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Research Round Up October 2020

The theme of this issue of Research Round Up is renal manifestations of TSC.  We have summarised two recent, important research studies.  We are also delighted to include a video interview with Dr Sean Kennedy, one of TSA’s medical advisors, who kindly agreed to talk with us about the current management of kidney tumours associated with TSC. 

An interview with Dr Sean Kennedy on renal tumours in TSC

Click here to view the interview with Dr Sean Kennedy

This interview is based on a review recently published by Dr Sean Kennedy and Dr Peter Trnka. In this, they discuss the current management of kidney tumors associated with TSC,
including the diagnosis, surveillance, and treatment options.

Trnka P, Kennedy SE.  Renal tumors in tuberous sclerosis complex. Pediatr Nephrol. 2020 Oct 1. doi: 10.1007/s00467-020-04775-1. Online ahead of print. PMID: 33006051

Full paper available (at extra cost) at: https://link.springer.com/article/10.1007/s00467-020-04775-1

Key findings from the TOSCA study focussing on renal angiomyolipomas (AMLs)

TOSCA (TuberOus SClerosis registry to increase disease Awareness) is a large-scale non-interventional study in patients with TSC.  It was designed to provide detailed focus on various aspects of TSC including sub studies on TSC-associated neuropsychiatric disorder (TAND), epilepsy and quality of life.  The TOSCA study has provided valuable real-world data collected from 170 sites across 31 countries worldwide, including Australia.

About this TOSCA study

This study focussed on renal angiomyolipomas (AMLs). It looked at the prevalence and outcome of renal AMLs in patients with TSC.  Of the 2,211 eligible patients enrolled in the study, 1,062 (48%) reported a history of renal AMLs.

Outcomes of the study

  • The median age of diagnosis of renal AML was 13 years (the median age of TSC diagnosis for those enrolled in the study was 1 year)
  • Less than 10% of children aged 2 years or younger had AML
  • The presence of AMLs increased with the age of patients.  In those over 40 years in age nearly 80% had an AML in their kidneys
  • Renal AMLs were more common in females than males
  • More females than males had renal AMLs larger than 3cms
  • Females had more commonly received treatment for renal AMLs
  • Children were less likely to have interventions than adults
  • Renal AMLs in people with a TSC1 mutation develop at a later age, are relatively smaller in size and less likely to be growing
  • Renal AMLS in people with TSC2 mutations also had significantly higher rates of multiple renal AMLS that were bilateral, growing and more than 3cm
  • Polycystic kidney disease was only found in those with TSC2 mutations
  • Appearance of new renal AMLs was observed to peak in those aged between 18 and 40 years
  • In the study 82% of those with renal AMLs were asymptomatic.

Recent improvements in the preventative and early management intervention options available (embolization, surgery and/or mTOR inhibitors) has dramatically improved outcomes but the authors stress that, given that AMLs can occur later, lifelong surveillance is necessary.  The authors conclude that the information gained through the TOSCA study validates the policy of surveillance and pre-emptive intervention recommended by the TSC clinical guidelines.

For more information on surveillance visit https://tsa.org.au/information/surveillance/

Kingswood, J. C., Belousova, E., Benedik, M. P., Carter, T., Cottin, V., Curatolo, P., Dahlin, M., D’Amato, L., Beaure d’Augères, G., de Vries, P. J., Ferreira, J. C., Feucht, M., Fladrowski, C., Hertzberg, C., Jozwiak, S., Lawson, J. A., Macaya, A., Marques, R., Nabbout, R., O’Callaghan, F, Sauter, M. (2020). Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas. Frontiers in neurology, 11, 972.

Full paper available (without charge) at: https://doi.org/10.3389/fneur.2020.00972

Use of low dose everolimus as a treatment for TSC-associated renal angiomyolipoma (AML)

The aim of this study was to evaluate the safety and efficacy of low dose everolimus treatment in patients with TSC-associated angiomyolipoma (AML) with renal dysfunction (poor kidney function) or low body weight.

About TSC-associated AMLs

AMLs are seen in 50-80% of people with TSC and they are different from AMLs seen in those who do not have TSC. TSC-associated AMLs are more likely to be present in multiple locations and in both kidneys. Most TSC-associated AMLs do not cause symptoms or problems with renal function.

TSC-associated AMLs are rare in infant children, and generally develop when a person is in their twenties or thirties. If the AML is greater than 4cm it is more likely to be faster growing and the risk of bleeding is increased.

About this study

This study took place in Japan. 50 adult patients were treated with everolimus for TSC-associated AMLs.

Low dose group: 20 patients with renal dysfunction or low body weight (body weight less than 35 kg) were treated with 5 mg of everolimus daily.

Conventional dose group: 30 patients without renal dysfunction or low body weight were treated with 10 mg of everolimus daily.

The treatment effects and adverse events were compared between the two groups.

Outcomes of the study

The good news is that both groups had a reduction in the size of AMLs. The average reduction rate in the low dose group was 52% versus 60% in the conventional dose group. The low dose group was treated for a median of 17 months and the conventional dose group was treated for a median of 19 months. The most common reported adverse side effects were stomatitis (mouth ulcers) and irregular menstruation (periods) with both being experienced significantly less in the low dose group than the conventional dose group.

The authors of the study suggest that low dose everolimus treatment for TSC-associated AML is safe and effective and may minimise adverse events associated with treatment. In the low dose group the treatment was well tolerated and adverse events were mild in all cases. The authors believe that based on their results, low dose everolimus can be considered a treatment option for patients with TSC-associated AML, especially those who have renal dysfunction or low body weight. They suggest that further studies should be performed to broaden knowledge on the safety and efficacy of low dose everolimus for TSC-associated AML.

For more information on TSC and kidney visit https://tsa.org.au/information/kidneys/

Hatano, T., Endo, K. & Tamari, M. Efficacy and safety of low-dose everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. Int J Clin Oncol (2020). 

Full paper available (at extra cost) at: https://doi.org/10.1007/s10147-020-01792-w