rahman Salman Rahman Jamalia Rahmat Purnima Rajkarnikar Rajesh Ramanjulu Aparna Ramasubramanian Marco A Ramirez-Ortiz Léa Raobela Riffat Rashid M Ashwin Reddy Ehud Reich Lorna A Renner David Reynders Dahiru Ribadu Mussagy M Riheia Petra Ritter-Sovinz Duangnate Rojanaporn Livia Romero Soma R Roy Raya H Saab Svetlana Saakyan Ahmed H Sabhan Mandeep S Sagoo Azza M A Said Rohit Saiju Beatriz Salas Sonsoles San Román Pacheco Gissela L Sánchez Phayvanh Sayalith Trish A Scanlan Amy C Schefler Judy Schoeman Ahad Sedaghat Stefan Seregard Rachna Seth Ankoor S Shah Shawkat A Shakoor Manoj K Sharma Sadik T Sherief Nandan G Shetye Carol L Shields Sorath Noorani Siddiqui Sidi Sidi Cheikh Sónia Silva Arun D Singh Niharika Singh Usha Singh Penny Singha Rita S Sitorus Alison H Skalet Hendrian D Soebagjo Tetyana Sorochynska Grace Ssali Andrew W Stacey Sandra E Staffieri Erin D Stahl Christina Stathopoulos Branka Stirn Kranjc David K Stones Caron Strahlendorf Maria Estela Coleoni Suarez Sadia Sultana Xiantao Sun Meryl Sundy Rosanne Superstein Eddy Supriyadi Supawan Surukrattanaskul Shigenobu Suzuki Karel Svojgr Fatoumata Sylla Gevorg Tamamyan Deborah Tan Alketa Tandili Fanny F Tarrillo Leiva Maryam Tashvighi Bekim Tateshi Edi S Tehuteru Luiz F Teixeira Kok Hoi Teh Tuyisabe Theophile Helen Toledano Doan L Trang Fousseyni Traoré Sumalin Trichaiyaporn Samuray Tuncer Harba Tyau-Tyau Ali B Umar Emel Unal Ogul E Uner Steen F Urbak Tatiana L Ushakova Rustam H Usmanov Sandra Valeina Milo van Hoefen Wijsard Adisai Varadisai Liliana Vasquez Leon O Vaughan Nevyana V Veleva-Krasteva Nishant Verma Andi A Victor Maris Viksnins Edwin G Villacís Chafla Vicktoria Vishnevskia-Dai Tushar Vora Antonio E Wachtel Werner Wackernagel Keith Waddell Patricia D Wade Amina H Wali Yi-Zhuo Wang Avery Weiss Matthew W Wilson Amelia D C Wime Atchareeya Wiwatwongwana Damrong Wiwatwongwana Charlotte Wolley Dod Phanthipha Wongwai Daoman Xiang Yishuang Xiao Jason C Yam Huasheng Yang Jenny M Yanga Muhammad A Yaqub Vera A Yarovaya Andrey A Yarovoy Huijing Ye Yacoub A Yousef Putu Yuliawati Arturo M Zapata López Ekhtelbenina Zein Chengyue Zhang Yi Zhang Junyang Zhao Xiaoyu Zheng Katsiaryna Zhilyaeva Nida Zia Othman A O Ziko Marcia Zondervan Richard Bowman

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

International Centre for Eye Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.

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

Aqueous Humor Is Superior to Blood as a Liquid Biopsy for Retinoblastoma.

Ophthalmology 2020 04 31;127(4):552-554. Epub 2019 Oct 31.

Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

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http://dx.doi.org/10.1016/j.ophtha.2019.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093221PMC
April 2020

Myopathic Blepharoptoses: A New Classification System.

Ophthalmic Plast Reconstr Surg 2019 Nov/Dec;35(6):525-534

Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of USC, Los Angeles, California, U.S.A.

Purpose: Myopathic blepharoptoses (ptoses) is a complex group of disorders. To date, no formal categorization scheme has been developed based on associated ocular and systemic findings, genetic fingerprint, treatment, and prognosis for each ptosis in this group. We report a new classification scheme for myopathic ptoses.

Methods: Literature review and classification development.

Results: A new classification scheme of myopathic ptoses includes isolated static myopathic ptosis (congenital ptosis), static myopathic ptosis associated with aberrant innervation and those associated with periocular abnormalities, and progressive myopathic ptoses that affect the levator muscle and other muscle groups in childhood and adulthood.

Conclusions: Making the distinction of myopathic ptosis type early will maximize patient outcomes by optimizing surgical and systemic management and facilitating the recruitment of subspecialists to care for patients with these challenging conditions.The authors present a comprehensive and effective myopathic ptosis classification scheme to optimize surgical management and facilitate subspecialty care.
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http://dx.doi.org/10.1097/IOP.0000000000001405DOI Listing
January 2020

Tumour size criteria for Group D and E eyes in the International Classification System for Retinoblastoma: effects on rates of globe salvage and high-risk histopathologic features.

Acta Ophthalmol 2020 Feb 17;98(1):e121-e125. Epub 2019 Aug 17.

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

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.
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http://dx.doi.org/10.1111/aos.14222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448756PMC
February 2020

Posterior Vitreous Detachment and the Associated Risk of Retinal Toxicity with Intravitreal Melphalan Treatment for Retinoblastoma.

Ocul Oncol Pathol 2019 Jun 2;5(4):238-244. Epub 2018 Nov 2.

USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

Background/aims: The presence of a posterior vitreous detachment (PVD) may play a role in the development of severe retinal toxicity following intravitreal melphalan (IVM) injection for vitreous seeding. We aimed to evaluate the incidence of PVD in retinoblastoma eyes and its association with retinal toxicity after IVM.

Methods: We reviewed 112 eyes of 81 retinoblastoma patients with B-scan images available for review from 2010 to 2017. A cohort with vitreous seeding treated with IVM was compared to a cohort that did not undergo injection. The primary outcome measure was the presence of PVD at diagnosis and after treatment. Secondary measures included IVM-associated retinal toxicity and other ocular complications.

Results: The incidence of PVD was 20% at diagnosis, and in eyes with B-scans available both at diagnosis and after treatment 18% of eyes developed a PVD over the course of therapy, more frequently after IVM ( = 0.05). Of 34 eyes receiving IVM treatment, the incidences of posterior segment toxicity and globe salvage were similar between eyes with and without PVD ( = 0.4015 and 0.52, respectively).

Conclusion: In this cohort of patients, there did not appear to be an association with the presence of PVD during IVM and the development of retinal toxicity.
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http://dx.doi.org/10.1159/000493687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615322PMC
June 2019

Changes in Retinal Thickness on OCT from Intravitreal Melphalan.

Ophthalmol Retina 2019 03 5;3(3):288-289. Epub 2018 Oct 5.

Roski Eye Institute, University of Southern California, Los Angeles, California; The Vision Center, Children's Hospital Los Angeles, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1016/j.oret.2018.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668990PMC
March 2019

Late Apical Recurrence of Choroidal Melanoma 10 Years after Successful Treatment with Brachytherapy.

Ocul Oncol Pathol 2018 Jun 22;4(4):225-229. Epub 2017 Dec 22.

University of Southern California Roski Eye Institute, Los Angeles, CA, USA.

Purpose: To describe late apical relapse of a choroidal melanoma at the site of fine needle aspiration biopsy 10 years following successful treatment with I brachytherapy.

Methods: Retrospective case report of a 78-year-old male presenting 10 years following successful I brachytherapy for a choroidal melanoma with a medium-sized nodular amelanotic tumor recurrence at the site of the prior tumor biopsy.

Results: Fundus photography and B-scan ultrasound documented the findings at presentation at our institution. The patient was followed closely for 8 weeks while information was retrieved from the treating institution. During this short period, there was significant apical tumor growth. Additionally, there was a clear clinical change compared to the last documented photos from 5 years prior at the treating institution. Enucleation was recommended. Pathological analysis confirmed the diagnosis of recurrent choroidal melanoma at the apex of the treated lesion, at the site of prior biopsy. Systemic surveillance was negative for metastatic disease.

Conclusion: Current literature suggests the majority of choroidal melanoma recurrences occur within 5 years following treatment. However, this case of recurrence 10 years after brachytherapy emphasizes the importance of life-long ophthalmic care for these patients. Additionally, this case demonstrates the possibility of a rare recurrence at a prior biopsy site.
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http://dx.doi.org/10.1159/000485131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322081PMC
June 2018

Integrated Treatment during the Intravitreal Melphalan Era: Concurrent Intravitreal Melphalan and Systemic Chemoreduction.

Ocul Oncol Pathol 2018 Nov 13;4(6):335-340. Epub 2018 Jun 13.

USC Roski Eye Institute, Los Angeles, California, USA.

Background: Intravitreal injection of melphalan (IVM) is safe and effective for the treatment of seeding in retinoblastoma. Current protocols require weekly injections during examination under anesthesia (EUA). To avoid additional anesthesia exposure for these children, IVM was initiated at the EUA concurrent with the 4th cycle of systemic chemoreduction in a series of 6 patients with persistent seeding.

Methods: A retrospective review was completed to assess treatment response compared to all patients at our center treated with IVM and systemic chemotherapy. Overall, 6 eyes of 6 patients were included; salvage therapy included systemic chemoreduction with vincristine, etoposide, and carboplatin and IVM for persistent seeding.

Results: IVM was initiated in all eyes at cycle 4 of their chemotherapy. Success in eradicating vitreous seeds was 100%; overall salvage rate was 67%. Anterior toxicity was observed in 2 out of 6 eyes and posterior toxicity in 4 out of 6 eyes.

Conclusion: The concurrent chemoreduction and IVM protocol demonstrated a similar efficacy of globe salvage while sparing children additional EUAs. However, the increased rates of observed melphalan-related toxicities for concurrent therapy are concerning. Further clinical experience is necessary to define the best initiation time and dosing schedule for IVM.
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http://dx.doi.org/10.1159/000486098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288714PMC
November 2018

Lens Dose-Response Prediction Modeling and Cataract Incidence in Patients With Retinoblastoma After Lens-Sparing or Whole-Eye Radiation Therapy.

Int J Radiat Oncol Biol Phys 2019 04 8;103(5):1143-1150. Epub 2018 Dec 8.

Department of Radiation Oncology, Keck School of Medicine of USC and Children's Hospital Los Angeles, Los Angeles, California. Electronic address:

Purpose: We retrospectively assessed the incidence of cataracts in patients with retinoblastoma (Rb) treated with either lens-sparing radiation therapy (LSRT) or whole-eye radiation therapy (WERT). A secondary aim of this study was to model the dose-response risk of cataract.

Methods And Materials: We reviewed 65 patients with Rb treated with radiation therapy (RT) at Children's Hospital, Los Angeles from 1997 to 2015. Eyes that were enucleated before RT or lacked follow-up eye examinations were excluded. All patients underwent computed tomography simulation, and mean lens dose data were collected. Follow-up ophthalmologic examinations and intraocular lens implant history were reviewed for cataracts. The primary event-free survival (EFS) outcome was cataract development. Eyes without cataracts were censored on the last date of eye examination or post-RT enucleation, if applicable. Kaplan-Meier estimates were used to compare EFS outcomes, and dose response was projected with Cox regression and logistic regression models.

Results: Sixty-one patients (94 eyes) were analyzed with a median follow-up of 51.8 months. For eyes treated with WERT, cataracts developed in 71.7% versus 35.3% for LSRT. Median EFS for WERT and LSRT were 20.8 and 67.9 months, respectively. Compared with WERT, a significant EFS benefit was demonstrated for LSRT (P < .001). Mean lens dose had a significant effect on cataracts in both Cox regression and logistic regression models (P < .01). The mean lens dose of 7 Gy was projected to have a 5-year cataract incidence of 20% and 25% with the logistic and Cox regression models, respectively.

Conclusions: We report the first clinical data demonstrating significantly improved EFS in patients with Rb treated with LSRT. Through lens dose-response modeling, we validate a mean lens dose threshold of 7 Gy to keep cataract risk below 25%. Although RT is used less often for Rb owing to advances in chemotherapy delivery options, these findings are relevant for refining lens dose constraints, particularly in children who have received radiation dose near the orbit.
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http://dx.doi.org/10.1016/j.ijrobp.2018.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667833PMC
April 2019

Atypical Retinal Pigment Epithelial Hyperplasia and Glial Proliferation Masquerading as Progressive Recurrent Retinoblastoma: A Case Report Review and Clinicopathologic Correlation.

Ocul Oncol Pathol 2018 Sep 16;4(2):116-121. Epub 2017 Sep 16.

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

Background: Recurrences of retinoblastoma tumors, particularly scar recurrences, are a common phenomenon in the management of this cancer. Consolidative treatment with laser and cryotherapy are required for local control of disease. It is known that consolidative therapy can induce retinal pigment epithelium (RPE) hyperplasia and gliosis. Herein we report extensive RPE hyperplasia and gliosis during laser therapy for a focal scar recurrence, which presented as a progressive retinal opacification mimicking active retinoblastoma.

Method: This is a retrospective case review.

Results: A 2-month-old premature male was diagnosed with sporadic bilateral retinoblastoma (International Intraocular Retinoblastoma Classification [IIRC] group B in the right eye and IIRC group A in the left eye). The patient underwent laser therapy for a focal recurrence which demonstrated a white lesion during therapy and was subsequently enucleated. While there was a focal recurrence and infiltration of the retina (seen both on optical coherence tomography and histopathologic section), the majority of the white, progressive lesion was from extensive RPE hyperplasia and gliosis secondary to laser therapy.

Conclusion: Clinicopathologic correlation of the active recurrence and adjacent gliosis is demonstrated.
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http://dx.doi.org/10.1159/000479741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167681PMC
September 2018

Extending far and wide: the role of biopsy and staging in the management of ocular surface squamous neoplasia.

Clin Exp Ophthalmol 2019 03 13;47(2):193-200. Epub 2018 Nov 13.

Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California.

Importance: Although the most recent American Joint Committee on cancer staging guidelines for ocular surface squamous neoplasia place a heightened emphasis on biopsy and histopathologic analysis, the interpretation and clinical relevance of these staging criteria are not always clear. We address limitations of using histopathologic analysis to predict clinical outcomes and suggest less-invasive assessments.

Background: To investigate the impact of histopathologic depth of invasion on outcomes for tumours with the common presentation of multiple structure involvement.

Design: Retrospective chart review at tertiary institution.

Samples: Of 41 eyes with ocular surface squamous neoplasia between 2012 and 2017, 27 tumours involving multiple ocular structures clinically were included.

Methods: Biopsied tumours were determined to be invasive beyond the basement membrane or non-invasive; non-biopsied tumours were clinically identified with unknown depth of invasion. Outcomes were compared using Fisher's exact or Student's t tests.

Main Outcome Measures: Proportion of tumours cured, recurred and/or persisting.

Results: Twelve tumours (44%) received primary excisional biopsy, 10 (37%) received chemotherapy without biopsy and 5 (19%) received chemotherapy and biopsy. Clinical diagnosis was correct in all biopsied cases. While there were no significant differences in outcomes between invasive vs non-invasive tumours or treatments, there was a trend toward larger basal diameter in recurrent tumours regardless of treatment.

Conclusions And Relevance: When ocular surface squamous neoplasia tumours with similar clinical involvement were compared, histopathologic depth of invasion was not predictive of clinical outcomes. Future staging criteria may consider the potential of largest basal dimension for more accurate prognostication.
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http://dx.doi.org/10.1111/ceo.13382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613563PMC
March 2019

Reply.

Ophthalmology 2018 09 21;125(9):e64-e65. Epub 2018 Aug 21.

The Retinoblastoma Center of Houston, Houston, Texas; Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas; Departments of Pathology and Genomic Medicine and Ophthalmology, Houston Methodist Hospital, Houston, Texas; Departments of Pathology and Laboratory Medicine and Ophthalmology, Weill Cornell Medical College, New York; Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas; Center for Cell and Gene Therapy, The Texas Children's Cancer Center, and Department of Ophthalmology, Baylor College of Medicine, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2018.03.030DOI Listing
September 2018

Lurking below: massive choroidal invasion under a calcified tumor after attempted conservative therapy for retinoblastoma.

Ophthalmic Genet 2018 10 24;39(5):653-657. Epub 2018 Aug 24.

a USC Roski Eye Institute, Department of Ophthalmology , University of Southern California , Los Angeles , CA , USA.

Background: In the conservative management of retinoblastoma, detection of tumor activity beneath large, calcified tumors presents a challenging aspect of care as local consolidation is limited in this area. Routine imaging modalities, including magnetic resonance imaging, B-scan ultrasound, and optical coherence tomography, are also limited in providing appropriate surveillance for recurrent disease.

Materials And Methods: Medical records were reviewed to evaluate patients' demographic data, ophthalmic exams, imaging studies, and histopathologic reports.

Results: Three patients (two females and one male) were diagnosed with retinoblastoma (two bilateral and one unilateral) and managed with intravenous chemotherapy and local consolidation. In all three cases, the initial tumors regressed to form large, predominantly calcified tumors. However, it was observed that there continued to be nodular recurrences on the surface of the calcium without visible clinical activity at the base of the calcified lesion. All three cases ultimately required enucleation for these active nodular recurrences and massive choroidal invasion was noted under the calcified tumor. Ophthalmic exams and imaging studies did not provide consistent indication of choroidal disease in these cases, and the extensive calcification prevented detection of active disease at the tumor base on fundoscopy.

Conclusions: Active choroidal disease at the base of large, calcified tumors cannot be ruled out with ophthalmologic examination and noninvasive imaging; suspicion of disease activity at the base should remain high for patients presenting with multiple recurrent nodules over a calcified tumor.
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http://dx.doi.org/10.1080/13816810.2018.1513535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613565PMC
October 2018

Outcomes of choroidal melanomas treated with eye physics plaques: A 25-year review.

Brachytherapy 2018 Nov - Dec;17(6):981-989. Epub 2018 Aug 3.

USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA; The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA. Electronic address:

Purpose: To review long-term outcomes of the University of Southern California Plaque Simulator (PS) software and Eye Physics (EP) plaques. We hypothesize that the PS/EP system delivers lower doses to critical ocular structures, resulting in lower rates of radiation toxicity and favorable visual outcomes compared to Collaborative Ocular Melanoma Study plaques, while maintaining adequate local tumor control.

Methods And Materials: Retrospective review of 133 patients treated for choroidal melanoma with I brachytherapy, using PS software and EP plaques, from 1990 through 2015. A dose of 85 Gy at a rate of 0.6 Gy/h was prescribed to the tumor apex (with a typical margin of 2 mm) over 7 days. Primary outcomes were local tumor recurrence, globe salvage, and metastasis. Secondary outcomes were changes in visual acuity and radiation complications.

Results: With median followup of 42 months, 5-year Kaplan-Meier estimated rates for tumor control, globe salvage, and metastatic-free survival were 98.3%, 96.4%, and 88.2%, respectively. Median doses to the macula and optic nerve were 39.9 Gy and 30.0 Gy, respectively. Forty-three percent of patients developed radiation retinopathy, and 20% developed optic neuropathy; 39% lost ≥6 Snellen lines of vision.

Conclusions: The PS/EP system is designed to improve the accuracy and conformality of the radiation dose, creating a steep dose gradient outside the melanoma to decrease radiation to surrounding ocular structures. We report favorable rates of local tumor control, globe salvage, metastases, and radiation complications when compared to the Collaborative Ocular Melanoma Study and other studies. Overall, the PS/EP system results in excellent tumor control and appears to optimize long-term visual and radiation-related outcomes after brachytherapy.
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http://dx.doi.org/10.1016/j.brachy.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613587PMC
April 2019

Genomic cfDNA Analysis of Aqueous Humor in Retinoblastoma Predicts Eye Salvage: The Surrogate Tumor Biopsy for Retinoblastoma.

Mol Cancer Res 2018 11 30;16(11):1701-1712. Epub 2018 Jul 30.

Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California.

Tumor-derived cell-free DNA (cfDNA) has biomarker potential; therefore, this study aimed to identify cfDNA in the aqueous humor (AH) of retinoblastoma eyes and correlate somatic chromosomal copy-number alterations (SCNA) with clinical outcomes, specifically eye salvage. AH was extracted via paracentesis during intravitreal injection of chemotherapy or enucleation. Shallow whole-genome sequencing was performed using isolated cfDNA to assess for highly recurrent SCNAs in retinoblastoma including gain of 1q, 2p, 6p, loss of 13q, 16q, and focal amplification. Sixty-three clinical specimens of AH from 29 eyes of 26 patients were evaluated; 13 eyes were enucleated and 16 were salvaged (e.g., saved). The presence of detectable SCNAs was 92% in enucleated eyes versus 38% in salvaged eyes ( = 0.006). Gain of chromosome 6p was the most common SCNA found in 77% of enucleated eyes, compared with 25% of salvaged eyes ( = 0.0092), and associated with a 10-fold increased odds of enucleation (OR, 10; 95% CI, 1.8-55.6). The median amplitude of 6p gain was 1.47 in enucleated versus 1.07 in salvaged eyes ( = 0.001). The presence of AH SCNAs was correlated retrospectively with eye salvage. The probability of ocular salvage was higher in eyes without detectable SCNAs in the AH ( = 0.0028), specifically 6p gain. This is the first study to correlate clinical outcomes with SCNAs in the AH from retinoblastoma eyes, as such these findings indicate that 6p gain in the aqueous humor is a potential prognostic biomarker for poor clinical response to therapy. The correlation of clinical outcomes and SCNAs in the AH identified in the current study requires prospective studies to validate these finding before SCNAs, like 6p gain, can be used to predict clinical outcomes at diagnosis. .
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214755PMC
November 2018

Iris Hypoplasia as the Presenting Sign of Retinoblastoma in a Child With a 13q Deletion.

J Pediatr Ophthalmol Strabismus 2018 Apr 23;55:e10-e13. Epub 2018 Apr 23.

Germline partial chromosomal deletions of the entire RB1 gene (13q deletions), account for 6% of the RB1 mutational spectrum. The authors report the rare case of one patient with suspected bilateral iris heterochromia who actually had iris hypoplasia (often masquerading as heterochromia) and bilateral retinoblastoma, due to 13q deletion syndrome. [J Pediatr Ophthalmol. 2018;55:e10-e13.].
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http://dx.doi.org/10.3928/01913913-20180215-02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444716PMC
April 2018

Porous orbital implant after enucleation in retinoblastoma patients: indications and complications.

Orbit 2018 Dec 20;37(6):438-443. Epub 2018 Feb 20.

a USC Roski Eye Institute , Keck School of Medicine of the University of Southern California , Los Angeles , CA , USA.

This study aims to identify risk factors associated with complications in retinoblastoma patients following primary and secondary enucleations with porous implant placement. A retrospective case-control study was performed between 2010 and 2015. Data pertaining to subjects' demographics, medical history, clinical, and pathological findings, implant characteristics and complications were collected. The analysis included 103 eyes of 101 patients age 27.8 ± 21.9 months undergoing enucleation for retinoblastoma. Postoperatively, 19/103 (18%) eyes developed exposure, extrusion, or hematoma requiring subsequent surgery. Exposure was the most common postoperative complication (12/19, 63%). Age at enucleation 24 months or younger, Hispanic ethnicity, female gender, and intravenous chemotherapy prior to enucleation were associated with increased odds of implant complications. In contrast, patients who were given intravitreal melphalan (IM), subtenons carboplatin (SC), or external beam radiation therapy (EBRT) did not demonstrate an increased risk of complications. In this cohort of retinoblastoma patients undergoing primary or secondary enucleation with porous implants, implant exposure was the most common postoperative complication. Our findings suggest that female gender, Hispanic ethnicity, age at enucleation 24 months or younger, and intravenous chemotherapy prior to enucleation may increase the risk of complications.
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http://dx.doi.org/10.1080/01676830.2018.1440605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613564PMC
December 2018

Quadruple Neoplasms following Radiation Therapy for Congenital Bilateral Retinoblastoma.

Ocul Oncol Pathol 2017 Dec 6;4(1):33-37. Epub 2017 Jul 6.

Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Purpose: The aim of this study was to describe a 34-year-old male with hereditary bilateral retinoblastoma treated with radiotherapy as a child who developed 4 distinct tumors within the radiation field.

Methods: A 34-year-old male with bilateral retinoblastoma status postradiation therapy and recurrence requiring enucleation presented with left-eye visual acuity changes. Magnetic resonance imaging demonstrated a left orbital mass and a right parasellar complex lobulated mass (right sphenoid and right cavernous sinus). Two weeks later, the patient underwent excision of the orbital mass and biopsy of an upper-lid nodule. This was followed by craniotomy for removal of the complex mass.

Results: Histology revealed 4 distinct tumors, including an undifferentiated pleomorphic sarcoma (left orbit), a radiation-induced meningioma (right sphenoid), a schwannoma (right cavernous sinus), and a basal-cell carcinoma (left lid).

Conclusion: Although occurrence of a second neoplasm is a well-known outcome following radiation treatment in patients with hereditary retinoblastoma, the diagnosis of 4 additional neoplasms is rare. Pleomorphic sarcoma, radiation-induced meningioma, and schwannoma are uncommon tumors and not well represented in the literature describing irradiated retinoblastoma patients. Secondary malignancies are a leading cause of early death in retinoblastoma survivors, and long-term follow-up is crucial for patient care.
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http://dx.doi.org/10.1159/000477410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757554PMC
December 2017

Optic Nerve Obscuration in Retinoblastoma: A Risk Factor for Optic Nerve Invasion?

Ocul Oncol Pathol 2017 Nov 7;3(4):283-291. Epub 2017 Apr 7.

USC Roski Eye Institute, Keck Medical School of the University of Southern California, California, USA.

Background: The objective of this study is to evaluate the risk of optic nerve invasion associated with optic nerve obscuration at diagnosis or persisting during treatment.

Methods: Retrospective review from 2011-2016 of patients with advanced retinoblastoma (Group D/E) with complete obscuration of the nerve at diagnosis and a second group of patients with persistent, complete obscuration throughout treatment.

Results: Advanced retinoblastoma was diagnosed in 102 eyes of 86 patients. The optic nerve was obscured in 69 eyes (68%) at diagnosis. Of these, 30 (43%) underwent salvage therapy and 39 (57%) primary enucleation. Histopathologic analysis of primarily enucleated eyes showed 41% prelaminar and 15% postlaminar invasion. Four eyes in the salvage group demonstrated persistent nerve obscuration; 2 were subsequently enucleated without evidence of nerve invasion. Average follow-up was 23.5 months (range 1-62 months).

Conclusions And Relevance: Optic nerve obscuration at diagnosis may be associated with postlaminar optic nerve invasion. While persistent, complete obscuration of the optic nerve by retinoblastoma during treatment is a poor prognostic sign for both globe salvage and vision, it does not appear, in this small cohort, to increase the risk of optic nerve invasion. With appropriate control of the intraocular tumor, these eyes can be salvaged.
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http://dx.doi.org/10.1159/000464468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757559PMC
November 2017