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CHECT projects under way

Audit of clinical genetic and molecular genetic information and reproductive issues known to retinoblastoma families.


Project Leader: Dr Trevor Cole, Consultant Clinical Geneticist, Birmingham Women's Hospital

Funding awarded: £30,000

Project duration , Start date: 2 years starting in October 2008.  The project overran and finished in late 2012, we await a final report.

Project summary (as written by Dr T Cole): The differing and complex genetics underlying the majority of unilateral and bilateral retinoblastoma means that many families have to be given genetic counselling advice on an ongoing and rather piecemeal basis.
We therefore suggest that we need to work with families currently undergoing treatment and, families discharged from follow up, to see if further genetic counselling input is necessarily to ensure families have the best information we are currently able to provide. We would suggest that this is important baseline data and would facilitate periodic review or audit that is likely to be necessary until all families are able to have a "definitive genetic explanation" to all at risk family members. Evidence on the practical benefits perceived by patients, in addition to the theoretical medical and cost benefits reported by Richter et al 2003, from molecular studies could then be assessed. This study would be timely as it could collect data prospectively from families yet to have definitive molecular answers and subsequent to these answers becoming available.

Progress report (As written by Dr T Cole): In early 2012 attempts to contact the remaining list of people was drawn to a close and we decided at this stage all remaining contact would be via letters to the participant’s GPs.  Since this time several hundred further patient replies have been reviewed and letters to GPs are being produced and sent out to the remaining families.

Project status: Completed, awaiting final report.

Epigenetic Mechanisms in Retinoblastoma Tumourigenesis


Project Leader: Dr Carmel McConville at the CRUK Institute for Cancer Studies at the University of Birmingham.

Funding awarded: £50,500

Project duration , Start date: 1 year from February 2012

Project summary (As written by Dr C McConville) : Research into new treatments for all types of cancer is increasingly focusing on the development of 'targeted therapy'. There is a need to develop new drugs which are very specific in their action and which target cancer genes that are known to be defective in particular types of cancer. In the case of retinoblastoma it is known that a gene called 'DEK' is present at abnormally high levels in approximately 50% of cases. It is possible that DEK might contribute to the growth of the retinoblastoma and perhaps also to its spread outside the eye. It could therefore be a target for therapy in these retinoblastomas.

The purpose of our research is firstly to find out what effect DEK has on retinoblastoma cells. Does it make them grow faster? Does it make them more mobile and invasive? Or does it influence their ability to carry out the specialized functions of the retina? We will also try to find out exactly how DEK works. Current evidence suggests that the protein encoded by the DEK gene works in association with other proteins to 'switch on' or 'switch off' other genes. This might include genes which are important for normal retinal development and function. Understanding exactly how DEK does this will be the key to developing new drugs to block its action.

Our research will involve growing retinoblastoma cells in the laboratory. We will use a specialized genetic technique ('gene knockdown') to silence the DEK gene and we will then monitor the changes which occur. We will also investigate the interactions between DEK and other proteins in order to understand the mechanisms involved.

Project status: Project completed, final report here. Awaiting publication of results.

Autonomic reflexes and cardio-respiratory instability during super-selective intra-arterial chemotherapy in the management of children with Rb.


Project Leader: Dr S P McGuirk et al. at Great Ormond Street Hospital and Birmingham Children’s Hospital.

Funding awarded: £18,000

Project duration , Start date: 1 year, planned start date 1 July 2013.

Project summary (as written by Dr S P McGuirk): Conventional management of retinoblastoma is associated with excellent long-term outcome. However, some children with advanced retinoblastoma do not respond to conventional management while others develop recurrent disease following initially successful treatment. Traditionally, the management of these children has involved external beam radiation or surgical removal of the eye. A number of new treatment modalities have been developed that can be used to treat children with advanced disease and also preserve the function of the affected eye. One of these new treatment options is super-selective intra-arterial chemotherapy. This involves the insertion of a small tube or catheter into the ophthalmic artery so that chemotherapy can be delivered selectively to the affected eye. The advantage of this technique is that it delivers a high concentration of chemotherapy to the tumour with few systemic side effects.

Previous studies have reported that intra-arterial chemotherapy is a safe and effective treatment in children with advanced disease. It causes complete regression of the tumour and preservation of vision in most cases. However, we have observed that a significant proportion of children developed severe adverse cardio-respiratory responses during the procedure. These reactions have occurred only during the second catheterisation procedure and are characterised by the sudden development of acute bronchospasm, impaired ventilation and marked haemodynamic instability. Patients have been resuscitated with intravenous fluids, intravenous atropine and intramuscular epinephrine with rapid restoration of normal cardio-respiratory function. None of the children had any adverse sequelae following these events.

We do not currently understand why these responses occur, why they occur in some children but not others, or why they are only clinically evident during the second catheterisation procedure. We believe that they represent an autonomic reflex response, which is qualitatively similar to the trigemino-cardiac and trigemino-respiratory reflexes observed during corrective surgery for strabismus, cranial and maxillofacial surgery, and skull base surgery. We propose to undertake this prospective case-controlled study to examine the pathophysiological events in detail. In particular, this study will determine the incidence of the trigemino-cardiac and trigemino-respiratory reflexes and quantitatively measure the effect of these reflex responses on haemodynamic and respiratory function. Ultimately, this information may allow us to identify adverse responses before they become clinically apparent, thus improving the safety of this procedure. The findings of this study are, therefore, of potentially immediate clinical application.

Project status: In progress. Link to article in Pediatric Anesthesia.

Role of SLRP family members in malignant progression of retinoblastoma.


Project Leader: Professor Shin-ichi Ohnuma Co-investigator: Dr Mandeep Sagoo

Funding awarded: £15,000 Joint funding applied for through CHECT and Fight for Sight

Project duration, Start date: 01/01/2013 for 1 year.

Project summary:
Retinoblastoma is the most common childhood cancer of the eye, affecting 1 in 20,000 live births, with 40-50 new cases diagnosed each year in the UK. Many children develop tumours that are aggressive and refractory to treatment, often requiring eye removal (enucleation), whereas some respond to local treatment and chemotherapy. Some years ago, it was reported that inhibition of a gene named as RB1 is important for initiation of retinoblastoma. However, recent studies have shown that the inhibition of RB1 gene is not sufficient to develop aggressive retinoblastoma and alternation of additional genes is required. However, little is known about additional genes that may be involved. If we can understand the detailed mechanism of retinoblastoma development, it might be possible to improve treatments.

This project will investigate the role of a family of genes which produce secreted proteins around the cancer cells. This family of genes are highly produced in the normal eye and known to be involved in formation of non-eye cancers. Moreover, our previous studies using cells isolated from retinoblastoma patients showed that amounts of some of the family members are altered in association with retinoblastoma development. Firstly, we will examine the change of gene expression in the process of retinoblastoma development using human retinoblastoma tissues. Then, we will examine their function on retinoblastoma progression using cells isolated from retinoblastoma tissues.

If we can prove the importance of the gene family in retinoblastoma, it becomes possible to develop new diagnosis and treatment of retinoblastoma.

Project status: Awaiting ethical approval.

Understanding and overcoming barriers to living with an artificial eye


Project leaders: Tara Shea and Laura Rouse

Funding awarded: £14,339

Project duration, Start date:

Project summary:
Understanding the experiences of children and their families following enucleation will help to develop some clear best practice guidelines regarding clinical management of this population. We hope to promote innovation in the development of clinical resources to support adaptation to living with an artificial eye. By better understanding the scope of the barriers (physical, mental and emotional) that may be encountered by children and young people and their families who have experienced adjusting to living with an artificial eye, the research team can explore the support services and strategies used by children and their families who have  undergone enucleation in order to address these barriers.

In order to understand the experiences of children and their families following enucleation the study will involve conducting interviews with three groups: children over five years of age who have experienced a unilateral enucleation; parents of children who have experienced enucleation; and teachers of children who have experienced enucleation.

It is anticipated that the findings of this study will increase our understanding of how to provide the most appropriate and research based strategies so that future families do not suffer further emotional distress relating to artificial eye problems.

Project status: Awaiting ethical approval

Retinal vessel architecture in retinoblastoma patients - a predictor of progression?


Project Leader: Dr Clare Wilson

Funding award: £10,500

Project duration, Start date: Estimated start date 01/08/13

Project summary: (as written by Dr Clare Wilson)
Retinoblastoma treatment has developed leading to vastly improved survival rates. However, detecting early disease progression is challenging for experienced retinoblastoma surgeons who see over 20 new patients a year. It is even more problematic for surgeons working in countries with smaller populations. An objective assessment that can alert the surgeon to progression of the cancer would be of great benefit.

New software can measure changes in blood vessels at the back of the eye. Eye cancer doctors have made the clinical observation that these vessels change when disease worsens, and so could be used to detect eye needing more treatment. At The Royal London Hospital we have a large set of digital images from children who have had eye cancer and we are analyzing them with new software to see if the vessel changes can be used to accurately detect progression of the tumour.

If we get positive results, we could make the follow up visits for these children with eye cancer a more pleasant experience, yet just as accurate.

Project status: In progress.

Development of a next generation sequencing analytical pathway for improved test sensitivity and enhanced detection of low level RB1 mutations in retinoblastoma patients.


Project Leader: Dr Simon Ramsden Co-investigator: Dr Sarah Waller

Funding awarded: £13,810 Joint funding applied for through CHECT and Fight for Sight

Project duration, Start date: December 2013 for 1 year.

Project summary:
Mutations in the retinoblastoma gene RB1 cause the childhood eye cancer retinoblastoma. Traditional Sanger sequencing technology reliably detects mutations in RB1 in tumour tissue in the majority of patients from whom tumour is available, and detection of a germline mutation permits predictive testing of at risk family members. In our laboratory Sanger sequencing detects germline mutations in ~92% of patients with bilateral tumours and ~16% of patients with unilateral tumours.

Whilst Sanger sequencing offers appropriate test sensitivity for most cases there remain a small number of familial mutations undetected and also it has limited utility when trying to detect mosaicism. Emerging sequencing technologies (so called “Next Generation”) are showing great promise in both the academic and service environment and offer significant advantages over conventional Sanger testing. We feel that Next Generation Sequencing could offer us a means of overcoming both of these obstacles.

Project status: Requires institutional board approval before commencing.

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