Departure Lounge

It is 31st of January, the day Britain leaves the European Union, and two travelling companions on the flight from Manchester to Milan sit in silence. The arrival of in-flight meals, however, loosens our tongues and we discover that, despite our age difference, we have much in common. We both are teachers and we both were raised on an obscure north-western peninsula which juts out into the Irish Sea. We exchange reminiscences of football and convent schools in Birkenhead. She talks of her twin sister  who, like her, rebelled against the authoritarian nature of a school system that could not understand why a teenager would want to wear odd socks. I confide that, coincidentally, I am, in fact, wearing odd socks; something I do because it reminds me of my own daughter’s unconventional fashion choices.

She asks me why I am visiting Milan and I explain I am going to a conference.

‘Health,’ I say, evasively, a term less alarming term than cancer.

We part company as Ryanair offloads its passengers and we follow our separate paths into Italy's most fashionable city. As I finally arrive at the Marriott hotel, I read a notice explaining that Milan will ban all cars from driving within the city this weekend, a measure aimed at tackling high pollution levels. I check the time on my watch; it is after midnight GMT, which means that Brexit has finally broken.

Welcome to the 21st Century, I think.

Photos: ARTIS

The conference I have come to attend is for SPAEN, the Sarcoma Patients Euronet, a continental coalition of cancer patient advocacy groups, which is also well-connected with the research community and industry. The annual gathering therefore reflects a good range of lay and professional perspectives, and this year it has partnered with ESMO, the European meeting on adult oncology, which runs immediately afterwards in the same Milan location. 

The European epithet no longer adequately describes the global nature of the annual SPAEN event. Transatlantic connections are represented, not only through the US Sarcoma Coalition, but also the SELNET project which has extended links to Latin America as far as Chile. South Africa also makes its mark in a pre-breakfast (!) session, in which Lauren Pretorius lays down standards of excellence for patient organisations. Other stand-out sessions, from a patient perspective, include Amy Bruno-Lindtner, a language specialist from the University of Vienna, on ‘Techniques for sharing information in a patient-friendly way’ and psychologist, Lesley Storey, on the measures developed at  the University of Birmingham for reflecting patient experience. The comprehensive nature of the patient advocacy perspective, however, is probably best demonstrated by Roger Wilson’s paper on ‘The challenge of sarcomas,’ which offers an overview of developments in research, treatment and the wider care environment - well worth a read. 

A final indication of the can-do nature of this assembly is that my own session on age-inclusive research, late on the Sunday afternoon, is greeted with a commitment to adopt the FAIR Trials objectives as SPAEN policy, an offer also taken up by Sarcoma UK.

  Speakers at SPAEN: Kathrin Schuster, Chris Copland and  Ornella Gonzato*

The Sunday ban on traffic in Milan unfortunately fails to prevent smog enveloping Linate airport that evening, holding up flights out of the airport, including my own. Catching a connecting flight in Brussels therefore involves a half-K sprint  across the airport concourse. As I pursue a slalom course through the duty-free fragrance counters, it occurs to me that, although I am returning to the UK, I am not leaving Europe. For this weekend has brought home to me that Europe is not a political entity, but a state of mind - and one that I do not expect to lose any time soon.

* Photos: ARTIS

Cool is not the word

A lifelong Star Wars fan, Jeff Skolnik sometimes laughs that he has gone over to the 

'Dark Side.’ It is a joke commonplace amongst those who work in the pharmaceutical industry, a sector often treated with as much derision as tobacco manufacture or the arms trade. 

A physician at the Children’s Hospital of Philadelphia, Jeff has also held senior positions at AstraZeneca and Glaxo Smith-Kline, one of the biggest drug companies in the world. His career has not however, been so much about scrabbling to the top of the corporate sector but of trying to find his place in the complicated patchwork of private, public and philanthropic interests that make up medical research in the USA. Three years ago, he left GSK to join a tiny research outfit with a combined workforce of thirty people and he is now vice-president at another Biotech with a similar ‘small is beautiful’ ethos.

The Biotech sector enjoys a rosy image as the ‘counterculture’ of the life-sciences industry so I am interested to find out from Jeff, as an insider, the difference between the myth and the reality. Before we begin, Jeff explains that his opinions are his own, and don’t represent the Pharma or Biotech industries, or that of his current or past companies.  He made me say this, so I guess he is a little bit entrenched in that ‘Dark Side’ after all.

Sitting opposite him in a village coffee shop in Philadelphia, I begin with the  simple question, ‘What is the difference between Pharma and Biotech?’

‘Big Pharma,’ he explains, ‘involves tens of thousands of individuals working for a multinational corporation. Biotechs are  smaller and supposed to be more nimble. Their research is usually at an early phase focusing on a single product which is often not yet on the market.’

There is a more fundamental difference, which is people hear about Biotech and they think of venture capitalism. These companies are often funded by one or two very wealthy individuals wanting to quickly make a lot of money.’

I think it has always been the assumption that Biotech is, cooler is the wrong word, more innovative with their resources because they have less of them.’

People think of Biotechs generating new ideas while Pharma is selling old stuff. But that’s not really true. Plenty of Pharma companies have very robust Research  and Development pipelines. But some of them supplement their R and D by buying out small companies.’

To me one of the quintessential Biotech companies is BioMarin. It’s in the name. It’s based in Marin County, California, a place which has two things for which it is famous, one negative and one positive. The negative one is that it has one of the highest rates of unvaccinated children in the USA; it is located next to San Francisco, the historical epicentre of free thinking ideas. The positive thing is that it is the home of the Skywalker Ranch where George Lucas lives.’

BioMarin generates products for diseases for which there are literally single digit numbers of patients, which is not something a Pfizer or a BMS is going to do. How on earth does a company like BioMarin monetise that? They have an idea. They figure out how to bring it to patients, figure out how to generate revenue and they do it again.’

For some they are heroes because they develop drugs for patients for whom no-one else would generate.’

They are treating diseases for which the answer is far less complicated than for cancer. For diseases like that, if you can supply a missing enzyme, you can cure the disease, and you can charge $450,000 because your drug is literally life -saving. So that’s what they do.’

Companies like BioMarin, he explains, are more likely to apply for the vouchers the federal government offers as incentives for neglected areas of drug development. The US Food and Drug Administration gives priority to a company holding a voucher, which means it can get a product onto the market more quickly. In the world of pharmaceuticals, this can mean significant revenue, particularly as the voucher can  be sold onto another company to apply to another drug. Under the Creating Hope Act, the last voucher sale was for $350 million.

‘Smaller companies are aware of the opportunities a voucher can provide,’ says Jeff. ‘For a big Pharma company, that may be small potatoes but for a small Biotech that would make all the difference. $300 million is a big difference.’

Biotechs are squeezed between tight budgets and a high risk of failure. A start-up may focus on developing a drug from a single molecule and, should the research and development be inconclusive, the company will shutter. I thus ask Jeff what tempted him into this precarious world.

‘Larger companies have struggled with vision, with governance. Why the heck would you spend money on cancer medicine when ulcer medicine is much more profitable?

In a smaller space. If you can convince someone it’s a good idea and you can get funding for it, you can run with it. For me, it has been fundamentally different. I don’t present slides to a governance  body. I get to make decisions.’

In Biotech, you still have to return shareholder value or you don’t exist. We have a choice. We can run out of money and go out of business or we can make medicines that benefit patients’ lives and do it again and again.’

Eventually, I ask him, though do small companies not have to sell up to Pharma? If a Biotech develops a successful drug, does it not need to turn to a major company to manufacture and market it as a commercial product?

‘You don’t have to sell out,’ he says, ‘but at some point you have to scale up. What Big Pharma do best is they commercialise and sell molecules. Biotechs do the R and D better.  At some point, though, if you’re going to sell, by that I mean if you want to get the drug

 to patients, you need to get help, you need to cross over.’

In this world of board room deals, I ask, how can the community have a say so research does not just follow the money, it responds to patient need. Do vouchers make a difference?

‘I am absolutely not convinced the voucher programme has been the answer. There are a couple of successful examples but those drugs might well have been developed anyway.’

He does not show much more enthusiasm for the Race for Children Act that was recently passed by Congress and which places an obligation on companies to research the benefits for children of drugs being developed for adults. His preference, clearly, is for the carrot rather than the stick.

‘Are we  going to hit a company over the head,’ he asks,’ and say you’re going to make a drug whether you like it or not.? Or are we going to give them another shot on a programme with an adult cancer. It won’t generate much money. But rather  than it costing $350 million, we’re going to find a way that the study costs are negligible, regulatory costs are minimal and in return, the company can recoup its outlay.‘

Here, he is moving away from venture capitalism to venture philanthropy, where a charity or public body does not donate money to a research programme, it invests in it, with the proviso the public body gets a return if the project is successful, a return that can be reinvested in more new therapies.

‘For me, it’s all about risk share. It’s my drug. I’ll market it, sell it and make money on it. When I do, I’ll give you your investment back. I’ve argued that’s the best way to do it.’

For Jeff, this is not just about combining the public and the private, it’s about putting together research for adults and children. He talks about Gleevec, the first new agent that was developed for leukaemia, but one that reached adults long before it did children.

‘Why did it take so long to get this into kids?’ he asks. ‘The way we should have approached this from the beginning is that here there are two small opportunities (i.e. one  for adults and one for children); let’s put them together and make one big opportunity. Where there is overlap between the potential of a drug for adults and children, bring the age of entry to the trial down to twelve.’

Jeff and I are both, in fact, members of a working group that aims to do precisely that, make research more age inclusive. When I have presented on the topic I relate how, Chloe, the daughter of a friend was barred from a clinical trial because she was two months short of her eighteenth birthday. When she was old enough, the cancer had progressed to its final stage and soon after she died. One might expect the company that turned Chloe away to be a giant like Pfizer or GSK but that company was in fact BioMarin, a reminder that nothing is simple in the world of the drug industry.

Notes

You can find out more about Creating Hope and the RACE for Children Act from the advocacy group that got them on the statute book, Kids v Cancer.

Three sides of a triangle

It is Columbus Day, a public holiday in Washington DC, but Jeff Toretsky has been at work for several hours by the time he ushers me into his lab at Georgetown University. Clearly proud of the work they do there, he is particularly keen for me to see a small piece of desktop equipment resembling a budget photocopier. This is a Surface Plasmon Resonance Biosensor, he explains, and worth a cool half a million dollars. It is the only one in the world in the possession of a university and has played a pivotal role in his quest for a molecule that can split the cancer he has stalked for nearly all of his working life - Ewing’s sarcoma.

Jeff’s  first encounter with Ewing’s was as an undergraduate back in 1980. He still remembers the name of the friend and fellow freshman at Wisconsin University, who died of the the illness. Jeff was to come into contact with more Ewing’s patients, during his fellowship at the National Cancer Institute, so when he started his research career, ‘it seemed like Ewing’s would be a good place to go.’ A few months after Jeff joined his first laboratory, a French scientist, Olivier Delattre, published a groundbreaking paper identifying the molecular target at the heart of disease. From then on, as far as Toretsky was concerned, ‘the race was on.’

What Delattre had discovered was ‘one of the most highly specific molecular targets in all of oncology.’ This was the result of a translocation in the DNA, in which one chromosome had broken off and fused to another to create a chimera, a mutation which takes its name from a mythological beast with the head of a lion and tail of a snake. Delattre’s achievement had been to identify what the two chromosomes were (eleven and twenty two) and the chimera that was the result, EWS- FLI1. Twenty years on, I had come to Georgetown to talk to Toretsky about the drug he has developed to tame this beast.

I was interested in what he has done, not only for what it tells us about medicine, but for what it says about economics. His achievement has not been just to pinpoint a molecule that can shrivel the sarcoma; universities are, after all, littered with discoveries that never get further than the laboratory bench. Jeff has had the chutzpah to go beyond this and set up his own biotech to manufacture the drug and get it into clinical trials. His drug, TK216, is now well into a phase 1 study and showing promising results.

How has he succeeded where so many others have failed?

START-UP

He harks back several years to when Georgetown was first trying to commercialise TK216 or, in the form it then took,YK-4-279. He reels off the names with excitement, like they were characters in a Star Wars movie. Ewing’s, he explains, has far too few patients to arouse the interest of conventional pharma, so around 2009, he decided to form his own company. He started showing up at something Americans call ‘entrepreneur breakfasts,’ early morning gatherings where people with ideas can hook up with people who have money. Soon he had put together a team.

‘I thought I was doing great, but I didn’t really know what I was doing. Worse than that, they didn’t know either.

‘Then this guy, Scott Glenn, got in contact.

‘He was a very successful start-up entrepreneur from San Diego. And we talked almost daily for a month about what we wanted to do. And it finally came down to two things: he knew what it was to take a company from an idea to a funded entity; and he had a rolodex of people he had already engaged in business ventures.

‘He flipped the lights on in the company on January 1st 2010. Within six  months, he had raised enough capital to get the initial studies off the ground. The discovery was only first published in 2009 and, despite all the difficulties, our clinical trial was ready to go in January 2016. I have to pinch myself sometimes. That was just 7 years.’

Apart from anything else, I ask him, how did you cut through all the red tape?

‘A lot of people think it is the government bureaucracy that holds research up,’ he replies. ’In our case, the Food and Drug Administration  was absolutely A+ smooth. The FDA had the paperwork on their desk for less than one month before we were  approved.

‘The FDA required the first three patients to be age eighteen. And what was truly remarkable was they allowed us to go to twelve after that, because of the population with Ewing’s Sarcoma.

The few things FDA asked for were because they knew we were going to children that age  in the next cohort. They wanted us to have higher purity material, and we were happy to do that in order to get this trial going.’

THE TRIANGLE

Toretsky explains how they got so far so fast in terms of a simple model -  a  triangle. The first side of this, he explains is government. In 2009, President Obama signed into law the Recovery Act, in response to the ‘crash’ of the year before. In this initiative, Obama offered  a bolus of money to different sectors of the economy, including pharmaceuticals. Toretsky was one of two recipients of RC4 grants from the National Cancer Institute and received $4 million towards his work on EWS-FLI1. This grant was pivotal, he stresses, because it allowed him to do studies that could persuade someone like Scott Glenn that this was a project with potential.

Jeff with Presidents Obama and Washington

He was only able to win the $4 million grant, though, on the basis of results from primary research over several years funded by small charities like the Children’s Cancer Foundation of Baltimore. This funding had been precarious to say the least; CCF, was run out of the basement of the townhouse where its director, Shirley Howard, lived and it literally had no overheads.

‘Shirley was in her 70’s at the time and  started giving me small grants of about $100 - 150,000 a year. This five to six  years support allowed me to do all the preliminary work, including the screening. Nobody else would give me a grant for this crazy idea I had which was  to keep these two  proteins apart and find a drug to do it.’

This kind of contribution made up the second side of the triangle - philanthropy. He acknowledges though that the haphazard nature of such funding can be a challenge.

‘There’s a Ewing’s sarcoma charity in virtually every town,’ he says. ‘None of them raise enough money by themselves to have a major impact. There’s a guy called Bruce Shriver, who lost his own daughter to Ewing’s, and he had this interesting idea of reaching out to these small organisations and bundling them into bigger proposals.’

He makes a comparison with cystic fibrosis, which has a strong national presence and which has been used as a model for how to raise money, have an impact on a disease and get a return on investment.

Moving on to the third side, business, he begins by voicing his disillusionment with Big Pharma.

‘The only pharma company that I know that’s doing active Research  and Development at the basic scientific level is Novartis. It’s not like it used to be. I know a lot of scientists who got laid off from other companies who closed down their R and D operations, again at the level of basic science. I don’t think the novel ideas are going to come out of Pharma, they are going to come out of academics.’

In Toretsky’s triangle, the people that researchers should therefore go to if they want to get drug discoveries manufactured and on the market are the small start-ups, like Oncternal Therapeutics, the company he set up with Scott Glenn.

But how, I ask, were investors persuaded to put big money into such a small venture. He comes back with an unscientific reply.

‘Simple answer. Scott Glenn. He is an angel.’

Glenn had the vision to set up a company with a social goal that could only be achieved in the long term. But on top of the idealism, he also had the business acumen to persuade hard-headed investors that this long shot was worth the risk. Toretsky explains how this can be made to work in this unusual corner of venture capitalism.

‘The investors  know in the back of their minds that they are going to make, say, ten  investments like this and if one works out, they are happy. But when one hits, it often hits really big.’

THE BIGGER PICTURE

Is his drug, TK216, going to be the big one then, I ask him, at least for Ewing’s Sarcoma? How does it compare with all the other long shots of the past decades at one of cancer’s most intractable illnesses?

‘One of the issues is toxicity,’ he replies. ‘If you can’t survive the treatment, it won’t cure you. One of the reasons that I started to develop the drug that I did was my belief that if you targeted EWS-FLI1, we wouldn’t cause as many side effects. And as we learn more about it, we’ll just have to hope and see.’

Then he says something to suggest that this is something bigger, that this phase 1 trial is significant beyond the world that he and I inhabit, the tiny, lonely communities of those caring for children with an illness no-one else has ever heard of.

‘You know, I believe that, in the history of science, some of the best discoveries were made by the simplest scientific models, which were extrapolated to other things.’

As Delattre had acknowledged in his original study back in the nineties, the simplicity of the translocation in EWS-FLI1 not only makes this target easily identifiable but one which can teach us about more complex chimeras.

‘My excitement is that we are looking at our inhibitor having effect in other diseases. Francisco Bertoni, a collaborator has found activity of our drug in hard to treat lymphomas and I’m very excited about that. We’ve found pre-clinical data in some other models too. Although the work has been in Ewing sarcoma, we’re beginning to see benefits outside of that as well.’

If Toretsky is right, Ewing’s children could thus start to emerge from the shadows. For investing in them might not only, as with Obama’s Recovery Act, pump-prime a key part of the economy, it could also bring hope to patients, both young and old, with other cancers. If you join up the molecular dots in Toretsky’s imagination, Ewing’s suddenly becomes everybody’s business, its cure a cause in which we all have a stake.

Special Relationship: Jeff with British scientist, Sue Burchill, at the Euro-Ewing's meeting in London where he spoke this January to European researchers about TK216.

You can read more about the Toretsky Lab here:

http://toretsky.georgetown.edu/

His paper on the new drug, YK-4-279, is published here:

Zöllner, S.K. et al., 2017. Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma. Science signaling, 10(499). Available at: http://dx.doi.org/10.1126/scisignal.aam8429.

The website of Oncternal Therapeutics, the company that is developing the drug is here:

http://www.oncternal.com/index.htm

Background on Delattre’s original discovery is outlined here:

Longtin - Journal of the National Cancer Institute, R. & 2003, 2003. Ewing’s sarcoma: a miracle drug waiting to happen? academic.oup.com. Available at: https://academic.oup.com/jnci/article-abstract/95/21/1574/2520536

Postscript

'If you save one life, it's as if you save the world.'

Paraphrased from the Talmud

Dramatic developments during the phase 1 trial of TK216 are related in this recent Business Wire story. 

This is a presentation Dr Toretsky gave in Autumn 2020 for the Ari's Bears charity. Adapted for the general public, this talk is delivered in Plain English (American?) and is thus an easy to follow narrative of his work so far.

Video

Bitter Oranges

Marisa points out the landmarks on the city skyline and I am just able to make out the glint of the wings of the Vittorio Emanuele monument.  We are only the other side of the river from the Capitoline Hill, but from the refuge of this roof terrace, the frantic clamour of the centre of Rome seems many miles away. La Casa di Peter Pan is sheltered by the leafy slopes of the Janiculum Hill and lies on the edge of the city’s Botanic Garden, though, as Marisa explains, their more immediate neighbour is the men’s prison.

She indicates the shuttered windows of the high brick building opposite.

 ‘Do you ever visit your neighbour?’ I joke.

‘Oh yes,’ she replies. ’The governor invited me to speak there, after the prisoners gave money for the Casa.’

The House of Peter Pan has had a remarkable effect on many lives over the years, not just in its immediate neighbourhood but across Italy and beyond.  Since it opened its doors in 1994 to children coming to Rome for treatment for cancer, more than 600 families have been accommodated in the House, all gratuito - free of charge. 

There are now 33 ‘living units,’ purpose built accessible apartments, situated in the Casa and two adjoining buildings. Hospitality extends beyond shelter to the provision of community for families facing the trial of their lives far from home. The communal kitchens are a good example; each has six ‘work units’ with cookers grouped in a block of six in the middle of the room, so that residents face each other when they are preparing food and thus, by design, are brought together.

Everything is spotlessly clean, the kind of cleanliness necessary for patients whose immune systems have been compromised by chemo or radiotherapy. Children return to the Casa between bouts of hospital treatment and indeed there are facilities for some to be treated on site. There are common play and activity areas; an art and craft centre with a kiln for firing clay, a ‘chill-out room’ for teenagers which offers  computers, a plasma screen and a place to escape.  Italian lessons are provided for those who don’t speak the language, for patients do not just come from other regions of Italy but from across Europe and the world.

‘There are many Romanians,’ explains Marisa and she is obviously proud that they have hosted a little girl from China and a boy from Iraq.

Nine  salaried staff organise services and co-ordinate the support of a network of 150 volunteers. She shows me the bedroom for the pipistrelli, the shift members who stay overnight. There is someone on call, she explains, 24 hours a day, 365 days a year.

‘Even on Christmas Day?’ I ask.

‘On Christmas Day, I am the pipistrello, ‘ she declares.

Marisa and I have known each other for four years. Although we are of different generations and nationalities, we have a mutual bond; we both lost children to the same rare illness, Ewing’s Sarcoma. We first met at a conference in Sweden on childhood cancer, where she recalls she was shocked when I explained in a presentation how little improvement there had been in cure rates for Ewing’s. This was not just since my daughter had died less than ten years before but since the loss of her son back in the 1980s.

As we sit drinking cola in her office, she explains how her boy, Emanuele, was the inspiration for the Peter Pan project. He had been diagnosed with Ewing’s when he was twelve and when the option for experimental treatment from the United States arose, they took the opportunity. The gamble appeared to pay off.  His cancer went into remission and, after five years, it was assumed he was in the clear.

With Ewing’s, though, nothing is ever simple and the following year, the cancer returned. Once again, they turned to the United States and Emanuele was offered a bone marrow transplant in Minnesota. Again the family raised the finance, but they would not have been able to accompany him if they had not been given a place in ‘Ronald McDonald House,’ purpose-built accommodation provided free by the fast food corporation.  She remembers Emanuele asking her why there couldn’t be something like this in Italy.

After his death, the question wouldn’t let her go and she set herself the task of creating a similar facility in Rome.  Working with other parents, she went about raising the money to buy a suitable property. The obvious starting point was with MacDonald’s. She sweet-talked a sympathetic local executive into offering financial support and made a bid for a suitable property. However, with three days to go to sign the documents, she heard the executive had been moved on and the funding was being withdrawn. But Marisa, being Marisa, went ahead and signed anyway, even though she did not have the money to cover it.

‘It might have been you in the prison!’ I laugh.

‘I don’t think so,’ she says. ‘But they could have taken my house and put me on the street!’

I suggest that perhaps it is all for the best for now they have their independence. She nods.

‘All these years, I would have had a big ‘M’ hanging over me,’ she says and makes the sign of the arches above her head and shudders.

She shows me a photograph on the wall of the original building, a derelict art school daubed with anarchist graffiti. Money was raised for renovation in one way or another and when the House finally opened, instead of calling it after a fast food clown, they used the name of the character from the children’s play, Peter Pan.

She walks me around the premises, showing me the veneer mosaic of Captain Hook that the workman who laid the block wood flooring insisted on adding as a finishing touch. On the walls are framed prints of the original Edwardian illustrations from the J.M. Barrie play and there are, of course, the inevitable friezes of the characters from the 1950s cartoon.

There is an element of the disneyfication that exists in many projects for children with cancer but there is no sentimentality here. Marisa emphasises that the Italian word in the foundation’s title, Onlus, does not mean charity; it is something more business-like than that. We struggle for a translation and I suggest ‘not-for-profit enterprise.’ Supported by a government scheme which allows Italian taxpayers to select which good causes should benefit, Peter Pan Onlus now has an annual expenditure of around one million Euros.

We continue our tour up the hill to the garden, which the convent allows them to use as a playground.

‘So you get help from both convicts and nuns?’ I ask

 ‘The nuns charge us rent,’ she points out. ‘But they do give us bitter oranges from their orchard, which we make into marmalade and sell.’

We pass two small boys in grey tracksuits running down the hill. She exchanges smiles with the parents who are walking in tow.

‘They are Romanians,’ she explains.

I ask her about the mechanisms that enable children from other countries to be treated in Italian hospitals. She gives a vague answer about EU arrangements but I get the impression she is not very interested in the politics of it.  These are simply people like ourselves who need help and she is going to make sure they receive it.

I continue following her up the hill, past an arbour of roses, while Marisa mutters to me about Brexit.

It is estimated that survival rates for children with cancer are 10 – 20% lower in Eastern Europe, a disparity which becomes even greater for forms of the illness that already have poor outcomes[1]. Although minimum standards of care are now set for all health services in Europe, it is recognised that there is still a need for referral to specialist centres within EU member states and across borders. It is within this context that the work of associations like Peter Pan Onlus remains so important.

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[1] SIOPE Strategic Plan 2015