Impact case study database

Anal cancer is diagnosed in over 4,300 patients per year in Europe and 8,600 in the United States and its incidence has increased by 75% in the last three decades. It is predominantly a pelvic disease with a relatively low rate of metastases, where successful local treatment to eradicate the disease and to prevent recurrence is of crucial importance to achieve long-term survival. The progressive improvement in radiotherapy technique, influenced by the findings from Sebag-Montefiore’s research, has led to substantial patient benefit by reducing severe acute treatment-related side effects, avoiding interruption in radiotherapy, ensuring the full dose delivery of radiotherapy and chemotherapy, resulting in high rates of locoregional control and overall survival.

The shrinking field radiotherapy approach was used in the Cancer Research UK ACT2 trial co-led by Sebag-Montefiore. It is the largest global phase III randomised anal cancer trial and recruited 940 patients between 2000 and 2008. 75% of patients completed planned radiotherapy and delays in treatment of 7 or more days occurred in 15% of patients. 3-year progression free survival was 71% and overall survival 83%, compared with 65% overall survival in ACT1. In 94/940 patients a delay in overall treatment beyond 42 days resulted in 78% 3-year overall survival.

As anal cancer is relatively uncommon and in the absence of detailed treatment guidelines, centres in the UK and internationally used the ACT2 radiotherapy protocol in their routine clinical practice and this remained the standard treatment approach for more than a decade.

Increased uptake of IMRT improves health outcomes

The UK adoption of IMRT is evidenced by a publication of a Royal College of Radiologists audit led by Sebag-Montefiore and colleagues [ A]. Performed between February and July 2015, 242 cases from 40/56 UK radiotherapy centres were analysed. This is the largest published prospective multicentre experience of IMRT in routine clinical practice. The UK IMRT protocol was used in 65% of cases, the remainder using the ACT2 protocol or a modified IMRT approach. Using IMRT the planned radiotherapy dose was delivered in 96% cases and radiotherapy interrupted in only 4% of cases, representing a substantial improvement compared with the ACT2 trial outcomes.

Overall, 41% of IMRT-treated patients experienced severe grade 3/4 toxicity. One-year survival was 94%. One-year patient reported outcome assessments of the IMRT treated patients found significant improvements in buttock pain, blood and mucous in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. There was no evidence of clinically significant deteriorations at one year for diarrhoea, bowel frequency, and flatulence [ B, C].

IMRT has dramatically impacted on the lives of anal cancer patients internationally, resulting in substantial reductions in the acute toxicity of treatment and the avoidance of interruptions in radiotherapy treatment delivery that are associated with worse survival outcomes [ D, E, F].

Further evidence of implementation of IMRT in routine clinical practice in the English NHS is provided by the National Cancer Registration and Analysis Service, Public Health England. Prior to publication of the protocol IMRT was used in 13% of all anal cancer patients. This increased steadily to reach 78% by 2019 [ G].

Inclusion of IMRT in national and international guidelines

The national and international reach of the shrinking field technique and IMRT is evidenced through direct reference in national and international guideline documents.

The Association of Coloproctology Great Britain and Ireland (ACPGBI) guidelines [ H] for the management of cancer of the colon, rectum and anus state:

“Definitive CRT is the standard treatment for all anal cancers that are not amenable to local excision…and the minimum radiation dose for microscopic disease should be 40 Gy in 28 fractions over 5.5 weeks using IMRT or 30.6 Gy in 17 fractions over 3.5 weeks using the original ACT2 protocol.”

They further state: “IMRT should be considered for all patients in whom definitive CRT is intended, in order to reduce acute toxicity and possibly late toxicity. Standardization of radiotherapy volume outlining, planning and delivery should be based on published consensus guidelines…A UK consensus document for outlining, planning, dose objectives and constraints and dose delivery is available on-line at http://www.analimrtguidance.co.uk/. This consensus has taken into account the excellent results achieved in the ACT2 trial, together with a review of radiotherapy planning and dose delivered to patients in the trial and has resulted in an adaptation of the recommended dose prescription.”

The European Guidelines of the Medical Oncology, Surgical and Radiotherapy Organisations (ESMO-ESSO-ESTRO) guidelines [ I] cite the ACT2 dose and radiotherapy technique and provide it as an example regimen of curative CRT for anal cancer. The United States National Comprehensive Cancer Network (NCCN) guidelines for anal carcinoma [ J] cite the ACT2 trial outcomes, noting that “the absence of a planned treatment break in the ACT2 trial was considered to be at least partially responsible for the high colostomy-free survival rates observed in that study (74% at 3 years).”

The IMRT solution has been integrated into the CRUK-funded UK PLATO platform trial protocol, which aims to optimise radiotherapy dose for anal cancer patients with low-, intermediate- and high-risk disease. Sebag-Montefiore is Chief Investigator and has recruited over 400 patients to date in this uncommon disease. The trial platform includes three anal cancer trials (ACT) 3,4 and 5. The above IMRT technique is used to allow the ACT4 trial to test the benefit of de-escalation of radiotherapy dose in early stage disease and ACT5 trial to test the benefit of dose escalation in locally advanced disease.

CAD is a leading cause of death and disability worldwide, and the leading single cause of mortality in Europe, responsible for 862,000 deaths a year (19% of all deaths) among men and 877,000 deaths (20%) among women. In the UK, there are an estimated 1.98 million people suffering with symptoms of angina, and CAD costs the UK economy GBP9 billion a year. Our CE-MARC trial provided the largest real-world evidence of the diagnostic accuracy of CMR, its prognostic ability and cost effectiveness, showing superiority over the current NHS reference standard. As a result, CE-MARC provided the evidence base leading to the first inclusion of CMR into international clinical guidelines for chest pain investigation (European & US). This contributed to CMR for stable CAD detection being rapidly introduced across the NHS.

Inclusion of CMR for the first time in international guidelines

The CE-MARC trial results underpin the high level of evidence (Class 1) and are cited to support the use of CMR for stable chest pain investigation in the European and US clinical guidelines. US guidelines on appropriate use criteria for the detection and risk assessment of stable CAD cite the CE-MARC trial as evidence supporting the utility and accuracy of stress CMR [ A]. European guidelines on the management of stable CAD cite the CE-MARC trial as evidence for the diagnostic accuracy of CMR perfusion imaging compared with MPS [ B]. Additionally, Greenwood is on the writing committee for the 2021 AHA/ACC/ASE/ASNC/ CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain. Notably, this writing group is normally comprised of American experts. Greenwood was invited to be a part of this group in view of “professional standing, expertise, and track record of managing patients with chest pain, which was superior to any other colleagues in the US and indeed globally” [ C]. The results of CE-MARC and CE-MARC 2 have been cited as underpinning evidence to support the recommendation for stress CMR to be used as an effective frontline investigation in the diagnosis of stable chest pain.

The CEO of the Society for Cardiovascular Magnetic Resonance has acknowledged the “ground-breaking” CE-MARC and CE-MARC-2 trials, which have significantly impacted the practice of cardiology globally, saving money to healthcare systems, reducing patients’ risk and improving patients’ quality of life on clinical cardiology practice and improving patients’ management using CMR globally [ C]. The significant contribution the trials have had on international guidelines for the management of chest pain has also been emphasised:

“Stress CMR is now recommended in Class I (which means there is evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective) with the level of evidence A (which means the data is supported by randomised trials). Class IA is the highest level of recommendation and evidence in ESC/AHA/ACC guideline documents. Guidelines from leading scientific societies such as the European Society of Cardiology are the reference documents that cardiologists in Europe and worldwide use to guide clinical practice” [ C].

Cost-effectiveness of CMR over other diagnostic strategies

The availability of a more accurate diagnostic test reduces the need for down-stream investigations, including expensive invasive coronary angiography. Health economic analysis of CE-MARC showed that CMR was more cost effective for the NHS than MPS-SPECT (which was the prior clinical reference standard). The results from this economic evaluation suggest that CMR should be considered as part of a diagnostic strategy for the identification of patients with CAD suitable for revascularisation.

Economic evaluation of CE-MARC 2 to assess the cost-effectiveness of CMR, MPS and NICE guidelines showed CMR had the highest estimated quality-adjusted life year (QALY) gain overall (2.21 (95% credible interval 2.15, 2.26) compared with 2.07 (1.92, 2.20) for NICE and 2.11 (2.01, 2.22) for MPS) and incurred comparable costs (overall GBP1625 (GBP1431, GBP1824) compared with GBP1753 (GBP1473, GBP2032) for NICE and GBP1768 (GBP1572, GBP1989) for MPS) [ D]. Overall, CMR was the cost-effective strategy, being the dominant strategy (more effective, less costly) with incremental net health benefits per patient of 0.146 QALYs (−0.18, 0.406) compared with NICE guidelines at a cost-effectiveness threshold of GBP15 000 per QALY (93% probability of cost-effectiveness).

Data from CE-MARC and its economic model have also been used internationally to show CMR cost-effectiveness, e.g. in Switzerland [ E] and Australia [ F].

Dramatic uptake in stress perfusion CMR services across UK

Results from the CE-MARC and CE-MARC 2 trials showing the high diagnostic accuracy and cost effectiveness of CMR have directly impacted on NHS practice. This is evidenced by the dramatic uptake in stress perfusion CMR services across the UK and also uptake in Europe/globally.

In 2008, survey data revealed 20,597 CMR scans were performed in the UK. This compares to 114,967 scans in 2018, representing a remarkable 5-fold increase over 10-years. Additionally, 100,386 scans were performed in 2017, representing a single year increase of 14.7%. In total, ~24% of all UK CMR was for CAD [ G]. When focusing on a single Trust, Leeds Teaching Hospitals confirmed that the number of CMR scans has dramatically increased by 135% in the last 10 years (1001 scans in 2010 compared to 2348 in 2020), while numbers of MPS activity have reduced in support of a shift in referrals based on the CE-MARC and CE-MARC-2 trials (1715 scans for the 2014-15 financial year, compared with 1021 for the 2019-20 financial year) [ H].

The European CMR Registry (EuroCMR) with over 37,000 patients from 57 European centres has demonstrated the impact of CMR on clinical diagnosis and management in Europe. The US multi-centre SPINS registry has shown that CMR in stable chest pain syndromes was a highly effective prognostic test associated with low healthcare costs spent on downstream cardiac testing [ I].

The burden of RA is of great economic significance. Treating RA costs the NHS an estimated GBP560M per year. The estimated costs are as high as GBP3.8 billion per year with the inclusion of nursing costs and private expenditure, while the costs associated with sick leave (up to 30 days per patient) and work-related disability are GBP1.8 billion per year. It is estimated that 90% of the overall rheumatology health budget is spent on biologics drugs for just 10% of patients. New patients using biologics increase yearly, hence the urgent need to establish new tools to stratify patients in order to: (a) use less expensive therapies to induce remission as early as possible; (b) limit costs of drugs when no longer necessary (once remission is achieved) while maintaining patients’ quality-of-life.

The translational research delivered by Leeds has transformed the current management of RA from diagnostic/prognostic uncertainties (prescribing drugs with a “trial-and-error” approach) towards true precision medicine.

Impact on technologies

Imaging technology is one of the flagships of UK musculoskeletal research, while imaging biomarker research has been a strength in Leeds for over two decades. Since 2010, Leeds has provided leadership and professional representation in international organisations - notably within the European League Against Rheumatism (EULAR) with presidency and chairing of executive committees and taskforces ( Emery), and within the international Outcome Measures in Rheumatology Clinical Trials group ( Emery/Conaghan/Wakefield). Leeds was instrumental in establishing the technological gold standards needed for reproducible evaluation of RA worldwide [ 4].

Immunological biomarkers: Following the discovery of dysregulation of certain circulating CD4 and T-cells subsets in early RA ( Ponchel/Emery/Conaghan), a novel stratification tool for managing RA was developed using flow cytometry technology [ 5, 6]. We transferred this technology to the LTHT immunology service (2014), which has demonstrated the feasibility and value of all blood tests being performed in NHS routine settings [ 5]. These data leveraged the design of two studies: (i) an industry sponsored trial randomising patients for standard-of-care versus biological therapy based on a low/high T-cell risk; (ii) a protocol integrating patients into the decision for tapering of therapy based on good prognostic using imaging and T-cell biomarkers. [Both studies were delayed due to Covid-19 although both have now restarted.]

Impact on health and welfare

Our research led to the development of effective treatment pathways for RA, improving patients' quality of life. Leeds demonstrated the need for and impact of early aggressive strategies (the T2T model) in RA (2007-2014). The T2T model was universally adopted in Europe (2016) and in the UK (2018), generating novel National Institute for Health and Care Excellence (NICE) guidelines for standard-of-care [ A, D].

According to Emeritus Professor and Emeritus Chairman, Department of Medicine, Medical University of Vienna, and former EULAR President:

*“The dissemination of this approach has dramatically transformed the way RA is treated in the UK and internationally. It allowed rheumatologists to understand the importance of having the right treatment target (i.e. remission)...The ways in which RA is managed and treated today, undoubtedly would not be the same if it were not for Paul Emery’s commitment to RA patients and his leadership in the T2T Steering Committee [ A].”*

The T2T model has transformed the care of RA patients across the globe. We ensured the work had maximum impact by creating an international clinical fellowship programme in Leeds, hosting over 20 delegates (including professors and clinical fellows) from many countries. Visitors who attended the programme provided positive feedback, stating how the learning acquired in Leeds has changed rheumatology clinical practice in their countries of origin [ E]:

• One delegate from Japan testified that the training was later applied to clinical practice in Japan. They stated that clinical practice in Japan was advanced as a result of integrating imaging techniques into the implementation of T2T strategies with anti-rheumatic drugs including biological agents [ Ei].

• A delegate from France stated that during their time at Leeds, they were trained in a medical technique that could not be learnt in France: arthroscopic synovial biopsy for patients with chronic inflammatory rheumatism. They also testified that the advancement of their career (i.e. professorship) was directly related to the experience they gained in Leeds and multiple continued collaborations since then [ Eii].

• Another visiting professor from France stated that they could directly apply the standardised approach to RA care learnt in Leeds, integrating imaging research into the clinical pathway for patients in France. As a result, they were able to initiate several research programmes focused on ultrasound in RA, Scleroderma and Psoriatic Arthritis. Furthermore, this experience directly contributed to their career progression and appointment as head of a rheumatology institute in Rome (August 2020) [ Eiii].

The most evident beneficiaries of this research are patients with early RA (about 25,000 new cases per year). Nevertheless, ~40% of patients do not achieve the T2T goal with NICE approved drugs. Our immunological biomarker research has produced a new tool to identify these patients [ 5], enabling tailoring of standard-of-care (i.e. current T2T) versus a more aggressive therapy for poor prognosis patients (ongoing TEEMS trial, delayed by Covid-19 pandemic). The creation of remission clinics has allowed such patients to become part of the decision to taper their treatment. The Leeds prospective joint research/NHS remission clinic (2016) has ~60 patients in remission per month, is run by two clinical nurse specialists (CNS) (one research, one NHS), and is overseen by a dedicated research fellow and a consultant ( Emery) [ F].

Leeds Biomedical Research Centre (BRC) is an international centre of excellence in musculoskeletal disease research that provides infrastructure supporting research based on NIHR grant income (partnership between LIRMM, University of Leeds, and LTHT). Since its inception it has received GBP20 million in funding. Patients within the Leeds BRC set-up are in direct proximity to our research facility. We run PPI groups and organise events to allow the public to contribute to basic science research [ G]. During our PPI events, patients visit our laboratory facilities while our staff/students demonstrate the use and value of several techniques and pieces of equipment. This set-up has improved our patient-researcher relationship, allowing us to include PPI groups in refining clinical objectives.

Impact on public policy and services

Leeds research was instrumental in informing the creation of national (NICE guidelines) and international guidelines (EULAR guidelines) around the early management of RA [ B, D] and once remission is achieved (American College of Rheumatology guidelines) [ H].

Emery was a key member of the International T2T Steering Committee (sole UK representative), which has developed 10 recommendations aimed at informing patients and rheumatologists about the T2T model to reach optimal outcomes early in the RA disease course (2010-2013). The committee met regularly over the REF2021 assessment period and amended the recommendations considering new research, and directly involving patients’ contributions, which emphasised the importance of a shared decision-making process. The Steering Committee was instrumental in changing national/international guidelines. For example, their recommendations were incorporated into EULAR international guidelines in 2016 and UK NICE guidelines in 2018 [ A, B, C, D]. The NICE guideline additionally provides recommendations around monitoring RA after achieving the T2T (i.e. remission).

For patients in remission, the previous practice was to continue drugs but some drugs have significant side effects and high costs. Emery contributed to the establishment of an international agreement on the clinical rational for discontinuing drugs. In 2013, an international EULAR imaging taskforce was initiated ( Conaghan, leader and UK representative) and this provided guidance for the management of RA (2016-2017) [ 4]. Our work on defining the depth of remission with imaging and T-cell biomarkers [ 4, 5, 6] led to the discontinuation of the use of drugs which were no longer necessary but had potential side effects (notably biologics). Our work also incorporated imaging of the joints in the clinical pathway (2017, Wakefield). The EULAR guidelines were revisited by the taskforce, and updates released in 2017 [ 4].

In 2015, following consultation with Emery, the American College of Rheumatology released recommendations for the treatment of RA patients in remission where the tapering of drugs (notably biologics) was outlined [ H].

The LVM has produced three types of impact in three areas.

A. New digital pathology products

Software: The LVM research produced intellectual property spanning novel software [ 3,4,6], know-how and patents (US8970618; EP3489733). That intellectual property was assigned in 2016 to Roche-Ventana [ A] for a value that cannot be disclosed. Roche is a top 3 laboratory vendor (turnover GBP45 billion, 94,000 employees), with commercial distribution in over 100 countries and established relationships with anatomic pathology laboratories with over 50% market share worldwide [ B].

The LVM was the basis of a fundamental redesign of the entire Roche digital pathology system in 2016-2018 to provide users with “ an innovative and intuitive way of interacting with their digital pathology cases” [ B]. Treanor and Ruddle acted as consultants during the prototyping and detailed design phases for the new software (2016-2017) and were part of its beta-testing team (2018). Since the software’s commercial launch as the uPath digital pathology enterprise software in 2019 [ C], Roche have issued over 100 active uPath licences in Australia, Europe, the USA and other countries [ B].

Scanner hardware: FFEI (a British Small & Medium-sized Enterprise) are the Original Equipment Manufacturer (OEM) developer and manufacturer of the Roche DP 200 scanner, which is an integral part of the Roche’s uPath system and compatible with the LVM. In 2012, FFEI started discussions with Leeds about the LVM, under a non-disclosure agreement. The “ market established by LVM//uPath” helped FFEI secure internal and external investment to fund new imaging technology developments, upgrade R&D and production facilities, and retrain staff, driving their future business strategy [ D].

FFEI have supplied WSI devices to over 27 countries in North and South America, Europe, the Middle East and Africa, and the Asia-Pacific region. From 2016-2019 their revenues from medical imaging grew from 20% to 50% of total revenue (GBP12,000,000 per annum), and FFEI expect this trend to continue and include “ direct-to-market products as a diversification of FFEI's current OEM business model” [ D].

B. Influence pathology practice

The LVM underpinned pathology going fully digital in 2018 at the Leeds Teaching Hospitals NHS Trust (LTHT). LTHT is a major cancer centre and tertiary referral pathology laboratory serving a population of 3 million people, and England’s second largest acute hospital trust.

After pilot evaluations during the LVM development [ 3,4], LTHT chose the LVM as the digital pathology platform for a 15,000-slide validation study ( https://doi.org/10.1111/his.13403) that directly led to national Royal College Guidelines for the pathology profession (Jan 2018; https://www.rcpath.org/resourceLibrary/best-practice-recommendations-for-implementing-digital-pathology-pdf.html).

When LTHT pathology went digital, the LVM was rolled-out to the entire department. Benefits include efficiency (“ really speeded up interpretation and turnaround times of some of the most complex cases”), understanding of disease “ much clearer appreciation of low power distribution of the interstitial abnormalities”), reducing delays for patients (“ more timely delivery of second opinions between hospital sites”), and organisational change (“ allowed us to reframe our thinking around future Cellular Pathology strategy for the region”) [ E].

C. Shaping research & development programmes

As well as Roche and FFEI, the LVM also shaped the R&D programmes of two other companies under non-disclosure agreements.

Display hardware: Barco dominates the global medical display market ( https://www.marketsandmarkets.com/ResearchInsight/medical-display-market.asp). From 2012, the LVM team worked with Barco and gave privileged access to research results. Barco gained confidence that “ ultra-high definition medical displays made sense commercially” [ F], invested in developing a new product to double display resolution (to the 12 megapixel Coronis Unit) that thousands of doctors now benefit from, and in 2017 started a four-year project to develop a new collection of high-resolution pathology displays. Barco draws parallels between the MIT Media Lab and the way the LVM team “ had a visionary idea … quickly assembled a real working example, and sat people in front of it to see what it looked like” before “deploy[ing] it in a hospital to see how it should be improved” [ F].

Pathology software: The LVM influenced the Swedish multinational Sectra Ltd, whose products are used in 2,000 hospitals and clinics around the world. The LVM provided Sectra with “ two foundational insights”: (i) “ it was possible to develop a digital viewer with performance matching diagnosis with a conventional microscope, which was under much debate at the time”, and (ii) there was “ great potential” for digital diagnosis to go “beyond what was possible in the traditional microscope”. This “ had a great positive influence on the Sectra business decision to invest and start a branch in pathology” [ G].

The LVM’s success cemented Leeds as the go-to place for digital pathology R&D, evidenced by the Leeds-led National Pathology Imaging Collaborative (NPIC) [ H] (GBP30,000,000 Innovate UK/ GBP11,000,000 industry funding and Leeds Centre for Doctoral Training (GBP6,000,000 UKRI funding) in Artificial Intelligence for Medical Diagnosis and Care [ I]. They include Roche, FFEI, Sectra and NHS England as partners.

This research, jointly conducted with Professor John Burn (University of Newcastle), resulted in impacts on health benefits and policy change [ A]. The UK has an estimated 175,000-200,000 Lynch Syndrome patients; about 62% of this population is aged 30 years or above (according to Gov.UK). Therefore, they are in the risk period for colorectal cancer; that is approximately 110,000 people with LS across the UK. Far fewer are known at this time because genetic testing is currently only conducted on those with a notable family history, but this will change as genetic analysis becomes routine. Patient groups such as Bowel Cancer UK (www.bowelcanceruk.co.uk\) and Lynch Syndrome UK (www.lynch\-syndrome\-uk.org/\) encourage patients with a family history of CRC to seek advice from geneticists and support the dissemination of the findings to the public [ B].

Impact on Policy

Most direct is the beneficial effect on LS patients who can combine aspirin and regular colonoscopic screening to reduce the morbidity associated with the Syndrome. Clinical guidance reflecting this, is now the standard-of-care for LS and has been issued by institutes nationally and internationally.

National Impact

In 2019, the British Society of Gastroenterology made a strong recommendation that individuals with LS should be advised that regular use of daily aspirin reduces CRC risk (GRADE of evidence: moderate; Strength of recommendation: strong). The moderate ranking for the grade of evidence reflects the extensive challenges of performing studies on such patients [ C].

In 2020, the U.K. National Institute of Clinical Excellence (NICE) provided guidance on aspirin for LS patients. Their commentary indicates that the benefits of aspirin are likely to outweigh any risks associated predominantly with bleeding for patients with this syndrome. A trial is necessary to determine the optimal dose (as is being conducted under the CAPP3 trials), and since aspirin is now commonly used for this condition, aspirin should be considered for those at risk [ D].

International impact

A European group of clinical experts, independently convened, whose focus is on the identification and clinical management of LS, reviewed the CAPP2 trial evidence and determined that there was sufficient evidence to warrant regular aspirin for LS patients with evidence level 1b. This guideline was originally published in 2013, and the 2020 guidelines sustained the recommendation [ E]. The guidance is addressed to all clinical specialists managing LS patients.

In 2017, the Cancer Council of Australia: Clinical guidelines network conducted an evidence-based review and recommended that regular aspirin should be started at the same age as colonoscopic screening (age 25 years) and the evidence of reduced colorectal cancer incidence has evidence level A (Body of Evidence can be trusted to guide clinical practice) [ F]. The evidence quoted the CAPP2 trial plus evidence from randomised trials of other clinical phenotypes which were also associated with an increased risk of colorectal cancer. The latter randomised trials also found a reduced risk of colorectal neoplasia after regular aspirin. This perspective is endorsed by the Australian National Health and Medical Research Council [ G]. EviQ, an Australian online resource of evidence-based, consensus driven cancer treatment protocols and information for use at the point of care developed for the Australian context to support health professionals in the delivery of cancer treatments, also recommends regular aspirin [ G].

In 2015, the American Gastroenterological Association (AGA) recommended that aspirin be offered to LS patients for colorectal cancer risk reduction [ H]. After summarizing the evidence, the authors concluded that while the trial was high quality, the overall evidence was low because the confidence interval of the risk reduction estimate was too great. This review occurred soon after the first publication of the CAPP2 group [ 2] therefore not all data has been taken into account. The updated information shows greater precision [ 3] but the AGA has not updated their conclusions to date. However, US non-profit organisation, AliveAndKickn, supporting people with hereditary cancer advocates the use of aspirin and educates their community of the benefits resulting from our research [ I].

Impact on Health Benefits

While the impact of aspirin on colorectal cancer incidence is too recent to allow a measurement of the reduced mortality, there is evidence that LS patients are being offered the information on the benefits of aspirin in terms of morbidity reduction and in terms of giving patients opportunities to help reduce their own risk [ A]. As noted by the UK NICE Guidelines [ D], aspirin has been offered to LS patients at risk. For instance, the Bowel Cancer UK Survey reported that 62% of patients had been recommended aspirin [ J]. The same survey also disseminates the advice on taking aspirin and publicises the research to the public by promoting our CAPP3 trials.

In the USA, while there has been no central guidance on the benefits of aspirin for LS patients, the clinical centres are offering aspirin routinely. Director of Lynch Syndrome Center at the Dana Farber Cancer Institute, one of the 51 Comprehensive Cancer Centers in the USA, writes that he has seen the benefits of aspirin for his patients’ health and has helped “ put prevention into their hands” [ K].

Impact on Clinical Research

The success of the CAPP2 trial required extensive activity and interactions with clinical genetics groups both in the UK and worldwide [ A]. In order to participate, both clinical and molecular genetic expertise is required, which limits the potential number of clinical centres in a position to participate. In total, 43 centres from 16 countries participated; for many of these centres, it was the first trial that they had been involved in. Clinical centres also benefited as they were provided with technical expertise and advice for positive care, thus improving the clinical research capabilities in this domain. The benefit for this network has been further elucidated by the fact that their work, as yet unpublished, to determine the benefits of regular dosing with resistant starch (an indigestible fibre) demonstrated it reduces the risk of upper gastrointestinal cancer also by about 50%. These cancers make up about a quarter of the cancer spectrum in LS, they are among the hardest cancers to identify and screen for and are major causes of LS mortality.

The success of CAPP2 is clearly a major reason why CAPP3, the latest trial, could recruit 1,879 participants [ A] who were randomised to three different doses of per day (100 mg, 300 mg, 600 mg). This double-blind trial is in progress, to compare the effectiveness of the different aspirin dosages and establish the benefits of using aspirin against increasing risks of bleeds.

The ROLARR study was undertaken during a period of great uncertainty about the benefits of robotic surgery and whether it offered value for money and should be more widely adopted. The work was presented at the world’s foremost surgical congresses, including the American Society of Colon and Rectal Surgeons (ASCRS; USA, 2015), the European Society of Coloproctology (Hungary, 2015), the Asian Robotic Camp for Colorectal Surgeons (S Korea, 2018), and the Association of Coloproctology of Great Britain and Ireland (UK, 2016), and is regarded as an exemplar study by the IDEAL (Idea, Development, Exploration, Assessment, Long-term Follow-up, Improving the Quality of Research in Surgery) Collaboration (UK, 2018).

ROLARR galvanised the robotic surgical community, clarified international opinion and put robotic surgery in the public spotlight through national media coverage. The JAMA manuscript [ 2] was named “Paper of the month” by the European Society of Coloproctology in January 2018 [ A] and to date has been cited 324 times on Web of Science, indicating its importance to the surgical community.

Patient and healthcare provider impact

The most important beneficiaries of robotic surgery are patients. Demonstration that robotic rectal cancer surgery was safe, with good oncological and functional outcomes [ 2], and evidence of factors enabling safe technology adoption [ 5, 6], provided reassurance to clinicians and patients. Although robotic surgery was more expensive than laparoscopic surgery, the differential costs were less than previously reported [ 3], providing encouragement to healthcare providers to invest in the technology and widening access for patients to benefit from minimally invasive surgery [ B].

The adoption and utilisation of robotic surgery for rectal cancer has increased markedly since the ROLARR presentations and publications [ 2- 6]. In the National Bowel Cancer Audit 2020, 30 NHS Trusts were regularly performing robotic colorectal cancer surgery with the number of cases more than doubling over the previous 4 years [ B]. Importantly, almost two-thirds of robotic surgery was performed in males and for low rectal cancer – the technically difficult sub-groups identified in ROLARR [ 2]. Similar patterns of robotic adoption have been seen in the US with rates of laparoscopic rectal cancer surgery plateauing at 19%, whilst robotic surgery has increased from 1% to 13% [ C].

Previous single institution studies have suggested that the learning curve for robotic rectal cancer surgery was ~30 patients. ROLARR showed this to be an underestimate, with the true learning curve, even in experienced laparoscopic surgeons, not plateauing until ~90 patients [ 4]. This has had major implications for robotic training programmes, surgeon accreditation, patient safety, and the future design of surgical technology evaluations. It informed the design of further research exploring the subgroups (males, obese patients, low rectal cancers) identified within ROLARR where there was likely to be maximal benefit, including the European RESET trial aiming to recruit 1300 patients with low rectal cancers [ D].

Policy and implementation impact

The importance of ROLARR in determining future healthcare policy is illustrated by its inclusion in an NIHR Signal Report [ E]. NICE guidance on the treatment of colorectal cancer published in 2014 failed to mention robotic surgery. Updated guidance published in 2020 supported the use of robotic rectal cancer surgery within established robotic programmes that have appropriate audited outcomes, affirming the learning curve [ 4] and human factors findings [ 5, 6] of ROLARR [ F]. The potential benefits highlighted by ROLARR for increasing patient access to minimally invasive surgery were formalised within the Royal College of Surgeons of England “Future Surgery” report [ G]. Building on the success of ROLARR, RCS England set up a national research initiative to undertake further research to demonstrate the benefits of robotic surgery.

Commercial impact

Presentation of the ROLARR results at the ASCRS meeting in 2015 had an immediate impact on the commercial robotics sector. US financial markets showed particular interest with investor speculation on Intuitive Surgical Inc., the manufacturer of the da Vinci system. The markets reacted favourably, reassured by the safety and high quality of robotic surgery [ H].

Confidence in robotic surgery was reassured, paving the way for the development and commercialisation of other robotic systems. Manufacturers have taken on board the health economic lessons from ROLARR, in particular the need to reduce capital and instrument costs to make the technology more affordable. Companies, such as CMR Surgical (UK) and Distalmotion (Switzerland), have been consulting with the ROLARR team to better understand the implications of ROLARR and how to develop the next generation of more versatile, affordable systems [ I, J]. Specific influences of ROLARR cited by manufacturers include a focus on colorectal surgery as a strategic market, increased investor confidence, use of health economics data to guide market positioning, and the importance of independent clinical evaluation to facilitate EU and US regulatory approvals.

Improvements in cancer death rates and quality of life for TYA

In 2005, research from Leeds was influential in the development of NICE guidance for improving cancer outcomes [ A]. There are 1,400 TYA diagnosed annually across various types of cancer in England. In 2019, NHS England published data comparing death rates for TYA between 2001 and 2013. Reductions in mortality have been revealed despite an increase in cancer incidence from 240 to 300 per million population (pmp). In 2001, the mortality for TYA was 44 pmp. In 2007, only 2 years after NICE guidance implementation, mortality was reduced to 42. Finally, in 2013, it was reduced to 32, resulting to a total of 27% reduction.

The BRIGHTLIGHT cohort study, to which the Leeds research team contributed key underpinning methods, reached over 1,200 TYA with cancer in over 100 NHS trusts in England between 2013 and 2017. Analyses indicate a significant positive impact from receiving specialised TYA cancer care [ B]. We observed improved metrics of care quality:

• 78% had multi-disciplinary team involvement in specialised care compared to 50% in non-specialised care;

• 44% of the TYA in specialised care who could benefit had their cancer precisely defined by contemporary molecular techniques compared to 22% in non-specialised care;

• 60% were assessed by rehabilitation services compared to 38%;

• 73% of females received future fertility care compared to 43%.

• On a 0-100 score, where 0 is poorest quality of life, patients receiving specialist cancer care improved by 15 points over 3 years, whereas those with no specialised care improved by 10 points. The patients treated in specialised care were also more severely unwell at the outset. A similar pattern of improved psychological morbidity was observed.

Internationally, cancer survival analyses have started to indicate the impact of our work. In the Nordic countries, Rostgaard et al have widely cited the application of our work, and analysed Nordic cancer registers to examine cancer survival for TYA. In 1999, cancer survival was 58%. In 2013, this increased to 77% survival [ C].

Impact upon clinical services and corresponding patient confidence

United Kingdom

The impacts since 2013 upon outcomes are mediated by changes within the 2005 NHS policy. Wilkinson et al [ 1] was cited within the NICE policy document (2005), mandating the creation of specialist cancer services for TYA within the NHS, and specifying the features of this specialised care [ D]. These services were gradually embedded within the NHS after 2005.

In 2001, there were 5 TYA cancer services in the world; one of which was in Leeds. By 2018, these increased to 26 in the UK due to our collaborative efforts. An independent patient experience analysis of surveys by Furness et al, using data from all TYA with cancer in England, demonstrated that TYA have more confidence in their care in specialised units [ E]. Moreover, improvement in satisfaction with care was revealed.

International Reach

There are indications that the process of specialisation in the UK is also improving cancer services internationally. Lewis was Co-Chair of Clinical Care Models within the US National Institutes of Health, National Cancer Institute and US Department of Health for Adolescent and Young Adult (AYA). This formed a Progress Review Group in 2006, which discussed the need for treating AYAs as a distinct group with special needs for clinical care and psychosocial support services. An infographic from Lewis’ research entitled ‘Key Elements of Patient-Centred Pathway’ was used to drive the panel’s discussion on the definition of a new model of care. The outcomes were published in the Report “Closing the gap: Research and care imperatives for adolescents and young adults with cancer. Report of the Adolescent and Young Adult Oncology Progress Review Group”, whereby three main priorities were identified to promote a consistent standard for delivery of care to the AYA population [ F]. This report led to the creation of a workshop, sponsored by the American National Cancer Institute, entitled “Next Steps in Adolescent and Young Adult Oncology” which determined key decisions around AYA specialist care [ G]. These resulted in creating more AYA specialist clinical teams within US hospitals. By 2020, AYA specialist clinical teams were established within 42 US hospitals [ H] compared to 2 hospitals up to 2012.

Stark and Lewis led the TYA cancer research within the EU-FP7 European Network for Cancer in Children and Adolescents, for the period 2011-2016 [ I]. The network began with only 10 people working just in the UK, France and Germany, and received funds from the European Union to bring specialists together to achieve a shared understanding in treating TYA. By the end of 2016, the network consisted of approximately 350 people and had members from all but two EU nations. Since 2013, clinical networks of specialist TYA cancer wards were founded in 5 further regions of France, and entirely new networks and services were dedicated to TYA within the national Cancer Plans of Netherlands, Denmark and Eire.

Stark and Lewis were the invited international keynote speakers for the inauguration policy forum between the German adult and paediatric cancer societies in 2013. Their involvement resulted in the establishment of a new professional transition group; the Arbeitsgemeinschaft Adoleszenten junge Erwachsene. Stark was also an invited expert by the Indian Cancer Services in 2017, and his role was key for their launch of specialist TYA services [ J].

**Impact on international professional education

Stark is an inaugural member of the Adolescent and Young Adult education committee, jointly run by the European Society of Medical Oncology (ESMO) and Societe Internationale Oncologie Pediatrique European (SIOPE). He was a keynote speaker at the first ESMO medical training course on TYA oncology in 2018. His lectures addressed 39 oncology specialists from 18 nations for a Europe-wide professional certification and received excellent feedback. Delegates responded that following this course, they would change the selection of treatment for TYA, include multidisciplinary team advice, provide TYA specific psychological support and introduce improved patient assessments [ K].

Worldwide incidence of MM is currently 160,000, and mortality is 106,000. In the UK, there are around 5,800 new myeloma cases every year, with incidence rates projected to rise by 11% between 2014 and 2035, to 12 cases per 100,000 people. The introduction of ASCT to support high-dose melphalan in patients with MM in the 1980s represented a step change in the management of this disease, with randomised trials confirming its clinical use to be better than conventional chemotherapy in terms of progression-free and overall survival. Consequently, the procedure is regarded as standard care for the treatment of patients with newly diagnosed MM up to the age of 65–70 years without significant comorbidities. The incorporation of novel drugs (thalidomide, bortezomib, and lenalidomide) into the first-line management strategy during induction, consolidation, or maintenance in the past 15 years has further contributed to improving patient outcomes. However, for the vast majority of patients, cure remains elusive and the disease will eventually relapse.

The NCRI-badged UK Myeloma Forum Myeloma X trial, designed and delivered by Leeds researchers (Cook, Brown and Cairns) is the only global, prospective interventional study in this setting, and demonstrated a superior durability of response (time to progression and progression-free survival) when sASCT is used compared to non-transplant consolidation [ 2, 3].

Furthermore, Myeloma X showed the durability of response is maintained in the subsequent line of therapy (time to second objective disease progression), and demonstrated a superior survivorship advantage [ 3]. This provides the first, and only, randomised evidence to suggest a survivorship benefit for sASCT [ A], with no significant influence being inferred by β2-microglobulin at relapse and age, though adverse molecular markers continue to show poorer response [ 4]. Myeloma X demonstrated that this survivorship advantage is not at the expense of quality of life measurements [ 6].

Inclusion in national guidelines increases uptake and improves patient outcomes

The trial output has delivered the necessary prospective evidence in an up-to-date clinical treatment scenario to demonstrate the clinical effectiveness of sASCT in first relapsed MM. Consequentially, the study has informed the recommendations of national guidelines in the UK. A sASCT is considered ‘standard’ by the British Society of Blood and Marrow Transplantation (BSBMTCT) Indications Committee [ B], and has been approved and recommended by the National Institute for Health and Care Excellence [ C].

Updates to the UK Myeloma Forum guidelines on the diagnosis and management of multiple myeloma, produced on behalf of the British Committee for Standards in Haematology in 2014, reflected our trial outcomes on the clinical utility of sASCT, with Cook a contributing author for both the original guideline and amendment [ D].

This has resulted in MM being the first disease group to have the baseline commissioning policy approval for sASCT in first relapse by NHS England (and devolved governments). This, in turn, has led to a change in clinical practice, with recorded increase in the number of patients undergoing sASCT in the UK (from 160 per annum in 2012 to 293 per annum in 2019) [ E].

The MM care pathway is multi-faceted, and continually evolving, but sASCT is a recognised clinical utility. The survivorship of patients is the culmination of all treatment lines but Myeloma X has shown that use of sASCT has a positive impact on survivorship. Real-world outcomes in 50-69 year olds eligible for sASCT, show a 2.3% point improvement in the 50-59 age group at 5 years from diagnosis, and a 4% improvement in the 60-69 age group [ F]. This is the effect of several evolutions in clinical care but includes the impact of sASCT, and is not related to the impact of the (very) recently adopted monoclonal antibody therapy (daratumumab).

Sole global data on sASCT for relapse MM leads to adoption in international guidelines

The Myeloma X trial results have been pivotal to formulating the recommendations for international guidelines. The International Myeloma Working Group (IMWG) emerged through the International Myeloma Foundation in order to promote collaborative research, and reach consensus for guidelines. Together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation (ESBMT), IMWG produced guidelines that included our recommendations [ G].

The Deputy Division Head of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, who co-led the guidelines, said:

*“Dr Cook and his colleagues from Leeds University have been instrumental not only in filling the knowledge gap, but in encouraging others to study this important and potentially more cost-effective strategy for remission consolidation in patients with myeloma failing primary therapy [ H].”*

These guidelines have led to increased uptake of sASCT into routine clinical practice as a standard of care in the United States since 2015, with the Leeds research having a:

“direct impact on the improved survival of multiple myeloma patients” [ I].

It is estimated that 100 patients a year in the US have benefitted from this treatment [ H]. Similar benefits have been reported in France and other European countries [ J].

Our trial results have also been adopted in the American Society of Clinical Oncology and Cancer Care Ontario joint clinical practice guideline on the treatment of MM [ K], and incorporated into a ESBMT report addressing the issue of myeloma treatment relapse options following a previous autologous transplantation, where it recognised the Leeds research as:

*“offering a dataset on which to base clinical decision making [ L].”*

The consequence of this research is shown through real-world evidence demonstrating increased uptake of sASCT into routine practice as a standard of care as a consequence of presenting and publishing the results (BSBMT and ESBMT registries). Taken together, the results of this study are already having an impact on the clinical management pathway in myeloma and helping the decision-making process for both physicians and myeloma patients.

Worldwide, rare diseases affect 3.5–5.9% of the population, equivalent to around 300 million people. In the UK this figure is higher, with around 3.5 million people (7% of the population) affected. Babies and children are most likely to be affected, with as many as 30% of those who have a rare disease dying before their fifth birthday . Our research has identified 109 genes which, when mutated, cause diverse rare human conditions. This has resulted in laboratories across Europe screening for these genes, the identification of these genes on the UK national test directory, and the successful completion of clinical trials involving these genes [A].

Influencing new diagnostic technologies and screening programmes worldwide

Our research has had a profound impact on the development of new diagnostic technologies, and on national and international screening programmes globally. The Orphanet website [B] lists the European Medical Laboratories that provide diagnostic tests for specified genes or diseases. If we take the representative genes that were highlighted in section 3, Orphanet shows that SAMHD1 was tested in 54 laboratories, PMS2 was tested in 183 laboratories, HEATR2 in 7 laboratories, MICU1 in 15 laboratories, CCND2 in 11 laboratories, and DRAM2 in 11 laboratories. Other notable genes implicated in disease by our researchers and widely screened by European laboratories include CEP290 (142 laboratories), TMEM67 (93 laboratories), and LRP5 (86 laboratories).

Commercial sensitivities mean that the precise number of tests cannot be calculated, but we surveyed 134 European genetic testing laboratories, which allowed us to estimate that over 50,000 tests were carried out in 2019 in Europe alone for genes implicated through our research [C].

The worldwide figure is likely to be much higher, and major genetic sequencing companies globally are testing for genes associated with disease through our research. For example, the Illumina sequencing company (revenue USD3,543 million in 2019) included the genes TET2 and PMS2 in their widely used Illumina TruSight Oncology 500 NGS assay launched in 2018 [D]. The world-renowned geneticist and President of US company ‘PreventionGenetics’, said:

“Tests for all of the genes listed [SAMHD1, PMS2, ASPM, TMEM67, NMNAT1] are on our test menu…. We have identified many patients who carry pathogenic variants in these genes” [E_i].

The Director of Spanish biotechnology company, Sistemas Genómicos, said:

“These genes are crucial in genetic diagnosis, and in our experience, fundamental in this field due to the relatively high number of patients suffering from these genetic conditions. Specifically, in the oncogenetics area, the study of PMS2 is very important….During the year 2019, we carried out 568 genetic analyses, which included this gene. Some of these studies confirmed the suspected clinical diagnosis, which allowed offering [sic] an adequate genetic counselling and appropriate medical management to the patient and their families” [E_ii].

The extent of the impact can also be seen within government documentation on commissioning of genetic tests. For example, the UK National Genomic Test Directory specifies which genomic tests are commissioned by the NHS in England, and lists a core set of genes that must be tested in NHS laboratories. Ninety eight of the genes associated with rare diseases by our researchers since 2000 are on the UK list [F], which features a total of 5851 genes (i.e. we have contributed 1.67% of identified genes). The President of the UK Clinical Genetics Society, confirmed that:

“The over one hundred genes linked to human inherited diseases by researchers in Leeds are screened regularly in laboratories across the UK to support clinical diagnosis for patients” [E_iii].

The Clinical Lead for the DECIPHER and the Deciphering Developmental Disorders project based at the Wellcome Sanger Institute, Hinxton, acknowledged that:

“tests for dozens of genes linked to human inherited diseases by researchers in Leeds…. account for a significant and important contribution to our diagnostic yield” [E_iv].

The impact of our research is further evidenced by its influence within major genomics projects. For example, the 100,000 Genomes Project, completed in 2018, sequenced 100,000 whole human genomes from patients with rare diseases and their families, and patients with common cancers. The Clinical Director of Genomics England, confirmed that the genes we identified:

“accounted for a significant proportion of activity across the 100,000 Genomes Project” [E_v].

The co-lead investigator of the Scottish Genomes partnership said that:

“The many rare disease genes discovered by researchers in Leeds played a key role in helping to understand causes, diagnosis and potential treatments for such inherited diseases” [E_vi].

New understanding underpins clinical trials of novel therapies

The genetic research findings from Leeds have allowed clinicians to compare patients from different centres who have variants in a single gene. This has guided clinical decision-making, as well as the novel research insights informing clinical trial design. Examples include drug trials in patients with TREX1 and PLA2G6 mutations; personalised medicine approaches and drug trials for specific cancer subgroups (including PMS2 and TET2 mutation carriers); CEP290 variants targeted by antisense oligo therapy; a vaccine targeting cells over-expressing TBXT to treat certain tumour types; drug, dietary and physiotherapy approaches being tested in Primary Ciliary Dyskinesia (PCD) patients; and the use of anti-ADAM9 antibodies as a tumour therapy [G]. For example, a clinical trial of azithromycin maintenance therapy in PCD, caused by mutations in six of the genes implicated through Leeds research, showed this halved the rate of respiratory exacerbations [H]. In addition, our research on AGS, caused by mutations in SAMHD1 and four other genes (all identified by Leeds researchers) led directly to a clinical trial of the drug baricitinib, which proved effective in improving neurologic outcomes in patients [I].

Improved health and wellbeing through diagnosis, counselling and better treatment

Discovery of the 109 genes through research at the University of Leeds has enabled early diagnosis, better management, and improved outcomes for patients, and better counselling and prenatal screening for families. The importance of this impact was highlighted by inherited retinal dystrophy (IRD) patients (19 genes implicated through Leeds research) who reported that they strongly supported the provision of publicly funded genetic testing. The IRD patients valued the greater understanding and knowledge about the genetic basis of their condition, and valued the resulting early access to emerging therapies. The patients also reported benefits to family members and future generations, as well as to society in general [J].

Our research has also allowed charities to support families living with rare conditions. According to the CEO of Unique (a charity supporting people with rare chromosome and gene disorders):

“The [Leeds] research has provided important insights that directly benefit those affected by genetic mutations. In particular, the discovery that blindness is due to mutations in splicing factors PRPF8 and 3, the identified relationship between retinal vascular disease and TSPAN12 variants, and the finding of diverse immunological phenotypes due to CARD11 mutations has allowed a genetic diagnosis to be made – diagnoses which directly improve the quality of life for affected individuals within the UK and throughout the world” [E_vii].

The CEO of Cerebra, a charity that helps children with genetic brain conditions, said:

“….the fundamental genetics research at the University of Leeds has led to improvements in genetic identification that have significantly improved the lives of our members and have given them and us new hope for the future….. This new understanding allows our members to obtain a genetic diagnosis, which gives them a much better idea of what the future holds for them, something in which we and they place great value. It also gives information about risk for other family members and future generations, is the first step towards better treatments and new therapies and is an essential prerequisite for recruitment to clinical trials” [E_viii].

The CEO of Retina UK, a patient-led charity supporting people with retinal diseases, confirmed:

“the Leeds Vision Research Group has played a world-leading role in the drive towards a genetic diagnosis for everybody with inherited retinal disease. Knowledge of their genotype is something our members value very highly indeed, since it is the essential first step in the journey towards understanding their condition and accessing the best possible treatment” [E_ix].

The Board of the Ciliopathy Alliance have recognised the vital importance of the Leeds research and the impact it has had on families affected by ciliopathies:

“Leeds geneticists have excelled over the past 10 years, identifying over 100 genes linked to inherited diseases. These include 29 genes that, when mutated, cause ciliopathies. This is a huge contribution to the worldwide human genetics revolution from a single centre. Linking genes with inherited diseases means patients and their families can plan their lives knowing how their condition is likely to progress and what risk it poses to relatives” [E_x].

The impact of this research is best expressed by the patients who benefit from the findings. For example, a patient with VEXAS syndrome (due to a somatic mutation in UBA1) wrote that:

“For four years I have battled with a progressive illness… Last year I was told that I was unlikely to survive more than another 6-12 months, and to complete a DNR Form, write my will, etc. It therefore came as a massive relief to discover at the end of last year that your team had described a syndrome that exactly matched my own illness…. I feel that my symptoms are benefiting from a combination of steroids and a monoclonal antibody” [K].