2 N E W S & M A NAG E M E N T AI in clinical practice Hospitals must think big, small and new AI in healthcare has been a trending, sometimes head-spinning topic for a few years – and, with the Covid-19 pandemic, clinicians have been presented with a whole new range of AI products that may or may not meet their needs. When it comes to choosing one’s own set of tools, which criteria should pre- vail? A panel of European and US experts gave concrete examples of AI’s current implementation in clini- cal practise and shared tips on how to start working with AI from scratch during the online Healthcare Information and Management Systems Society (HIMSS) Conference. Report: Mélisande Rouger Diagnosis and triage have become two of the most interesting indica- tions for AI deployment in clini- cal practice, according to a recent initiative by the NHSX, a joint unit from National Health Service (NHS) England and the Department of Health and Social Care. The organi- sation launched the AI in Health and Care Award (AI award) to support solutions addressing the strategic aims of the NHS across the whole development pathway, by funding AI tools with over £50 million to kick- start their deployment into the real word and research. With an overwhelmingly positive response, the first selection of sub- r i i m d a l V o k n e h c n a P / k c o t s r e t t u h S © mitted projects spans a wide scope of applications, such as breast can- cer screening and emergency stroke assessment, according to Indra Joshi, Director of AI for NHSX. ‘About 500 people applied and we selected 42 projects, ranging from image recog- nition that help recognise pathology, to how to triage images. In the UK, we’re experiencing a huge rise in the production of images that need triage, in the acute setting as well as in routine care. We’ve selected tools for triaging appointments, to help clinicians understand when to move patients to different wards in the hospital.’ The importance of thinking small When talking about AI, people usu- ally think big. AI’s ability to diagnose or treat is an important role, and much tackled by developers. But, one should also include ‘little AI’ in the equation. Utility functions such as voice recognition are often disre- garded, but are widely used in clini- cal practice, and they deserve much more attention, Christopher Ross, Chief Information Officer for Mayo Clinic in Rochester, USA, explained. ‘One thing that’s unheralded is those small places where AI is being employed and helps make a differ- ence – things like computer assisted coding, annotation and enrichment of text, so that we can enrich data to make it meaningful signals that can be used by others.’ Regarding AI for diagnosis, Ross’s team has developed algorithms to estimate kidney volume, an infor- mation obtained from radiological images that is used for a variety of therapeutic purposes. The Mayo Clinic has also published work on surveillance of patient populations for purposes of palliative care – nota- bly to identify patients who are in decline or distress, and engage pal- liative care sooner and better. The clinic’s work on AI near the bedside includes identifying atrial fibrillation by looking at an ECG when a patient is not experienc- ing an event. ‘It’s been tricky to identify people with rhythm pro- blems if you’re not looking at them when they’re having that problem,’ he pointed out. ‘The ability to look at a normal ECG and predict from that whether someone has a rhythm problem is very promising.’ In total, the Mayo is using or developing about 200 AI products from discovery to bedside, in various disciplines including radiology, neu- rology, cardiology, gastroenterology. Starting AI from scratch Not every organisation has such capacities as the Mayo or NHS. Developing one’s own solutions is not a prerequisite for all institutions though. When thinking about AI, cli- nicians should rather look at a very important criterion: novelty. ‘We’re Christopher Ross is Chief Information Officer for Mayo Clinic. He has has 32 years prior experience in healthcare, technology, and government. He is also Chair of HIMSS North America Board of Directors, and serves on the board of directors of Zipnosis, an emerging tel- ehealth vendor. He was a member of the Health IT Standards Committee for the U.S. Department of Human Services from 2009-2016 and former chair of the board of the eHealth Initiative. He has a Bachelor of Science degree in econom- ics from the University of Minnesota and MBA degree from the Yale School of Management. His areas of interest are digitization of medicine, artificial intelli- gence, patient empowerment. always looking at new technologies and don’t use only things we develop ourselves.’ Ross said. For organisations more stretched for resources, a reasonable place to start is to determine which AI they can use. There might be areas where a simple “little AI” tool is all that’s needed. Not every organisation needs to develop machine learning. It’s all about using the right tool for the right problem,’ Ross observed. Healthcare systems that want to start using AI should draw road maps to describe how to adopt tech- nologies to prepare adequately, he advised. The recent Covid-19 crisis has put a magnifying glass on how to imple- ment AI in a low resource setting, Joshi explained. ‘At the peak of the epidemic, a number of companies came to sell their solutions,’ she said. Cardiac troponin I concentration measured at POC Triage aided by a quick sensitive test Large proportions of patients can be safely triaged either to rule out discharge or rule in lifesaving management – if following the European Society of Cardiology (ESC) Guidelines Class I recommendation of two serial measurements of hs-cTnI on admission and after one hour, if there are assay specific cut off values for the 0/1 algorithms. The Pathfast hs-cTNI assay is an approved system to determine highly sensitive troponin I recommended in the ESC Guidelines 2020, with- in the quick 0/1 hour rule out diagnostic algorithm. The manufacturer, LSI Medience Corporation, reports: is a Pathfast hs-cTnI sensi- tive Chemiluminescent Enzyme Immunoassay the quantitative measurement of car- diac troponin I (cTnI) concentration (CLEIA) for in whole blood or plasma at the point-of-care (POC). The Pathfast assays are designed for Near Patient Testing (NPT) and can be used as an aid in the diagnosis of acute coronary syndromes (ACS) and in the risk stratification of patients pre- senting with suspected acute coro- nary syndromes such as chest pain in a hospital. Reagents are single use in all-in-one cartridges and up to six tests in parallel can be tested in one run. Besides highly sensitive troponin I, additional biomarkers as NT-pro BNP, D-Dimer, Myoglobin, CK-MB mass, hs-CRP and the new innovated emergency sepsis marker Presepsin can be measured at the same time with superior quality. In less than 17 minutes the Pathfast system provides highly accurate, precise test results out of whole blood, plasma and serum similar to central laboratory ana- lyser. In clinical studies, Pathfast hs- cTnI assay has been evaluated for a 99th percentile upper reference limit of 29.0 ng/L at an imprecision of 6.1%, which fits the criteria of hs-cTnI assays recommended by IFCC and ESC. Moreover, gender spe- cific cut off values were established and a 0/1 hour Rule-out and Rule-in algorithms of NSTEMI patients were evaluated. Recommended by the 2015 and 2020 ESC guidelines cTnI concentration were measured from 1,221 patients with suspicion of NSTEMI (669 for derivation and 610 for validation) using the Pathfast hs- cTnI assay in EDTA plasma samples obtained at 0 hour and one hour after admission of patients to the chest pain unit (CPU). As presented in recent publication, the identi- fied cut offs for 0 hour rule-out showed 100% and for 0/1 hour rule out 99.7% negative predictive value (NPV). For 0/1hour rule-in 80.1% positive predictive value (PPV) were EUROPEAN HOSPITAL Vol 29 Issue 4/20

4 S U RG E RY One year as a Senhance reference centre Robotic system for surgeons and patients In August 2019, the Evangelische Krankenhaus Wesel (EVK) was the first hospital in the Lower Rhine region in Germany to invest in a robotic system for abdominal sur- gery in one of its operating rooms (ORs). In the beginning, the Senhance Surgical Robotic System, developed by Transenterix, was used for mini- mally invasive interventions in gen- eral surgery but today, its field of application has widened consider- ably. The EVK team is extremely happy with the new technology, says Managing Director Heino ten Brink: ‘We’d make this decision again any time. For us, this type of OR support is the way forward and we are convinced that it will prevail.’ In addition to EVK, the operator Evangelisches Krankenhaus Wesel GmbH runs two community medi- cal centres, three nursing homes, an out-patient nursing service and an out-patient palliative care service. A fourth nursing home and a hospice are scheduled to be opened within the next three years. The facilities cater primarily to patients in the region; two depart- ments however have larger catch- ment areas: the neurology depart- ment, including a Stroke Unit and an early rehab centre, as well as visceral surgery, which is part of the oncology department. In the past two years the hospital invested heavily in digitisation: the HIS was updated and all employees were equipped with iPads to enable them to access clinical reports from any- where. ‘This digital support takes a huge load off our shoulders”, says ten Brink and adds that “the Senhance system fits very well in our current strategy.’ In the beginning, the surgeons used the system only for less severe hernia and gall bladder interven- tions, but in the meantime they have gained sufficient experience and choose it for abdominal pro- cedures such as diaphragmatic her- nias, chronic reflux or intestinal conditions as well as in oncological tumour surgery. Gynaecology will be added in early 2021 when a new medical director will start his watch. Initially, the future head of depart- ment was sceptical about robotic surgery, ten Brink remembers, but after he had familiarised himself with the Senhance system he was excited and is now looking forward to the possibilities this new technol- ogy opens up. The system provides the surgeon, who is comfortably seated patient- side at an open console, with detailed high resolution images in up to 6x magnification. The camera is equipped with an eye tracker, i.e. it is controlled by the surgeon’s eye movements; the instruments inside the patient’s body are controlled manually. An integrated tremor fil- ter eliminates the minute – and natural – shivering movements of the human operator, thus enabling a degree of precision human hands would never be able to achieve. The advantages for the patients are obvious: smaller incisions, smaller scars, less pain – in total, a less stressful operation. In the meantime, the hospital’s new technology has become the talk of the town – and the region. ‘Many patients choose our facility because they have heard Please! No cables in our operating theatres On 1 July 2020, Heino ten Brink began his role as Managing Director of Evangelisches Krankenhaus Wesel GmbH (EVK) when his predecessor Rainer Rabsahl took early retirement. Ten Brink, who studied business administration, had been deputy Managing Director at EVK Wesel since 2016. Before he joined EVK he was administrative director of Immanuel Hospital Bernau – Heart Centre Brandenburg and Head of Strategic Controlling, Business Development and a member of the administrative board at Evangelisches Krankenhaus in Mülheim an der Ruhr, Germany. about our state-of-the-art equip- ment,’ ten Brink said, adding: ‘peo- ple are confident that they receive best possible care and specifically inquire about our Senhance system.’ His initial fear the patients might be put off by the OR robot turned out to be unfounded: ‘The patients’ confidence in our hospital pays off.’ EVK Wesel is one of two refer- ence centres for Senhance Robotic Systems in Germany and among 25 worldwide; in addition, interested surgeons and medical students are welcome to spend time at the hos- pital in order to gain a first-hand impression of the new technology – and their potential future employer. The current team, ten Brink reports, is proud to work in a facility that heavily invests in the future: ‘For us, the robotic system is a USP in the region, which puts us ahead of the competition. In the longer term I‘m sure this will translate into eco- nomic benefits.’ Refurbishment success in seven surgical units ‘From our point of view, both coor- dination and delivery were perfect and always on schedule.’ Flawless live operation in under a year Hamburg is highly satisfied with the progress. Since the end of 2019 the systems have run flawlessly in live operation in four completed thea- tres. ‘Rein Medical has impressed us with the quality of the PCs and mon- itors, and also with the professional execution of the project,’ Rathjen reiterated. ‘The co-operation, also with the other service providers we commissioned, was uncomplicated and problem-free.’ Currently, phase three construc- tion is underway at Marien Hospital, covering the refurbishment and pre- fabrication of the last three operat- ing theatres, in which Rein Medical is also responsible for the IT equip- ment, analogous to the already ren- ovated and newly equipped operat- ing theatres. ‘In future projects, too,’ emphasised Rolf Rathjen, Head of Medical Technology. ‘We will cer- tainly be happy to return to the specialist knowledge and products of Rein Medical.’ EUROPEAN HOSPITAL Vol 29 Issue 4/20 at Rein Medical who was respon- sible for this undertaking. ‘We are proud to have accomplished our first project with a 4K UHD display in Germany.’ In all, Rein Medical supplied two 27” Operion displays with PC for wall installation and one 55” Operion display (4K) each for each operating theatre. The company also provided a 24” Clinio PC with touch screen for the introduction. All monitors and PCs were installed on site by a team from Rein Medical, which is also responsible for training the Hamburg personnel. ‘We could rely on our partner at all times in the project, Rathjen happily concluded. Among refurbishments at seven operating theatres at Marien Hospital in Hamburg, Germany, are new PCs and wall-mounted monitors supplied by the Mönchengladbach- based medical IT manufacturer and developer of software and hardware Rein Medical GmbH. ‘It was impor- tant to find a supplier which special- ised in hardware for the operating theatre and who could supply high- quality products,’ said Rolf Rathjen, Head of Medical Technology at the Marien Hospital in Hamburg. ‘In addition, the PCs and monitors should integrate into the walls very well – we didn’t want to see any cables in the operating theatre.’ Simultaneously, the hospital com- missioned a different company to supply the OT integration software – not an unusual situation from Rein Medical’s point of view. ‘The special feature is the 4K UHD imag- ing: Our Operion three monitors are also available in UHD versions and are offered with various dis- play diagonals,’ explained Roland Schleberger, Key Account Manager

6 L A B O R AT O RY Perspectives on challenges to POCT use in acute care Understanding sources of error In an emergency, point-of-care-testing can provide results in minutes. However, sources of error must be understood to ensure result accuracy and confident diagnosis (particularly important during the current pandemic). Medical teams frequently use POCT devices to assess acutely ill patients; a hospital’s diagnos- tic laboratory is responsible for the analysers, plus training non-laboratory staff in their use. To explain the challenges in POCT use from different perspectives, Dr Ulf Martin Schilling (Consultant in Emergency Medicine, University Hospital of Linköping, Sweden), Dr Andrei Tintu (Clinical Chemist/Laboratory Data Officer, Erasmus University Medical Centre, Rotterdam, the Netherlands) and Professor Suzanne Bench (Professor of Critical Care Nursing, London South Bank University and the Royal National Orthopaedic Hospital, United Kingdom) spoke at a workshop sponsored by the medical technology firm BD (Becton, Dickinson and Company) during the 23rd IFCC-EFLM European Congress of Clinical Chemistry and Laboratory Medicine. A&E (Accident and Emergency) teams often deal with acutely-ill patients where the time to diagnosis and treatment can have a direct impact on their health and outcomes. If the patient is unconscious, the clinician has no ready means of obtaining a medical history or details of relevant events that led to hospitalisation. In this situation, the doctor would typi- cally run through a list of obvious potential causes of clinical presenta- tion. For example, are the patient’s airways clear? Is breathing difficult? Is there a problem with circulation, as in a stroke or heart attack? Are there signs of trauma or seizure? If there are no obvious reasons for the patient’s state, a more detailed investigation is necessary. According to Dr Martin Schilling, the reasons for a patient being unconscious are generally ‘70 percent metabolic and 30 percent structural’, though the percentages vary with the patient’s age, so analysis of patients’ blood samples can help with early diagno- sis and POCT typically gives results within a few minutes (a key advan- tage, compared to specimens tested in the laboratory). Preanalytical variability is a key cause of poor diagnostic quality in the lab- oratory, shown to cause greater than 60 percent of all laboratory errors (Lippi G., et al. Preanalytical quality improvement: from dream to reality. Clinical Chemistry and Laboratory Medicine. 2011;49(7):1113–1126). Likewise, preanalytical variability is also critical in POCT. For example, exposure of a blood gas sample to air can result in gaseous exchange between the air and sample. This may result in the measured values of the different gases not reflecting the patient’s physiological levels. ‘Sodium,’ Schilling pointed out, ‘may be diluted if a sample is taken from the same arm in which intravenous fluids were given’ and, he reminded us, potassium levels are often elevat- ed in haemolysed samples. Inaccurate results can lead to misdiagnosis In the stressful environments of an A&E and critical care units, there is the potential risk of misidenti- fication of samples from different patients, leading to analysis of the wrong sample and resulting in the communication of erroneous values. These types of preanalytical error which cause inaccurate results can lead to misdiagnosis and, critical- ly, potentially incorrect treatment. POCT results can help to support different potential diagnoses and may indicate which laboratory tests or imaging techniques are warranted to make a definite diagnosis and start appropriate treatment. But, according to Schilling, this is helpful only if the POCT results are accu- rate, as he suggests ‘we know that one in 20 results will be aberrant even by accreditation standards’. Nurses in critical care often maintain a presence at the patient bedside, to provide physical and psychological care to the patient and support for relatives, whilst also managing complex equipment. According to Professor Suzanne Bench, this requires ‘effective com- munication within the wider health- care team, supervision of junior colleagues and maintenance of accu- rate documentation’. Nurses are the biggest users Studies show that nurses value POCT because it can ‘help to speed- up decision-making and delivery’ yet, Bench acknowledged, POCT can impact on nursing workload and time management. From focus group discussions with UK A&E and critical care nurses, Bench revealed that ‘nurses are the biggest users of POCT in critical care’ and nurs- es have a significant responsibil- ity to clean and quality control the equipment, particularly out of hours and in smaller hospitals. Training in these operations is essential; if the equipment is not maintained proper- ly, this can lead to inaccurate results. Nurses report that training is nec- essary to ensure they understand the whole process, such as how to ensure that an accurate sample is obtained, why this is critical, and how to analyse the sample correctly. Nurses are also concerned about how POCT affects patient experi- ence and health outcomes. POCT blood specimen volumes are generally small (around one ml), but laboratory samples may be three ml or more. Because acutely-ill patients are monitored frequently, the volume of blood drawn may become significant, potentially lead- ing to anaemia and, in extreme cases, requiring a blood transfusion. Preanalytical errors can exacerbate this problem, another reason why diagnostic sampling needs to be ‘right first time’. Frequent collections from patients also cause concern about infection control and patient comfort. Bench noted that ‘the time taken for POCT also impacts on other aspects of care delivery and can lead to omis- sions in care provision for both the patient and the family’. For example, if the local POCT device is unavail- able, a nurse may have to leave the patient and find an alternative instrument, possibly some distance away. The knock-on effect: the other nurses in the department may have to re-task to ensure coverage while their colleague is away. Therefore, having POCT systems that give reli- able results are vital in critical care nursing. Quality management POCT devices are analytical instru- ments that fall within the domain of the hospital laboratory quality management, but are widely dis- persed in many locations in different departments across a hospital. This creates a challenge for maintaining quality assurance and, in rare cases, the documentation of results for compliance purposes. Generally, users of the POCT instruments are not experts in all aspects of the testing process but are medical professionals who use the instruments on an ad-hoc basis. Thus, the instruments need to be robust, fast and easy to use, and also deliver reliable results. Training clinical staff in the use of POCT instruments is a key laboratory role in many hospitals. Dr Andrei Tintu used the example of the Erasmus University Medical Centre (4,500 POCT users) to indi- cate that the number of users need- ing training, together with the large number of POCT devices available, makes provision of the training dif- ficult. This is an extra workload that the clinical laboratory is required to absorb. Tintu commented that, in theory, the easier a POCT instrument is to use, the simpler the training requirements should be. This may help to increase the operational efficiency and reduce costs of the clinical laboratory. Clinical staff education Tintu indicated that, given high staff numbers and turnover, there can be a challenge in maintaining accurate records for compliance purposes, to identify which staff are trained to use specific pieces of equipment. Educating staff on the POCT testing process and how preanalytical fac- tors impact on sample quality, and hence the reliability of analytical results, is another vital laboratory responsibility. This helps to ensure early availability of results and fewer adverse patient events due to fewer blood re-collections. Moreover, POCT instruments in a hospital must be verified for each sample type and test. By managing those devices, the laboratory quanti- fies the accuracy and reliability for the tests when conducted on these sample types, ensuring the staff obtains high quality results. The temptation for clinical users may be to test sample types which have not been verified by the laboratory’s quality management system. The reliability and accuracy of these tests will not have been deter- mined, increasing the risk of aber- rant diagnostic results, and the even- tual possibility of patient harm. To manage such use of non-vali- dated tests, Tintu believes the best solution is robust communication between the laboratory and clini- cal teams. By the laboratory listen- ing to the needs of POCT users, he believes further services could be provided to increase satisfaction among those users and ultimately improve patient care. Clearly, different groups of health- care professionals have differing views on what POCT should pro- vide. Dr Ulf Martin Schilling, Consultant in Emergency Medicine, University Hospital of Linköping, Sweden Professor Suzanne Bench, Professor of Critical Care Nursing, London South Bank University and the Royal National Orthopaedic Hospital, United Kingdom Dr Andrei Tintu, Clinical Chemist/Labora- tory Data Officer, Erasmus University Medical Centre, Rotterdam, the Netherlands What should or could POCT provide? Blood collection devices and prac- tices have evolved alongside the requirements of traditional diagnos- tic laboratory analytical instruments and, as such, are not optimised for use with POCT instruments, which are relatively new devices. Blood collection practices need to be designed and standardised to meet the different requirements of these devices. This would help to eliminate the non-standard practical methods that healthcare professionals have adopt- ed to provide workarounds for prob- lems found in real clinical situations. The current COVID-19 pandemic has reminded us that safety is also critical when considering POCT, with infection control impacting on patient and staff safety. Managing acute cases increasingly depends on POCT devices main- tained by healthcare science staff, operated by nurses (and others), and the results acted upon imme- diately by medical staff. However, despite good device maintenance and user training, sample quality and preanalytical errors can have an adverse effect on result accuracy. * This opinion piece is based on the authors’ presentations at the BD-sponsored work- shop during the 23rd IFCC-EFLM European Congress of Clinical Chemistry and Laboratory Medicine. With many years’ experience in sample collection BD is investigating how to decrease preanalytical issues, to improve care of acutely-ill patients and experiences of POCT users. The new POCT BD Veritor (TM) System also allows for the rapid detection of influ- enza A and B, Group A Strep, RSV and SARS- CoV-2 (CE approved). EUROPEAN HOSPITAL Vol 29 Issue 4/20

8 L A B O R AT O RY Improve Covid-19 testing Gargle and use mass spectrometry A UK biotech laboratory has used mass spectrometry in a new approach to coronavirus testing. MAP Sciences developed a gargle test, which collects samples from the back of the throat, and avoids the unpleasant sensation of the current PCR (polymerase chain reaction) swab tests. From there, the sample is tested for coronavirus using mass spectrometry (MS) with high levels of accuracy. Sciences had initially developed the technology with a view to screening populations for haemoglobinopa- thies and the most common genetic diseases, such as sickle cell disease or alpha or beta thalassemia from a pin-prick blood test. The biotech firm developed these tests and proved their validity with colleagues at Addenbrooke’s Hospital in Cambridge and Cam- bridge University, while also work- ing with partners in the United Arab Emirates and the United States to confirm the technique works on their mass spectrometers. Then the coronavirus pandemic Lab technician Vicky Lewis prepares the matrix plate for the mass spectrometer With an under one hour turnaround, the developers believe the test is quicker, easier, cheaper and as accu- rate as current PCR testing and has the ability to pick up other viruses – as well as Covid-19 – such as H1N1 flu. Professor Ray Iles, Chief Scientific Officer of MAP Sciences, based in Bedford, UK, says the test has been validated, with data now being gath- ered for regulatory approval, using samples from trials at Addenbrooke’s Hospital in Cambridge and col- laborators in the USA at Northern Illinois University. The company seeks to take its gargle test to market and, as part of the UK’s Covid-19 mass testing regime, to liaise with the country’s government, which aims to ramp up testing capacity to 500,000 a day by the end of October. Having spent many years work- ing in the university sector, setting up biomedical and health science facilities and as a Dean at Colleges of Health, Iles set up MAP Sciences five years ago with the vision that MALDI-ToF could move from the research lab to being the ‘go-to’ clin- ical diagnostic tool. Underpinning this is the amount of information Readout of the mass spec analysis on the computer available from MS, an analytical technique that measures the mass- to-charge ratio of charged molecules or ions. Ionising whole proteins without fragmenting MALDI-ToF MS utilises an advanced method of protein pattern recogni- tion – obtained from blood, urine or saliva - to diagnose various diseases and health disorders and rapidly deliver test results economically. In a typical MS procedure, a sample is ionised by bombarding it with electrons. But this breaks them into many small fragments. In MALDI, whole proteins are ‘soft’ ionised without fragmentation, and can then be analysed as single intact ions, creating simpler spectra within the mass spectrometer. This enables complex biofluids samples to be analysed and subjected to re-interro- gation for further results. Professor Iles said cost and time taken for diagnostics remains a major hurdle in global healthcare, but MS screen- ing offers a quick and cost-effective alternative for a range of tests. MAP measure heartbeat, ECG and blood oxygen. If these measurements are used for healthcare purposes, they have, for several reasons, to be treated with utmost caution. Firstly, we don’t know the quality of the measurements and we don’t know which malfunction might hap- pen. Moreover, if the user does not select properly, the results might show more healthy people than ill ones. Operated by lay users even good quality testing equipment can show the monitored person as healthy, despite suspicious results. Integration into existing struc- tures encompasses the human aspects, i.e. organisational or responsibility aspects, and tech- nical aspect, such as integration into existing LIS or HIS. Have those issues been solved, or are they solvable. Is this an ongoing problem? Today the known problems can be solved. There are many stable options for a hospital to integrate POCT equipment in their LIS or HIS. If some of the stakeholders don’t want such integration, problems arise – but they are non-technical. Today, however, we see new issues. Lab results, for example, are expect- ed to be recorded – in addition to many other data – in the electronic patient file. Particularly with POCT, it is dif- ficult to record test results so that they can be interpreted correctly later on. For many tests, the POCT equipment shows considerable dif- ferences in quality. Moreover, the reliability of the tests depends to a large extent on The clinical potential of POCT Continued from page 7 who performs the test: the patient, healthcare staff or a lab staff. Success and failure are close- ly related to quality and thus responsibility. How, in your opin- ion, should these issues be settled? In Germany we have a rather posi- tive situation: we have guidelines for quality assurance of laboratory exams published by the nation- al physicians’ association, the so- called Rili-BÄK. These guidelines define minimum quality standards for POCT. Within this framework the individual facilities can decide on the organisational structure that best suits their needs. One of the key aspects of POCT is the fact that, for it to be successful, different departments such as the wards, the lab and IT have to coop- erate. Thus, a platform should be struck. However, this unexpected- ly presented a new opportunity. ‘I always felt that the next step would be to use mass spectrometry and take samples and look for viruses, because viruses are packages of proteins,’ Iles explained. From early March, MAP Sciences teamed up with Professor Jonathan Heeney at Cambridge University to understand the biology of the virus, and devel- oped the biochemical approach for a new MS Covid-19 test. The team specifically used the compact Shimadzu MALDI-ToF 8020 mass spectrometer to detect proteins associated with Covid-19 and cre- ated the new gargle test, which also overcomes the relatively unpleasant approach of PCR testing with swabs of the throat and up the nose. How does the gargle test work? ‘What we’ve developed,’ Iles explained, ‘is ways of enriching the virus in the sample, breaking the viral envelope, releasing these large glycoproteins and then identifying these glycoproteins on the mass spectrometer.’ Someone with suspected Covid-19 gargles with 10mls of water for 30 seconds and spits into a pot, which is then delivered to the lab where ice cold acetone is added to the solution to kill the virus and cause precipitation of large molecules. The sample is spun in the centrifuge with a chemical solution added to break up the virus and release the viral proteins, and then transformed into a small pellet and placed on a matrix plate. It’s these viral proteins we look for to tell whether some- one has Covid-19 or not, but it also means we can identify any other virus there as well – for example H1N1 flu.’ The matrix pellet is placed in the MALDI-ToF mass spectrometer. A readout on the computer screen produces peaks highlighting the presence – or absence – of the coronavirus, or any other virus. The mass spectrometer is looking for the SARS-CoV-2 Spike Glycoprotein-S1 Protein. ‘We’ll only get the S1 spike Professor Ray Iles is Chief Scientific Officer with the MAP Sciences Group, which develops medical and digital diag- nostics (https://mapsciences.com/). His specific expertise lies in the assessment and measurement of biomarkers in bio- logical fluids, with a passion for the finer details of clinical diagnostics and the instrumentation, and in developing new techniques. With a BSc in Bioanalysis, MSc in Immunology, and PhD in Molecular Pathology, he is a Fellow of the Royal Society of Chemistry, the Society for Biology and a Chartered Biologist and the founding Dean of Abu Dhabi University’s College of Health Sciences. with virus being present,’ explained Iles, who adds that the gargle test is a fraction of the cost of the PCR swab test for coronavirus and sam- pling can be performed at home and sent through the post to labo- ratories. Mass spec – compact size and flexible software With data still being collated, Iles maintains that the gargle MS test is as accurate, if not more so, as the PCR test, believed to be about 80% accurate and with an unclear false positive rate. ‘We are cheaper, we are faster and we are an alternative technique that can confirm or refute a PCR test. We also have quality controls in place and we are ready to go,’ the professor confirmed. Iles favours the Shimadzu MALDI- ToF 8020 because of its software flexibility and compact size. It can conduct about 500 tests a day, meaning significant investment in MS hardware will be required if the gargle test is to contribute to the UK government’s testing aspirations, though Iles’ team is working closely with Shimadzu over potential modi- fications. Yet, he believes their sophisticated and affordable testing technology, with fewer consumables than other Covid-19 tests, will complement the simple binary Covid-19 tests cur- rently in use and produce accurate results with fewer false positives as the global fight against coronavirus continues. established where these stakehold- ers can regularly exchange ideas and experiences. In the end, how- ever, there is one person who needs to be responsible, and it makes a lot of sense for this person to be an expert in laboratory analytics. EUROPEAN HOSPITAL Vol 29 Issue 4/20

1 0 O N C O LO G Y The massive Pan-Cancer Project Cancer development begins within the genes Visualisation of diversity of B-cell lymphoma. Each circle represents a tumour (patient), with the colours differentiating between the different types across Germany we con- tributed towards a better understanding of lym- phoma, which mecha- nisms lead to its origin and development; why the affected cells degenerate… yes, this was a vast amount of data involving millions of sequence positions in around 20,000 genes, from hun- dreds to a few thousand patients respectively, which the bioinforma- ticians prepared in such a way that conclusions can be drawn.’ Launched in 2011, the Pan-Cancer Project involved more than 1,300 scientists and clinicians in 37 countries, and analysed more than 2,600 genomes of 38 tumour types. Discovery: The first indications of cancer development can be found in genes at a very early stage, which triggers new opportunities for treatment. Within the pro- ject, Leipzig-based scientists specifically analysed the DNA material. Initially in our interview, Dr Hans Binder, Managing Director and research leader at the Interdisciplinary Centre for Bioinformatics (IZBI) at Leipzig University explained how the cancer cells examined. Interview: Katrin Schreiter ‘Doctors took tissue samples from patients and diagnosed the cancer. Pathologists examined the tissue to make further, detailed diagnoses and laboratory medics and molecu- lar biologists extracted the DNA and sequenced it. The sequence data provided information about the mutations. We have developed bioinformatical methods and used them to derive mutations and fur- ther information such as activity of the genes and possible problems with biological functions from the sequence data. This makes it pos- sible to differentiate between types of cancer through a comparison of the nucleotide sequences along the DNA, or respectively the fre- quency of RNA copies read out in samples from the cancer patients.’ The findings: ‘With our partners Can those conclusions be gener- alised? Cancer is a complicated disease which develops because of defects in the genome. Strictly speaking, with each patient it is not a disease but actually a multitude of defects which can have different effects. For the first time, the project gave an overview of the possible defects. Could these then be addressed with targeted treatments? Unfortunately, a genetic defect can- not simply be repaired, as side effects of treatment are not predicta- ble and controllable. This makes the disease so difficult. But research is progressing. It is important to learn how cancer works. We have already developed improved diagnosis- and treatment options, such as immuno- therapy. Apart from fighting cancer we also need to adjust treatment in Biophysicist Hans Binder has been Managing Director of the Interdisciplinary Centre for Bioinformatics at Leipzig University since its foundation in 2002. He leads the research group on ‘Omics, bioin- formatics for health and systems biology’ at the IZBI. He focuses on transcriptome and genome data from sequence analy- ses to understand the molecular and sys- temic mechanisms of diseases, particularly cancer. His team develops bioinformatical procedures using machine learning, and is involved in several international and national research consortia. such a way that patients can live with the disease as best and for as long as possible. Have you gained any insights on how cancer presents in the initial stage? On a DNA level you mostly find so- called driver mutations. This often affects genes with key functions and leads, for instance, to increased cell division, i.e. the cells infiltrating healthy tissue. Some of these chang- es can be detected in the genes, decades before the disease mani- fests. But simple and standardised treatment is not possible: Mutations make the cancer very variable; it adapts and becomes hard to fight. This sounds like a multitude of cell changes. Yes, the variety is enormous. The important thing is knowing that each person’s genome is unique – which is why every cancer, as a dis- ease of the genome, is also unique. However, the variants can often be grouped to devise specific treatment rules. Are these insights a further step towards personalised medicine? Most definitely. It will be the respon- sibility of Cancer Research Centres (and already is in parts) to analyse the DNA of each patient to under- stand the specific characteristics of their disease and then tailor their treatment accordingly. Detection during, not between screenings is best Study delivers breast cancer advice Tumours with the same biology have different prognoses based on their method of detection, and this information should be taken into account when deciding which treatments might be needed, a Dutch researcher explained at the 12th European Breast Cancer Conference. High-risk breast cancers detected in screening program mammograms have a better prognosis than those cancers detected in the interval between screening rounds, suggests an analysis of results from over eight years’ follow-up of a major international clinical trial. A team of Dutch researchers looked at cancers that had been identified as being high risk by the 70-gene signature test, but differed in the way they were detected, i.e. either during the biannual national screening program or in the two- year interval between screenings, typically when a lump or other abnormality is detected at the GPs and a mammography is prescribed. The researchers compared the data of over 1,000 Dutch breast cancer patients aged 50-70 who had enrolled in a European phase III clinical trial and participated in the Dutch national biannual screening program. The authors found that although some tumours may have the same genetic make-up, the way they are detected makes a significant differ- ence to the period of time before the disease starts spreading or results in death – a lapse of time known as the distant metastasis-free interval (DMFI). ‘We found a signifi- cant difference in survival between high-risk cancers detected during screening or in the interval between screenings. The eight-year DMFI rate was higher among women with screen- detected cancers than for women with interval cancers: 93.8% ver- sus 85.2%,’ said PhD candidate Dr Josephine Lopes Cardozo at the Netherlands Cancer Institute (NKI) in Amsterdam, and medical fellow at the European Organisation for Research and Treatment of Cancer (EORTC) in Brussels. Dr Josephine Lopes Cardozo is a PhD candidate at the Netherlands Cancer Institute in Amsterdam, and a medi- cal fellow at the European Organisation for Research and Treatment of Cancer (EORTC) in Brussels, Belgium. Her lengthy interest in breast cancer continues with a focus on the role of the 70-gene signa- ture for clinical decision-making in breast cancer, to evaluate how to select those patients who would benefit from adjuvant systemic therapies or not. Additionally, those patients with high-risk tumours detected in the interval between screenings had a 2.4-fold increased chance of devel- oping distant metastases compared to those whose cancer was detected during screening. These findings complement pre- vious research done by the same group showing that interval can- cers more often have a high-risk genetic profile, as shown by the 70-gene signature, and are therefore at higher risk of distant metastases. ‘We know these interval cancers are more aggressive and thus also have a worse prognosis,’ Cardozo explained. ‘However, there are also screen-detected cancers with a high- risk 70-gene signature.’ MINDACT In their current work, Lopes Cardozo and colleagues looked at the data of 1,102 Dutch patients enrolled in the MINDACT study, a large prospective trial testing the 70-gene signature MammaPrint as guidance for adju- vant chemotherapy in breast can- Different proportions of 70-gene signature results among screen-detected and interval cancers cer patients across nine European countries. The team calculated dif- ferences in DMFI for high, low and ultra-low risk tumours, as classified by the 70-gene signature, which EUROPEAN HOSPITAL Vol 29 Issue 4/20

1 2 D I G I TA L PAT H O LO G Y Detected and defined: two distinct immunopathological profiles Experts unlock Covid-19 secrets Experts have identified two distinct immunological and cellular profiles in the lungs of Covid-19 patients which they believe could help define treatment pathways. Dr Kirsten Mertz is a senior pathologist at the Institute of Pathology and Head of the Molecular Pathology and Cytopathology service at the Cantonal Hospital Basel, Liestal, Switzerland. Her research focuses on molecular diagnostics of cancer, immu- nopathology and the (molecular) pathology of infections. ISGhigh profile to a ISGlow profile. ‘Our study may help to guide the selection process of specific clinical biomarkers that correlate with the course of disease,’ said Dr Kirsten Mertz, Senior Pathologist at the Institute of Pathology, Liestal. ‘It also could be informative for patient stratification and personalised treat- ment. These findings potentially could help to better assign specific drugs to Covid-19 patients.’ Anti-viral medication may be of key relevance to ISGhigh patients, she added, while immune-modula- tory drugs and drugs targeting the complement system as well as tissue remodelling may be of relevance in the second group. Study team (from left: Kirsten Mertz, Ronny Nienhold, Tobias Junt, Viktor Koelzer, Franscesca Demichelis, Yari Ciani Professor Viktor Kölzer is Attending Pathologist at the Institute of Pathology and Molecular Pathology, University Hospital Zürich; Assistant Professor and Lead for Digital Pathology, University of Zürich, and Honorary Senior Clinical Researcher, Department of Oncology, University of Oxford. His research aims to improve patient care through the imple- mentation of high quality, science-driven, computational image analysis approaches with a focus on gastrointestinal disease, immunology and immunotherapy. Better understanding the disease stages The researchers say the findings could deliver a better understand- ing of the disease stages and pro- gression of Covid-19, and help to achieve more personalised and more effective treatment for patients, with the right drug to the right patient at the right time and informed by the underlying biology of disease. The research was also an ‘uplift- ing experience’ for the researchers during the difficult period of lock- down. ‘Everyone could use their skills to contribute and unlock some of the secrets of this coronavirus,’ Mertz said. ‘We were making a dif- ference, and that kept us going.’ Lung of ISGlow patient who initially defeated the virus but suffered massive damage to lungs and other organs due to the body’s virus response and eventually died during the course of Covid-19 part were experts in immunology, molecular, digital and viral patholo- gy, Professor Francesca Demichelis, Dr Yari Ciani, Dr Tobias Junt, Dr Ronny Nienhold and Professor Kölzer and Dr Mertz in the study working in close collaboration. (Link: https://rdcu.be/b8GFm). While the study sheds further light on Covid-19 lung disease, researchers say it is too early to reach clear conclusions on thera- peutical approaches. However, they feel the findings are suggestive of a natural disease course of Covid-19 in lungs from an Report: Mark Nicholls From some of the earliest Covid- 19 autopsies conducted in Europe, Swiss-based researchers have per- formed integrative digital pathology and transcriptomic analyses of lung tissues of 16 coronavirus patients who died from respiratory failure during the first wave of Covid-19 and found striking histopathologic changes in the lungs. ‘These two distinct patterns of immune pathology of pulmonary Covid-19 may give an insight into the natural progression of Covid-19 in the lungs,’ said Professor Viktor Kölzer, head of the Digital Pathology department at the University of Zurich. The distinct patterns were defined by their differential expres- sion of interferon stimulated genes (ISGs) and by their infiltration with immune cells/immune infiltration patterns. The ISG subgroups – termed ISGhigh and ISGlow – differ with regards to the characteristics and extent of pulmonary damage, pulmonary viral loads, immune infil- tration, and time from hospitalisa- tion to death. ‘We combined digital pathology analysis for the quantitative study of immune cell infiltration in diseased lung tissue with transcriptomic anal- ysis of key pathways involved in the immune response and PCR-testing of SARS-COV2 viral loads,’ Kölzer explained Integrative analysis ‘This integrative analysis enabled us to detect and define two dis- tinct immunopathological profiles of lethal Covid-19 based on gene expression and immune infiltration patterns. These profiles may point to distinct stages of disease progres- sion with potential to guide specific therapeutic interventions.’ The ISGhigh profile showed high local expression of interferon stimu- lated genes and cytokines, high viral loads and limited pulmonary damage; while the ISGlow profile showed severely damaged lungs, low ISGs, low viral loads and abun- dant infiltrating activated CD8+ T cells and macrophages. Patients in the ISGhigh group died at an early time point from a high viral load in the lungs as the immune system did not manage to suppress the virus. However, while ISGlow patients can initially defeat the virus, the activity of the immune response resulted in massive dam- age to the lungs and other organs and they died after several days or weeks. ‘Patients who die early cannot adequately control SARS-CoV-2,’ Dr Mertz, Senior Pathologist at the Institute of Pathology, Liestal, explained, ‘while patients who die late suffer from diffuse alveolar damage and immune-pathology with increased lung remodelling. Infectious dose and individual predisposition to mount immune responses are to define whether or not a patient survives Covid-19.’ likely The autopsy data provided an important opportunity to better understand tissue damage patterns in lethal Covid-19 in the patient group, which was also high-risk due to age and other conditions, such as hypertension, heart disease and diabetes. With the pandemic now in a sec- ond wave, the researchers have a ‘pressing need to better understand the pathogenesis of Covid-19 for personalised risk stratification and treatment of critically ill patients.’ The collaborative study embraced molecular pathology, digital pathol- ogy, and bioinformatics, to deliver findings with potential clinical and biological implications and assess the immune response to Covid-19 from a multitude of aspects. Taking No compression. No superimposition. JUST GREAT IMAGING www.ab-ct.com Malta: Moira Mizzi Spain: Mélisande Rouger, Eduardo de la Sota The Netherlands: Madeleine van de Wouw USA: Cynthia E. Keen, Lisa Chamoff Subscriptions Dorothea Fleischer, Theodor-Althoff-Str. 45, 45133 Essen, Germany Subscription rate 4 issues: 32 Euro, Single copy: 8 Euro. 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1 4 R A D I O LO G Y Significant advances in medical physics Imagine: 30 radiation sessions reduced to five To target ionised radiation as precisely as possible, imaging a tumour is vital in radiotherapy planning. ‘Today, imaging is used increasingly during the therapy itself,’ explained Professor Mark Ladd, Head of Medical Physics in the Department of Radiology at the German Cancer Research Centre (DKFZ) in Heidelberg, Germany, and President of the German Society for Medical Physics (DGMP), during the society’s 51st annual meeting. one of the key development areas in medical physics. Since 2017, the first systems have been certified for clini- cal exams, initially limited to head scans and smaller joints. The advan- tage of a 7-T MRI scanner is not only resolution. ‘There is an interdepend- ence of sensitivity and time.’ Ladd said, adding ‘with a field strength of 1.5-T we can examine about every- thing that we can examine with 7-T – but at a much slower speed.’ 3-T scanners are mostly used to perform exams faster than with a 1.5-T scanner. By contrast, a 7-T scan- ner not only reduces exam time but also offers enhanced spatial resolu- tion and more detail. “You can com- pare it with standard and HD resolu- tion of a TV screen: suddenly you see things you could not see before,’ Ladd said. For example, the so-called swallow tails in the basal ganglia, whose lack indicates Parkinson’s dis- ease, can only be vaguely seen in a 3-T scan – but they are clearly visible in a 7-T scan. Gradient coils: pushing the envelope of physics Ladd sees larger gradient fields as an overall trend in MRI. The faster the gradient, the higher the risk of peripheral nerve stimulation. This fact has limited the use of larger gra- dient fields. GE Healthcare, however, has developed a 3-T system for the head only, which is equipped with a faster gradient since, in head-only exams, the problem of nerve stimula- tion is less pronounced. Some research teams have man- aged to simulate nerve stimulation caused by gradient coils prior to the actual scan. Before, the degree of nerve stimulation was measured using fully developed gradient coils and a performance cap for this par- Having joined the German Cancer Research Centre (DKFZ) in Heidelberg in 2013, today Professor Mark Ladd heads Medical Physics in its Department of Radiology. He is also President of the German Society for Medical Physics (DGMP). His research focus is magnetic resonance imaging (MRI), particularly the launch and further development of new methods using ultra-high-field strengths and MRI in image-guided radiotherapy. He studied electrical engineering at the University of Michigan in Ann Arbor and Stanford University in California. In 1998, and received his doctorate from ETH Zurich in the context of a research cooperation project between the University Hospital Zurich and GE. In 2004 he became Professor of Biomedical Imaging at Essen University Hospital, where he increasingly focused on ultra-high-field MRI. ticular coil was determined. Today, computer programs can predict the degree of peripheral nerve stimula- tion, thus the coils can be optimised in the development phase. ‘Over the next few years, we will see sig- nificantly stronger gradient systems,’ Ladd predicts. PET-CT and the 2 metre detector Last, but not the least in PET-CT, the first whole-body scanner may be in the wings. The Chinese company United Imaging developed a detector that measures two metres! Siemens is working on a system that combines four conventional detectors and thus enables a PET-CT scan of more than a metre. ‘Whole-body PET-CT could open up new possibilities in imaging, which were unrealistic before due to the exceedingly high radiation expo- sure,’ Ladd explained, ‘including new options for visualising the course of a therapy.’ EUROPEAN HOSPITAL Vol 29 Issue 4/20 Interview: Daniela Zimmermann This new imaging role is possible due to the magnetic resonance linear accelerator, MR-Linac for short, which combines a linear accelerator with a MRI scanner. ‘It shows, in real- time, how the tumour moves with breathing,’ Ladd explained during our European Hospital interview regard- ing current trends in medical physics. Continuous MR-Linac scanning during radiotherapy enables track- ing of breathing-induced movement and thus adjust the therapy; it also records any change in location and size of the tumour during the weeks of therapy. ‘Rather sooner than later, we’d like to control the collimators in real-time so as to adjust radiation in view of the changes, compared to the initial therapy plan. In short: we want to tailor the therapy plan in real-time,’ Ladd underlined. The more precisely the tumour can be targeted, the high- er the dose can be. ‘Thus the patients wouldn’t have to undergo 30 radia- tion sessions but maybe only five,’ he pointed out. At DKFZ a project-team is looking for new approaches to adjust the collimators quickly. Another research project in particle therapy deals with the exact recogni- tion of the Bragg peak, i.e. the point when the energy of the ion beam reaches its peak and then sharply decreases. Since scientists are still uncertain where exactly the Bragg peak ends in the body, a compara- tively large safety margin is defined around the tumour to reach as much of the tumour tissues as possible. ‘With current technology the safety margin has to be so large that, in fact, we cannot realise the full potential of proton therapy,’ Ladd reported. Thus, researchers are trying to develop different methods to determine the Bragg peak in vivo. One of these approaches tries to detect secondary gamma rays triggered by the proton beam in the body. Better insights: photon-counting CT Photon-counting CT is another remarkable development in radiol- ogy. DKFZ houses one of three CT prototypes worldwide that feature a unique component: a photon-count- MR-Linac (Unity, Elekta AB, Sweden) at the University of Tübingen (DFG ZI 736/2-1): a hybrid system combining a 1.5-T MRI scanner with a 7-MV linear accelerator for online adaptive MR-guided radiotherapy ing detector made of a semi-conduc- tor material that can directly convert X-rays into electrical signal impulses, making it particularly efficient. ‘I do hope that this technology will one day be clinical routine,’ Ladd said. While photon-counting detectors are expensive, they offer better resolu- tion and allow imaging with sig- nificantly lower contrast doses. ‘With regard to the current debate about contrast media, photon counting is a very promising approach,’ he said. MRI with new elements and high field strength Another trend in medical physics is X-core MRI. While in conven- tional MRI the spin of the hydrogen nucleus is measured, X-core MRI determines the magnetic moment of isotopes of other nuclei, e.g. sodi- um-23 (Na-23), oxygen-17 (O-17), potassium-39 (K-39) or chlorine-35 (Cl-35). Problem: these isotopes are rather rare. Only 0.04 percent of oxy- gen, for example, is O-17. In a DKFZ research project, patients inhale a gas enriched with O-17 during the MRI scan. The oxygen travels through the blood and as soon as it reaches the mitochondria in the cells and is con- verted into water it can be visualised. Oxygen imaging at 7-Tesla ‘This enables us to precisely measure the local oxygen metabolism in the brain and in other parts of the body,’ Ladd explained. Currently, one team is trying to detect whether regional differences in metabolism might indi- cate which areas of the brain will recover after a stroke and which ones won’t. Visualising the distribution of O-17 and other isotopes in MRI requires a field strength of 7-Tesla. Indeed, beyond this application 7-T MRI is MR-guided high precision radiotherapy of a liver metastasis. (A) Native planning CT; target delineation is not possible without implanted markers or contrast agent injection. (B) Excellent visualisation of the target region using navigated T2-weighted MRI (red arrow). (C) Markerless MR-guided stereotactic body radiotherapy of a liver metastasis using the 1.5 T MR-Linac (Unity, Elekta AB, Sweden) 09/2020 at the University Hospital for Radiation Oncology Tübingen. Photon-counting detectors are a major innovation in clinical CT. These directly converting detectors register photons and record their energy. Moreover, their pixels are much smaller than those of conventional detectors. The new technology promises spectral resolution comparable to dual energy CT, significantly smaller doses and greatly enhanced spatial resolution. The images of an inner ear were acquired with an experimental photon-counting whole-body CT scanner (Somatom CounT, Siemens Healthineers) at DKFZ More than just MRI accessories www.allmri.com

1 6 R A D I O LO G Y Anatomy meets astronomy French radiologists set their eyes on the stars About 2,200 satellites are currently orbiting the Earth and soon space stations may be equipped with the latest medical imaging technology, including interventional radiology devices. In France, radiologists and astro- nauts are putting their heads togeth- er to make this vision materialise in a unique partnership between the French Society of Radiology (SFR) and the French Space Agency (CNES). Alain Luciani, President of the JFR 2020, the SFR’s annual meeting, explained how this alliance could help not only advance healthcare in space but also knowledge of space travel’s impact on the body and population health. ‘Human spaceflights beyond the Earth orbit and to the Moon and Mars trigger an accelerated but potentially reversible ageing pro- cess,’ explains radiology Professor Everywear experience on board the International Space Station Luciani. ‘Strain on the body is mul- tiple, impacting not only the MSK system but also the central nervous system, with ocular complications.’ Advanced imaging techniques can help to anticipate, understand and potentially correct disorders result- ing from travelling into and back from space. MRI or CT can help evaluate bone density, reduction of the muscular mass and modifi- cations of the cerebrospinal fluid, which are also challenges for popu- lation health. For example, muscular mass evaluation is a relevant prog- nostic marker for patient survival in oncology, as recent studies on sarcopenia have shown. ‘The perspective of human space- flights raises the questions of moni- toring astronauts’ health and poten- tially implementing remote treat- 7 1 0 2 , / / A S A N A S E © ment. The SFR wishes to bring its expertise to develop innova- tive and miniaturised technology to help monitor astronauts’ health beyond current use of ultrasound devices, and transfer interventional radiology techniques, i.e. minimally invasive procedures, to help treat emergencies directly inside inhab- ited spaceships and stations,’ said Luciani Are you considering sending radiologists into space? 7 1 0 2 , / / A S A N A S E © Left: French aerospace engineer, pilot and European Space Agency astronaut Thomas Pesquet in his spacesuit on a spacewalk. Below: Thomas Pesquet spacewalking during the Proxima mission. 7 1 0 2 , / / A S A N A S E © 7 1 0 2 , / S O M S O C S O R © appreciate the effect of both heavy particles, which are rather applied in radiotherapy, and chronic expo- sure to lower intensity radiation, which is more similar to the expo- sure to ionising radiation induced by X-ray-based diagnostic radiology. There is also an issue concern- ing equipment, notably radiation protection strategies and imaging equipment selection, since X-ray sources have not yet been embarked during space travels, except in min- iaturised osteodensitometry projects for animal testing. These challenges can be transposed to patients on Earth, notably through the develop- ment of miniaturised sources and devices that could one day be used, for example, close to intensive care beds, as patient travel is increasingly complex. What about interpreting images from space? Space offers exploration possibilities for teleradiology, to which French radiologists wish to make a substan- tial contribution. Sharing complex data, such as radiological images on long distances, opens investigation in data accelerated transmission and compression, without losing imag- ing data, which can also be applied on Earth, for example remote radi- ology services for places difficult to access. Will the partnership tackle celes- tial as well as human images? The CNES produces Earth imag- es that are acquired from space and space images to explore the universe. The agency must there- fore handle huge quantities of data, develop autonomous image analysis Ultrasound experience aboard the International Space Station (ISS). We can ask that question; it has already been tackled in the lit- erature (Kansagra et Coll. JVIR 2015;26:825-828). But beyond this discussion, we want to promote the development of remote monitoring tools and bring our expertise to accompany space travels from Earth and create training programs with expert radiologists. What is the risk of ionising radi- ation? Cosmonauts and astronauts are exposed to ionising radiation, cos- mic rays, galactic rays and particles that are emitted by solar eruptions and Van Allen belts when in orbit around the Earth. These so-called heavy rays are very different from the low dose radiation that is emit- ted by radiological devices on Earth. Nonetheless, the development of radiation protection tools for astro- nauts is a shared preoccupation for both the SFR and the CNES. Here again, space is a model to Radiologists must learn to distinguish signs of two arteriopathies Deterring paediatric acute stroke Acute stroke in children has the same incidence as brain tumours and can seriously affect a patient’s life. Two kinds of arteriopathies are common drivers of paediatric acute stroke and radiologists must learn to distinguish their signs as early as possible to improve prog- nosis, according to Béatrice Husson, a paediatric radiologist at Le Kremlin Bicêtre Hospital in Paris. Report: Mélisande Rouger ‘Acute stroke can trigger focal motor deficit in so-far healthy children. There can be diagnostic wander- ing because deficit, before being definitive, can regress and fluctuate for many hours or even days, and because knowledge of this ischemic aetiology is still insufficient and wrongly attributes diagnosis to migraine or epileptic seizures with Todd’s paresis,’ said Husson at the recent JFR, the French Society of Radiology’s annual meeting, online. Unlike adults, a leading cause of acute stroke in children is arterio- pathy, especially focal cerebral arte- riopathy, which causes 30 to 40% of paediatric strokes, with unilateral damage of anterior circulation, and vertebral arteriopathy, a less com- mon yet typical condition of the paediatric age. ‘The first thing to remember when imaging a child with sus- pected stroke is to avoid using seda- tion, which could complicate patient neurological monitoring and is no longer necessary given the impor- tant reduction of acquisition times in MRI,’ she advised. Tending to the child in a calm and comforting atmosphere without losing time is paramount. MRI is the first choice modality in these patients, except when they present with consciousness disorders. “In this case,’ Husson added, ‘we’ll carry out a CT scan with an anaes- thetist resuscitator at our side.’ MRI protocol includes a diffusion sequence, T2 or magnetic suscepti- bility sequence, FLAIR axial study, TOF MRA at the level of the circle of Willis, MRA of cervical arteries, non-contrast perfusion – if possible – and a T1 sequence. For CT, radiologists should per- form non-contrast head CT, followed by arterial CT angiogram of the head and neck. Husson shared several clinical cases with the audience, including the images of a child presenting with deep left ischemic stroke and occlusion of the left middle cerebral artery. Thrombectomy was initiated and recanalization looked satisfying on angiographic images before and right after procedure, however fol- lowing MRI showed renewed occlu- sion and stroke extension a few hours later. ‘This evolution, and these possible complications, can be explained by the aetiology of this focal brain arte- riopathy, which we believe is linked to arterial wall inflammatory dam- age that may be caused by infection. The most common infectious agents are varicella and zona viruses, and so we will systematically look for Two and a half year old boy. Left hemiplegia discovered as the patient woke in the morning. Varicella episode had occurred four months before neurological event. Acute stroke in the deep right middle cerebral artery (MCA) secondary to focal arteriopathy, probably post infectious (varicella) Figure B: Flair T2 sequence. Hypersignal of the right lenticular nucleus (arrow) confirming constituted stroke four hours earlier Figure A: axial diffusion sequence. Hypersignal of the right lenticular nucleus (arrow) linked to acute stroke in deep right MCA Figure C: Face reconstruction of the Willis polygon (acquisition with a TOF MRA sequence), showing distal stenosis of the M1 segment in the right MCA (arrow) varicella infection 12 months before stroke in a child presenting with such symptoms, ‘ Husson explained. MRI follow-up was able to show recovery and stabilisation of arterial lesions, enabling an end to anti- platelet treatment 18 to 24 months after the event. The second arte- EUROPEAN HOSPITAL Vol 29 Issue 4/20

1 8 U LT R A S OU N D Improving men’s infertility diagnosis Multiparametric ultrasound finds causes Infertility has long been attributed to women alone, but medical advances have shown it really is a couple’s problem, with 20% of couples presently having trouble conceiving. Medical imaging, in par- ticular ultrasound, can help identify underlying causes of men’s infer- tility and other related health issues, an Italian radiologist explained during the last European Congress of Radiology. Multiparametric (MP) ultrasound is the imaging modality of choice to evaluate findings that, when cross- checked with patient history and physical and laboratory examina- tions, can help identify potential causes of infertility in men. ‘The presence and site of an obstruction of the seminal tract, tes- ticular volume and characteristics, cryptochidism – absence of one or both testes – varicoceles and focal lesions can all be assessed with MP ultrasound,’ said Michele Bertolotto, Associate Professor of Radiology at the University of Trieste, Italy. A complete examination The examination must be performed carefully to evaluate size, echogeni- city and echotexture of testes; size and morphology of the epididymis; and evaluation of the vas deference, prostate, seminal vesicles and ejacu- latory ducts. The best way to evalu- ate volume of testicles is possibly using the Lambert formula, accord- ing to Bertolotto. In patients with testicular causes for infertility, MP ultrasound ena- bles to evaluate cryptorchidism, and to pick changes in the testicular parenchyma resulting from chromo- some abnormalities, orchitides and ischemic disease. In cryptorchidism, the modality helps identify the testes at the level of the inguinal canal and also some- times at the level of the abdomen. In some instances, MRI may help better identify cryptorchidism because of high signal intensity on T2 weight- ed images and diffusion-weighted images. However, radiologists must remember that when the testis is markedly hypothrophic, signal intensity in diffusion-weighted imag- ing is reduced. ‘Sometimes findings are more visible on ultrasound than MRI,’ he pointed out. In obstructive causes of infertility, ultrasound enables careful evalua- tion of the entire seminal tract, and can help spot congenital abnormali- ties and the obstruction site. ‘An epididemal head larger than 11mm can be considered a sign of obstruction if the level of epididymis and other causes of obstruction of epididymis are chronic epididemi- tis,’ he explained. ‘Cysts, interrup- tion and stenosis may also be identi- fied as signs of obstruction.’ MP ultrasound can also show obstruction in vas deferens and seminal vesicles, helping among others to recognise agenesis, a rare Chronic epididymitis causing obstructive infertility. The epididymis is enlarged and hyperemic. Obstruction is demonstrated by presence of dilated rete testis with intratesticular spermatoceles potentially correctable cause for men’s infertility. However there is a lot of confusion in the literature about how to perform the corre- sponding ultrasound examination and report it,’ he said. Radiology Earlier this year, the Scrotal and Penile Imaging Working Group the European Society of of Urogenital (ESUR- SPIWG) has released guidelines and recommendations on how to per- form MP ultrasound for varicoceles. The publication details how the examination should be performed in supine and erect position, at rest and during Valsalva. ‘Bilateral, grey scale, colour and spectral analysis should be used. Testicular and size of the largest vein should be meas- ured; reflux is considered pathologi- cal when longer than two seconds,’ Bertolotto said. Reporting should mention tes- tis volume, echogenicity and echo- Azoospermia caused by obstruction at the level of the ejaculatory ducts. The right duct is dilated, due to distal stenosis (not shown). The left duct is obstructed by a stone malformation commonly associat- ed with other abnormalities, such as absence of a vas deferens or absence of a kidney. Obstruction in the ejaculatory ducts may be caused by stenosis, stones or cysts, which can also be clearly shown by ultrasound. New European guidelines for varicoceles Varicoceles are varicose veins of the testicle and scrotum that may cause pain, testicular atrophy or shrinkage, or fertility problems. Varicoceles are a common urological problem and are often detected incidentally. The disease affects about 10 per- cent of all men and 30 percent of men among infertile couples; but the condition also can be corrected. ‘Varicoceles are the commonest Smartphone aids learning of brain US scans semeiotics Neurosurgical oncology Italian neurosurgeon Professor Francesco Di Meco, explored the cur- rent and potential role of intra-operative ultrasound in neurosurgical oncology during the annual meeting of the European Association of Neurosurgical Societies (EANS) this October. The extent of resection is considered a prognostic factor in operative neuro oncology surgery and image-guided surgery is being regarded as one of the major aids to increase the extent of resection of brain tumours. Image-guided surgery techniques include neuronavigation, intra oper- ative MRI, fluorescence and intra- operative ultrasound (US). The lat- ter presents with several benefits during and after surgery, although it remains an unusual imaging tech- nique for neurosurgeons, according to Francesco Di Meco, full professor of neurosurgery and maxillofacial surgery at Milan State University and head of the department of neu- rosurgery at C. Besta Neurological Institute Foundation in Italy. Real-time and dynamic ‘Intra-operative US is a real-time, dynamic and relatively inexpensive imaging technique. The improve- ment of the resolution and quality of images enables distinguishment between grey and white matter,’ he explained. Real time imaging is use- ful for anatomic structures identifi- cation, a challenging task even for very experienced neurosurgeons. The fusion of neuronavigation and intraoperative US has helped understanding the semiotics – the study of signs and symbols and their use or interpretation – of ultra- sound, and a number of softwares have been validated that combine the techniques, such as the Orion H2/US and Virtual Navigator. This fusion may also help to cor- rect one of the major drawbacks of neuronavigation: brain shift. ‘With neuronavigation,’ he explained, ‘two blended images of the tumour are not perfectly overlapping, there’s a gap.’ To correct this, surgeons can freeze one of the images, for exam- ple the MRI’s, and draw it over the image provided by ultrasound, and can repeat the operation as many times as necessary. ‘Having real-time images is useful at any point during surgery. You can check at any time how much tumour is left. And you can also check the end of resection, if there are some remnants of the tumour,’ Di Meco pointed out. Evolving role The neurosurgeon tackled the evolv- ing role of intraoperative US with features such as Doppler, elasto- sonography and the use of contrast. Doppler enables the identification of vessels, notably those that have been impacted in tumour resection, while elastosonography provides information about stiffness of the tissue, using the colour reference scale to evaluate hard or soft tissue. Elastosonography can also help to identify the borders of a tumour. ‘We found that elastosonography is superior to B-mode ultrasound for the definition of margins,’ he said. Research has shown that elastogra- phy is also useful to identify tumour remnants at the end of resection. Brain shift correction Integrated intraoperative MR/US neuronavigation Real time images for anatomical landmarks identification EUROPEAN HOSPITAL Vol 29 Issue 4/20

2 0 U LT R A S OU N D HartKliniek – cardiology with a Dutch twist Cardiology tends to be surrounded by a maze of regulations, responsibilities and red tape. Leave it to the traditionally mercantile Dutch to streamline things. Case in point: HartKliniek, a chain of medical specialist diagnosis and treatment centres in the Netherlands which aim to transform car- diology to a more effective model – less personnel, more time for patients. We spoke with Menno and Willem Baars, members of the founding trio, about the origins of the HartKliniek and how paring down structures to the essentials can benefit patient wellbeing. can differ greatly between sexes. It is not rocket science to fig- ure that treating fewer patients in the same time would generate less money. Thus, financing such a con- cept proved challenging – but the founders came up with a solution: By trimming management layers, medical assistants, nurses, expen- sive equipment and other redun- dancies, the centres are able to operate profitably. This means that the cardiologists themselves have to do tasks that are normally delegated HartKliniek was founded in 2014 by CEO Menno Baars, his brother Willem Baars as COO and CMO Chris Hie. Today, there are eleven centres under the group’s name located in Almere, Amsterdam, Den Haag, Dronten, Groningen, Hoorn, Lelystad, Nijmegen, Vlaardingen, Oisterwijk and Zandvoort, with 20 cardiologists employed. In 2019, more than 20.000 patients were treated, with an expected growth to 30.000 in 2020. The goal is to estab- lish several locations in each of the 12 Dutch provinces to support the notion of ‘bringing cardiology to the neighbourhood’. fundamental Cardiologists stretched to the max The idea behind HartKliniek is surprisingly old-fash- ioned: paying more attention to the individual patients. One evening, at the end of his working day at the hospital, cardiologist Menno Baars was fed up with spreading his working hours across 50 patients – clearly too many to treat with prop- er diligence in an eight-hour shift. Excessive time pressure had led to the fact that frequently, he observed, the correct diagnosis was not made during the first work-up and the cardiologists had to see the patients several times, observed. To fix this issue, Baars founded HartKliniek. In the HartKliniek centres, cardi- ologists are assigned a maximum of 15 patients per day, leaving con- siderably more room for thorough diagnosis, treatment and taking time to attend to the questions of each individual. A good doctor must listen This opens up opportunities to per- ceive a patient as more than just a collection of medical parameters with a malfunctioning part of their body’s machinery. ‘In many cases, you have to dig deeper to see where heart problems have their roots,’ Menno Baars points out. ‘To be a good doctor to your patients, it’s essential to listen,’ adds cardiolo- gist Bettina Massaar-Hagen. In this regard, HartKliniek just might fill a gap that has been present in cardiac care for far too many years. The concept of paying more atten- tion to patients especially appears to strike a chord with the female popu- lation, the COO notices. Women appreciate doctors who put greater emphasis on communication rather than just performing the required examinations. Taking this into account, a more precise diagnosis can be established in female patients, since the symp- toms caused by cardiac problems to other staff: anamnesis, consult- ing with the GP or performing the actual examinations. This approach is well-received by the patients, as positive feedback shows. The HartKliniek centres boast top scores in patient satisfaction across the whole Netherlands, Baars states – not a mean feat in an area where many heart patients tend to faithful- ly stick to their trusted doctor rather than turning to a relative newcomer. GP, hospital and the HartKliniek makes three The centre’s profile is further sharp- ened by adhering to low-complexity procedures. Emergency or open- heart operations are not performed. Patients in need of stents, ablation or a bypass are referred to the respec- tive specialists in the surrounding institutions. This is also beneficial for the bigger hospitals as they can concentrate on more severely ill patients without less complex cases burdening their perpetually busy schedules. With this approach, the HartKliniek acts as the missing link between primary care at the GP and highly specialised cardiology departments of hospitals. This inter- play between healthcare providers works due to a well-maintained network that aims to assign the patients to the institution that best fits their needs through referrals in both directions. Chinese-Dutch collaboration in ultrasound For diagnostic work-up and patient monitoring, the HartKliniek centres Menno Baars is founder and CEO of HartKliniek, a chain of specialist medical diagnosis and treatment centers for car- diovascular diseases in the Netherlands. Born in Utrecht, Baars obtained his medi- cal degree at the University of Utrecht and Harvard Medical School in Boston, USA. After gathering practical work expe- rience as a general cardiologist in hospi- tals during for almost 20 years, he started HartKliniek in 2014. Along his medical expertise, Baars is also an internationally renowned artist with his paintings being displayed in worldwide art exhibitions. rely on ultrasound systems from Mindray. ‘Coming a bit from out- side ourselves, we wanted to go with a company not yet as well- established in the Netherlands,’ says Willem Baars explains. ‘After com- paring several systems, we decided to equip our centres with M9 port- able ultrasound systems from the Chinese manufacturer.’ 20 Mindray systems are now installed across the centres. Pivotal features were high resolution dis- plays as well as the capability to configure the devices to perfectly fit cardiologists’ requirements. At the HartKliniek centres, the Mindray systems are used for 2-D echocar- diography, Doppler exams, carotid IMT measurements and diagnosis of mitral valve abnormalities, says Massaar-Hagen. “We aren’t yet doing 3-D echocardiography exams.’ This led to a fruitful partnership between Mindray and HartKliniek; while the patients benefit from the advanced imaging possibilities pro- vided by the Mindray ultrasound systems, the cardiologists give valu- able feedback to the company to further gear the systems towards applications needed in the cardiol- ogy setting. The digital backbone is a DICOM PACS which serves as a platform for the images gener- ated. The ability to share image data across the HartKliniek centres and with external hospitals enhances the cooperation between the institu- tions and saves time and money by reducing unnecessary repetition of ultrasound exams. Neurosurgical oncology Continued from page 19 Using contrast helps to obtain ana- tomical evidence and histology, and also to identify tumour remnants. It then brings visibility of the tumour’s feeding artery and draining vessels, the cystic and solid components of the tumour, and other key findings that can be very important informa- tion for surgeons. Contrast also helps to obtain some hints about histology about grades of glioma, and, perhaps more importantly, may help to distinguish radiation-trig- gered necrosis from other cystic lesions. ‘With different degree of contrast uptake, you can differenti- ate between radiation necrosis and other cystic lesions such as metasta- ses and abscesses, because radiation necrosis will never show contrast uptake,’ he explained. Simulation training In addition, contrast uptake enables identification of tumour remnants, which is useful in the case of doubt about some possible presence of residual tumour. The EFSUMB recently revised its guidelines, introducing the indication for using contrast in ultrasound-guided neu- ro-oncological surgery procedures to assess tumour boundaries, perfu- sion patterns and residual tumour. Intraoperative ultrasound has its drawbacks. It is based on unusual imaging and presents orientation difficulties. It also needs specific training and a few solutions have been developed in that sense. Di Meco and team at C. Besta Institute have developed, within a wider neurosurgical simulation pro- gram, a simulator of intraopera- tive ultrasound for brain tumours. The simulator comes as a software, which, upon pairing their smart- phone to their computers, surgeons can rehearse intraoperative US cases just as in the operating room (OR). ‘Using a smartphone as a mock US probe and rehearsing intraop- erative US scans with co-planar neu- ronavigation images, surgeons and residents may practice and learn the semeiotics of brain US scans with- out having the pressure of being in the OR,’ he said. This simulator is freely available on https://neuro- stream.academy/. There is additional potential for ultrasound in neuro oncological surgery. For instance, high inten- sity focused ultrasound has been approved already to treat essen- tial tremor, Parkinson’s disease and pain. ‘You can either use thermal ablation or the capacity to induce blood brain barrier disruption,’ Di Meco said. Another interesting development is the use of an US transparent cranial prosthesis that provides a window in the skull for US scans, by replacing the cranial bone flap. ‘This can be useful in order to follow-up patients and to disrupt the blood-brain-barrier,’ he pointed out. ‘US is a polyvalent modality, which encompasses several tech- niques including Doppler, elasto- sonography, contrast, blood brain barrier disruption and focused ultra- sound – all of them,’ he concluded, ‘very promising in brain tumour treatment.’ (MR) EUROPEAN HOSPITAL Vol 29 Issue 4/20