2 N E W S & R E S E A RC H Will transplant medicine have a future in Germany? Numbers of organs and qualified surgeons drop Report: Anja Behringer ‘Do we want transplant medicine? And if yes, what are we prepared to change in public policy, society and medicine?’ This question character- ises the current situation within this medical discipline. Since the 2011 transplant scandal, there has been a steady decline in organ donations according to the German Foundation for Organ Donation (DSO). Although there were some 1,200 transplant donors annually from 2006 – 2011, the number of organs donated had already declined to just 800 in 2017. The reasons are numer- ous. Certainly, significant damage was done to the image and confi- dence in German transplant medi- cine. However, health policy and social structure improvements are also necessary: Despite measures taken to create transparency and quality assurance in the transplan- tation field – such as mandatory interdisciplinary case consultation in the transplant conference prior to a transplant and a newly introduced central registration at the German Medical Association – there were just as few organs transplanted in 2017 as had been in 2002, accord- ing to the German Foundation for Organ Donation (DSO). Some 10,000 patients await a donated organ. Media attention has been drawn to the discussion about the so-called opt-out solution proposed for a new organ donation bill, by German federal health minister Jens Spahn. However, the concept is nothing new. The opt-out option has already been used in many European countries for a long time: In line with societal consensus, the opt-out solution means that if one rejects a potential organ dona- tion, one must actively reject it when alive. Nonetheless, in most countries this does not happen without the consent of the patient’s family. This ‘double opt-out solution’ also applies in Spain, for example. That country has led Europe for years, in having 47 donors annually per million inhabitants. By contrast, Germany is closer to the bottom of Biomedical designers must increase safety the list with nine donors per million inhabitants. According to Professor Jörg C. Kalff, president of the German Society for General and Visceral Surgery (DGAV) and director of the clinic for general internal, vascular and thoracic surgery at University Hospital Bonn, the current debate is more than welcome. However, an introduction of the opt-out solution – double or simple – no matter how sensible, in isolation will probably not automatically yield higher donor numbers. A study in the German Ärzteblatt says there are also prob- lems in Germany both with register- ing potential organ donors and with accomplishing the donation itself. Economic pressure is high, espe- cially on small hospitals, if they are also to identify all potential donors and register them with the DSO. To do this, however, they need to employ specially trained trans- plant officers and the sensitivity and readiness of medical personnel to contribute to an organ donation has to be correspondingly high. If the identified potential organ donor is actually to be used, (i.e. with con- sent given and no medical objec- tions to an organ donation) then, following a process strictly regu- lated by law (here, cerebral death diagnosis), the extracting hospitals must maintain operative and inten- sive care capacities at high cost. As Kalff explains: ‘Assistance for organ donation and transplantation ought not to become a loss-making business for the extracting hospitals, otherwise higher registration rates will not be achievable in periods where economising is necessary. Cut device-related pressure ulcers Whilst acknowledging that state-of- the-art bioengineering approaches are being applied in preventing Medical Device Related Pressure Ulcers (MDRPUs), Professor Amit Gefen, from the Department of Biomedical Engineering at Tel Aviv University, believes there are gaps in knowledge and technology in this area and therefore more must be done to improve patient care and avoid additional healthcare costs. During a ‘Wound Care from Innovations to Clinical Trials’ (WCICT From Vision to Impact. That’s Excellence for Life. From University Spin-Off to High-Tech Solutions. biotronik.com 2018) conference held in Edinburgh last June his ‘Gaps in technology in prevention of MDRPUs’ presentation analysed approaches to mitigate the problem and discussed emerging technological solutions. ‘MDRPUs are injuries associated with the use of devices and equip- ment applied for diagnostic or thera- peutic purposes, where the injury has the same configuration as the applied device,’ explained Gefen, who is also the WCICT president. ‘In intensive care units, MDRPUs caused by endotracheal and nasogastric tubes are common, both in adult and paediatric settings.’ MDRPUs, which, by definition, are hospital-acquired pressure ulcers (HAPUs) and considered in many countries to be an adverse event, may also be associated with the use of electrodes and wiring, pulse oximeters, catheters, compression stockings, and even bedpans. ‘Studying the root causes of MDRPUs and effective means to mit- igate their risk will lead to improved quality of life for patients and con- siderable cost savings which can otherwise be invested in further prevention and treatment of the primary comorbidity,’ Gefen pointed out. ‘Development of experimental and computational biomechanical models is essential for creating labo- ratory standards to test the safety of medical devices which come in contact with the surface of the body.’ His team in Tel Aviv has developed experimental systems equipped with thin flexible force sensors, as well as models of adult and paediat- ric patient heads to simulate tissue loads during interactions with devic- es, such as tubing, electrodes and wiring, masks and head supports. ‘These physical and computational three-dimensional anatomical model systems facilitate rigorous empiri- cal and simulation-based investi- gations of commonly encountered conditions and scenarios at which MDPRUs may occur.’ ‘Based on our findings,’ he con- tinued, ‘we feel that the design of many edical devices and equipment used in ICUs should be revisited, since currently, there appears to be no attention to the safety of use with regard to the device-associated pres- sure ulcer risk.’ Gefen suggests that much can be done concerning the engineering design of device structures, selection of materials and integration of mech- anisms that minimise the risk. Tubes, wires, electrodes and other equip- ment can be made safer, he said, and selection of more adequate, softer materials and devices, such as development of soft electrodes made of conducting textiles and similar ideas, can reduce the occurrence of MDRPUs. Several examples were discussed during his presentation, based on data from the team’s recent experi- ments and computer simulations of scenarios where there is high risk for MDRPUs. Exploring new technologies Advanced materials (particularly smart materials and structures), sen- sors and tele-monitoring systems, physiological signal analysis and data management, all have a role to play. HAPUs are commonly considered an adverse event. MDRPUs, which are always HAPUs, compromise patient safety, lead to increased costs for potential additional hospitalisa- tion days, interventions and treat- ments to manage the MDRPU condi- tion, and also in association with the risk of litigation costs. ‘From all perspectives,’ he contin- ued, ‘the best strategy is prevention and dedicated technologies, includ- ing investments in new technolo- gies, are required for that,’ Gefen concludes. ‘MDRPUs are a major portion of HAPUs and hence, mitigating MDRPUs will save vast financial n o s l O r e l y T / k c o s r e t t u h s © EUROPEAN HOSPITAL Vol 27 Issue 5/18

4 N E W S & R E S E A RC H Chronic peripheral inflammation and schizophrenia France boosts mental illness research European Hospital correspondent Jane McDougall spoke with Dr Guillaume Fond, lead author of an excit- ing new paper* that explores the association between chronic peripheral inflammation and poor response to treatment in schizophrenia patients. to guidelines to be made and para- digm thinking to shift before new medical ideas and concepts are adopted. Concentrating on four disease areas: schizophrenia, bipolar dis- order, treatment-resistant depres- sion and high-level autism, in a multidisciplinary environment, the network provides newly referred patients with a two-day assessment, leading to a complete treatment plan tailored to their and the fami- lies’ needs. A comprehensive report, plus details of prescribed medica- tion, psychotherapy and suggested lifestyle changes are sent to the patient’s own psychiatrist or general practitioner (GP) while additional annual follow-up with the expert centre’s psychiatrists is proposed. This latest scientific publication from the network comes from draw- ing on their cohort of schizophren- ic patients and comparing them with the sub-population of patients within it (~10%), who develop ultra- resistance to psychotic medica- tion (ultra-resistance to treatment in schizophrenia [URTS]). These patients are defined in the paper as demonstrating symptoms with a score greater or equal to 70 on the Positive and Negative Syndrome scale for Schizophrenia (PANSS) despite being treatment compliant. Blood tests revealed that these patients had elevated levels of highly sensitive C-reactive protein (hsCRP), which was independently associated with chronic peripheral inflammation (OR = 2.6 [1.2–5.7], p = 0.01). Confirming results from other studies in which increases in inflammatory biomarkers have been associated with poorer outcomes and treatment response in schizo- phrenia. Inflammatory blood mark- ers have also been suggested to be predictive for treatment response to antipsychotics and high levels of CRP have been associated with cog- nitive impairment in both schizo- phrenia and Alzheimer’s disease. The mechanism whereby inflam- mation causes treatment resist- ance is as yet unknown. It may be speculated that chronic low-grade inflammation at the level of organs. such as the liver and pancreas, might alter drug absorption and/or metabolism, diffusion through mem- branes (blood/brain barrier) might also be compromised and possibly As European health services are pres- sured to provide the best possible care for best possible value, some medical fields are now very much the poor relation; this is particularly true for mental health. Mental illnesses represent a great health burden and cause huge financial and societal pressure in terms of direct and indirect costs from repeated hospitalisation and treatment failures, while funding for research directed to improve diagnosis and treatment into these disorders is lacking. To help rectify this problem and tackle the heterogeneity of available care and lack of organisation in the field, in 2007 the FACE network (FondaMental Academic Centres of Expertise) was set-up, with fund- ing from the French Ministry of Health. Encompassing 39 different expert clinical centres throughout France, the network has created an original and innovative model to treat patients with mental disor- ders. By integrating clinical research into the patient’s routine care, they have created a huge cohort of moti- vated individuals living with mental illnesses within society, but with closely monitored and carefully coordinated medical support. This allows observed findings to directly guide treatment changes in a way that circumvents the normal downtime required for adjustments n a m r e t e F a n a j i T © o t o h P Dr Guillaume Fond is associate professor, psychiatrist and coordinator of the national Schizophrenia Expert Centre Network and local head of the Resistant Depression and Schizophrenia Expert Centre, Marseille, France. He is affiliated with the AP-HM medical information department, researcher at the Group EA 3279: CEReSS – Health Service Research and Quality of Life Centre and Lecturer at the University Aix-Marseille-La Timone. Fond has coordinated the national Schizophrenia Expert Centre Network since November 2012. there is a more direct effect, on the brain receptors themselves, which has been postulated for Alzheimer’s disease. Therefore, should schizo- phrenics be prescribed complemen- tary anti-inflammatory treatment? Presently, Fond suggests patients should be actively encouraged to reduce inflammation by lifestyle changes, such as taking more exer- cise, having a healthy diet with plenty of vegetables and increasing their intake of vitamin D and omega 3. In this way the patient’s general physical health and wellbeing will improve, which can only be positive for their mental health. * Fond G et al. Chronic low-grade peripheral inflammation is associated with ultra-resistant schizophrenia. Results from the FACE-SZ cohort. Eur Arch Psychiatry Clin Neurosci. 2018 May 28. doi: 10.1007/ s00406-018-0908-0. [Epub ahead of print] PMID: 29808267 FACE-SZ details: www.fondation-fondamental.org/ c r a m i t p o / k c o t s r e t t u h s © The more powerful management is the least creative it becomes Dutch homecare goes global Home care in the Netherlands wors- ened. ‘The organisations grew big- ger, involving more and expensive management,’ observed nurse Jos de Blok. ‘Registration procedures became unnecessarily complicated. I enjoyed my job when I started in 1986, but that feeling changed. I knew there should be an easier way, without managers and at a lower cost. So, in 2006, I began the Buurtzorg concept.’ This is similar to the way district nurses in the Netherlands formerly worked: autonomously and using their own initiative. Buurtzorg has self-managing teams of ten to twelve people, who give one to one care for about fifty patients each. When multiple care or other expertise is needed, several team members can handle it. Patients know their carers and care is tailored to their current needs. ‘This makes it measurable: care becomes cheaper, less care is needed, and patient self-reliance can be increased,’ de Blok explained. planning, training, assessment, etc. Everything revolves around ques- tions: What’s happening? How are you solving it? What’s the result? There are no policy plans to meet, and therefore no complaints from employees; everyone focuses on their expertise and professionalism. ‘We started with four employees; now there are 14,000. I’m still impressed by all those who quit their jobs in the early days to work with us. Families also made Buurtzorg known around the country. It’s all viable now.’ Care at home is like invisible holding hands. The teams hire their own col- leagues and organise the work, e m n o l s / m o c . e b o d a . k c o t s / / : s p t t h The organisation is frequently acclaimed as the Netherlands’ most attractive employer. ‘We have just one office in Almelo to support the teams,’ de Blok explained. ‘All the support, including our software packages, were created by employ- ees. Sixty other Netherlands organi- sations now use Buurtzorg’s sup- porting software. Problems? No. But we face a shortage of new qualified staff.’ The concept’s first year was financed by De Blok’s consultancy firm, although his wish to intro- duce it to other organisations did not initially materialise. ‘My ideas about less management and autono- mous teams were too frightening. Some were willing to adjust, but all wanted to keep their management. I’m convinced that top down rules don’t work, so I started Buurtzorg as an autonomous company. The best ideas come from work in the field, not from management. People must have the opportunity to come up with their own solutions.’ Example: In 2010 an employee initiated the ‘walker race’, after an 87-year old said there are no races for people using a walker. ‘She raised 10,000 euros to get the race started. It became the Rolympiade, an annual walker race covering 400 or 800 metres. Last year six over 90-year- olds – oldest 104 years – partici- pated.’ This improves mobility, and reduces loneliness, he noted. There are around 100 more Buurtzorg pro- jects. Beyond the Netherlands De Blok now sells Buurtzorg abroad. ‘The concept runs in Japan, China, Australia, Germany, England, France, Switzerland and Austria. Recently, I explained at a conference how to implement the system in a test environment and adapt it to local conditions. The universal compo- nents, such as teams, self-organising process, back office and IT support, work everywhere.’ Financing can be done through government or insurer reimburse- ments and, for example, in partly through private contributions, as in China and India. In the Netherlands healthcare is covered by Social Security Systems and health insurers. In the early years, De Blok faced finance prob- lems: the system was too unfamiliar. ‘Now there are good agreements with insurers. We signed three-year contracts based on results and not, as with other care-giving organisations, on fees, costs and volumes.’ Nurse and entrepreneur Although De Blok sees himself primarily as an entrepreneur, he maintains patient contact. ‘It inspires me, he explained. ‘For example, I received a letter, after her death, from a 31-year-old breast cancer patient. She thanked us for the great last months of her life. ‘She had four new (caregiving) girlfriends who even took her on a stretcher to places she wanted to visit, one last time.’ The future ‘It’s crazy that management is the least creative when it has the most power,’ he observed. ‘Buurtzorg has 14,00 creative brains which invent and develop beautiful innovations with an enormous impact on self- EUROPEAN HOSPITAL Vol 27 Issue 5/18

6 I N T E N S I V E CA R E Discharged ICU patients need careful rehabilitation Aftercare after intensive care Care models that go beyond rehabilitation services and are aimed at a smooth transition from intensive to aftercare are not established in Germany. A working group around Professor Dr Christian Apfelbacher at the Institute for Epidemiology and Preventive Medicine, Regensburg University, is currently develop- ing a concept for intensive out-patient aftercare. ‘The project is to help improve the care of patients after prolonged treatment in the intensive care unit (ICU) and to close the gap in the transition from intensive care to aftercare,’ the professor explained during an interview with Sascha Keutel. Prolonged treatment in intensive care frequently leads to chronic physi- cal and psychological impairments, also described as Post Intensive Care Syndrome (PICS). This descrip- tion relates to new or worsening physical (pulmonary, neuromuscu- lar, physical-functional), cognitive (such as memory- or concentration problems) and psychological (anxi- ety disorders, post-traumatic stress disorder and depression) problems in patients, which occur due to ill- ness requiring treatment in inten- sive care and persist after hospi- tal treatment,’ Professor Christian Apfelbacher explains. ‘On-going, comprehensive diag- nostic investigation, as well as ade- quate multidisciplinary care with coordination of services, are impera- tive for patients who have received intensive care. Patients find coor- dinated, needs-based medical care after being discharged helpful. It can also help to reduce the large share of patients who have to be readmitted after being discharged: Care models would be desirable that go beyond the services provided by rehabilitation clinics and are cus- tomised to patients’ needs during the post-ICU phase.’ A continuum of care Patients who are discharged after a lengthy stay in intensive care are rarely completely recovered and most are still dependent on help. Therefore, the study project is not only aimed at patients but explic- itly also their relatives, as ‘they are also affected by the continuous morbidity. PTSD, depression, anxi- ety and adjustment disorders can be potential implications. In recent publications these psycho-patholog- ical reactions among relatives have also been described as PICS-Family (PICS-F),’ Apfelbacher adds. However, persistent psychologi- cal - and physical morbidity after discharge, or transfer, has so far not been sufficiently addressed; this is where the study comes in. The working group wants to specify patients and relatives needs, with the help of primary and second- ary data and to develop a concept for intensive out-patient aftercare on this basis. ‘Intensive out-patient aftercare would improve the pro- cesses - coordination of therapeutic services, referrals based on spe- cific medical needs, contact with GPs, involvement of relatives – and close the gap in care,’ Apfelbacher said, who also explained that the project is carried out along- side Professor Dr Thomas Bein from the Anaesthesiology Clinic at Regensburg University Hospital. A participative approach The study includes adult patients who have spent more than five days in intensive care, have had organ replacements and have a predicted life expectancy of more than six months. The first step is to inves- tigate the uptake of care as well as existing care requirements of patients and their relatives after dis- charge from the ICU, with the help of guided interviews. Recruitment of around 25 patients, plus their The interdisciplinary challenge In 2003, Professor Christian Apfelbacher PhD gained a master’s degree in philosophy at the Munich School of Philosophy, followed by a Master of Science in Public Health at the London School of Hygiene and Tropical Medicine (DLSHTM) in 2006. Two years later he became a Doctor of Humanistic Sciences at the Medical Faculty of Heidelberg University. Then came a PhD in Philosophy at Brighton & Sussex Medical School in 2013. In the same year he qualified to teach medical sociology. In spring 2014, Apfelbacher became Professor for Medical Sociology at the Institute for Epidemiology and Preventive Medicine at Regensburg University. relatives, is done via stratified quota sampling with regards to age, gen- der and severity of illness among the participants and consortium partners. In parallel, an analysis of Evaluating ICU care for cancer patients Progressive treatments offer new chances for cancer patients, but also could result in as yet unknown complications. The number of cancer patients transferred to the ICU for cancer-specific and internal medi- cine related reasons is on the increase. Caring for them on the ICU is a complex challenge, with interdis- ciplinary cooperation playing an essential part. Certain criteria need to be met for the admission of a cancer patient to the ICU, according to Dr Peter Schellongowski, specialist in internal medicine and intensive care and sen- ior consultant in the ICU at Vienna’s Medical University. The Austrian ICU specialises in the care of critically ill cancer patients suffering from, for instance, acute respiratory failure and infection related problems such as sepsis or toxic reaction. Admission criteria ‘We need to consider several fac- tors when deciding whether criti- cally ill cancer patients should be cared for in the ICU. Apart from the patient’s general condition, we must evaluate the probability of surviving acute organ failure(s) along with the expected long-term survival and therapy options after intensive care treatment. The latter can be very strenuous and even traumatising and affect the remaining quality of life, which is why the admission crite- ria are important,’ Schellongowski explains. ‘Patients in the early stage of a still treatable disease, whose life expectancy is likely to be more than a year, patients who should receive curative treatment, and patients in remission from their pri- mary disease are usually admitted. They are given a full code manage- ment, receiving the entire range of intensive care treatments available. However, if treatment options have been exhausted or intensive care is unlikely to improve a patient’s life expectancy or condition we would refrain from treatment.’ For patients receiving pallia- tive care who may have a good chance of longer-term survival due to treatment progression, such as patients with low-grade non-Hodg- kin Lymphoma, for instance, or patients in partial remission from diseases like multiple myeloma or solid tumours, admission to the ICU can also make sense. ‘The group of patients who may benefit from intensive care continu- ously expands due to the broad range of cancer treatments avail- able. Oncology is continuously evolv- ing, making a close cooperation between intensive care medics and oncologists so important: It guar- antees the best treatment for the patient,’ Schellongowski explains. Close examination Despite structured criteria and guide- lines, the decision-making process on treatment and admission objectives is often very complex. ‘A minimum “one-year survival” objective obvious- ly does not mean that a patient with an 11-months survival prognosis will immediately fall outside the scope. Each case is intensively examined. ‘If the situation is not clear-cut,’ he adds, ‘we often start a multi-day ICU trial to examine whether the patient responds positively to the treatment. Then we decide if it makes sense to continue with intensive care.’ the disease. Further, up to 18% of patients with aggressive, haematolog- ical cancers require intensive medical care during the early disease stage, either because of early complications or because of aggressive initial treat- ment that has caused secondary com- plications, both ultimately leading to organ dysfunction. Specific treatment The most common cause for ICU admission is acute respiratory failure, followed by complications from sep- sis. Haematological diseases in par- ticular often lead to pulmonary com- plications, caused by infections or complications arising from leukaemia itself. ‘This complicates treatment, because chemotherapy can aggra- vate an infection. At the same time, chemotherapy cannot be suspended for too long. In some cases, limited intensive care treatment is considered, exclud- ing certain procedures such as intu- bation. ‘A study has confirmed that this approach also helps many and that survivors suffer from post inten- sive care syndrome (leading to anxie- ty, depression or post-traumatic stress syndrome) no more frequently than patients without therapy limitations.’ Frequent ICU admissions Patients in the early stages of a can- cerous disease are in particular need of intensive care. Five to six percent of cancer patients with solid tumours are admitted to the ICU for primary surgical care in the early stage of ‘Close cooperation between haema- tologists and oncologists is therefore of extraordinary importance and very desirable,’ Schellongowski empha- sises. ‘It’s scientifically well docu- mented that intensive care patients with cancer, who receive intensive A a G K . o C & G A k r e w r e g ä r D f o y s e t r u o C EUROPEAN HOSPITAL Vol 27 Issue 5/18 ACEM SPA | Medical Company DivisionARGELATO, BO - ITALYPH +39 051 721844 | FAX +39 051 721855info@acem.it | WWW.ACEM.ITMEDICAL LIGHTING SYSTEM12-15 NOV 2018DÜSSELDORFHALL 10 | STAND B60ACEMSO15FFOCUSABLE LED LAMPFOR EXAMINATIONAND MINOR SURGERY

8 CA R D I O LO G Y Multidisciplinary care is key to cardiac disease management Research with 7-Tesla MRI Figure 1 Figure 2 Sodium mapping of the heart using 7 Tesla MRI Higher signal-to-noise ratio (SNR) using 7 Tesla MRI allows to map sodium in the human heart. The isolation of the long relaxation sodium component (using a long echo time) and the compen- sation of concomitant signal modulation (T2star and B1+/B1- from transmit-receive coil) allows for a single slice to be mapped within 5min at a resolution of 2x2x10 mm3. Reference sodium concentration vials attached to the coil serve as calibration of the sodium MRI signal. Figure 1: Top-left is B1+/B1- map, Top-right is T2star map, Bottom-left is anatomical MRI image of the heart using conventional 1H-MRI, and bottom-left is the map of long- relaxation sodium concentration after corrections of the sodium MRI signal using the maps at the top. Figure 2: Overlay of long-relaxation sodium map onto the anatomical MRI. New 7-T MR methods could potentially shed light on cardio- myopathies’ principles, according to a leading French radiologist who also stresses the importance of teamwork between radiolo- gists, cardiologists, surgeons and anaesthesiologists. Report: Mélisande Rouger Morphologic and dynamic informa- tion of the myocardium is achieved with millimetric resolution (0.9x0.9 mm2). Strong intensity variations characteristic of 7-Tesla MRI can be observed from anterior to posterior myocardial segments. New tools provided by indus- trial partners and used by cardio- vascular surgeons and radiologists are improving treatment of thoracic aorta pathologies. An increasingly used technique is fusion imaging, in which pre-treatment MR and CT scans of the patient are being fused with angiography images to guide stent-graft navigation through the vascular structures of the patient during the intervention, according to Alexis Jacquier, cardiovascular radiologist at Timone University Hospital in Marseille. ‘Fusion imaging enables to lower radiation dose and to reduce the amount of contrast media that are traditionally required in this type of surgery. It avoids having to inject iodine to know where we’re at,’ he explained. The hospital also hosts the Timone Aortic Centre (CAT in French), a leading regional multidisciplinary centre that covers full aortic pathol- ogy management, from diagnosis to patient care and follow-up, with a strong connection with the univer- sity. The CAT includes vascular and cardiac surgeons, radiologists, car- diologists, vascular physicians and anaesthesiologists. The objective is to provide a mul- tidisciplinary approach to provide the best medical care; for instance all thoracic stent-graft procedures are performed by a multidiscipli- nary team comprised of vascular surgeons, radiologists and anaesthe- siologists at CAT. Imaging has become key in tho- racic aorta treatment with the boom of minimally invasive procedures. Besides thoracic disease, Timone Hospital is one of the main cen- tres in France offering endovascu- lar interventional radiology skills to treat patients with carotid and renal disease, which Jacquier and colleague Vincent Vidal perform daily, along with the full suite of cardiovascular interventional radi- ology procedures – endoprosthe- ses and stent placement, small ves- sels and tumour embolisation, etc. Furthermore, the hospital is located close to the medical and biology MR centre (CRMBM), one of the few labs in Europe that work with 7-T MRI for diagnostic imaging research. This proximity enables Jacquier Accutron® CT-D New with Pre-Inject Testing of the patient’s access prior to the injection! Easy activation with a single keystroke! Automatic profile adjustment! Update now! Contrast medium injectors and consumables for CT, MRI and angiography Hauptstrasse 255 · 66128 Saarbruecken For more info: www.medtron.com Cardiovascular radiologist Professor Alexis Jacquier, at Timone University Hospital, Marseille, France, trained in Marseille and Lyon and gained his PhD in San Francisco, USA, supervised by Maythem Saeed and Charles Higgins. In 2006 he integrated the cardiovascular group in the CEMEREM research lab (http://crmbm.univ-amu.fr). He is author and co-author of more than 90 peer-reviewed publications and has presented numerous lectures, tutorials and refresher courses internationally. He also chaired the European Society of Cardiac Radiology membership committee and is current vice president of the French Society of Cardio-Vascular Radiology (Société Française d’Imagerie CardioVasculaire, SFICV). French Society of Radiology estab- lished a working protocol in 2005; according to this, the cardiologist prescribes the CT and MR scans and radiologist performs the technical assessment and writes the report – and then sends it to the cardiolo- gist. Jacquier: ‘This division of tasks promotes the best possible medical care, but everything really depends on the physician’s skills. A lot of things may need to be updated as we gradually introduce artificial intelligence.’ Radiologists must also homoge- nise the way they write the imaging report. Introducing the structured report to exploit data at nation- al level will prove essential for their future. Another priority is to improve communication not only with patients but also other medical specialties, he said. Jacquier will participate in the International Day of Radiology (8 November 2018), an initiative to highlight the radiologist’s role in cardiac care. ‘Radiology is not a medico-tech- nical specialty, although French administration still classifies us as such. We’re a medical discipline. The old-fashioned image of the radiolo- gist reading scans alone in a base- ment and not having contact with anyone else in a hospital is outdat- ed. The radiologist,’ he emphasised, ‘is now at the centre of patient care and healthcare.’ and team to test 7-T methods using sodium instead of proton imag- ing, a possibility that opens brand new perspectives in heart imaging. ‘Sodium electrolytic disorganisation in the myocardium can have an electrical and mechanical impact on heart function. 7-T will enable the development of new applications in the field. It is still a complex task, but we are working hard on differ- ent papers on sodium quantification in the myocardium and potential clinical applications’ he explained. Cooperation with cardiologists is essential in myocardial disease man- agement, according to Jacquier, who again stressed the importance of the multidisciplinary approach dur- ing patient treatment. ‘Patients are now being care for within the heart team, a model increasingly followed by healthcare facilities in France and beyond,’ he explained, adding, ‘whether it’s for TAVI procedures, diagnosis or follow-up. Medicine is becoming hyper specialised and mixing profiles and specialties ena- bles us to significantly improve patient care.’ Another significant develop- ment in France was the reform of the radiology residents’ train- ing scheme, which was introduced in 2017. Radiology residents must The Council now undergo a three-step training, including successively: base training (one year), dedicated to emergency radiology; in-depth training (three years), to ensure that every subspe- cialty in radiology has been covered in their education; and consolida- tion training (one or two years), providing certification for one or two subspecialties. French of the Teachers of Radiology (CERF) has been piloting the change for radiology. The French Society of Cardiovascular Radiology now pro- vides e-learning material to ensure homogeneous teaching and train- ing program across the country. In September, the series became freely available for French residents on the CERF website, and also available for all radiologists on the website of the French Society of Radiology. This change is a substantial improvement in the training scheme, because it reflects daily routine bet- ter, Jacquier added. ‘Cardiac imaging studies are being prescribed every day by all sorts of physicians: GPs, endocrinologists, surgeons, and even oncologists, for instance in pre- and post-chemotherapy evalu- ation.’ As for cardiology, the French the Society of Cardiology and High-resolution Simultaneous Multi-Slice (SMS) dynamic MRI of the heart at 7 Tesla Increased signal-to-noise ratio from the 7 Tesla MRI is harnessed for refined imaging of heart. Simultaneous Multi-Slice (SMS) cardiac dynamic MRI (cine) permits the acquisition of three thin- slices (4 mm) within a 10 s breath-hold. Robustness to patients motion and limited breath-hold capacity is guaranteed through a dedicated self-calibrated SMS technique tailored for cardiac imaging. Morphologic and dynamic information of the myocardium Figure 3: SMS cine acquired within 10s showing diastole (relaxed phase of the cardiac cycle) of the apex (a) mid- ventricular (b) and base (c) slices. is achieved with millimetric resolution (0.9x0.9 mm2). Strong intensity variations characteristic of 7 Tesla MRI can be observed from anterior to posterior myocardial segments. a b c EUROPEAN HOSPITAL Vol 27 Issue 5/18

1 0 R A D I O LO G Y Coping with individual patient’s characteristics Refined imaging despite movements The new 1.5 Tesla MRI from Siemens Healthineers, Magnetom Sola, is packed with helpful algorithms and other functions. AI-supported systems monitor patients and scan parameters and ensure consistent image quality. Whilst visitors at this year’s ECR-Expo admired the new device, Prof. Ulrike Attenberger has already tested it in practice. The Vice Chair at the Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim, talks about the effect of the new functions in clinical routine. Simultaneous Multi-Slice (SMS) allows the acquisition of multiple slices in parallel for complete orthopaedic exams. Report: Wolfgang Behrends BioMatrix is the technology used by Siemens Healthineers to partially con- trol MRI scanning with the help of artificial intelligence (AI). The focus is on three new functions: heartbeat, head movements and breathing – the biggest interference factors to date – which are calculated out of the image in real-time. ‘This is a central issue for the precision medicine which we are aiming for,’ Attenberger explained. ‘We need standardised, robust and compa- rable diagnostics for this purpose, but this has not yet been possible because the examination result is strongly influenced by which doctor or MRI assistant carries out the respective scan.’ With long-term investigations in particular, this reduces the compa- rability of data enormously, even for the same patient in the MRI scanner. Different patients’ individual charac- teristics also cause additional incon- sistencies: ‘Obesity impacts on image quality and so, does arrhythmia, for example. Some patients cannot hold their breath, which used to cause us huge problems.’ The new technology also helps the examiners here. ‘We enter patient data into the system, i.e. height and weight, how long they can hold their breath, and then the algorithm calculates the settings that will achieve the best image quality,’ Attenberger said. ‘This has worked very well during the first practice runs.’ The manufacturer already imple- mented the new functions in the 3-Tesla System Magnetom Vida. ‘However, the introduction in the 1.5-T range makes the technology available to a much larger range of users, especially in clinical practice,’ added Dr Christoph Zindel, Senior Vice President and General Manager of MRI at Siemens Healthineers. Even MRI novices adapt quickly to the system ‘During the test phase,’ Attenberger pointed out, ‘we made a point of selecting our most junior MRI assis- tants who are being coached by skilled assistants but don’t yet have much MRI experience. After three days of training on the simulator they then used the device in practice, and it turned out the handling is so intuitive that there were no problems during the introduction.’ The first test phase began with only one of the three sensors, i.e. the res- piratory sensor, and even just this one component convinced Attenberger and her team. ‘The system works per- fectly in practice. Movement is always a big problem for us: patients in our centre are becoming increasingly older and sicker, which leads to high fault rates through motion artefacts with conventional MRI scanners. The BioMatrix technology now counters this problem very effectively. The new system makes the image quality far better.’ It also has a significant impact on the examination time: ‘We aim to reduce the time spent in the examina- tion room by around 50%, from an average 50 minutes to 25 minutes. Having used the new device for the first few weeks now, we can foresee this should be achievable.’ The new simultaneous multi-slice technology also contributes towards this because it facilitates simultaneous images of several slices. This function really excels during musculoskeletal examinations. In cardiac and abdominal imag- ing, patients benefit from compressed sensing. The technology enables the examination of cardiac function with free breathing through mathemati- cal reduction of the acquired data. ‘You simply start scanning and con- Professor Ulrike Attenberger is Vice Chair and Medical Director at the Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim. After gaining her medical degree in Munich, a doctorate focused on ‘The importance of MRI in the diagnosis of pulmonary hypertension’ followed in 2006. Her current research is on MRI for tumour diagnosis and capturing therapy response. The professor received an RSNA Fellow Award for her work on optimisation and dose reduction for contrast-enhanced MR angiography. tinuously acquire images over a three- minute period, without the need for the usual breath-holding commands,’ Zindel observed. ‘Afterwards, the intel- ligent algorithm automatically selects the best images from this data jungle.’ Wish list during development It is no coincidence that the Mannheim- based radiologist is currently carrying out the test run with the Magnetom Sola. Her institute collaborated with Siemens Healthineers during the con- ception of the new device and provid- ed input for the developers. ‘We con- tributed our ideas and requirements from a clinical routine perspective,’ Attenberger said. ‘This type of coop- eration with Siemens Healthineers has a long tradition.’ Is she pleased with the result? Yes. ‘All our suggestions have been imple- mented.’ Along with the new functions these also include connection to the Teamplay software, which delivers an analysis of the clinical processes and optimises MRI capacity. Simultaneous Multi-Slice TSE enables full hand coverage with thinner slices and all relevant contrasts More than just MRI accessories www.allmri.com EUROPEAN HOSPITAL Vol 27 Issue 5/18 “Why do more clinicians prefer SonoSite ultrasound systems than any other brand?” ContactvusvonlinevandvavSonoSitevultrasoundvexpertvwillvbevinvtouchvvforvavconsultation,vin-personvorvvirtualvdemovofvanyvofvourvultrasoundvsystems.vwww.sonosite.com/uk/sales/contactSONOSITE ULTRASOUND HAS LED THE MARKET FOR THE PAST 20 YEARSFujifilmvSonoSitevcelebratedvitsv100,000thvsystemvinstalledvworldwidevandvremainsvfocusedvonvthevsamevmissionvthatvstartedvthevcompany:vHelping clinicians bring ultrasound to any patient, anywhere, anytime.SONOSITE and the SONOSITE logo are trademarks and registered trademarks of FUJIFILM SonoSite, Inc. in various jurisdictions. FUJIFILM is a trademark and registered trademark of FUJIFILM Corporation in various jurisdictions. All other trademarks are the property of their respective owners.Copyright © 2018 FUJIFILM SonoSite, Inc. All rights reserved. Subject to change. MKT03222_UK 07/18

1 4 N U C L E A R M E D I C I N E Comparison is still pending On-going malignant astrocytoma vaccine tests A new vaccination for malignant astrocytoma brings such patients hope. However, research is still in its infancy. Eva Britsch of European Hospital spoke with Professor Michael Platten, Medical Director of the Neurological Clinic at Medical University Mannheim, about the present state of research and the serious opportunities this presents. During the interview, he also revealed how cooperation with the pharmaceu- tical industry is developing and why the current results are only conditionally resilient. From July 2015 to July 2017 Professor Michael Platten and colleagues treated 33 patients with newly diag- nosed malignant astrocytoma with a novel vaccine. What is the current state of affairs? MP: ‘We have completed the study and are in the follow-up phase. The patient data are currently evaluated. However, over the next few months we will collect and evaluate further data on the patients’ progress. At the same time, we are currently conducting intensive research on the patients’ blood samples to gain a better understanding of the immune reactions.’ EB: Can definitive statements be made about the vaccination reducing the risk for astrocytoma and oligodendroglioma* patients to recur? ‘No. In addition to vaccination all patients received effective radia- tion and chemotherapy, which also prevents recurrent tumour growth, even if only for au limited period. Whether this recurrence risk is fur- ther reduced by vaccination can only be answered in a comparative study. We can start such a study once we have fully evaluated the current study.’ How does the new vaccination work and how can it be seen in combination with previously known treatment options? p039P p031P 15 μm 15 μm 15 μm 15 μm I P A D A L P I P A D H 2 3 1 R 1 H D I A L P Brain tumour cells producing the mutated protein molecule IDH1R132H (green) carry this on their cell surface (seen in red). Thus, tumour-specific changes are visible to the immune system ‘The vaccination is intended to sen- sitise the immune system of patients concerned to a protein molecule that is characteristically altered in the tumours of the patients, name- ly by the exchange of a single building block. We call this change IDH1R132H. With the vaccination we can sen- sitize the immune system so spe- cifically that only the altered pro- tein molecule in the tumour cells, IDH1R132H, but not the healthy form, IDH1wt, which can be found in all healthy body cells, is recog- nized. We hope that this specific sensitization of the immune system through vaccination will lead to the targeted treatment of tumours, as we have observed in animal experi- ments. We also assume that radia- tion therapy of the tumour, a proven therapy for these tumours, helps the sensitized immune system to fight the tumour. You and colleagues are currently evaluating the immune reactions of patients to the vaccine – how do you evaluate the reactions? Very positive. The vast majority of patients develop specific antibod- ies against IDH1R132H as a result of vaccination, but also T-cells, two important components of the immune system. We are currently evaluating which factors influence the strength of the immune reac- tions and, of course, whether these have an influence on the further course, i.e. freedom from recur- rence. We are also interested in finding out why individual patients have not experienced an adequate or delayed immune reaction.’ Does the vaccination have (previ- ously known) risks? ‘The only relevant risks we have observed are vaccination reactions at the injection site with redness and itching. This reaction is to be expected and is mainly the result of the necessary vaccination booster.’ Could a similar vaccine be devel- oped for other cancers? ‘In rare cases IDH1R132H can also occur in other types of tumours, for example in bile duct carcinomas. In principle, all tumour types in which IDH1R132H is present are suitable for vaccination. ‘On a super-ordinate level, mutat- ed protein molecules are found in practically all tumours, but they are usually patient-specific. If we succeed in defining these specifi- cally modified protein molecules for each individual patient and in developing a tailor-made vaccina- tion therapy, then such a vaccina- tion could in principle be used for all types of tumours. However, this would then be a real individualised cancer immunotherapy that could Michael Platten MD is Medical Director of the Manheim Medical University Neurological Clinic and professor of clinical neurology, neuroimmunology and neuro-oncology at Heidelberg University. In recent years he has also led brain tumour immunology at the German Cancer Research Centre (DKFZ) in Heidelberg, Germany. not simply be taken out of the medi- cine cabinet.’ Could your research lead to new treatments for multiple sclerosis, which you are also researching? ‘We always try to learn from other diseases. For the current vaccination we use many findings and models, including multiple sclerosis, because an unwanted excessive immune reaction occurs in the brain there. If we understand the mechanisms that lead to this excessive immune response, then we can better con- trol the immune responses in brain tumours. ‘Conversely, many of the break- through technologies we use to analyse immune responses in brain tumour patients can also contribute to a better understanding of multi- ple sclerosis.’ How does the pharmaceuti- cal industry respond to your research? ‘Let’s say: with cautious interest. But, we have now begun a cooperation with the industry that combines our vaccination approach with an approved cancer immunotherapy drug. Through this intelligent com- bination, we hope to make our vac- cination therapy even more effec- tive. This clinical trial will start in the next few weeks.’ What hampers your work? ‘Financing is certainly a major obsta- cle; so far we have financed all studies from public subsidies. The German Cancer Research Centre, the National Centre for Tumour Disease, German Cancer Aid and the Federal Ministry of Education and Research have given us considerable sup- port, for which we are very grateful. Without this support, implementa- tion would not have been possible. ‘We are also very grateful for the good cooperation with the Paul Ehrlich Institute, which actively sup- ports us in these innovative thera- peutic approaches.’ Could patients hope to receive vac- cination beyond their research status? ‘It’s probably too early for now. We are currently focusing all our efforts on the follow-up study. Until we can say for sure whether the vaccination therapy will actually work and, if so, in which patients and under what conditions, research in the form of clinical studies will be a priority. ‘However, we are very pleased that the patients affected and their relatives are supporting us by par- ticipating in the studies.’ * A rare, slow-growing tumour that begins in oligodendrocytes – the cells covering and protecting nerve cells in brain and spinal cord. EUROPEAN HOSPITAL Vol 27 Issue 5/18 Main Themes Medical Imaging Compuyed Maxillofacial Imaging Image Processing and Visualizayion Mulyidisciplinary Compuyayional Anayomy E-Healyh and IHE Compuyer Aided Diagnosis Compuyer Assisyed Radiayion Therapy Image and Model Guided Therapy Personalized Medicine Surgical Navigayion Surgical Roboyics and Insyrumenyayion Surgical Simulayion and Educayion Compuyer Assisyed Oryhopaedic and Spinal Surgery Compuyer Assisyed Head and Neck, and ENT Surgery Image Guided Neurosurgery Minimally Invasive Cardiovascular and Thoracoabdominal Surgery Informayion Processing in Compuyer-Assisyed Inyervenyion Digiyal Operaying Room Human-Machine Inyerface Payhology Informayics Machine Inyelligence Inyegrayed Payieny Care Tumor Boards Innovayive Clinical InvesyigayionsCoMpuTer AssisTed rAdiology And surgeryCARS 201933rd Inyernayional Congress and Exhibiyionwww.cars-iny.orgCArs 2019 presidentPierre Jannin, PhD (F)Congress organizing Committee Christos Angelopoulos, DDS (USA)Elicabeth Beckmann, BSc (UK)Leonard Berliner, MD (USA)Ulrich Bick, MD (D)Davide Caramella, MD (I)Kevin Cleary, PhD (USA)Mario A. Cypko, PhD (NL)Takeyoshi Dohi, PhD (J)Kunio Doi, PhD (USA)Volkmar Falk, MD, PhD (D)Allan G. Farman, PhD, DSc (USA)Hubertus Feussner, MD (D)Guy Frija, MD (F)Miguel Ángel Goncálec Ballester, PhD (E)Makoto Hashicume, MD, PhD (J)Yoshihiko Hayakawa, PhD (J)Javier Herrero Jover, PhD (E)David Hilderbrand (USA)Kiyonari Inamura, PhD (J)Pierre Jannin, PhD (F)Leo Joskowicc, PhD (IL)Tina Kapur, PhD (USA)Heinc U. Lemke, PhD (D) (Chair)Kensaku Mori, PhD (J)Hironobu Nakamura, MD, PhD (J)Nassir Navab, PhD (D)Terry M. Peters, PhD (CDN)Osman M. Ratib, MD, PhD (CH)Hans G. Ringertc, MD, PhD (S)Yoshinobu Sato, PhD (J)Ramin Shahidi, PhD (USA)Akinobu Shimicu, PhD (J)Hiroyuki Yoshida, PhD (USA)June 18–21, 2019Rennes, France

1 6 L A B O R AT O RY This research is as vital as understanding the human genome Exploring the human microbiome During the International Forum for Laboratory Medicine, being held at MEDICA 2018, one seminar (on 12 November} will focus on infectious diseases. Professor André Gessner, from the Medical Microbiology and Hygiene Department at Regensburg University, will lecture on ‘The human microbiome, an explosive ‘climate’ topic,’ he explained to EH reporter Walter Depner. WD: Generally you know the kind of audience you face during gatherings of specialists in your field. However, there’s no certain- ty about who will be among the MEDICA delegates attending your lecture. Could this make your job difficult or perhaps more exciting? AG: I have given many lectures to heterogeneous audiences and find the challenge of explaining complex relationships in the most compre- hensible way to be very exciting and positive. Often, I have received very stimulat- ing questions – especially from col- leagues in other fields. About three years ago, at the University of Regensburg, you lec- tured on The Intestinal Microbiom as the Centre of Health and Illness, and included in the invitations physicians, chemists, nutrition- ists, microbiologists, dieticians, technical consultants and health journalists – a very heterogeneous audience. Could that experience help with the Düsseldorf seminar? Yes, certainly. The conference is a good example for what the partici- pants see as a successful interdisci- plinary forum. Modern medicine and healthcare demands an interdisciplinary approach. Do such events, as in Regensburg and now Dusseldorf, help to reach this goal? The challenge is to transmit the latest scientific knowledge, with a critical appraisal, in such a way that it is well understood and to ‘condense’ without over-simplification, which distorts the information. For me it is important to stay realistic and above all not to raise hopes among physi- cians and their patients too early that cannot (yet) be fulfilled. There is considerable focus on the role of microbial intestinal flora as a basic component for staying healthy. You have described mod- ern, high-throughput sequencing technology as a source of dramat- ic knowledge growth. Why? Without high throughput sequencing technology, together with appropri- ately qualified bioinformatics, micro- biome analysis would be impossible. It was this technology that first made this enormous knowledge growth possible – currently more than 65,000 publications in just over ten years. MEDICA’S LABMED FORUM Monday, 12 Nov 2018 10.45 – 11.15 a.m. The human microbiome – diagnostic and therapeutic aspects Speaker: Prof. André Gessner, Director of the Institute for Medical Microbiology and Hygiene at Regensburg University Are their approaches going in the right direction? The technological potential in analy- sis is developing rapidly. Here we need improved standardisation of analyses, quality controls and hope to gain ever increasing ‘read lengths’, that is to say DNA sections that can be sequenced in one piece, lower sequencing error rates and naturally lower costs for examinations. Especially important here is also a significantly better comprehension of the functional relationships between microbiome and various diseases, so that rational new therapies can be developed in the future. Along with interdisciplinary scope, the internationality ques- tion plays an important role. What is the state of cooperation, exchange in research, teaching and practice? Microbiome research is particu- larly characterised by numerous already well-established international cooperation efforts, among academic institutions such as universities, and increasingly among very many firms. The exchange is extremely inten- Having studied medicine and molecular biology at the University of Hamburg, Professor André Gessner received his medical doctorate in infection immunology and a PhD in molecular virology. Following five years’ basic research at the Heinrich- Pette Institute, Hamburg, he established his research group at the University of Erlangen, where he qualified as a specialist in medical microbiology and infectious disease epidemiology. His scientific work focuses on molecular infection immunology, infectious diseases and the role of the microbiome for diseases. He is an expert and reviewer for several international journals and scientific societies and, between 2008 and 2010 he received four calls regarding chairs for medical microbiology. Since 2010 he has been a professor and director of the Institute for Medical Microbiology and Hygiene at Regensburg University, where 150 employees focus on all aspects of infectious diseases. In 2015, Gessner became the Dean of research at the Regensburg medical faculty. sive, not only through scientific pub- lications but also via Internet fora and more than a dozen international congresses annually on microbiome topics. Local antibiotics improve results Infection control in orthopaedics and trauma surgery ble for PJI should be considered. The COPAL bone cements Copal G+C and Copal G+V, for instance, contain combinations of antibiot- ics (gentamicin and clindamycin and gentamicin and vancomycin respectively) that tackle most of the microorganisms responsible for PJI. Synergistic effects of the combina- tions of antibiotics enable a high local antibiotic concentration in situ. In revision, the range of treatments includes one-stage replacement with good soft tissue conditions and known susceptible pathogens, as 69% reduction in the rate of deep infections following femoral neck fracture when using high-dose antibiotic-loaded bone cement. Source: Sprowson et al. well as two-stage replacement with precarious soft tissue conditions and unknown resistant pathogens. In both cases the effectiveness of the treatment can be increased by using bone cement with combinations of antibiotics. The combination of anti- biotics used should be determined after completing diagnostics and an antibiogram. Hip and knee joint surgeries are among the most common proce- dures in orthopaedics and trau- ma surgery and complications can occur. Rare, but serious, among these is periprosthetic infection (PJI), which causes high costs in healthcare and stress for patients. PJI is caused by microorganisms that form a biofilm on the surface of the implant and, in this sessile state, they are difficult to diagnose and treat. Successful management of a PJI is therefore based on prevention and prophylaxis so that infections cannot develop in the first place. Antibiotic prophylaxis using antibiotic-loaded bone cement Polymethylmethacrylate (PMMA) bone cement, which is primarily used to fix prosthetic implants, can support effective infection manage- ment in primary arthroplasty, revi- sion and the treatment of peripros- thetic infections. The local release of the antibiotic from the bone cement supplements standard systemic anti- biotic prophylaxis. The advantage lies in the considerably higher local concentration of the antibiotics with a low systemic load. Choosing the right treatment algo- rithm is a critical factor for success- ful prevention and reduction of PJI. Combinations of antibiotics – sys- temic and local – are advantageous for effective infection management for revisions, in trauma cases after femoral neck fracture and occasion- ally in primary arthroplasty. When choosing the antibiotic, the cur- rent resistance situation and preva- lence of microorganisms responsi- For revisions due to verified resist- ant microorganisms (MRSA/MRSE), the use of Copal ® G+V is recom- mended. This contains the antibiotic gentamicin combined with vanco- mycin which, as a reserve antibiotic, is an option for use with known bacterial resistance to MRSA/MRSE, for example. For septic loosening or chron- ic infections, a spacer made of antibiotic-loaded bone cement is often inserted as a temporary joint replacement to eliminate infec- tion. Articulating spacers with an implant-like design, e.g. from Copal knee moulds, should be given pref- erence here to preserve the joint function and to prevent the forma- tion of contractures and scar tissue. Risk of deep infections can be considerably reduced In primary arthroplasty patients, who are particularly at a high risk of infection, are recommended for combinations of antibiotics for anti- biotic prophylaxis, and thus the use of Copal G+C bone cement. The risk factors that can increase the likelihood of infections include dia- betes, osteoporosis, limited mobility, excess weight and dementia. When treating femoral neck frac- tures with a cemented hemiarthro- plasty using Copal G+C, it can be verifiably demonstrated that the risk of deep infections (surgical site infections, SSI) can be considerably reduced by using dual antibiotic- loaded bone cement. EUROPEAN HOSPITAL Vol 27 Issue 5/18

1 8 L A B O R AT O RY Analysing physical/chemical properties of particles Flow cytometry rises to new challenges standardisation; for example, the Euroflow group is working to create standardised panels of reagents in Europe and has made some pro- gress. The issue, he said, is more problematic in the USA, with little incentive for labs to adopt such pan- els, although an exception has been in minimal residual disease testing, where the FDA has required stand- ardised testing for certain clinical trials. ‘Some manufactures are begin- ning to make reagent combinations that are premixed in a stabilised format, so that makes it easier for people to bring that data and to standardise them,’ Wood said. ‘That may have been a step forward,’ Report: Mark Nicholls Flow cytometry has proved an invalu- able diagnostic tool for leukaemia and lymphoma for almost three dec- ades. Now, however, this is evolving in applications to seek out residual disease in cases and in fusion with molecular testing to advance its diagnostic potential. However, although Wood addressed recog- nised as fast, flexible and accu- rate, flow cytometry suffers from a lack of standardisation, according to Professor Brent L. Wood from the University of Washington (UW) School of Medicine in Seattle. those issues when describing the impact of flow cytometry on the clinical laboratory at the joint European Federation of Clinical Chemistry and Laboratory Medicine/European Union of Medical Specialists (EFLM/UEMS) conference, which was held this October in Turkey. Flow cytometry is a technolo- gy that analyses the physical and chemical characteristics of particles in a fluid as it passes through a laser. Wood, who directs UW Medicine’s Haematopathology and SCCA Pathology, could reflect on his experiences with flow cytometry for over 20 years. He has been involved in develop- ing flow cytometry in various con- texts, such as identifying residual leukaemia after therapy and demon- strating its clinical utility and signifi- cance in assessing patient outcome. Flow cytometry has been a tech- nique for diagnosis since the 1970s, particularly of neoplasms, and came to the fore in clinical laboratories in a t s i l u a p / k c o t s r e t t u h s © the 1980s with the spread of HIV before evolving as a methodology in the 1990s for diagnostics of leukae- mia and lymphoma and diseases that were easier to create cell suspen- sions from such as peripheral blood and bone marrow. Recently this advanced to focus on next generation sequencing and examining the concordance and rel- ative merits of those two techniques. As a technology, flow cytometry is flexible, facilitating the design of a variety of different assays to create panels of re-agents that are suit- able for diagnosing leukaemia and lymphoma. ‘The application to monitoring for residual disease involves looking for much smaller populations of cells of similar type and distinguishing them from their normal counter- parts,’ Wood said. ‘That’s one of the thing’s that this technology is particularly adept at doing – distinguishing normal from abnormal.’ However, he emphasised that looking for relatively small popula- tions of cells is a more technically- demanding process, requiring more attention to detail in terms of tech- nique, consistency and artefacts, and interpretation. An area of concern, said Wood, is that while the technol- ogy is widespread, it is ‘very poorly standardised’. This can see different laboratories having their own panel of reagents that they have validated themselves and their own ways of processing samples and collecting and interpreting data. ‘Interpreting data is the subjective component of this type of analysis, which requires someone with expe- rience and training,’ he pointed out. ‘In that sense it is different to many other tests we do in clinical labora- tories, where instruments provide a numerical data or results that are reviewed and released.’ Steps are being taken to address Where flow cytometry shows a clear advantage is its speed. ‘When a sample arrives in the laboratory,’ Wood explained, “it can be pro- cessed rapidly and results are gener- ated in a few hours; that’s difficult to match with antibody-based tech- niques that require a more lengthy process. ‘It is also inherently multi-para- metric with its ability to look at large numbers of individual single cells very rapidly in a multi-parametric fashion, and so provides a high degree of sensitivity and specificity for the identification of abnormal hematic cell populations.’ As for the future, Wood believes flow cytometry technology is capa- ble of providing more information about the inherent biology of leu- kaemia and lymphomas. ’We can begin to understand the end-line biology and which has the mark- ers or antigens associated with a particular response to a therapy or outcomes,’ he explained. ‘There is a potential role to assess the biomark- ers as they are identified in a rela- tively efficient or cost-effective man- ner, but it requires some discovery of what those markers are to drive the application.’ Another area of potential is in residual disease monitoring, where the assessment of both prognosis or Pathologist Professor Brent L Wood is director of UW Medicine’s Haematopathology and SCCA (Seattle Cancer Care Alliance) Pathology laboratories and UW professor of Laboratory Medicine and Pathology. A past president of the International Clinical Cytometry Society, his laboratory serves as one of two national reference laboratories in Canada for flow cytometric identification of minimal residual disease in childhood. eventual outcome and response to therapy is becoming an application increasingly carried out by a variety of laboratories.’ Of further interest is to extend the technology to solid tumours, although this has been more chal- lenging because preparing samples for them is difficult and there is a limited amount of data known about the expression patterns of proteins and antigens in solid tumours. ‘One of the real opportunities lies in the fusion of flow cytometric tech- nology with molecular testing,’ he said, ‘increasing capability to do sin- gle cell molecular-based techniques that can incorporate some of the flow cytometric features to a system identifying cell populations, but also then extensively characterising them at a molecular level and providing much more insight into the biologic nature of subpopulations of cells in any given tumour and potentially their relative response to therapy. ‘I think hybridisation of flow cytometry with molecular testing is an important area going forward,’ Wood concludes. Liquid biopsy has enormous potential An asset to improve cancer management Report: Mark Nicholls It is non-invasive, delivers a chance of early diagnosis, prognostic infor- mation and sequential monitoring, and, believes Professor Francesco Salvatore, the enormous poten- tial of liquid biopsies has still to be reached. However, the positive results obtained so far have ‘opened the door to a promising new multi- faceted group of tumour markers, at present collectively designated “liquid biopsy”,’ he explained. While liquid biopsy is a rela- tively new term, Salvatore suggested the real essence of its meaning is much older in laboratory medicine: haemochromocytometric analysis to search for altered blood cells was one of the first tests used in medical diagnostics and thus can be consid- ered the first real liquid biopsy. With the test later extended to molecular aspects of nucleic acids (DNA and RNA) in terms of their quali-quantitative analyses, the diag- nostic performance of oncohaema- tological tests became more sensi- tive. Today, femtomole amounts of specific nucleic acid sequences are routinely used in leukaemia and lymphoma patients. In 1997, Salvatore’s group was among the first to produce evidence of the presence of RNA sequences in the blood of patients with solid tumours. Soon after, the molecular analysis of nucleic acids was inte- grated into pathology practice. The concept of liquid biopsy is evolving, he said, with clinical tri- als under way with various tech- nologies – such as next genera- tion sequencing of nucleic acids and other high productivity ‘omics, analyses – to try to reach high diagnostic sensitivity in body fluids. With cellular and molecular markers that can be visualised, analysed and investigated, there is great potential for cancer treatment. ‘Since cancer is a genetically driven disorder the sequencing of tumour derived DNA and RNA is very promising, not only in terms of understanding the pathogenesis of cancer, but also in the early identification and moni- toring of tumour derived material thereby acting as biomarkers of the affected tissue or organ.’ One of the benefits of liquid biopsy, he added, is the ability to identify tumour-associated cells and molecules within body fluids, pri- y r a h d u a h C v a n i h b A / k c o t s r e t t u h s © marily blood, at the earliest oppor- tunity – leading to better prognosis. ‘Obviously, this procedure must be accompanied by highly sensi- tive methodology that can capture even minute amounts of material. Consequently, nucleic acid sequenc- es, which may be amplified also in the case of a tumour, are crucial for an early diagnosis,’ Salvatore pointed out. Because it is minimally-invasive – unlike needle biopsy – the liquid biopsy approach can be repeated and used to monitor tumour pro- gression and therapy. Other advantages of liquid biop- sy include: prognostic information; easy sequential monitoring; plan- ning treatment monitoring; identi- fication of molecular modifications before and during tumour develop- ment; RNAseq studies; detection of infectious agents; and post trauma monitoring, plus the technological advantage of increased sensitivity and specificity of nucleic acid NGS and other products of omic sciences. Among the tumour components that are shed into the circulation, Salvatore explained, the three that are most likely to be clinically useful and have the greatest potential are: circulating tumour cells, circulating tumour DNA, and tumour derived exosomes. ‘Evidence is increasingly appear- ing regarding the possibility of using these cells and cell compo- nents as markers of early diagnosis, recurrence and metastatic spread- ing, which will also serve to charac- terise tumour material at molecular level with a view to customised treatment,’ he said, predicting that this could see clinical advances over the next decade, in the fight against cancer diseases, particularly in the standardisation of samples from patients affected by tumours; their conservation; transport to spe- cialised analytical centres and stor- age in certified biobanks; continu- ous improvements in technological approaches and methods in terms of increased analytical sensitivity and the detection of minute variations; as well as advances in sophisticated bioinformatic tools and methodolo- gies that can help cancer scientists to identify novel gene pathogenic variations. However, markers have, so far, been approved for only a few exam- ples of specific tumour types and therapy. Convinced there is a bright future for new tumour markers – at pre- sent collectively designated ‘liquid biopsy’ – he said that, in time, EUROPEAN HOSPITAL Vol 27 Issue 5/18

2 0 D I G I TA L PAT H O LO G Y Raising the chances of survival for cancer patients Hungary is steadily digitising pathology In 2004 László Fónyad MD PhD o t o h P y t i s r e v i n U s i e w l e m m e S - s c á v o K a l i t t A : Hungary has one of the worst outcomes when it comes to cancer. Early detection and accurate diagnosis could significantly reduce the costs of oncological treatment. Pathology plays a crucial role in diagnoses, but is crippled by severe shortage and fragmentation. Digital pathology could help overcome those dif- ficulties – and two projects underway seem particularly fit to help, László Fónyad, a pathologist from Semmelweis University, Budapest, explained during ECP 2018 held last September in Bilbao, Spain. The distortion of resources for pathol- ogy impacts on efficiency and simul- taneously worsens the quality of and access to healthcare, according to pathologist László Fónyad. ‘We have 76 hospital pathology departments in Hungary and around 200 patholo- gists, who deal with approximately 550,000 cases per year. ‘In terms of pathology service diversity, the situation is frightening,’ he said. ‘Some labs only have a thou- sand cases while others have 30,000. There are numerous small labs with no fulltime pathologist available, or only one –usually a retired patholo- gist who is still working. It’s unjusti- fiable and everybody knows that the result is long turn around times of findings, which can take two to four weeks, a lack of consultations that would be needed in complicated cases, and lack of rapid diagnostic aid during surgeries,’ he said. Individual digital initiatives Digital pathology solutions could potentially improve the situation, Fónyad explained, and there have been a number of initiatives in that sense in Hungary since 1994, with the implementation of an early tele- pathology network connecting vari- ous hospitals and pathology labs, using still images and sharing live images of robotised microscopes. From the mid 2000s, digitisation has spread to other fields of patholo- gy, such as graduate and postgradu- ate histopathology teaching, research and routine diagnostics, thanks to the cooperation between Semmelweis University and a Hungarian spin- off company in digital pathology. ‘For many years, efforts to introduce telepathology on a local, regional and national level have been driven by enthusiastic volunteer patholo- gists and have not been financed by the Hungarian government,’ Fónyad pointed out. Recent developments In 2015 the European Union and the Hungarian government co-financed the Social Renewal Operational Programme and issued a nationwide comprehensive report on pathology services in Hungary, which high- lighted the importance of enhanced laboratory automatisation, workflow management and digitisation as tools to improve quality. In 2016 the Human Resources Development Operational Program, also co-financed by the EU and Hungary, launched an initiative to develop pathology services through- out the country, with a budget of approximately €11 M. The objective is to provide labs with both traditional and high-end equipment – tissue processors, microtomes, strainers, etc. – and equipment of safe lab sample track- ing, such as cassette and slide print- ers, and barcode readers. Another goal is to develop a nationwide dedicated pathology information system (nwPIS), which will connect all the pathology labs and be interfaced with each lab’s own hospital information system (HIS). ‘The nationwide pathology infor- mation system will enable real time data collection of all aspects of pathology workflow and resource management. Synoptic reporting and solutions for automated or semi- automated medical coding and bill- ing are also planned,’ Fónyad said. The system will be integrated into the Electronic Health Care Service System, a recently installed cloud computing service connecting vari- ous HISs throughout the country. Pathologists will be supplied with computers suitable for digital pathol- ogy with ultra-high resolution large- format displays. A nationwide telepathology consultation network Hungary is also working on a nationwide telepathology consulta- tion network, to digitise, store and share slides for intraoperative fresh frozen specimens, second opinion and primary diagnosis. graduated from the Faculty of Medicine at Semmelweis University (SU), in Budapest. Following his pathology residency, he became a faculty member at the first Department of Pathology and Experimental Cancer Research, in SU. There, in 2015, Fónyad received his PhD in digital pathology, an interest that began when a student. He was the first to introduce digital slides into graduate education in Hungary, and has headed numerous pilot projects to adopt digital slides in routine surgical pathology. As a part of his PhD program he received a grant from the Hungarian-American Enterprise Scholarship Fund’s (HAESF) and was a visiting research fellow at the Pathology Imaging and Communication Technology (PICT) Centre, Massachusetts General Hospital, in Boston, USA, where he worked with Yukako Yagi, and John Gilbertson. matters of patient privacy, security of patient data and informed consent, licensure, malpractice and liability or reimbursement,’ he added. The current decentralised model of pathology departments is a chal- lenge to good service, and digitisa- tion could also help overcome this difficulty, he explained. ‘We have a physically fragmented service. We’re The project is primarily being con- ducted by Semmelweiss University, which recently received a €6.72 million grant from the public health program of the Norwegian Financial Mechanism, an organisation that reg- ularly injects money into EU states initiatives. The project also includes the design of a qualification program for histotechnicians, expanding their competence to handle surgical sam- ples that are intended for intraop- erative pathology telediagnostics, a quality assurance system for the digital network and a detailed pro- ject plan for the implementation of the network when resources become available. Discussions about funding the implementation have begun with the Ministry for Innovation and Technology. Ideally, the teleconsulta- tion system should be fully equipped by 2019, but workshops should be held for users and the medico-legal aspect should be clarified before the network launches, Fónyad point- ed out. ‘If necessary, the pathology community should address the issue and counsel the governing bodies on thinking of a reasonable centralisa- tion of the pre-analytical processes into several labs, and to distribute the task. or several tasks. of the ana- lytical phase. This is where digital pathology comes in. ‘If you want to centralise, you end up with enormous amounts of data and physical samples to process. You need to have a dedicated infor- mation system and software to track your samples and trace back any errors. The planned nationwide tele- pathology consultation network ena- bles distribution of diagnostic tasks between pathologists all around the country.’ The consultation network could improve the human resources capac- ity of pathology services, but will not solve the low-cost effectiveness rooted in fragmentation, Fónyad warned. ‘It has to be clear that implement- ing digital pathology could help to overcome some of our difficulties but not all, while it is a prerequisite for lab centralisation.’ ‘Digital pathology is just a tool, not an end,’ he concluded. MR EUROPEAN HOSPITAL Vol 27 Issue 5/18 We listened.We learned.Now we lead.Find out more atekfdiagnostics.comAnalytical performance of POC instruments for HbA1c can be seen to be continually improving. However, there are still some instruments that do not perform to the desired level when different quality targets are applied.Quo-Lab met all criteria.“ ”Lenters-Westra E, English E. Evaluation of Four HbA1c Point-of-Care Devices Using International Quality Targets: Are They Fit for the Purpose? Journal of Diabetes Science and Technology. 2018; 12: 762-770. WSI Web Slide Portal•ForPC, Tablet, Smartphone•For E-learningor consultation•Any browser, no installations Digital PathologySolutionswww.vmscope.com

2 2 D I G I TA L PAT H O LO G Y Aims to liberate labs from manual processes Striding towards automation Often referred to as the ‘Achilles’ heel’ of histopathology, the sample entry has posed considerable chal- lenges in pre-analytics for several decades. European Hospital visited the Munich-based lab automation start-up Inveox GmbH. Is digitisa- tion and automation really a game- changer in histopathology? A decades-old problem Time-intense, highly manual pro- cesses in labs are expensive, error- prone and the most common reason for irregularities in cancer diagno- ses. In Germany alone, every year hundreds of patients are misdiag- nosed or treated incorrectly due to false-positive/negative laboratory findings, that cause fatal medicinal, psychological and personal conse- quences for patients and families. Of course, that is the worst-case scenario. However, the traditional process of sample entry in histo- pathology labs is almost always described as very lengthy and inef- ficient. The exposure of lab staff to the carcinogenic substance formalin, in which the tissue samples are transported, is often associated with occupational health hazards. The solution: innovation and automation Inveox has developed an automa- tion system consisting of three com- ponents –a data and communication platform, proprietary biopsy con- tainers and an innovative automa- The project was carried out in a multistep setup, and divided into three phases: creating the platform (call and set up phases), testing the feasibility of the platform and digi- tal service in general (test phase), and starting the production and the actual use (production phase). This approach enabled re-evalua- tion of results after each step and to assess different kinds of obstacles that were faced, and already been thoroughly described in the litera- ture. By mid-2015, the SecundOS team began an eight-month test phase to study project workability, to iden- tify functional problems, issue rec- ommendations, establish expertise flows and make improvements for optimal use. ‘Our team had many difficulties during that phase, as did all those who have tried to set up digital pathology in the lab,’ Ramadhan recalled. ‘We first bought a scanner and put it in DIAPath, where we used to do the scans, and deliv- ered the slides through shuttle bus and received the images though our web-based sharing system. We noticed a lot of disadvantages: turn- around time went really high, and we had considerable risk for slides loss and breaking. So, we stopped, and bought another scanner to put in our hospital.’ The SecundOS team also noticed there was no perfect link between the platform and the hospital’s labo- tion device for the sample entry. ‘It defines a new standard in patient safety while providing a long-sought boost in lab efficiency and profit- ability’ co-founder and CEO Maria Driesel claims. An innovative biopsy vessel with integrated filter facilitates automated processing of tissue samples. Web-based data and communication platform The diagnostically relevant data (e.g. imaging, precise macroscopy, track- ing) which could not be recorded and leveraged in the traditional process, are now collected in an IT database and made available to pathologists in their existing labora- tory information system. Using the inveox web-based, encrypted data and communication platform, physi- cians and pathologists are automati- cally informed about the status of a sample in real time - from the extraction of the tissue sample to diagnosis. Intelligent sample container Whilst nowadays biopsies must be manually repacked into different vessels and re-labelled several times in the process, Inveox has com- bined these vessels into a single sample container with an integrated filter. This way, the sample always remains in a single container, elimi- nating potential mix-ups, loss or contamination. Furthermore, the sample container is provided with a unique and permanent ID, addition- ally increasing processual safety and allowing for data transfer, track & trace and process control. t r e k c E d i r t s A © An automation device for sample entry The is designed to enable several dozens of sample containers to be inserted lab automation device The revolution escalates Continued from page 21 Team SecundOS. Ramadhan: ‘You still need an excellent team with the motivation and spirit working with you to make use of the tool.’ ratory information system (LIMS). ‘Instead of making benefit of time, we had to do all the addition- al administrative work. This was a burden to the technologist and pathologists, and was not practi- cal,’ he confirmed. ‘Eventually we succeeded in performing matches between the platform and LIMS. Both systems linked perfectly and it became a matter of mouse-clicks. All the information was uploaded and sent remotely.’ After they analysed the statis- tics of the test phase, the Belgian pathologists launched the produc- tion phase and noticed encourag- ing data concerning the numbers of cases sent for second opinion for around 600 cases, compared to the 100 cases that were sent during the test phase. ‘We also observed increased and more diversified uses of the platform, as we added multi- ple features. Besides second opinion (24%) and primary diagnosis (2%), new applications, such as using the t r e k c E d i r t s A © Inveox founders Dominik Sievert (left) and Maria Driesel (right) discussing details of the automation device with two of their engineers. Pathology 4.0 – The laboratory of the future Every good therapy begins with a precise, reliable and comprehensive diagnosis. Therefore, the future of healthcare begins in the laboratory. ‘Our goal is a fully automated, con- nected laboratory including sample tracking as well as collection and leveraging of process data. Process mining and an algorithm to under- stand what happens to a sample on its long journey from tissue collec- tion to diagnosis are sources for fur- ther insights.’ Maria Driesel points out. Combined with diagnostic data, e.g. from pathologists and radiolo- gist, as well as patient profiles, this could form the basis for a reliable, holistic diagnosis – cross-location and in real time. at a time and, be processed auto- matically, seamlessly and simultane- ously: The sample data is collected, formalin removed, and the tissue photographed 360° for documen- tation and additional diagnostical information. The subsequent innovative tech- nology computer vision opens up a multitude of new possibilities in Visual ID, Machine Learning/AI, which are yet to be explored and leveraged in processual, analytical and diagnostic terms. The sample is then discharged from the machine, still sitting in the same coded part of the original sam- ple container, the biopsy cassette, and can be seamlessly transferred to the next step in the lab’s work- flow. ‘Inveox is also working and actively researching artificial intel- ligence. We are determined to cre- ate the greatest possible impact and improve lives.’ co-founder Dominik Sievert emphasises. images for teaching purposes, MDT meetings and research, have been successfully added.’ A topic that still triggers discus- sion and controversy is the wide use of the platform for academic purposes at the expense of clini- cal uses such as primary diagnosis, second opinion and frozen section consultations, he noted. A motivated team The adoption of the SecundOS by all the pathologists inside the depart- ment proved particularly challeng- ing. ‘You can have the perfect work- flow, perfect DX platform, but you still need to have an excellent team with the motivation and spirit work- ing with you to make use of the tool,’ Ramadhan said. Not having a properly specialised technician to work in this environ- ment as it develops complicated things. ‘Image quality was not sat- isfying at first, we had to work on that,’ said Ramadhan, who also rec- ommended having an IT specialist on a daily basis for the platform to run smoothly. Further issues are compatibility with the rest of the IT systems inside the hospital, to rely on strict criteria upon selecting second opin- ion experts and to comply with the Belgian and European Union legislation in this framework. The platform must be used across all departments in the hospital to have real value. ‘This must be a multidis- ciplinary tool: we need to make a stand in our network, make it mul- tidisciplinary, and all specialists are welcome,’ he said. Ramadhan and team must now to link the platform to their biobank. ‘We need a digital library, an archiv- ing system, which is going to be a very important source of informa- tion for researchers, patients, stake- holders… We’ve done fifty percent of the job and we still have to do the remaining half.’ Integration of artificial intelli- gence tools to obtain diagnosis and access the biobank is also a sig- nificant goal, and cooperation with the DIAPath team, who are already using the technology in their daily work, will be central. Connected to pathology image server Other objectives are including more users on the platform and having LIMS connected to the pathology image server, to use all the data in teleconsultation, primary diagnosis, second opinion analysis, interdis- ciplinary meetings, education and archive. ‘Having a platform is a long jour- ney, you have to work in a team and overcome different kinds of problems. It’s a must, but not an option to have a digital platform in a hospital,’ he concluded. ‘It takes a lot of time to integrate this platform into our daily work, but it will be worthy and cost effective.’ EUROPEAN HOSPITAL Vol 27 Issue 5/18

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