Heritable Retinoblastoma Research Articles

Second neoplasms in patients with hereditary retinoblastoma.

10620 Background: Patients with hereditary retinoblastoma have an increased risk of developing second tumors during adolescence and adulthood. The incidence of second malignant neoplasms (SMNs) is a concern, since SMNs are the leading cause of death in these patients. This risk is increased in patients who have received external radiation therapy as part of treatment but is also increased in non-radiated patients. Increased sarcoma and melanoma risks after hereditary retinoblastoma are well established. Methods: We present a cohort of patients with hereditary retinoblastoma assessed in our multidisciplinary pediatric and adult genetic predisposition cancer unit (UPGeCI) from September 2018 to December 2023. During this period, 62 patients with retinoblastoma were attended, all with RB1 gene mutation. Of these, 84% of patients had bilateral retinoblastoma, and 16% had unilateral retinoblastoma. They ranged in age from 6 months to 55 years (median 13 years). 18 patients (29%) were treated with external beam radiation therapy. Clinical follow-up and orbital magnetic resonance imaging were performed every two years. Results: Six cases of SMNs were detected in 5 patients (9.3%), all soft tissue sarcomas. The mortality rate was 60% (3/5 patients). Four patients (80%) had received external radiotherapy as part of the treatment of retinoblastoma. Three patients presented 3 sarcomas in the facial region within the irradiated area, of which one was an osteosarcoma and the other two leiomyosarcomas. Two of them presented in adulthood, and one at 9 years old. One of the patients died, the other two are living disease-free. The fourth patient who had received external radiotherapy presented with osteosarcoma of the femur at 15 years of age. She died of septic shock. The patient who had not received external radiotherapy presented with osteosarcoma of the tibia at 6 years of age and later with osteosarcoma of the contralateral femur at 10 years of age. She died of progression. Conclusions: There is an increased risk of SMNs in patients with hereditary retinoblastoma, mainly soft tissue sarcomas, with high mortality. This risk increases if they have received external radiation therapy. Therefore, screening for SMNs is essential for of follow-up in patients with heritable retinoblastoma.

Danish heritable retinoblastoma survivors' perspectives on reproductive choices: "It's important for me, not to pass on this condition".

Despite reporting an overall normal life, survivors of heritable retinoblastoma face numerous physical and psychosocial issues. In particular, reproductive decision-making is often complex and difficult. This study aims to examine survivors' reflections on passing on heritable retinoblastoma to their children, how survivors approach their reproductive choices, and how the healthcare system can optimize counseling and support. Semi-structured interviews with Danish adult survivors of heritable retinoblastoma were qualitatively analyzed to explore their experiences. Participants were recruited from the Retinoblastoma Survivorship Clinic, Aarhus University Hospital, Denmark. Thematic data analysis was conducted followed by a condensing process specifically for the subthemes relating to reproductive choices. A common subtheme for all participants was a strong wish to avoid passing on retinoblastoma to their children. The participants emphasized the various medical, practical, emotional, and moral issues impacting their final reproductive choice in the process of family planning to conceive a child unaffected by retinoblastoma. Some had no option other than to conceive naturally and hope for an unaffected baby; while others weighed the pros and cons of choosing natural conception with prenatal testing and then considering termination of pregnancy (in case of an affected fetus) versus choosing fertility treatment with preimplantation genetic testing to achieve an unaffected pregnancy. Several participants underlined the complexity of their decisions, and also expressed feelings of guilt, both toward their affected child, and guilt for putting their partner through many difficult decisions and obstacles due to their genetic condition. Our findings demonstrate how one family-planning decision is not unequivocally "better" or easier than another. Healthcare professionals must provide the necessary information and tools to support the individual's unique decision-making process. Survivors' autonomy and individual needs, as well as the numerous and diverse aspects of heritable retinoblastoma, should be carefully considered.

Genetic testing in adult survivors of retinoblastoma in Denmark: A study of the experience and impact of genetic testing many years after initial diagnosis

BackgroundSurvivors with heritable retinoblastoma (RB) face a high risk for second primary cancer and RB in their children. Knowledge of heredity can support second cancer surveillance, convey reproductive options or early diagnosis of RB in their offspring. Currently, all newly diagnosed Danish patients with RB are offered genetic testing, as opposed to a minority of survivors diagnosed before available DNA testing. ObjectiveTo examine RB survivors' response to unsolicited contact, uptake of genetic testing, and RB1 variant detection rate, and to qualitatively evaluate the experience and overall impact of genetic testing for heritable RB. MethodsGenetically untested adult RB survivors were invited to receive genetic counseling, undergo genetic testing for heritable RB and complete an eye examination. The number of responses, uptake of genetic testing and genetic results are descriptively reported.Additionally, responding survivors participated in a qualitative interview study of the perceived impact of genetic testing. Interviews were audio-recorded, transcribed verbatim and thematically analyzed. ResultsAmong invited RB survivors, 58% responded. Of these, 88% opted for genetic counseling and genetic testing. A diagnosis of heritable RB was established in 23% of RB survivors. Interestingly, all of these survivors were unilaterally affected. Analysis of data from the interviews revealed three recurring themes regarding the impact of genetic counseling and testing several years after initial diagnosis: ‘Risk of what?‘, ‘Knowledge is important’ and ‘Impact of the result’. The possible risk ofsecond cancer and RB in their children was new knowledge for several participants; however, in general, the participants appreciated receiving genetic information and certainty about heredity. Accordingly, the impact of genetic counseling and testing was perceived in a positive way. ConclusionOverall, RB survivors valued the opportunity to receive genetic counseling and undergo genetic testing many years after diagnosis. Responding RB survivors appreciated the invitation to test, felt well-informed and described little decisional conflict regarding their decision-making, valuing the genetic information and certainty. Heritable RB was confirmed in 23% of the previously untested RB survivors. These individuals emphasized the value of knowing and being proactive regarding both reproduction and cancer risk.

Parental age and retinoblastoma-a retrospective study of demographic data and genetic analysis.

To determine the association between the parental age gap and the absolute parental age with the risk of retinoblastoma (RB) development in an offspring. RB individuals diagnosed between March 2013 and December 2019 in a single tertiary eye care centre were included. We recorded the demographic data, parental age and RB1 gene mutation status in the patient's tumour, blood and the parental blood. We categorised RB1 mutation inheritance as sporadic RB with somatic mutations (only present in tumour), heritable RB with de novo (present in patient's blood) and familial (present in patient and parents' blood) germline mutations. The statistical significance was confirmed by Fisher's exact/Chi-square test. Out of 259 RB patients, 247 were included in our study. Heritable RB with de novo germline mutations was significantly less common (p value: 0.0387; 95% CI: 0.2676-0.9329) and sporadic RB with somatic mutations was more common (p value: 0.0545; 95% CI: 1.025-3.39), if the parental age gap was <10 years. There were increased odds of a heritable RB with de novo germline mutation with an increase in paternal age and this was more intensified when combined with parental age gap of more than ≥10 years. The heritable RB with de novo germline mutations significantly increased as maternal age progressed, only when it was adjusted to ≥10 years parental age gap (p value: 0.0262; 95% CI: 1.26-17.91). An increased parental age gap and increased paternal age are independent risk factors for the development of heritable RB with de novo germline mutation.

Living with heritable retinoblastoma and the perceived role of regular follow-up at a retinoblastoma survivorship clinic: ‘That is exactly what I have been missing’

ObjectiveTo explore living with heritable retinoblastoma, specifically survivors’ perceived role of regular follow-up at a retinoblastoma survivorship clinic.Methods and analysisAdult survivors of heritable retinoblastoma were recruited from the Retinoblastoma Survivorship...

Abstract 2247: Genomic heterogeneity in the aqueous humor cell-free DNA in a patient with bilateral retinoblastoma

Abstract Purpose: Germline alterations in the RB1 tumor suppressor gene predispose patients to developing retinoblastoma (RB) in both eyes. However, tumors in bilateral RB may not respond identically to treatment. The additional genomic events that occur independently in each eye during tumorigenesis are not well characterized. The aqueous humor (AH) provides a novel source of cell-free tumor-derived DNA (ctDNA) for liquid biopsy, enabling the in vivo study of RB tumors. In this case report, we use our AH liquid biopsy to compare genomic profiles between the right and left eyes of a single patient with heritable RB while also showing that ctDNA longitudinal dynamics correspond to therapeutic response. Methods: One patient with bilateral RB was included. Multiple samples of AH were obtained from each eye during routine intravitreal melphalan therapy and following enucleation of the left eye. Routine clinical blood testing was performed to determine germline RB1 status. CtDNA was isolated from the AH and sequenced on an Illumina platform to assess genome-wide somatic copy number alterations (SCNAs). The same sequencing libraries were used to identify somatic RB1 pathogenic variants using a custom hybridization and next generation sequencing panel targeting RB1. Tumor fraction (TFx) was estimated using ichorCNA software. Results: Five AH samples from both eyes (3 from the right eye and 2 from the left eye) were included. Peripheral blood RB1 testing detected germline 13q and 16p deletions. Targeted RB1 mutational analysis of AH ctDNA identified a different somatic RB1 mutation in each eye. At initial AH sampling, three SCNAs were present in the right eye and these same SCNAs persisted in further samples. Two SCNAs were initially detected in the left eye and were consistently identified in later sampling. Despite the same germline RB1 mutation, the second somatic mutation was different in each eye and there were distinct, non-overlapping patterns of SCNAs in each eye. In addition, the right eye demonstrated a progressive decrease in TFx corresponding with therapeutic responsiveness and ocular salvage. The left eye had persistently larger TFx values and required enucleation due to tumor recurrence. Conclusions: Our AH liquid biopsy detected distinct genomic events between eyes in a patient with bilateral RB and TFx changes corresponding with disease activity. Identifying inter-eye genomic heterogeneity without the need for enucleated tumor tissue may help direct active management of RB, with particular usefulness in bilateral cases. Citation Format: Elyssa Y. Wong, Liya Xu, Lishuang Shen, Mary E. Kim, Ashley Polski, Rishvanth K. Prabakar, Rachana Shah, Rima Jubran, Jonathan W. Kim, Jaclyn A. Biegel, Xiaowu Gai, Peter Kuhn, James Hicks, Jesse L. Berry. Genomic heterogeneity in the aqueous humor cell-free DNA in a patient with bilateral retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2247.

Asynchronous pineoblastoma is more likely after early diagnosis of retinoblastoma: a meta-analysis.

PurposeTo determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening.MethodsWe updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta‐analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis.ResultsSeventy‐nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs.ConclusionsAn MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma.

Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria.

Simple SummaryEye tumors in children are very rare. In Europe, these eye tumors are nearly always diagnosed early and cure rates are high. However, eye tumors in childhood often occur as the first sign of a genetic tumor predisposition syndrome. This study collected data of children with malignant eye tumors diagnosed in five years in Germany and Austria to learn about the association of eye tumors in childhood with tumor predisposition syndrome. The study recruited 300 children with malignant eye tumors in childhood. In the here-presented cohort, more than 40% of eye tumors were associated with rare tumor predisposition syndromes. For this reason, all children with eye tumors and their families should receive genetic counseling for a tumor predisposition syndrome. Children with a genetic predisposition to cancer should receive a tailored surveillance, including detailed history, physical examination and, if indicated, imaging to screen for other cancers later in life.Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013–2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in DICER1 was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.

Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma.

Simple SummaryHeritable retinoblastoma is a genetic disease that predisposes to develop multiple retinoblastomas in childhood and other extraocular tumors later in life. It is caused by genetic variants in the RB1 gene. Here we present a new classification for genetic variants in the RB1 gene (REC) that focuses on the variant’s effect. The different classes, REC-I to -V, correlate with different risks of tumor predisposition. REC correlated with different clinical courses when applied in our study cohort. REC aims to facilitate risk estimation for physicians, patients and their families, and researchers and to improve the definition of the necessity of screening examination.Constitutional haploinsufficiency of the RB1 gene causes heritable retinoblastoma, a tumor predisposition syndrome. Patients with heritable retinoblastoma develop multiple retinoblastomas early in childhood and other extraocular tumors later in life. Constitutional pathogenic variants in RB1 are heterogeneous, and a few genotype-phenotype correlations have been described. To identify further genotype-phenotype relationships, we developed the retinoblastoma variant effect classification (REC), which considers each variant’s predicted effects on the common causal mediator, RB1 protein pRB. For validation, the RB1 variants of 287 patients were grouped according to REC. Multiple aspects of phenotypic expression were analyzed, known genotype-phenotype associations were revised, and new relationships were explored. Phenotypic expression of patients with REC-I, -II, and -III was distinct. Remarkably, the phenotype of patients with variants causing residual amounts of truncated pRB (REC-I) was more severe than patients with complete loss of RB1 (REC-II). The age of diagnosis of REC-I variants appeared to be distinct depending on truncation’s localization relative to pRB structure domains. REC classes identify genotype-phenotype relationships and, therefore, this classification framework may serve as a tool to develop tailored tumor screening programs depending on the type of RB1 variant.

Living with satisfactory vision and no comorbidity 28 years after bilateral retinoblastoma: a case report and mini literature review

Background: Retinoblastoma is the most common primary intraocular malignancy in children, although it is a rare neural retinal tumor. Improving the quality of life is the next goal after the primary medical goal of life preservation. The genotype-phenotype correlation may vary with the progression of retinoblastoma. Expressivity is determined by different RB1 gene mutations among individuals. Herein, we share our experience on the evaluation of the long-term progression of retinoblastoma, its treatment consequences, its impact on the quality of life, and how the underlying genotypes are related to the phenotypes. We provide a review of the relevant literature and present a case of a sporadic heritable bilateral retinoblastoma.&#x0D; Case Presentation: We report the outcomes of a 28-year follow-up of a female diagnosed with an infantile disease. The patient’s best eye, according to the tumor classification and genetic results, was treated conservatively whereas the worst eye was enucleated. On re-examinations, she had complications of the treatment she received. Therefore, another intervention was administered for several years. The patient’s pathogenic variant and RB1 gene mutational inactivation were predispositions to the recurrence of the tumor and non-ocular primary malignancy. Nevertheless, the disease had no progression. The patient is stable despite her type of retinoblastoma, which is the sporadic heritable bilateral form.&#x0D; Conclusions: Each phenotype of bilateral retinoblastoma varies in progression. The nature of the genetic mutation may determine its expressivity. It is of great significance to individualize every decision. In each case, the sequelae of the disease and treatment-induced complications may have an impact on the quality of the patient’s life.

Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies.

Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the RB1 gene. Early diagnosis of children at risk of inheriting an RB1 mutation is crucial to achieve optimal clinical outcome. Currently, the majority of genetic testing is performed on newborns, which has multiple disadvantages for both families and the healthcare system. We have developed a non-invasive prenatal diagnosis (NIPD) service for retinoblastoma, available from 8 weeks’ gestation, which uses a combination of massively parallel sequencing (MPS) techniques, dependent on the inheritance model. Detection of paternal or suspected de novo RB1 variants is achieved through amplicon-based MPS. NIPD of a fetus at risk of maternal inheritance is performed using capture-based targeted sequencing and relative haplotype dosage analysis. In addition, we show proof of principle of how capture-based sequencing can be used for de novo variants unsuitable for amplicon-based testing. In total, we report the NIPD of 15 pregnancies, results of which show 100% concordance with all postnatal testing performed at the time of publication (n = 12) with remaining pregnancies ongoing. NIPD of retinoblastoma therefore offers a viable alternative to newborn genetic testing.

Incidence and Mortality of Second Primary Cancers in Danish Patients With Retinoblastoma, 1943-2013

In heritable retinoblastoma, there is a significantly increased risk of second primary cancers (SPCs). Improved knowledge about the incidence and influence of heritability and treatment is important during therapy for patients with retinoblastoma. To assess the incidence of SPC in patients diagnosed with retinoblastoma in Denmark from 1943 to 2013 with a focus on heritability and the association of external radiotherapy with mortality. In this retrospective cohort study, data were extracted from the Danish Ocular Oncology Group Database containing complete data on all patients diagnosed with retinoblastoma , and obtained from the Danish Cancer Registry, which includes information on all patients with cancer from 1943 to December 31, 2013. Data analysis was conducted from December 1, 2017, to October 1, 2019. Data on 323 patients were included. Heritability and retinoblastoma treatment. Standardized incidence rate, excess absolute risk, cumulative incidence of SPC, and mortality from SPC. Association of heritability and treatment with outcomes was estimated. Of the 323 patients included in the analysis, 181 were men (56%), 133 had heritable retinoblastoma (41%), and 190 had nonheritable retinoblastoma (59%). The median age at diagnosis of SPC was 32.4 (interquartile range, 15.4-43.9) years in patients with heritable retinoblastoma and 38.6 (interquartile range, 20.5-49.4) years in those with nonheritable retinoblastoma. Twenty-five SPCs were identified in patients with heritable retinoblastoma vs 14 in patients with nonheritable retinoblastoma. Standardized incidence rate (SIR) of SPC in patients with heritable retinoblastoma was 11.39 (95% CI, 7.37-16.81) with an excess absolute risk of 70 cases per 10 000 person-years; the highest SIRs were for sarcoma (181.13; 95% CI, 98.94-303.92) and malignant melanoma (26.78; 95% CI, 9.78-58.30). The SIR for SPC in patients with nonheritable retinoblastoma was 1.52 (95% CI, 0.81-2.60). The cumulative incidence of SPCs at age 60 years was significantly higher in patients with heritable retinoblastoma (51%) compared with those with nonheritable retinoblastoma (13%) (P < .001) (hazard ratio, 5.0; 95% CI, 2.5-10.3). No significant differences were identified in overall risk of SPC in patients with heritable retinoblastoma treated with 3 different modalities: external radiotherapy, plaque (but no external) radiotherapy, and enucleation only, but an increased proportion of sarcomas was noted in the irradiated field. Mortality due to SPC was also higher in survivors of heritable retinoblastoma compared with those with nonheritable retinoblastoma (cumulative mortality, 34% vs 12% at age 60 years; P = .03). The findings of this study suggest that the incidence and mortality associated with SPC were significantly higher in patients with heritable retinoblastoma vs patients with nonheritable retinoblastoma. The largest increases in risk were noted for sarcoma and malignant melanoma. External radiotherapy did not appear to increase the risk. These findings are relevant when treating patients with retinoblastoma to manage the risk for SPC.

Heritable Retinoblastoma and Risk of Developing Second Primary Cancer

Heritable Retinoblastoma and Risk of Developing Second Primary Cancer

The impact of RB1 genotype on incidence of second tumours in heritable retinoblastoma

BackgroundPatients with heritable retinoblastoma are at risk for bilateral retinoblastoma and second primary malignancies (SPMs). The incidence of SPM is significantly raised after radiotherapy. We analysed the impact of the class of constitutional RB1 variant on the incidence of SPM in survivors with and without previous radiotherapy. MethodsFrom 1940 to 2008, 655 national patients were treated for heritable retinoblastoma at the German referral centre. Data on SPM, therapy and constitutional RB1 variant were available for 317 patients (48.3%). Heterozygous RB1 variants were classified into variants with regular and incomplete penetrance for retinoblastoma. ResultsSPM occurred in 51 of 317 survivors of heritable retinoblastoma. The incidence rate (IR) of SPM per 1000 person years was 8.4 (95% confidence interval (CI): 6.3–11.1) in individuals heterozygous for an oncogenic RB1 variant and 2.1 (95% CI: 0.0–11.4) with RB1 mosaicism. The incidence of SPM was higher in patients with regular penetrance compared with incomplete penetrance RB1 variants (IR 10.3 [95% CI: 7.5–13.8] vs. IR 3.2 [95% CI: 1.0–7.5]; p < 0.05). In the subgroup without previous radiotherapy SPM were only observed in patients with regular penetrance variants (IR 6.3 [95% CI: 3.0–11.5]). Carriers of incomplete penetrance variants developed similar tumour entities as those with regular penetrance. ConclusionsPatients heterozygous for regular penetrance RB1 variants had a higher risk to develop SPM than patients with incomplete penetrance variants. Increased knowledge on genotype-phenotype relation regarding SPM may influence screening recommendations for SPM in survivors of heritable retinoblastoma.

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma

To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. Diagnosis and mortality from subsequent neoplasm. Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Preimplantation genetic diagnosis for retinoblastoma survivors: a cost-effectiveness study.

This study aimed to investigate the cost-effectiveness of preimplantation genetic diagnosis (PGD) for the reproductive choices of patients with heritable retinoblastoma. The study modelled the costs of three cycles of in-vitro fertilization (IVF) and PGD across all uptake rates of PGD, number of children affected with retinoblastoma at each uptake rate and the estimated quality-adjusted life years (QALYs) gained. Cost-effectiveness analysis was conducted from the Australian public healthcare perspective. The intervention was the use of three cycles (one fresh and two frozen) of IVF and PGD with the aim of live births unaffected by the retinoblastoma phenotype. Compared with the standard care pathway (i.e. natural pregnancy), IVF and PGD resulted in a cost-saving to 18 years of age of AUD$2,747,294 for a base case of 100 couples with an uptake rate of 50%. IVF and PGD resulted in fewer affected (n = 56) and unaffected (n = 78) live births compared with standard care (71 affected and 83 unaffected live births), and an additional 0.03 QALYs per live birth. This modelling suggests that the use of IVF and PGD to achieve an unaffected child for patients with heritable retinoblastoma resulted in an overall cost-saving. There was an increase in QALYs per baby across all uptake rates. However, in total, fewer babies were born following the IVF and PGD pathway.

8-Hydroxy-2'-Deoxyguanosine in Sperm DNA and Increased Risk of Nonfamilial Sporadic Heritable Retinoblastoma in the Child.

8-Hydroxy-2'-Deoxyguanosine in Sperm DNA and Increased Risk of Nonfamilial Sporadic Heritable Retinoblastoma in the Child.

Meaningful Patient Engagement in Research: Lessons From Retinoblastoma.

* Abbreviations: CIHR — : Canadian Institutes of Health Research CRRAB — : Canadian Retinoblastoma Research Advisory Board SPOR — : Strategy for Patient-Oriented Research At only 20 months old, I was diagnosed with bilateral, heritable retinoblastoma: an aggressive childhood eye cancer. The news was unexpected, because I was the first person in my family to be diagnosed with this cancer. With approximately 8000 new cases around the world each year and just 24 new cases annually in Canada,1 it is unsurprising that my family had never heard about retinoblastoma. My right eye was surgically removed (enucleated), and I received chemotherapy and cryotherapy over the course of about 1 year. That was when my family heard the good news: the treatment succeeded in saving my left eye with good vision. Growing up in Ontario, I received exceptional care and returned to the eye clinic and oncology clinic at The Hospital for Sick Children for annual appointments. However, as young adulthood emerged, I felt disheartened and overwhelmed in trying to understand the complexities behind retinoblastoma as a rare, heritable cancer. I had assumed it to be a childhood cancer that was behind me. I instead learned of the lifelong implications ahead of me: I could pass on a disease-causing gene to my future children and I carry a higher risk of developing second cancers.2 Through oncology appointments, genetic counseling, and my own research, I was able to gain a rudimentary understanding of retinoblastoma. However, I still felt that I lacked access to new, … Address correspondence to Helen Dimaras, PhD, Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada. E-mail: helen.dimaras{at}sickkids.ca

The Link between Oxidative Stress and Cancer: Prevention through Yoga

Sperm DNA damage induced by oxidative stress may lead to accumulation of mutations in sperm genome due to the presence of mutagenic oxidative adducts in DNA. This may contribute to the development of male infertility, recurrent pregnancy loss, congenital malformations, neurodevelopmental disorders, and childhood cancers. This article highlights the impact of lifestyle habits of father preconceptionally, its lifelong impact on offspring’s health and impact of yoga-based lifestyle intervention on sperm genome and epigenome. Sperm is transcriptionally and translationally inert with a very basic repair mechanism and is thus unable to repair DNA damage and this may persist postfertilization and lead to accumulation of damaged DNA in each cell of zygote. This DNA damage with high levels of mutagenic oxidative base adducts may lead to accumulation of mutations in both sperm DNA (germline) and zygote (somatic). Majority of mutations arise during cell replication and as sperm has a limited capacity for DNA damage detection and repair, it is highly susceptible to accumulation of mutations. Paternal unhealthy lifestyle habits like smoking, alcohol, or tobacco consumption are positively associated with the risk of childhood cancers like nonfamilial sporadic heritable retinoblastoma. Lifestyle interventions like yoga improve sperm DNA integrity by reducing levels of oxidative DNA damage, optimizing oxidative stress, and by increasing the expression of genes responsible for DNA repair, cell-cycle control, and anti-inflammatory effects. Thus, social habits affect sperm DNA health and as such, it is recommended that simple lifestyle modifications (diet rich in fruits and vegetables, yoga, meditation) improve DNA health and may thereby decrease the incidence of childhood morbidity and cancer. Hence, biological parenting commences well before birth and even prior to conception, which highlights the need for fathers to adopt a healthy lifestyle.

Impact of yoga based lifestyle intervention on sperm oxidative DNA damage: study on fathers of non-familial sporadic heritable retinoblastoma patients

Sperm chromatin integrity is essential for fertilization, proper embryonic development and birth of healthy offspring. Sperm is highly vulnerable to oxidative damage to both nuclear and mitochondrial DNA due to minimal cytosolic anti-oxidants. Retinoblastoma is the most common childhood malignancy where the de novo germ line mutations are mainly inherited from paternal allele. The present study is planned as a case control study on the fathers of children affected with affected with non-familial sporadic heritable retinoblastoma to see the effect of yoga based lifestyle intervention on the decline in oxidative stress and oxidative DNA damage. A case control study with 75 fathers of children affected with non-familial sporadic heritable retinoblastoma cases and 50 fathers of healthy children were enrolled as healthy controls. Study duration was 6 months. Fathers of children affected with non-familial sporadic heritable retinoblastoma were enrolled in a yoga-based lifestyle intervention programme. Semen samples were collected at base line (day 0), after 1 month, 3 months and 6 months of yoga intervention. ROS, DNA fragmentation index (DFI) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) levels were estimated at base line (day 0), 1 month, 3 months and 6 months duration. ROS, DFI, 8-OHdG were also assessed in fathers of healthy children. Semen parameters were assessed as per the WHO, 2010 guidelines. The seminal mean ROS levels (p<0.05), sperm DFI (p<0.001), 8-OHdG (p<0.01) levels were significantly higher in fathers of children with non-familial sporadic heritable retinoblastoma as compared to fathers of healthy children. There was a reduction in mean DFI levels post yoga-based lifestyle intervention at 1 month (p=0.63), 3 months (p=0.046) and 6 months (p=0.032). Similarly, there was a reduction in seminal mean ROS levels at 1 month (p=0.74), 3 months (p=0.039) and 6 months (p=0.006). The levels of DNA oxidative base adduct i.e., 8-OHdG were also significantly reduced at 1 month (p=0.68), 3 months (p=0.043) and 6 months (p=0.022) with respect to its base line levels (day 0). Yoga-based simple lifestyle intervention meditation may significantly lower oxidative stress and oxidative DNA damage, and levels of mutagenic base 8-OHdG in the sperm DNA. Thus, yoga-based intervention is alternative and complementary treatment for maintaining/restoring sperm DNA integrity and hence, can reduce the prevalence of childhood cancers where poor sperm DNA integrity could be one of the reason.