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1. Differentiating MYCN-amplified RB1 wild-type retinoblastoma from biallelic RB1 mutant retinoblastoma using MR-based radiomics: a retrospective multicenter case–control study

Author: Christiaan M. de Bloeme, Robin W. Jansen, Liesbeth Cardoen, Sophia Göricke, Sabien van Elst, Jaime Lyn Jessen, Aparna Ramasubramanian, Alison H. Skalet, Audra K. Miller, Philippe Maeder, Ogul E. Uner, G. Baker Hubbard, Hans Grossniklaus, H. Culver Boldt, Kim E. Nichols, Rachel C. Brennan, Saugata Sen, Mériam Koob, Selma Sirin, Hervé J. Brisse, Paolo Galluzzi, Charlotte J. Dommering, Matthijs Cysouw, Ronald Boellaard, Josephine C. Dorsman, Annette C. Moll, Marcus C. de Jong, Pim de Graaf, and European Retinoblastoma Imaging Collaboration
Subjects: Retinoblastoma, MRI, radiomics, MYCN-amplification, Medicine, Science
Abstract: Abstract MYCN-amplified RB1 wild-type (MYCN amp RB1 +/+) retinoblastoma is a rare and aggressive subtype, often resistant to standard therapies. Identifying unique MRI features is crucial for diagnosing this subtype, as biopsy is not recommended. This study aimed to differentiate MYCN amp RB1 +/+ from the most prevalent RB1 -/- retinoblastoma using pretreatment MRI and radiomics. Ninety-eight unilateral retinoblastoma patients (19 MYCN cases and 79 matched controls) were included. Tumors on T2-weighted MR images were manually delineated and validated by experienced radiologists. Radiomics analysis extracted 120 features per tumor. Several combinations of feature selection methods, oversampling techniques and machine learning (ML) classifiers were evaluated in a repeated fivefold cross-validation machine learning pipeline to yield the best-performing prediction model for MYCN. The best model used univariate feature selection, data oversampling (duplicating MYCN cases), and logistic regression classifier, achieving a mean AUC of 0.78 (SD 0.12). SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCN amp RB1 +/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCN amp RB1 +/+ and RB1 -/- retinoblastoma subtypes.
Published: 2024
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2. Retinoblastoma with and without Extraocular Tumor Extension

Author: Swathi Kaliki, MD, Vijitha S. Vempuluru, MD, Ido Didi Fabian, MD, Elhassan Abdallah, MD, Shehu U. Abdullahi, MD, Rula A. Abdulqader, MD, Aminatu A. Abdulrahaman, MD, Sherif Abouelnaga, MD, Dupe S. Ademola-Popoola, FMCOph, FWACS, Adedayo Adio, FWACS, Mahmoud A. Afifi, MD, Armin R. Afshar, MD, Priyanka Aggarwal, MD, Ada E. Aghaji, FMCOph MSc, Alia Ahmad, MRCPCH UK, Marliyanti N.R. Akib, MD, Adeseye M. Akinsete, MBBS, Lamis Al Harby, MD, Saleh A. Al Mesfer, MD, Mouroge H. Al Ani, MD, Silvia Alarcón Portabella, MD, Safaa A.F. Al-Badri, MD, Ana Patricia A. Alcasabas, MD, Saad A. Al-Dahmash, MD, Amanda Alejos, MD, Ernesto Alemany-Rubio, MD, Amadou I. Alfa Bio, MD, Yvania Alfonso Carreras, MD, Christiane E. Al-Haddad, MD, Hamoud H.Y. Al-Hussaini, MD, MSc, Amany M. Ali, MD, Donjeta B. Alia, MD, Mazin F. Al-Jadiry, MD, Usama Al-Jumaly, MD, Hind M. Alkatan, MD, Charlotta All-Eriksson, MD, PhD, Ali A.R.M. Al-Mafrachi, FIBMS, Argentino A. Almeida, MD, Khalifa M. Alsawidi, MD, Athar A.S.M. Al-Shaheen, MD, Entissar H. Al-Shammary, MD, Doreen Amankwaa-Frempong, MBChB, Primawita O. Amiruddin, MD, Inggar Armytasari, MD, Nicholas J. Astbury, FRCS, FRCOphth, Hatice T. Atalay, MD, Eda Ataseven, MD, La-ongsri Atchaneeyasakul, MD, Rose Atsiaya, OCO, Rudolf Autrata, MD, PhD, Julia Balaguer, MD, PhD, Ruhengiz Balayeva, PhD, Honorio Barranco, MD, PhD, Paulina Bartoszek, MD, Katarina Bartuma, MD, PhD, Covadonga Bascaran, MD, MSc, Nikolaos E. Bechrakis, MD, Maja Beck Popovic, MD, Ainura S. Begimkulova, MD, Sarra Benmiloud, MD, Rokia C. Berete, MD, PhD, Jesse L. Berry, MD, Anirban Bhaduri, MD, Sunil Bhat, MBBS, MD, Arpita Bhattacharyya, MD, Eva M. Biewald, MD, Elaine Binkley, MD, Sharon Blum, MD, Nadia Bobrova, MD, H. Culver Boldt, MD, Maria Teresa B.C. Bonanomi, MD, PhD, Gabrielle C. Bouda, MD, Hédi Bouguila, MD, PhD, Rachel C. Brennan, MD, Bénédicte G. Brichard, MD, PhD, Jassada Buaboonnam, MD, Aléine Budiongo, MD, Matthew Burton, FRCOphth, Patricia Calderón-Sotelo, MD, Doris A. Calle Jara, MD, Jayne E. Camuglia, FRANZCO, Miriam R. Cano, MD, MSc, Michael Capra, FRCPI, Shani Caspi, MD, Nathalie Cassoux, MD, PhD, Guilherme Castela, MD, Luis Castillo, MD, Jaume Català-Mora, MD, PhD, Isabel Caviedes, MD, Arthika Chandramohan, MD, Guillermo L. Chantada, MD, PhD, Shabana Chaudhry, MD, Bhavna Chawla, MD, Wensi Chen, MD, Faraja S. Chiwanga, MSc, Tsengelmaa Chuluunbat, MD, PhD, Krzysztof Cieslik, MD, Antony Clark, FRANZCO, Ruellyn L. Cockcroft, MB ChB , M Med Paed, Codruta Comsa, MD, Maria G. Correa Llano, MD, Timothy W. Corson, PhD, Line Couitchere, MD, Kristin E. Cowan-Lyn, MD, MBBS, Monika Csóka, MD, PhD, Wantanee Dangboon, MD, Anirban Das, MD, Pranab Das, MD, Sima Das, MS, Jacquelyn M. Davanzo, BSN, BSPH, Alan Davidson, MBChB, MPhil, Sonia De Francesco, MD, Patrick De Potter, MD, PhD, Karina Q. Delgado, MD, PhD, Hakan Demirci, MD, Laurence Desjardins, MD, Rosdali Y. Diaz Coronado, MD, Helen Dimaras, PhD, Andrew J. Dodgshun, M Phil, Carla R. Donato Macedo, MD, Monica D. Dragomir, MD, PhD, Yi Du, MD, Magritha Du Bruyn, MD, Johannes P. Du Plessis, MMed (Paed), Gagan Dudeja, MBBS, MS, Katrin Eerme, MD, I Wayan Eka Sutyawan, MD, Asmaa El Kettani, MD, Amal M. Elbahi, MD, James E. Elder, MBBS, Alaa M. Elhaddad, MD, PhD, Moawia M.A. Elhassan, MD, Mahmoud M. Elzembely, MD, Connor Ericksen, MD, Vera A. Essuman, FWACS, Ted Grimbert A. Evina, MD, Ifeoma R. Ezegwui, FMCOph, FWACS, FAEH, Zehra Fadoo, MBBS, Adriana C. Fandiño, MD, Mohammad Faranoush, MD, Oluyemi Fasina, FWACS, Delia D.P.G. Fernández, MSc, Ana Fernández-Teijeiro, MD, PhD, Allen Foster, FRCOphth, Shahar Frenkel, MD, PhD, Ligia D. Fu, MD, Soad L. Fuentes-Alabi, MD, MPH, Juan L. Garcia, MSc, David García Aldana, MD, Henry N. Garcia Pacheco, MD, Jennifer A. Geel, MBChB, MMed, Fariba Ghassemi, MD, Ana V. Girón, MD, Marco A. Goenz, MD, Aaron S. Gold, OD, Hila Golberg, MD, Glen A. Gole, MD, FRANZCO, Nir Gomel, MD, Efren Gonzalez, MD, Graciela Gonzalez Perez, MD, Liudmira González-Rodríguez, MD, Malka Gorfine, PhD, Jaime Graells, MD, Pernille A. Gregersen, MD, Nathalia D.A.K. Grigorovski, MD, Koffi M. Guedenon, MD, D Sanjeeva Gunasekera, MD, Ahmet K. Gündüz, MD, Himika Gupta, MD, Sanjiv Gupta, MS, Vineeta Gupta, MD, Theodora Hadjistilianou, MD, Patrick Hamel, MD, Syed A. Hamid, FCPS, Norhafizah Hamzah, MSc, Eric D. Hansen, MD, J William Harbour, MD, M. Elizabeth Hartnett, MD, Murat Hasanreisoglu, MD, Sadiq Hassan, MD, FWACS, Shadab Hassan, FRCS, FCPS, Wojciech Hautz, MD, Huda A. Haydar, CHD, Stanislava Hederova, MD, Laila Hessissen, MD, Hoby Lalaina, MD, Suradej Hongeng, MD, Diriba F. Hordofa, MD, G. Baker Hubbard, MD, Marlies Hummlen, MD, Kristina Husakova, MD, Allawi N. Hussein Al-Janabi, MD, Affiong A. Ibanga, MB.BCh, FMCOph, Russo Ida, MD, Vesna R. Ilic, MD, Ziyavuddin Islamov, MD, Vivekaraj Jairaj, DNB, Teyyeb A. Janjua, MD, FCPS, FRCSEd, Irfan Jeeva, FRCOphth, Xunda Ji, MD, Dong Hyun Jo, MD, PhD, Michael M. Jones, MD, PhD, FRANZCO, Theophile B. Amani Kabesha, MD, PhD, Rolande L. Kabore, MD, Abubakar Kalinaki, MD, Pius Kamsang, MD, Mehmet Kantar, MD, Noa Kapelushnik, MD, Tamar Kardava, PhD, Rejin Kebudi, MD, Jonny Keomisy, MD, Tomas Kepak, MD, Petra Ketteler, MD, Zohora J. Khan, MD, Hussain A. Khaqan, MD, Vikas Khetan, FRCS, FACS, Alireza Khodabande, MD, Zaza Khotenashvili, MD, Jonathan W. Kim, MD, Jeong Hun Kim, MD, PhD, Hayyam Kiratli, MD, Tero T. Kivelä, MD, Artur Klett, MD, PhD, Irem Koç, MD, Jess Elio Kosh Komba Palet, MD, Dalia Krivaitiene, MD, PhD, Mariana Kruger, Mmed Paed, PhD, Kittisak Kulvichit, MD, Mayasari W. Kuntorini, MD, Alice Kyara, BA, Geoffrey C. Lam, FRANZCO, Scott A. Larson, MD, Slobodanka Latinović, MD, PhD, Kelly D. Laurenti, MD, Yotam Lavi, MD, PhD, Alenka Lavric Groznik, MD, Amy A. Leverant, MD, Cairui Li, MD, Kaijun Li, MD, Ben Limbu, MD, Chun-Hsiu Liu, MD, Quah Boon Long, FRCS (Ed), MMed ( Ophth), FAMS, Juan P. López, MD, Robert M. Lukamba, MD, Sandra Luna-Fineman, MD, Delfitri Lutfi, MD, Lesia Lysytsia, MD, Shiran Madgar, MD, George N. Magrath, MD, Amita Mahajan, MD, Puja Maitra, MD, Erika Maka, MD, Emil K. Makimbetov, MD, Azza M.Y. Maktabi, MD, Carlos Maldonado, MD, Ashwin Mallipatna, MD, Rebecca Manudhane, MD, Lyazat Manzhuova, MD, Nieves Martín Begue, MD, PhD, Sidra Masud, MBBS, Ibrahim O. Matende, MD, M. Med (Oph), Clarissa C.D.S. Mattosinho, MD, Marchelo Matua, BAPH, Ismail Mayet, MD, Freddy B. Mbumba, MD, MMed Paed, John D. McKenzie, MD, Azim Mehrvar, MD, Aemero A. Mengesha, MD, Vikas Menon, MD, Gary John V.D.D. Mercado, MD, Marilyn B. Mets, MD, Edoardo Midena, MD, PhD, Audra Miller, MD, Divyansh K.C. Mishra, DNB, Furahini G. Mndeme, MD, Ahmed A. Mohamedani, FRCPath, Mona T. Mohammad, MD, FRCS, Annette C. Moll, MD, PhD, Margarita M. Montero, MD, Claude Moreira, MD, PhD, Prithvi Mruthyunjaya, MD, MHS, Mchikirwa S. Msina, MMed Ophth, Gerald Msukwa, MMed Ophth, Sangeeta S. Mudaliar, DNB Pediatric, Hassan Muhammad, MD, Kangwa I. Muma, MMed Ophth, FCOphth, Francis L. Munier, MD, Timothy G. Murray, MD, MBA, Kareem O. Musa, FWACS, FMCOphth, FICO, Asma Mushtaq, MD, Anne A. Musika, MD, Hamzah Mustak, MD, Tajudeen Mustapha, MBBS, FWACS, Okwen M. Muyen, MD, Khumo H. Myezo, Msc, Gita Naidu, MMed Paed, PhD, Natasha Naidu, MBCHB, FCS Ophthalmol, Akshay Gopinathan Nair, MD, Sundaram Natarajan, FRCS, Larisa Naumenko, MD, PhD, Paule Aïda Ndoye Roth, MD PhD, Yetty M. Nency, MD, Vladimir Neroev, MD, PhD, Yvonne Ng, MBChB ( Auckland) , FRANZCO, Marina Nikitovic, MD, PhD, Elizabeth D. Nkanga, FMCOph, Henry E. Nkumbe, MD, Marcel N. Numbi, MD, Kalle Nummi, MD, Murtuza Nuruddin, FRCS, Mutale Nyaywa, MD, MMed Ophth, FCOphth, Chinsisi Nyirenda, MD, Ghislaine Obono-Obiang, MD, Scott C.N. Oliver, MD, Joaquin Ooporto, MD, Miriam Ortega-Hernández, MD, Alexander Oscar, MD, Diego Ossandon, MD, Halimah Pagarra, MD, PhD, Vivian Paintsil, FWACP, Luisa Paiva, MD, Mahesh Shanmugam Palanivelu, FRCSED, Ruzanna Papyan, MD, Raffaele Parrozzani, MD, PhD, Claudia R. Pascual Morales, MD, Katherine E. Paton, MD, FRCSC, Jacob Pe'er, MD, Jesús Peralta Calvo, MD, Sanja Perić, MD, PhD, Chau T.M. Pham, MD, Remezo Philbert, MD, David A. Plager, MD, Pavel Pochop, MD, PhD, Rodrigo A. Polania, MD, Vladimir Polyakov, MD, Jimena Ponce, MD, Ali O. Qadir, MD, Seema Qayyum, FCPS, Jiang Qian, MD, Ardizal Rahman, MD, Purnima Rajkarnikar, MD, Rajesh Ramanjulu, MD, Aparna Ramasubramanian, MD, Marco A. Ramirez-Ortiz, MD, MPH, Jasmeen K. Randhawa, BA, Léa Raobela, MD, Riffat Rashid, MS, M. Ashwin Reddy, FRCOphth, Lorna A. Renner, FRCPCH (UK), David Reynders, MD, Dahiru Ribadu, FMCOph, Petra Ritter-Sovinz, MD, Anna Rogowska, MD, Duangnate Rojanaporn, MD, Livia Romero, MD, Soma R. Roy, DCO, Raya H. Saab, MD, Svetlana Saakyan, MD, PhD, Ahmed H. Sabhan, MD, Mandeep S. Sagoo, FRCS (Ed), Azza M.A. Said, MD, Rohit Saiju, MD, Beatriz Salas, MD, Sonsoles San Román Pacheco, MD, Gissela L. Sánchez, MD, Alma Janeth Sanchez Orozco, MD, Phayvanh Sayalith, MD, Trish A. Scanlan, MRCPI, MSc, Christoph Schwab, MD, Ahad Sedaghat, MD, Rachna Seth, DNB MNAMS, Mariana Sgroi, MD, Ankoor S. Shah, MD, PhD, Shawkat A. Shakoor, MS, Manoj K. Sharma, MD, Sadik T. Sherief, MD, Carol L. Shields, MD, David Sia, MB ChB, FRANZCO, Sorath Noorani Siddiqui, MD, Sidi Sidi cheikh, MD, PhD, Sónia Silva, MD, Arun D. Singh, MD, Usha Singh, MS, Penny Singha, MD, Rita S. Sitorus, MD, PhD, Alison H. Skalet, MD, PhD, Hendrian D. Soebagjo, MD, PhD, Tetyana Sorochynska, MD, PhD, Grace Ssali, MD, Andrew W. Stacey, MD, Sandra E. Staffieri, PhD, Erin D. Stahl, MD, David M. Steinberg, PhD, David K. Stones, MBChB, FCPaed, Caron Strahlendorf, MD, Maria Estela Coleoni Suarez, MD, Sadia Sultana, FCPS, Xiantao Sun, MD, Rosanne Superstein, MD, Eddy Supriyadi, MD, PhD, Supawan Surukrattanaskul, MD, Shigenobu Suzuki, MD, PhD, Karel Svojgr, MD, PhD, Fatoumata Sylla, MD, Gevorg Tamamyan, MD, PhD, Deborah Tan, MBBS, Alketa Tandili, MD, PhD, Jing Tang, MD, Fanny F. Tarrillo Leiva, MD, Maryam Tashvighi, MD, Bekim Tateshi, MD, PhD, Kok Hoi Teh, MD, Edi S. Tehuteru, MD, Luiz F. Teixeira, MD, Manca Tekavcic Pompe, MD, PhD, Abdullah Dahan M. Thawaba, MD, Tuyisabe Theophile, MSc, Helen Toledano, MBChB, Doan L. Trang, MD, Fousseyni Traoré, MD, Devjyoti Tripathy, MD, Samuray Tuncer, MD, Harba Tyau-Tyau, MD, Ali B. Umar, MD, FMCPath, Emel Unal, MD, Ogul E. Uner, BA, Steen F. Urbak, MD, PhD, Tatiana L. Ushakova, MD, Rustam H. Usmanov, MD, Sandra Valeina, MD, Paola Valente, MD, Milo van Hoefen Wijsard, MD, Jacqueline Karina Vasquez Anchaya, MD, Leon O. Vaughan, FRCS (Ed), Nevyana V. Veleva-Krasteva, MD, PhD, Nishant Verma, MD, Andi A. Victor, MD, PhD, Maris Viksnins, MD, Edwin G. Villacís Chafla, MD, Victor M. Villegas, MD, Victoria Vishnevskia-Dai, MD, Keith Waddell, DM, FRCP, FRCS, FRCOphth, Amina H. Wali, MD, FMCOph Nigeria, Yi-Zhuo Wang, MD, Nutsuchar Wangtiraumnuay, MD, FICO, Julie A. Wetter, MMed Rad Onc, FCRad Onc, Widiarti P. Riono, MD, Matthew W. Wilson, MD, Amelia D.C. Wime, MD, Atchareeya Wiwatwongwana, MD, Damrong Wiwatwongwana, MD, Charlotte Wolley Dod, MD, Emily S. Wong, FCOphth HK, FHKAM, Phanthipha Wongwai, MD, PhD, Si-qi Wu, MSc, Daoman Xiang, MD, PhD, Yishuang Xiao, MSc, Bing Xu, MD, Kang Xue, MD, Antonio Yaghy, MD, Jason C. Yam, FRCSEd, Huasheng Yang, MD, Jenny M. Yanga, MD, Muhammad A. Yaqub, MD, FCPS, FRCSEd, Vera A. Yarovaya, MD, Andrey A. Yarovoy, MD, PhD, Huijing Ye, MD, Roberto I. Yee, MD, Yacoub A. Yousef, MD, Putu Yuliawati, MD, Arturo M. López, MD, Ekhtelbenina Zein, MD, Yi Zhang, MD, PhD, Katsiaryna Zhilyaeva, MD, Nida Zia, MBBS, MCPS, Othman A.O. Ziko, MD, PhD, Marcia Zondervan, MBA, Sabrina Schlüter, MD, and Richard Bowman, FRCOphth
Subjects: External beam radiotherapy, Extraocular extension, Multimodal treatment, Retinoblastoma, Tumor, Ophthalmology, RE1-994
Abstract: Purpose: To study the treatment and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). Design: Multicenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naive patients. Cases with microscopic orbital extension detected postenucleation were excluded from the study. Participants: A total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE. Intervention: Chemotherapy, enucleation, exenteration, radiotherapy. Main Outcome Measures: Systemic metastasis and death. Results: Of the 3435 RB patients included in this study, 309 (9%) were from low-income countries (LIC), 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from LIC, 197 (6%) lower-middle income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (P = 0.0001). The outcomes were statistically significant for RB-EOE compared with RB-w/o-EOE: systemic metastasis (32% vs. 4% respectively; P = 0.0001) and metastasis-related death (63% vs. 6% respectively; P = 0.0001). Multimodal treatment was the most common form of treatment (n = 177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n = 97; 30%). Adjuvant external beam radiotherapy (EBRT) after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan–Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk of death from RB-EOE was greater in patients aged >4 years than
Published: 2025
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3. Multi-view convolutional neural networks for automated ocular structure and tumor segmentation in retinoblastoma

Author: Victor I. J. Strijbis, Christiaan M. de Bloeme, Robin W. Jansen, Hamza Kebiri, Huu-Giao Nguyen, Marcus C. de Jong, Annette C. Moll, Merixtell Bach-Cuadra, Pim de Graaf, and Martijn D. Steenwijk
Subjects: Medicine, Science
Abstract: Abstract In retinoblastoma, accurate segmentation of ocular structure and tumor tissue is important when working towards personalized treatment. This retrospective study serves to evaluate the performance of multi-view convolutional neural networks (MV-CNNs) for automated eye and tumor segmentation on MRI in retinoblastoma patients. Forty retinoblastoma and 20 healthy-eyes from 30 patients were included in a train/test (N = 29 retinoblastoma-, 17 healthy-eyes) and independent validation (N = 11 retinoblastoma-, 3 healthy-eyes) set. Imaging was done using 3.0 T Fast Imaging Employing Steady-state Acquisition (FIESTA), T2-weighted and contrast-enhanced T1-weighted sequences. Sclera, vitreous humour, lens, retinal detachment and tumor were manually delineated on FIESTA images to serve as a reference standard. Volumetric and spatial performance were assessed by calculating intra-class correlation (ICC) and dice similarity coefficient (DSC). Additionally, the effects of multi-scale, sequences and data augmentation were explored. Optimal performance was obtained by using a three-level pyramid MV-CNN with FIESTA, T2 and T1c sequences and data augmentation. Eye and tumor volumetric ICC were 0.997 and 0.996, respectively. Median [Interquartile range] DSC for eye, sclera, vitreous, lens, retinal detachment and tumor were 0.965 [0.950–0.975], 0.847 [0.782–0.893], 0.975 [0.930–0.986], 0.909 [0.847–0.951], 0.828 [0.458–0.962] and 0.914 [0.852–0.958], respectively. MV-CNN can be used to obtain accurate ocular structure and tumor segmentations in retinoblastoma.
Published: 2021
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4. High-Level MYCN-Amplified RB1-Proficient Retinoblastoma Tumors Retain Distinct Molecular Signatures

Author: Khashayar Roohollahi, MSc, Yvonne de Jong, PhD, Saskia E. van Mil, MSc, Armida W.M. Fabius, PhD, Annette C. Moll, MD, PhD, and Josephine C. Dorsman, PhD
Subjects: Methylation analysis, MYCN, RB1, Retinoblastoma, Transcriptomics, Ophthalmology, RE1-994
Abstract: Purpose: Retinoblastomas are malignant eye tumors diagnosed in young children. Most retinoblastomas are genetically characterized by biallelic inactivation of the RB1 gene. However, 1.5% of tumors demonstrate high-level amplification of the proto-oncogene MYCN. Patients with MYCN-amplified RB1-proficient retinoblastoma receive a diagnosis at an earlier age and show a clinically and histologically more malignant phenotype. This study aimed to identify genome-wide molecular features that distinguish this subtype from other retinoblastomas. Design: Cohort study. Participants: Forty-seven retinoblastoma tumors, comprising 36 RB1–/–, 4 RB1+/–, and 7 RB1+/+ tumors. In total, 5 retinoblastomas displayed high-level MYCN amplification, with 3 being RB1+/+, 1 being RB1+/–, and 1 being RB1–/–. Methods: Integrated analysis, based on gene expression, methylation, and methylation-expression correlations, was performed to identify distinct molecular components of MYCN-amplified RB1-proficient retinoblastomas compared with other retinoblastoma subtypes. The methylation and methylation-expression correlation analysis was initially conducted within a subset of samples (n = 15) for which methylation profiles were available. The significant findings were cross-validated in the entire cohort (n = 47) and in publicly available data. Main Outcome Measures: Differentially expressed genes/pathways, differentially methylated genes, and methylation-driven differential gene expression. Results: A large number of genes (n = 3155) were identified with distinct expression patterns in MYCN-amplified RB1-proficient retinoblastomas. The upregulated and downregulated genes were associated with translation and cell-cycle processes, respectively. Methylation analysis revealed distinct methylated patterns in MYCN-amplified RB1-proficient tumors, many of which showing significant impact on gene expression. Data integration identified a 40-gene expression signature with hypermethylated state resulting in a significant downregulation in MYCN-amplified RB1-proficient retinoblastomas. Cross-validation using the entire cohort and the public domain expression data verified the overall lower expression of these genes not only in retinoblastomas with a MYCN-amplified RB1-proficient background, but also in MYCN-amplified neuroblastomas. These include the metabolism-associated TSTD1 gene and the cyclin-dependent kinase inhibitor gene CDKN2C. Conclusions: MYCN-amplified RB1-proficient retinoblastomas display significantly distinct molecular features compared with other retinoblastomas, including a set of 40 hypermethylation-driven downregulated genes. This gene set can give insight into the biology of MYCN-amplified retinoblastomas and may help us to understand the more aggressive clinical behavior.
Published: 2022
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5. Collaboration Around Rare Bone Diseases Leads to the Unique Organizational Incentive of the Amsterdam Bone Center

Author: Elisabeth M. W. Eekhoff, Dimitra Micha, Tymour Forouzanfar, Teun J. de Vries, J. Coen Netelenbos, Jenneke Klein-Nulend, Jack J. W. A. van Loon, Wouter D. Lubbers, Lothar Schwarte, Patrick Schober, Pieter G. H. M. Raijmakers, Bernd P. Teunissen, Pim de Graaf, Adriaan A. Lammertsma, Maqsood M. Yaqub, Esmée Botman, Sanne Treurniet, Bernard J. Smilde, Arend Bökenkamp, Anco Boonstra, Otto Kamp, Jakko A. Nieuwenhuijzen, Marieke C. Visser, Hans J. C. Baayen, Max Dahele, Guus A. M. Eeckhout, Thadé P. M. Goderie, Cas Smits, Marjolijn Gilijamse, K. Hakki Karagozoglu, Paul van de Valk, Chris Dickhoff, Annette C. Moll, Frank F. D. Verbraak, Katie K. R. Curro-Tafili, Ebba A. E. Ghyczy, Thomas Rustemeyer, Peeroz Saeed, Alessandra Maugeri, Gerard Pals, Angela Ridwan-Pramana, Esther Pekel, Ton Schoenmaker, Willem Lems, Henri A. H. Winters, Matthijs Botman, Georgios F. Giannakópoulos, Peter Koolwijk, Jeroen J. W. M. Janssen, Peter Kloen, Nathalie Bravenboer, Jan Maerten Smit, and Marco N. Helder
Subjects: rare bone diseases, amsterdam bone center (ABC), collaborative organization, non-hierarchical, research, clinical, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the “collaborative organizational model” of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition.
Published: 2020
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6. The EMIF-AD PreclinAD study: study design and baseline cohort overview

Author: Elles Konijnenberg, Stephen F. Carter, Mara ten Kate, Anouk den Braber, Jori Tomassen, Chinenye Amadi, Linda Wesselman, Hoang-Ton Nguyen, Jacoba A. van de Kreeke, Maqsood Yaqub, Matteo Demuru, Sandra D. Mulder, Arjan Hillebrand, Femke H. Bouwman, Charlotte E. Teunissen, Erik H. Serné, Annette C. Moll, Frank D. Verbraak, Rainer Hinz, Neil Pendleton, Adriaan A. Lammertsma, Bart N. M. van Berckel, Frederik Barkhof, Dorret I. Boomsma, Philip Scheltens, Karl Herholz, and Pieter Jelle Visser
Subjects: Preclinical Alzheimer’s disease, Amyloid, Cognitively normal, Monozygotic twins, [18F]flutemetamol, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Amyloid pathology is the pathological hallmark in Alzheimer’s disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. Methods From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [18F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. Results We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. Conclusions A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.
Published: 2018
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7. Concurrence of sleep problems and distress: prevalence and determinants in parents of children with cancer

Author: Niki Rensen, Lindsay M. H. Steur, Sasja A. Schepers, Johannes H. M. Merks, Annette C. Moll, Martha A. Grootenhuis, Gertjan J. L. Kaspers, and Raphaële R. L. van Litsenburg
Subjects: sleep, psychological stress, parents, child, cancer, oncology, Psychiatry, RC435-571
Abstract: Background: Parents of children with cancer are at risk for sleep problems. If these problems persist, an important perpetuating factor might be ongoing parental distress. Objective: The aim of this study is to assess the prevalence of sleep problems and the concurrence with distress in parents of children treated for cancer, and to identify predictors of this symptom clustering. Method: Parents completed the Medical Outcomes Study (MOS) Sleep Scale and Distress Thermometer for Parents (DT-P). Clinically relevant sleep problems were defined as a score >1SD above the norm and clinical distress as a thermometer score above the established cut-off of 4. Four parent categories were constructed: neither sleep problems nor distress; no distress but sleep problems; no sleep problems but distress; both sleep problems and distress. Predictive determinants (sociodemographic, medical, psychosocial) for each category were assessed with multilevel multinomial logistic regression. Results: Parents (202 mothers and 150 fathers) of 231 children with different cancers participated. Mean time since diagnosis was 3.3 ± 1.4 years (90% off-treatment). The prevalence of sleep problems was 37%. Fifty percent of parents reported neither sleep problems nor distress, 9% had only sleep problems, 13% only distress, and 28% reported both. Compared to parents without sleep problems or distress, parents who reported both were more likely to report parenting problems (OR 4.4, [2.2–9.1]), chronic illness (OR 2.8, [1.2–6.5]), insufficient social support (OR 3.7, [1.5–9.1]), pre-existent sleep problems (OR 6.2, [2.0–18.6]) and be female (OR 1.8, [1.1–4.2]). Conclusions: Sleep problems are common in parents of children treated for cancer, and occur mostly in the presence of clinical distress. Future research must show which interventions are most effective in this group: mainly targeted at sleep improvement or with prominent roles for stress management or trauma processing.
Published: 2019
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8. Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression

Author: Irsan E. Kooi, Berber M. Mol, Annette C. Moll, Paul van der Valk, Marcus C. de Jong, Pim de Graaf, Saskia E. van Mil, Antoinette Y.N. Schouten-van Meeteren, Hanne Meijers-Heijboer, Gertjan L. Kaspers, Hein te Riele, Jacqueline Cloos, and Josephine C. Dorsman
Subjects: Retinoblastoma, Retina, Pediatric oncology, Cancer, Expression profiling, Progression, Medicine, Medicine (General), R5-920
Abstract: Background: Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1−/− retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods: Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings: RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1−/− tumors seemed more dichotomous, differences within the RB1−/− tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation: Molecular, clinical and histopathological differences between RB1−/− tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression. Research in context: Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with a different etiology, our data suggests that this diversity is a result of tumor progression driven by cumulative genetic alterations. Therefore, retinoblastomas should not be categorized in distinct subtypes, but be described according to their stage of progression.
Published: 2015
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9. MRI Features for Identifying MYCN-amplified RB1 Wild-type Retinoblastoma

Author: Robin W. Jansen, Christiaan M. de Bloeme, Liesbeth Cardoen, Sophia Göricke, Sabien van Elst, Jaime Lyn Jessen, Aparna Ramasubramanian, Alison H. Skalet, Audra K. Miller, Philippe Maeder, Ogul E. Uner, G. Baker Hubbard, Hans Grossniklaus, H. Culver Boldt, Kim E. Nichols, Rachel C. Brennan, Saugata Sen, Selma Sirin, Hervé J. Brisse, Paolo Galluzzi, Charlotte J. Dommering, Jonas A. Castelijns, Paul van der Valk, Ronald Boellaard, Josephine Dorsman, Annette C. Moll, Marcus C. de Jong, Pim de Graaf, University of Zurich, Radiology and nuclear medicine, Human genetics, CCA - Cancer biology and immunology, Pathology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Amsterdam Neuroscience - Brain Imaging, CCA - Imaging and biomarkers, Amsterdam Reproduction & Development (AR&D), Ophthalmology, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, CCA - Cancer Treatment and quality of life, and AII - Cancer immunology
Subjects: 10036 Medical Clinic, Radiology, Nuclear Medicine and imaging, 610 Medicine & health
Abstract: Background MYCN-amplified RB1 wild-type (MYCNARB1+/+) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCNARB1+/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCNARB1+/+ retinoblastoma and age-matched children with RB1-/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing (RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCNARB1+/+ retinoblastoma and 88 control children with RB1-/- retinoblastoma. Children in the MYCNARB1+/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1-/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCNARB1+/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCNARB1+/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCNARB1+/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.
Published: 2023
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10. Automatic segmentation and quantification of the optic nerve on MRI using a 3D U-Net

Author: Sabien van Elst, Christiaan M. de Bloeme, Samantha Noteboom, Marcus C. de Jong, Annette C. Moll, Sophia Göricke, Pim De Graaf, Matthan W. A. Caan, Radiology and nuclear medicine, Anatomy and neurosciences, Ophthalmology, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, CCA - Cancer Treatment and quality of life, CCA - Imaging and biomarkers, Amsterdam Reproduction & Development (AR&D), AII - Cancer immunology, and CCA - Cancer biology and immunology
Subjects: Radiology, Nuclear Medicine and imaging
Abstract: PURPOSE: Pathological conditions associated with the optic nerve (ON) can cause structural changes in the nerve. Quantifying these changes could provide further understanding of disease mechanisms. We aim to develop a framework that automatically segments the ON separately from its surrounding cerebrospinal fluid (CSF) on magnetic resonance imaging (MRI) and quantifies the diameter and cross-sectional area along the entire length of the nerve.APPROACH: Multicenter data were obtained from retinoblastoma referral centers, providing a heterogeneous dataset of 40 high-resolution 3D T2-weighted MRI scans with manual ground truth delineations of both ONs. A 3D U-Net was used for ON segmentation, and performance was assessed in a tenfold cross-validation (n=32) and on a separate test-set (n=8) by measuring spatial, volumetric, and distance agreement with manual ground truths. Segmentations were used to quantify diameter and cross-sectional area along the length of the ON, using centerline extraction of tubular 3D surface models. Absolute agreement between automated and manual measurements was assessed by the intraclass correlation coefficient (ICC).RESULTS: The segmentation network achieved high performance, with a mean Dice similarity coefficient score of 0.84, median Hausdorff distance of 0.64 mm, and ICC of 0.95 on the test-set. The quantification method obtained acceptable correspondence to manual reference measurements with mean ICC values of 0.76 for the diameter and 0.71 for the cross-sectional area. Compared with other methods, our method precisely identifies the ON from surrounding CSF and accurately estimates its diameter along the nerve's centerline.CONCLUSIONS: Our automated framework provides an objective method for ON assessment in vivo.
Published: 2023
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11. Cognitive Functioning and Hippocampal Connectivity in Patients With Longstanding Type 1 Diabetes and Apolipoprotein E ɛ4

Author: Annette C. Moll, Michaela Diamant, Martin Klein, Richard G. IJzerman, Frederik Barkhof, Frank J. Snoek, Eelco van Duinkerken, Medical Psychology, Internal medicine, ACS - Diabetes & metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, Ophthalmology, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, Medical psychology, APH - Mental Health, Amsterdam Reproduction & Development (AR&D), CCA - Cancer Treatment and quality of life, and CCA - Imaging and biomarkers
Subjects: Advanced and Specialized Nursing, Apolipoprotein E, education.field_of_study, medicine.medical_specialty, endocrine system diseases, business.industry, Endocrinology, Diabetes and Metabolism, Population, Neuropsychology, nutritional and metabolic diseases, Cognition, Audiology, Hippocampal formation, Neuroimaging, Internal Medicine, Medicine, Effects of sleep deprivation on cognitive performance, business, education, Blood sampling
Abstract: OBJECTIVE While the apolipoprotein E ε4 allele (ApoE-ε4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-ε4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-ε4 effects in adult patients with T1DM. RESEARCH DESIGN AND METHODS Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-ε4 presence was investigated and adjusted for age and mean systolic blood pressure. RESULTS ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-ε4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-ε4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-ε4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. CONCLUSIONS The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies.
Published: 2021
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12. Subsequent Malignant Neoplasms in Retinoblastoma Survivors

Author: Annette C. Moll, Flora E. van Leeuwen, Armida W. M. Fabius, and Milo van Hoefen Wijsard
Subjects: Oncology, Cancer Research, medicine.medical_specialty, heritable Rb, Tumor suppressor gene, trilateral Rb, Review, medicine.disease_cause, lcsh:RC254-282, retinoblastoma, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Genetic predisposition, Patient group, long-term surveillance, Cause of death, Mutation, Retinoblastoma, business.industry, Incidence (epidemiology), subsequent malignant neoplasms, Malignant Eye Tumor, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, second primary malignancies, eye diseases, 030220 oncology & carcinogenesis, 030221 ophthalmology & optometry, business
Abstract: Simple Summary Currently survival from retinoblastoma exceeds 95% in high-income/resource countries. Life expectancy within the heritable retinoblastoma population is mainly threatened by trilateral retinoblastoma in early childhood and subsequent malignant neoplasms throughout life. In this review the risks of specific subsequent malignant neoplasms and trilateral Rb, age at onset and influence of therapy are examined. Furthermore, long-term surveillance guidelines in the heritable retinoblastoma survivors are discussed. Abstract Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence of a mutation in the RB1 tumor suppressor gene. In addition, Rb therapy choices also influence SMN incidence in this patient group. The incidence rates and age of occurrence for the most frequent SMNs and TRb will be discussed. In addition, the impact of genetic predisposition and Rb treatments on the development of SMNs will be evaluated. Furthermore, screening and other prevention methods will be reviewed.
Published: 2021
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13. Workflow and treatment results for computer-aided design and 3D-printed conformer therapy of congenital anophthalmia and microphthalmia

Author: Annabel L W Groot, Jelmer S Remmers, Birgit I Lissenberg-Witte, Simon T J de Meulenaere, Duygu Talan, Niels P T J Liberton, Pim de Graaf, Annette C Moll, Peerooz Saeed, Dyonne T Hartong, Ophthalmology, Epidemiology and Data Science, Radiology and nuclear medicine, ACS - Diabetes & metabolism, Graduate School, CCA -Cancer Center Amsterdam, and Other Research
Subjects: Cellular and Molecular Neuroscience, Ophthalmology, child health (paediatrics), cosmesis, treatment other, prosthesis, Sensory Systems, orbit
Abstract: Background/aimsTo evaluate treatment with custom, three-dimensional (3D) printed conformers for socket expansion in congenital microphthalmia and anophthalmia (MICA).MethodsRetrospective analysis of prospective cohort from 2016 to 2020. All children received custom-made 3D-printed conformers increasing in size. We measured height, width, thickness, surface and volume of first and consecutive conformers, as well as horizontal palpebral fissure length (HPF) at start and follow-up visits. We analysed these parameters for severely (45%–75%) affected children, based on affected axial length on ultrasonography.ResultsWe included 18 cases (9 severe, 9 moderate) with a total of 174 conformers (88 severe, 86 moderate) and a mean follow-up of 2.8 years (range 1.3–4.8). The mean relative HPF increased from 77% to 93% with 16/17 cases reaching >80%, and 12/17 cases >90% symmetry. Horizontal and vertical conformer dimensions increased up to 10 months of treatment, with a steeper slope for the severe group (10.5% vs 5.5% for height and 9.0% vs 6.1% for width gain per treatment month, for severe and moderate MICA, respectively). After 10 months of treatment conformer height and width increased only slightly. No serious complications were observed.Conclusion3D-design and printing of solid conformers results in highly acceptable horizontal eyelid symmetry in the treatment of congenital MICA. The mean increase in conformer height and width in the first 10 months should be about 170% for moderate and about 200% for severe MICA. The presented conformer size formulas can aid ophthalmologists and ocularists to plan conformer treatment.
Published: 2022
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14. High-Level

Author: Khashayar, Roohollahi, Yvonne, de Jong, Saskia E, van Mil, Armida W M, Fabius, Annette C, Moll, and Josephine C, Dorsman
Abstract: Retinoblastomas are malignant eye tumors diagnosed in young children. Most retinoblastomas are genetically characterized by biallelic inactivation of theCohort study.Forty-seven retinoblastoma tumors, comprising 36Integrated analysis, based on gene expression, methylation, and methylation-expression correlations, was performed to identify distinct molecular components ofDifferentially expressed genes/pathways, differentially methylated genes, and methylation-driven differential gene expression.A large number of genes (n = 3155) were identified with distinct expression patterns in
Published: 2022

15. Classification for treatment urgency for the microphthalmia/anophthalmia spectrum using clinical and biometrical characteristics

Author: Daphne L. Mourits, Jelmer Remmers, Dyonne T. Hartong, Annabel L.W. Groot, Annette C. Moll, Peerooz Saeed, Pim de Graaf, Asra Gilani, Maayke M P Kuijten, Petra J. G. Zwijnenburg, Elke Kraal-Biezen, Stevie Tan, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Ophthalmology, Radiology and nuclear medicine, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, ACS - Diabetes & metabolism, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Radiology and Nuclear Medicine, Human Genetics, and Other Research
Subjects: medicine.medical_specialty, child health (paediatrics), Anophthalmia, eye (globe), business.industry, medicine.medical_treatment, Ultrasound, General Medicine, Original Articles, medicine.disease, Microphthalmia, Prosthesis, Ophthalmology, medicine.anatomical_structure, Palpebral fissure, Medicine, Original Article, genetics, Eyelid, prosthesis, business, Prospective cohort study, orbit, Orbit (anatomy)
Abstract: PURPOSE: Current clinical classifications do not distinguish between the severity of the MICrophthalmia/Anophthalmia (MICA) spectrum with regard to treatment urgency. We aim to provide parameters for distinguishing mild, moderate and severe MICA using clinical and biometrical characteristics.METHODS: We performed a single-centre, cross-sectional analysis of prospective cohort of 58 MICA children from September 2013 to February 2018 seen at the Amsterdam University Medical Center, The Netherlands. All patients with a visible underdeveloped globe were included. We performed full ophthalmic evaluation including horizontal palpebral fissure length, axial length by ultrasound and/or MRI measurements, paediatric and genetic evaluation. Cases were subdivided based on clinical characteristics. Biometrical data were used to calculate the relative axial length (rAL) and the relative horizontal palpebral fissure length (rHPF) compared with the healthy contralateral eye for unilateral cases.RESULTS: In previously untreated patients, a strong correlation exists between rAL and rHPF, distinguishing between severe, moderate and mild subjects using rAL of 0-45%, 45-75% and 75%-100%, respectively. Clinical subgroups were randomly dispersed throughout the scatterplot.CONCLUSION: Current classifications lack clinical implications for MICA patients. We suggest measuring eyelid length and axial length to classify the severity and determine treatment strategy. The 'severe' group has obvious asymmetry and abnormal socket configuration for which therapy should quickly be initiated; the 'moderately' affected group has normal socket anatomy with a microphthalmic eye with disturbing asymmetry for which treatment should be initiated within months of development; the 'mild' group has a slightly smaller axial length or less obvious eyelid asymmetry for which reconstructive correction is possible, but expansive conformer treatment is unnecessary.
Published: 2020
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16. Comparing the Efficacy of Bevacizumab and Ranibizumab in Patients with Diabetic Macular Edema (BRDME)

Author: Janneke J.C. van Lith-Verhoeven, Annette C. Moll, Leonoor I. Los, Ann Sofie M.E. Schauwvlieghe, Bevacizumab, Tunde Peto, Maartje J.C. Vader, Reinier O. Schlingemann, Carel B. Hoyng, Johanna M. M. Hooymans, Johannes R. Vingerling, Greetje Dijkman, Marcel G. W. Dijkgraaf, Aeilko H. Zwinderman, Redmer van Leeuwen, and Frank D. Verbraak
Subjects: medicine.medical_specialty, Visual acuity, genetic structures, Bevacizumab, Visual impairment, Subgroup analysis, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Ophthalmology, Medicine, 030304 developmental biology, 0303 health sciences, business.industry, eye diseases, Confidence interval, Clinical trial, 030221 ophthalmology & optometry, sense organs, medicine.symptom, Ranibizumab, business, medicine.drug
Abstract: Purpose: To generate conclusive evidence regarding the noninferiority of intravitreal bevacizumab compared with ranibizumab in patients with diabetic macular edema (DME). Design: Comparative, randomized, double-masked, multicenter, noninferiority clinical trial. Participants: Eligible patients were older than 18 years, diagnosed with type 1 or type 2 diabetes mellitus, with glycosylated hemoglobin of less than 12%, central area thickness of more than 325 mm, and visual impairment from DME with a best-corrected visual acuity (BCVA) between 24 letters and 78 letters. Methods: From June 2012 through February 2018, a total of 170 participants were randomized to receive 6 monthly injections of either 1.25 mg bevacizumab (n ¼ 86) or 0.5 mg ranibizumab (n ¼ 84). Main Outcome Measures: Primary outcome was change in BCVA from baseline to month 6 compared between the 2 treatment arms. The noninferiority margin was 3.5 letters. Results: The difference in mean BCVA between treatment arms was 1.8 letters in favor of ranibizumab after 6 months of follow-up; BCVA improved by 4.96.7 letters in the bevacizumab group and 6.78.7 letters in the ranibizumab group. The lower bound of the 2-sided 90% confidence interval (CI) was e3.626 letters, exceeding the noninferiority margin of 3.5 letters. Central area thickness decreased more with ranibizumab (138.2114.3 mm) compared with bevacizumab (64.2104.2 mm). In a post hoc subgroup analysis, participants with a worse BCVA at baseline (69 letters) improved by 6.77.0 letters with bevacizumab and 10.410.0 letters with ranibizumab, and central area thickness decreased significantly more in the ranibizumab arm of this subgroup compared with the bevacizumab arm. Participants with an initially better BCVA at baseline (70 letters) did not demonstrate differences in BCVA or OCT outcomes between treatment arms. Conclusions: Based on change in BCVA from baseline to month 6, the noninferiority of 1.25 mg bevacizumab to 0.5 mg ranibizumab was not confirmed. Only the subgroup of patients with a lower BCVA at baseline showed better visual acuity and anatomic outcomes with ranibizumab. Our study confirmed the potential differential efficacy of antievascular endothelial growth factor agents in the treatment of DME as well as the difference in response between patient groups with different baseline visual acuities
Published: 2020
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17. Screening for Pineal Trilateral Retinoblastoma Revisited

Author: Furqan Shaikh, Wijnanda A. Kors, Brenda L. Gallie, Annette C. Moll, Tero Kivelä, Robin W. Jansen, Helen Dimaras, Pim de Graaf, Sameh E. Soliman, Marcus C. de Jong, and Jonas A. Castelijns
Subjects: Pineoblastoma, endocrine system, medicine.medical_specialty, Pediatrics, Trilateral retinoblastoma, Retinoblastoma, business.industry, medicine.disease, Intraocular Retinoblastoma, Asymptomatic, 3. Good health, 03 medical and health sciences, Ophthalmology, 0302 clinical medicine, Interquartile range, 030220 oncology & carcinogenesis, Epidemiology, 030221 ophthalmology & optometry, medicine, Pinealoblastoma, medicine.symptom, 10. No inequality, business
Abstract: Topic To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms. Clinical relevance Approximately 45% of patients with retinoblastoma—those with a germline RB1 pathogenic variant—are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued. Methods We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus. Results One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9–29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively. Conclusions Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low.
Published: 2020
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18. Determinants of health-related quality of life proxy rating disagreement between caregivers of children with cancer

Author: Annette C. Moll, Raphaële R. L. van Litsenburg, Niki Rensen, Lindsay M.H. Steur, Gertjan J.L. Kaspers, Johannes H. M. Merks, Martha A. Grootenhuis, Sasja A. Schepers, Pediatric surgery, CCA - Cancer Treatment and quality of life, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, APH - Methodology, ACS - Diabetes & metabolism, Paediatric Oncology, CCA - Cancer Treatment and Quality of Life, Child and Adolescent Psychiatry & Psychosocial Care, APH - Mental Health, and ARD - Amsterdam Reproduction and Development
Subjects: Adult, Male, Parents, Quality of life, medicine.medical_specialty, Adolescent, Emotions, Mothers, Article, Correlation, 03 medical and health sciences, Fathers, 0302 clinical medicine, Neoplasms, Surveys and Questionnaires, medicine, Humans, 030212 general & internal medicine, Social determinants of health, Patient Reported Outcome Measures, Proxy reports, Proxy (statistics), Child, Cancer, Patient-reported outcomes, business.industry, Public health, Public Health, Environmental and Occupational Health, Middle Aged, Proxy, Distress, Quartile, Caregivers, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Respondent, Chronic Disease, Female, business, Demography
Abstract: Purpose Proxy reports of health-related quality of life (HRQoL) are commonly used in pediatric oncology. However, it is not known if caregivers’ reports differ. This study therefore aims to compare paternal and maternal proxy reports, and explore determinants of couple disagreement (sociodemographic and medical characteristics, and parental QoL and distress). Methods Both parents completed the PedsQL generic (child’s HRQoL), Short Form-12 (own QoL) and Distress Thermometer for Parents. To assess agreement in child HRQoL, intra-class correlation coefficients (ICCs) were calculated. Differences between fathers/mothers were assessed with paired t tests. Systematic disagreement patterns were visualized with Bland–Altman plots. Characteristics of parental couples with a mean proxy difference in the highest quartile (highest proxy score minus lowest proxy score) were explored with multiple logistic regression analysis. Results Parents of 120 children with cancer (87% post-treatment, mean age 11.0 ± 5.7 years) participated. No significant differences were found between paternal and maternal proxy scores, and agreement was good on all scales (ICCs 0.65–0.83). Bland–Altman plots revealed no systematic disagreement patterns, but there was a wide range in magnitude of the differences, and differences went in both directions. Couples with a mean proxy difference (irrespective of which direction) in the highest quartile (± 20 points) were more likely to have a child in active treatment, with retinoblastoma or relapsed disease, and to diverge in their own QoL. Conclusions If proxy reports of only one parent are available, clinicians may reasonably assume that paternal and maternal reports are interchangeable. However, if in doubt, respondent’s sex is not of major importance, but clinicians should be aware of patient’s and family’s characteristics.
Published: 2020
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19. Full-width postlaminar optic nerve tumor invasion of retinoblastoma as risk-factor for leptomeningeal spread of retinoblastoma. A case report and review of the literature

Author: Marcus C. de Jong, Paul van der Valk, Pim de Graaf, Jonas A. Castelijns, Floor Abbink, Annette C. Moll, Machteld I. Bosscha, Robin W. Jansen, Radiology and nuclear medicine, Pathology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Pediatric surgery, CCA - Cancer Treatment and quality of life, Ophthalmology, ACS - Diabetes & metabolism, APH - Quality of Care, and APH - Health Behaviors & Chronic Diseases
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, genetic structures, Retinal Neoplasms, 030105 genetics & heredity, Metastasis, 03 medical and health sciences, Fatal Outcome, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Neoplasm Invasiveness, Child, Genetics (clinical), Optic nerve tumor, Pia mater, Retinoblastoma, business.industry, Optic Nerve Neoplasms, Leptomeninges, medicine.disease, eye diseases, Ophthalmology, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, 030221 ophthalmology & optometry, Optic nerve, Resection margin, sense organs, business, Meningeal Carcinomatosis, Unilateral Retinoblastoma
Abstract: We present a 6-year-old boy with unilateral retinoblastoma of the left eye. MRI showed an intraocular tumor that extended into the optic nerve beyond the lamina cribrosa. The affected eye was enucleated and the optic nerve resection margin proved to be free. Following protocol, this patient received six courses of adjuvant systemic chemotherapy. Unfortunately, after 5 months this patient returned with the leptomeningeal spread of the tumor and died quickly thereafter.Histopathologic analysis of the enucleated eye and distal optic nerve revealed that the postlaminar tumor cells occupied the entire width of the optic nerve, extending all the way up to the pia mater, whereas, more often the tumor invasion is restricted to the center of the optic nerve. This was also visible on the MR images where contrast enhancement occupied the entire nerve width. A resection margin with tumor cells is recognized as a risk factor for metastasis, but perhaps the proximity of tumor cells to the leptomeninges should also be judged with caution as a potential increased risk for metastatic spread.
Published: 2020
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20. Asynchronous pineoblastoma is more likely after early diagnosis of retinoblastoma : a meta-analysis

Author: Charlotte J. Dommering, Brenda L. Gallie, Helen Dimaras, Sameh E. Soliman, Tero Kivelä, Wijnanda A. Kors, Robin W. Jansen, Marcus C. de Jong, Manohar Shroff, Furqan Shaikh, Pim de Graaf, Annette C. Moll, HUS Head and Neck Center, Silmäklinikka, Helsinki University Hospital Area, Radiology and nuclear medicine, Pediatric surgery, CCA - Cancer Treatment and quality of life, Human genetics, Ophthalmology, ACS - Diabetes & metabolism, APH - Quality of Care, and APH - Health Behaviors & Chronic Diseases
Subjects: Pediatrics, medicine.medical_specialty, PNET, MRI-BASED ASSESSMENT, Trilateral retinoblastoma, pineal gland, Retinal Neoplasms, Asymptomatic, retinoblastoma, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, magnetic resonance imaging, QUALITY, In patient, 3125 Otorhinolaryngology, ophthalmology, Stage (cooking), 10. No inequality, pineoblastoma, Pineoblastoma, AGED 0-5 YEARS, medicine.diagnostic_test, Brain Neoplasms, Retinoblastoma, business.industry, Infant, Magnetic resonance imaging, General Medicine, medicine.disease, Ophthalmology, Early Diagnosis, TRILATERAL RETINOBLASTOMA, PINEAL-GLAND, Meta-analysis, 030221 ophthalmology & optometry, medicine.symptom, LARGE POPULATION, business, CONSENSUS, Pinealoma, 030217 neurology & neurosurgery, MRI
Abstract: PURPOSE: To determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening.METHODS: We updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta-analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis.RESULTS: Seventy-nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs.CONCLUSIONS: An MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma.
Published: 2022
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21. Magnetic Resonance Imaging Can Reliably Differentiate Optic Nerve Inflammation from Tumor Invasion in Retinoblastoma with Orbital Cellulitis

Author: Robin W. Jansen, Sophie van der Heide, Liesbeth Cardoen, Selma Sirin, Christiaan M. de Bloeme, Paolo Galluzzi, Sophia Göricke, Hervé J. Brisse, Philippe Maeder, Saugata Sen, Eva Biewald, Jonas A. Castelijns, Annette C. Moll, Paul van der Valk, Marcus C. de Jong, Pim de Graaf, Radiology and nuclear medicine, Ophthalmology, CCA - Imaging and biomarkers, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, ACS - Diabetes & metabolism, Pathology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Otolaryngology / Head & Neck Surgery, AII - Cancer immunology, CCA - Cancer biology and immunology, and CCA - Cancer Treatment and quality of life
Subjects: Inflammation, Optic Neuritis, genetic structures, Choroid, Retinal Neoplasms, Medizin, Retinoblastoma, Optic Nerve, Orbital Cellulitis, Magnetic Resonance Imaging, eye diseases, Eye Enucleation, Cohort Studies, Ophthalmology, Necrosis, Case-Control Studies, Humans, Neoplasm Invasiveness, sense organs, Retrospective Studies
Abstract: Purpose: To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion. Design: A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case–control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls. Participants: A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis. Methods: In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case–control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons. Main Outcome Measures: Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed. Results: The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P < 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16–52) to 89% (95% CI, 72–98). Conclusions: Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes.
Published: 2021
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22. Multi-view convolutional neural networks for automated ocular structure and tumor segmentation in retinoblastoma

Author: Huu-Giao Nguyen, Marcus C. de Jong, Annette C. Moll, Pim de Graaf, Robin W. Jansen, Christiaan M. de Bloeme, Martijn D. Steenwijk, Hamza Kebiri, Victor I. J. Strijbis, Merixtell Bach-Cuadra, Radiation Oncology, Radiology and nuclear medicine, Otolaryngology / Head & Neck Surgery, Ophthalmology, CCA - Imaging and biomarkers, Anatomy and neurosciences, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, and ACS - Diabetes & metabolism
Subjects: Male, genetic structures, Mathematics and computing, Eye, Convolutional neural network, 030218 nuclear medicine & medical imaging, Automation, 0302 clinical medicine, Engineering, Medicine, Pyramid (image processing), Child, Cancer, Multidisciplinary, Retinoblastoma, Computational science, Retinal detachment, Magnetic Resonance Imaging, Sclera, medicine.anatomical_structure, Oncology, Child, Preschool, Female, Anatomy, Biomedical engineering, medicine.medical_specialty, Science, Retinal Neoplasms, Article, Eye cancer, 03 medical and health sciences, Deep Learning, Imaging, Three-Dimensional, Medical research, Retinal Diseases, Ophthalmology, Lens, Crystalline, Ocular structure, Humans, Eye diseases, Vitreous detachment, Retrospective Studies, Vitreous humour, business.industry, Infant, Newborn, Retinal Detachment, Infant, Translational research, medicine.disease, eye diseases, Vitreous Body, Neural Networks, Computer, sense organs, business, 030217 neurology & neurosurgery, Magnetic Resonance Angiography, Tumor segmentation
Abstract: In retinoblastoma, accurate segmentation of ocular structure and tumor tissue is important when working towards personalized treatment. This retrospective study serves to evaluate the performance of multi-view convolutional neural networks (MV-CNNs) for automated eye and tumor segmentation on MRI in retinoblastoma patients. Forty retinoblastoma and 20 healthy-eyes from 30 patients were included in a train/test (N = 29 retinoblastoma-, 17 healthy-eyes) and independent validation (N = 11 retinoblastoma-, 3 healthy-eyes) set. Imaging was done using 3.0 T Fast Imaging Employing Steady-state Acquisition (FIESTA), T2-weighted and contrast-enhanced T1-weighted sequences. Sclera, vitreous humour, lens, retinal detachment and tumor were manually delineated on FIESTA images to serve as a reference standard. Volumetric and spatial performance were assessed by calculating intra-class correlation (ICC) and dice similarity coefficient (DSC). Additionally, the effects of multi-scale, sequences and data augmentation were explored. Optimal performance was obtained by using a three-level pyramid MV-CNN with FIESTA, T2 and T1c sequences and data augmentation. Eye and tumor volumetric ICC were 0.997 and 0.996, respectively. Median [Interquartile range] DSC for eye, sclera, vitreous, lens, retinal detachment and tumor were 0.965 [0.950–0.975], 0.847 [0.782–0.893], 0.975 [0.930–0.986], 0.909 [0.847–0.951], 0.828 [0.458–0.962] and 0.914 [0.852–0.958], respectively. MV-CNN can be used to obtain accurate ocular structure and tumor segmentations in retinoblastoma.
Published: 2021
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23. Current Indications of Secondary Enucleation in Retinoblastoma Management: A Position Paper on Behalf of the European Retinoblastoma Group (EURbG)

Author: Helen Jenkinson, Francis L. Munier, Philippe Maeder, Christina Stathopoulos, Livia Lumbroso-Le Rouic, François Doz, Maja Beck Popovic, Guillermo L. Chantada, Annette C. Moll, Manoj Parulekar, Ophthalmology, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, CCA - Cancer Treatment and quality of life, CCA - Imaging and biomarkers, and Amsterdam Reproduction & Development (AR&D)
Subjects: Cancer Research, medicine.medical_specialty, Conservative management, Enucleation, Guidelines, survival, retinoblastoma, intra-arterial chemotherapy, External beam irradiation, 03 medical and health sciences, 0302 clinical medicine, Medicine, metastasis, Intensive care medicine, RC254-282, Biologic marker, intravenous chemotherapy, business.industry, Retinoblastoma, Disease progression, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, eye diseases, Oncology, 030220 oncology & carcinogenesis, 030221 ophthalmology & optometry, Position paper, secondary enucleation, external beam irradiation, business, Disease persistence
Abstract: Simple Summary Although secondary enucleation (SE) is the treatment of choice for retinoblastoma eyes that did not respond favorably to conservative therapies, clear criteria for its indication are, however, currently missing. In this position paper on behalf of the European Retinoblastoma Group (EURbG), we discuss the available literature on SE, including its influence on metastases rate and survival, and propose guidelines to assist decision-making to interrupt eye-preserving therapies depending on the availabilities of advanced diagnostic and therapeutic modalities. Absolute indications to SE may be restricted to eyes with refractory tumor activity resisting all salvage treatments or eyes under apparent tumor control but no visual potential and irreducible complications. In contrast, eyes with an obscured optic nerve head and/or ocular complications amenable to specific surgical or medical management can be considered relative indications, provided that appropriate follow-up can be implemented and that parents are fully aware of a residual risk. Abstract Secondary enucleation (SE) puts an irreversible end to eye-preserving therapies, whenever their prolongation is expected to violate the presumed state of metastatic grace. At present, it must be acknowledged that clear criteria for SE are missing, leading to empiric and subjective indications commonly related to disease progression or relapse, disease persistence masking the optic nerve head or treatment-related complications obscuring the fundus view. This absence of evidence-based consensus regarding SE is explained by the continuously moving frontiers of the conservative management as a result of diagnostic and therapeutic advances, as well as by the lack of studies sufficiently powered to accurately stratify the risk of metastasis in conservatively treated patients. In this position paper of the European Retinoblastoma Group (EURbG), we give an overview of the progressive shift in the indications for SE over the past decades and propose guidelines to assist decision-making with respect to when SE becomes imperative or recommended, with corresponding absolute and relative SE indications. Further studies and validation of biologic markers correlated with the risk of metastasis are expected to set more precisely the frontiers of conservative management and thus consensual criteria for SE in the future.
Published: 2021
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24. Benign Tumors in Long-Term Survivors of Retinoblastoma

Author: Jasmine H. Francis, Lindsay M. Morton, Annette C. Moll, Milo van Hoefen Wijsard, Johanna M. Seddon, Sara J. Schonfeld, Margaret A. Tucker, Ruth A. Kleinerman, David H. Abramson, Armida W. M. Fabius, Flora E. van Leeuwen, Ophthalmology, Epidemiology and Data Science, ACS - Diabetes & metabolism, CCA - Cancer Treatment and quality of life, APH - Quality of Care, and APH - Health Behaviors & Chronic Diseases
Subjects: 0301 basic medicine, Oncology, subsequent benign tumor, Cancer Research, medicine.medical_specialty, retinoblastoma survivor, lipoma, lcsh:RC254-282, Article, retinoblastoma, Benign tumor, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, leiomyoma, Epidemiology, medicine, RB1, Cumulative incidence, Family history, cumulative incidence, Retinoblastoma, business.industry, subsequent malignant neoplasms, Lipoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, Leiomyoma, 030220 oncology & carcinogenesis, Hereditary Retinoblastoma, epidemiology, hereditary retinoblastoma, business
Abstract: Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914–2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%, 95% confidence interval [CI] = 12.9–22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%, 95%CI = 2.2–6.4%), corresponding to 4.9-fold (95%CI = 2.8–8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%, 95%CI = 7.7–22.1%) and leiomyoma among females (8.9%, 95%CI = 5.2–13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0–6.1) increased risk of developing a benign tumor, the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1–2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.
Published: 2021
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25. Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG)

Author: Angelika Eggert, Nadezhda Fedorovna Bobrova, Madlen Reschke, Doris Hadjistilianou, Hatice Tuba Atalay, Annette C. Moll, Martin Ebinger, Eva Biewald, Katarzyna Pawinska-Wasikowska, Catriona Duncan, Hayyam Kiratli, Karel Svojgr, David Garcia Aldana, François Doz, Ines B Brecht, Francis L. Munier, Constantino Sábado Álvarez, Erika Maka, Yelena Diarra, Floor Abbink, Nikolaos E. Bechrakis, Beate Timmermann, Nathalie Cassoux, Tomáš Kepák, Maja Beck Popovic, Petra Ritter-Sovinz, Vicktoria Vishnevskia-Dai, Shani Caspi, Guillermo Chantada, Guilherme Castela, Artur Klett, Olga Rutynowska-Pronicka, Enrico Opocher, Ida Russo, Sabine Dittner-Moormann, Jelena Rascon, Isabelle Aerts, Helen Jenkinson, Petra Ketteler, Sonsoles San Roman Pacheco, Pediatric surgery, CCA - Cancer Treatment and quality of life, Ophthalmology, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, ACS - Diabetes & metabolism, Institut Català de la Salut, [Dittner-Moormann S] Department of Pediatric Hematology and Oncology, University Duisburg-Essen, University Hospital Essen, Essen, Germany. [Reschke M] Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany. [Abbink FCH] Amsterdam UMC, Location VU University Medical Centre, Amsterdam, The Netherlands. [Aerts I] Institut Curie, PSL Research University and University of Paris, Paris, France. [Atalay HT] Gazi University School of Medicine, Ankara, Turkey. [Fedorovna Bobrova N] Filatov Eye Institute Odessa, Odessa, Ukraine. [Sábado Álvarez C] Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Investigative Techniques::Epidemiologic Methods::Data Collection::Surveys and Questionnaires [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Oncology, genetic structures, medicine.medical_treatment, Medizin, childhood cancer, chemotherapy, terapéutica::tratamiento combinado [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], metastasis, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols, biomarker, Child, Retinoblastoma, Extraocular Retinoblastoma, Hematology, Prognosis, Combined Modality Therapy, RB1 gene, 3. Good health, Europe, Chemotherapy, Adjuvant, Child, Preschool, 030220 oncology & carcinogenesis, Resection margin, neoplasias::neoplasias::neoplasias::neoplasias::neoplasias por localización::neoplasias del ojo::neoplasias de la retina::retinoblastoma [ENFERMEDADES], Adjuvant, medicine.medical_specialty, Retinal Neoplasms, Enucleation, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Enquestes, Intraocular Retinoblastoma, Eye Enucleation, 03 medical and health sciences, Internal medicine, medicine, Adjuvant therapy, Humans, Neoplasms::Neoplasms::Neoplasms::Neoplasms::Neoplasms by Site::Eye Neoplasms::Retinal Neoplasms::Retinoblastoma [DISEASES], radiotherapy, Retina - Càncer - Radioteràpia, business.industry, técnicas de investigación::métodos epidemiológicos::recopilación de datos::encuestas y cuestionarios [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.disease, eye diseases, Retina - Càncer - Quimioteràpia, Therapeutics::Combined Modality Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Radiation therapy, Pediatrics, Perinatology and Child Health, Radiotherapy, Adjuvant, sense organs, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], business, 030215 immunology
Abstract: Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia 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. Open access funding enabled and organized by Projekt DEAL.
Published: 2021
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26. Ocular characteristics and complications in patients with osteogenesis imperfecta: a systematic review

Author: Ralph de Vries, Nathalie Bravenboer, Ebba A E Ghyczy, Frank D. Verbraak, Stuart H. Ralston, Sanne Treurniet, Elisabeth M.W. Eekhoff, Katie R Curro-Tafili, Annette C. Moll, Dimitra Micha, and Pia Burger
Subjects: Connective Tissue Disorder, medicine.medical_specialty, genetic structures, Eye Diseases, Eye disease, Blindness, Collagen Type I, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cornea, Ophthalmology, medicine, Humans, In patient, Bone mineral, business.industry, General Medicine, Osteogenesis Imperfecta, medicine.disease, eye diseases, Sclera, medicine.anatomical_structure, Phenotype, Osteogenesis imperfecta, Minor trauma, Mutation, 030221 ophthalmology & optometry, sense organs, business, 030217 neurology & neurosurgery
Abstract: Purpose Osteogenesis imperfecta (OI) is a rare inherited heterogeneous connective tissue disorder characterized by bone fragility, low bone mineral density, skeletal deformity and blue sclera. The dominantly inherited forms of OI are predominantly caused by mutations in either the COL1A1 or COL1A2 gene. Collagen type I is one of the major structural proteins of the eyes and therefore is the eye theoretically prone to alterations in OI. The aim of this systematic review was to provide an overview of the known ocular problems reported in OI. Methods A literature search (in PubMed, Embase and Scopus), which included articles from inception to August 2020, was performed in accordance with the PRISMA guidelines. Results The results of this current review show that almost every component of the eye could be affected in OI. Decreased thickness of the cornea and sclera is an important factor causing eye problems in patients with OI such as blue sclera. Findings that stand out are ruptures, lacerations and other eye problems that occur after minor trauma, as well as complications from standard surgical procedures. Discussion Alterations in collagen type I affect multiple structural components of the eye. It is recommended that OI patients wear protective glasses against accidental eye trauma. Furthermore, when surgery is required, it should be approached with caution. The prevalence of eye problems in different types of OI is still unknown. Additional research is required to obtain a better understanding of the ocular defects that may occur in OI patients and the underlying pathology.
Published: 2021
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27. Incidence of Retinoblastoma Has Increased: Results from 40 European Countries

Author: Andrew W. Stacey, Richard Bowman, Allen Foster, Tero T. Kivelä, Francis L. Munier, Nathalie Cassoux, Ido Didi Fabian, Lamis Al Harby, Silvia Alarcón Portabella, Donjeta B. Alia, Charlotta All-Eriksson, Romanzo Antonino, Nicholas J. Astbury, Julia Balaguer, Walentyna Balwierz, Honorio Barranco, Covadonga Bascaran, Maja Beck Popovic, Eva M. Biewald, Nadia Bobrova, Norbert Bornfeld, Bénédicte G. Brichard, Sharon Blum, Michael Capra, Guilherme Castela, Jaume Català-Mora, Guillermo L. Chantada, Violeta S. Chernodrinska, Krzysztof Cieslik, Codruta Comsa, Maria G. Correa Llano, Monika Csóka, Patrick De Potter, Laurence Desjardins, Monica D. Dragomir, Ana Fernández-Teijeiro, David García Aldana, Pernille A. Gregersen, Nir Gomel, Theodora Hadjistilianou, Stanislava Hederova, Marlies Hummlen, Kristina Husakova, Russo Ida, Vesna R. Ilic, Helen Jenkinson, Noa Kapelushnik, Tamar Kardava, Naama Keren-Froim, Tomas Kepak, Zaza Khotenashvili, Artur Klett, Dalia Krivaitiene, Slobodanka Latinović, Livia Lumbroso, Lesia Lysytsia, Erika Maka, Nieves Martín Begue, Edoardo Midena, Annette C. Moll, Gabriela Murgoi, Larisa Naumenko, Vladimir Neroev, Marina Nikitovic, Andrzej Olechowski, Ruzanna Papyan, Raffaele Parrozzani, Manoj V. Parulekar, Katarzyna Pawinska-Wasikowska, Sanja Perić, Pavel Pochop, Vladimir G. Polyakov, M. Ashwin Reddy, Petra Ritter-Sovinz, Svetlana Saakyan, Mandeep S. Sagoo, Sonsoles San Román Pacheco, Stefan Seregard, Sónia Silva, Tetyana Sorochynska, Christina Stathopoulos, Branka Stirn Kranjc, Karel Svojgr, Gevorg Tamamyan, Alketa Tandili, Bekim Tateshi, Manca Tekavcic Pompe, Steen F. Urbak, Tatiana L. Ushakova, Sandra Valeina, Milo van Hoefen Wijsard, Nevyana V. Veleva-Krasteva, Maris Viksnins, Werner Wackernagel, Charlotte Wolley Dod, Vera A. Yarovaya, Andrey A. Yarovoy, Katsiaryna Zhilyaeva, Marcia Zondervan, Ophthalmology, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, CCA - Cancer Treatment and quality of life, CCA - Imaging and biomarkers, and Amsterdam Reproduction & Development (AR&D)
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Retinal Neoplasms, MEDLINE, 03 medical and health sciences, 0302 clinical medicine, Familial, Genetic, Fitness, Medicine, Humans, Child, business.industry, Retinoblastoma, Incidence (epidemiology), Incidence, Infant, Newborn, Infant, medicine.disease, Europe, Ophthalmology, Cross-Sectional Studies, 030220 oncology & carcinogenesis, Child, Preschool, 030221 ophthalmology & optometry, Female, business
Published: 2021
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28. MR Imaging Features to Differentiate Retinoblastoma from Coats' Disease and Persistent Fetal Vasculature

Author: Annette C. Moll, Paul van der Valk, Marcus C. de Jong, Sabrina Schlueter, Paolo Galluzzi, Nathalie Cassoux, Robin W. Jansen, Sophia Göricke, Liesbeth Cardoen, Philippe Maeder, Christiaan M. de Bloeme, Hervé J Brisse, Francis L. Munier, Pim de Graaf, Theodora Hadjistilianou, Jonas A. Castelijns, Arnaud Gauthier, Radiology and nuclear medicine, CCA - Imaging and biomarkers, Pathology, Ophthalmology, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, and ACS - Diabetes & metabolism
Subjects: Cancer Research, medicine.medical_specialty, Pathology, Medizin, lcsh:RC254-282, Article, retinoblastoma, 030218 nuclear medicine & medical imaging, Lesion, 03 medical and health sciences, 0302 clinical medicine, medicine, pseudoretinoblastoma, Coats’ disease, Coats' disease, Persistent fetal vasculature, persistent fetal vasculature, Retinoblastoma, business.industry, nutritional and metabolic diseases, food and beverages, Retinal detachment, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Pediatric cancer, eye diseases, medicine.anatomical_structure, Oncology, 030221 ophthalmology & optometry, Histopathology, medicine.symptom, business, MRI, Optic disc
Abstract: 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&rsquo, 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 (p &lt, 0.001&ndash, 0.022, specificity 93&ndash, 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 (p &lt, 0.022, specificity 91&ndash, 100%). Additionally, three newly identified imaging features were exclusively present in pseudoretinoblastoma: intraretinal macrocysts (p &lt, 0.001, 38% [9/24] in Coats&rsquo, disease and 20% [2/10] in PFV), contrast enhancement outside the solid lesion (p &lt, 0.001, 30% [7/23] in Coats&rsquo, disease and 57% [4/7] in PFV), and enhancing subfoveal nodules (38% [9/24] in Coats&rsquo, disease). An assessment strategy was proposed for MR imaging differentiation between retinoblastoma and pseudoretinoblastoma, including three newly identified differentiating MR imaging features.
Published: 2020
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29. Collaboration Around Rare Bone Diseases Leads to the Unique Organizational Incentive of the Amsterdam Bone Center

Author: Dimitra Micha, Teun J. de Vries, Thadé Goderie, Elisabeth M.W. Eekhoff, Frank F. D. Verbraak, Marjolijn Gilijamse, Jakko A. Nieuwenhuijzen, Lothar A. Schwarte, Jack J. W. A. van Loon, Pieter G. Raijmakers, Annette C. Moll, Angela Ridwan-Pramana, Max Dahele, Otto Kamp, K. Hakki Karagozoglu, Ebba A. E. Ghyczy, Henri A. H. Winters, Thomas Rustemeyer, Paul van de Valk, Nathalie Bravenboer, Marco N. Helder, Adriaan A. Lammertsma, Alessandra Maugeri, Bernd P. Teunissen, Peter Kloen, Jenneke Klein-Nulend, Peeroz Saeed, Arend Bökenkamp, Hans J. C. Baayen, Georgios F. Giannakópoulos, Jan Maerten Smit, Tymour Forouzanfar, Cas Smits, Maqsood M. Yaqub, Pim de Graaf, Patrick Schober, Chris Dickhoff, J. Coen Netelenbos, Willem Lems, Anco Boonstra, Guus A. M. Eeckhout, Wouter D. Lubbers, Peter Koolwijk, Sanne Treurniet, Jeroen J. W. M. Janssen, Katie K. R. Curro-Tafili, Ton Schoenmaker, Esther Pekel, Marieke C. Visser, Gerard Pals, Esmée Botman, Matthijs Botman, Bernard J. Smilde, Surgery, AMS - Tissue Function & Regeneration, AMS - Musculoskeletal Health, APH - Personalized Medicine, APH - Quality of Care, Orthopedic Surgery and Sports Medicine, Maxillofacial Surgery (VUmc), Periodontology, Oral Cell Biology, Academic Centre for Dentistry Amsterdam, Amsterdam Movement Sciences, Amsterdam Movement Sciences - Rehabilitation & Development, AGEM - Endocrinology, metabolism and nutrition, ACS - Diabetes & metabolism, Internal medicine, Human genetics, Amsterdam Movement Sciences - Restoration and Development, Oral and Maxillofacial Surgery / Oral Pathology, Anesthesiology, Radiology and nuclear medicine, Amsterdam Reproduction & Development (AR&D), Pediatric surgery, Pulmonary medicine, ACS - Heart failure & arrhythmias, Cardiology, Urology, Other Research, Neurosurgery, Radiation Oncology, Otolaryngology / Head & Neck Surgery, APH - Aging & Later Life, Pathology, Cardio-thoracic surgery, APH - Health Behaviors & Chronic Diseases, Ophthalmology, Dermatology, Rheumatology, Plastic, Reconstructive and Hand Surgery, ACS - Microcirculation, Physiology, Clinical chemistry, APH - Methodology, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
Subjects: 0301 basic medicine, Knowledge management, Bone disease, Interprofessional Relations, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, Organizational model, 030209 endocrinology & metabolism, non-hierarchical, lcsh:Diseases of the endocrine glands. Clinical endocrinology, clinical, Competition (economics), 03 medical and health sciences, collaborative organization, Rare Diseases, Endocrinology, 0302 clinical medicine, SDG 17 - Partnerships for the Goals, Multidisciplinary approach, amsterdam bone center (ABC), Research environment, medicine, Humans, Center (algebra and category theory), Cooperative Behavior, Netherlands, media_common, Patient Care Team, Motivation, lcsh:RC648-665, research, business.industry, medicine.disease, Quality Improvement, 030104 developmental biology, Incentive, Perspective, rare bone diseases, Business, Bone Diseases, Delivery of Health Care, Autonomy
Abstract: In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the “collaborative organizational model” of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition.
Published: 2020
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30. Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries

Author: Tero Kivelä, Marina Nikitovic, Dalia Krivaitiene, Tamar Kardava, Stefan Seregard, Kristína Husáková, Fousseyni Traore, Claude Moreira, Vera Yarovaya, Donjeta B. Alia, Chatonda Manda, Mariana Kruger, Ghislaine Obono-Obiang, Argentino A. Almeida, Nevyana V. Veleva-Krasteva, Petra Ritter-Sovinz, Bekim Tateshi, Dupe S Ademola-Popoola, Sanja Perić, Oluyemi Fasina, Jennifer Geel, Steen F Urbak, Grace Ssali, Katsiaryna Zhilyaeva, Nieves Martín Begue, Aemero A. Mengesha, Gerald Msukwa, Larisa Naumenko, Monica D. Dragomir, Gabrielle C. Bouda, P. Kemilev, Henry Nkumbe, Amany M. Ali, Slobodanka Latinović, Amaria Boumedane, Ido Didi Fabian, Jaume Català-Mora, Walentyna Balwierz, Theodora Hadjistilianou, Marlies Hummlen, Laila Hessissen, Shelley J. Biddulph, Vesna R. Ilic, Okwen M. Muyen, Michael Capra l, Edoardo Midena, Shehu U. Abdullahi, Ruzanna Papyan, Allen Foster, Annette C. Moll, Laurence Desjardins, Covadonga Bascaran, Sónia Silva, Ahmed A. Mohamedani, Krzysztof Cieslik, Naama Keren-Froim, Milo van Hoefen Wijsard, Mahmoud M. Elzembely, Marchelo Matua, Sidi Sidi Cheikh, Charlotta All-Eriksson, Ana Fernández-Teijeiro, Furahini G. Mndeme, Karin Lecuona, David Garcia Aldana, Katarzyna Pawinska-Wasikowska, Maja Beck Popovic, Léa Raobela, Vladimir Neroev, Remezo Philbert, Kareem Olatunbosun Musa, Gita Naidu, Mutale Nyaywa, Rolande L. Kabore, Shirley Sharabi, Erika Maka, Abubakar Kalinaki, Alaa Elhaddad, Charlotte Wolley Dod, Stanislava Hederová, Jenny M. Yanga, Nissrine Bennani Guebessi, Helen Jenkinson, Sally Painter, Russo Ida, Werner Wackernagel, Harba Tyau-Tyau, Honorio Barranco, Sadik Taju Sherief, Diriba F. Hordofa, Jonathan J. Pons, Bénédicte Brichard, David K Stones, Guilherme Castela, S.V. Saakyan, Peter Osei-Bonsu, Amal M. Elbahi, Zelalem Gizachew, Codruta Comsa, Ali Bala Umar, Mussagy M. Riheia, Manca Tekavčič Pompe, Elhassan Abdallah, Noa Kapelushnik, Sadiq Hassan, Magritha Du Bruyn, Rose Atsiaya, Robert M Lukamba, Tomáš Kepák, Freddy B. Mbumba, Karel Svojgr, Asmaa El Kettani, Branka Stirn Kranjc, Monika Csóka, Norbert Bornfeld, Pavel Pochop, Sonsoles San Roman Pacheco, Silvia Alarcón Portabella, Amelia D.C. Wime, Ngozi C Oguego, Keith M. Waddell, Nathalie Cassoux, Dina Elgalaly, Eva Biewald, Fatoumata Sylla, Pernille Axel Gregersen, Hamzah Mustak, Lamis Al Harby, Ada Aghaji, Othman Ao Ziko, Sharon Blum, Theophile B Amani Kabesha, Nick Astbury, Rokia C. Berete, Andrew W. Stacey, V.G. Polyakov, Kangwa I. Muma, Marianna Boehme, Vivian Paintsil, Richard Bowman, Vera Adobea Essuman, Koffi M. Guedenon, Amina H Wali Nigeria, Julia Balaguer, Maris Viksnins, Ismail Mayet, Tetyana Sorochynska, Patrick De Potter, Alketa Tandili, Lesia Lysytsia, Tatiana L Ushakova, Judy Schoeman, Sandra Valeina, Moawia Mohammed Ali Elhassan, Moira Gandiwa, Alice Kyara, M. Ashwin Reddy, Livia Lumbroso, Isac V. Da Gama, Marcia Zondervan, Zaza Khotenashvili, Hédi Bouguila, Azza Ma Said, Nadia Bobrova, Faraja S. Chiwanga, Christina Stathopoulos, Alan Davidson, Sarra Benmiloud, Francis L. Munier, Mayuri Makan, Eva S Lachmann, Gevorg Tamamyan, Romanzo Antonino, Ibrahim O. Matende, Guillermo Chantada, AO Adio, Jess Elio Kosh Komba Palet, Manoj Parulekar, Luisa Paiva, Trish A. Scanlan, Nir Gomel, Khalifa M. Alsawidi, Artur Klett, Violeta Chernodrinska, Ekhtelbenina Zein, Mandeep S. Sagoo, Sahadatou Adamou Boubacar, A. Oscar, Raffaele Parrozzani, McHikirwa S. Msina, David Reynders, Elizabeth D Nkanga, Gabriela Murgoi, Andrey A. Yarovoy, Dahiru Ribadu, PD Wade, Amadou I. Alfa Bio, Lorna Renner, Ted Grimbert A. Evina, Paule Aïda Ndoye Roth, Maria G. Correa Llano, Tuyisabe Theophile, and Andrzej Olechowski
Subjects: medicine.medical_specialty, Referral, Epidemiology, Retinal Neoplasms, Medizin, Disease, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Risk Factors, Neoplasia, Medicine, Humans, business.industry, Retinoblastoma, Extraocular Retinoblastoma, medicine.disease, eye diseases, Sensory Systems, 3. Good health, Ophthalmology, Cross-Sectional Studies, 030220 oncology & carcinogenesis, Africa, 030221 ophthalmology & optometry, Health education, Residence, Presentation (obstetrics), Epidemiology, Neoplasia, business, human activities, Demography
Abstract: BackgroundThe 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.MethodsA 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.ResultsCapture 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, pConclusionsFewer 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.
Published: 2020
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31. Optical coherence tomography (OCT) to image active and inactive retinoblastomas as well as retinomas

Author: Johannes F. de Boer, Frank D. Verbraak, Marie-Claire Gaillard, Nuray A. McNeill-Badalova, Machteld I. Bosscha, Armida W. M. Fabius, Francis L. Munier, Annette C. Moll, Oleg Nadiarnykh, Biophotonics and Medical Imaging, Amsterdam Neuroscience - Brain Imaging, LaserLaB - Biophotonics and Microscopy, Amsterdam Reproduction & Development (AR&D), Ophthalmology, Amsterdam Neuroscience - Systems & Network Neuroscience, CCA - Imaging and biomarkers, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, and ACS - Diabetes & metabolism
Subjects: Adult, Male, medicine.medical_specialty, retina, Supine position, Adolescent, genetic structures, Retinal Neoplasms, Age at diagnosis, retinoblastoma, 03 medical and health sciences, 0302 clinical medicine, Optical coherence tomography, SDG 3 - Good Health and Well-being, Ophthalmology, Medicine, Humans, optical coherence tomography, paediatric oncology, regression patterns, retinoma, Child, medicine.diagnostic_test, business.industry, Retinoblastoma, Paediatric oncology, Infant, General Medicine, Original Articles, Middle Aged, medicine.disease, eye diseases, Neoplasm Regression, Spontaneous, Child, Preschool, 030221 ophthalmology & optometry, Original Article, Female, sense organs, business, 030217 neurology & neurosurgery, Tomography, Optical Coherence
Abstract: PurposeTo illustrate Optical Coherence Tomography (OCT) images of active and inactive retinoblastoma (Rb) tumours.MethodsCurrent 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.ResultsTwelve 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.ConclusionOptical 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.
Published: 2020
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32. Comparing the Efficacy of Bevacizumab and Ranibizumab in Patients with Diabetic Macular Edema (BRDME): The BRDME Study, a Randomized Trial

Author: Maartje J C, Vader, Ann-Sofie M E, Schauwvlieghe, Frank D, Verbraak, Greetje, Dijkman, Johanna M M, Hooymans, Leonoor I, Los, Aeilko H, Zwinderman, Tunde, Peto, Carel B, Hoyng, Redmer, van Leeuwen, Johannes R, Vingerling, Annette C, Moll, Janneke J C, van Lith-Verhoeven, Marcel G W, Dijkgraaf, and Reinier O, Schlingemann
Subjects: Male, Vascular Endothelial Growth Factor A, Diabetic Retinopathy, Visual Acuity, Angiogenesis Inhibitors, Middle Aged, Macular Edema, Bevacizumab, Treatment Outcome, Double-Blind Method, Ranibizumab, Intravitreal Injections, Humans, Female, Macula Lutea, Prospective Studies, Tomography, Optical Coherence, Follow-Up Studies
Abstract: To generate conclusive evidence regarding the noninferiority of intravitreal bevacizumab compared with ranibizumab in patients with diabetic macular edema (DME).Comparative, randomized, double-masked, multicenter, noninferiority clinical trial.Eligible patients were older than 18 years, diagnosed with type 1 or type 2 diabetes mellitus, with glycosylated hemoglobin of less than 12%, central area thickness of more than 325 μm, and visual impairment from DME with a best-corrected visual acuity (BCVA) between 24 letters and 78 letters.From June 2012 through February 2018, a total of 170 participants were randomized to receive 6 monthly injections of either 1.25 mg bevacizumab (n = 86) or 0.5 mg ranibizumab (n = 84).Primary outcome was change in BCVA from baseline to month 6 compared between the 2 treatment arms. The noninferiority margin was 3.5 letters.The difference in mean BCVA between treatment arms was 1.8 letters in favor of ranibizumab after 6 months of follow-up; BCVA improved by 4.9±6.7 letters in the bevacizumab group and 6.7±8.7 letters in the ranibizumab group. The lower bound of the 2-sided 90% confidence interval (CI) was -3.626 letters, exceeding the noninferiority margin of 3.5 letters. Central area thickness decreased more with ranibizumab (138.2±114.3 μm) compared with bevacizumab (64.2±104.2 μm). In a post hoc subgroup analysis, participants with a worse BCVA at baseline (≤69 letters) improved by 6.7±7.0 letters with bevacizumab and 10.4±10.0 letters with ranibizumab, and central area thickness decreased significantly more in the ranibizumab arm of this subgroup compared with the bevacizumab arm. Participants with an initially better BCVA at baseline (≥70 letters) did not demonstrate differences in BCVA or OCT outcomes between treatment arms.Based on change in BCVA from baseline to month 6, the noninferiority of 1.25 mg bevacizumab to 0.5 mg ranibizumab was not confirmed. Only the subgroup of patients with a lower BCVA at baseline showed better visual acuity and anatomic outcomes with ranibizumab. Our study confirmed the potential differential efficacy of anti-vascular endothelial growth factor agents in the treatment of DME as well as the difference in response between patient groups with different baseline visual acuities.
Published: 2020

33. Non-invasive tumor genotyping using radiogenomic biomarkers, a systematic review and oncology-wide pathway analysis

Author: Catharina W Menke-van der Houven van Oordt, Adrianus J. de Langen, Marcus C. de Jong, Jonas A. Castelijns, Roland M. Martens, Josephine C. Dorsman, Irsan E. Kooi, Pim de Graaf, B.H.E. Jansen, Paul van Amstel, Robin W. Jansen, Annette C. Moll, and Pieter Wesseling
Subjects: Oncology, medicine.medical_specialty, precision medicine, radiogenomics, non-invasive, Radiogenomics, Review, Disease, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Glioma, medicine, Genotyping, business.industry, Non invasive, Pathway analysis, Precision medicine, medicine.disease, genotyping, 030220 oncology & carcinogenesis, biomarker, Biomarker (medicine), business
Abstract: With targeted treatments playing an increasing role in oncology, the need arises for fast non-invasive genotyping in clinical practice. Radiogenomics is a rapidly evolving field of research aimed at identifying imaging biomarkers useful for non-invasive genotyping. Radiogenomic genotyping has the advantage that it can capture tumor heterogeneity, can be performed repeatedly for treatment monitoring, and can be performed in malignancies for which biopsy is not available. In this systematic review of 187 included articles, we compiled a database of radiogenomic associations and unraveled networks of imaging groups and gene pathways oncology-wide. Results indicated that ill-defined tumor margins and tumor heterogeneity can potentially be used as imaging biomarkers for 1p/19q codeletion in glioma, relevant for prognosis and disease profiling. In non-small cell lung cancer, FDG-PET uptake and CT-ground-glass-opacity features were associated with treatment-informing traits including EGFR-mutations and ALK-rearrangements. Oncology-wide gene pathway analysis revealed an association between contrast enhancement (imaging) and the targetable VEGF-signalling pathway. Although the need of independent validation remains a concern, radiogenomic biomarkers showed potential for prognosis prediction and targeted treatment selection. Quantitative imaging enhanced the potential of multiparametric radiogenomic models. A wealth of data has been compiled for guiding future research towards robust non-invasive genomic profiling.
Published: 2018
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34. Persistent socket pain postenucleation and post evisceration: a systematic review

Author: Daphne L. Mourits, Dyonne T. Hartong, Charlotte S. E. Hogeboom, Johannes C.F. Ket, Annette C. Moll, and H. Stevie Tan
Subjects: medicine.medical_specialty, Eye Diseases, medicine.medical_treatment, Enucleation, Eye Enucleation, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Orbital Diseases, medicine, Eye Pain, Humans, Evisceration (ophthalmology), Pain, Postoperative, Trochleitis, business.industry, Chronic pain, General Medicine, Evidence-based medicine, medicine.disease, Surgery, Ophthalmology, Dry socket, 030221 ophthalmology & optometry, business, Phantom pain, Eye Evisceration, 030217 neurology & neurosurgery
Abstract: Purpose To investigate causes, diagnostics and treatment modalities for persistent socket pain (PSP) after enucleation and evisceration. Methods A systematic search was undertaken in accordance with the PRISMA Statement, in PubMed, Embase.com and Thomson Reuters/Web of Science. We searched for relevant papers until the 28th of July 2016. Inclusion criteria were (1) patients with a history of enucleation or evisceration, (2) PSP, (3) report of the cause and/or used diagnostics and/or treatment modality, (4) full text in English, Dutch or Spanish language. Excluded were (1) review articles, (2) comments, and publications concerning, (3) nonhumans, (4) exenterated patients, (5) acute postoperative pain, or (6) periorbital pain without pain in the socket. Given the lack of high quality evidence from randomized controlled trials, we examined all available evidence from primary observational studies and assessed quality within this lower level of evidence. Results A total of 32 studies were included. Causes of PSP found were prosthesis-related (n = 5), dry socket (n = 2), trochleitis (n = 3), compression of the trigeminal nerve (n = 2), implant-related (n = unknown), inflammation (n = 5), surgery-related (n = 4), neuromas (n = 8), malignant tumours (n = 3), psychiatric/psychosocial (n = 2), phantom pain (n = 149), rarer entities (n = 3) or unknown (n = 14). Nonsurgical treatments suffice for conditions as trochleitis, prosthesis-related pain, dry socket and for phantom pain. Other causes of pain may require more invasive treatments such as implant removal. Conclusion Careful history and examination can give some direction in the diagnostic procedure; however, PSP is probably multifactorial and the specific origin(s) may remain uncertain. Implant replacement can be an effective treatment. Studies to identifiy less invasive procedures are required.
Published: 2018
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35. Cosmetic results of enucleation and/or external beam radiation therapy in 195 retinoblastoma survivors

Author: Daphne L. Mourits, Machteld I. Bosscha, Annette C. Moll, H. Stevie Tan, Dyonne T. Hartong, Birgit I. Lissenberg-Witte, Ophthalmology, Amsterdam Reproduction & Development (AR&D), CCA - Cancer Treatment and quality of life, Epidemiology and Data Science, APH - Methodology, ACS - Diabetes & metabolism, APH - Quality of Care, and APH - Health Behaviors & Chronic Diseases
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Retinal Neoplasms, Enucleation, Prosthesis, Eye Enucleation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Ptosis, medicine, Humans, Survivors, Child, Survival rate, Aged, Netherlands, Retrospective Studies, Aged, 80 and over, business.industry, Retinoblastoma, Retrospective cohort study, General Medicine, Middle Aged, Surgery, Survival Rate, Ophthalmology, medicine.anatomical_structure, Cross-Sectional Studies, Patient Satisfaction, Child, Preschool, 030221 ophthalmology & optometry, Female, Eyelid, Implant, medicine.symptom, business, Orbit, 030217 neurology & neurosurgery, Orbital Implants
Abstract: Purpose: To report the cosmetic outcome and late effects of enucleation and/or irradiation for retinoblastoma and to evaluate the role of orbital implants. Methods: Patients (age >4 years) enucleated and/or irradiated for retinoblastoma, visiting the hospital for routine follow-up (April 2013 to May 2015), were included in our cross-sectional study. Data were obtained via clinical records, questionnaires, physical measurements and standardized photographs. Two independent observers scored the cosmetic features: upper eyelid position, lower eyelid position, volume deficiency, and prosthesis motility and overall cosmetic appearance. Results: A total of 195 patients participated. Ptosis was seen in 45 (28.3%) patients, lower lid sagging in 45 (28.3%). Both complications were associated with the orbital implant; ptosis being more common with increasing implant size (5.6% without implant, 16.7% with small implant, 37.1% with medium implant and 76.9% with large implant) and lower lid sagging being more common in patients without implant (20% with implant versus 37.5% without). Volume loss of the superior sulcus was seen in 107 sockets (66.9%), most frequent in additionally irradiated patients (χ2(2) = 42.7, p
Published: 2018
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36. 9.4T and 17.6T MRI of Retinoblastoma: Ex Vivo evaluation of microstructural anatomy and disease extent compared with histopathology

Author: Paul van der Valk, Jonas A. Castelijns, Jeroen J. G. Geurts, Louise van der Weerd, Petra J. W. Pouwels, Jan-Willem M Beenakker, Annette C. Moll, Robin W. Jansen, Marcus C. de Jong, and Pim de Graaf
Subjects: Pathology, medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, business.industry, Retinoblastoma, Enucleation, Population, Magnetic resonance imaging, medicine.disease, Intraocular Retinoblastoma, eye diseases, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030221 ophthalmology & optometry, Medicine, Radiology, Nuclear Medicine and imaging, Histopathology, Choroid, business, education, Ex vivo
Abstract: Background Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. Purpose To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. Study type Prospective case series. Population Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). Field strength/sequence In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. Assessment After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). Results Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 μm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 μm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. Data conclusion Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. Level of evidence 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.
Published: 2017
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37. Feasibility of RetinoQuest: e-health application to facilitate and improve additional care for retinoblastoma survivors

Author: Armida W. M. Fabius, Wijnanda A. Kors, Annette C. Moll, Ton Houffelaar, Machteld I. Bosscha, Nuray A. McNeill, Irma M. Verdonck-de Leeuw, Jennifer van Dijk, CCA - Cancer Treatment and quality of life, Pediatric surgery, Ophthalmology, Medical psychology, APH - Personalized Medicine, APH - Mental Health, Otolaryngology / Head & Neck Surgery, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, Amsterdam Reproduction & Development (AR&D), and ACS - Diabetes & metabolism
Subjects: Male, Quality of life, medicine.medical_specialty, Adolescent, Referral, Clinical practice, Health informatics, Article, Proxy (climate), 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Cancer Survivors, Surveys and Questionnaires, medicine, Humans, Patient Reported Outcome Measures, 030212 general & internal medicine, Child, Patient reported outcomes, Structured communication, E-health, Oncology (nursing), Retinoblastoma, business.industry, Public health, medicine.disease, humanities, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Physical therapy, Feasibility Studies, Female, business, Psychosocial
Abstract: Purpose The current study aimed to evaluate the feasibility of RetinoQuest in clinical practice, from survivors and healthcare professionals’ (HCPs) point of view. Methods RetinoQuest is a touch screen computer program to monitor health-related quality of life (HRQoL) of retinoblastoma survivors via patient-reported outcome measures (PROMs) targeting children (4–10 years) as evaluated by their parents (proxy measures), adolescents (11–18 years), and adults. Feasibility was evaluated by the actual time taken to complete the PROMs, acceptability of the time as perceived by the users, the content of PROMs in RetinoQuest, and overall satisfaction with RetinoQuest. Results Ninety-six survivors participated: 41 parents of children, 38 adolescents, and 17 adults. Mean time to complete the evaluation form was 7.8 min (median 6.7, range 2.4–24.5), and 90% of the users stated that the time needed to complete PROMs in RetinoQuest was acceptable. The majority of users reported that it was important to answer the questions (88% of the parents, 66% of the adolescents, and 76% of the adult survivors) and that all important issues were covered, e.g., no missing questions (78, 84, and 76%, respectively). Satisfaction rate was high, 7.8 according to parents, 8.1 according to adolescents, and 7.7 for adults. Conclusions RetinoQuest is a feasible e-health application to monitor HRQoL in retinoblastoma survivors in clinical practice. Implications for cancer survivors This tool allows for open and structured communication which can lead to early detection of psychosocial impacts on quality of life and referral of the retinoblastoma survivors. Electronic supplementary material The online version of this article (10.1007/s11764-017-0642-z) contains supplementary material, which is available to authorized users.
Published: 2017
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38. An international survey of classification and treatment choices for group D retinoblastoma

Author: Andrey Yarovoy, Timothy G. Murray, Santosh G Honavar, Miguel A. Materin, Islamov Ziyovuddin, Anthony B. Daniels, David A. Plager, Carol L. Shields, Vikas Khetan, Christina Scelfo, Jacob Pe'er, Tatiana L Ushakova, Evelyn A. Paysse, David H. Abramson, Brian P. Marr, Sidnel Epelman, Annette C. Moll, Marco A. Ramirez-Ortiz, Carlos A. Leal, Xun Da Ji, Fousseyni Traore, Jesse L. Berry, Jose W. Cursino, Pooja Bhagia, Vicktoria Vishnevskia-Dai, Charlotta All-Ericsson, Francis L. Munier, Evandro Lucena, Jeanie D Ling, Rejin Kebudi, Samuray Tuncer, Hayyam Kiratli, Jasmine H. Francis, J. William Harbour, Guillermo L. Chantada, Rodrigo Polania, Thomas L. Jenkins, CCA - Cancer Treatment and quality of life, Ophthalmology, Amsterdam Reproduction & Development (AR&D), APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, and ACS - Diabetes & metabolism
Subjects: 0301 basic medicine, retina, medicine.medical_specialty, Enucleation, Classification scheme, chemotherapy, retinoblastoma, intra-arterial chemotherapy, 03 medical and health sciences, Department of Surgery, 0302 clinical medicine, lcsh:Ophthalmology, Statistical significance, medicine, cancer, Initial treatment, USA, Investigation, Treatment choices, business.industry, General surgery, International survey, 3. Good health, Surgery, Ophthalmology, New York 10065, 030104 developmental biology, Memorial Sloan Kettering Cancer Center, lcsh:RE1-994, Treatment modality, oncology, 030221 ophthalmology & optometry, Primary treatment, ophthalmic artery chemosurgery, business, enucleation
Abstract: • AIM: To determine which IIRC scheme was used by retinoblastoma centers worldwide and the percentage of D eyes treated primarily with enucleation versus globe salvaging therapies as well as to correlate trends in treatment choice to IIRC version used and geographic region. • METHODS: An anonymized electronic survey was offered to 115 physicians at 39 retinoblastoma centers worldwide asking about IIRC classification schemes and treatment patterns used between 2008 and 2012. Participants were asked to record which version of the IIRC was used for classification, how many group D eyes were diagnosed, and how many eyes were treated with enucleation versus globe salvaging therapies. Averages of eyes per treatment modality were calculated and stratified by both IIRC version and geographic region. Statistical significance was determined by Chi-square, ANOVA and Kruskal-Wallis tests using Prism. • RESULTS: The survey was completed by 29% of physicians invited to participate. Totally 1807 D eyes were diagnosed. Regarding IIRC system, 27% of centers used the Childrenfs Hospital of Los Angeles (CHLA) version, 33% used the Childrenfs Oncology Group (COG) version, 23% used the Philadelphia version, and 17% were unsure. The rate for primary enucleation varied between 0 and 100% and the mean was 29%. By IIRC version, primary enucleation rates were: Philadelphia, 8%; COG, 34%; and CHLA, 37%. By geographic region, primary enucleation rates were: Latin America, 57%; Asia, 40%; Europe, 36%; Africa, 10%, US, 8%; and Middle East, 8%. However, systemic chemoreduction was used more often than enucleation in all regions except Latin America with a mean of 57% per center (P
Published: 2017
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39. Long-term audiologic follow-up of carboplatin-treated children with retinoblastoma

Author: Madelon L. Geurtsen, Annette C. Moll, Wijnanda A. Kors, Cas Smits, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), CCA - Cancer Treatment and quality of life, Ophthalmology, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Otolaryngology / Head & Neck Surgery, and ACS - Diabetes & metabolism
Subjects: Male, Pediatrics, medicine.medical_specialty, Hearing Loss, Sensorineural, Retinal Neoplasms, Antineoplastic Agents, Audiology, Single Center, Carboplatin, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ototoxicity, Medicine, Humans, Genetics (clinical), Retrospective Studies, No-Observed-Adverse-Effect Level, medicine.diagnostic_test, business.industry, Retinoblastoma, Incidence (epidemiology), Infant, Retrospective cohort study, medicine.disease, Ophthalmology, chemistry, 030220 oncology & carcinogenesis, Child, Preschool, Pediatrics, Perinatology and Child Health, 030221 ophthalmology & optometry, Audiometry, Pure-Tone, Female, Audiometry, business, Cohort study, Follow-Up Studies
Abstract: BACKGROUND: Children treated for retinoblastoma with carboplatin have an increased risk for ototoxicity. Impaired hearing may have major consequences for these children, because they often suffer from reduced vision. Previous studies have shown limited information on the incidence and severity of carboplatin-induced ototoxicity and the used audiologic methods. The frequency of audiological testing is often limited and the audiologic follow-up time is relatively short.OBJECTIVE: The aim of this study was to determine the long-term effects of carboplatin ototoxicity in children with retinoblastoma.MATERIALS AND METHODS: In this retrospective non-randomized single center cohort study, we reviewed audiologic results of 25 patients. Experienced audiologists analyzed the pure-tone audiograms.RESULTS: All patients had normal hearing prior to therapy and had a mean age of 11 months at first carboplatin administration. The mean audiologic follow-up was 12.0 years with a median of 11.6 (IQR 4.8) years. Three patients were excluded: two passed away and one could not participate in the audiologic tests. One of the 22 included patients developed sustained low-grade bilateral high-frequency hearing loss between 2 and 7 years after the last carboplatin dose. In one patient it was not possible to make a reliable conclusion due to a conductive hearing loss component. Twenty patients had normal hearing.CONCLUSIONS: We observed no clear effect between carboplatin administration in young children and clinical significant ototoxicity in the long term. One child showed low-grade bilateral high-frequency hearing loss.
Published: 2017
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40. Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma

Author: Annette C. Moll, Lindsay M. Morton, Charlotte J. Dommering, Michael Walsh, Machteld I. Bosscha, Kevin C. Oeffinger, Ruth A. Kleinerman, Ira J. Dunkel, Danielle Novetsky Friedman, Flora E. van Leeuwen, Mary-Louise C. Greer, Petra Temming, Dana Barnea, Pim de Graaf, Margaret A. Tucker, Guillermo L. Chantada, Armida W. M. Fabius, Suzanne Laughlin, Emily S. Tonorezos, David H. Abramson, Wijnanda A. Kors, Jasmine H. Francis, Ophthalmology, Human genetics, Radiology and nuclear medicine, Pediatric surgery, CCA - Cancer Treatment and quality of life, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, Epidemiology and Data Science, and ACS - Diabetes & metabolism
Subjects: Pediatrics, medicine.medical_specialty, Retinal Neoplasms, Population, Medizin, MEDLINE, Guidelines as Topic, Disease, Global Health, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, Retinoblastoma, business.industry, Incidence (epidemiology), Incidence, medicine.disease, Ophthalmology, 030221 ophthalmology & optometry, Sarcoma, Risk assessment, business, Follow-Up Studies
Abstract: OBJECTIVE: Generate recommendations for long-term follow-up for adult survivors of heritable retinoblastoma.DESIGN: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence.SUBJECTS: Retinoblastoma is a rare childhood cancer of the retina. Approximately forty percent of retinoblastoma cases are heritable, due to a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. Survivors of heritable retinoblastoma, however, have significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. In spite of these risks, no surveillance recommendations for this population are currently in place and surveillance practices vary widely by center.METHODS: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 papers; after abstract and full text review, 37 papers underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations.MAIN OUTCOME MEASURES: Diagnosis and mortality from subsequent neoplasm.RESULTS: While evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent.CONCLUSIONS: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors, but found little evidence for a benefit to currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.
Published: 2019
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41. Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. 'Alive, with good vision and no comorbidity'

Author: Maja Beck-Popovic, Tero Kivelä, Ciara Bergin, Dietmar R. Lohmann, Annette C. Moll, Francis L. Munier, Paul J. Dyson, Susan Houghton, Francesco Puccinelli, Philippe Maeder, Guillermo Chantada, Paula Schaiquevich, Alexandre Moulin, Yvan Vial, David Cobrinik, Angel M. Carcaboso, Marie-Claire Gaillard, Christina Stathopoulos, HUS Head and Neck Center, Department of Ophthalmology and Otorhinolaryngology, and Silmäklinikka
Subjects: genetic structures, INTRA-ARTERIAL CHEMOTHERAPY, medicine.medical_treatment, intracameral chemotherapy, Medizin, Visual Acuity, Comorbidity, Conservative Treatment, intra-arterial chemotherapy, Metastasis, 0302 clinical medicine, Quality of life, purl.org/becyt/ford/3.2 [https], INTRACAMERAL CHEMOTHERAPY, 0303 health sciences, treatment, intravitreal chemotherapy, Retinoblastoma, COMPLICATION, INTRAVITREAL CHEMOTHERAPY, TREATMENT, Sensory Systems, 3. Good health, diffuse infiltrating retinoblastoma, long-term survivors, Intravitreal Injections, purl.org/becyt/ford/3 [https], ophthalmic-artery-chemosurgery, 2nd primary malignancies, medicine.medical_specialty, Retinal Neoplasms, RETINOBLASTOMA, complication, Antineoplastic Agents, Eye Enucleation, 03 medical and health sciences, Therapeutic approach, medicine, metastasis, Humans, Infusions, Intra-Arterial, 3125 Otorhinolaryngology, ophthalmology, External beam radiotherapy, Intensive care medicine, radiation-induced cataracts, 030304 developmental biology, external-beam radiotherapy, optical coherence tomography, liquid biopsy, business.industry, medicine.disease, eye diseases, high-risk retinoblastoma, Review article, Radiation therapy, rhegmatogenous retinal-detachment, Ophthalmology, quality-of-life, METASTASIS, Quality of Life, 030221 ophthalmology & optometry, LIQUID BIOPSY, Neoplasm Recurrence, Local, business
Abstract: 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.
Published: 2019
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42. Concurrence of sleep problems and distress: prevalence and determinants in parents of children with cancer

Author: Johannes H. M. Merks, Annette C. Moll, Sasja A. Schepers, Niki Rensen, Martha A. Grootenhuis, Raphaële R. L. van Litsenburg, Gertjan J.L. Kaspers, and Lindsay M.H. Steur
Subjects: 儿童, 050103 clinical psychology, Stress management, lcsh:RC435-571, Psychological intervention, • Pediatric cancer diagnoses are traumatic for parents and can precipitate insomnia. If insomnia persists, an important perpetuating factor might be ongoing distress.• This study in 352 parents of children treated for cancer shows a high prevalence (37%) of sleep problems, in the majority of parents occurring in concurrence with clinical distress. Several predictors were identified.• Future research should reveal which interventions are most effective: targeted at sleep improvement, or at stress management and trauma processing, padres, 心理压力, 癌症, 03 medical and health sciences, Social support, 0302 clinical medicine, cáncer, lcsh:Psychiatry, 肿瘤科, cancer, Medicine, 0501 psychology and cognitive sciences, sleep, psychological stress, Multinomial logistic regression, Clinical Research Article, child, business.industry, 05 social sciences, niño, parents, Sleep in non-human animals, 030227 psychiatry, Distress, estrés psicológico, 父母, El Niño, dormir, oncology, 睡眠, business, oncología, Psychosocial, Clinical psychology
Abstract: Background: Parents of children with cancer are at risk for sleep problems. If these problems persist, an important perpetuating factor might be ongoing parental distress. Objective: The aim of this study is to assess the prevalence of sleep problems and the concurrence with distress in parents of children treated for cancer, and to identify predictors of this symptom clustering. Method: Parents completed the Medical Outcomes Study (MOS) Sleep Scale and Distress Thermometer for Parents (DT-P). Clinically relevant sleep problems were defined as a score >1SD above the norm and clinical distress as a thermometer score above the established cut-off of 4. Four parent categories were constructed: neither sleep problems nor distress; no distress but sleep problems; no sleep problems but distress; both sleep problems and distress. Predictive determinants (sociodemographic, medical, psychosocial) for each category were assessed with multilevel multinomial logistic regression. Results: Parents (202 mothers and 150 fathers) of 231 children with different cancers participated. Mean time since diagnosis was 3.3 ± 1.4 years (90% off-treatment). The prevalence of sleep problems was 37%. Fifty percent of parents reported neither sleep problems nor distress, 9% had only sleep problems, 13% only distress, and 28% reported both. Compared to parents without sleep problems or distress, parents who reported both were more likely to report parenting problems (OR 4.4, [2.2–9.1]), chronic illness (OR 2.8, [1.2–6.5]), insufficient social support (OR 3.7, [1.5–9.1]), pre-existent sleep problems (OR 6.2, [2.0–18.6]) and be female (OR 1.8, [1.1–4.2]). Conclusions: Sleep problems are common in parents of children treated for cancer, and occur mostly in the presence of clinical distress. Future research must show which interventions are most effective in this group: mainly targeted at sleep improvement or with prominent roles for stress management or trauma processing.
Published: 2019
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43. Phase-based OCT angiography in diagnostic imaging of pediatric retinoblastoma patients: abnormal blood vessels in post-treatment regression patterns

Author: Annette C. Moll, Johannes F. de Boer, Maximilian G. O. Gräfe, Valentina Davidoiu, Oleg Nadiarnykh, Machteld I. Bosscha, Biophotonics and Medical Imaging, LaserLaB - Biophotonics and Microscopy, Amsterdam Neuroscience - Brain Imaging, Amsterdam Reproduction & Development (AR&D), Ophthalmology, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, and CCA - Imaging and biomarkers
Subjects: medicine.medical_specialty, Nerve fiber layer, 01 natural sciences, Article, 010309 optics, 03 medical and health sciences, Optical coherence tomography, SDG 3 - Good Health and Well-being, 0103 physical sciences, medicine, Medical imaging, 030304 developmental biology, 0303 health sciences, Retina, Retinal pigment epithelium, medicine.diagnostic_test, business.industry, Retinoblastoma, Magnetic resonance imaging, medicine.disease, Atomic and Molecular Physics, and Optics, eye diseases, medicine.anatomical_structure, Angiography, Radiology, business, Biotechnology
Abstract: Phase-based OCT angiography of retinoblastoma regression patterns with a novel handheld 1050 nm clinical imaging system is demonstrated for the first time in children between 0 and 4 years old under general anesthesia. Angiography is mapped at OCT resolution by flow detection at every pixel with en-face projection from the volume between nerve fiber layer and retinal pigment epithelium. We show a striking difference between blood vasculature of healthy retina, and retinoblastoma regression patterns after chemotherapy, as well as varying complexity of abnormal vasculature in regression patterns types 2, 3, and 4. We demonstrate abnormal, tortuous and prominent vasculature in type 3 regression patterns having the highest risk of tumor recurrences and a lower probability to reduction into flat scars. The ability to visualize 3-D angiography might offer new insights in understanding of retinoblastoma development and its response to therapy.
Published: 2019
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44. Principles of Cancer Epidemiology

Author: Nakul Singh, Annette C. Moll, Lex M. Bouter, Michiel R. de Boer, Ophthalmology, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, APH - Quality of Care, CCA - Cancer Treatment and quality of life, CCA - Imaging and biomarkers, Amsterdam Reproduction & Development (AR&D), Epidemiology and Data Science, and APH - Methodology
Subjects: Selection bias, 0303 health sciences, business.industry, media_common.quotation_subject, Confounding, Hazard ratio, Odds ratio, 03 medical and health sciences, 0302 clinical medicine, Systematic review, Relative risk, Epidemiology of cancer, 030221 ophthalmology & optometry, Medicine, Information bias, business, 030304 developmental biology, Demography, media_common
Abstract: A clinical epidemiological study must address a research question, which can be explanatory or descriptive and which can be categorized as etiological, diagnostic, or prognostic. The main outcome measures of cancer epidemiology studies are prevalence, incidence, mortality, time to event, and quality of life. Surrogate endpoints are sometimes used instead of clinical endpoints but are controversial. There are many measures of association, which include relative risk, hazard ratio, odds ratio, differences in risk, and differences in mean score. The precision of estimates is described by p values and confidence intervals. Inaccuracies can be caused by various forms of bias, such as confounding, selection bias, and information bias. There are several research designs, which include case series, cross-sectional studies, cohort studies, randomized controlled trials, case-control studies, pilot studies, and systematic reviews.
Published: 2019
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45. At What Age Could Screening for Familial Retinoblastoma Be Discontinued? A Systematic Review

Author: Milo van Hoefen Wijsard, Machteld I. Bosscha, Saskia H. Serné, Annette C. Moll, René H. J. Otten, Armida W. M. Fabius, Charlotte J. Dommering, Ophthalmology, Human genetics, ACS - Diabetes & metabolism, CCA - Cancer Treatment and quality of life, APH - Quality of Care, and APH - Health Behaviors & Chronic Diseases
Subjects: 0301 basic medicine, Cancer Research, Pediatrics, medicine.medical_specialty, Age at diagnosis, CINAHL, Cochrane Library, familial retinoblastoma, 03 medical and health sciences, 0302 clinical medicine, Medicine, Family history, Adverse effect, RC254-282, Familial Retinoblastoma, business.industry, Retinoblastoma, screening, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, eye diseases, 030104 developmental biology, Patient burden, Oncology, age at diagnosis, Commentary, 030221 ophthalmology & optometry, business
Abstract: Simple Summary Offspring of patients with heritable retinoblastoma have a high risk of developing retinoblastoma themselves. Ophthalmological screening from birth in at-risk children ensures early detection and increases survival. As not every at-risk child develops retinoblastoma it should be determined until what age familial retinoblastoma can occur, so that ophthalmological screening could safely be stopped at that age. Extended screening beyond this age would result in unnecessary patient burden and costs. By systematically searching the medical literature for latest age at diagnosis in this population, we ascertained that among adequately screened patients the oldest age at diagnosis is 48 months. Therefore, screening for familial retinoblastoma can safely be stopped at four years of age. Abstract The aim of this systematic review is to assess the latest age at diagnosis for detection of familial retinoblastoma in order to evaluate at what age screening of at-risk children could be discontinued. Extended screening beyond this age would result in unnecessary patient burden and costs. However, discontinuing screening prematurely would have the adverse effect of missing tumors. We performed a literature search (PubMed, Embase, CINAHL and the Cochrane Library) up until February of 2021 and systematically included studies where patients had a family history of retinoblastoma, a known age at diagnosis, and who were ophthalmologically screened for retinoblastoma from birth. A total of 176 familial retinoblastoma patients from 17 studies were included in this review. Based on 48 months of age being the latest age of diagnosis, ophthalmological screening for familial retinoblastoma could safely be discontinued at age four years.
Published: 2021
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46. Genomic landscape of retinoblastoma inRb−/−p130−/−mice resembles human retinoblastoma

Author: Josephine C. Dorsman, Gertjan J.L. Kaspers, Saskia E. van Mil, Jacqueline Cloos, Berber M. Mol, David MacPherson, Annette C. Moll, Hanne Meijers-Heijboer, Irsan E. Kooi, and Hein te Riele
Subjects: 0301 basic medicine, Genetics, Cancer Research, Somatic cell, Retinoblastoma, Wild type, Cancer, Biology, medicine.disease, SCNA, HMGA1, eye diseases, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, embryonic structures, biology.protein, medicine, Cancer research, Mdm2, biological phenomena, cell phenomena, and immunity, Gene
Abstract: Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb-/- p107-/- retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma. In our study, we determined SCNAs in retinoblastomas developing in Rb-/- p130-/- mice and compared this to murine Rb-/- p107-/- tumors and human tumors. Chimeric mice were made by injection of 129/Ola-derived Rb-/- p130-/- embryonic stem cells into wild type C57BL/6 blastocysts. SCNAs of retinoblastoma samples were determined by low-coverage (∼0.5×) whole genome sequencing. In Rb-/- p130-/- tumors, SCNAs included gain of chromosomes 1 (3/23 tumors), 8 (1/23 tumors), 10 (1/23 tumors), 11 (2/23 tumors), and 12 (4/23 tumors), which could be mapped to frequently altered chromosomes in human retinoblastomas. While the altered chromosomes in Rb-/- p130-/- tumors were similar to those in Rb-/- p107-/- tumors, the alteration frequencies were much lower in Rb-/- p130-/- tumors. Most of the Rb-/- p130-/- tumors (16/23 tumors, 70%) were devoid of SCNAs, in strong contrast to Rb-/- p107-/- tumors, which were never (0/15 tumors) SCNA-devoid. Similarly, to human retinoblastoma, increased age at diagnosis significantly correlated with increased SCNA frequencies. Additionally, focal loss of Cdh11 was observed in one Rb-/- p130-/- tumor, which enforces studies in human retinoblastoma that identified CDH11 as a retinoblastoma suppressor. Moreover, based on a comparison of genes altered in human and murine retinoblastoma, we suggest exploring the role of HMGA1 and SRSF3 in retinoblastoma development. © 2016 Wiley Periodicals, Inc.
Published: 2016
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47. The cataract situation in Suriname: an effective intervention programme to increase the cataract surgical rate in a developing country

Author: Ruth M. A. van Nispen, Cindy M. Forster-Pawiroredjo, Janna Minderhoud, Anne Marie T. Bueno De Mesquita-Voigt, Michael R. Siban, Hans Limburg, Annette C. Moll, Jerrel C. Pawiroredjo, Herman C.I. Themen, Dennis R. A. Mans, Ophthalmology, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Amsterdam Reproduction & Development (AR&D), and ACS - Diabetes & metabolism
Subjects: Male, Pediatrics, medicine.medical_specialty, Visual acuity, genetic structures, Cross-sectional study, medicine.medical_treatment, Population, Visual Acuity, Developing country, Cataract Extraction, Blindness, Cataract, 03 medical and health sciences, Cellular and Molecular Neuroscience, Age Distribution, 0302 clinical medicine, Epidemiology, Prevalence, medicine, Humans, Sex Distribution, education, Developing Countries, Aged, Retrospective Studies, education.field_of_study, Suriname, 030505 public health, business.industry, Retrospective cohort study, Phacoemulsification, Middle Aged, Cataract surgery, eye diseases, Sensory Systems, Ophthalmology, Cross-Sectional Studies, 030221 ophthalmology & optometry, Optometry, Female, sense organs, medicine.symptom, 0305 other medical science, business
Abstract: Aims To provide an overview of cataract data in Suriname and to describe and evaluate a programme to control cataract blindness in a developing country. Design Evaluation of hospital data and findings from a population-based cross-sectional survey. Methods The implementation of a new cataract surgical intervention programme was described and retrospectively evaluated by analysing the number of cataract operations and other related indicators at the Suriname Eye Centre (SEC) in the period 2006-2014. Findings of the recent Rapid Assessment of Avoidable Blindness (2013-2014) survey were used to evaluate the national cataract situation in Suriname in people aged ≥50 years (n=2998), including prevalence of cataract blindness, outcome and cataract surgical rate (CSR). Results Since the implementation of a new cataract intervention programme, the number of cataract operations at the SEC has increased from 1150 in 2006 to 4538 in 2014, leading to an estimated national CSR of 9103 per one million inhabitants. The prevalence of bilateral cataract blindness in Suriname was 0.8% (95% CI 0.2% to 1.3%) in individuals aged ≥50 years. The proportion of eyes with a postoperative visual acuity 5%.
Published: 2016
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48. Diabetes and diabetic retinopathy in people aged 50 years and older in the Republic of Suriname

Author: Anne-Marie T. Bueno de Mesquita-Voigt, Hans Limburg, Janna Minderhoud, Dennis R. A. Mans, Herman C.I. Themen, Annette C. Moll, Jerrel C. Pawiroredjo, Ruth M. A. van Nispen, Cindy M. Forster-Pawiroredjo, Michael R. Siban, Ophthalmology, and EMGO - Quality of care
Subjects: Blood Glucose, Male, medicine.medical_specialty, Pediatrics, Population, Visual Acuity, Ethnic group, Blindness, Risk Assessment, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Risk Factors, Diabetes mellitus, Epidemiology, Diabetes Mellitus, Prevalence, Humans, Medicine, 030212 general & internal medicine, education, Aged, Retrospective Studies, Aged, 80 and over, education.field_of_study, Diabetic Retinopathy, Suriname, medicine.diagnostic_test, business.industry, Public health, Age Factors, Retrospective cohort study, Diabetic retinopathy, Middle Aged, Prognosis, medicine.disease, Health Surveys, Sensory Systems, Ophthalmoscopy, Ophthalmology, Eye examination, 030221 ophthalmology & optometry, Optometry, Female, business
Abstract: Background/Aims Population-based surveys on diabetes and diabetic retinopathy (DR) are necessary to increase awareness and develop screening and therapeutic programmes. The aim was to estimate the prevalence of DR in older adults of different ethnic backgrounds in Suriname. Methods Fifty clusters of 60 people aged ≥50 years were randomly selected with a probability proportional to the size of the population unit. Eligible people were randomly selected through compact segment sampling and examined using the Rapid Assessment of Avoidable Blindness plus Diabetic Retinopathy (RAAB + DR) protocol. Participants were classified as having diabetes if they: were previously diagnosed with diabetes; were receiving treatment for glucose control; had a random blood glucose level >200 mg/dL. These participants were dilated for funduscopy, assessed for DR following the Scottish DR grading protocol and evaluated for ethnicity and DR ophthalmic screening frequencies. Results A total of 2806 individuals was examined (response 93.6%). The prevalence of diabetes was 24.6%. In these patients any type of DR and/or maculopathy occurred in 21.6% and sight-threatening DR in 8.0%. Of the known diabetics, 34.2% never had an eye examination for DR and in 13.0% the last examination was >24 months ago. The prevalence of diabetes was significantly higher in Hindustani people compared with other major ethnic groups. Conclusions The prevalence of diabetes and diabetics without regular DR control in people aged ≥50 years in Suriname was higher than expected. The uptake for special services for DR has to be expanded to decrease patient delay and DR-induced blindness.
Published: 2016
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49. Subgenual Cingulate Cortex Functional Connectivity in Relation to Depressive Symptoms and Cognitive Functioning in Type 1 Diabetes Mellitus Patients

Author: Frederik Barkhof, Annette C. Moll, Martin Klein, Christopher M. Ryan, Menno M. Schoonheim, Richard G. IJzerman, Frank J. Snoek, Michaela Diamant, Eelco van Duinkerken, Medical Psychology, Internal medicine, Medical psychology, ICaR - Circulation and metabolism, Anatomy and neurosciences, Amsterdam Neuroscience - Brain Imaging, Radiology and nuclear medicine, Ophthalmology, and EMGO - Lifestyle, overweight and diabetes
Subjects: Adult, Male, Cingulate cortex, medicine.medical_specialty, Population, Precuneus, Prefrontal Cortex, Inferior frontal gyrus, Poison control, Gyrus Cinguli, 03 medical and health sciences, 0302 clinical medicine, Parietal Lobe, Internal medicine, Connectome, medicine, Humans, Cognitive Dysfunction, Prefrontal cortex, education, Applied Psychology, education.field_of_study, Resting state fMRI, Depression, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, Psychiatry and Mental health, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Cardiology, Major depressive disorder, Female, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract: Objectives Patients with Type 1 diabetes mellitus (T1DM) are at an increased risk for major depression, but its underlying mechanisms are still poorly understood. In nondiabetic participants, mood disturbances are related to altered subgenual cingulate cortex (SGC) resting-state functional connectivity. We tested for SGC connectivity alterations in T1DM, whether these alterations were related to depressive symptoms, and if depressive symptoms were associated with cognition.Methods A bilateral SGC seed-based resting-state functional magnetic resonance imaging analysis was performed in 104 T1DM patients and 49 controls without known psychiatric diagnosis or treatment. Depressive symptoms were self-reported using the Center for Epidemiological Studies Depression scale. Cognition was assessed with a battery of standardized tests.Results In patients versus controls, SGC to right inferior frontal gyrus and frontal pole connectivity was decreased (52 voxels, z valuepeak = 3.56, pcluster-FWE = .002), whereas SGC to bilateral precuneus (33 voxels, z valuepeak = 3.34, pcluster-FWE = .04) and left inferior parietal lobule (50 voxels, z valuepeak = 3.50, pcluster-FWE = .003) connectivity was increased. In all participants, increased depressive symptoms was related to lower SGC to inferior frontal gyrus and frontal pole connectivity (β = −0.156, p = .053), and poorer general cognitive ability (β = −0.194, p = .023), information processing speed (β = −0.222, p = .008), and motor speed (β = −0.180, p = .035).Conclusions T1DM patients showed a pattern of SGC connectivity that is characterized by lower executive control and higher default mode network connectivity. Depressive symptoms are partially related to these alterations and seem to exacerbate T1DM-related cognitive dysfunction. Future studies should detail the effect of diagnosed major depressive disorder in this population and establish what alterations are diabetes specific.
Published: 2016
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50. 3D orbital reconstruction in a patient with microphthalmos and a large orbital cyst

Author: Daphne L. Mourits, Angela Ridwan-Pramana, Jan Wolff, Jelmer S. Remmers, P. de Graaf, Elke Kraal-Biezen, Dyonne T. Hartong, Annette C. Moll, Tymour Forouzanfar, ACTA, MKA VUmc (ORM, ACTA), Academic Centre for Dentistry Amsterdam, Maxillofacial Surgery (VUmc), Ophthalmology, Oral and Maxillofacial Surgery / Oral Pathology, MOVE Research Institute, EMGO - Quality of care, ICaR - Circulation and metabolism, and Clinical pharmacology and pharmacy
Subjects: Male, genetic structures, medicine.medical_treatment, Ophthalmologic Surgical Procedures, Prosthesis, Cystectomy, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Orbital Diseases, medicine, Humans, Microphthalmos, Cyst, Child, Genetics (clinical), Cysts, Eye, Artificial, business.industry, 030206 dentistry, Anatomy, Plastic Surgery Procedures, medicine.disease, Magnetic Resonance Imaging, eye diseases, Prosthesis Failure, Ophthalmology, medicine.anatomical_structure, Orbital cyst, Printing, Three-Dimensional, Pediatrics, Perinatology and Child Health, 030221 ophthalmology & optometry, Eyelid, sense organs, Tomography, X-Ray Computed, business, Orbit, Orbit (anatomy)
Abstract: Background: Orbital cysts are rare developmental anomalies that can occur in microphthalmic and anophthalmic patients. Such cysts can promote orbital growth and subsequently markedly increase the size of the orbit, which is commonly underdeveloped in these patients. Cyst removal is therefore generally dissuaded (at least) in the first 5 years.Clinical case: A 6-year-old boy with a microphthalmos and a cyst developed protrusion of his prosthetic eye and a swelling of the lower eyelid. MRI showed a large cyst causing distortion of the right orbit. Due to the expansive orbital growth and subsequent misfitting of the prosthesis, cystectomy and orbital floor reconstruction was performed using 3D technology.Conclusion: 3D imaging and printing enables exact delineation of orbital cysts and the adjacent bony structures. Furthermore it offers the possibility to plan an individual surgical approach and to design and fabricate a custom fit orbital floor implant.
Published: 2016
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