No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Knowledge of genetics in familial retinoblastoma
Abstract
Purpose:
To evaluate knowledge of retinoblastoma inheritance among parents of children with familial retinoblastoma, and to compare this to timing of eye examination for at-risk children, disease severity at diagnosis, treatment burden, and outcome.
Methods:
A retrospective review of familial retinoblastoma cases that presented at Alexandria Main University Hospital was performed. Primary outcome measures were parental knowledge of familial retinoblastoma (disease, heritability) and subsequent action (early screening or not) and their impact on tumor burden (classification at diagnosis, potential threat to vision, ocular salvage, and life), treatment burden, and treatment success (avoidance of enucleation and irradiation).
Results:
Twenty-three eyes of 13 familial retinoblastoma cases were included. Probands were parents in 9 (69%) and older siblings in 4 (31%) cases. At time of diagnosis of the first affected children, none (0%) of the parental probands knew that newborns should be screened, in contrast to all parents with a child proband (4/4, 100%; p = 0.004). Early eye screening was significantly associated with lower tumor burden (p = 0.03), lower treatment burden (p = 0.04), higher rate of ocular salvage (p = 0.01), and better visual outcome (p = 0.01).
Conclusion:
Parental knowledge of retinoblastoma nature and heritability is crucial to good patient outcomes, but translating this knowledge into appropriate action (i.e. screening of at-risk children) is still deficient.
... Non-heritable RB (85% unilateral RB) is caused by the inactivation of both alleles in somatic cells. Approximately 5-10% of patients with RB have a positive family history of cancer (2,(7)(8)(9). ...
... Genetic testing is essential for the comprehensive treatment and management of patients with RB. Genetic testing identifies individual risks in more than 95% of bilateral and unilateral RB patients (8). Lack of facilities for genetic testing adds burden on the clinical teams and families, excessively increases the need for follow-up visits. ...
... Only one patient with unilateral RB showed RB1 deletions. However, only 15% of unilateral RBs are heritable and carry a germline RB1 mutation (8). ...
Background
Retinoblastoma (RB) is the most common primary intraocular malignant tumor in children. RB is mostly caused by biallelic mutations in RB1 and occurs in hereditary and non-hereditary forms according to the “two-hit” theory. RB1 mutations comprise point mutations, indels, large deletions, and duplications. Genetic testing is essential for the comprehensive treatment and management of patients with RB.
Aim
The aim was to evaluate RB1 copy number variations (CNVs) using MLPA versus FISH assays in group of Egyptian patients with RB.
Results
16.67% showed an RB1 deletion, abnormal methylation status, or both.
Conclusion
Our results suggested MLPA is a fast, reliable, and powerful method and should be used as a first-line screening tool for detecting RB1 CNVs in patients with RB. Moreover, MLPA is advantageous as it evaluates the methylation status/inactivation of RB1, not possible by FISH.
... Therefore, the diagnosis of Rb in the first child (proband) is often delayed. However, once the family is aware of the risk of developing Rb in their other newborns (non-probands), they become more alert to any abnormal sign, and so they may get the non-probands screened (9,10). ...
... Our study results support the importance of screening high-risk patients for achieving better management outcomes in terms of eye salvage as well as visual outcome. Screening has guaranteed Rb early detection in 100% of our patients who were all diagnosed with early intraocular stages grouped as A, B, or C. In comparison to patients diagnosed with Rb based on presenting signs and symptoms, where 52% of these patients were found to have advanced ocular stage and were grouped accordingly as D or E. A parallel study for screening high-risk Rb patients was conducted in Egypt, and came out with similar results emphasising the need for Rb screening programs (9). When comparing the screening rates among LMIC and the USA, Chantada et al. found that the screening of Rb was significantly less in LMIC (Argentina, Brazil, Jordan, Turkey, and Venezuela) than in HIC (19,20). ...
... Eye salvage rate as an indicator of management outcome has reached 100% of affected eyes in the screening group, and 66% in the other group. Such results back up what Soliman et al. as suggested that Rb screening with early detection decreased tumor burden as well as treatment burden (9). Screening permits physicians to defer longer, complicated, expensive treatment regimens and stick to highly effective simple and much cheaper treating modality as focal therapy. ...
Purpose: To study the impact of a Retinoblastoma (Rb) screening program in the absence of genetic testing on the management and outcome of high-risk children.
Methods: This is a retrospective, clinical case series of 76 children from families involved in a Rb screening program as they had higher than normal risk as calculated by the conventional ways without genetic testing. Data included calculated risk, method of diagnosis, demographics, tumor features, treatment modalities, and management outcome.
Results: Out of the 76 children screened, 46 children were diagnosed with Rb (12 by screening and 34 had signs of Rb), the other 30 were free of disease. Patients diagnosed by screening were younger (mean; 2.4 months vs 15.8 months for the group with signs of Rb), had significantly earlier tumor stage at diagnosis (p = .0001), higher eye salvage rate (p = .0001), less need for systemic chemotherapy (p = .022), and better visual outcome (p = .0017) than the other group. None of the eyes were group D or E, enucleated or irradiated. Six (50%) patients were cured without chemotherapy, and the visual acuity was 0.5 or better in 55% of eyes. Of interest, 71% of tumors were diagnosed by the age of 6 months, 90% by the age of 1 year, and no new tumor appeared after the age of 2 years.
Conclusion: Even in the absence of genetic testing, screening for children with high risk for Rb is effective in enhancing early diagnosis, improving visual outcome, and increasing eye salvage rate with limited exposure to treatment burden.
... We assume that the parental awareness may help in early diagnosis and better outcome among the nonprobands. Soliman et al., while conducting a study in Egypt, had proposed a similar hypothesis and has shown that awareness increased among parents with a proband child as compared to those without proband and further improved the outcome [9]. ...
... A similar retrospective study by Soliman et al. found that at the time of probands, none of the parents without probands knew about screening for Rb among newborns, whereas all parents with probands knew about it at the time of the second child [8]. The results of our study and those by Soliman et al. show that the screening for Rb among at risk patients helps in earlier diagnosis of Rb in countries like Jordan and Egypt, respectively [9]. This increasing trend of screening and awareness was significantly less than the developed world a few years back. ...
... The enucleation rate was lower in the nonproband group. Soliman et al. have also shown that early eye screening decreased the tumor burden (p = 0 03), lowered the treatment burden (p = 0 04), and had a higher rate of ocular salvage (p = 0 01) and better visual outcome (p = 0 01) [9]. ...
Purpose . To study the impact of awareness of retinoblastoma in the affected families on the management and outcome of familial retinoblastoma patients. Methods and Materials . This is a retrospective, clinical case series of 44 patients with familial retinoblastoma. Collected data included patient’s demographics, laterality, family history, age at diagnosis, presenting signs, treatment modalities, tumor stage, eye salvage rate, metastasis, and mortality. Results . Out of 200 retinoblastoma patients in our registry, 44 (22%) patients were familial, 18 were probands, and 26 were second, third, or fourth affected family members. There were 76 affected eyes: 31 eyes of probands and 45 eyes of the other affected family members. Among probands, all patients (100%) had at least one eye enucleated: 58% (18 eyes) of the affected eyes were enucleated and 32% (10 eyes) of the affected eyes were radiated. On the other hand, among the nonprobands, only 20% had one eye enucleated, and only 4 eyes (9%) received radiation. The eye salvage rate was significantly higher in the nonprobands than in the probands in this series ( p=0.00206 ). Patients diagnosed by screening (38%) had excellent visual outcome, and both eyes were salvaged. Conclusion . Awareness of families of the possibility of retinoblastoma and adequate screening led to a significantly higher rate of eye salvage in patients with familial retinoblastoma.
... A study reported that parental knowledge of retinoblastoma nature and heritability is essential for good patient outcomes. 12 Translating this knowledge into appropriate screening of at-risk children however is still deficient according to the above study. 12 Similarly it is important to develop a means of tracing defaulters as enucleating the eye without further monitoring may not achieve the desired treatment goal. ...
... 12 Translating this knowledge into appropriate screening of at-risk children however is still deficient according to the above study. 12 Similarly it is important to develop a means of tracing defaulters as enucleating the eye without further monitoring may not achieve the desired treatment goal. ...
Retinoblastoma very rarely presents as total hyphema. Our patient presented at an early age of 7months. Follow-up of 3years shows that unilateral group E retinoblastoma was treated successfully with enucleation and adjuvant chemotherapy. The fellow eye remained normal during this period. The factors associated with delay in treatment are also described. Reports like the present case add to the information available about advanced staging of retinoblastoma at the time of presentation, seen in cases with spontaneous hyphema due to the tumor.
... In developing countries, proper genetic counseling for parents and retinoblastoma survivors is an important strategy to improve early diagnosis; stressing on the genetic nature of retinoblastoma and the importance of screening the offspring of individuals affected by retinoblastoma by regular ocular examinations under anesthesia, beginning shortly after birth and continuing up to the age of 7 years. 22,23 Other proposed strategies to overcome delay presentation maybe using social media for public awareness of retinoblastoma symptoms, screening of children at time of routine vaccination especially for red reflex, improvement of health insurance resources to cover treatment costs, increased training courses of ophthalmologists, improved research and introduction of instruments for diagnosis and treatment. 1,11,23,24 It is recommended that healthcare planning should include measures to improve ophthalmologic screening for at-risk neonates, ensure proper management of emotional reactions to both diagnosis and treatment to prevent shopping for second opinions and providing health education and promotion opportunities for surviving retinoblastoma patients concerning education, psychological support, occupational training, cosmetic rehabilitation and genetic counseling. ...
... 22,23 Other proposed strategies to overcome delay presentation maybe using social media for public awareness of retinoblastoma symptoms, screening of children at time of routine vaccination especially for red reflex, improvement of health insurance resources to cover treatment costs, increased training courses of ophthalmologists, improved research and introduction of instruments for diagnosis and treatment. 1,11,23,24 It is recommended that healthcare planning should include measures to improve ophthalmologic screening for at-risk neonates, ensure proper management of emotional reactions to both diagnosis and treatment to prevent shopping for second opinions and providing health education and promotion opportunities for surviving retinoblastoma patients concerning education, psychological support, occupational training, cosmetic rehabilitation and genetic counseling. 25 Setting national strategic guidelines for nationwide retinoblastoma management; encompassing the aforementioned factors; was successfully done in Canada 22 and Kenya 26 . ...
Objective: To evaluate the clinical presentation of retinoblastoma in Alexandria, Egypt, correlate the timing of accurate diagnosis with the presence of advanced disease and identify causes of delayed presentation.
Methods: Retrospective noncomparative single institution study reviews demographic and clinical data of all new children with retinoblastoma presenting to Alexandria Main University ocular oncology clinic (OOC) from January 2012 to June 2014. Diagnosis time was from initial parental complaint to retinoblastoma diagnosis and referral time was from retinoblastoma diagnosis to presentation to the Alexandria OCC. Delayed Diagnosis and referral were counted if >2 weeks. Advanced presentation is defined as clinical TNMH (8th edition) staging of cT2 or cT3 (international intraocular retinoblastoma classification group D or E) in at least one eye or the presence of extra-ocular disease (cT4).
Results: Seventy eyes of 47 children were eligible: 52% unilateral, 7% with family history and 96% presented with leukocorea. Sixty-four percent of children had advanced intraocular disease and none had extra-ocular disease. Delayed presentation occurred in 58% of children and was significantly associated with advanced disease in both unilaterally and bilaterally affected children (p = 0.003, 0.002 respectively). The delay in diagnosis was more in unilateral cases while the delay in referral was more in bilateral cases. The main cause of delayed presentation in unilateral retinoblastoma was misdiagnosis (30%) while parental shopping for second medical opinion (30%) was the main cause in bilateral children.
Conclusions: Delayed diagnosis is a problem affecting retinoblastoma management. Better medical education and training, health education and earlier screening are recommended to achieve earlier diagnosis.
... Retinoblastoma is the most common primary intraocular tumor in childhood with an incidence of 1:16,000 livebirth, accounting for 2-4% of all childhood malignancies [1]. The mean age at diagnosis is 27 month for unilateral and 15 month for bilateral cases [2]. There are different mechanisms and several mutations involved in RB development which has been defined as a multi-step process from normal retinal tissue towards RB tumor [3]. ...
Background:
Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances.
Objective:
This study was designed to investigate the involvement of retinoic acid receptor alpha (RARα) in RB progression and chemoresistance as well as the impact of miR-138, a potential RARα regulating miRNA.
Methods:
RARα and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RARα on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance.
Results:
A binding between miR-138 and RARα was shown by dual luciferase reporter gene assay. The study presented revealed that RARα is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RARα and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment.
Conclusions:
Our findings show that RARα acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RARα may contribute to the development and progression of RB chemo-resistance.
... Each type of lesion has rather characteristic, but not pathognomonic, clinical features. Moreover, because of different knowledge levels among people, the tumor may be missed or misdiagnosed, causing the tumor burden and treatment burden could to be unbearable for children and their caregivers [12] . Therefore, a relatively comprehensive eye cancer study in children provides strong support for clinicians in diagnosis and treatment. ...
Aim:
To describe the clinicopathologic features and classification of pediatric and adolescent ocular tumors and tumor-like lesions.
Methods:
A total of 719 cases of pathologically confirmed ocular tumors and tumor-like lesions in a pediatric population from two academic institutions over an 18-year period were retrospectively analyzed. The main outcome measures were the clinical and pathological features of the cases.
Results:
Benign tumors accounted for 92.1% of all cases while malignant tumors accounted for 7.9%. The most common ocular benign tumors were (epi-)dermoid cysts (19.8%), nevi (15.2%), corneal dermoid tumors (9.8%), and calcified epitheliomas (8.8%). The most common ocular malignant tumors were retinoblastoma (80.8%), and rhabdomyosarcoma (3.9%). Eyelid and ocular surface tumors comprised 73.3% of benign tumors while intraocular and orbital cavity comprised 94.2% of malignant tumors. For tumor site, the upper eyelid was up to 1.79 times more than lower eyelid (P<0.05). Age at surgery and sex also had an association with different lesions (P=0.006, P=0.035, respectively).
Conclusion:
Most ocular tumors and tumor-like lesions in children and adolescents are benign. Pediatric ocular tumors are distinct from those in adults in terms of histological origin. (Epi-)dermoid cysts are the most common benign tumors while retinoblastomas the most common malignant tumors.
... Most published surveys have primarily focused on the knowledge of practitioners, rather than parents, and found that most first contact physicians lack sufficient knowledge of retinoblastoma [10]. A handful of studies on parental awareness have concentrated on the subset of familial retinoblastoma patients and consistently found that raised awareness improved early diagnosis and outcome [11,12]. More recently, a qualitative study from Canada explored knowledge of retinoblastoma genetics among retinoblastoma survivors and parents of children with retinoblastoma, and it revealed that knowledge of retinoblastoma genetics was variable and often limited [13]. ...
Purpose:
To evaluate parent knowledge of screening and genetic testing for retinoblastoma and its potential correlation with demographics, clinical features, and socioeconomical factors.
Methods:
It was a cross-sectional study conducted at the ocular oncology unit of a tertiary ophthalmic center in Southern China. A face-to-face interview was administered to parents of retinoblastoma children during hospitalization. Parent knowledge was assessed using the sum score of a 7-item questionnaire. Demographics and socioeconomic status were collected from the interview, and clinical data were retrieved from the medical records.
Results:
A total of 126 parents of retinoblastoma children were included. Parents accurately answered 66.7% to 84.9% of each item in the questionnaire. Only 37 (29.4%) parents correctly answered all 7 questions. Parent knowledge was positively correlated with education, but it was not associated with patients' laterality, sex, or household income. Physicians and the Internet were the major sources of parental health-related information. During the median follow-up of 492 days, 13 (61.9%) of 21 patients in the full-score group without genetic testing at baseline actually conducted testing during follow-up compared to 29 of 67 (43.3%) in the less-than-full-score group (P=0.136).
Conclusion:
Overall parent knowledge about retinoblastoma screening and genetic testing was moderate. Higher education was associated with greater parent knowledge. Future studies should validate our findings in other populations, especially in those with different cultural background and healthcare systems.
... This highlights the importance of secondary prevention to facilitate early diagnosis and treatment, so that these children have preserved vision and avoid systemic therapies and eye loss. 2 Secondary prevention typically starts with genetic counseling of survivors regarding risk to offspring. 24 Molecular diagnosis of the exact pathogenic RB1 variant in the proband improves risk determination and standardizes guidelines for screening (clinic visits vs. EUA). 6 Screening by OCT entails examining the newborn at risk within the first few days after birth followed by meticulous follow-up schedule to detect tumors at the smallest possible size and stage. ...
Objective
Invisible retinoblastoma tumors are now detected with screening for retinal tumors in at risk neonates (those inheriting RB1 pathogenic alleles from affected parents) using handheld optical coherence tomography (OCT). Laser photocoagulation is challenging, requiring exact localization of a tumor invisible to indirect ophthalmoscopy and standard imaging. Herein, we describe OCT-guided localization and photocoagulation of theses invisible tumors with 1-year follow-up.
Design
Retrospective, non-comparative single-institutional observational case series
Participants
Children with any clinically invisible retinoblastoma tumor that was detected on OCT posterior pole screening.
Methods
OCT revealed round homogeneous invisible tumors within the inner nuclear layer. Software calipers placed beside anatomical retinal landmarks (branched/curved vessels, fovea or optic disc) mapped the tumor location and extent. A single laser (532 nm) burn flagged the location and OCT evaluated the tumor-laser burn relationship; laser treatment was then continued in the correct location. Post-laser OCT ensured complete treatment.
Main outcome measures
Accuracy (frequency of geographic miss and skip areas), effectiveness (recurrence rate) and burden (scar size and characteristics at final follow-up) of laser treatment.
Results
Eleven new invisible posterior pole tumors in 7 eyes of 5 children were treated by this technique. Localization and tumor-laser burn relationships were accurate in 11/11 tumors (100%, 95% CI: 49.9-100%) and all showed swelling and hyper-reflectiveness of the tumor in post-laser OCT. Two photocoagulation sessions (2 weeks apart) were sufficient to successfully manage 9/11 (82%, 95% CI; 37.4-100%) tumors with resulting permanent flat scars. One tumor (9%, 95% CI: 0.2-50.6%) developed OCT-detected subclinical recurrences within 3 months, treated by one laser session. No treatment scar showed gliosis, foveal involvement or retinal traction at 1 year follow-up. Scar expansion occurred in one tumor (9%, 95% CI: 0.2-50.6%) and all scars (100%, 95% CI: 49.9-100%) showed pigmentary changes.
Conclusion
OCT-guided localization and photocoagulation technique is valuable in achieving precision results in managing invisible new retinoblastoma tumors. This technique shows a potential to improve outcomes of secondary prevention screening for retinoblastoma.
... Counseling about reproductive risks is important for families affected by retinoblastoma, including unilateral probands. 41 Current optimized therapies result in very low mortality, and most retinoblastoma patients survive and may consider having children. Prenatal diagnosis enables preimplantation screening to ensure an unaffected child and informs parents who may wish to terminate an affected pregnancy. ...
Purpose : Familial retinoblastoma can be predicted by prenatal RB1 mutation detection. Early delivery following prenatal detection to enable treatment of the smallest tumors may achieve optimized outcomes. We performed a retrospective, observational study to compare overall outcomes and intensity of treatment for children with familial retinoblastoma diagnosed postnatal or by obstetrical ultrasound, and those diagnosed by prenatal RB1 mutation identification and delivered preterm.
Methods : For this retrospective, observational study at The Hospital for Sick Children (SickKids) all children born between 1 June 1996 and 1 June 2014 with familial retinoblastoma participated. Cohort 1 consisted of infants delivered spontaneously with postnatal RB1 testing. Cohort 2 consisted of infants identified by amniocentesis to carry the affected relative’s known RB1 mutant allele, planned for early term or late preterm delivery (36-37 weeks gestation). All children received standard treatment for eye tumors. Primary study outcome measurements were gestational age, age at first tumor, eye classification, visual outcome, treatments given, number of anesthetics, pregnancy or delivery complications and estimated treatment burden.
Results : Of Cohort 1 eyes, 47% (8/17) of were tumor-free at birth (IIRC 0), compared to 79% (19/24) Cohort 2 eyes (P=0.03). Of Cohort 1 infants, 67% (6/9) already had vision-threatening tumors at birth. Of Cohort 2 infants, 9 were electively induced at 36-38 weeks gestation and 3 were born spontaneously preterm; 25% (3/12) had vision-threatening tumors at birth. Both Cohorts eventually developed tumors in both eyes. Acceptable vision (better than 0.1) was achieved for 78% of Cohort 1 compared to 100% of Cohort 2 (p<0.02). At first eye tumor diagnosis, 11% of Cohort 1 had both eyes Group A (smallest and least vision-threatening tumors) compared to 67% of Cohort 2 (p<0.01). Eye salvage (defined as avoidance of enucleation and external beam irradiation) was achieved in 33% of Cohort 1 compared to 97% of Cohort 2 (p<0.002). There were no complications related to preterm delivery.
Conclusions : Prenatal molecular diagnosis with late preterm/near-term delivery resulted in more eyes with no detectable retinoblastoma tumors at birth, and better vision outcomes with less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory planning for both child and family.
... 11 Previous studies have documented a less than desired level of knowledge among parents regarding more serious issues like obesity and eye cancer in their ward. 12,13 In addition to one-on-one counseling of parents with strabismus, provision of relevant sources to seek knowledge on strabismus is recommended to improve the level of knowledge among caregivers of children with strabismus. 14 Among the participants, the level of knowledge was uniformly low, whether it was related to epidemiology, presentation or mode of management. ...
Background: For early detection and timely management of strabismus in children, parent’s cooperation is essential. It depends upon their level of awareness. The objective was to describe the determinants and the level of knowledge and attitude towards strabismus among parents of children with strabismus in Saudi Arabia.Methods: This cross-sectional study was conducted in 2018 at a hospital in Qaseem, Saudi Arabia. Consented parents of children with strabismus presenting to Qaseem University eye clinic were interviewed. Data were anonymously collected on participant demographics and the child’s strabismus. The survey interview consisted of 8 questions related to signs, symptoms, and management of strabismus. Three questions related to the attitude towards strabismus among parents/caregivers. Two separate questions queried the source of knowledge and possible barriers, respectively.Results: Each parent of 81 children was interviewed. An excellent level of knowledge of strabismus was noted for 41 participants (50.6% at 95%CI 39.7-61.5). A positive attitude towards strabismus was noted in 57 participants (70.4% at 95% CI 60.4-80.3). No history of surgery was statistically associated to an excellent level of knowledge (P<0.001). Gender (P=0.7), age (P=0.7), father’s education (P=0.3), mother’s education (P=0.5), type of strabismus (P=0.8) were not associated with the level of knowledge. High cost (43.2%) and false beliefs (53.1%) were the main barriers to medical consultations.Conclusions: Parents of children with strabismus presenting to a tertiary care eye hospital had good knowledge about the signs, symptoms and management of strabismus. Addressing barriers perceived by parents may improve early presentation rates of children with strabismus allowing timely management.
... Invisible tumors ( Figure 5) can be anticipated in children carrying a pathogenic variant of the RB1 tumor suppressor gene, detected either prenatally or postnatally, because they have a positive parental family history of retinoblastoma [55][56][57]. These children are classified now by the 2017 Tumor Node Metastasis Heritability cancer staging for retinoblastoma to be 'H1' even if they do not yet have detectable cancer [5,25]. ...
Introduction: Laser therapy is a cornerstone for control of intraocular retinoblastoma, after chemotherapy has brought the disease under initial control. Since first described over 6 decades ago, laser technologies and approaches have evolved to improve tumor control. Despite its important role, few publications describe techniques, types of lasers, and modes of delivery for retinoblastoma.
Areas covered: The physical and optical properties of lasers, mechanisms of action, delivery systems and complications are described. Hand-held optical coherence tomography (OCT) detects microscopic retinoblastoma tumors and guides treatment, achieving precision primary therapy and elimination of recurrences.
Expert commentary: In all the excitement of new therapies to cure intraocular retinoblastoma, laser treatment always compliments but is rarely mentioned. Hand-held OCT now adds precision to put laser in the forefront in achieving cure of retinoblastoma.
... If the RB1 mutation is not detected, risk for retinoblastoma is that of the general population (1:17000 live births). [2][3][4] Familial retinoblastoma management requires close collaboration among ophthalmologists, oncologists, obstetricians, imaging specialists, neonatologists, genetic counselors, social workers, nursing and booking coordinators. It also requires an understanding of retinoblastoma management and compliance by parents. ...
... Counseling about reproductive risks is important for families affected by retinoblastoma, including unilateral probands. 41 Current optimized therapies result in very low mortality, and most retinoblastoma patients survive and may consider having children. Prenatal diagnosis enables preimplantation screening to ensure an unaffected child and informs parents who may wish to terminate an affected pregnancy. ...
Purpose:
To compare overall outcomes of conventional postnatal screening of familial retinoblastoma and prenatal RB1 mutation identification followed by planned early-term delivery.
Design:
Retrospective, observational study.
Participants:
Twenty children with familial retinoblastoma born between 1996 and 2014 and examined within 1 week of birth.
Methods:
Cohort 1 included spontaneously delivered neonates examined within 1 week of birth and confirmed postnatal to carry their family's RB1 mutant allele. Cohort 2 included infants identified by amniocentesis to carry their family's RB1 mutant allele, and therefore scheduled for early-term delivery (36-38 weeks' gestation). Treatment for retinoblastoma was performed at the Hospital for Sick Children, Toronto, Canada.
Main outcome measures:
Age at first tumor in each eye, eye stage, treatments given, ocular salvage, treatment success (defined as avoidance of enucleation, external-beam irradiation, or both), visual outcome, number of anesthetics, pregnancy or delivery complications, and estimated treatment burden.
Results:
Vision-threatening tumors were present at birth in 4 of 8 infants in cohort 1 and in 3 of 12 infants in cohort 2. Eventually, all infants demonstrated tumors in both eyes. At the first treatment, 1 of 8 infants in cohort 1 had eyes in stage cT1a/cT1a or cT1a/cT0 (smallest and least vision-threatening tumors), compared with 8 of 12 infants in cohort 2 (P = 0.02). Null RB1 germline alleles induced earlier tumors than low-penetrance alleles (P = 0.03). Treatment success was achieved in 3 of 8 children in cohort 1 compared with 11 of 12 children in cohort 2 (P = 0.002). Acceptable vision (better than 0.2 decimal) was achieved for 8 of 16 eyes in cohort 1 compared with 21 of 24 eyes in cohort 2 (P = 0.014). Useful vision (better than 0.1, legal blindness) was achieved for 8 of 9 children in cohort 1 compared with 12 of 12 children in cohort 2. There were no complications related to early-term delivery. Median follow-up was 5.6 years, cohort 1 and 5.8 years, cohort 2.
Conclusions:
When a parent had retinoblastoma, prenatal molecular diagnosis with early-term delivery increased the likelihood of infants born with no detectable tumors, better vision outcomes, and less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory planning for both the child and family.
Introduction:
The number of children surviving cancer in Africa is increasing. Knowledge about late effects of survivors is lacking. Our study maps literature regarding late effects of childhood cancer survivors in Africa.
Methods:
Scoping review was performed following JBI-guidelines. Systematic literature search was conducted in: Medline, Embase, African Index Medicus, Web of Science, Scopus, Psycinfo. Titles and abstracts were screened by two reviewers, followed by full-text analysis by the lead reviewer.
Results:
Sixty-eight studies were included for content analysis. Studies originated from 10 of 54 African countries. Most studies had retrospective study design, 2-5 years follow-up, solely chemotherapy as treatment modality, Egypt as country of origin. Fifty-three studies described physical, and seventeen studies described psychosocial late effects.
Conclusion:
Literature concerning late effects is available from a limited number of African countries. Psychosocial domain lacks attention compared to the physical domain. More countries should report on this topic to prevent, identify and monitor late effects.
Retinoblastoma is the prototypic genetic cancer, revealing much about the fundamentals of cancer genomics over the past 50 years. The majority of retinoblastoma tumors are initiated by biallelic loss (M1 and M2) of the retinoblastoma tumor suppressor gene, with progression driven by subsequent recurrent genomic changes (M3 to Mn). Knowledge of retinoblastoma genetics has transformed all aspects of clinical care. High-sensitivity molecular RB1 testing and counseling stratify both ocular and second cancer risks for the proband and family members. Prenatal diagnosis of familial retinoblastoma enables early detection of tumors and improves outcomes. Aqueous humor is a promising “liquid biopsy” with potential diagnostic and prognostic applications. Current advances in retinoblastoma genomics will pave the way toward individualized, precision medicine in which early intervention follows subclinical detection. Outcomes for children and families will be optimized through collaborative, multicenter, prospective clinical trials, targeted molecular therapies, and genotypic prognostication.
Recent advances in genomic technologies have enabled increasing identification of children who carry a germline pathogenic variant in a cancer predisposition gene. This development has led to increasing numbers of children being offered cancer-related genetic or genomic testing. Early identification of an underlying cancer predisposition syndrome may influence treatment approaches for children with cancer, as well as guiding longer-term surveillance and risk reduction for at-risk children and their family members. Despite this exciting potential, there is little data available on the short- and long-term impacts on children and their families. In this chapter, we review the available evidence regarding the psychosocial impact of genetic testing on children and their families while also summarizing current research on family attitudes toward genetic testing, the impact of surveillance, and any influences on reproductive decision-making. The chapter focuses on families affected by Li-Fraumeni syndrome, familial adenomatous polyposis, retinoblastoma, von Hippel-Lindau syndrome, and multiple endocrine neoplasia type 2. The chapter also addresses recent innovations, such as the adoption of precision medicine, and explores their potential impacts on well-being. We present recommendations for providing tailored psychosocial support to families, as well as offering guidance for future rigorous psychosocial research. Understanding more about the psychosocial aspects of childhood cancer genetics will be essential in enabling us to determine the impact of advancing technologies and to provide effective psychosocial support to vulnerable children and their families.
Retinoblastoma management is a success story of a genetic cancer. Nowadays, advances in diagnostic and therapeutic approaches have provided approximately 99% survival in developed countries. Later diagnosis lowers survival in developing countries. In this chapter, we present the concepts of pathogenesis, diagnosis, treatment, and long-term surveillance for retinoblastoma patients and their families.
Background: Primary prevention of primary congenital glaucoma (PCG) includes improving families of children with PGC. We evaluated the level of knowledge and attitudes of parents of children on PCG in Saudi Arabia.
Methodology: This was a personal interview-based survey of parents of children with PCG at a tertiary eye hospital in Saudi Arabia. The study was conducted in 2018. A close-ended questionnaire in Arabic was used. Demographic data were collected on the children and parents. Clinical data on PCG were collected from electronic case records. Five questions each on knowledge and attitudes toward genetic counseling were queried. A Likert-type scale was used to collect the responses. Rasch analysis was carried out for knowledge and attitudes. The score was correlated with demographics and clinical determinants. p < 0.05 was considered statistically significant.
Results: The study sample comprised 60 participants. The median Rasch score for knowledge on genetic counseling for PCG was -4.57 [interquartile range (IQR) -7.28; -1.0]. The median Rasch score for attitudes toward genetic counseling for PCG was -8.9 (IQR -11.6: -5.9). Parents with more than one family member with PCG had a significantly higher knowledge than those with one family member with PCG (p = 0.007). Knowledge of
etiology and genetic counseling was significantly better if the child had residual vision amenable to low vision care (p < 0.001). The Rasch scores for knowledge and attitude were positively correlated (p < 0.001).
Conclusion: Knowledge of the cause of PCG and genetic counseling was high among parents. The positive attitude toward genetic counseling could be useful for the primary prevention of CG in Saudi Arabia. [JBCGenetics 2021; 4(1.000): 22-26]
Objectives:
To investigate the myelogram characteristics of RB with extraocular tumor extension and the morphological characteristics of tumor cells in bone marrow and cerebrospinal fluid.
Methods:
The clinical data of 18 cases in our hospital from May 2011 to February 2015 diagnosed with metastatic RB in the extraocular and other distant regions associated with clear bone marrow metastasis were analyzed. The morphology of tumor cells in bone marrow and cerebrospinal fluid were retrospectively analyzed after staining with Wright-Giemsa stain. A summary of the cytological characteristics was also presented.
Results:
RB tumor cells in bone marrow and cerebrospinal fluid not only appeared as aggregated clumps, but also was distributed in a scattered manner. The tumor cells may present different characteristic morphologies in different cases, even the different tumor cell smears made from the same tumor mass may show different morphological features. According to the degree of tumor metastasis, changes in myelogram were significantly different.
Conclusion:
The tumor cells of RB patients show unique morphological characteristics in bone marrow and cerebrospinal fluid. Therefore, correct identification of the cells is of great value in the diagnosis, staging and prognosis of RB.
Good understanding of the genetics causing retinoblastoma improves outcomes for patients and families. Accurate and easily understood genetic counseling is important to help families embrace the opportunity of accurate care and surveillance. The 8th edition of the AJCC cancer staging for retinoblastoma includes heritability (H) and simplifies discussion and planning. This chapter describes the state-of-the-art scientific knowledge of the retinoblastoma tumor suppressor gene (RB1), the types of RB1 pathogenic variants that lead to retinoblastoma, and how to apply this knowledge to individual members of a family affected by retinoblastoma. A checklist is provided to assist genetic counselors and all in the circle of care to assure that each family member clearly understands the essential elements of retinoblastoma genetics in order to achieve optimal outcomes.
Outcomes from retinoblastoma are affected not just by biological and clinical factors of the tumour but also by a number of interrelated social factors. This chapter will explore the social determinants of health affecting retinoblastoma outcomes and discuss the role of multidisciplinary partnerships and organizations in creating advocacy and interventions to reduce the effects of social disparities in health.
Purpose:
To discuss the importance of routine ophthalmic examination of parents and siblings of retinoblastoma (RB) patients.
Methods:
Prospective nonrandomized observational/interventional case series of consecutive families of 131 RB patients.
Results:
Routine ophthalmic examination of families (parents and siblings) of 131 consecutive newly diagnosed RB patients, including 262 parents and 23 siblings, revealed spontaneously regressed RB in at least 1 parent of 10 (8%) patients and active RB in at least 1 sibling of 3 (2%) patients. Of the 10 parents with spontaneously regressed RB, the lesions were unilateral (n = 7) or bilateral (n = 3). The regression patterns (n = 13) were comparable with postirradiation regression patterns Type 1 (n = 3), Type 2 (n = 2), Type 3 (n = 2), and Type 4 (n = 3), and spontaneous phthisis bulbi (n = 3). Fundus screening of siblings revealed active RB in at least 1 sibling of 3 (2%) patients. Of these 3 siblings, 2 had unilateral and 1 had bilateral disease. The mean age at detection of RB was 15 months (median, 6 months; range, 2-36 months). The disease was unilateral in 2 and bilateral in 1 patient. Based on International Classification of Intraocular Retinoblastoma, the tumors (n = 4) were classified as Group A (n = 2) and Group B (n = 2).
Conclusion:
Routine fundus screening of siblings allows for early detection of RB in otherwise asymptomatic children. Detection of spontaneously regressed RB in parents may act as a surrogate marker for germline RB1 mutation and is helpful in genetic counseling.
Retinoblastoma is the prototype genetic cancer: in one or both eyes of young children, most retinoblastomas are initiated by biallelic mutation of the retinoblastoma tumor suppressor gene, RB1, in a developing retinal cell. All those with bilateral retinoblastoma have heritable cancer, although 95% have not inherited the RB1 mutation. Nonheritable retinoblastoma is always unilateral, with 98% caused by loss of both RB1 alleles from the tumor, whereas 2% have normal RB1 in tumors initiated by amplification of the MYCN oncogene. Good understanding of retinoblastoma genetics supports optimal care for retinoblastoma children and their families. Retinoblastoma is the first cancer to officially acknowledge the seminal role of genetics in cancer, by incorporating "H" into the eighth edition of cancer staging (2017): those who carry the RB1 cancer-predisposing gene are H1; those proven to not carry the familial RB1 mutation are H0; and those at unknown risk are HX. We suggest H0∗ be used for those with residual <1% risk to carry a RB1 mutation due to undetectable mosaicism. Loss of RB1 from a susceptible developing retinal cell initiates the benign precursor, retinoma. Progressive genomic changes result in retinoblastoma, and cancer progression ensues with increasing genomic disarray. Looking forward, novel therapies are anticipated from studies of retinoblastoma and metastatic tumor cells and the second primary cancers that the carriers of RB1 mutations are at high risk to develop. Here, we summarize the concepts of retinoblastoma genetics for ophthalmologists in a question/answer format to assist in the care of patients and their families.
This is the first of a two-part review that aims to report the current knowledge of retinoblastoma (Rb) and its implications in Mexico (including the authors’ experience at the leading Rb centers), identify the gaps in practice, and propose solutions to improve diagnosis, treatment, and patient uptake. In this first part, general knowledge of Rb diagnosis and management is summarized with a focus on the latest advances in chemotherapy. A general review of peer-reviewed literature of Rb was conducted on PubMed. Key findings were summarized.
Provided there is early detection and referral of patients followed by appropriate conservative management, Rb is curable. In developed countries, the primary treatment outcome is ocular salvage with sight preservation. Advanced chemotherapeutic options such as intra-arterial and intravitreal chemotherapy can now save even the most advanced tumors.
Advances in Rb therapy are generally limited to developed countries. The implications in Mexico, of the findings from this review will be discussed in Part 2, which will be a comprehensive situational analysis of the state of Rb programming in Mexico, including a review of current demographic data available from hospitals that have Rb programs or treat Rb.
Retinoblastoma is a rare cancer of the infant retina that is diagnosed in approximately 8,000 children each year worldwide. It forms when both retinoblastoma gene (RB1) alleles are mutated in a susceptible retinal cell, probably a cone photoreceptor precursor. Loss of the tumour-suppressive functions of the retinoblastoma protein (pRB) leads to uncontrolled cell division and recurrent genomic changes during tumour progression. Although pRB is expressed in almost all tissues, cone precursors have biochemical and molecular features that may sensitize them to RB1 loss and enable tumorigenesis. Patient survival is >95% in high-income countries but <30% globally. However, outcomes are improving owing to increased disease awareness for earlier diagnosis, application of new guidelines and sharing of expertise. Intra-arterial and intravitreal chemotherapy have emerged as promising methods to salvage eyes that with conventional treatment might have been lost. Ongoing international collaborations will replace the multiple different classifications of eye involvement with standardized definitions to consistently assess the eligibility, efficacy and safety of treatment options. Life-long follow-up is warranted, as survivors of heritable retinoblastoma are at risk for developing second cancers. Defining the molecular consequences of RB1 loss in diverse tissues may open new avenues for treatment and prevention of retinoblastoma, as well as second cancers, in patients with germline RB1 mutations.
Retinoblastoma is the prototypic genetic cancer. India carries the biggest burden of retinoblastoma globally, with an estimated 1500 new cases annually. Recent advances in retinoblastoma genetics are reviewed, focusing specifically on information with clinical significance to patients. The Indian literature on retinoblastoma clinical genetics is also highlighted, with a comment on challenges and future directions. The review concludes with recommendations to help clinicians implement and translate retinoblastoma genetics to their practice.
To assess the needs related to prenatal genetic counselling in a developing country.
The prospective observational study was conducted at the Prenatal-Genetic Counselling Clinic of Aga Khan University Hospital, Karachi, from October 2007 to September 2010. In-depth interviews were conducted and the data was stored in the form of patient charts. Information was then extracted from the charts and entered into a structured questionnaire.
Of the 93 couples in the study, 49 (53%) were in the self-referral group and 44 (47%) were in the physician- referral group. Diagnosis was not given for previously affected children by the paediatrician or by obstetrician for recurrent miscarriages in 68 (73%)cases. Besides, 20 (22%) couples had voluntarily terminated a pregnancy without any tests because of the fear of having a diseased child. Eleven (12%) couples were looking for amniocentensis or chorionic villus sampling. Death in previous children was the main reason to seek genetic counselling and was seen in 57 (61%) couples. Consanguinity was seen in 77 (83%) couples.
A clear deficiency of knowledge of genetics was seen among the non-genetic healthcare providers. Demand of antenatal genetic testing among the public was also seen, highlighting the need of diagnostic facility for genetic and metabolic disorders. However, this needs to be explored in the context of the existing healthcare infrastructure.
The retinoblastoma tumor suppressor gene (RB1) is a key regulator of cell cycle control, most notably through E2F transcription factor binding. Deregulation of RB1 is important in many cancers. Survivors of hereditary retinoblastoma, caused by a germline mutation in RB1, experience substantially elevated risks for subsequent neoplasms, particularly bone and soft tissue sarcomas and melanomas. Oncogenic RB1 mutations arise from a range of DNA alterations and occur throughout the gene. No previous study has evaluated how the specific location and functional consequences of these RB1 mutations may differentially confer risk for specific subsequent neoplasms. As part of a biomarker study nested within a long-term follow-up study of the risk of subsequent cancers in retinoblastoma survivors, we identified germline RB1 mutations in 76/80 (95%) survivors of hereditary retinoblastoma who developed at least one subsequent neoplasm and had sufficient DNA for mutation testing (median follow-up time=47 years, range 7-71 years). Survivors were classified into four groups according to whether they ever developed a soft tissue sarcoma (STS, N=47), melanoma (without STS, N=10), bone tumor (without STS, N=5), or another type of subsequent malignant neoplasm (N=14). The identified mutations were distributed throughout RB1, from the promoter through exon 25. Nonsense, frameshift, or splice mutations that resulted in premature termination of the RB1 residue sequence were identified in 51 (67%) survivors, with the remaining classified as having loss of multiple exons (N=6), loss or rearrangement of a single exon (N=5), a splice mutation (N=7), a missense mutation (N=4), or an intronic substitution with unknown consequence (N=3). Preliminary analyses indicated that RB1 mutations resulting in loss of >2 exons were more common in survivors with a subsequent STS (40/47, 85%) than those with a subsequent melanoma (6/10, 60%) or bone tumor (2/5, 40%; Fisher's exact P<0.001). In an analysis of the RB1 regions impacted by the mutation, those that affected E2F binding (including mutations affecting the E2F binding site, Domain B, or Domain C) were more common in survivors with a subsequent STS (46/47, 98%) or melanoma (9/10, 90%) than those with a bone tumor (2/5, 40%; Fisher's exact P=0.020). Further analyses will include 14 additional survivors who developed a subsequent neoplasm for whom mutation testing is ongoing, and comparison of the spectrum of RB1 mutations in these survivors to hereditary retinoblastoma survivors without a subsequent neoplasm. If confirmed, such correlations between specific RB1 mutations and subsequent neoplasm risk may inform long-term surveillance practices for hereditary retinoblastoma survivors and provide insight into the key role of RB1 in oncogenesis.
Citation Format: Lindsay M. Morton, Jeannette R. Wong, Brenda L. Gallie, David H. Abramson, Johanna M. Seddon, Michael Dean, Bert Gold, Alisa M. Goldstein, Ruth A. Kleinerman, Margaret A. Tucker. Specific RB1 mutations and risk of subsequent neoplasms among survivors of hereditary retinoblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2013-1333
Background/aims:
Clinical cancer genetics is an integral part of cancer control and management, yet its development as an essential medical service has been hindered in many low-and-middle-income countries. We report our experiences in developing a clinical cancer genetics service for retinoblastoma in Kenya.
Methods:
A genetics task force was created from within the membership of the existing Kenyan National Retinoblastoma Strategy group. The task force engaged in multiple in-person and telephone discussions, delineating experiences, opinions and suggestions for an evidence-based, culturally sensitive retinoblastoma genetics service. Discussions were recorded and thematically categorized to develop a strategy for the design and implementation of a national retinoblastoma clinical genetics service.
Results:
Discussion among the retinoblastoma genetics task force supported the development of a comprehensive genetics service that rests on 3 pillars: (1) patient and family counseling, (2) community involvement, and (3) medical education.
Conclusions:
A coordinated national retinoblastoma genetics task force led to the creation of a unique and relevant approach to delivering comprehensive and accurate genetic care to Kenyan retinoblastoma patients. The task force aims to stimulate innovative approaches in cancer genetics research, education and knowledge translation, taking advantage of unique opportunities offered in the African context.
Retinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype-phenotype correlations.
The peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old.
Thirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations.
Our results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB.
Background:
Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations.
Methods:
Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1(+/+)) with tumours carrying a mutation in both alleles (RB1(-/-)). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data.
Findings:
No RB1 mutations (RB1(+/+)) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1(+/+) tumours had high-level MYCN oncogene amplification (28-121 copies; RB1(+/+)MYCN(A)), whereas none of 93 RB1(-/-) primary tumours tested showed MYCN amplification (p<0·0001). RB1(+/+)MYCN(A) tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1(-/-) tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1(+/+)MYCN(A) retinoblastoma. One additional MYCN(A) tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1(+/+)MYCN(A) tumours was 4·5 months (IQR 3·5-10), compared with 24 months (15-37) for 79 children with non-familial unilateral RB1(-/-) retinoblastoma.
Interpretation:
Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1(+/+)MYCN(A) retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis.
Funding:
National Cancer Institute-National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.
This brief report displays comprehensive details of health services provided by Children's Welfare Teaching Hospital, medical city, Baghdad. In 2010; 366 children with newly diagnosed cancer were admitted for treatment, two thirds were leukemia and lymphoma cases followed by other solid tumors except brain tumors. With this large number of patients; there are shortcomings in provision of health services in many aspects including professional manpower, infrastructure, diagnostic and therapeutic facilities, supportive and palliative care. The previous wars and sanction and the current instability of the country added to the socioeconomic difficulties of the families jeopardizing the appropriate therapy and ultimately the poor treatment outcome. Since 2003 an international collaboration had a major contribution in many aspects like provision of drugs and medical supplies, attendance of scientific workshops, and updating doctor's knowledge and experience through telemedicine programs which resulted in decreasing the induction mortality in acute lymphoblastic leukemia from 24% in the year 2007% to 10% in 2010 after introduction of pre-phase steroids and in acute promyelocytic leukemia from 95% to 5% after introduction of all trans-retinoic acid. A collaborative work with Rome University resulted in changing diagnosis of 20% of pathological samples sent there for reevaluation. Iraqi pediatric oncologists still need real attempts to improve infrastructure and human resources in addition to twinning programs with internationally recognized cancer centers to face these management challenges.
Retinoblastoma is an aggressive eye cancer of infancy and childhood. Survival and the chance of saving vision depend on severity of disease at presentation. Retinoblastoma was the first tumour to draw attention to the genetic aetiology of cancer. Despite good understanding of its aetiology, mortality from retinoblastoma is about 70% in countries of low and middle income, where most affected children live. Poor public and medical awareness, and an absence of rigorous clinical trials to assess innovative treatments impede progress. Worldwide, most of the estimated 9000 newly diagnosed patients every year will die. However, global digital communications present opportunities to optimise standards of care for children and families affected by this rare and often devastating cancer. Parents are now leading the effort for widespread awareness of the danger of leucocoria. Genome-level technologies could make genetic testing a reality for every family affected by retinoblastoma. Best-practice guidelines, online sharing of pathological images, point-of-care data entry, multidisciplinary research, and clinical trials can reduce mortality. Most importantly, active participation of survivors and families will ensure that the whole wellbeing of the child is prioritised in any treatment plan.
To assess if systematic fundus screening according to an 'intensive' schedule alters ocular outcome and to propose fundus screening schedule guidelines for children related to a retinoblastoma patient.
For children with a positive family history of retinoblastoma, we perform fundus exams shortly after birth under general anaesthesia and then at regular intervals according to schedules based on the risk. Familial retinoblastoma cases seen at our institution from January 1995 to December 2004 were retrospectively classified as 'screened' or 'non-screened' (NS) and, among the 'screened' patients, as 'intensively screened' (IS) if screening matched our recommendations or 'non-intensively screened' (S). Groups were compared by Fisher exact test for categorical variables and Kruskal-Wallis test for continuous variables.
Among the 547 retinoblastoma patients managed at our institution during this period, 59 were familial cases. In all, 20 were in the NS group, 23 in the S group, and 16 in the IS group. The number of children enucleated was, respectively, 13, 2, and 0 (P<10(-4)); external beam radiation (EBRT) was required for, respectively, 6, 0, and 2 children (P<0.009). Chemotherapy burden and visual acuity were not significantly different between groups.
An 'intensive' fundus screening schedule decreased the need for enucleation and EBRT. Therefore, despite the heavy burden of the screening schedule, we recommend physicians and health-care professionals to better inform and refer children with a family history of retinoblastoma for genetic counselling and proper fundus screening in specialized centres.
Little is known about the impact of retinoblastoma (RB) on the health status of survivors in terms of disabilities and worries, both of which may restrict participation in activities of daily life.
In this population-based cross-sectional study, content analysis was used to extract data on perceived restrictions and worries, from semi-structured interviews held with 156 RB survivors aged 8-35 years. The International Classification of Functioning Disabilities and Health (ICF) was used as a framework.
Of all survivors, 55% perceive RB-related restrictions in daily life activities (school, professional career, mobility, self-care, intimate relationships). Young/adolescent survivors (6%) and adult survivors (15%) frequently report anxiety about developing a second primary tumor (SPT). Compared with the general population, RB survivors did not differ in rates of employment or marital status. However, special educational services were more frequently offered, and the level of completed education was lower.
RB has influenced the lives of most survivors and, even though their prognosis was good, illness-related restrictions are common. Especially fear of developing SPT and of further loss of vision are important life-long problems, and many survivors had special education needs. The ICF might serve as a bridge between families and professionals, because this classification may facilitate early detection of problems.
The RB1 gene mutation detection rate in 1,020 retinoblastoma families was increased by the use of highly sensitive allele specific-PCR (AS-PCR) to detect low-level mosaicism for 11 recurrent RB1 CGA>TGA nonsense mutations. For bilaterally affected probands, AS-PCR increased the RB1 mutation detection sensitivity from 92.6% to 94.8%. Both RB1 oncogenic changes were detected in 92.7% of sporadic unilateral tumors (357/385); 14.6% (52/357) of unilateral probands with both tumor mutations identified carried one of the tumor mutations in blood. Mosaicism was evident in 5.5% of bilateral probands (23 of 421), in 3.8% of unilateral probands (22 of 572), and in one unaffected mother of a unilateral proband. Half of the mosaic mutations were only detectable by AS-PCR for the 11 recurrent CGA>TGA mutations, and not by standard sequencing. This suggests that significant numbers of low-level mosaics with other classes of RB1 mutations remain unidentified by current technology. We show that the use of linkage analysis in a two-generation retinoblastoma family resulted in the erroneous conclusion that a child carried the parental mutation, because the founder parent was mosaic for the RB1 mutation. Of 142 unaffected parental pairs tested, only one unaffected parent of a proband (0.7%) showed somatic mosaicism for the proband's mutation, in contrast to an overall 4.5% somatic mosaicism rate for retinoblastoma probands, suggesting that mosaicism for an RB1 mutation is highly likely to manifest as retinoblastoma.
To assess the diagnostic process of retinoblastoma in a developing country.
Prospective survey of 95 consecutive parents of patients with retinoblastoma.
Fifty six parents consulted initially with a paediatrician. Their children tended to be younger, with a significantly higher frequency of advanced disease. Only half of the patients who consulted with a paediatrician were appropriately referred to an ophthalmologist; the paediatrician underestimated the complaints in the remainder. Children taken to an ophthalmologist were older and had less advanced disease. In about three quarters of these children, a diagnosis of retinoblastoma was suspected by the ophthalmologist on the first visit. Parents of patients with more advanced disease consulted significantly later. Poor parental education correlated significantly with late consultation. Lack of health insurance and living outside Buenos Aires City correlated significantly with an increased risk of extraocular disease.
Paediatricians are the first health professional seen by most children with retinoblastoma. However, the diagnosis is not readily established. There is also a delay in consultation by parents, which is significantly longer in cases with advanced extraocular disease. Socioeconomic factors and access to health care might play a role in delayed diagnosis.
In the Netherlands a comprehensive programme for screening just after birth for familial retinoblastoma is taking place. In this report the stage of the disease at the time of detection, by way of screening, and the long term visual outcome in these patients was evaluated.
A nationwide, retrospective study. From January 1992-July 2004, patients at risk for familial retinoblastoma were screened 1-2 weeks after birth, and investigated for laterality, Reese-Ellsworth classification/International Classification of Retinoblastoma, macular involvement, age of primary retinoblastoma, initial therapy, and visual outcome.
17 patients were diagnosed with familial retinoblastoma. 88.3% developed bilateral, 11.7% unilateral retinoblastoma. Of the 34 eyes, 56% were R-E group I, 16% were group II A-B, 16% were group III A-B, 9% were group IV, 3% were group V. Using the International Classification of Retinoblastoma, 72% were group A, 19% were group B, 6% were group C, 3% were group E. The visual outcome revealed 73.5% of eyes with 20/20-20/40, 26.5% eyes with < or = 20/100-no light perception; 5.9% of eyes were enucleated, all other eyes were treated with local or conservative treatment methods. Of all eyes, 59% had extramacular retinoblastoma, 98% of patients had at least one eye with extramacular retinoblastoma.
Most familial retinoblastoma patients present as a R-E group I or group A when screened within 2 weeks after birth. Nearly 90% of patients had a long term visual acuity of 20/20-20/40. Despite the common occurrence of macula involvement, bilateral macula involvement was infrequent, and since most eyes were salvaged, good vision was obtained in the majority of patients.
Purpose:
Molecular genetic diagnostics for retinoblastoma are prerequisite for accurate risk prediction and effective management. Developing a retinoblastoma diagnostic model to establish a flow for laboratory tests is thus a necessity for tertiary ophthalmic institutions. An efficient diagnostic model could reduce the overall health care costs, redirect the resources to the high risk group and also avoid unnecessary worry for families. To the best of our knowledge there has hitherto been no comprehensive diagnostic model for retinoblastoma implemented in any institution in India.
Methods and discussion:
The diagnostic model demonstrates the logical and practical flow of various genetics tests like karyotyping, loss of heterozygosity analysis, molecular deletion, linkage analysis (familial cases), mutation screening of -CGA exons first and then non-CGA exons, methylation screening of RB1 and essential promoter regions screening in a laboratory.
Conclusions:
The diagnostic model proposed offers acomprehensive methodology to identify the causative two-hits for retinoblastomas that could be used while genetic counseling families. This model is applicable in tertiary hospitals in India and neighboring countries, which have the highest incidence of retinoblastoma and fertility rates in the world. We suggest that this diagnostic model could also be applied with modification for other cancers.
Mothers of survivors of Retinoblastoma (Rb) experience unique challenges communicating with their child about the condition. Children are mostly diagnosed within their first year but the consequences continue into young adult life. Here 39 mothers of Rb survivors (23 males, mean age = 10.26 years) were interviewed about their experiences. Mothers were asked about communication with their children about Rb, and future health risks. Interviews were analysed using thematic analysis. Mothers reported that they had informed children about past diagnosis and treatment but had spoken less about genetic risk or risk of secondary cancer. The child's age and information-seeking behaviour were associated with mothers' disclosure, along with mothers' perceptions that information would facilitate child coping. Findings suggest that mothers may need more guidance during follow-up care in communicating about the disease and its consequences for future health. Medical staff should also take extra care to ensure that mothers are aware of genetic counselling services and how to access them before the child is discharged from specialist care.
India has the highest number of retinoblastoma (RB) patients among the developing countries owing to its increasing population. Of the patients with RB, about 40% have the heritable form of the disease, making genetic analysis of the RB1 gene an integral part of disease management. However, given the large size of the RB1 gene with its widely dispersed exons and no reported hotspots, genetic testing can be cumbersome. To overcome this problem, we have developed a rapid screening strategy by prioritizing the order of exons to be analyzed, based on the frequency of nonsense mutations, deletions and duplications reported in the RB1-Leiden Open Variation Database and published literature on Indian patients. Using this strategy for genetic analysis, mutations were identified in 76% of patients in half the actual time and one third of the cost. This reduction in time and cost will allow for better risk prediction for siblings and offspring, thereby facilitating genetic counseling for families, especially in developing countries.Journal of Human Genetics advance online publication, 18 June 2015; doi:10.1038/jhg.2015.62.
To identify the socioeconomic and psychosocial impacts of clinical treatment decisions for advanced unilateral intraocular retinoblastoma.
Retrospective observational case series.
Setting: institutional study at Alexandria Main University Hospital.
records of 66 unilateral retinoblastoma cases treated from May 2005 to May 2013 were retrospectively reviewed. Sixty cases were eligible (International Intraocular Retinoblastoma Classification [IIRC] group C, D or E).
two treatment groups were compared: enucleation vs. salvage treatment. Salvage treatment eyes were further subdivided based on IIRC group. Six socioeconomic parameters (financial burden, financial impact, psychological, social, medical and tumor impacts) were scored. Parameter scores ranged from 0 to 3, for overall score range 0 (no adverse impact) to 18 (severe adverse impact).
derived Socioeconomic scores were correlated with treatment and outcomes.
The enucleation group (28 eyes) had a median overall Socioeconomic score of 4/18, significantly lower than the salvage treatment group (32 eyes), median score 11/18 (P<0.01). Socioeconomic score varied with IIRC group. Attempted eye salvage failed in 25 children, due to uncontrolled tumor (44%) and socioeconomic impact of cumulative therapies (56%). Treatment duration and Socioeconomic score were higher for the 5 children in the salvage treatment group who developed metastatic disease compared to those without metastasis (P<0.01).
The socioeconomic and psychosocial impacts of attempted ocular salvage for unilateral intraocular retinoblastoma are severe, in comparison to primary enucleation. Primary enucleation is a good treatment for unilateral retinoblastoma.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Retinoblastoma is a rare primary intraocular malignancy. Presentation in the neonatal period is not common. With improved genetic testing, screening of the unborn child and neonate is taking on a greater role in the management of these patients. Treatment of retinoblastoma in the neonate is complex and requires a multidisciplinary and highly individualized approach. If possible, focal modalities should be used and external beam radiation avoided. Systemic intravenous chemotherapy may be necessary with regimens including carboplatin, vincristine and etoposide. Such cases are best managed by specialist centers with access to experts in oncology, ophthalmology, radiation therapy, genetics, pathology and anesthesia.
The most frequent neoplasm of the eye in children is retinoblastoma. It is a rare disease with an average incidence of 1 in 14,000 to 18,000 live births. The incidence is greater in developing countries. Early detection may allow widespread use of eye-sparing treatments, minimizing the morbidity of this disease. Although leukocoria is usually the first sign that parents notice especially when a flash photograph is taken, the diagnosis is not performed since this presentation is not known by health care providers and the public. Improving public awareness and knowledge of the early signs may lead to early diagnosis, which can save more eyes and lives. Advances in both the basic science and clinical applications of new therapies continue to emerge for this rare cancer. We expect that all conservative treatments will be available worldwide and consequently more children will be cured and maintain the vision.
Most RB1 mutations are unique and distributed throughout the RB1 gene. Their detection can be time-consuming and the yield especially low in cases of conservatively-treated sporadic unilateral retinoblastoma (Rb) patients. In order to identify patients with true risk of developing Rb, and to reduce the number of unnecessary examinations under anesthesia in all other cases, we developed a universal sensitive, efficient and cost-effective strategy based on intragenic haplotype analysis.
This algorithm allows the calculation of the a posteriori risk of developing Rb and takes into account (a) RB1 loss of heterozygosity in tumors, (b) preferential paternal origin of new germline mutations, (c) a priori risk derived from empirical data by Vogel, and (d) disease penetrance of 90% in most cases. We report the occurrence of Rb in first degree relatives of patients with sporadic Rb who visited the Jules Gonin Eye Hospital, Lausanne, Switzerland, from January 1994 to December 2006 compared to expected new cases of Rb using our algorithm.
A total of 134 families with sporadic Rb were enrolled; testing was performed in 570 individuals and 99 patients younger than 4 years old were identified. We observed one new case of Rb. Using our algorithm, the cumulated total a posteriori risk of recurrence was 1.77.
This is the first time that linkage analysis has been validated to monitor the risk of recurrence in sporadic Rb. This should be a useful tool in genetic counseling, especially when direct RB1 screening for mutations leaves a negative result or is unavailable.
Dommering CJ, van den Heuvel MR, Moll AC, Imhof SM, Meijers-Heijboer H, Henneman L. Reproductive decision-making: a qualitative study among couples at increased risk of having a child with retinoblastoma.
Little is known about the reproductive decision-making process of couples with an increased risk of having a child with retinoblastoma (Rb). A qualitative study was conducted to explore the impact of prospective risk on reproductive decisions, factors influencing these decisions, and the needs of couples with regard to reproductive counselling. Fourteen couples of childbearing age who received genetic counselling between 2002 and 2006 participated in semi-structured interviews in 2008. The risk of having a child with Rb ranged from less than 1% to 50%. In most cases, the diagnosis of Rb influenced subsequent family planning. Prenatal diagnosis was used by two couples, while others refrained from having more children. Reproductive decisions were influenced by the burden of the disease for the patient and family members, the impact of ophthalmological screening under anaesthesia, and couples' perceived risk, which did not always relate to their actual risk. Reproductive choices with regard to the number of children wanted changed over time. Our findings indicate topics to be discussed during genetic counselling of couples at increased risk for a child with Rb. We suggest continued access to genetic counselling also after the initial diagnosis and treatment.
Although screening for familial retinoblastoma has been shown to be beneficial we suspected that such screening programs may be less than optimal in developing countries (DC).
Retrospective cohort study comparing patients with familial retinoblastoma from five centers in DC (Argentina, Brazil, Turkey, Jordan, and Venezuela) versus a reference center in the USA.
Ninety-two (32 from the USA and 60 from DC) patients were included. Forty-one (44.6%) patients avoided enucleation, 42 (45.7%) had 1 eye removed, and 9 (9.8%) underwent bilateral enucleation. Eleven (11.9%) had major pathology risk factors at enucleation. There were no cases of metastatic disease at diagnosis. Detection via screening was significantly less common in DC than in the USA (23.3% vs. 71.8%, P < 0.0001). Patients in DC were diagnosed at a significantly later age and with more advanced intraocular disease that led to increased risk of bilateral enucleation. Patients detected by screening in DC were significantly younger at diagnosis, had less advanced intraocular disease, better ocular preservation rates and survival results than those whose retinoblastoma was not detected via early screening. Five-year pEFS was 0.92 for the patients treated in the USA and 0.81 for the patients in DC (P = 0.42). Seven events occurred (extraocular relapse four in patients from DC and second malignancies in three).
Patients with familial retinoblastoma are less likely to be diagnosed by screening in DC and had higher morbidity and mortality caused by recurrent extraocular retinoblastoma.
Parents must rapidly assimilate complex information when a child is diagnosed with cancer. Education correlates with the ability to process and use medical information. Graphic tools aid reasoning and communicate complex ideas with precision and efficiency.
We developed a graphic tool, DePICT (Disease-specific electronic Patient Illustrated Clinical Timeline), to visually display entire retinoblastoma treatment courses from real-time clinical data. We report retrospective evaluation of the effectiveness of DePICT to communicate risk and complexity of treatment to parents. We assembled DePICT graphics from multiple children on cards representing each stage of intraocular retinoblastoma. Forty-four parents completed a 14-item questionnaire to evaluate the understanding of retinoblastoma treatment and outcomes acquired from DePICT.
As a proposed tool for informed consent, DePICT effectively communicated knowledge of complex medical treatment and risks, regardless of the education level. We identified multiple potential factors affecting parent comprehension of treatment complexity and risk. These include language proficiency (p=0.005) and age-related experience, as younger parents had higher education (p=0.021) but lower comprehension scores (p=0.011), regardless of first language.
Provision of information at diagnosis concerning long-term treatment complexity helps parents of children with cancer. DePICT effectively transfers knowledge of treatments, risks, and prognosis in a manner that offsets parental educational disadvantages.
About 10% of the human genome has now been mapped and for more than 1000 diseases closely linked DNA polymorphisms or the responsible genes have been identified. These developments have extended the scope of (prenatal) diagnosis and carrier detection which already was possible by biochemical analysis of protein defects in some 400 Mendelian disorders. Together with the study of chromosomal aberrations these activities form the basis for genetic counselling and carrier screening programmes. A brief overview of the activities in clinical genetics will be presented and their importance for the prevention of congenital disorders and for informed decisions of couples at risk will be emphasized. Reproductive decisions are, however very closely related to culture, religion, education and the socioeconomic status of individuals and populations. Up to now genetic services have mainly been developed in wealthy postindustrial countries with a low infant mortality. But even among these countries there are major differences in the implementation of gene technology as will be shown by comparisons of the United States, Europe and Japan. In the developing countries where about 95% of the world's future children will be born there are major hindrances in the development of clinical genetics such as poverty, illiteracy of women, low contraceptive use and a high infant mortality. There are, however, examples of developing countries that give high priority to the application of gene technology such as Cuba and China. While the developing countries are struggling to improve their basic health care, research on gene technology in the western countries proceeds fast. The early identification of a particular gene constitution will show whether a young adult is at higher risk of important diseases such as various forms of cancer, cardiovascular disease, diabetes or psychiatric disorders. The therapeutical, preventive, psychological and some ethical aspects of this new era of predictive medicine will be discussed.
The proposed new group classification of intraocular retinoblastoma serves as a guide for the clinician in the selection of initial therapy and the determination of the likelihood of treatment failure followed by enucleation or EBR before treatment begins. It is not an absolute or dictatorial set of rules. The presence of vitreous or subretinal seeding is the major ophthalmologic feature that separates eyes with a low risk for enucleation (groups A and B) from those containing more advanced tumors (groups C and D) with a moderate to high risk. In the low-risk eyes, a small subset designated group A is projected to be associated with the least treatment morbidity and retain the best visual acuity. When the tumor in an eye has features that might allow the clinician to place it into either of two groups, it is recommended that the eye be upgraded or placed in the next higher risk group to receive therapy that is more intensive. In my experience, undertreating an eye is a frequent cause of failure to salvage that eye. A major international validation effort currently underway is collecting intraocular tumor details and clinical outcomes via a secure Web site. To date, 20 retinoblastoma centers on five continents have submitted classification and outcome data on more than 1500 eyes in 1200 patients. Preliminary analysis of the data reveals excellent segregation of outcome by group.
To investigate the compliance and non-compliance of retinoblastoma patients/siblings with their appointments at the Retinoblastoma Clinic in the Pediatric Division of a tertiary eye care center, and to evaluate the contributing factors.
This descriptive type of case series was conducted between May 1999 and May 2002 at the Retinoblastoma Clinic of King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. Retinoblastoma patients/siblings were surveyed when they attended the clinics. Each family was interviewed with the help of a close-ended questionnaire. The sample of patients and their siblings were selected based on inclusion and exclusion criteria, and their charts were reviewed.
The study included 260 retinoblastoma patients and their siblings, 134 (51.5%) were males, and 126 (48.5%) were females. One hundred and forty-seven (56.5%) of the retinoblastoma patients/siblings in the sample were scheduled for follow up. One hundred and sixty-eight (64.6%) of retinoblastoma families were contacted by phone and reminded of their children's appointments, 37 (14.2%) were not contacted, and for 55 (21.2%) of the sample subjects, it was not known whether contact was made or even attempted. The compliance rate was 86.2%. One hundred and ninety-five (95.1%) of non-contacted patients/siblings' families attended subsequently. One hundred and thirty-six (52.3%) felt they faced barriers to treatment. Sixty-eight (26.2%) completed treatment, and 175 (67.3%) were still being followed up in the Retinoblastoma Clinic. Six factors were found to influence compliance with clinic appointments: type of appointment, frequency of no shows per clinic, frequency of no shows per patient/sibling, number of non-contacted patients/siblings, telephone contact, and patients with no contact details.
There was a high compliance rate among those scheduled for check up or follow-up. Family education and continuous updating of patients' phone contact numbers can overcome non-compliance and maximize the benefits of the phone call mechanism. Factors affecting compliance found in this study should be used for improving the compliance rate.
The childhood eye cancer retinoblastoma is initiated by the loss of both alleles of the prototypic tumor suppressor gene, RB1. However, a large number of cytogenetic and comparative genomic hybridization (CGH) studies have shown that these M1 and M2 mutational events--although necessary for initiation--are not the only genomic changes in retinoblastoma. Some of these subsequent changes, which we have termed M3 to Mn, are likely crucial for tumor progression not only in retinoblastoma but also in other cancers. Moreover, genes showing genomic change in cancer are more stable markers and, therefore, possible therapeutic targets than genes simply differentially expressed. In this review, we provide the first comprehensive summary of the genomic evidence implicating gain of 1q, 2p, 6p, and 13q, and loss of 16q in retinoblastoma oncogenesis, including karyotype, CGH, and microarray CGH data. We discuss the search for candidate oncogenes and tumor suppressor genes within these regions, including the candidates (KIF14, MDM4, MYCN, E2F3, DEK, CDH11, and others), plus associations between genomic changes and clinical parameters. We also review studies of other regions of the retinoblastoma genome, the epigenetic changes of aberrant methylation of MGMT, RASSF1A, CASP8, and MLH1, and the roles microRNAs might play in this cancer. Although many candidate genes have yet to be functionally validated in retinoblastoma, work in this field lays out a molecular cytogenetic pathway of retinoblastoma development. Candidate cancer genes carry diagnostic, prognostic, and therapeutic implications beyond retinoblastoma.
One Retinoblastoma World is a global network with the bold idea that all children with retinoblastoma can have equal opportunity to optimal care. We aim for global collaboration to deliver coordinated, evidence-based retinoblastoma care
One Retinoblastoma World. 2015; One Retinoblastoma World is
a global network with the bold idea that all children with retinoblastoma can have equal opportunity to optimal care. We aim for
global collaboration to deliver coordinated, evidence-based retinoblastoma care. Available at: http://1rbw.org/. Accessed August
31, 2015.
- H Dimaras
- K Kimani
- E A Dimba
Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet
2012;379(9824):1436-1446.
- H Dimaras
- T W Corson
- D Cobrinik
Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma.
Nature Reviews Disease Primers 2015:15021.
- Y Bhurgri
- S Muzaffar
- R Ahmed
Bhurgri Y, Muzaffar S, Ahmed R, et al. Retinoblastoma in
Karachi, Pakistan. Asian Pacific J Cancer Prev 2004;5:159-163.
Canadian guidelines for retinoblastoma care
- N Weizblit
- P Gronsdahl
- H Dimaras
Weizblit N, Gronsdahl P, Dimaras H, et al. Canadian guidelines
for retinoblastoma care. International Society of Eye Genetic
Disease and Retinoblastoma; 2008; Strasbourg, France.