2 N E W S & M A NAG E M E N T Opening in just under a decade Nantes CHU – designed to fit 21st century medicine Report: Jane MacDougall 21st century challenges are multitudi- nous for all. Ageing populations, a changing disease burden; increasing obesity with associated morbidities – Type 2 diabetes, cancer and car- diovascular disease; climate change pressures and more. Any new build plan demands a low carbon foot- print; respect for the environment is paramount. To capture all those elements, the plan to regenerate a previously 10 hectare industrial site on the ‘Ile de Nantes’, a central region of the largest city in Western France, by creating a ‘Healthcare zone’ is exceedingly ambitious. Since 2015, when the choice of architect was made, the initial plan- ning stage has involved the input of more than 850 people from the key areas concerned. In the two years since the project was first mooted, over 150 meetings have taken place between the 57 differ- ent working groups involved. Each group is always headed by a trio of medical, ancillary and administra- tive staff and held in the presence of the architects. More than 1,200 modifications were made before the final plan was made public in June 2017. Central to the hospital’s architec- ture is the ease of the patient’s jour- ney through the hospital. Medical professionals and patient user groups have been working together to produce the best possible patient journey, which provides the ability to exchange medical information and ensure the correct care at the right time. Patient groups have also been consulted to understand their major wishes in terms of privacy and patient confidentiality, reduction of waiting times and so on. Within this framework, the need for an agreeable working environment for the many hundreds of professionals who will be based here every day cannot be ignored. Using the mantra ‘high technol- ogy and humanity’, the project has objectives to provide healthcare, teaching and research on a human- scale at the heart of the community it serves. In practical terms, the new hos- pital will serve to re-home the cur- rent hospital group, which includes the medical and surgical obstetrics capacity of the Hôtel-Dieu and North Laennec Hospitals, as well as their emergency and ambulance services. Space has also been planned for the eventual inclusion of the René Gauducheau Oncology Institute and teams from the highly respected medical university research cen- tres (DHU), which cover specialties such as thoracic medicine, diges- tive tract medicine, immunology, nuclear medicine, kidney transplan- tation, etc. The new hospital has been con- ceived with the knowledge that medicine is evolving. This future has been considered for planning under four ‘Ps’ – prevention, antici- pation of risks and programmes to modify behaviour; prediction, the s e t n a N U H C : e c r u o S USA nurses augment their role in hospital care coordination Improving patient experiences Report: Lisa Chamoff A nurse-led team has worked for three years to reorganise the elec- tronic health records system at the Carolinas HealthCare System, a large healthcare organisation in the state of North Carolina, with more than 900 locations and 7,600 licensed beds. Becky Fox, who spearheaded the effort as the health system’s chief nursing informatics officer — a growing specialty in nursing, though a relatively rare position for a hospi- tal — noted that by making the EMR workflow easier to use and reducing unnecessary documentation, they could eliminate an estimated 18 million clicks and decrease the time it takes for nurses to do a head-to- toe assessment of patients by about 20 percent, resulting in a return of 35,000 hours of nursing care. ‘There is a clinical informatics coordinator at each facility and some have been nurses,’ says Fox, who has a background as medical surgical nurse and had stints in the emergency department, cardiac care and was a clinical nurse specialist before transitioning into her infor- mation technology position. ‘They really need to have a foot in both worlds – in the clinical world and the informatics role.’ Hospital nurses in the USA have always been the providers of direct patient care but, as the health- care system there undergoes rapid changes, they are increasingly work- ing behind the scenes, improving hospital technology and making key purchasing decisions, as well as preventing medical errors, improv- ing patient satisfaction and reducing hospital admissions and readmis- sions by helping to improve popula- tion health. Hospital nurses may now ensure a patient has the essential tools to recover at home, thus preventing a return to the hospital, and run programs to help ensure those in the community are leading healthy lives and receiving the proper pre- ventive care. ‘The question is not going to be, “What does the doctor do; what does the nurse do; or what does the social worker do?’’’ Fox says. ‘It’s going to be, “What is the best thing to do for the patient?”’ In the state of Texas, at JPS Health Network, nurses helped select a monitoring system for observing patients at high risk for injury, such as those with behavioural health issues, or elderly patients who may fall if they get out of bed, instead of paying a staff member to sit with the patients and watch them. After installing the system, which provides video observation and a way for nurses and patients to com- municate, falls decreased 13 percent during the first seven months of 2016 and more patients could be monitored. ‘For any purchases, you’re going to want the nurses’ input,’ says Trudy Sanders, vice president, patient care services at JPS Health Network. ‘Those are the users of the equipment.’ After the passage of the Patient Protection and Affordable Care Act in 2010 and the transition from a volume- to a value-based system caused consolidation in the healthcare industry, nurses have had a bigger role in care coordination in the USA’s hospitals. Becky Fox is the Chief Nursing Informatics Officer at Carolinas HealthCare System in Charlotte, USA. ‘There has always been some form of case management in hos- pitals,’ adds Seun Ross, director of nursing practice and work envi- ronment for the American Nurses Association. ‘As hospitals are con- solidating, nurses are managing a patient from the moment they hit hospital doors.’ Nurses also play a key role in ensuring high patient satisfaction scores, which are tied to Medicare reimbursement. ‘It’s everyone’s job to make sure a patient has a good experience.’ the Chief Nursing Informatics Officer underlines. EUROPEAN HOSPITAL Vol 26 Issue 4/17

4 N E W S & M A NAG E M E N T App accelerates first responders’ deployment ‘Shareconomy’ technology enters patient care Point-of-care diagnostics (POC) has been established for 20 years. Comprehensive smartphone cover- age and ‘shareconomy’ technology are now helping to push the devel- opment from previous business models towards a point of patient model. The question is whether medical apps will have the same benefit as those employed for eve- ryday use. Dr Christian Elsner, Director of the University Hospital Schleswig- Holstein (UKSH), presented his find- ings on the subject of first respond- ers at the POCT Symposium in Munich. ‘The first responder figures in Europe vary a lot. Four years ago, the figure for Germany was only 25%. Now it’s 31%, but we obviously want to increase it still further,’ he told our European Hospital corre- spondent Anja Behringer. e d . t e t t e r - t d a t s - e n i e m w w w . : e c r u o S A first responder app can reduce the time it takes until help arrives on site in an emergency. is required, In each emergency case where resuscitation first responders should intervene within a matter of minutes. ‘There are different concepts to achieve this, such as increasing the availability of defibrillators, telephone support for resuscitation, or the utilisation of first responders who are alerted via our app,’ Elsner explains. Methods – A first responder app and emergency unit plugin can locate app users near an emergency potential sudden cardiac arrest. This allows the emergency medical dis- patcher to call for additional help alongside the primary rescue chain, if feasible. The UKSH also recruited qualified medical (semi-) profes- sionals with knowledge of CPR, and a comprehensive medico-legal evaluation and guideline develop- ment were also undertaken. An atrial fibrillation (AF) app was then developed which can test for atrial fibrillation via the standard flash- LED through the app users. Results – A clear-cut SOP and medico-legal evaluation were devel- oped and implemented for the first responder app in a partnership with the city of Lübeck. Most of the budget (42%) had to be spent on the medico-legal evaluation and the obstacles presented by legal standards and data security, with the second largest amount spent on the socio-political discussion on how to implement the technology. User recruitment was successfully car- ried out via 1:1 marketing and viral marketing. After 12 months, more than 380 people were recruited as CPR lay people, with most of them already being pre-qualified. In the first eleven real cases for the app, 36% of the first responders arrived on site more than three minutes before the emergency rescue vehi- cles. ‘It used to take 9-12 minutes before emergency staff reached the patient once the alarm was raised, but our dense network has now reduced this to 1-3 minutes,’ Elsner points out. A test study protocol for the atrial fibrillation app was developed and is being implemented in a primary AF (patients aged over 65) and secondary AF (patients after abla- tion) screening population. The use of this app is being discussed with health insurers and various hospi- tals, with a medico-legal evaluation still in progress. Utilising potential where it presents itself have a lot of very good data availa- ble. However, this requires software in surgeries and hospitals to be well maintained. The big problem is the consolidation of this data for adequate evaluations, and we are only just starting out here.’ A Canadian-Chinese research group, for instance, has been able to prove a connection between a lack of vitamin A and Alzheimer’s disease. ‘Many Alzheimer’s patients have a lack of vitamin A, which suggests a link,’ says Margraff. ‘I therefore wanted to correlate these results with data from our labora- tory, but out of the 2,600 eligible results from the last three years only a few hundred correlated with the respective statistics. This is not enough for a statistical evaluation. We lack the clinical patient data required to carry out such stud- ies.’ Making validated statements for publications and studies is therefore almost impossible. Big data in the laboratory Useful IT tools are abundant in today’s laboratories – ranging from software to evaluate analyses to spe- cialist software for quality control, and middleware linking different devices. However, all these tools gen- erate data, the adequate utilisation of which is not an easy task, said Udo Margraff, CEO of Laboratoires Réunis in Luxembourg, during our European Hospital interview. Among other issues, data protection proves to be a limiting factor, with the meaningful use of big data falling by the wayside. Report: Marcel Rasch ‘The laboratory has always been very focused on IT,’ Udo Margraff points out. ‘With around 400,000 analyses per year, we generate around five million medically validated results. However, this is just a part of the data packet. Every analytical result we release additionally contains countless data on the traceability of samples. This could be the date the sam- ple was taken, specific data for the validation of the laboratory results, the clinical anamnesis, any possible difficulties encountered when blood was taken etc. Altogether we gener- ate up to 100 million data sets in our IT system that the doctor doesn’t even get to see – and these are just the figures from our relatively small, private laboratory.’ All data is evaluated for differ- ent processes. ‘If, for instance, we receive feedback from the doctor that the potassium levels of a sample are too high, we test for the cause,’ the CEO explains. ’We investigate how the sample was transported, or whether there was a problem with the centrifuge or reagents. These analyses are incredibly complex but of no interest to the referring doctor as long as they receive the reason for the increased levels.’ To Margraff, statistics and studies are additionally available tools for statistical evaluations in light of the data volume. Unfortunately though, big data analyses entail two major difficulties, as Udo Margraff admits: ‘Everybody talks about big data, but ultimately this data cannot be utilised in the best possible way we like to imagine. ‘It is no longer a big problem to obtain validated data due to certi- fications and standardisations. We k c o t s r e t t u h S / n o c i m o o B l : e c r u o S The managing director of the German University Hospital Schleswig Holstein, Lübeck Campus (turnover €300+ million) since 2010 and, from 2015, managing director of its Out-patient Care Centre, Dr Christian Elsner is also acting director of the Diagnostics and Radiology Centre in the Kiel Campus. He is also Assistant Director of the Hospital Manager degree course at Kiel University. In the past, Elsner was Division Manager for the consultancy Pharma, Healthcare and Medical Technology in Munich, Germany, (2006- 2009). Elsner is a member of the board at the European Heart Rhythm Association (EHRA). Conclusions – Point of care test- ing can receive impulses from the market trends of ‘shareconomy’ and mobile internet technologies. Completely new business models and use cases must be discussed and must seem feasible in a first proof of concept. Achieving these new use cases will take great effort and require a lot of energy, time and money to be invested in a combi- nation of social, legal and medical evaluations, in close cooperation with the technological development of such apps. The findings from the two use cases and field tests should give first insights on how to proceed and which problems to tackle. Studies like this would be very interesting for health insurers, espe- cially with a view to prevention. ‘Prevention should begin in child- hood, with a healthy diet. Laboratory data is also of interest for research into prevention with regards to next generation sequencing in genetics or the microbiome: Diabetes, car- diac disease, autism, Alzheimer’s disease and multi-resistance are all areas where good studies could facilitate fantastic preventative work,’ Margraff emphasises. When it comes to big data analy- ses, cost is also a big factor because, he underlines, ‘laboratory diagnos- tics is expensive, therefore not utilis- ing the data adequately is a shame. Laboratory and imaging diagnostics play a central role in medicine: 60-70% of all diagnoses are made with the help of the laboratory or imaging.’ The Agence eSanté founded in Luxembourg is the first eHealth authority to establish itself in the EU. ‘I hope we will succeed in set- ting up a server for laboratory data that consolidates all relevant data, making data processing for publi- cations and studies, and those on prevention, epidemics, and infec- tions more efficient and effective,’ Margraff hopes. However, in this, data protection is proving a big obstacle. ‘Only by anonymising and stand- ardising data can we satisfy data protection regulations,’ Margraff points out. ‘But, I’m hopeful that we will find a solution for the future. Transregional data usage is also of interest for everyone against the backdrop of cross-border health- care. There is a growing trend towards people living and working across, and without, borders.’ EUROPEAN HOSPITAL Vol 26 Issue 4/17

6 U LT R A S OU N D Regional anaesthesia is quicker, safer and mor Point-of-care ultrasound Ultrasound guidance has proven invaluable for the regional neurosur- gical centre at the Salford Royal Hospital, helping to improve safety, save time and enhance the patient experience. Here, Jim Corcoran, consultant neuroanaesthetist and clinical director for perioperative care at the hospital, outlines the uses of this technique. When I joined the Salford Royal in 2006, my initial interest in ultra- sound grew out of a need to allevi- ate the delays experienced by trau- ma patients needing a cardiac echo. Training opportunities for regional anaesthesia in the North West were very limited, but we realised that training clinicians to use point-of- care (POC) echo could significantly reduce delays in excluding aortic stenosis. At the same time, we took the opportunity to introduce train- ing on the use of ultrasound for regional anaesthesia. Interest in this field has grown considerably since then, and for the past nine years we have worked with Fujifilm SonoSite to run twice- yearly courses in ultrasound-guided regional anaesthesia. Before ultrasound guidance regional became commonplace, anaesthesia was performed using nerve stimulators. Although this worked, the procedure wasn’t slick. Ultrasound offers an improved way of administering the anaesthetic, which is quicker, safer and more comfortable for the patient. It allows you to visualise the nerve, giving assurance that the needle is cor- rectly positioned, and gives you confidence that the block will work; there is always a degree of uncer- tainty if ultrasound is not used. We can also dramatically reduce the amount of anaesthetic used with ultrasound-guided procedures, decreasing the likelihood of side effects. Whereas previously 30 or 40 ml of anaesthetic would be injected – because it was hard to target a specific area with certainty – you now know exactly where the needle is, and can see the anaes- thetic spreading across the area. As a result, as little as 10 to 20 ml of anaesthetic is required, which is a huge reduction. Today, we use ultrasound-guided regional anaesthesia for both awake surgery and analgesia, for example, interscalene blocks for patients hav- ing shoulder surgery under general anaesthesia. Regional anaesthesia has totally transformed shoulder surgery, significantly reducing the length of patient stays. Ten years ago, patients were admitted for one or two days, but subacromial decompressions, for example, are now treated as day cases, and even a shoulder replacement is only an overnight stay. I also use ultrasound to place catheters in some of the more chal- lenging shoulder replacement cases, which makes a big difference; the interscalene groove is a difficult area, and knowing the exact loca- tion of the needle is really impor- tant. The efficiency of our hand sur- Versatile invention tackles several routine exams 4G CMUT – opening the door to the next stage in ultrasound Holding Hitachi’s newest ultrasound probe in your hand, it looks and feels like any other ultrasound trans- ducer. ‘Yet, you are actually holding a marvel of ultrasound engineering, a true break-through in transducer architecture that performs so well across so many types of exams that you may never want to let it go,’ the manufacturer reports. Hitachi’s next generation linear matrix transducer is the first and only commercially available in daily practice, Capacitive Micro-machined Ultrasound Transducer (CMUT), a technology so advanced that the inventors at the prestigious Stanford University in Palo Alto, California could take it no further than a pro- totype. After more than 12 years’ work, the engineers at the Hitachi Ultrasound Research & Development Centre, in Tokyo, overcame the tech- nical challenges to bring this innova- tive probe into daily practice. No switch from high to low frequency sessions ‘The most important thing about this new transducer is that clinicians no longer need to switch probes between high frequency and low so the ultrasound pulses smoothly from the probe and through the human body,’ Tanaka explained. ‘This architecture is more direct and pre- cise with no deflection using very short pulses with no refraction wave. Because it transmits broadband, all frequencies are sending pure signals and nothing gets lost.’ Hitachi engineers also solved the problem of applying high power lev- els to the CMUT cell, an achievement that has created a stir in the engi- neering community and has further enhanced the reputation of Hitachi as the most innovative developer in the field of ultrasound, the com- One probe, yet the device can perform many examinations frequency sessions,’ said Hiroki Tanaka, one of the lead developers. ‘Physicians can now use Hitachi’s 4G CMUT for superficial examinations of the breast, for example, by apply- ing a high frequency; then with this same probe, they can perform low frequency exams of the abdomen, liver or pancreas, for example. With this one probe, they can cover almost all applications in daily routine.’ Introduced at the 2017 European Congress of Radiology, the Hitachi 4G CMUT is actually the fourth gen- eration of this technology, he pointed out. Hitachi released the first-ever CMUT in 2009, which could generate excel- lent B-mode images using low power, but which limited its application pri- marily to breast exams. The next generation offered an increased bandwidth, enabling higher two-dimensional quality with Tissue Harmonic Imaging and an increased sensitivity for Doppler and Colour Doppler to image blood flow. The new linear matrix probe expands even further the bandwidth capacity to a range from 22 MHz down to 2 MHz, the low frequency needed to examine deeper structures in the human body. All on a single wafer Open up any other ultrasound transducer and you will find hard ceramic crystals that have been hard- wired to generate and receive sound waves. Inside the CMUT you will find a soft membrane embedded with electrodes that vibrate to trans- mit an ultrasound signal. The break-through with 4G CMUT is the micro-machined architecture on a silicon wafer. The membrane is less than three microns thick and behind this is a cavity of just 100 nanometres. The transducer array is constructed by combining a large number of these CMUT cells. ‘The CMUT membrane is very close to the human body for its softness, pany points out. ‘Hitachi released the world’s first diagnostic ultrasound system in 1960, the world’s first real- time colour flow Doppler in 1983, and invented ultrasound elasto- graphy in 2003.’ With high-energy pulses, the Imaging 4G CMUT is able to gener- ate higher amplitude sig- nals, which allow Tissue Harmonic thanks to yet another Hitachi innovation for modulating the tude, c o m p a n y adds. 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8 U LT R A S OU N D 1st trimester scan should check for congenital heart defects All unborn babies need foetal echocardiography Acknowledging the need for faster ultrasound automation, during our European Hospital interview Dr Alexander Weichert, gynaecologist and obstetrician at the Charité University Hospital Berlin, explained how automated procedures can assist in the early detection of cardiovascular disease and prenatal dia- gnostic testing, and why a detailed prenatal diagnosis can reduce mortality and morbidity. ‘Congenital heart defects are among the most common congenital defects, so they are of great importance in prenatal diagnostics,’ Alexander Weichert pointed out. ‘Unfortunately, they are often still not diagnosed. ‘Under optimum conditions they can be diagnosed from the first tri- mester scan, i.e. between the 12th and 14th week of pregnancy. Most heart defects are diagnosed at the mid-pregnancy scan, i.e. between the 20th and 22nd week of pregnancy - but still not often enough. ‘Only a minority of heart defects is diagnosed prenatally because not all pregnant women are systematically scanned by an echocardiographer. Only when risk factors, such as multiple pregnancy, growth delays, or other suspicious factors come into play these cases are referred to specialists. Specialist diagnosis or screening for cardiovascular patho- logy is therefore rarely carried out. ‘This can be fatal because, unlike CT or MRI, ultrasound is a proce- dure that very much depends on the skills of the user. The ability to dia- With transposition of the great arteries (TGA), the aorta (blue) rises from the right ventricle; the pulmonary artery (red) from the left ventricle and the foetal echocardiogram shows the typical parallel connection gnose congenital heart defects takes years of practice. There are obviously guidelines for the visualisation of certain examination planes, but this in turn also requires intensive expe- rience with ultrasound procedures. This is common in many countries.’ Prenatal intervention ‘Some heart defects can already be treated prenatally. This includes aor- tic stenosis, which can be treated via cardiac catheterisation. Early diagno- sis in itself – even without immediate treatment – has further, fundamental benefits, as confirmed by numerous studies: If congenital heart defects are diagnosed in time, this results not only in lower mortality and mor- bidity but also in less time spent on intensive care wards and improved surgery results. Early diagnosis facili- tates optimum preparation, as con- genital heart disease may require fast action after birth, especially for defects affecting the ductus arterio- sus. ‘Before birth, there are connec- tions in the atrial septum (foramen ovale) and between the large blood vessels (ductus arteriosus), which form a parallel connection of the pulmonary and systemic circulation. ‘Heart defects where the blood cannot flow directly to the lungs or the body, due to an obstruction, but with a detour via the ductus arte- riosus, are known as patent ductus arteriosus. ‘Before birth this is unproblem- atic because there is a connection between the two circulations. After birth, however, this connection, which is vital for children with patent ductus arteriosus, closes, leading to a life-threatening lack of oxygen and a race against time. If the heart defect is known in advance, the ductus arteriosus can be kept open through the administration of Prostaglandin Nine examination planes are extracted from a volume data set of a foetal heart after marking seven reference points Senior Consultant Obstetrician and Gynaecologist at the Charité University Hospital in Berlin, Alexander Weichert MD heads the Maternal-Foetal Medical Unit. His magna cum laude doctorate was gained at the Charité and he is a DEGUM level II certified sonographer. His specialties include prenatal diagnostics and therapy, special obstetrics, premature delivery and perinatal medicine. He is also a member of the German Societies of Ultrasound in Medicine (DEGUM), Perinatal Medicine (DGPM), Gynaecology and Obstetrics (DGGG), the Empress Auguste Victoria Society for preventive paediatrics (KAV) as well as the International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG). E1. The medication keeps the paral- lel connection intact and buys the paediatric cardiologist or heart sur- geon time for detailed surgical plan- ning. A situation that may become life threatening can be significantly eased through early diagnosis.’ Which ultrasound procedures do you use for diagnoses? ‘In the first instance, the common B-mode image and the “simple”, two- dimensional ultrasound, then also colour or pulsed Doppler ultrasound. Further methods are not needed for precise diagnosis. However, for teaching and documentation, 3-D or 4-D technologies are of advantage. ‘When it comes to patient contact, 3-D representation helps with our main objective, i.e. to build trust and to still expectant mothers’ fears. 3-D- and 4-D methods are also important for cooperation with the paediatric cardiologist, as the prenatal exami- nation planes do not correspond with those important for postnatal examinations. 3-D or 4-D diagnostic results can simplify the dialogue with the cardiologist and bridge the gap between diagnosis and therapy. Automated procedures to improve ultrasound use ‘There is currently a heated discus- sion around this under the key words “operator support”. There are differ- ent approaches to automation, one of the most prominent being so-called foetal intelligent navigation echocar- diography, or FINE technology. The procedure entails using a cardiac volume data set where seven central points are marked. The system then automatically generates nine scan- ning planes for diagnosis. ‘This technology was published in 2013 under the direction of Dr Roberto Romero and Dr Lami Yeo from Detroit. The algorithm has the potential to improve the use of ultra- sound – but only if the quality of the data set used to generate the scan- ning planes is sufficient. ‘Therefore, I am advocating the development of technology that facilitates automatic quality controls, and which gives automatic feedback, whether certain requirements are being met even during the scan. Another desirable feature would be a type of autofocus that automatically centres and sharpens an image, just like a camera – but this is still pie in the sky. Until then, it will remain our heartfelt wish that all unborn babies will be given a routine foetal echocardiography as a preventive measure.’ Ultra-early ultr detect foetal cardiac def Study shows a simplified examination can be per tions during the first trimester of pregnancy In just two weeks Dr Edwin Quarello, from St. Joseph Hospital in Marseille, had the answer to a clinical question he had been asking for years: Is it possible to check for major con- genital heart defects (CHD) across the general population of pregnant women before the second trimester? Over the past 15 years foetal echocardiography exams have been increasingly used to detect CHD in high-risk populations, yet a 2004 study published in Prenatal Diagnosis showed that most cases of CHDs would occur in low-risk populations. Heart defects are a leading cause of death during the first year of life, touching five to nine newborns in the general population, and nearly every case of CHD is already estab- lished in the foetus by the first trimester. Quarello has been preaching the benefits of early detection in the first trimester, and teaching col- leagues in the south of France how to perform what he calls the basic exam for the past 10 years. Last year he decided to use a novel methodology called a ‘flash study’, supported by the French College of Foetal Ultrasound (CFEF), to find out if the basic protocol could be competently performed by someone with basic ultrasound skills. That French twist in clinical stud- ies was introduced at the 2010 meet- ing of CFEF by Dr Laurent Salomon, who participated in this study and is a co-author of the resulting paper. The focus for a flash study must be narrowed to a single question, Quarello explained, and it must be conducted in a very short period, in this case just two weeks. More than 150 physicians and midwives responded to his invita- tion to participate in the study. ‘What we asked was whether it would be possible for the partici- pant to include all the views of the EUROPEAN HOSPITAL Vol 26 Issue 4/17

1 0 S U RG E RY 3-D visualisation is like ‘body cinema’ Cinematic Rendering undergoes tests for surgical procedures A physician has basically two possibilities to look inside a body: putting a scalpel to the patient’s skin or using an imaging device. Both options have advantages and disadvantages. Now, Siemens Healthineers has combined the advantages of both methods and developed Cinematic Rendering, a new 3-D visuali- sation approach. The name already points to the roots of the technique – the cinema. But it does much more than providing impressive images. Report: Wolfgang Behrends The human body is a marvel, the anatomy highly complex. ‘This com- plexity is difficult to grasp, par- ticularly in the operating room,’ says surgeon Dr Christian Krautz, who is heading the current clinical evaluation of Cinematic Rendering for surgery purposes at Erlangen University Hospital in Germany. The photo-like 3-D display of conven- tional DICOM images offered by the new procedure allows quick orientation inside the body. ‘The technique makes it much easier for us to get an overview of indi- vidual anatomy,’ Krautz explains. And, Professor Robert Grützmann, Director of the Surgery Department, adds: ‘That’s like body cinema. Even seasoned surgeons are wowed – it’s a real help for our brains.’ Better overview in difficult situations But how do spectacular images contribute to positive surgical out- comes? ‘Take liver surgery,’ suggests Christoph Löhr, Senior Manager for Strategy at Siemens Healthineers. ‘The liver is a highly perfused organ surrounded by a thick layer of fatty tissue. Interlinked and adjacent ves- sels are visible neither with the naked eye nor on images. Even experienced surgeons have to use the combination of years of experi- ence and haptics: they feel the ves- sels with their hands.’ But things are easily overlooked – or rather “over- felt” – with potentially fatal conse- quences for the patient. Thus, 3-D visualisation of the layout is a huge help. ‘This is exactly what Cinematic Rendering does per mouse click,’ Löhr explains. One of the main design ideas was to keep the operating concept of the software minimalistic: filter n i a t i r B t a e r G , r e t n e C g n i g a m I h c r a e s e R n i a r B y t i s r e v i n U f f i d r a C © Fibre bundles of the brain – Cinematic Rendering based on data gleaned from magnetic resonance imaging. s d n a l r e h t e N e h t , h c s o b n e g o t r e H - s ‘ , l a t i p s o H h c s o B n e o r e J © View of the breast and breast tissue; the red spot at the centre is a tumour – Cinematic Rendering based on tomosynthesis dataical functions can show and hide bones, vessels and tissue. This provides images that immediately show clini- cal issues. In the clinical study, cases are examined retrospectively to test the new procedure. Löhr: ‘Surgeons see 2-D DICOM images as well as Cinematic Rendering images and are asked how they would decide based on these two types of images. We are particularly interested in complex cases such as pancreas or liver. These are organs where we expect the new technology to offer the greatest value-add and more security.’ The developers are confident that there are many more areas where Cinematic Rendering will prove its mettle. ‘We see enormous potential in teaching, in patient communica- tion and in forensics,’ explains Dr Klaus Engel, Principal Key Expert at Siemens Healthineers and inventor of Cinematic Rendering. ‘Moreover, tumour boards will benefit from the new technology because the images are easier to interpret. This will lead to a democratisation of the boards, faster agreement and hopefully to better decisions for the patients,’ Grützmann believes. Sophisticated algorithms for real-life applications The hyper-realistic computer-gener- ated images often resemble objects in the ‘Body worlds’ exhibitions. They are based on a sophisticated algorithm that creates spectacu- lar effects, very much like in a Hollywood blockbuster: ‘Unlike previous 3-D imaging procedures, Cinematic Rendering is based on physics,’ Engel points out. ‘While previously raycasting was used, which treats light rays as straight lines, the new technology includes a number of much more complex factors such as reflection and scatter. ‘This results in 3-D images in cinematic quality but more impor- tantly with added clinical value. ‘A crucial feature is realistic shading,’ the inventor adds. ‘The human eye is trained from day one to recog- nise minute differences in shading and deduct the spatial location of an object. A shadow, for example, can indicate the depth of a given structure. ‘Until today, we did not have this kind of information in 3-D imag- ing, which made the evaluation of spatial relationships, such as over- lappings, very difficult. The new method offers a more sculptural approach. We consider surgery to be an important field of application where this innovation will be highly useful.’ While Cinematic Rendering is technologically extremely sophis- ticated, it is versatile in its potential application. ‘Today, PCs with the necessary computing power are eas- ily available; the same holds true for imaging modalities, such as CT, MRI, PET and ultrasound. The system is DICOM-compatible, particular standards are not required,’ Engel underlines. Augmented reality – coming soon to your local operating theatre! Currently Cinematic Rendering is under development for surgery application. ‘In the prototype study we focused on therapy planning,’ says Dr Stefan Assmann, Director of Adjacent Fields at Siemens Healthineers. ‘The surgeons’ feed- back that Cinematic Rendering may help to save time.’ indicates , s u a h n e k n a r K n e h c s t i l e a r s I m l i i e i g o o d a R © y n a m r e G , g r u b m a H Musculoskeletal structures in the head and neck region The realistic depiction of volume datasets could make Cinematic Rendering a highly valuable addition for surgical departments. Gaining the greatest practical guidance A chance to choose a top tutor for a surgical skill A French start-up eases international peer-to-peer teaching in TAVI, PRP or S-ICD and other leading medical procedures by taking physi- cians directly in the operating suites, Mélisande Rouger reports. Mentors play a tremendous role in every profession but perhaps nowhere else as in medicine. As technology advances and proce- dures multiply at the speed of light, physicians increasingly need tutors to deliver optimal care. What better place to learn than with experts in their own environment? Bordeaux-based start-up Invivox is taking on the challenge to bring peer-to-peer teaching onto the glob- al level, by enabling physicians to train with experts directly in surgi- cal suites. ‘Our goal is to become the Airbnb or Uber of medical train- ing, by enabling physicians to find and book training opportunities with the best experts in their field,’ explained Julien Delpech, CEO of Invivox. Training slots in surgery, car- diology, urology and gynaecology are available on the platform, and the company plans to have every specialty on-board shortly. Invivox offers insight into medical practice by enabling participants to book entire days with experts while they are performing the procedures they have mastered on patients. Experts are chosen by a scientific committee and can then sell train- ing slots directly on the Invivox website. Typically, specialists invite two to three peers to spend a day with them, during which they will deal with both clinically and techni- cally pertinent cases. Personalised training proves invaluable The solution answers a long time demand from physicians to receive personalised training in procedures that are proving indispensable in their field, according to Delpech: ’Whereas meetings, conferences and workshops are excellent for networking, they only partially meet physicians’ needs for training in particular techniques.’ Having worked in the medical field for over 15 years, he believes this ability to connect physicians to living legends in their field is the added value of the tool. For instance, the company attracted world famous cardiologist EUROPEAN HOSPITAL Vol 26 Issue 4/17

1 2 O N C O LO G Y Facing spectacular outcomes or dramatic side effects? Understanding and utilising immuno-oncology A medicine graduate from the University of Padua/Italy in 1978 and in 1991, three years later Antonio Pezzutto was appointed Director at the Charité, Campus Benjamin Franklin and, in 2001, became Deputy Director of the Department of Haematology-Oncology, Charité Medical School at Campus Virchow Hospital, Berlin. The professor also carries out translational research at the Berlin Institute for Health (BIH) in cooperation with Charité and the Max Delbrück Centre for Clinical Research. In 1997 he initiated and led the Molecular Immunotherapy Group at Max Delbrück Centre for Molecular Medicine in Berlin-Buch. He has been member of the German Medical Associations’ Somatic Gene Therapy Commission since 2000 and is also a member of the American Society of Haematology, the German Society of Haematology/Oncology and the German Society of Rheumatology. case. However, as Dr Pezzutto points out, tumour sequencing generates information that is relevant for con- ventional therapies. Since only very few patients benefit from the many new and expensive therapies that were developed over the past few years, the process to identify can- didate patients is being constantly improved. ‘If only 20% of the patients benefit from a therapy – a therapy that might be associated with danger- ous side effects caused by unspecific activation of the immune system – it is crucial that we try to precisely identify the patients who might ben- efit. If we don’t do that, we expose 80% to an unnecessary risk,’ Pezzutto explained. European Hospital asked Dr Lothar Kanz, haematologist and oncologist, Medical Director and tenured profes- sor at University Hospital Tübingen, which of the immuno-therapies cur- rently being applied offer the highest patient benefit. ‘Monoclonal antibod- ies’, he immediately responded, ‘since several antibodies, such as anti-CD20, are already in successful clinical use. Moreover, there are enhancements, such as Fc optimisation, that offer increased biological effect.’ In addi- tion to checkpoint inhibitors, Kanz also uses monoclonal antibodies with ers can predict the likely success of an immunotherapy even before treatment onset. Professor Antonio Pezzutto, Medical Director of the Medical Department, Division of Haematology and Oncology at Charité Campus Benjamin Franklin and Lead Researcher at Max Delbrück Centre in Berlin-Buch, explained: ‘The tumour sample obtained by the surgeon is sequenced to iden- tify all mutations in the tumour cells. Only mutations that are essential for tumour cell growth are taken into consideration for a personalised immunotherapy. If we have, let’s say 2,000 mutations in a tumour cell, it may well be that only 100 of those modify the structure of important proteins. The mutated protein pieces have to reach the cell surface for the immune cells to be able to recognise and attack them. In the end, maybe only a handful of potential targets materialise.’ In a large project carried out by the Berlin Institute of Health (BIH) along with Charité and the Max Delbrück Centre, the potential of such individualised cancer therapies is being explored and the foundation for initial clinical studies is being laid. The team encompasses computer scientists, oncologists and internal medicine specialists; biologists create specific immuno-cells, gene trans- fer specialists are on board as well as specialised ‘mice immunologists’ whose task it will be to validate the efficacy of the therapies in the animal model. It takes months of intensive research until tumour cell sequencing of a single tumour sample generates candidate cells. The costs of new immunotherapy approaches using the so-called adoptive T cell transfer can significantly exceed €100,000 per T cells are modified specifically to the patient’s particular cancer Report: Anja Behringer Every cancer is differ- ent and every patient is different. This insight gained in personalised medicine prompted oncology researchers to focus more on the individual patient’s immune system. It is particularly the immune system’s to destroy cancer cells that raised hope. ability Today, a number of can- cer therapies harnessing this ability are being applied suc- cessfully. The underlying idea is more than 150 years old. In the 19th century it was reported that a cancer patient in a hospital in Bonn, Germany, had suffered from erysip- elas, an acute infection, which caused the tumour to shrink. However, only in the past two decades did we begin to better understand the complex interaction between cancer cells and the immune system, knowledge that allowed us to venture into unchar- tered treatment terrain. Although there have been impres- sive successes, in particular with malignant melanoma and advanced lung cancer, scientists continue to face major challenges. A close coop- eration of researchers, researching physicians and clinicians is needed to unlock the cancer cells’ secrets. Generally speaking there are two types of immune responses: the innate immune system responds in a generic way to all pathogens and wards off most infections. By contrast, the acquired (or adaptive) immune system eliminates specific pathogens with the help of B cells and T cells ‘despatched’ as soon as certain structures of pathogens and cells, so-called antigens, are detected. The acquired immune system stores information on any initial response to an antigen in a memory, i.e. it recog- nises this antigen later and responds accordingly. The immune system recognises cancer cells by the so-called tumour- associated antigens (TAA) on their surface. Many tumour cells, how- ever, have developed strategies to mask their malignant identity, for example by not presenting antigens. Alternatively, the tumour cells interact with the t-cells via so-called immune checkpoints. While these molecules normally prevent an over-reaction of the immune system, tumour cells use this mechanism to avoid their own destruction. This is where immune checkpoint inhibitors come in: drugs that undo the cancer-caused blockage and stim- ulate the immune system to destroy tumour cells. In 2001, ipilimumab, the first immune checkpoint inhibi- tor was approved to treat advanced melanoma. A second drug, nivolum- ab, shown in clinical studies to sig- nificantly prolong survival, received approval in 2015 to treat advanced lung cancer. Renal cell carcinoma, Hodgkin lymphoma and carcinoma of the bladder have been treated successfully with checkpoint inhibi- tors and further immuno-oncological drugs are likely to be available in the future. S o u r c e : m o l e k u u l _ b e / S h u t t e c k r s t o Antibodies such as anti- CD20 are already in successful clinical use. Unmasking strategies Another promising immuno-oncolog- ical approach is the adoptive T cell therapy (ACT): patient T cells are removed, transfected ex vivo with tumour-specific T cell receptors and re-infused into the patient to rec- ognise and destroy tumour cells. In therapies involving chimeric antigen receptors (CARs) T cells are removed from a patient, modified with a CAR specific to the patient’s particular cancer and re-inserted. The modified T cells recognise corresponding anti- gens, such as CD19, which is present in most B cell melanoma. They dock onto the antigen and destroy the tumour cells. The German Cancer Society reports successful application of this method: In several therapy studies on anti- CD19-CAR T cell transfer, patients with pre-B-cell acute leukaemia (ALL), chronic lymphocytic leukaemia (CLL) or B-cell lymphoma showed remis- sion rates of 30 to 90 percent. Bespoke therapies Cancer researchers aim to fine-tune these therapies ever more precisely to the individual disease pattern. With the help of molecular high-through- put analysis they can indeed identify target structures on the cancer cells for the individual tailor-made immu- notherapies. Even more: biomark- k c o t s r e t t u h S / s o t o h P I C : e c r u o S A medical graduate from Freiburg University Hospital in Germany in 1995 Lothar Kanz MD became Medical Director and tenured professor at Eberhard Karl University, Tübingen, Department of Oncology, Haematology, Immunology, Rheumatology and Pulmonology at the Medial Clinic and Policlinic. In 1996, he received the European Research Award for Haematology. Since that year he has been Lead Scientist of the bi-annual ‘International Stem Cell Conferences’. His research focus is haematopoiesis, immunotherapy and clinical oncology (Phase I/II studies on solid tumours; multiple myeloma). Kanz is member of the International Society for Experimental Haematology (ISEH), the American Societies of Haematology (ASH) and Clinical Oncology (ASCO) as well as the European Society of Blood and Marrow Transplantation (EBMT). attached toxins (antibody-drug conju- gates/immunotoxins), bispecific anti- bodies, for example against advanced lymphocytic leukaemia. He will soon add CART cells, patient lymphocytes that are genetically modified in the lab, to his therapy portfolio. Side effects: dramatic auto- immune responses While most side effects associated with immunotherapies are considered acceptable in view of the severity of the diseases, some dramatic autoim- mune responses were reported, such as the rejection of the patient’s own heart, and further rare adverse reac- tions to checkpoint inhibitors have to be expected. It is crucial to strike a balance between stimulating and inhibiting the immune system in order to avoid the negative effects of an over-active immune system. Infections of the hypophysis, eyes, lungs, kidneys liver, colon or skin can occur and the therapy has to be discontinued. While study results on tailor-made immunotherapies are promising, the practical application of these therapies is a long way away. The major translational obstacle, accord- ing to Kanz, is compliance with the strict regulations regarding Good Manufacturing Practice (GMP), i.e. the production of cells for cell thera- pies. In addition, he points out, the approval procedure for Investigator- Initiated Studies (IITs) is complex, long and expensive. Immunotherapy going forward Cancer researchers not only aim to develop new drugs, they also try to find out whether combinations of immunotherapies and conventional therapies, such as radiation or chem- otherapy, or the combination of two immunotherapies, yield long-term successful outcomes. However, they have to acquire an in-depth under- standing of the complex mechanisms of the immune system before they can develop strategies to reliably and effectively fight cancer with the body’s own defence system. The most recent research results on these issues will be presented at the annual congress of the German, Austrian and Swiss Societies for Haematology and Medical Oncology (Stuttgart. 29 September to 3 October). EUROPEAN HOSPITAL Vol 26 Issue 4/17

1 4 CA R D I O LO G Y The simple, efficacious technique that revolutionised cardiology Coronary angioplasty is 40 years old Report: Mark Nicholls Coronary angioplasty is arguably the most revolutionary breakthrough in the history of cardiology. While the technique is today performed on millions of patients worldwide, its origins can be traced back to the work of Dr Andreas Grüntzig in Zurich, Switzerland, in the late 1970s. Tragically, Grüntzig never lived to see the impact of his research, hav- ing died in a plane crash in 1985. Yet, across the world, his work has an enduring legacy and changed the face of cardiology forever. Later this summer – on 16 September - the world of medicine will be marking the 40th anniversary of the first coronary angioplasty. Before Grüntzig embraced the concept, others had experiment- ed in the field. The technique of angiography was first developed in 1927 by the Portuguese physi- cian Egas Moniz at the University of Lisbon for cerebral angiography while, in the 1960s, American inter- ventional radiologist Charles Dotter pioneered angioplasty and the cath- eter-delivered stent, which were first used to dilate peripheral arteries by inserting sequential catheters with increasing diameters through the narrowing artery. In 1958, Dr Mason Sones per- formed the first selective coronary angiogram and a few years later, Melvin Judkins introduced catheters shaped to reach the coronary arter- ies to perform selective coronary angiography. It was this work that Grüntzig built on to perform the first success- ful percutaneous transluminal coro- nary angioplasty (PTCA) – or percu- taneous coronary intervention (PCI) – on a human on 16 September 1977 at University Hospital, Zurich. Born in 1939 in Dresden, Germany, Grüntzig studied medicine at Heidelberg University, graduating in 1964. He rotated through a series of internships in Mannheim, Hanover, Bad Harzburg, and Ludwigshafen, before moving to the department of Angiology at the University Hospital of Zurich in 1969. His initial procedure used an k c o t s r e t t u h S / s d r a w y h : e c r u o S expandable balloon based on bal- loons for use in peripheral arteries, created on a kitchen table in his apartment, helped by his assistant Maria Schlumpf. This was used on 38-year-old severe angina patient Adolph Bachman – the same age as Grüntzig. He successfully dilated a stenosed short non-branching sec- tion of the Left Anterior Descending (LAD) artery and presented the Stent angioplasty procedure with placing a balloon results of the procedure at the American Heart Association meet- ing two months later to widespread acknowledgement. Grüntzig per- formed coronary angioplasties on further patients in Zurich and taught the technique to other cardiologists, as the field evolved. Contribution through example Professor Tony Gershlick, consultant cardiologist at Leicester’s Hospitals and Honorary Professor of Interventional Cardiology at the University of Leicester, reflects on Andreas Grüntzig’s legacy… ‘Whilst not part of the original cohort who visited Grüntzig at the very beginning, my recollections of the procedure go back to an impressionable and formative age for me as a junior doctor at the National Heart Hospital in 1980, when Tony Rickards undertook what I believe to be the first UK balloon angioplasty patient. ‘There was clearly a lot of excitement and undoubtedly something going on, so I decided I’d make a rare trip to the catheter laboratory. It was not possible… there were crowds of people.’ Inspired, Professor Gershlick became closely linked to the evolution of interventional cardiology, through the ’90s – the decade of invention – and later was the first UK cardiologist to implant a drug eluting stent (DES) and first to implant a bio-absorbable stent. Awarded the inaugural British Cardiovascular Intervention Society (BCIS) Lifetime Achievement Career Award in January, recognising his ‘outstanding contribution to the speciality of coronary intervention’, he reflects on the door that Grüntzig opened. ‘All of what we do now – radial day case intervention with great outcomes, especially in STEMI and even in complex surgical cases – would not be possible without Gruntzig’s far-reaching insights. More important is the capturing of great minds and innovators by his original work. That legacy continues unabated today. ‘He was a clinical scientist and his original studies taught us careful clinical studies, meticulous honest observations and robust reporting and interpretation of outcomes. Most importantly he never oversold the procedure. ‘His contribution through example was and remains immense. Now, if by chance the first five patients had died - which was clearly a possibility considering the kit and lack of understanding regarding risk – then that would have been a completely different story. Maybe his real contribution was that in his hands, despite all, they didn’t.’ Tony Gershlick is a consultant cardiologist at Leicester’s Hospitals and Honorary Professor of Interventional Cardiology at the University of Leicester. For more than two decades he has been at the forefront of developments in interventional cardiology in the UK and was the first cardiologist in the UK to implant a drug eluting stent (DES) and a bio-absorbable stent. In January 2017 he was awarded the inaugural British Cardiovascular Intervention Society (BCIS) Lifetime Achievement Career Award in recognition of his outstanding contribution to the speciality of coronary intervention. Naturally, there were complica- tions, such as abrupt vessel closure after balloon angioplasty and reste- nosis but from the initial percuta- neous balloon angioplasty; intrac- oronary stents were deployed in the mid-1980s. Through the ’90s and beyond, various incremental improvements in balloon and stent technology arrived, along with newer devices and medicine regimens resulting in the drug eluting stent, designed to help reduce in-stent restenosis. These also reduced the risk of stent thrombosis. former Chairman Coronary angioplasty is now the mainstay of cardiac care those recalls One man who is Bernhard early procedures Meier, and Professor of Cardiology and cur- rent Senior Consultant at the Swiss Cardiovascular Centre at Bern University Hospital. He worked with Grüntzig during the early develop- ment of the technique, and also ‘found’ the first patient to undergo the procedure. Meier has been involved in cor- onary angioplasty as a specialist in interventional cardiology since the first case Grüntzig performed in Zurich 1977, having joined the team in 1976. ‘I watched him doing peripheral angioplasty and helped him accumulate the respective data. The former Chairman and Professor of Cardiology at the Swiss Cardiovascular Centre in Bern University Hospital, Bernhard Meier is currently Senior Consultant developing the centre into the most active for interventional cardiology in Switzerland. A close associate of Dr Andreas Grüntzig, Meier has been involved in coronary angioplasty as an interventional cardiology specialist since the first case in 1977. He was involved in the development of structural interventions such as closure of the patent foramen ovale (PFO) and the left atrial appendage (LAA), and in the introduction of transarterial aortic valve implantation (TAVI) in Switzerland. I also suffered with him through more than a year of the desper- ate search for a patient suitable to become the first-in-man PCI recipi- ent,’ Meier recalled. ‘Serendipity led me to find the first patient and assist Dr Grüntzig. Finding this patient when he was away and presenting the case to him upon his return was certainly one of my career high- lights. ‘I’ve been able to take care of this patient up to now. He’s still doing extremely well, 40 years after his historical intervention, without ever needing coronary artery bypass surgery.’ When, in 1980, Grüntzig left Switzerland for the USA, Meier fol- lowed and spent three years with him in Atlanta, undergoing his cardi- ology training at Emory University. Back in Switzerland, Meier fur- ther developed the technique as head of invasive cardiology at University Hospital, Geneva (1983- 92). In 1992, he became chairman of the Cardiology Department at Bern University Hospital, turning it into the most active interventional cardi- ology centre in Switzerland. Meier recalls Grüntzig (11 years his senior) as a role model: ‘He was good looking, a sociable person, and full of great ideas with the nec- essary energy to pursue them even against a headwind from sceptics and envious – and sometime mis- chievous – colleagues and superiors. ‘He also liked and lived simplic- ity as the basis of successful medi- cine. The balloon catheter to treat coronary artery stenosis is about as simple and as efficacious as it gets. Will software steal the heart of cardiology? Continued from page 13 with the medical device manu- facturer Medtronic before joining the venture fund New Enterprise Associates, where he partnered Dr Scott Gottlieb who, in May 2017, was appointed new Commissioner of the USA’s Food & Drug Administration. Confounding the audience When Oesterle shifted his talk from hardware to software he began to confound the audience. The next big thing in the cardio- vascular space, he said, is not in the room today – unless you count the smart phones in everyone’s pocket. The research and development budget at Apple is $17 billion annu- ally, and what they are working on will make the future iPhone a healthcare companion, he said. Google Life Sciences, now called Verily, has invested $4 billion over the past two years to create part- nerships with Johnson & Johnson’s surgical division and glucose moni- toring specialist Dexcom, as well as several major pharmaceutical com- panies. IBM has declared that healthcare is the future of the company, he said, and the Watson super-comput- er is not meant to play games, hav- ing already shown it can outperform radiologists. Data analytics coupled with cog- nitive computing will take over healthcare, Oesterle predicted. ‘We have come to a point where com- puting power is massive, it is fast and it is incredibly cheap. Your next-generation competitor will come from software.’ As a venture capitalist, he noted that less than 10 percent of pri- vate equity funding goes to medical technologies, that 20 percent goes to biotechnologies and ‘70 percent goes into the software that is going to disrupt our practice, just as it has disrupted other industries.’ ‘No one wants to back a new stent, distributed healthcare is where the money is going,’ he said, adding that consumer-oriented medical technol- ogies aim to pass up the clinician in order to go directly to the patient. Vice President for Medical Affairs at Medtronic Vascular, Martin Rothman spoke up to say: ‘I just can’t see these next big things.’ And he agreed the next big cardiovas- cular enterprise based on software would not be Medtronic. ‘It’s not our core skill. We do some software engineering but what we really do is micro-engineering and that is our skill.’ Then he added: ‘When we talk about what will be the next big application in data handling, we quickly come to the important ques- tion: Where is the revenue? When we sell a stent or a TAVR [transcathe- ter aortic valve replacement], we get revenue. How do you get revenue when you sell a software click? How do you make that work? We don’t understand it,’ he said. With the authority of his white- haired seniority, Eberhard Grube, the Chief of the Department of Cardiology and Angiology at the Heart Centre in Siegburg, Germany, followed up on these comments: ‘We are speaking of things that may come in 20 years. It makes me dizzy talking about five billion here and 50 billion there. ‘Perhaps,’ he suggested, ‘we are more down-to-earth.’ Then he cau- tioned colleagues, ‘We hear about an unlimited imagination in what software can do, and then we look at what happened with a hospital in the United Kingdom when it no longer had access to its data. We have created a monster we do not know how to control.’ EUROPEAN HOSPITAL Vol 26 Issue 4/17

1 6 CA R D I O LO G Y We must protect cardiologists from cancer risk CorPath enters the vascular highway stand of Robocath, in his role as a key opinion leader for the company, which is also based in Rouen. He discloses that he has no finan- cial interest in the company but an enthusiasm for a system that can put a shielding wall between him and the irradiating X-ray projector that, as he points out, hovers just inches from his head during some time- long procedures. The R-One system from Robocath is not the first remote stenting robot for cardiology. Two systems approved by the USA’s Food & Drug Administration are commercialised by Corindus, based in Waltham, Massachusetts, which during EuroPCR 2017 cel- ebrated what it called a milestone for the 100th percutaneous coronary intervention (PCI) performed using the second generation CorPath GRX System. Although Corindus systems hold a CE Mark, the company has yet to sell a CorPath robot in Europe. Robocath is currently complet- ing pre-clinical trials as part of its submission for a CE Mark approval that it hopes to receive in 2018. A submission of the device to the FDA is expected in 2019. The results of a single-centre REMOTE-PCI [percutaneous coro- nary intervention] study spon- sored by Corindus were pub- lished in the January 2017 edi- tion of EuroIntervention, the jour- nal of the European Association of Percutaneous Cardiovascular Interventions the European Society of Cardiology (ESC). (EAPCI) and PCI was successfully performed on 19 of 22 target lesions using radial access, the first demonstration of the ability to perform PCI from outside the confines of the cath lab by using a combination of robotics and telecommunications. The CorPath 200 cockpit to con- trol the robot was installed in a separate room, roughly 17 meters from the patient table, isolating the operator but maintaining continu- ous video and audio contact with both the patient and any personnel in the lab. Principal investigator Ryan Madder MD, a cardiologist and researcher Neuroradiologist Philippe Bencteux, is the founder of Robocath, based in Rouen, France. with the Spectrum Medical Group based in Grand Rapids, Michigan, told European Hospital that, in addi- tion to the stenting procedures, he has successfully utilised the CorPath robot to perform the diagnostic procedure of fraction flow reserve (FFR) to assess lesion severity. Potentially, Madder said the remote robotic system can be installed anywhere there is a fluor- oscopy suite, and that it suggests a potential for tele-stenting, an ability to perform procedures in regions where PCI is currently unavailable by utilising a robotic cockpit located in a distant expert centre. ‘We are still very early in this study; there’s a lot of work to be done,’ he noted. ‘We are ways off from deploying a system to commu- nity hospitals.’ Shielding cardiologists from harmful radiation is the goal for two systems capable of navigat- ing the vascular highway, John Brosky reports ‘We cannot continue to accept work- ing in conditions that put our lives in danger,’ says Alain Cribier, the pioneering cardiologist from the University Hospital of Rouen, who first implanted an aortic heart valve via a catheter in 2002. ‘You don’t feel anything; radiation is not pain- ful, but there is an accumulation of dose when you do this for decades, day-in and day-out,’ he explained. A study, published by the American Heart Association in August 2016, demonstrated a direct relation between working in a cath- eterisation lab and developing radi- ation-induced cancer, cataracts and skin lesions. According to the study, interven- tional cardiologists accumulate sig- nificant lifetime radiation exposure in the range of 50 milliseverts to 200 mSv, which corresponds to a whole body dose equivalent to 10,000 chest X-rays. ‘I have lost several col- leagues to brain can- cer,’ Alain Cribier told European Hospital. ‘We all have mus- culoskeletal prob- lems,’ he said, bringing out of a closet the 12-kilo lead apron he wears during 12-hour work shifts that can result in aggra- vated orthopaedic maladies. At EuroPCR in May 2017 in Paris, Cribier met with fellow cardiologists on the Cardiologists must keep up We must embrace the potential of digital data Report: Mark Nicholls Leading cardiologist and healthcare researcher Professor Harlan Krumholz has warned that medical practitioners must embrace the potential of digital data generated by patients if they are to avoid being left behind as the digital revolution moves forward at an ever-advancing pace. As Professor of Medicine (Cardiology) at Yale School of Medicine, he delivered the prestig- ious Paul Wood Lecture at the June conference in Manchester, UK, of the British Cardiovascular Society on a theme of ‘Personalised medicine and computational cardiology – enhanc- ing cardiovascular care and health in the next era’. Tex vector / Shutterstock ‘Data generated every day for a variety of practical purposes can serve as an inexhaustible source of knowl- edge to fuel learning in a healthcare system,’ he said, but warned that if medicine wants to take advantage of technology, it has to catch up with the digital revolution. He pointed to statis- tics that show the average American Prof. Alain Cribier, MD, is head of Cardiology at the Charles Nicolle Hospital , in Rouen University, France. Back at the R-One robotic system from Robocath, Cribier provided a demonstration. ‘This is not a totally new idea,’ he said. ‘There are sur- gical robots, orthopaedic robots, robots for brain surgery. But it was not considered possible for cardi- ology. I was sceptical myself but, over 10 years, I have followed the progress step-by-step as they solved technical problems.’ At the patient table, Cribier feeds the catheter into a single-use car- tridge, an integral part of the robotic mechanism that contains the grasp- ers that advance and turn the guide- wire. Walking from the patient table to the control panel behind a radiation shield, he said, ‘The robot does not perform anything itself, everything is controlled by the operator’s hand,’ he pointed out. ‘I can do exactly the same things using the robot that I would do with my hands, advance the wire, retreat, rotate and push.’ At the controls he advances and rotates the guidewire simultaneous- ly, pushing and turning, something the CorPath robot cannot do. Cribier expects in a next step the robot can be applied to periph- eral artery procedures as it uses the same sized wire. Corindus has already been granted an extended indication by the FDA to apply the CorPath for peripheral procedures. As for the transcatheter aortic valve replacement procedures that he pioneered, Cribier said, ‘There is no question the system can be adapted to accept these larger cath- eters. This system will allow physi- cians to go anywhere on the vascu- lar highway.’ spend 5.6 hours on digital devices every day, including those in older age groups, and that medicine has to recognise the power of this trend. Krumholz also suggested that medi- cine has not learned to communicate as rapidly, effectively and simply with its audience in the way that other sectors, such as weather forecasters, retailers, and traffic bulletins, have. Medicine, he said, had been slow to find ways of integrating digital data into practice, pointing to the tran- sition to electronic health records, where he feels health professionals in the USA were slow to get involved as hospitals made the transition - eased with $50bn of funding. In 2008, 9.4% of records were electronic health records (HER) but, by 2015, it was 83.8%. He also felt patients should have access to their own record to share it in ways that can improve their care and augment research, being partners as ‘citizen scientists’. The most important element about precision medicine, Krumholz con- tinued, is that it can be driven with patients as partners and that the doc- tors and researchers should recognise the value of patient reported outcome data that are generated from wearable EUROPEAN HOSPITAL Vol 26 Issue 4/17

1 8 CA R D I O LO G Y New scan detects inflammation after heart attack Exciting hyperpolarised MRI Report: Mark Nicholls A new type of scan that can detect cardiac inflammation may help tai- lor treatment for patients who have suffered a heart attack, according to research findings presented at the British Cardiovascular Society (BCS) conference in June. Developed in the UK, hyperpolarised MRI (h-MRI) enables cardiologists to see more detail of healthy and diseased hearts than conventional scans, including the level of inflammation post-myo- cardial infarction. Detecting inflammation in the heart the British Heart Funded by Foundation (BHF) the University of Oxford researchers now believe h-MRI could help scientists develop and monitor the effects of new, inflammation-targeting treatments that may improve the heart’s heal- ing process in heart attack patients. The discovery could have signifi- cant benefits because the hearts of patients who have suffered a myo- cardial infarction (MI) can undergo continued inflammation even during the healing process, and despite receiving emergency treatment. Yet research into why this may happen remains limited as con- ventional scans cannot detect or measure inflammation in the heart, whereas h-MRI can. Conventional MRI measures how protons change position when exposed to a magnetic field, but h-MRI works by producing images from carbon molecules, which make up the energy sources needed to help the heart pump and can offer doctors a clearer picture of inflam- mation in the heart. h-MRI as biomarker and pharmacological target For the study, the team measured production of lactate in the dam- aged heart tissue of rats and found that after a heart attack immune cells within the injured heart mus- cle become active and are repro- grammed to make lactate, leading to inflammation in the heart. By monitoring how much lactate is pro- duced in the damaged tissue, they were able to identify and measure the level of inflammation in the heart. Following on from that, the team administered the experimental drug 2-deoxyglucose (2-DG) to the rats after the heart attack, to try and combat the inflammation. to monitor Using h-MRI the heart’s response, they found that 2-DG reduced lactate production and inflammation, and improved the heart’s function. The cutting edge scanning system They showed that high hyperpolar- ised lactate signal in the days after myocardial infarction is caused by macrophage-driven inflammation, and reflects not just the number of inflammatory cells infiltrating the myocardium but also the inflamma- tory phenotype of those cells. The Oxford scientists – one of the first groups to use h-MRI to study the human heart – believe that h-MRI will not only detect inflammation in damaged heart tis- sue but also could provide a novel method for the detection of myocar- dial inflammation with high transla- tional potential as both a biomarker and novel potential pharmacological target. ‘H-MRI is a cutting-edge scanning system which allows doctors to bet- ter understand the innermost work- ings of the heart non-invasively, and how they become abnormal in heart The Oxford University team used the hyper- polariser laboratory to investigate how the experimental drug 2-deoxyglucose (2-DG) may improve heart function after a heart attack Andrew Lewis MD is a Specialist Registrar in Cardiology at the Great Western Hospital in Swindon, UK, and won the Young Investigator’s Prize Competition at the British Cardiovascular Society conference in Manchester for his research into myocardial inflammation imaging. disease,’ Dr Andrew Lewis, Specialist Registrar in Cardiology at the Great Western Hospital in Swindon, summed up. ‘In this research, we used h-MRI imaging to capture the healing processes in experimental models after a heart attack, and also tested new treatments to improve the heart’s recovery. More studies needed ‘Our work has identified several forms of heart disease where this technique could be used to improve diagnosis and treatment,’ Lewis added. This is incredibly exciting, and we intend to move forward with patient studies as quickly as possible.’ Lessons gained from an EHRA 2017 Symposium Cardiac resynchronisation therapy improvements Which CRT patients can be ‘downgraded’ from a CRT-D device with defibrillator function to a CRT-P with just a pacemaker function? This, with two further current CRT issues – chronotropic incompe- tence and telemonitoring of CRT patients – featured prominently at the Europace-Cardiostim Congress in Vienna. For more than 20 years, cardiac resyn- chronisation therapy (CRT) has been a pillar in the treatment of chronic heart failure (CHF). CRT devices are either pacemakers (CRT-Ps) or implantable defibrillators (CRT-Ds), which are implanted in the patient’s chest. These are connected to the heart with three leads, the third one linking to the left ventricle which pumps blood through the body. While both types of devices synchronise the heartbeat, CRT-Ps prevent the heart from beating too slowly and CRT-Ds prevent it from beating too quickly. At a satellite symposium at the Europace-Cardiostim Congress (EHRA 2017) experts debated whether patients who respond well to a CRT-D and show improved heart function should receive a CRT-P in the next scheduled device replacement. The background: Many patients respond so well to CRT that their heart function markedly improves and a CRT-D might not be needed; indeed between 10-25% are so-called super-responders, i.e. their cardiac device restores a normal ejection fraction in the left ventricle, lowering the risk of sudden cardiac arrest to that of a healthy person. At EHRA 2017, Dr. Jacques Mansourati from Brest University Hospital in France, presented a study investigating this very issue: The BioContinue study is observing 277 CRT patients in eight countries to determine which patients need a defibrillator. According to pre- liminary study data, 39% of patients who receive a CRT replacement do not need a defibrillator because the therapy increased the ejection frac- tion of the left ventricle by at least 40% and no ventricular tachycardia was reported. ‘During a scheduled replacement of the device, respond- ers and super-responders can be downgraded from a CRT device with defibrillator to one without this function,’ Mansourati explained. The second controversial issue in CRT is chronotropic incompetence: In 20-40% of all CRT patients, heart rate does not increase commensu- rate with increased physical activity. ‘Chronotropic incompetence could be a major factor in patients who do not respond to CRT,’ said Dr. Mattias Roser from Charité Berlin. In these cases, Roser points out, rate- adaptive pacing might provide a solution, as indicated by BioCreate, a pilot study conducted at Charité to investigate whether Closed Loop Stimulation in heart failure patients with chronotropic incompetence can improve clinical outcomes. This technology, developed by Biotronik, responds naturally to patients’ phys- ical and mental activity or stress, adapting heart rates physiologically. Roser is optimistic: ‘We consider this a highly potential approach to significantly improve the treatment of CRT patients,’ he said. The third, but by no means least, important issue is remote monitor- ing of ICD patients. Ever since the IN-TIME study showed Biotronik Home Monitoring reduced mortal- ity in heart failure patients, the use of this technology has been included in the clinical guidelines. However, data presented at EHRA 2017 indicate that not all tele-mon- itoring systems are created equal: they do offer different clinical out- comes. TRUECOIN, a meta-analysis, showed Biotronik Home Monitoring to reduce mortality in all types of ICD patients. EUROPEAN HOSPITAL Vol 26 Issue 4/17

13 –16 NOVEMBER 2017 DÜSSELDORF GERMANY www.medica.de/MLF2 NEW at MEDICA THE INTERNATIONAL FORUM FOR LABORATORY MEDICINE Organization Prof. Dr. med. Georg Hoffmann Trillium GmbH Medical Publishing House and Deutsches Herz- zentrum München Doctors and patients, health policymakers and healthcare providers, media representatives and all other visitors of the world’s largest medical trade fair are invited to four exciting focal days with top-class lectures and panel discussions. The event takes place each day from 11 a.m. to 4 p.m. in the new hall 18 and is free of charge for trade fair visitors. The conference language is English. Early detection of cancer and cardiovascular diseases Monday, 13 November 2017: Oncology – Can cancer be detected by a blood test? Tuesday, 14 November 2017: Cardiology – More diagnostic confi dence with myocardial infarction and heart insuffi ciency Prof. Dr. med. Stefan Holdenrieder, Deutsches Herzzentrum München The laboratory comes to the patient Wednesday, 15 November 2017: Diabetology – From self-test to continuous glucose measurement Prof. Dr. med. Peter Luppa, Klinikum rechts der Isar der TU München Dangerous travel companions Thursday, 16 November 2017: Infectiology – New multi-resistance in the age of migration Priv.-Doz. Dr. med. Beniam Ghebremedhin, Universität Witten/Herdecke, HELIOS Universitätsklinikum Wuppertal Messe Düsseldorf GmbH Postfach 10 10 06 _ 40001 Düsseldorf _ Germany Tel. + 49(0)2 11/ 45 60-01 _ Fax + 49(0)2 11/ 45 60-6 68 www.messe-duesseldorf.de

2 2 L A B O R AT O RY @ I N F E C T I O N C O N T R O L ‘We must act now – or we may run out of options’ Antibiotics don’t generate large profits During our European Hospital interview with specialist in microbiol- ogy, virology and infection epidemiology Beniam Ghebremedhin MD, from the University Hospital Wuppertal, spoke about the impact of migration on infections, and ways to tackle the problem of multire- sistant pathogens ‘There is a lack of specialists in infec- tious diseases, for direct patient care on hospital wards as well as in the field of infectiology and diagnos- tics,’ infections specialist Dr Beniam Ghebremedhin agreed. ‘We are also short of specialists in infection pre- vention and control, along with microbiologists and virologists. In these times of multiresistant bacteria and large-scale microbial infections we should be promoting and sup- porting a new generation of spe- cialists to strengthen research and diagnostics.’ This June, the EU published guidelines on dealing with anti­ biotics to help contain the spread of resistance. Could this help? ‘The topic is of great importance as there are still many areas where anti-infectives are prescribed too quickly and not in a targeted man- ner. Due to time constraints in outpatient care for instance, anti- biotics are often prescribed so that patients can be treated as quickly as possible. However, Amoxycillin or Cefuroxim are the wrong drugs to treat viral infections. There should be much more emphasis on treating patients with more precision, and on adapting treatment to their indi- vidual risk factors. ‘Apart from the EU guidelines, there are already other recommen- dations on how adequate treat- ment should commence, such as the “Tarragona Strategy”. This is the basic concept for adequate, initial treatment of bacterial infections with antibiotics. It includes the recom- mendation that the patient should receive a systematic examination if there is a lack of relevant informa- tion, such as where the patient is from and their local epidemiology (frequency of infections and resist- ance), because appropriate treat- ment cannot be given when these factors are not known. The focus should be on the dose, length of treatment and monitoring, along with the severity of the disease, all of which also requires as much information as possible about the patient. It is critical for the prognosis that adequate treatment commences without delay and with a high dose.’ In Germany, there is no specific training programme for doctors wishing to qualify in infectious disease treatments. However, additional qualifications can be obtained. Once someone has qualified as a specialist registrar and worked in infectiology for at least three years they can obtain a Certificate for Infectiology DGI, after attending the respective course. The lack of a specific area and course of studies for infectious diseases is a German particularity. The EU, including England, along with Switzerland and the USA all have respective training programmes in this field. At Medica 2017 you will focus on ‘Infectiology – New Multiresistance in Times of Migration’. Why? ‘Viruses and bacteria know no bor- ders. Worldwide migration is very much on the increase, not only as waves of refugees but also because of open borders and changes in trav- el habits. Holidays abroad and work- ing on different continents have become the norm. However, this also means that locally occurring infections no longer remain local. A pathogen such as an influ- enza virus can quickly spread glob- ally. Bacteria are carried from one country to another in suitcases. If we want to treat patients correctly we therefore need to know where they are from, which pathogens they could have brought with them, or which multi-resistant pathogens they may have been exposed to. ‘This is of particular importance in the case of multiresistant patho- gens. In my lecture, I will talk about gram-negative bacteria such as Escherichia coli, Klebsiella pneu- moniae or Acinetobacter baumannii, all of which have taken on greater significance. The latter in particular has made the headlines, in Kiel for instance and in Stuttgart at the beginning of this year.’ What can be done against mul­ tiresistant pathogens? ‘This is a very important and also difficult question. Germany must definitely improve its procedures for infection prevention and detec- tion. Infected patients need to be isolated earlier. In the Netherlands, the isolation of risk patients on admission is standard practice, in Germany; however, the capacities for isolation procedures are often insufficient. This is a strong point of criticism, as things are getting serious: the last weapons we can utilise in the fight against mul- tiresistant pathogens are becoming ever blunter. New anti-infectives are rarely approved and only have specific effects. Around thirty new substanc- es are currently being examined in studies, but only four or five of those are likely to make it to the market. However, rather than multi-purpose weapons, these will be substances working against very specific patho- gens only. Furthermore, resistance is developing much more quickly now. Where some substances used Moving towards deeper diagnostics Continued from page 21 Beniam Ghebremedhin MD PD will discuss ‘Infectiology – New Multiresistance in Times of Migration’ at the Medica Labmed Forum 2017, on 16 November 2017 in Düsseldorf, Germany. The free discussions will normally take place between 11am and 4pm in the new exhibition Hall 18, Conference language: English. to be effective for up to ten years, this is now wishful thinking.’ Is the pharmaceutical industry active in this area? ‘Not as much as we’d like it to be; unlike cancer drugs, antibiot- ics don’t generate large profits. Investment in studies is expensive, and treatment with antibiotics is not always comprehensive enough to regain the money invested.’ Another major problem: viola­ tion of hospital guidelines on infection prevention and control. ‘Correct – and hand hygiene is critical here. This could help avoid a third of all transmissions of patho- gens. Many places now have special- ly trained nurses who work in this field. Unfortunately, they have to fight obstinate colleagues on a daily basis. However, hygiene knows no hierarchy and a bacterium is not interested in chains of command. We must act now – otherwise we may well run out of options in the fight against multiresistance.’ and Dr R. Fried, from Zurich, Switzerland, spoke about nation­ al issues when it came to regula­ tory requirements for POCT. Their respective contributions were enti­ tled requirements for POCT in Switzerland, and ISO 22870 in Austrian Practice. Is there still considerable work to do in Europe on the development of unified standards, definitions and values etc.? ‘Some European guidelines exist the ISO already. For example, 22870 is now not only used in all European countries but also world- wide. However, when it comes to the respective translation and imple- mentation into national laws there can be inconsistencies. This is why we took a closer look at these two countries. We saw that the ring trials carried out for quality assurance, for instance, are organised on a national level, i.e. EU law is being converted into national law. In some other countries, such as France, we can see that the conversion is organised in a different way. Is there European or interna­ tional cooperation, for example working groups, commissions, or committees? ‘There are many active European and international committees in this field. It has become apparent that the Asian region needs to reposition itself, and we are working inten- sively on this. In the past, Asia has almost exclusively aligned itself with the FDA, based on the motto that whatever they approve automatically F K E f o y s e t r u o C becomes licensed in Asia. But there has been a change here recently: both India and China, for instance, have now also developed analogue and national systems. ‘International cooperation is in good shape. The ISO norms are an excel- lent example here as, once they have been introduced, a country cannot really opt out again. However, the application is not compulsory, which means that national requirements can still be considered. In any case, i t ’s beneficial that ISO norms are now used as a foundation worldwide. ‘This trend is reinforced by the fact that the industry, which revolves only around a small number of man- ufacturers here, is not interested in national solo efforts.’ When the medical trade show Medica takes place in a few months’ time, Georg Professor Hoffmann, from Trillium Verlag, will hold a four­day ‘LabMed Forum Medica’. On 15 November you will preside over the topic ‘From self­test to continuous glu­ cose monitoring’. Will this focus exclusively on POCT for diabetes? ‘Obviously the focus will be on diabetology, but we are not limiting ourselves and can also accommodate the interests of our participants. The event will be held for the first time and we are curious about how it will develop. Previously at Medica sev- eral working groups and symposia focused on POCT, when diagnostics still played an important part at this Düsseldorf-based event. That’s why we will now observe developments and draw our conclusions. ‘So, this time, we will mainly focus on continuous glucose monitoring. For other parameters that can be continuously monitored, such as lac- tate or other cardiac markers, the applications are still more straight- forward.’ ‘We are sitting on a ticking time bomb’ Multidrug-resistant organisms (MDRO) are keeping infection specialists worldwide on their toes. One of these specialists travelled all the way from Leipzig to India to gain insights in one of the sources of the problem. Report: Katrin Schreiter Dr Christoph Lübbert, infection spe- cialist at University Hospital Leipzig, Germany, is deeply concerned about the global risk multidrug-resistant bacteria are causing – well know- ing that the problem is anything but new. Between 2010 and 2013, his very institution, Leipzig University Hospital, suffered, up to then, the largest known and highly alarming outbreak of KPC (Klebsiella pneumo- niae carbapenemase-producing bacte- ria) in Germany. A fatal chain of events A 66-year-old male patient had been transferred from a hospital on the Greek island of Rhodes to University Hospital Leipzig. The patient, who needed mechanic ventilation, was ini- tially admitted to the hospital‘s ICU. Later, he was moved to a general ward, at a point when the exact type of pathogen the patient had acquired abroad was not yet microbiologically determined. The situation spiralled out of control: in the ensuing months patients primarily at the interdisci- plinary surgical ICU were diagnosed with infections. Spreading of the pathogen, from patient to patient, most likely via staff hands and exacerbated by contami- nated surfaces, is thought to be the most likely cause of the extended outbreak, which was only stopped after an internal task force strictly enforced a combat strategy. The com- monly used antibiotics did not yield the desired results; in short, the most effective weapon in the fight against this pathogen had turned blunt. Forty- two of the 100+ infected, mostly severely ill patients died, seven of them most likely as a direct conse- quence of the KPC infection. ‘Back then we saw what happens when all of a sudden certain anti- biotics don’t work any more – and we learnt how decisively we have Journalist Christine Adelhardt, conservationist Anil Dayakar, infectiologist Christoph Lübbert and cinematographer Tilo Gummel take samples in a lake in an industrial area of Hyderabad EUROPEAN HOSPITAL Vol 26 Issue 4/17

2 4 L A B O R AT O RY @ I N F E C T I O N C O N T R O L Going international – the only way to win Combating CRAB and carbapenem resistant bacteria Antimicrobial resistance mortality is set to surpass cancer and traffic-related deaths by 2050, according to the UK National Health Service (NHS). Carbapenem-resistant Acinetobacter (CRAB) and carbapenem resistant Enterobacteriaceae, two of the most common bacteria involved in these types of infections, are the object of the COMBACTE-CARE’s EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA). European Hospital asked Belén Gutiérrez-Gutiérrez, coordinator of the project, how it will improve knowledge of risk and prognosis factors, and what is the best avail- able treatment. Report: Melisande Rouger ‘According to a report published by the UK National Health Service (NHS) in 2016, antimicrobial resist- ance mortality will increase from the current 700,000 to 10 million annual deaths by 2050 – unless extraordinary steps are taken to control it,’ Belén Gutiérrez-Gutiérrez pointed out. ‘To give an idea, 10 mil- lion deaths per year are more than the current number of cancer or traffic-related deaths. UN declaration acknowledges the gravity ‘The United Nations member states also signed a declaration acknowl- edging the gravity of drug resistant bacteria. ‘Carbapenem-resistant gram-neg- ative bacteria Acinetobacter bau- mannii, carbapenem-resistant Pseudomonas-aeruginosa, and car- bapenem and 3rd generation cepha- losporin-resistant have been defined as first priorities by the WHO in its list of antibiotic resistant bacteria that are a risk to human health.’ Currently 53 hospitals in ten coun- tries take part in the study, with 836 patients enrolled – so 40% of the total estimate. These patients will serve to improve knowledge of risk and prognosis factors, and best available treatment in infections due to CRAB and carbapenem resistant Enterobacteriaceae. They will also serve as a historical comparative cohort for new clinical trials to develop new antibiotics. First results to be aired at ECCMID 2018 ‘The study will close by February 2018 and we hope to communicate our first results during the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), which will take place in Madrid in April next year.’ ‘First, we must raise public aware- ness of increasing antibiotic resist- ance and its relationship with anti- biotic overuse. It’s key is to raise not only public awareness but also among HC professionals and the pharmaceutical industry of how important it is not to abuse antibiot- ics and use them only when strictly necessary. ‘Then we must analyse how these microorganisms are transferred and prevent them in the hospital and the community. ‘We must also reduce the unnec- essary use of antibiotics in animals for human purposes, and promote new diagnostic tools to early detect infection and reduce the unneces- sary use of antibiotics when there is no infection. ‘Last but not least, we must devel- op new antibiotics and optimise antibiotics that are already avail- able.’ How the coordination role began ‘We had just finished including cases from INCREMENT, another international observational study on bloodstream infections (BSIs) due to extended spectrum β-lactamase- producing Enterobacteriaceae (ESBL) and/ or carbapenemase-pro- ducing Enterobacteriaceae, when Dr Jesús Rodriguez-Baño, who leads the EURECA study, asked me to coordinate it. I am part of a great local team of seven professionals, who help me coordinate and man- age the study together with the COMBACTE Clin-Net, Stat-Net and Lab-Net networks. Other research projects Until recently I was coordinating the INCREMENT project. Now I’m coordinating INCREMENT-SOT, a study in transplanted patients with BSIS due to extended spec- trum β-lactamase-producing Entero- bactamase (ESBL) or carbapene- mase-producing Enterobacteriaceae, together with Reina Sofia Hospital in Cordoba and 12 October Hospital in Madrid. ‘I am also part of the research team in another international pro- ject, the MODERN study, on ESBL transmission and epidemiology.’ nosocomial Facing the challenges of drug resistant bacteria ‘At the Infectious Diseases and Clinical Microbiology Unit in Virgen Macarena University Hospital, in Seville, we have a team of spe- cialists who are responsible for controlling and managing patients with infection. Multidisciplinary work, joining infectious diseases physicians, microbiologists, nurses, pharmacists and preventive medicine specialists, is essential for these patients. We need to diagnose the infection due to a drug resistant bacteria early, to treat it with the best available therapy, and to rigorously manage treatment to guarantee a successful outcome. Also, it’s key to take isola- tion measures and develop antimi- crobial stewardship.’ Effective prophylaxis beats the best treatment A specialist in internal medicine, Belén Gutiérrez-Gutiérrez MD works in the Infectious Diseases and Clinical Microbiology Unit at Virgen Macarena University Hospital, Seville, Spain. Gaining her PhD at Seville University and a degree in epidemiology and clinical research from the University of Granada, today she is involved in various international antimicrobial resistance research projects. The importance of a multi- disciplinary international network ‘In our daily work as infectious diseases physicians, we increasingly have to manage patients with infec- tion due to bacteria resisting almost any type of antibiotics. You realise how necessary and important it is to have a multidisciplinary and interna- tional network such as COMBACTE. Our objective is to work all together in the same direction to fight these infections.’ EURECA is a prospective observational study within the COMBACTE-CARE project, which is promoted by the Innovative Medicines Initiative (IMI), a consortium between the EU and the European Federation of Pharmaceutical Industry Associations (EFPIA). The project focuses on combating carbapenem-resistant Gram- negative bacteria. Antibiotic-loaded bone cement cuts costs The basic principle of any ther- apy is to select the least invasive treatment option depending on the present features with the best func- tional result. Guidance is provid- ed by the recently updated Pocket Guide to Diagnosis & Treatment of Periprosthetic Joint Infection (PJI) published by the Pro-Implant Foundation (www.pro-implant-foun- dation.org). Antibiotic-loaded bone cement is a cost-efficient periprosthetic joint infection prophylaxis after knee and hip joint arthroplasty. Periprosthetic joint infection (PJI) is a dreaded post-surgical compli- cation occurring in one to three percent of knee and hip joint arthro- plasties. ‘With PJI, the five-year survival rate is significantly lower than for testicular cancer, Hodgkin lymphoma, melanoma and breast cancer,’ explained Nils P Hailer, Professor of Orthopaedics at the Department of Surgical Sciences/ Orthopaedics at Uppsala University Hospital, Sweden. ‘The good news: there is an effec- tive prophylaxis,’ the expert told del- egates at the 18th EFORT Congress 100 95 90 85 SC C S N 0 2 4 6 8 10 12 14 16 Years after surgery SC – systemic and in the cement C – in the cement S – systemic N – no antibiotic Norwegian Hip Registry: Revision risk is lowest if systemic and local antibiotic prophylaxis are combined (Vienna. 31 May - 2 June) 2017, during a satellite symposium on anti- biotic-loaded bone cement (ALBC) organised by Heraeus Medical, a German medical device manufac- turer. PJI is caused by biofilms forming on the implant surface. ‘It takes very few – only about 200 – bacteria to trigger the biofilm,’ said Dr Andrej Trampuz, Head of the Infectious Diseases Research Laboratory at Charité Medical University in Berlin, Germany. In acute infections (< three weeks), retention of the prosthesis is the treatment of choice. However, in chronic infections, exchange of the prosthesis is crucial to achieve high treatment success, Trampuz added. ‘A mature biofilm – older than three weeks – is impossible to eradicate without implant removal.’ Infection is the best possible complication ‘To achieve high treatment success, a concerted surgical and antimicrobial concept is needed,’ Trampuz empha- sised. Such a planned approach can indeed achieve success rates of over 90 percent. Even further, he said: ‘Infection is the best possible com- plication, if appropriate diagnosis is combined with correct surgery and efficient anti-biofilm agents.’ Effective prophylaxis beats the greatest treatment Many studies involving different methodologies support the use of single dose antibiotic-loaded bone cement to reduce the risk of infec- tion after knee and hip arthroplasty. A Spanish study shows that the introduction of antibiotic-loaded bone cement (ALBC) Palacos R+G in knee and hip joint procedures in Spain in 2011 lowered PJI rates by 72% in hip procedures and 60% in knee procedures (including arthro- plasty and fractures). Despite these data, there are still some European countries where ALBC is not used due to additional costs of $200-500 compared to plain bone cement. If those one-off costs are compared to the costs generated by PJI, con- sistent use of ALBC is significantly cheaper: according to the Spanish study cost reductions of €2,672 per patient receiving hip procedure were realised. Dual ALBC proves effective in hip hemiarthroplasty In the treatment of high risk patients with intracapsular neck of femur Concentration of local and systemic antibiotics. If applied locally up to a thousandfold higher concentration is possible fractures, dual impregnated bone cement (Copal G+C) has proven to reduce infection rates for deep surgical site infections (SSI) by 68%, according to Professor Mike R Reed, consultant trauma and orthopaedic surgeon at Northumbria NHS Trust, EUROPEAN HOSPITAL Vol 26 Issue 4/17

2 6 L A B O R AT O RY @ I N F E C T I O N C O N T R O L Savers, healers or threats to life? CRISPR/Cas9 and Sherlock Report: M van de Wouw Modifying a DNA sequence to alter a cell to cure a disorder, prevent a genetic disease being passed on to next generations, or to use genetic modification as a way to diagnose a virus: yes, these tasks are possi- ble. The recently discovered CRISPR technique can do it all. 1987 research- Already in er Yoshizumi Ishino, at Osaka University, described the possibility of genome editing. In 2012-2013 scientists discovered genetic modi- fication of a specific DNA sequence in a cell and gave it the name CRISPR. The discovery was runner up in 2012 and 2013 in Science Magazine’s Breakthrough of the Year award. CRISPR won the award eventually in 2015. Largely due to its simplicity and adaptability the technique rapidly became one of the most popular approaches for genome engineering. And so the development goes on. CRISPR is - an abbrevia- tion of Clustered Regularly Interspaced Short Palindromic Repeats. These short segments of repeated codes in DNA were first discovered in bacteria, where they play a key roll as part of the bac- terial defence mechanism against viruses. So far, three distinct bacte- rial CRISPR systems, types I, II and III have been identified. The Type II system is the basis for genome engineering technology available at this moment. Cas (CRISPR Associated System) is the name for different enzymes/ proteins. Cas 9 is protein 9 and, together with CRISPR, is the basis for the technique used to edit the human genome. Cas9 is program- mable and works in any type of cell. How it works - CRISPR/Cas9 allows permanent modification of genes within organisms, therefore manipulating the code of life. It works like a pair of molecular scis- sors: when CRISPR is used to edit genes in a cell, a small strip of RNA directs an enzyme capable of cutting DNA at a desired location within a genome. This allows existing genes to be removed and/or new ones added. The cell recognises the dam- age done by the cut and ‘glues’ the pieces back together. And, although the cell is a bit shorter after the cut, it functions again. Genome editing techniques have many potential applications, such as to target virulence factors, genes encoding antibiotic resistance, can- cer, inflammation, foetal haemoglo- bin and even eradicate viral DNA in the case of Epstein-Barr virus (EBV). There are more than 3,000 genetic diseases, such as colour blindness or Huntington’s disease, caused by one wrongly placed nucleotide in the DNA. CRISPR may even revive the con- cept of transplanting animal organs into humans. The biggest problems in transplant rejection are the retro- viruses present in animal genomes. Researchers are working on elimi- nating those retroviruses DNA. Ethical issues - OHSU scientists recently used CRISPR on a human embryo to correct a mutation in nuclear DNA that causes a com- mon genetic heart disease, leading to sudden cardiac death and heart failure. By removing the disease- k c o t s r e t t u h S / n g i s e D n a c l o S : e c r u o S causing gene variant from the line- age, every future generation would carry the repair. It was a success. However, the potential to alter DNA in human cells needs more investigation, because it is still unknown what the long-term side effects will be. In future, potentially infected diseases may occur. The use on human embryos also causes an ethical issue. How far should we go? Policy regulations for the CRISPR/cas9 system vary inter- nationally. Researchers in China, Sweden and the United Kingdom are allowed to use human embryos for CRISPR interventions, although in the UK it is forbidden to implant the embryos. They must be destroyed after seven days. The Netherlands does not permit the use of human embryos. According to some, the potential danger in the long run is the temp- tation to treat children not only for genetic disorders but also to make them perfect: superior intelligence, better eyes, and better muscles. Rules for applying CRISPR/Cas9 are therefore necessary. Sherlock - Besides being able to repair DNA, CRISPR could soon also become a low-cost diagnostic tool to detect infectious diseases such as Zika or dengue. According to a recent article published in Science researchers have devel- oped the Specific High-sensitivity Enzymatic Reporter (SHERLOCK), which stands for ‘to make accurate, fast diagnoses’. This uses a differ- ent enzyme, Cas13a, which goes to RNA, rather than DNA. It chops through any RNA encountered and does not stop until that has gone. The development of Sherlock gave medical labo- ratories a new diagnostic tool. And the scientific community is excited. Sherlock can detect pathogens in extremely small amounts of genet- ic matter and in an earlier stage. Besides that, tests can be performed using urine and/or saliva rather than blood. Quoted from Science: ‘The detection sensitivity of the new CRISPR-Cas13a system for specific genetic material is one million times better than the most commonly used diagnostic technique’. The technique is also highly port- able, needs no refrigeration and costs as little as 61 cents per test in the field. Therefore Sherlock would be extremely useful in remote plac- es without electricity or access to a diagnostic laboratory, providing clinicians the possibility to diagnose and treat illnesses. CRISPR/Cas9 and Sherlock can change and save lives. Professor and Director Scott Weaver PhD, at the Institute for Human Infections and Immunity, University of Texas Medical Branch in Galveston, states in an article on Big Think: ‘It looks like one significant step on the path- way that is the Holy Grail, which is developing point-of-care, or bed- side detection, that doesn’t require expensive equipment or even reli- able power.’ Source: https://www.washingtonpost. com/news/speaking-of-science/ wp/2015/12/01/historic-summit-on-gene- editing-and-designer-babies-convenes-in- washington/?utm_term=.765ca64aafaf http://science.sciencemag.org/ content/356/6336/438 An intelligent blood sample sor Inspirational middlewar The sorting devices SortPro of the young German supplier ASP Lab Automation AG take over the collec- tion and pre-sorting of the samples in the Accessioning area of clinical laboratories. The universally applica- ble devices, of which about 100 have been installed worldwide in the past 24 months, are characterised by high processing speed and easy operation. As with comparable devices from other manufacturers, these have so far exclusively passed on the data they have collected to the laboratory information system (LIS) and received from there their commands to distrib- ute the samples. With a new option package, for the first time, leading intelligence is used directly in the sorter and opens up new opportuni- ties in the optimisation of the process sequences in the sample entry. In July, ASP presented this mid- dleware package to the public at the world’s largest clinical chemistry conference, the American Association of Clinical Chemistry (AACC) in San Diego, California. This option pack- age includes several features that improve handling in everyday opera- tion and, in particular, a complete PC. A greatly extended graphical user interface is running on a large touch- screen monitor. A special service tool counts every work step and deter- mines any service requirement, which is displayed to the operator in time to arrange an appointment. Shortest standstill times with minimum service effort are thus realised. The most important function, how- ever, is the acquisition and evaluation of each individual sample processed by the device. The time course of the sample quantity, the frequency of individual requirements and other statistics can be called up in the extensive protocol function. The data EUROPEAN HOSPITAL Vol 26 Issue 4/17 POCT at its BestPrecise. mlexible. 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2 8 L A B O R AT O RY @ I N F E C T I O N C O N T R O L Blood test could help predict which patients survive surgery High troponin levels yield a clue k c o t s r e t t u h S / e b _ l u u k e l o m : e c r u o S Report: Mark Nicholls at the James Researchers Cook University Hospital, in Middlesbrough, UK, have developed a highly sensitive blood test that could be used before surgical opera- Troponin may be an indicator for an underlying inflammation, researchers suggest. tions to predict which patients are at risk of complications will survive in the long-term. Presenting their findings at the British Cardiovascular Society conference this June, they explained that they measured the level of troponin in blood samples taken from 993 patients before elec- tive or emergency surgery. None of the patients had cardiac surgery. The team found that 25% of the patients who had troponin levels of 50ng/l, or over, before their surgery died within six months, rising to 37% dying within 12 months of the operation. In comparison, only 2.5% of patients with a pre-operative tro- ponin level of less than 17ng/l died within six months. Only 3.7% of these patients died within a year of their operation. The troponin test is routinely used in Accident and Emergency depart- ments to diagnose a heart attack and measures blood levels of the molecule troponin, which is released into the blood stream when heart muscle is injured. However, in this study 10% of patients had raised troponin levels without having suffered any previ- ous cardiovascular events. Dr Matthew Jackson, a Research Fellow at the James Cook University Hospital, emphasised that the study group of patients that were exam- ined all came in for surgery at the hospital without being pre-selected for the research. ‘That’s how this study differs from previous studies in this area that looked at selected high-risk groups or people under- going specific high-risk surgery,’ Jackson added. While the link between the raised troponin levels and an increased death rate after surgery remains unclear, the researchers suggest that a high troponin level may show that a person is suffering from underly- ing inflammation. To see wheth- er inflammation could explain the increase in death rates, the research- Matthew Jackson MD is an interventional cardiology trainee and Research Fellow at James Cook University Hospital, Middlesborough, UK ers are now testing the blood sam- ples for other signs of inflammation, such as raised inflammatory markers (C-reaction proteins). The team hopes their work will lead to new ways to improve patients’ survival after undergoing an opera- tion. ‘By helping us to better predict how patients will fare after surgery, this test may help doctors to iden- tify patients who could benefit from additional tests and medication to get them ready for their surgery and more intensive monitoring as they recover after their operation,’ Jackson said. ‘Now we need to find out why troponin levels are raised in some patients before surgery, and why these patients are more likely to die, in order to identify treatments that could reduce the risk of death following non-cardiac surgery.’ Further studies are planned to repeat the data in a more prospec- tive way and look at areas such as inflammation markers. Blood test could help predict which patients survive surgery A new generation of coagulation analysers Teco Medical Instruments has pro- duced coagulation analysers for a quarter of a century. Its new instru- ment line of manual and semi- automatic coagulation analysers – available in three versions, Coatron X Eco, Coatron X Pro and Coatron X Top, Coatron X – offer one, two and four channel optics and selected Coatron Coagulation analysis at the highest standard and reliability. Meet the new generation of coagulation analysis. We proudly introduce Coatron X. Highest optical resolution. Enlarged optic range, smallest sample and reagent volume 0,1 mOD – 3500 mOD, just with 75µL sample and reagent volume Complete optical analysis. No further parts required, like balls, stirrers etc. Adaptation of the light level. Automatic light level adjustment of the optic channels to each sample Exclusion of disturbance. Stray light reduction, exact temperature control, all parameter are preset Proven and improved usability. Operation via intuitive, colored touchscreen Downloads/Information: www.teco-medical.com/coatron-x Choose models from 1 to 4 optical channels. Coatron® X Eco, Coatron® X Pro, Coatron® X Top MADE IN GERMANY TECO Medical Instruments, Dieselstr. 1, 84088 Neufahrn, Germany, Tel.: +49 (0) 8773 70780-0, E-mail: info@teco-gmbh.com sample and reagent positions and, the firm points out, adding that the equipment provides the highest optical resolution; enlarged optic range; smallest sample and reagent volume 0,1 mOD – 3500 mOD, with 75µL sample and reagent volume, to provide a complete optical analysis. Additionally, no further parts, e.g. balls, or stirrers, are needed, Teco points out. The light level adjustment of the optic channels for each sam- ple is automatic. Stray light reduc- tion, exact temperature control, all parameter are preset. The internal barcode reader scans a patient’s identification on the pri- mary tube before measurement and this is combined with the result. If the instrument is connected to a Laboratory Information System (LIS) or Tecam Software, the patient ID and results are directly transmit- ted to the LIS. The Barcode reader reads reagent ID (Lot and Expiry) and consumable ID for verification and release. ‘The remarkable details in every single component are achieved by selecting only premium suppliers,’ Teco adds. ‘The performance of a high level instrument strongly depends on the concept in general and the perfect usability to reach the requirements of a modern labo- ratory analyser. Priority number one was to achieve daily routine reliabil- ity and easy-to-use operation.’ EUROPEAN HOSPITAL Vol 26 Issue 4/17

3 0 D I G I TA L PAT H 0 LO G Y Computational pathology The tipping point for digital pathology camelyon16.grand-challenge.org and http://camelyon17.grand-chal- lenge.org) – a valuable instrument in medical image analysis, in which every researcher or research group is invited to develop an algorithm for a given problem. All participants solve the same problem, using the same set of data, and the chal- lenge organisers evaluate all sub- missions in exactly the same man- ner. Therefore this is a great way to compare different approaches to problem solving. In the Camelyon16 challenge, we offered participants a large number of full WSI of sentinel lymph node sections of breast cancer patients Digital pathology has been the next big thing for about a decade. Yet, today only a few pathology labora- tories are fully equipped to digitise their workflow, mainly for legal or financial reasons. In the USA, for example, the ‘struggle’ with the FDA has prevented large-scale introduc- tion of whole slide images (WSI) in pathology for years. Nevertheless, it remains to be seen whether many pathology labs would invest the required (large) amount of money in a technique that still has to substan- tiate those high expectations. Will WSI be the disruptive inno- vation, as some experts believe? I think it will, but only under the right conditions. Yes, it may streamline the laboratories’ diagnostic work- flow, but only if fully and properly integrated with current workflows and information systems within the pathology department. WSI may be disruptive in the way we practice pathology at large, but only if we can create the right infrastructure to support networks of collaborating pathologists. Then it will be possible to practice ‘pathology in the cloud’ and instantly reach the right (sub- specialised) pathologist for every difficult case. Disruptive as this organisation may be, perhaps the most important promise of digital pathology is the development of computational pathology algorithms for WSI. Once a computer can help a pathologist to interpret histopatho- logical images, digital pathology will realise its full potential. Almost all research so far has been devoted to quantifying immunohistochemistry. The next step will be assessment of regular H&E stained sections. There are three (overlapping) areas in which computational pathology will have a major affect pathology diagnostics, with increasing level of impact and complexity. • Computational pathology will increase efficiency of routine tasks. The first use cases for computational pathology will probably address tedious rou- tine diagnostic tasks needing great accuracy, e.g. finding metastases in lymph node sec- tions, or counting mitotic fig- ures in breast cancer sections. Most pathologists are not fond of such tasks though they must be done well – they have high relevance for patient treatment planning. A computational pathology algorithm that can automatically detect metastases or count mitoses will alleviate these tasks and increase accu- racy. • Computational pathology can improve accuracy of tasks in which some grading is involved. Pathologists possess, at best, moderate reproducibil- ity in such (semi-)quantitative tasks. A well-known example is Gleason scoring for prostate cancer. Computational pathol- ogy may offer a powerful alter- native, by quantifying tissue changes that correspond with tumour grade in an accurate and reproducible manner. • Computational pathology may yield relevant information for diagnosis and prognosis that the human eye and mind are unable to recognise or appreci- ate. Instead of using a com- puter to mimic a pathologist in, for instance, grading a tumour, we could also try to obtain rel- evant quantitative data directly from WSI. These ‘imaging bio- markers’ may drastically change the way we extract information from tissue sections. While promising, a significant amount of research and validation is needed before a patient ben- efits from this type of applica- tion. Researchers will have to devel- op and validate algorithms before computational pathology will really take off. Deep learning, a modern pattern recognition technique, is extremely powerful in many dif- ferent disciplines and for a wide variety of problems. We have recent- ly shown (Litjens et al. Scientific Reports 2016) that deep learning is also particularly suited for analysing WSI. We found that deep learning yielded computational pathology systems that are close to being clini- cally useful. The ‘Camelyon’ grand challen ges To get a broader view and estab- lish the current state-of-the-art of computational pathology for a spe- cific application, we organised the ‘Camelyon’ grand challenges (http:// Dutch platform going live within 12 months Augmenting pathology image exchange exchange images, especially whole slide ones. ‘It means if there are cases where we want to do an exter- nal consultation, we can do that through that platform and if there are revision cases where patients move from one hospital to the next and the pathology material needs to be re-evaluated or revised, we can do that much quicker than we now do by regular mail of the tissue sec- tions,’ van Diest said. Report: Mark Nicholls A national pathology image exchange platform for The Netherlands is expected to be in place and opera- tional within the next 12 months. The Pathology Image Exchange (PIE), which unites 45 pathology laboratories across The Netherlands, will facilitate quicker revision and re-evaluation of images and second opinions leading to more rapid diag- nosis and better care for patients. This December, Paul van Diest, Professor of Pathology at the University Medical Centre in Utrecht, will update the Digital Pathology Congress in London on the progress of PIE, the Dutch National Platform for IT in Pathology. Pathologists’ meetings are no longer physical Speaking ahead of the event, he told European Hospital that he expected the tender process to be complete by December and in working with a chosen partner, hoped the plat- form would be operational by as early as summer 2017. All pathology laboratories in the country will be able to connect to the platform and rather Another benefit: than pathologists physically meeting to review interesting cases and come up with a consensus diagnosis, they will be able to do that through the platform. The time is right to move to digital Why had the Dutch pathology net- work embarked on this initiative now? ‘I think the best answer to that is simply that the time is right,’ Diest replied. ‘Many Dutch labs are now turning digital and we realise there are a lot of things we can do quicker and with much higher qual- ity and lower threshold consultation through such a platform. k c u t s r e t t u h S / i u j n u N m o o p k a P : e c r u o S So, when we started talking about this, we quite quickly agreed on the fact that it was a good idea. Big advantage: A national pathology database ‘I think a number of different coun- tries around the world would like to have such a platform because the advantages are so obvious and hopefully we can serve as an exam- ple of what can be done and be copied by other countries.’ However, Professor van Diest does point out that the Netherlands has a significant advantage in this respect with a Dutch national pathology database – The PALGA Foundation (the nationwide network and reg- istry of histo- and cytopathology in the Netherlands) – already in place, having been set up in 1971. All Dutch pathology labs are con- nected to the database and over- EUROPEAN HOSPITAL Vol 26 Issue 4/17

3 2 D I G I TA L PAT H 0 LO G Y The Leeds Digital Pathology Project Europe’s most advanced histopathology unit Among the earliest centres to embrace the concept of digital pathol- ogy, the Leeds Digital Pathology Project began in 2003 thanks to a Department of Health grant. Today the centre is Europe’s largest. Led by consultant histopatholo- gist Dr Darren Treanor and covering research and clinical applications, the centre has eight scanners to scan 3-5,000 slides a month. It also has the world’s largest digital pathology website, with 100,000-page requests in April 2017 and 10,000 visits a month (www.virtualpathology.leeds. ac.uk), and a slide library with 6,500 whole slide images. ‘We believe we have the largest single site digital pathology installation in Europe, in terms of scanning instruments and scan throughput,’ Treanor estimates. The Leeds research covers two main areas: (a) supporting preclini- cal and clinical research with digital pathology offering scanning servic- es, as well as some 3-D reconstruc- tion and image analysis services for researchers; and (b) research into digital pathology. The centre runs about 30 clinical trials ‘We aim to understand and push the boundaries of digital pathol- ogy,’ Treanor adds. ‘Our research divides into technical innovations, having developed multiple systems at Leeds, and clinical applications where the team is interested in the adoption of digital pathology including understanding the barriers to adoption, and the safe uptake of digital pathology.’ Work to perform the first syste- matic review of the accuracy of digi- tal pathology led to follow on work from Dr Bethany Williams – the first digital pathology leadership fellow in the world. With its early start, Leeds could lead the way in technical advan- ces and develop systems for sev- eral applications including: tissue microarray analysis; in-house image analysis; 3-D registration and recon- struction software; and systems for manual assessment of tumour stro- ma ratio (a web-based tool for sys- tematic random sampling of virtual slides). The centre also developed colour measurement and a colour calibration slide for digital pathol- ogy in collaboration with a vendor, FFEI Ltd. ‘This is the only tissue-mimicking colour calibration slide available, a prerequisite for accurate colour calibration of digital pathology,’ Treanor points out. However, the major development has been the Leeds Virtual Microscope (LVM). ‘We identified a big pro blem with digital pathol- ogy – that the software used to view images was 60% slower than the microscope.’ Working with collabora- tors in the university’s School of Computing (Professor Roy Ruddle), they set out to create a viewer as fast as a microscope. The suc- cessful output was software, licenced to Roche. The LVM runs on sys- tems that range from lap- tops, to high-definition medical displays, and 50 megapixel ‘Powerwalls’, used to train patholo- gists. It has been deployed across the Yorkshire and the Humber region’s 16 pathology laboratories for pathology training. The LVM also won the Medipex innovation award for medical ima- ging in 2014. The Leeds unit is nearing com- plete digitisation. In the univer- sity laboratory, virtually all research slides are scanned, and is now developing within the NHS depart- ment. ‘In 2016, we started a pilot deployment in breast pathology and have seen very reassuring results of this, with four pathologists using digital pathology for their diagnostic work,’ says Treanor. years to digital pathology adoption, particularly in four critical areas: virtual slides were slower than the microscope; confidence in accuracy was not assured; the cost-benefit was not established; and patholo- gists were reluctant to adopt. For Leeds, LVM addressed the speed issue, and a systematic review showed that, while there have been many valida- tion studies, the overall qua- lity of the evidence has not been uniformly high. ‘From this, we developed our own validation proto- col that allows pathologists to learn by comparing the microscope and virtual slide over a period of several weeks during normal clini- cal practice. So far,’ he adds, ‘this has allowed us to be much more confident when diagnosing digitally.’ This year saw a partnership with Leica to deploy digital pathology for primary diagnosis across all clinical specialties. This involves 45 consultants, 30 trainees, 250,000 slides per year and 100TB of data. It also includes workshops about digital pathology, including labora- tory implementation and clinical validation. However, Treanor acknowledges there have been challenges over the The team now plans to address the issues of cost benefit and wider adoption of the tech- nology. ‘Pathologists need evidence that it works,’ Treanor remarks. ‘If we can provide them with an effec- tive user interface, good workflows, and assure them of diagnostic qual- ity, while establishing the cost-ben- efit, we see no reason why Digital Pathology would not be adopted for clinical practice.’ The Leeds team collaborates with Dr Darren Treanor is Consultant Histopathologist at Leeds Teaching Hospitals NHS Trust and Honorary Clinical Associate Professor at the University of Leeds,UK. He is also Guest Professor in Digital Pathology at Linköping University, Sweden, where he works with the university and hospital teams on digital pathology research in a well-established project where 100% of clinical slides are scanned. a number of companies – Leica cus- tomers from the beginning; develop- ing a colour calibration system for digital pathology imaging with FFEI Ltd; and selling the LVM system to Roche. Considerable benefits and opportunities ‘On the research side, it would be unthinkable to run a clinical research lab without digital pathol- ogy,’ Treanor believes. The ‘enor- mous advantages include workflow; archiving and image analysis ‘On the clinical side, our breast patholo- gists report great satisfaction with their digital pathology adoption so far. They love the improved work- flow, and the ability to work without glass slides. Ordering and reviewing additional stains, for example in immunochemistry, is much easier.’ From the university aspect, the team manages its own data stor- age, presently with about 160TB, with a large number of application servers hosting the different sys- tems. Within the NHS element, they expect to produce 100TB of data annually, when the full deployment is up and running. However, he suggests the amount of data should not be daunting – when they began doing digital pathology in 2003, a 4TB system cost over £100,000. That amount of data can now be stored on a single disk drive. ‘A modern hospital should be able to handle large data sets and I’m confident that data storage requirements will become less of an issue as storage systems improve in future. Hospitals also need to under- stand that, while the data volume may be large, only a small percent- age of that needs to be on fast stor- age systems and digital pathology is very amenable to inexpensive archiving solutions.’ Sharing slides with other patholo- gists is a major part of the Leeds team’s ethos and service. From its website, all educational and research slides are freely available for patho- logists, scientists, medical students and the general public. On the clinical side, the system allows easy access over a secure VPN connection for Leeds patholo- gists to view the images remotely. Sharing work is a key benefit of digital pathology, he says, point- ing to two benefits. We can give second opinions for colleagues in regional district general hospitals; but with digital pathology we can give feedback immediately, with live interaction. Secondly, as a large teaching hospital, we see opportuni- ties to use digital pathology to share work around the region, ironing out peaks and troughs in our capacity and demand.’ EUROPEAN HOSPITAL Vol 26 Issue 4/17 WSI Web Slide Portal•ForPC, Tablet, Smartphone•For E-learningor consultation•Any browser, no installations Digital PathologySolutionswww.vmscope.com