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www.KUGEL-medical.de C O LO R U P YO U R L A B Equipment for Histo-Pathology Labs Azg_KM_European-Hospital_103x133.indd 1 11.02.16 09:32 www.healthcare-in-europe.com 33 LABORATORY Datasets like TCGA are ‘the ultimate commodity’ Severe infection evaluation needs cooperation between many laboratory disciplines Benefits from The Cancer Genome Atlas Calculated therapy is the objective Report: Lisa Chamoff Last year, scientists at the University of California San Francisco (UCSF) revealed that by measuring the pro- portion of both immune and can- cerous cells in tumours, or ‘tumour purity,’ clinicians could more pre- cisely predict the success of certain precision therapies. A key aspect of the discovery was access to over 10,000 samples constituting 21 differ- ent cancers. This wealth of data came from The Cancer Genome Atlas, a vast public resource, which is a joint initiative of the National Cancer Institute and the USA’s National Human Genome Research Institute. The database con- tains genomic profiles of over 10,000 cancer patients, including mutations, copy number variations, gene expres- sion, DNA methylation and proteins profiling, as well as pathology slides and full clinical information. ‘There’s no equivalent to this resource with so many “omics” char- acter ratios for so many patients,’ says Dvir Aran, a research scientist in the laboratory of Atul Butte at UCSF’s Institute for Computational Health Sciences. Aran will discuss the team’s use of the database At a recent focus meeting held in Berlin by the Association of Accredited Laboratories in Medicine, Dr Andreas Weimann, managing director at the Laboratory Berlin – Charité Vivantes Services, spoke of the challenges that laboratories working with hos- pitals face due to the management of pathogens and the diagnosis of infections. ‘We are clinging to red tape. Instead of prevention, our focus is on those who are already ill,’ Weimann explains, in the “Five Bad Habits of Healthcare” drafted by the World Economic Forum 2012. Demographically, the focus is increas- ingly on older, multi-morbid patients who are particularly exposed to infectious agents due to their com- plex clinical pictures. Weimann refers to patients who have had organ transplants as an example. There are no reference values for this group. ‘Can you spontaneously state the ref- erence value for liver function tests in a 75-year-old, immune-suppressed liver transplant patient? We don’t know it!’ Yet it is precisely these kind of questions that clinicians want laboratory medics to answer. Is an infection local or is it sep- sis? Is it bacterial or viral? Should I administer effective, anti-infective chemotherapy or not? What is the severity? Can I make a prognosis? Weimann emphasises that, particular- ly in the field of intensive care medi- cine, one should be realistic enough to anticipate that some patients will not survive. Effective screening of pathogens and the effectiveness of medication with regards to selected biomarkers can help doctors in their decisions as to whether treatment should be continued or whether life- preserving measures should cease – from a cost perspective, as well. Such screening should ‘…buy the intensive care medic time to actively wait,’ Weimann points out. Sometimes, such a comprehensive, sufficient diagnosis also allows the doctor to ‘do nothing for a day’. It also makes significant contributions towards cost efficiency, allowing bet- ter control over the development of multi-resistant pathogens. With these multi-resistant patho- gens in mind, Weimann talks of the current practice of antibiotics prescriptions in Germany: 85% of all antibiotics are administered in veterinary medicine. Of the 15% pre- scribed in human medicine only 0.5% are used in intensive care medicine. Weimann calls this a ‘topsy-turvy world’. One large problem in anti-infec- tious therapy is the high rate of wrongly prescribed antibiotics, i.e. unnecessary prescriptions and those inappropriate for the respective path- ogens. ‘The current best practice appears to be to shoot sparrows with cannons,’ Weimann says wryly. Over the last ten years, in coop- eration with medical company Sysmex, the Berlin Laboratory, at the Charité, has been developing the sepsis ‘Intensive Care Infection Score’ (ICIS), which is based on cellular values and aims to facilitate a better prognosis. A combination of 10 readings, evaluated and scored, could then for instance be displayed over an intensive care patient’s bed. This would allow doctors to quickly orient their strategy based on the respec- tive prognosis. The ICIS is available 24/7/365 in all locations in the hos- pital, but requires specific staff train- ing as to the score values used in on-going treatment. Weimann quotes an example from the Charité. When a sepsis patient is treated with antibiotics it needs suffi- cient drug monitoring. In the case of multi-morbid, intensive care patients particularly, the doctor will usually prescribe not just one antibiotic but a combination. The objective of thera- peutic drug monitoring (TDM) is suf- ficient control of pathogens, as well as the prevention of toxic effects. Weimann points out that affected patients are typically not ‘male, aged around 20 and with a weight of 70kg, such as described in text books’ but ‘old and sick’, with several potential sources of infection arising from vari- ous access ports to the body. Furthermore, the interactions between various different types of medication that most people are pre- scribed due to multi-morbidity must be taken into consideration. ‘Nobody can do this. But what we can do is determine the concentration from the serum.’ This means different concen- trations and different effective dos- ages in different patients. Sufficient drug monitoring and close coopera- tion between clinicians and labora- tory staff enables the development of a personalised TDM record for each individual patient. Calculated therapy is the objec- tive. The development of a ‘house standard, adapted to the existing mix of patients’ is the method of choice. The interdisciplinary working group ABx has developed a web-based pro- gramme of recommendations (www. dgai-abx.de) to treat infections in intensive care and emergency medi- cine. The ABx programme offers evidence-based recommendations while taking into consideration the national and international guidelines for calculated antimicrobial therapy. ‘Why are we making these huge efforts?’ the expert asks at the end of his lecture, before concluding: Antimicrobial Stewardship Concepts (AST) are integral to sepsis treatment. Consistent AST appears to reduce time spent in the hospital, reduces antibiotics prescriptions and lowers the cost per intensive care patient. ‘The evaluation of severe infections requires cooperation between many different laboratory disciplines – methodically as well as organisation- ally,’ Weimann confirms in his talk, ‘Studying the Tumour Microenvironment with Big Data’, at the Cambridge Healthtech Institute’s Liquid Biopsy Summit (June. S.F.) For the study, published in the 4/11/2015 issue of Nature Communications, the team combined four previously developed algorithms to estimate tumour purity. They found ‘immense differences’ in tumour purity lev- els among cancer types and among patients with the same type of cancer, which may be a major factor when analysing gene expression, Aran says. ‘For example, we measure an expression of a gene that’s expressed only from the cancer cells, but one of the samples is 90 percent pure and another is only 50 percent. A naive interpretation might suggest that the first sample is activating this gene, while this is only a result of the difference in purity,’ Aran explains. ‘Our analysis showed that this biases interpretations and leads to false conclusions of many bioinformat- ics analyses, such as constructing co-expression networks, clustering tumours to molecular subtypes and finding genes that are (differentially) expressed in tumours compared to normal samples.’ The estimate has an impact on tests used to predict the effectiveness of checkpoint inhibitor drugs, a popular cancer immunotherapy, the research- ers found. When immune cell infiltra- tion was measured, predicting the likely success of this expensive treat- ment was much more accurate. ‘In this study we showed that the influence of tumour purity on the results of genomic analyses is much stronger than previously appreciated, and ought to be included as a covariate in any future analysis,’ Aran says. ‘Tumour purity differences result- ing from sampling variation exceed intrinsic individual differences. Lower purity samples, by influencing genomic data, may make precision medicine efforts more challenging. We urge cancer researchers and cli- nicians to take tumour purity in to account when analysing genomic data from patient samples.’ Studying the tumour as a whole, including the non-cancerous cells that are part of it, was not possible before TCGA was available, Aran points out. Researchers previously used genomic data from cell lines, which charac- terise only the cancer cells, and not tissue from real patients. Announcing the study, Butte said datasets like TCGA are ‘the ultimate commodity. Unlike oil or water that can only be used once, data continu- ally generates new insights.’ The data, which is completely free, can be downloaded from the TCGA data portal. For the study, Aran and team combined DNA, RNA, epigenet- ic and pathology analyses to create a consensus measurement of tumour purity, which is the percentage of cancer DNA in the sample, and stud- ied the measurement in the context of the patient’s clinical information. ‘For bioinformaticians like me, this is a goldmine,’ Aran says. Dvir Aran, laboratory of Atul Butte, UCSF’s Institute for Computational Health Sciences, USA Andreas Weimann is Managing Director of Laboratory Berlin – Charité Vivantes Services The Cancer Genome Atlas (TCGA) is a project to catalogue genetic mutations responsible for cancer, using genome sequencing and bioinformatics Azg_KM_European-Hospital_103x133.indd 111.02.1609:32

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