#AskLuiza: How is the neuroblastoma stage determined and how does this impact treatment?

The determination of the tumour stage is an important step after a neuroblastoma diagnosis. The stage of neuroblastoma is determined depending on tumour location and if it has spread to other parts of the body. This will guide risk group assignment and treatment choice. 

The first staging system for neuroblastoma, the International Neuroblastoma Staging System (INSS), was developed in 1986 and is based on the pathological evaluation of the tumour after a removal surgery. In 2005, The International Neuroblastoma Risk Group Staging System (INRGSS) started to be used. This system is based on tumour images before any surgery. Therefore, it is based on image-defined risk factors to determine the tumour stage (see table below). It also uses clinical, pathologic, and genetic markers to determine the risk groups, which can be low-risk, intermediate-risk, or high-risk.  

Reference: Neuroblastoma – Childhood: Stages and Groups, Cancer.net

Recently, the Children’s Oncology Group (COG), a clinical trial group dedicated to paediatric cancer research revised the classification system they use to determine tumour stage for enrolment in clinical trials1. Previously, they have been defining the tumour stage based on the INNS system. Now they proposed a revised classification that takes into account the INRGSS and chromosomal alterations.  

Key clinical and biological factors used in the neuroblastoma risk classification include age at diagnosis, disease stage, tumour tissue appearance under a microscope (histology), the status of the gene MYCN that affects tumour growth, the amount of DNA in a tumour cell (called tumour cell ploidy), and alterations in the DNA.  

They analyse the outcome of almost 5,000 patients to define risk groups based on the INRGSS, using alterations in the DNA of tumour cells as a biomarker and considering current therapy modalities. In general, they found that the correlation of stages between systems is not exact. However, the differences in survival were minimal when comparing staging systems, which corroborates the use of the revised version.  

In general, the new version classifies L1 and L2 tumours as low risk, except for L1 tumours with alteration in the gene MYCN and that cannot be removed by surgery, which is high-risk. For L2 tumours, MYCN status and age can be used to evaluate prognosis. Stage M tumours can be classified as high risk or intermediate-risk depend on age, MYCN status and DNA alterations. In conclusion, low-risk groups have excellent outcomes with any or limited therapy, the intermediate-risk group have very good outcomes and high-risk groups have inferior outcomes despite therapy. 

This new version of the COG classifier will provide a uniformization of patient risk classification for clinical trials, ultimately enabling the comparison between different trials.  

Written by Luiza Erthal

Reference: 

1. Irwin, M. S. et al. Revised Neuroblastoma Risk Classification System: A Report From the Children’s Oncology Group. J. Clin. Oncol. JCO.21.00278 (2021)  

#AskLuiza about neuroblastoma biology

#AskLuiza

We are launching a new initiative #AskLuiza to help the public and patients know more about advances and current trends in neuroblastoma.

Luiza is a research writer at the Cancer Bioengineering Research Group. She holds a PhD in Biomedical Sciences from Trinity College Dublin. You will ask a question and Luiza will look for the answer in peer-reviewed research papers that the research community trust.

Leave your question and follow our blog to read the answer soon: https://forms.gle/vrgwKoZivyUVawk9A

Models to study neuroblastoma in the laboratory

Finding suitable research models to study disease is a big challenge for researchers around the world. In cancer research, it is essential to work with models that can recapitulate tumour characteristics as much as possible. This is important to test chemotherapeutic drugs, understand tumour behaviour and have higher chances of translating the finds from the laboratory to clinical practice.  

Multiple factors influence tumour behaviour and disease progression. The most important is the tumour microenvironment, which comprises different cells and molecules that surround the tumour and the extracellular matrix, a network of molecules that provides support to the cells in the body.  

Most cell studies in a laboratory are based on 2D cell culture models in which the cells grow in a monolayer. Although this approach has a low cost and it is easy to use, it lacks the complexity observed in the clinical scenario. It is true that no model can recapitulate all the complexity found in the body. However, scientists were able to develop interesting approaches to study different tumour characteristics with relatively good approximation1.  

Specifically for neuroblastoma, the most common solid tumour that affects children, scientists developed 3D models in which neuroblastoma cells grow interacting with the surrounding environment and with each other in a vial. Examples of 3D models include cells grown in hydrogels or scaffolds and multicellular tumour spheroids (see image below). Spheroids are formed through the self-adhesion of tumour cells growing in the form of very small balls. They can be maintained in the laboratory on their own or supported by scaffold-based platforms (jelly-like or porous materials). Scaffolds essentially support the cell resembling the extracellular matrix and surrounding tissue in the body. 

In the Cancer Bioengineering Research Group, we work with neuroblastoma models such as organoids, a more complex type of spheroid, to understand neuroblastoma migration and invasion2. Moreover, we recently shared with the research community a protocol at jove.com describing the development of a 3D neuroblastoma model using collagen-based scaffolds3.  

Time-lapse video of neuroblastoma organoids’ growth. Accompanying experimental data published in Gavin et al., Cancers 2021. Source: the Cancer Bioengineering Research Group 

These models have the potential to advance drug tests performed in the laboratory providing better clinical translation, ultimately contributing to improving the quality of life and survival of children diagnosed with neuroblastoma.  

The work with 3D models at the Cancer Bioengineering Research Group is supported by the Irish Research Council, the Conor Foley Neuroblastoma Cancer Research Foundation, Neuroblastoma UK and National Children’s Research Centre. 

Written by Luiza Erthal

References 

1. Nolan, J. C. et al. Preclinical models for neuroblastoma: Advances and challenges. Cancer Lett. 474, 53–62 (2020). 

2. Gavin, C. et al. Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix. Cancers 13, 736 (2021). 

3. Gallagher, C., Murphy, C., O’Brien, F. J. & Piskareva, O. Three-dimensional In Vitro Biomimetic Model of Neuroblastoma using Collagen-based Scaffolds. J. Vis. Exp. 62627 (2021) doi:10.3791/62627. 

A 30km Dublin Mountain Way in A Day

And the story began with a meeting of fantastic 7 at the very beginning of Dublin Mountains Way in Tallaght at 6.30 am on September 25th. The spirit, cheer, backpacks with essentials and branded tops were on, Strava was launched and we swiftly headed off.

It was quiet, dark and cheering. No one was on the streets, a few cars passed by. We took towards Bohernabreena reservoir through the sleepy estates of Tallaght, sensing the sunset. Clouds were low and the highest peaks in the Dublin Mountains including Seefingan, Corrig and the highest, Kippure were in the mist. Nevertheless, we were full of energy and hopes to see it later.

Cheat chats and jokes were here and there, we walked in small dynamic groups recalling our pre-covid life and stories that happened during the lockdown. A mix of newbies and maturating research students. We met some in person for the first time since the COVID restrictions admitting that our visual senses are extremely important to memorise a person and recognise him/her on the next occasion. We were enjoying this face-to-face communication and our team re-connection.

The first 8 km flew in a flash. We stopped for our breakfast in Dublin Mountains. The grass was wet, the sky was blue. Mountains started to draw their shape through the clouds. Yoghurts, fruits, bars immediately disappeared in our stomachs. Everyone was happy to lighten their backpack. Every little helps!

A few plasters were glued, and we continued on at a very good pace. The sky was changing with sunny spells. We travelled around Spinkeen and Killakee at their base doing up and downhills and verifying our route with the hiking app. At the 20 km mark, we stopped for lunch. Sandwiches, grapes, mandarines and sweets were shared and eaten and then polished with chocolates from the recent Nadiya’s home trip. Jellies left untouched.

At 25 km, our blisters reminded us of being humans. Our pace slowed down and we started a very mild ascent to Tibradden Mountain leaving the Pine Forest or Tibradden Wood behind. We climbed further to Fairy Castle, the highest point on the Dublin Mountains Way (537m). Throughout the entire way, Dublin showed its best views of the Phoenix Park and the Pope Cross, house roofs, Aviva Stadium, two Chimneys, Dublin Port… The scenery was fascinating and breathtaking. We saw Howth and Dun Laoghaire, Sugar Loaf… We met groups of Germans, French, Irish and many others.

At Three Rocks Mountain/Fairy Castle, we started our descent and entered Tiknock forest. This part was steep. We crossed the Gap Mountain Bike Adventure Park to reach Glencullen. Got lost at the end but just for a sec and reached the Glencullen junction at 2.30pm. It took us 8 hours with walks and stops from start to finish to complete the 30 km challenge in a day. We got tired but felt happy and satisfied.

We aimed to raise awareness of childhood cancer in general and neuroblastoma in particular as well as honour children with cancer, their parents, siblings, friends and careers, doctors and nurses, volunteers in the hospitals and researchers working to find cancer weaknesses and develop new treatments that are friendly to patients and target cancer aggressiveness.

We will count our tally in the coming days and transfer it to three wonderful charities that support childhood cancer research.

We thank everyone who supported this challenge!

Go raibh maith agat!

I’m Ronja

I’m Ronja, I’m from Germany, but have spent my entire adult life in the English-speaking parts of this world. Right after school, I interned with a PhD student working on cystic fibrosis for a couple of months. Having the chance to culture airway epithelial cells myself made me certain I was on the right track with biomedical sciences. So, I studied Biomedical Sciences (Anatomy) in Aberdeen. The best part of that degree was my introduction to dissections. I enjoyed them so much that I even considered becoming a full-time prosector. But that does not count as essential work, so I found a remote master’s degree in Health Research instead. Studying remotely gave me the fabulous opportunity to structure my own time. I could go and explore Scotland during the day and work in the evenings. But after 5 years of studying, I was finally ready to start a PhD and was ever so delighted when I heard I could weave in some dissections at RCSI. Now, I’m looking forward to discovering what Dublin has to offer and to getting stuck in my research project!

While I didn’t know much about the particulars of my PhD before starting, I had an idea about the project from the application and I knew accommodation was sorted out for me, but I had never seen the place or my future flatmates. The one thing that I was made aware of far in advance of moving to Dublin was that September was Child Cancer Awareness Month, for which the team was going to do a charity event. Based on past years I was expecting it to be a 10km run, which was pretty daunting to me. So, I prepared. I started running and cycling over the summer until 10km weren’t an issue anymore. But in the first lab meeting plans shifted. We were going to do the Dublin Mountains Way in a day. The 10km were tripled and depending on donations maybe even quadrupled. Quite a different challenge! But I believe my summer prepared me well for that too. Alongside running I started cycling a little as well. And because there was a free bike in Aberdeen for me, I cycled it down to Stirling. Let’s hope that the endurance needed to cycle 200km translate to hiking 30-42km!

Ronja Struck

Dublin Mountain Way in A Day, September 25th 2021

Here are our plans. This year we have upped the challenge, taking on the Dublin Mountain’s Way in a Day ⛰ We will hike through the Dublin Mountains from Tallaght to Glencullen, and maybe even all the way to Shankill on September 25th! Our challenge is not only to do #DMW in a Day & support three wonderful charities CMRF Crumlin/National Children’s Research Centre, Neuroblastoma UK and the Conor Foley Neuroblastoma Cancer Research Foundation but also beat our past fundraising records! If we raise 2K+, we’ll do 30km in a day. If 3K+ then 42km! Can u challenge us?  All funds raised will go to the 3 selected charities. Every donation big or small is hugely appreciated!

Please support us by donating to our Gofundme

https://gofund.me/ec59f131

Childhood Cancer Awareness Month 2021

Every 100th cancer patient is a child. Cancer is the 2nd most common cause of death among children after accidents. 

Childhood cancer is an umbrella term for many other types of this disease. Every September, many charities, researchers and parents of children with cancer work hard to raise awareness of this cancer. You may learn more about kids with cancer, their loving families, the doctors and caregivers who looking after them and treating them, the young survivors of cancer and those kids and teens who lost their battle, and the scientists who working hard to find a way to stop childhood cancer.

This year our research team will hike Dublin Mountain Way in One Day on the 25th of September 2021 whatever the weather in honour of Childhood Cancer Awareness Month. For every one euro donated to research only 1 cent of this goes to ALL childhood health conditions including cancer. Therefore, the donations we receive will be split equally among some wonderful children’s charities. These charities include the Conor Foley Neuroblastoma Research Foundation (CFNRF), Neuroblastoma UK (NBUK), Children’s Research & Medical Foundation (CRMF) Crumlin.

If you would like to get involved in this amazing challenge and help us raise vital funds for childhood cancers, you can contribute to our fundraising page:

A warm welcome to our new PhD students!

A warm welcome to our new PhD students Ronja and Erin! Both received the prestigious Irish Research Council – Enterprise Partnership Scheme Award. Indeed, I am a proud PI. This competitive scheme brings the most promising researchers to advance our knowledge across many disciplines, e.g. Law, Astronomy, Sociology, Biomedical Sciences and many more. A key element of this scheme is to work together with an Enterprise Partner.

We will work closely with the Conor Foley Neuroblastoma Cancer Research Foundation – a research charity led by the family who lost their child to neuroblastoma. An inspirational example of never giving up.

We will continue to dissect neuroblastoma biology using innovative platforms such as tumour-on-chip and 3D scaffold-based models in collaboration with our colleagues in the Tissue Engineering Research Group at RCSI and the Fraunhofer Project Centre at DCU.

This announcement is timely to celebrate Childhood Cancer Awareness Month in September.

Two talented and dedicated young scientists are joining our team. In 4 years time, we will have another pic of their graduation on the same stairs.

Upwards and onwards!!

Remote Research Projects

Regardless COVID19 pandemic, we continue to host undergraduate students from various Universities for their research projects. Two students, Carla and Chris, from the Technical University of Dublin, carried out BSc projects remotely. Having in-house datasets and many more published in open access, their projects were focused on bioinformatics, re-analysing them and giving a second look. Both Carla’s and Chris’ research received the highest score in their classes. Many congratulations – well deserved!! We wish to thank both for their kind words and willingness to share their story.

Chris Sheridan, the final year student in Biomolecular Science at the Technical University of Dublin, 2021

My project concerned analysing the exosomal miRNA expression of neuroblastoma cells in response to chemotherapy. Though the project was not too large, it certainly was the largest project I have ever taken part in. The work Dr. Piskareva and her team are conducting is so interesting and novel that I felt very fortunate to be participating in such an exciting field. Despite the novel and complex nature of the topic, the project was extremely engaging, allowing for an opportunity to learn new valuable research and data analysis skills. I was able to get very useful and helpful feedback regularly from everyone on the research team, where there was a very welcoming and positive attitude. This made the topic seem less daunting and my goals more achievable. I was really happy with my results, and I am excited to see where they may lead in the future. Some of the miRNAs identified in the analysis may represent potential biomarkers or therapeutic targets for high-risk neuroblastoma patients. As I have yet to experience any lab-based research, it was cool to see the team’s approaches and applications of lab techniques and analysis strategies to see how research is conducted in the “Real World” after seeing these topics before only in lecture notes. Overall, the project was challenging but very rewarding and enjoyable. Throughout the project, the overall experience, the excitement of the results coming together, and the realisation that I may have something to contribute to this field of research cemented the idea in me that this is certainly the path I wish to pursue in science and for that, I would like to thank Dr. Piskareva and her team for such a positive and educational experience during my time with them.

Carla Tejeda Monné, the final year Technological University of Dublin Biomolecular Science Student, specialising in Biotechnology, Therapeutics, and Drug Development, 2021

During my final year project, I had the unique and amazing opportunity to work under the supervision of Dr. Olga Piskareva. The purpose of my thesis was to assess the clinical significance of Tumour Necrosis Factor Receptor Superfamily Member 1B and Member 4 (TNFRSF1B and TNFRSF4) in neuroblastoma patients. I accomplished this by analysing the gene profiles of several tumours using bioinformatic tools. In addition, I investigated the potential of microRNAs as therapeutic agents for neuroblastoma treatment. I thoroughly enjoyed carrying out this research project, and I hope the findings from my thesis can aid future research into the pathogenesis of neuroblastoma and the development of effective treatments for these children.

Best of luck to Chris and Carla in their next endeavour!

In the Spotlight at EACR Virtual Congress

In early April, shortly after attending the Irish Association for Cancer Research (IACR) virtual conference, I was delighted to find out I had been selected for a “Poster in the Spotlight” presentation at the European congress in June. I was invited to give a 10-minute presentation about my research on finding new immuno markers for drug-resistant neuroblastoma. This would be my first time presenting at a conference outside of Ireland (though I remained in my home in Dublin and not in the hoped destination of Turino) and so it was a very exciting experience!

On the morning of my talk, I logged onto zoom to meet the EACR session organisers and the other speakers in my session – a mixture of PhD students and Post-doc researchers from Germany, Spain, Italy and the UK. Each of our talks was then broadcasted to the virtual congress platform where cancer researchers around Europe could tune in.

After the presentations, we joined a “Meet the Speakers” session where we could chat with those who had tuned in, answer questions and open up some research discussions. I was asked one question from a researcher doing similar work to me on how I investigate the relationships between certain genes in cancer, and I was able to refer her onto the software I use – I hope this aids her research, as that’s the real aim of attending these conferences!

Following this, it was time to relax and watch some of the other interesting talks taking place in the congress. The EACR were running a photo competition to show where you were watching from in order to win a place at the 2022 congress in Seville. So, I took this opportunity to take my laptop out to the back garden and watch the congress in the sun, getting a selfie for twitter with #NotQuiteTorinoEACR2021. Fingers crossed by this time next year travelling for international conferences will be a reality for researchers once again!

Catherine Murphy, Neuroblastoma UK funded PhD student