Publications by authors named "Craig Donaldson"

21 Publications

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Global Retinoblastoma Presentation and Analysis by National Income Level.

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

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

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

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

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

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

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

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

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

Chemotherapy-induced genotoxic damage to bone marrow cells: long-term implications.

Mutagenesis 2018 09;33(3):241-251

Centre for Research in Biosciences, University of the West of England, Coldharbour Lane, Bristol, UK.

Mesenchymal stem/stromal cells (MSCs) within the bone marrow (BM) are vitally important in forming the micro-environment supporting haematopoiesis after myeloablative chemotherapy. MSCs are known to be damaged phenotypically and functionally by chemotherapy; however, to the best our knowledge, the persistence of genotoxic effects of chemotherapy on the BM micro-environment has not been studied. We therefore aimed to evaluate genotoxic effects of chemotherapy on the BM both in vitro and in vivo, using the comet and micronucleus assays, focussing on the persistence of DNA lesions that may contribute to complications in the patient. The MSC cell line (HS-5) and primary cord blood mononuclear cells (CBMNCs: a source of undamaged DNA) were exposed to the chemotherapeutic agent cyclophosphamide (CY) within a physiologically relevant in vitro model. CY treatment resulted in significant increases in CBMNC DNA damage at all time points tested (3-48 h exposure). Similarly, HS-5 cells exposed to CY exhibited significant increases in DNA damage as measured by the comet assay, with increased numbers of abnormal cells visible in the micronucleus assay. In addition, even 48 h after removal of 48-h CY treatment, DNA damage remains significantly increased in treated cells relative to controls. In patients treated with chemotherapy for haematological malignancy, highly significant increases in damaged DNA were seen in BM cells isolated from one individual 1 year after completion of therapy for acute leukaemia compared with pretreatment (P < 0.001). Similarly, two individuals treated 7 and 17 years previously with chemotherapy exhibited significant increases of damaged DNA in MSC compared with untreated age- and sex-matched controls (P < 0.05). Unlike haematopoietic cells, MSCs are not replaced following a stem cell transplant. Therefore, long-term damage to MSC may impact on engraftment of either allogeneic or autologous transplants. In addition, persistence of DNA lesions may lead to genetic instability, correlating with the significant number of chemotherapy-treated individuals who have therapy-related malignancies.
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http://dx.doi.org/10.1093/mutage/gey014DOI Listing
September 2018

Integrative review of cervical cancer screening in Western Asian and Middle Eastern Arab countries.

Nurs Health Sci 2017 Dec 23;19(4):414-426. Epub 2017 Oct 23.

School of Biomedical and Healthcare Sciences, Plymouth University, Plymouth, UK.

Population-based screening programs have resulted in minimizing mortality and morbidity from cervical cancer. The aim of this integrative review was to explore the factors influencing access of women from Western Asian and Middle Eastern Arab countries to cervical cancer screening. A systematic search for studies conducted in Arab countries in those regions, and published in English between January 2002 and January 2017, was undertaken. Thirteen papers were selected and subjected to quality appraisal. A three step analysis was used, which involved a summary of the evidence, analysis of both quantitative and qualitative data, and integration of the results in narrative form. Few population-based cervical cancer screening programs had been implemented in the relevant countries, with low knowledge of, and perceptions about, cervical screening among Arab women, the majority of whom are Muslim. Factors affecting the uptake of cervical cancer screening practices were the absence of organized, systematic programs, low screening knowledge among women, healthcare professionals' attitudes toward screening, pain and embarrassment, stigma, and sociocultural beliefs. Policy changes are urgently needed to promote population-based screening programs. Future research should address the promotion of culturally-sensitive strategies to enable better access of Arab Muslim women to cervical cancer screening.
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http://dx.doi.org/10.1111/nhs.12374DOI Listing
December 2017

Photographic assessment of retinal hemorrhages in infant head injury: the Childhood Hemorrhagic Retinopathy Study.

J AAPOS 2017 02 16;21(1):28-33.e2. Epub 2017 Jan 16.

Faculty of Medicine, University of New South Wales (UNSW), Sydney NSW, Australia; Department of Ophthalmology, Prince of Wales and Sydney Children's Hospital, Randwick, NSW, Australia.

Background: Retinal hemorrhages (RH) in babies in the absence of severe trauma or a medical cause have been strongly associated with abusive head trauma (AHT). We examined the pattern of RH in accidental head injury and AHT objectively using widefield retinal imaging.

Methods: A total of 118 infants and children 1-36 months of age admitted with head injuries at two centers were included in this prospective, consecutive, comparative cohort study. Dilated fundus examination was performed with indirect ophthalmoscopy and widefield imaging. Designation of AHT was made using predetermined criteria independent of retinal findings. Retinal images were graded by two independent observers.

Results: There were 21 cases of AHT. RH were present in 14 cases (66%); macular retinoschisis or retinal folds, in 8 (38%). There were 86 cases of accidental head injuries, with RH present in 2 (2%); there were none with retinal folds or retinoschisis. In cases of head injury with intracranial hemorrhage, the positive likelihood ratio of AHT with RH was 5.7 (95% CI, 2.6-12.00) and negative likelihood ratio was 0.26 (95% CI, 0.11-0.62). A severe, panretinal pattern with multilayered hemorrhages was the most specific for AHT.

Conclusions: Our imaging study confirmed that RH in infants with head injury have a high positive likelihood ratio for AHT. A severe hemorrhagic retinopathy, particularly in association with perimacular folds or macular retinoschisis, has the highest positive predictive value for AHT.
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http://dx.doi.org/10.1016/j.jaapos.2016.11.020DOI Listing
February 2017

Malignant Hypertensive Retinopathy in an Infant with Mid-Aortic Occlusion.

Case Rep Ophthalmol Med 2016 5;2016:8162687. Epub 2016 Oct 5.

Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia.

Case report describing an eight-month-old infant presenting with intermittent esotropia and irritability who was found to have malignant (grade 4) hypertensive retinopathy and mid-aortic syndrome. Visual acuity was 6/140 in the right eye and not recordable in the left eye. Blood pressure was as high as 230/120 mmHg. Fundoscopy revealed bilateral optic disc swelling, macular stars, and serous retinal detachment in the left eye, findings that are consistent with malignant (grade 4) hypertensive retinopathy. CT abdominal angiogram revealed a severe mid-aortic syndrome with occlusion of the abdominal aorta at T12. The patient was treated with medical management of his hypertension, improving the subretinal exudate. Binocular visual acuity improved to 6/9.5 over 9 months. There was a persistent left relative afferent pupillary defect and moderate left esotropia. This is the first reported case of malignant hypertensive retinopathy in an infant with concomitant mid-aortic occlusion. The authors emphasize the need for an ophthalmological and pediatric examination in a child presenting with intermittent squint and irritability. The esotropia was found to be a false localizing sign of raised intracranial pressure secondary to the severe mid-aortic syndrome.
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http://dx.doi.org/10.1155/2016/8162687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071550PMC
October 2016

Grading system for retinal hemorrhages in abusive head trauma: clinical description and reliability study.

J AAPOS 2014 Dec;18(6):523-8

Faculty of Medicine, University of New South Wales (UNSW), Sydney, NSW, Australia; Department of Ophthalmology, Prince of Wales and Sydney Children's Hospital, Randwick, NSW.

Purpose: There is currently no universally accepted grading system for describing retinal hemorrhages (RH) in abusive head trauma (AHT). The purpose of this study was to devise and evaluate a novel grading system and descriptive nomenclature for RH in AHT for clinical and research purposes.

Methods: A traumatic hemorrhagic retinopathy (THR) grading system was developed for assessing and quantitatively analyzing retinal findings in abusive head trauma. The criteria for the THR grade included the extent, spread, and morphology of RH. Extent was classified as region 1 (posterior pole) or region 2 (peripheral). Spread, based on number of retinal hemorrhages, was classified as mild (10 or fewer RH), moderate (more than 10 RH) and severe (more than half of involved regions covered by RH). Morphology was classified by its intraretinal or extraretinal involvement. Two independent graders calculated the THR grade from RetCam images of 38 eyes of 19 patients <3 years of age with retinal hemorrhages associated with head injury. Grading was performed on two separate occasions. Intra- and interobserver reliability was assessed with Spearman correlation coefficient (r) and intraclass correlation coefficient (ICC).

Results: There was a high level of intraobserver agreement across both assessments (97% agreement [Spearman r = 0.997; P < 0.0001] and 100% agreement [Spearman r = 1.0; P < 0.0000]). Intraclass correlation (ICC, 0.995; 95% CI, 0.991-0.997; P < 0.0001) confirmed a very high level of agreement overall.

Conclusions: The traumatic hemorrhagic retinopathy grading system demonstrated excellent intraobserver and interobserver reliability. The nomenclature is easily understood and may be useful in medical records and medicolegal reports.
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http://dx.doi.org/10.1016/j.jaapos.2014.09.006DOI Listing
December 2014

Advantage of Whole Exome Sequencing over Allele-Specific and Targeted Segment Sequencing in Detection of Novel TULP1 Mutation in Leber Congenital Amaurosis.

Ophthalmic Genet 2015 19;36(4):333-8. Epub 2014 Feb 19.

b Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead , Sydney , NSW , Australia .

Background: Leber congenital amaurosis (LCA) is a severe form of retinal dystrophy with marked underlying genetic heterogeneity. Until recently, allele-specific assays and Sanger sequencing of targeted segments were the only available approaches for attempted genetic diagnosis in this condition. A broader next-generation sequencing (NGS) strategy, such as whole exome sequencing, provides an improved molecular genetic diagnostic capacity for patients with these conditions.

Materials And Methods: In a child with LCA, an allele-specific assay analyzing 135 known LCA-causing variations, followed by targeted segment sequencing of 61 regions in 14 causative genes was performed. Subsequently, exome sequencing was undertaken in the proband, unaffected consanguineous parents and two unaffected siblings. Bioinformatic analysis used two independent pipelines, BWA-GATK and SOAP, followed by Annovar and SnpEff to annotate the variants.

Results: No disease-causing variants were found using the allele-specific or targeted segment Sanger sequencing assays. Analysis of variants in the exome sequence data revealed a novel homozygous nonsense mutation (c.1081C > T, p.Arg361*) in TULP1, a gene with roles in photoreceptor function where mutations were previously shown to cause LCA and retinitis pigmentosa. The identified homozygous variant was the top candidate using both bioinformatic pipelines.

Conclusions: This study highlights the value of the broad sequencing strategy of exome sequencing for disease gene identification in LCA, over other existing methods. NGS is particularly beneficial in LCA where there are a large number of causative disease genes, few distinguishing clinical features for precise candidate disease gene selection, and few mutation hotspots in any of the known disease genes.
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http://dx.doi.org/10.3109/13816810.2014.886269DOI Listing
July 2016

Microphthalmia, anophthalmia, and coloboma and associated ocular and systemic features: understanding the spectrum.

JAMA Ophthalmol 2013 Dec;131(12):1517-24

Discipline of Ophthalmology, University of Sydney, New South Wales, Australia2Eye and Developmental Genetics Research Group, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia4Children's Medical Research Institute, Westmead, Sydney, New South Wales, Australia5Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.

Importance: Microphthalmia, anophthalmia, and coloboma form an interrelated spectrum of congenital eye abnormalities.

Objective: To document the ocular and systemic findings and inheritance patterns in patients with microphthalmia, anophthalmia, and coloboma disease to gain insight into the underlying developmental etiologies.

Design, Setting, And Participants: This retrospective consecutive case series was conducted at a tertiary referral center. Included in the study were 141 patients with microphthalmia, anophthalmia, and coloboma disease without a recognized syndromic etiology who attended the Westmead Children's Hospital, Sydney, from 1981-2012.

Exposure: Cases were grouped on the basis of the presence or absence of an optic fissure closure defect (OFCD); those with OFCD were further subdivided into microphthalmic and nonmicrophthalmic cases. Anophthalmic cases were considered as a separate group.

Main Outcomes And Measures: Associated ocular and systemic abnormalities and inheritance patterns were assessed.

Results: Of 141 cases, 61 (43%) were microphthalmic non-OFCD (NOFCD), 34 (24%) microphthalmic OFCD, 32 (23%) nonmicrophthalmic coloboma (OFCD), 9 (6%) anophthalmic, and 5 (4%) were unclassified. Sixty-three (45%) had bilateral disease. Eighty-four patients (60%) had an associated ocular abnormality; of these, cataract (P < .001) and posterior segment anomalies (P < .001) were most common in the NOFCD group. Forty-eight (34%) had an associated systemic abnormality, most commonly neurological, musculoskeletal and facial, urological and genital, or cardiac. Neurological abnormalities were most common in the anophthalmic group (P = .003), while urological abnormalities were particularly seen in the OFCD groups (P = .009). Familial cases were identified in both the OFCD and NOFCD groups, with a likely autosomal dominant inheritance pattern in 9 of 10 families.

Conclusions And Relevance: This series indicated that the OFCD/NOFCD distinction may be useful in guiding evaluation for ocular and systemic associations, as well as the direction and analysis of genetic investigation.
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http://dx.doi.org/10.1001/jamaophthalmol.2013.5305DOI Listing
December 2013

Development of a novel, physiologically relevant cytotoxicity model: application to the study of chemotherapeutic damage to mesenchymal stromal cells.

Toxicol Appl Pharmacol 2012 Sep 24;263(3):374-89. Epub 2012 Jul 24.

Centre for Research in Biosciences, Department of Applied Science, University of the West of England, Frenchay, Bristol, UK.

There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated. In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy. Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study.
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http://dx.doi.org/10.1016/j.taap.2012.07.013DOI Listing
September 2012

Evaluation of a method allowing preservation of fresh lymph nodes for flow cytometric immunophenotyping.

Cytometry B Clin Cytom 2012 Jul 26;82(4):245-51. Epub 2012 Apr 26.

Haematology Laboratory, Department of Pathology, Mater Dei Hospital, Malta.

Background: Flow cytometric immunophenotyping (FCI) of lymph nodes (LN) requires fresh unfixed tissue, with analysis being carried out within few hours post surgery. This study evaluated a novel method for fresh LN preservation, in order to allow histomorphology-based FCI.

Methods: This study was carried out prospectively on 30 LN with suspected involvement by haematolymphoid neoplasms (HLN). FCI was performed on each fresh and post cryopreserved LN cell suspension. Percentage positivities (PP) and mean fluorescent intensities (MFI) were calculated on both preparations for a combination of T and B-lymphoid antigens together with viability.

Results: The cryopreservation method applied in this study did not affect significantly PP and had minor impact on MFI of the tested antigens. Overall, there was minimal decrease in PP and MFI on the cryopreserved cells when compared with fresh cells, for most antigens with only a mild increase in apoptotic cells. However, these changes were not diagnostically significant, since both reactive processes and HLN present within analyzed LN could be identified and differentiated. Viability was more than 75% for all cryopreserved LN composed of haematolymphoid cells.

Conclusion: The method presented in this study confers the possibility of storing fresh LN biopsies for later FCI, thus allowing a morphology-based immunophenotypic approach. This would allow a more sensitive, specific, and cost-effective management of LN specimens, whilst maintaining the important benefits provided by FCI.
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http://dx.doi.org/10.1002/cyto.b.21021DOI Listing
July 2012

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

Ann Hematol 2011 Jul 14;90(7):777-89. Epub 2011 Jan 14.

Centre for Research in Biomedicine, Faculty of Applied Sciences, University of the West of England, Bristol, UK.

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.
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http://dx.doi.org/10.1007/s00277-010-1141-8DOI Listing
July 2011

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy.

Ann Hematol 2010 Jul 30;89(7):701-13. Epub 2010 Jan 30.

Center for Research in Biomedicine, Faculty of Applied Sciences, University of West of England, Bristol, UK.

Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDC-induced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.
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http://dx.doi.org/10.1007/s00277-009-0896-2DOI Listing
July 2010

Outcomes in retinoblastoma, 1974-2005: the Children's Hospital, Westmead.

Clin Exp Ophthalmol 2007 Jan-Feb;35(1):5-12

Department of Ophthalmology, The Children's Hospital, Westmead, New South Wales, Australia.

Background: To report the 31-year experience of outcomes in retinoblastoma from a single centre.

Methods: A retrospective analysis of consecutive cases of retinoblastoma diagnosed and treated at the Westmead Children's Hospital, Sydney between 1974 and 2005 was performed. The subjects were analysed as two groups: those diagnosed between 1974 and 1989 (series alpha) and those diagnosed between 1990 and 2005 (series beta).

Results: There were a total of 142 patients included in the study, with a median follow up of 72 months. There were 84 patients with unilateral disease and 58 patients (116 eyes) with bilateral disease. The total enucleation rate remained high throughout both series for those with unilateral disease: 89% (series alpha) and 95% (series beta). There was a reduction in enucleations performed for those with bilateral disease from 68.4% (series alpha) to 43.6% (series beta) (P < 0.025). There were no bilateral enucleations performed after 1995. Actuarial Kaplan-Meier curves showed that 56% of all preserved eyes had not recurred at a median follow up of 95 months and 78.1% had avoided enucleation. Overall 43% of preserved eyes attained a visual acuity better than or equal to 6/12 and 55% achieved a visual acuity better than 6/60. There were four deaths due to retinoblastoma. Five patients were diagnosed with a second non-ocular malignancy. The most common treatment-related complications were cataracts, facial deformity, sepsis and febrile neutropaenia.

Conclusions: The introduction of newer globe-preserving treatments for retinoblastoma was associated with equivalent visual outcomes, stable mortality rate and a greater number of short-term complications but avoided the late side-effects associated with external beam radiotherapy.
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http://dx.doi.org/10.1111/j.1442-9071.2006.01386.xDOI Listing
April 2007

The correlation between the percent of CD3- CD56+ cells and NK precursor function.

Iran J Allergy Asthma Immunol 2006 Dec;5(4):167-75

The Research Centre of Iranian Blood Transfusion Organisation, Hemmat express way, Next to the Milad tower, P.O.Box: 14665-1157, Tehran, Iran.

The number and function of human natural killer (NK) cells are generally assessed to monitor the baseline of immune function, the effect of treatment, the progress of malignancy or metastases and diseases. NK cells recognise and kill target cells in the absence of prior sensitisation and are able to defend the host from infection or prevent the progression of a disease. Human NK cells express CD16 and CD56 which are (massively) being used as a major hallmark for the NK cell. The purpose of this study was to identify the unique subsets of peripheral blood mononuclear cells (PBMC) (%CD3-CD56+ cells) by flow cytometry and to determine whether there is any correlation with functionally mature progeny of (NKp) precursor after five days of culture. The correlation was analysed using samples obtained from 120 Caucasian patients. 20-30ml of whole blood was collected in sterile tube containing preservative free sodium heparin and a similar sample was obtained after five days. Maturation of NKp required the continuous presence of recombinant interleukin 2 (rIL-2), or interleukin 15 (rIL-15) and functional maturity of NK cells was determined by their ability to lyse target cells from the K562 cell line. The NK precursor frequency was measured by limiting dilution analysis (LDA), which The NKpf assay was set up with a range of cell dilutions from 40,000 to 625 per 100ml/well in 96 well culture plates. At the end of the culture period the K562 cell line labelled with Europium (Eu-K562) was added and Eu release measured in culture supernatants using time-resolved fluorometry. The PBMC were set up in parallel cultures under various conditions . On day five cells were collected from culture plates and adjusted to 1x10 cells/ml and then mixed. The mixture was incubated and anti CD3 and anti CD56 were added. NK cells were enumerated in 120 patients by double staining with a combination of anti-CD3- and anti-CD56+. The results of these Immunophenotyping studies by flow cytometry showed no correlation between the NKpf (natural killer precursor frequency) and the percent of CD3-CD56+ cells expressed after five days confirming that CD56 was inadequate as a unique marker for functional NK cells.
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http://dx.doi.org/05.04/ijaai.167175DOI Listing
December 2006

Retinoblastoma in New South Wales 1975 to 2001.

J Pediatr Hematol Oncol 2006 Oct;28(10):642-6

The School of Public Health, The University of Sydney, Sydney, Australia.

Purpose: To examine the epidemiology of retinoblastoma in New South Wales (NSW), from 1975 to 2001, comparing the incidence with other parts of the developed world.

Methods: Examination of medical files for patients presenting to NSW retinoblastoma treatment centers between 1975 and 2001. Comparisons to international data were made.

Results: One hundred twenty-eight patients [63 (49.2%) male and 65 (51.8%) female] presented. The mean annual incidence of retinoblastoma in NSW was 8 per million children aged 0 to 6 years, per year.

Conclusions: The incidence of retinoblastoma in NSW is similar to other parts of the developed world.
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http://dx.doi.org/10.1097/01.mph.0000212983.51867.46DOI Listing
October 2006

Bone marrow-derived mesenchymal stem cells.

Leuk Lymphoma 2005 Nov;46(11):1531-44

Centre for Research in Biomedicine, Faculty of Applied Sciences, University of the West of England, Bristol, UK.

Human mesenchymal stem cells (MSCs) contribute to the regeneration of mesenchymal tissues, and are essential in providing support for the growth and differentiation of primitive hemopoietic cells within the bone marrow microenvironment. Techniques are now available to isolate human MSCs and manipulate their expansion in vitro under defined culture conditions without change of phenotype or loss of function. Mesenchymal stem cells have generated a great deal of interest in many clinical settings, including that of regenerative medicine, immune modulation and tissue engineering. Studies have already demonstrated the feasibility of transplanted MSCs providing crucial new cellular therapy. In this review, many aspects of the MSC will be discussed, with the main focus being on clinical studies that describe the potential of MSCs to treat patients with hematological malignancies who are undergoing chemotherapy and/or radiotherapy.
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http://dx.doi.org/10.1080/10428190500215076DOI Listing
November 2005

Management of Duane retraction syndrome.

J Pediatr Ophthalmol Strabismus 2005 Jan-Feb;42(1):13-7; quiz 45-6

Department of Ophthalmology, Children's Hospital at Westmead, New South Wales, Australia.

Background: Duane retraction syndrome is the most common cause of congenital aberrant ocular innervation. We report referral practices, clinical characteristics and complications, prevalence of congenital and familial anomalies, and management outcomes from a clinic-based series.

Methods: Retrospective clinic-based study of 65 patients with Duane retraction syndrome seen between January 1994 and March 2004.

Results: The majority of patients were girls with type I Duane retraction syndrome associated with esotropia in primary gaze. Twenty percent of cases were complicated by absent binocular stereoacuity and 16.9% had amblyopia. Family history of any ocular disorder was reported in 38.5% of cases, while an associated congenital abnormality was found in 46% of patients. There was a significant delay between the age when ocular abnormalities were first noticed and the age when patients presented at our tertiary referral center (P < .001). Twenty-two percent of patients underwent surgical correction at a mean age of 6 years. Most procedures were unilateral or bilateral medial or lateral rectus recessions. Postoperative ocular alignment < or = 15 prism diopters (PD) was achieved in 86% of cases, with 50% of cases having < or = 5 PD.

Conclusions: Amblyopia and absent binocular stereo vision affected one in five patients with Duane retraction syndrome. There was significant delay between identification of an abnormality and presentation at the eye clinic.
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April 2005

The Ahmed drainage implant in the treatment of pediatric glaucoma.

Am J Ophthalmol 2003 Jun;135(6):821-9

Department of Ophthalmology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Purpose: To report the safety and efficacy of Ahmed Glaucoma Valve (New World Medical, Inc., Rancho Cucamonga, California, USA) implantation for the management of pediatric glaucoma in the early and intermediate follow-up period.

Design: Consecutive interventional case series.

Method: A retrospective chart review was conducted on 60 eyes (44 patients, age range at surgery 1.5 months to 16 years, average 6 +/- 4.9 years), with pediatric glaucoma that underwent Ahmed Glaucoma Valve implantation for medically uncontrolled intraocular pressure (IOP) between the years 1995 and 2000. Outcome measures were control of IOP below 21 mm Hg, the need for antiglaucoma medications after surgery, and loss of 2 or more lines of Snellen acuity. Complications were monitored.

Results: The postoperative follow-up period for each eye averaged 24.3 +/- 16 months (range, 3 to 60 months). At last follow-up, IOP was controlled in 44 eyes (73%), 11 of which did not need antiglaucoma therapy. Kaplan-Meier life-table analysis showed probability of success with or without medications of 93% (95% confidence interval [CI], 86%-100%), 86% (95% CI, 77%-96%), 71% (95% CI, 59%-87%), and 45% (95% CI, 28%-80%) after 12, 24, 36, and 48 months of follow-up. Average IOP decreased from 32.8 +/- 6.2 before surgery to 16.6 +/- 8.0 postoperatively (P <.0001). The average number of medications used decreased from 4.4 +/- 1.97 to 2.0 +/- 2.0 (P <.0001). Kaplan-Meier survival analysis did not reveal any difference in survival profiles related to specific diagnosis of glaucoma, age (above or below 18 months), or prior surgery. Complications occurred in 30 eyes (50%). Although most resolved or were treated successfully, four patients had severe visual loss during the follow-up. Uveitis was a significant risk factor for tube exposure (Fisher exact test, P =.006).

Conclusions: Ahmed Glaucoma Valve implantation is an effective treatment for pediatric glaucoma, although patients frequently require antiglaucoma medications. However, a high rate of potentially sight-threatening postoperative complications warrants ongoing close follow-up.
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http://dx.doi.org/10.1016/s0002-9394(02)02274-2DOI Listing
June 2003

Adult bone marrow is a rich source of human mesenchymal 'stem' cells but umbilical cord and mobilized adult blood are not.

Br J Haematol 2003 Apr;121(2):368-74

Department of Transplantation Sciences, Paul O'Gorman Lifeline Centre, Division of Medicine, University of Bristol, Bristol, UK.

In postnatal life, mesenchymal stem cells (MSC) self-replicate, proliferate and differentiate into mesenchymal tissues, including bone, fat, tendon, muscle and bone marrow (BM) stroma. Possible clinical applications for MSC in stem cell transplantation have been proposed. We have evaluated the frequency, phenotype and differentiation potential of MSC in adult BM, cord blood (CB) and peripheral blood stem cell collections (PBSC). During culture, BM MSC proliferated to confluence in 10-14 d, maintaining a stable non-haemopoietic phenotype, HLA class-1+, CD29+, CD44+, CD90+, CD45-, CD34- and CD14 through subsequent passages. Using the colony forming unit fibroblasts assay, the estimated frequency of MSC in the BM nucleated cell population was 1 in 3.4 x 10(4) cells. Both adipogenic and osteogenic differentiation of BM MSC was demonstrated. In contrast, CB and PBSC mononuclear cells cultured in MSC conditions for two passages produced a population of adherent, non-confluent fibroblast-like cells with a haemopoietic phenotype, CD45+, CD14+, CD34-, CD44-, CD90- and CD29-. In paired experiments, cultured BM MSC and mature BM stroma were seeded with CB cells enriched for CD34+. Similar numbers of colony-forming units of granulocytes-macrophages were produced by MSC-based and standard stroma cultures over 10 weeks. We conclude that adult BM is a reliable source of functional cultured MSC, but CB and PBSC are not.
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http://dx.doi.org/10.1046/j.1365-2141.2003.04284.xDOI Listing
April 2003

Questioning the need for routine bone marrow aspiration and lumbar puncture in patients with retinoblastoma.

Clin Exp Ophthalmol 2003 Feb;31(1):57-60

Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Purpose: This study assesses the value of routinely investigating children with retinoblastoma with bone marrow aspiration and lumbar puncture, staging investigations not without risk and trauma to the patient, emotional stress on parents and financial cost to the community.

Methods: Medical files and specimens were obtained and examined for patients with retinoblastoma presenting to the Royal Alexandra Hospital for Children, Camperdown and the Children's Hospital at Westmead, Sydney, from 1975 to 2001.

Results: In total, 123 patients presented; 62 (50.4%) were boys and 61 (49.6%) were girls. Of these 123 patients, 74 (60.2%) had unilateral disease, 46 (37.4%) involving the left eye and 28 (22.8%) involving the right eye. There were 47 (38.2%) patients with bilateral disease, and two (1.6%) with trilateral disease. Mean age of presentation was 17.9 months (23.1 months for unilateral subjects; 10.3 months for bi-lateral subjects; 3.5 months for trilateral subjects). There were 13 (10.6%) with a positive family history. Of 74 unilateral subjects, 70 (94.6%) required enucleation and four (5.4%) were salvaged. Of 47 bilateral subjects, 13 (27.7%) did not require enucleation, 27 (57.4%) required unilateral enucleation and seven (14.9%) required bilateral enucleation. Both trilateral subjects died. Of all 123 subjects, 112 (91.1%) had bone marrow aspiration and lumbar puncture performed during initial assessment, and none showed evidence of malignancy.

Conclusions: Given the small but significant risks associated with these procedures, the results of this study cannot support bone marrow aspiration and lumbar puncture as routine investigations in all patients presenting with retinoblastoma, suggesting a more limited usage of these investigations is warranted.
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http://dx.doi.org/10.1046/j.1442-9071.2003.00601.xDOI Listing
February 2003

Chromosome translocations and covert leukemic clones are generated during normal fetal development.

Proc Natl Acad Sci U S A 2002 Jun 4;99(12):8242-7. Epub 2002 Jun 4.

Leukaemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK.

Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.
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http://dx.doi.org/10.1073/pnas.112218799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC123052PMC
June 2002