RESUMO
PURPOSE: The aim of this study was to document the available resources and needs for the detection, diagnosis, and treatment of retinoblastoma (RB) in Ethiopia. METHODS: A health services needs assessment focused on RB care in Ethiopia was conducted. Information was obtained through a web-based survey and field visits. Facilities offering RB service delivery were categorized into three tiers, on the basis of the ability to detect (tier 1) and manage simple (tier 2) or complex (tier 3) patients with RB. Descriptive statistics were performed to quantify human and material resources available at each facility. RESULTS: The web survey received 29 responses from ophthalmologists at 19 health care facilities. Of the 19 units surveyed, seven (36.8%) had an ophthalmologist dedicated to RB treatment, classifying them as either a tier 2 or 3 facility. All tier 3 facilities had an affiliated health facility offering access to off-site pediatric oncology and pathology services. Of the focal therapies offered at tier 3 facilities, none included local chemotherapy or brachytherapy. Enucleation was offered at all tier 2 facilities, but availability of orbital implants and ocular prostheses was variable. None of the health facilities offered genetics services. CONCLUSION: This study demonstrated that the human and material resources needed for RB care in Ethiopia are constrained. Tier 3 RB facilities are rare and concentrated in urban areas, which could make it difficult for many patients to access. With focused capacity-building efforts, it is possible to increase the efficiency of RB therapy.
Assuntos
Neoplasias da Retina , Retinoblastoma , Criança , Humanos , Etiópia/epidemiologia , Necessidades e Demandas de Serviços de Saúde , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Retinoblastoma/terapia , Serviços de Saúde , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/terapiaRESUMO
In this review we discuss several recent concepts regarding retinoblastoma control and its impact. In a cohort of 482 patients with solitary unilateral retinoblastoma revealed germline mutation in 16% and the likelihood of germline retinoblastoma was greater for younger children (≤1 year versus (vs.) >1 year at presentation) with odds ratio (OR) 2.96 (p = 0.001), and greatest for the youngest infants (≤3 months vs. >3-12 months) (OR 5.52) (p = 0.002). Retinocytoma/retinoma, a benign variant of retinoblastoma, was studied in 78 tumours and demonstrated transformation into retinoblastoma in 9.2% by 5 years and 15.3% by 10 years and 20 years. An international global study on retinoblastoma over 1.5 years revealed 4351 new patients and 85% from low- and middle-income countries, notably with older age at detection and greater risk for metastasis. Management of retinoblastoma in 964 eyes using intravenous chemotherapy showed 20-year globe salvage at 96% in group A, 90% in group B, 90% in group C, 68% in group D, and 32% in group E eyes. The 5-year globe salvage with intra-arterial chemotherapy for 160 eyes (655 infusions) with retinoblastoma showed success in 100% for group B, 80% for group C, 78% for group D, and 55% for group E. The psychological impact of retinoblastoma on the parents revealed depression (73%), anxiety (64%), and/or stress (100%), and on the patient revealed deficits in quality of life issues. Retinoblastoma is a challenging disease and chemotherapy provides reliable tumour control and globe salvage. Continuing efforts to improve quality of life issues is important.
Assuntos
Neoplasias Oculares , Neoplasias da Retina , Retinoblastoma , Criança , Lactente , Humanos , Retinoblastoma/tratamento farmacológico , Retinoblastoma/genética , Retinoblastoma/diagnóstico , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/genética , Neoplasias da Retina/diagnóstico , Carga Global da Doença , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Infusões Intra-Arteriais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Purpose: To describe methods of risk assessment in twins with retinoblastoma (RB). Methods: A case series of four RB probands with a twin sibling. Family status, clinical presentation, and RB1 germline status-based risk assessment were analyzed. Results: Two pairs had a positive family history (unilateral and bilateral RB in one of the parents (#1 and #2, respectively) and two pairs (#3 and #4) were sporadic. One of the familial twins (#1) had a high risk (90%) of manifesting RB in the twin. The other case (#2) with an absent RB1 germline mutation in the twin had a 0% risk of developing RB. Among sporadic cases of twins (#3), genetic testing did not identify a germline mutation (tumor sample unavailable) in the proband which downgraded the risk of germline mutation from 15% to <1%. The twin never developed RB (5 years of age at last follow-up). Pathogenic mosaicism for germline RB1 mutation (c.1723C>T) could be identified (tumor tissue available) in the proband (# 4). Identical germline mutation (and RB tumor) was also noted in the twin. In each case, there was concordance between the assessed risk and manifestation of RB. Conclusion: Assessment of risk of RB in a twin presents with a unique challenge. Depending upon the genotype variant, the risk of developing RB can vary from 0% to 90%. In addition to family history, clinical manifestation in the proband, zygosity status, and RB1 germline status are critical in formulating risk-appropriate surveillance guidelines.
Assuntos
Neoplasias da Retina , Retinoblastoma , Genótipo , Mutação em Linhagem Germinativa , Humanos , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/genética , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Retinoblastoma/genética , Medição de RiscoRESUMO
BACKGROUND: Intravitreal injection of chemotherapy in retinoblastoma eyes with vitreous seeds may lead to a risk of extraocular tumour dissemination that has not been assessed so far. AIMS: To develop a sensitive and clinically feasible technique to assess for potential retinoblastoma cell reflux after intravitreal injection of melphalan. METHODS: Filter papers were cut in 6 mm diameter circles and sterilised before use. Eyes with retinoblastoma vitreous seeds (group D, International Classification) received weekly intravitreal melphalan injections (20 µg or 30 µg/dose) followed by cryotherapy as part of local treatment. Immediately after finishing the injection and cryotherapy, filter papers were placed on the injection site and on the cryoprobe tip to assess for the expression of the cone-rod homeobox gene (CRX) by real-time qPCR as a surrogate of retinoblastoma RNA. The assay was developed and validated to determine sensitivity, linearity, recovery, repeatability and reproducibility. RESULTS: The assay for quantitation of CRX expression was linear in the range of 1 to 1000 cells. The lowest limit of detection was one retinoblastoma cell and allowed to recover 100% of the cell load in external supplementation. A total of 14 eyes received 22 cycles of intravitreal melphalan and were evaluated for potential extraocular tumour cell dissemination using the developed technique. None of the cycles were positive for CRX in samples from the scar or from the cryoprobe tip. CONCLUSIONS: A sensitive and simple method of tumour cell assessment has been developed that can be used in the clinics to assess for potential extraocular dissemination after intravitreal injections to assure its performance.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Proteínas de Homeodomínio/genética , Melfalan/administração & dosagem , Inoculação de Neoplasia , RNA Neoplásico/análise , Neoplasias da Retina/genética , Retinoblastoma/genética , Transativadores/genética , Biomarcadores Tumorais , Crioterapia , Humanos , Injeções Intravítreas , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Estudos Retrospectivos , Células Tumorais CultivadasAssuntos
Técnicas de Apoio para a Decisão , Pais/psicologia , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Economia , Enucleação Ocular/psicologia , Feminino , Aconselhamento Genético , Idade Gestacional , Indicadores Básicos de Saúde , Humanos , Recém-Nascido , Fotocoagulação a Laser/psicologia , Masculino , Gravidez , Qualidade de Vida/psicologia , Neoplasias da Retina/diagnóstico por imagem , Neoplasias da Retina/genética , Retinoblastoma/diagnóstico por imagem , Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Ultrassonografia Pré-NatalRESUMO
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.
Assuntos
Genes do Retinoblastoma , Testes Genéticos , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Pré-Escolar , Análise Custo-Benefício , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/métodos , Feminino , Testes Genéticos/economia , Testes Genéticos/métodos , Humanos , Índia , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase Multiplex/economia , Neoplasias da Retina/economia , Neoplasias da Retina/genética , Retinoblastoma/economia , Retinoblastoma/genética , Fatores de TempoRESUMO
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.
Assuntos
Atenção à Saúde/organização & administração , Neoplasias Oculares/genética , Serviços em Genética/organização & administração , Conhecimentos, Atitudes e Prática em Saúde , Retinoblastoma/genética , Adulto , Pré-Escolar , Participação da Comunidade , Atenção à Saúde/economia , Países em Desenvolvimento , Neoplasias Oculares/diagnóstico , Feminino , Serviços em Genética/economia , Humanos , Quênia , Retinoblastoma/diagnósticoRESUMO
Heritable retinoblastoma is caused by oncogenic mutations in the RB1 tumor suppressor gene. Identification of these mutations in patients is important for genetic counseling and clinical management of relatives at risk. In order to lower analytical efforts, we designed a stepwise mutation detection strategy that was adapted to the spectrum of oncogenic RB1 gene mutations. We applied this strategy on 20 unrelated patients with familial and/or de novo bilateral retinoblastoma from Tunisia. In 19 (95%) patients, we detected oncogenic mutations including base substitutions, small length mutations, and large deletions. Further analyses on the origin of the mutations showed mutational mosaicism in one unilaterally affected father of a bilateral proband and incomplete penetrance in two mothers. In a large family with several retinoblastoma patients, the mutation identified in the index patient was also detected in several non-penetrant relatives. RNA analyses showed that this mutation results in an in-frame loss of exon 9. In summary, our strategy can serve as a model for RB1 mutation identification with high analytical sensitivity. Our results point out that genetic testing is needed to reveal or exclude incomplete penetrance specifically in parents of patients with sporadic disease.
Assuntos
DNA de Neoplasias/genética , Família , Genes do Retinoblastoma/genética , Testes Genéticos/economia , Mutação , Linhagem , Retinoblastoma/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Testes Genéticos/métodos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/genética , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Fatores de Risco , Tunísia/epidemiologia , Adulto JovemRESUMO
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Algoritmos , Ligação Genética , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Pré-Escolar , Marcadores Genéticos , Haplótipos , Humanos , Lactente , Recém-Nascido , Perda de Heterozigosidade , Linhagem , Neoplasias da Retina/genética , Retinoblastoma/genética , Proteína do Retinoblastoma/genética , Medição de Risco , IrmãosRESUMO
Retinoblastoma (Rb) is the most common primary intraocular malignancy in children. It is brought about by the mutational inactivation of both alleles of RB1 gene in the developing retina. To identify the RB1 mutations, we analysed 74 retinoblastoma patients by screening the exons and the promoter region of RB1. The strategy used was to detect large deletions/duplications by fluorescent quantitative multiplex PCR; small deletions/insertions by fluorescent genotyping of RB1 alleles, and point mutations by PCR-RFLP and sequencing. Genomic DNA from the peripheral blood leucocytes of 74 Rb patients (53 with bilateral Rb, 21 with unilateral Rb; 4 familial cases) was screened for mutations. Recurrent mutations were identified in five patients with bilateral Rb, large deletions in 11 patients (nine with bilateral Rb and two with unilateral Rb), small deletions/insertions were found in 12 patients all with bilateral Rb, and point mutations in 26 patients (14 nonsense, six splice site, five substitution and one silent change). Three mutations were associated with variable expressivity of the disease in different family members. Using this method, the detection rates achieved in patients with bilateral Rb were 44/53 (83%) and with unilateral Rb, 5/21 (23.8%). This approach may be feasible for clinical genetic testing and counselling of patients.
Assuntos
Análise Mutacional de DNA/métodos , Mutação , Proteína do Retinoblastoma/genética , Retinoblastoma/diagnóstico , Adulto , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA/economia , Éxons/genética , Estudos de Viabilidade , Deleção de Genes , Duplicação Gênica , Testes Genéticos/economia , Testes Genéticos/métodos , Humanos , Pessoa de Meia-Idade , Mutagênese Insercional , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas/genética , Sítios de Splice de RNA/genética , Retinoblastoma/genética , Adulto JovemRESUMO
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.
Assuntos
Técnicas de Diagnóstico Oftalmológico , Modelos Biológicos , Neoplasias da Retina/diagnóstico , Proteína do Retinoblastoma/genética , Retinoblastoma/diagnóstico , Criança , Pré-Escolar , Análise Custo-Benefício , Testes Genéticos , Humanos , Índia , Neoplasias da Retina/genética , Retinoblastoma/genéticaRESUMO
INTRODUCTION: Genetic testing is increasingly being used to evaluate susceptibility to hereditary diseases because it is a cost effective screening method. Predictive testing for retinoblastoma can help to save the vision and avoid unnecessary (and invasive) eye examinations for probands and their close relatives. This study was undertaken to evaluate the cost effectiveness of the retinoblastoma genetic screening strategy established in our hospital. STUDY DESIGN: Cytogenetic study of peripheral blood, mutational, and methylation analyses from the tumor DNA of 25 patients with retinoblastoma was undertaken. The cost for retinoblastoma (RB1) gene screening was calculated based on the cost of the chemicals and consumables used and the clinical examination charges at our hospital. A comparison was made between the cost of genetic screening and clinical testing for retinoblastoma. Retinoblastoma patients underwent clinical management and genetic testing at Sankara Nethralaya, Chennai, India. RESULTS: By adopting a genetic screening strategy, a 3.5-fold cost saving was seen for a proband while a 6-fold saving was seen for a family with two sibs compared to the cost of clinical examination. The clinical examination fee and cost of genetic screening for a proband was dollarUS536 and dollarUS152, respectively, while for a nuclear family with two sibs the costs were dollarUS1071 and dollarUS175, respectively. DISCUSSION: Savings for a family will be higher if indirect costs, such as savings in travel times to and from the hospital and labor savings, were taken into account. Cost will be a major factor in determining the implementation of genetic screening for RB1 gene in the clinical practice. CONCLUSION: In our study in India, genetic screening for retinoblastoma was cheaper than conventional screening and was useful in the genetic counseling of the families.
Assuntos
Técnicas de Diagnóstico Oftalmológico/economia , Testes Genéticos/economia , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Pré-Escolar , Análise Custo-Benefício , Aconselhamento Genético , Predisposição Genética para Doença , Humanos , Índia , Linhagem , Neoplasias da Retina/genética , Retinoblastoma/genética , Proteína do Retinoblastoma/genéticaRESUMO
Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of RB1 mutations are unique and distributed throughout the RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations.
Assuntos
Genes do Retinoblastoma , Mutação , Retinoblastoma/genética , Algoritmos , DNA/análise , DNA/economia , DNA/genética , Metilação de DNA , Análise Mutacional de DNA , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Genótipo , Humanos , Leucócitos Mononucleares/química , Linhagem , Fenótipo , Vigilância da População , Sensibilidade e EspecificidadeRESUMO
AIMS: To investigate the relative benefits of retinoblastoma gene testing over conventional ophthalmological screening methods in a New Zealand setting, and to determine the importance of tumour material in resolving germline status. METHODS: Three cases of gene testing are described to illustrate the clinical advantages over conventional ophthalmological screening. To determine the role of tumour material in resolving germline status, 24 New Zealand families were tested, of which tumour material was available for eight. RESULTS: In the three cases reported, we found genetic testing of the RB1 gene resulted in clinically significant benefits and cost savings. When fresh tumour was available for high molecular weight DNA extraction, germline status was resolved in 8/8 (100%) cases. In these cases tumour mutations were not present in the corresponding peripheral blood DNA, indicating that the tumours were sporadic. In the absence of tumour DNA, mutations were identified in only 8/13 (62%) heritable cases. Germline status remains unresolved in all of the three cases of unilateral tumour without a family history or tumour DNA. CONCLUSIONS: Our experience indicates that retinoblastoma gene testing has significant benefits to the affected individuals and their families in New Zealand. Moreover, DNA extracted from fresh tumour allows retinoblastoma germline status in most cases to be defined. Without rumour material, the germline status of potentially sporadic cases will remain undetermined since the absence of detectable RB1 coding region mutations does not exclude all possible mutations in the RB1 gene, which is too large for DNA analysis. A lack of conclusive results will mean that infants will be subjected to the unnecessary inconvenience of surveillance under general anaesthesia.
Assuntos
Análise Mutacional de DNA , Genes do Retinoblastoma , Mutação em Linhagem Germinativa , Neoplasias da Retina/genética , Retinoblastoma/genética , Redução de Custos , Feminino , Testes Genéticos , Humanos , Lactente , Masculino , Linhagem , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnósticoRESUMO
BACKGROUND: Genetic testing for inherited predisposition to diverse cancers has recently become available as a clinical service. We conducted a follow-up study of the initial series of US families who underwent RB1 genetic testing to evaluate long-term effects of the service. PROCEDURE: We enrolled 52 of 71 eligible families who responded to a follow-up study questionnaire administered 3-10 years after receipt of their RB1 results. Each family had one proband with unilateral, non-familial retinoblastoma, which is associated with a 12% pre-test probability of hereditary retinoblastoma. RB1 testing identified germline RB1 mutations in five patients, lowered the carrier probability to 2% in 21 patients, and did not substantially modify the carrier probability in the remaining 26. RESULTS: Diverse medical specialists offered and arranged for RB1 testing, and their recommendation was the most influential factor in the decision to be tested. Pre-test counseling was provided by ophthalmologists (30), oncologists (11), and geneticists and genetic counselors (11). Most respondents, regardless of test result, were satisfied and perceived gains from their genetic testing. Based on small numbers, families with reduced likelihood of hereditary retinoblastoma reported more positive outcomes. Parents of RB1 carriers were more likely to seek medical services, worry, and decide against having more children. CONCLUSIONS: This study demonstrates the feasibility of follow-up studies of families who had genetic testing. Results from our small series suggest that genetic information and counseling are important components of RB1 clinical genetic testing, and long-term adverse effects of testing are uncommon.
Assuntos
Genes do Retinoblastoma/genética , Testes Genéticos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Neoplasias da Retina/genética , Retinoblastoma/genética , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Estudos de Amostragem , Sensibilidade e Especificidade , Inquéritos e Questionários , Estados UnidosRESUMO
Two-dimensional (2-D) gene scanning (TDGS) is a method for mutation detection based on the electrophoretic separation of PCR-amplified DNA fragments according to size and base pair sequence. The use of denaturing gradient gel electrophoresis (DGGE) as the second separation step provides virtually 100% sensitivity, while the 2-D format allows the inspection of multiple gene fragments simultaneously. Analysis of many exons in parallel is greatly facilitated by extensive PCR multiplexing based on preamplification by long-distance PCR. Recently, TDGS has been applied to detect mutations in the retinoblastoma tumor suppressor gene RB1. Using RB1 as a model, we have now analyzed each step of the protocol, presenting overall improvements and a detailed cost analysis, where the total cost of the assay is found to be about $40 (US). An overall picture of TDGS cost-performance, as compared to direct sequencing, is provided as a function of the number of target fragments.
Assuntos
Eletroforese em Gel Bidimensional/métodos , Genes do Retinoblastoma/genética , Testes Genéticos/métodos , Custos e Análise de Custo , Análise Mutacional de DNA , Eletroforese em Gel Bidimensional/economia , Éxons/genética , Testes Genéticos/economia , Heterozigoto , Humanos , Peso Molecular , Desnaturação de Ácido Nucleico , Ácidos Nucleicos Heteroduplexes , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Retinoblastoma/diagnóstico , Retinoblastoma/economia , Retinoblastoma/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Temperatura , Fatores de TempoRESUMO
To compare costs of molecular and conventional screening of retinoblastoma relatives, we evaluated the direct health care costs. With variables set at the most likely values (baseline), the expected cost (in 1994 Canadian dollars) of conventional screening was $31,430 for a prototype family consisting of seven at-risk relatives (three clinic exams and eight examinations under anaesthetic over the first 3 years of life for each relative). For the molecular strategy that involves looking for the RB1 gene mutation in the proband, testing the relatives for that mutation, and clinical follow-up similar to conventional strategy for relatives with mutation, the expected cost was $8,674, using baseline variables. Sensitivity analysis over the range of values for each variable revealed a significant saving of health care dollars by the molecular route, indicating the benefit of redirecting economic resources to molecular diagnosis in retinoblastoma.
Assuntos
Atenção à Saúde/economia , Testes Genéticos/economia , Relações Interpessoais , Retinoblastoma/economia , Risco , Árvores de Decisões , Eletrocardiografia/economia , Genes do Retinoblastoma , Humanos , Seguro Saúde , Mutação , Oftalmoscopia/economia , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Proteína do RetinoblastomaRESUMO
Childhood cancer survivors at highest risk of developing a secondary malignancy are those with hereditary retinoblastoma. The majority of such secondary cancers will be sarcomas, most commonly of bone. One-third of these occur outside a typical radiation field, commonly in an extremity. Bone sarcoma is also the most commonly reported secondary cancer to develop among survivors of Ewing's sarcoma. In this group, radiation doses greater than 60 Gy as well as alkylating agent chemotherapy have been identified as contributors to the increased risk. The prognosis for patients with a secondary sarcoma has been poor, with few cures reported to date. However, an aggressive, combined modality approach, including radical resection, postoperative radiation, and adjuvant chemotherapy, may improve the survival rate.
Assuntos
Neoplasias Ósseas , Neoplasias Oculares , Neoplasias Primárias Múltiplas , Retinoblastoma , Sarcoma de Ewing , Adolescente , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/terapia , Criança , Neoplasias Oculares/genética , Neoplasias Oculares/patologia , Neoplasias Oculares/radioterapia , Genes do Retinoblastoma , Humanos , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Primárias Múltiplas/etiologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Induzidas por Radiação/diagnóstico por imagem , Neoplasias Induzidas por Radiação/patologia , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/etiologia , Osteossarcoma/terapia , Radiografia , Radioterapia/efeitos adversos , Retinoblastoma/genética , Retinoblastoma/patologia , Retinoblastoma/radioterapia , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Sarcoma de Ewing/radioterapiaRESUMO
Here we provide a conceptual framework for the application of current approaches in the analysis of retinoblastoma to the clinical setting. The aim of genetic medicine is to minimize the burden of inherited disease through appropriate diagnosis and management of patients and to maximize information, so that families can make reasonable decisions about reproduction. Recent genetic, cytogenetic and molecular genetic approaches have improved our understanding of the biological events leading to the occurrence of retinoblastoma and, in addition, have provided tools for the enhanced assessment of risk for some individuals. The knowledge, however, is incomplete and the tools imperfect, as indicated by our continued provision of risk probabilities that are neither one nor zero. We therefore hope to emphasize both the scope and the limitations of these techniques so that their application can be effectively considered.
Assuntos
Cromossomos Humanos Par 13 , Neoplasias Oculares/genética , Aconselhamento Genético , Marcadores Genéticos , Retinoblastoma/genética , Criança , Mapeamento Cromossômico , Humanos , LinhagemRESUMO
Fifty retinoblastoma families have been studied. In 41 it has been possible to determine the esterase-D phenotypes in all family members. Seven families were informative for the enzyme polymorphism and in all cases cosegregation of the retinoblastoma gene and esterase-D alleles was demonstrated, giving a lod score of 2.61. When combined with other published reports the cumulative lod score is 13.69 with no recombination in 45 meioses. In 10-15% of retinoblastoma families therefore, it is possible to offer prenatal diagnosis using the ESD protein polymorphism. The application of this test to the retinoblastoma population in the UK is limited by the low frequency of the rarer allele (0.116) and, as a result of genetic counseling, the smaller families generally associated with retinoblastoma.