OCTOBER 2014 # 01
Upfront In Practice Profession Sitting Down With Ebola research gained How to minimize error in Where is the next generation Stephen Minger, Chief new insights but lost lives your molecular pathology lab of pathologists? Scientist, GE Healthcare
10 36 – 39 46 – 49 50 – 51
Facing the Digital Future of Pathology
Are concerns around digital pathology technology based on fear or fact? 16 – 25 Nanozoomer_WSI_210x266_Layout 1 09/09/2014 08:02 Page 1
Slide Scanning Solutions for Whole Slide Imaging
Hamamatsu has a NanoZoomer model to meet all your whole slide imaging needs, from a single slide or batch scans of up to 320 slides.
Ultra-fast, simple creation of high resolution digital slides Rapid image sharing for remote consultation via the internet or LAN Easy duplication, storage, archiving, retrieval, image analysis and annotation A digital pathology resource for education, training, presentations and meetings No image degradation or photobleaching of labile fluorescent probes Optional fluorescence optics
NanoZoomer-XR NanoZoomer 2.0-HT NanoZoomer 2.0-RS NanoZoomer SQ Ultra-fast scanning of up to 320, 76mm Ultra-fast scanning of up to 210, Fast scanning of up to 6, 76mm x 26mm New affordable desktop single x 26mm slides 76mm x 26mm slides slides or 2, 76mm x 52mm slides with slide scanner optional slide loader
www.nanozoomer.com Online this Month
Guest List Website “If your name’s not down, you’re not coming in!”
The website really comes alive when you register. You can access all the printed content, plus find online exclusives and sign up for newsletters and alerts with further benefits over The Pathologist website acts as a hub for both our content the next few months! thepathologist.com/login and our community. Visitors can access all articles, engage with multimedia elements and interact through comments. Regular electronic newsletters and social media drive further activity on the website.
Social Media Find more from ThePathologist. Connect and interact Everywhere You Go online through Facebook, LinkedIn, Google Plus, our YouTube channel and via Twitter (@pathologistmag) Content at 30,000 feet. The Pathologist iPad app is now available to download at the Apple App Store. Offering the ability to download and read content offline, it's easy to take The Pathologist wherever you go. The Dotted Line ...... To download the app and for updates on the upcoming To guarantee your next copy of The Pathologist, sign up Android version, visit: online and confirm your print subscription. And please feel thepathologist.com/app free to pass this invitation onto colleagues. Subscription is qualified but free: thepathologist.com/login Contents
46 50
03 Online This Month Upfront 10
10 Tracing the Ebola Genome 07 Editorial Welcome to The Pathologist 11 FDA Crackdown on Labs By Fedra Pavlou Feature 12 Unscrambling Schizophrenia 16 Facing the Digital Future 08 Contributors 13 Targeting Postpartum Depression of Pathology Digital Pathology is here to 14 The Survival Artists stay, but while some pathologists On The Cover have embraced it, others cite
OCTOBER 2014 # 01 15 To Use pCR, We Must First ongoing issues such as
Upfront In Practice Profession Sitting Down With Tracing the Ebola genome Best practice guide for Where is the next generation Stephen Minger, Chief molecular pathology labs of pathologists? Scientist, GE Healthcare
11 36 46 – 49 50 – 51 Digital pathology begins to take root Define It standardization, storage, workflow Facing the Digital Future of Pathology
Are concerns around digital pathology technology based on fear or fact? 16 – 25 in traditional pathology and security. We discuss the facts with the users and vendors. ISSUE 01 - OCTOBER 2014
Editor - Fedra Pavlou [email protected]
Associate Editor - Roisin McGuigan [email protected]
Associate Editor - Stephanie Sutton [email protected]
Senior Designer - Marc Bird [email protected]
Chief Executive Officer - Andy Davies [email protected]
Chief Operating Officer - Tracey Peers [email protected]
Publisher - Mark Goodrich [email protected]
Audience Development Manager - Tracey Nicholls 36 [email protected]
Digital Content Manager - David Roberts NextGen [email protected]
28 Human Proteome Maps - 40 Lab Turnaround Time Study Sets Traffic and Administration Manager - Claire Lally Two Perspectives Alarm Bells Ringing [email protected] Bernhard Kuster describes his Enrique Rodríguez-Borja ongoing work to map the human recounts his experience of Mac Operator Web/Print - Peter Bartley [email protected] proteome, including some surprising measuring turnaround time both findings, while Michael Tress adds inside and outside his laboratory. Social Media / Analytics - Stephen Mayers a question mark over accuracy. Do you know when clinicians [email protected] consult your reports? 31 Operating Within Molecular Margins Published by Texere Publishing Limited, Booths Hall, Sandro Santagata and Booths Park, Chelford Road, Knutsford, Cheshire, Nathalie Agar believe DESI Profession WA16 8GS, UK MS has the potential to transform intraoperative tissue analysis, and 46 Where is the Next Generation clinical mass spec has already of Pathologists? General enquiries: attracted industry attention. Why are fewer medical students www.texerepublishing.com [email protected] choosing a career in pathology? +44 (0) 1565 752883 Suzy Lishman tells us what she [email protected] thinks will help buck the trend. In Practice Distribution: 36 Minimize Errors, Report The Pathologist is distributed worldwide through 10,000 printed copies to a targeted European with Accuracy Sitting Down With mailing list of industry professionals and 22,500 Ian Cree talks best practice electronic copies worldwide. guidelines in the molecular 50 Stephen Minger, Chief Scientist, ISSN 2055-8228 pathology lab, including reflex Cellular Sciences, Life Sciences, testing, common blunders and the GE Healthcare, London, UK. need for clarity in increasingly complex molecular reports for patients with cancer. DigitaLDigitaL PatPatHoLogyHoLogy CongressCongress 4-5 December 2014 London, UK London Heathrow Marriott Hotel
Understanding and Utilizing digital Pathology as a tool for advancing Pathology Practice and enabling enhanced Patient care
Keynote sPeaKers
Jo Martin, Liron Pantanowitz, MarCiaL garCia roJo, national clinical director of associate Professor of Pathology & head of Pathology Pathology nhs england, biomedical informatics, director of the department, hospital Professor of Pathology, Queen Pathology informatics fellowship Program de Jerez de la frontera, Mary University of london, and associate director of the Pathology cádiz, spain director of academic health informatics division at the University of sciences, barts health nhs trust Pittsburgh Medical center, Usa
Day 1 Day 2 stream 1: digital Pathology - strategy and technology stream 1: digital image analysis stream 2: Pathology informatics stream 2: digital Pathology applications and research case studies Utilizing digital Pathology
gold sPonsor: silver sPonsors: reader discoUnt
save 10% with discount code: sPonsors: dPr/10
tel: +44 1865 849 841
email: [email protected]
www.globalengage.co.uk/digital-pathology.html
Digital Pathology Congress Advert.indd 1 22/09/2014 11:37:01 Welcome to The Pathologist Editorial From academic to clinical pathology, microbiology to molecular pathology, we promise to report on the issues and innovations at the heart of your field.
elcome to the first issue of The Pathologist. What is this new publication all about? Well, our aim is to provide you with insight into the latest research and technological breakthroughs that affect – or will affect – your work in the field of pathology. WFor example, our first issue focuses on a topic that has divided the community – digital pathology (see page 16). While it’s not a new phenomenon, opinions vary vastly. The general consensus: if you’re not using it, you probably will be in the next few years. And though cynicism remains, the digital pathology seminar held at this year’s European Congress of Pathology (ECP) was packed to the rafters and was followed by an extremely energetic discussion. Evidently, people are interested, but there are also concerns; cost, standardization, training, and privacy issues, for example, all need to be addressed. A senior manager of a company that’s actively involved in digital solutions admitted to me recently that pathologists will only adopt the technology if industry can demonstrate that there is a clear need. Despite opinions being divided, Berlin’s Manfred Dietl made an interesting point in his presentation at ECP: you cannot afford to ignore it. After all, bad press surrounding false diagnoses and inaccurate reports, in particular for patients with cancer, have publicly emphasized areas that need to be addressed. Although Dietl accepted there are downsides to integrating digital technology, the upsides – increased need for quantification, reduced variability and increased objectivity – are far greater. I hope such hot topics will fully engage each and every one of you. If you want to contribute to the ongoing debate on digital pathology, please drop me an email. In addition to offering in depth or high level coverage of topics that are destined to have a wide and great impact, we want to focus our editorial lens on other important areas that directly affect your daily work; we’ll look at changes in regulations, quality and standards, training and education, and funding, to name but a few. Importantly, we will also become the forum where you can learn from and communicate with your peers. Our vow is to use every avenue – the monthly print magazine, website (www.thepathologist.com), e-news, and social media (Twitter: @pathologistmag; Facebook: thepathologistmag) – to report on the people and subjects that are important to you. And, of course, if there’s something you’d like to share, please email me at [email protected]. Finally, I’d like to take this opportunity to offer my sincere thanks to our contributors and to the thought leaders who provided invaluable support and guidance in the run up to our launch. This is just the beginning of an exciting journey together.
Fedra Pavlou Editor Contributors
Share Suzy Lishman Best Share Specializing in gastrointestinal pathology, Suzy is a cellular pathologist in Practice Knowledge Peterborough and President Elect of the Royal College of Pathologists (RCPath). She leads the College’s public engagement program, which has seen over 2,000 events run to date. She wants to promote pathology and engage with students to encourage careers in the field. “The molecular revolution will transform the development of pathology. My job is to lead the College and ensure pathologists remain at the forefront of this research. I’d like to have pathology at the center of all health policy decisions.” Read about Suzy’s plans to maximize pathology’s profile on page 46.
Communication Ian Cree Ian is Professor of Pathology at Warwick Medical School in the UK, he chairs the inter-specialty committee on Molecular Pathology for the RCPath and sits on the Laboratories NICE diagnostics advisory committee. Trained as a general pathologist with a PhD in immunology, his research interests are mostly cancer-related; he has published over 200 papers and two books. Currently he’s involved in developing guidelines for molecular pathology testing for cancer patients, which he discusses on page 36. People “I would urge pathologists to look at the results of EQA schemes and look at the mistakes of others, and avoid them,” he says.
Enrique Rodríguez-Borja Network Enrique has headed the pre-analytical and LIS department at the University of Valencia Hospital Clinic, Spain since 2009. “Since I started working in pathology, I’ve been concerned about the lab’s role in coordination and ensuring appropriate Management utilization. Hospitals have evolved into larger and more complex systems, and laboratory professionals need to define new roles. After implementing computer provider order entry (CPOE) in our department and getting rid of paper documents, I wondered if available laboratory requests were consulted by clinicians and if so, Performance how fast – this was part of my improvement strategy.” Find out what Enrique’s research revealed on page 40.
Marcial García-Rojo Director of Pathology at der Jerez de la Frontera Hospital, Spain, Marcial’s research Change interests include informatics standards in digital and molecular pathology; he’s published three books and 125 scientific papers, and edits the Spanish Journal of Resources Pathology. An advocate of digital pathology, he’s keen to see it develop. “The problem is it’s evolving very quickly. Pathologists want to concentrate on their work, not on technology issues, so the discussion is around how to find solutions and make them easy to deliver.” Marcial outlines his experiences with digital pathology and his thoughts on how to improve it on page 20. See you at Lab Innovations 2014 Stand B7 Share Best Share Practice Knowledge
Communication
Laboratories
People
Network
Management
Performance
Change Resources
See you at Lab Innovations 2014 Stand B7 10 Upfront
Upfront
Reporting on research, innovations, policies and personalities that are shaping pathology today. Do you want to share some interesting research or an issue that will impact pathology? Email: fedra.pavlou@ texerepublishing.com was the finding that molecular testing Tracing the could prove inadequate – regions of the Sierra Leonean genomes used in Ebola Genome five separate PCR-based assays did not match the PCR probes. The sequencing of 99 Ebola With regards to transmission of genomes has not only the disease, no zoonotic sources were highlighted the likelihood of found to be involved in its spread. The viral adaption, but also the high genetic similarities suggested a single risks for researchers. transmission from the natural reservoir, followed by extensive human-to- More than 50 researchers from four human transmission. countries have collaborated to publish All of the genomic data has been made a collection of Ebola genome sequences available to the research community as it from the current outbreak in Sierra is generated. The team hope that their Leone. But with five co-authors dead work will aid diagnosis, the formation after contracting Ebola virus disease of public health strategies, and (EVD) before the paper was published, potentially guide research into Ebola it also highlights the devastating human treatments. “There’s nothing you should aspect of research into the disease. crowdsource more than an epidemic,” The team used massively parallel viral said co-author Pardis Sabeti. sequencing to gain information on the The current outbreak of the virus in West spread of the virus; 99 genome sequences Africa is the largest ever documented (2), were obtained from 78 patients (some with over 5,000 reported cases (3). Several genomes were sequenced twice) ahead authors of the genome study work at the of data analysis. Kenema Government Hospital (KGH), Worryingly, the team uncovered where the first case of Ebola in Sierra a total of 395 mutations (1), which Leone was diagnosed in May of this year. sets this outbreak apart from previous According to the researchers, the outbreak outbreaks. Arguably of equal concern in the country may have stemmed from Upfront 11
the funeral of a traditional healer who had been treating patients with EVD in neighboring Guinea. The original Ebola patient at KGH had attended the funeral, and tracing turned up 13 more cases in women who were also present. Study of the original patients and other infected individuals revealed that two genetically different strains of the virus appear to have spread to Sierra Leone from Guinea at around the same time – both were present in the original 14 patients and could have been contracted at the funeral. The loss of five co-authors of the study to EVD is a reminder of the risks faced by researchers; they were all experienced members of the hospital’s Lassa fever team and very familiar with regulations, while risk tests and tests the treatment of infectious disease. To FDA Crackdown for rare diseases, which do not have an date, Ebola has claimed the lives of more FDA-approved equivalent, may not than 20 nurses, doctors and support on Labs require no further guidelines (1). staff at KGH. The World Health Although some organizations have Organization (WHO) says that the Plans to regulate laboratory come forward to express their support number of medical staff now infected developed tests could stifle for the new regulations, such as the is “unprecedented” (4). More than 240 innovation American Association for Cancer healthcare workers in West Africa have Research, others aren’t so pleased by contracted the disease, and more than The US Food and Drug Administration the proposed changes. The American 120 have consequently died (5). RM (FDA) has announced its intentions Medical Association (AMA), the to regulate laboratory developed American Clinical Laboratory References tests (LDTs). The agency has Association (ACLA), and the 1. S. K. Gire et al., “Genomic Surveillance Elucidates had the authority to regulate Association for Molecular Pathology Ebola Virus Origin and Transmission During LDTs since 1976, but until now (AMP) have all met the proposed the 2014 Outbreak”, Science, (2014). doi: has refrained from doing so (1). regulations with some skepticism, 10.1126/science.1259657. US laboratories have instead been pointing to the regulations and 2. Centre for Disease Control and Prevention: regulated by the Centers for Medicare accreditation procedures already in Outbreaks Chronology: Ebola hemorrhagic fever. and Medicaid Services (CMS) using place. They also voiced concerns that http://www.cdc.gov/vhf/ebola/resources/outbreak- Clinical Laboratory Improvement further regulations could lead to the table.html. Amendments (CLIA), which have loss of patient access to required tests, 3. Centers for Disease Control – 2014 Ebola been in place since 1988. increased cost of testing, and stifled Outbreak in West Africa. http://www.cdc.gov/ So why is the FDA stepping in innovation in the laboratory. RM vhf/ebola/outbreaks/guinea/index.html. now? It cites the increasing complexity 4. World Health Organization Situation Assessment, of LDTs, and their roles in critical Reference August 2014: “Unprecedented Number of Medical decision making – in particular relating 1. The USA oodF and Drug Administration Staff Infected with Ebola”. http://www.who.int/ to personalized medicine. (FDA), “Framework for the Regulatory mediacentre/news/ebola/25-august-2014/en/. The agency intends to take a “risk- Oversight of Laboratory Developed Tests 5. G. Vogel, “Ebola’s Heavy Toll on Study based” approach (similar to the model (LDTs)”, 31 July 2014. Available at: http:// Authors”, Science (2014) http://news.sciencemag. it currently uses for assessing medical www.fda.gov/downloads/MedicalDevices/ org/health/2014/08/ebolas-heavy-toll-study- devices); LDTs considered high ProductsandMedicalProcedures/ authors. risk will be brought under the new InVitroDiagnostics/ucm407409.pdf. 12 Upfront
Unscrambling Schizophrenia
Despite numerous research efforts, schizophrenia remains a bit of a mystery. We know that both genetics and environmental factors play a part in its development, but the question of which genes and which environmental influences is clouded by uncertainty. Recently, two separate studies attempted to find new answers.
Team One: Genetic Factors Could this GWAS result in the first completely new drug treatment for schizophrenia since the 50s?
The Schizophrenia Working Group (SWG) of the Psychiatric Genomics Consortium conducted a multinational understanding of the disease etiology targets. In addition, despite the growing genome-wide association study is critical to breaking out of this body of information on schizophrenia (GWAS), that has identified 108 loci therapeutic stasis. risk factors, the likelihood of predicting associated with the risk of developing Perhaps unsurprisingly, many of the risk with accuracy remains low. He adds, schizophrenia, 83 of them new. It genes identified are expressed in the “I believe that at best, we may be able to marks the largest genomic study brain, especially ones involved in neuron add information to risk prediction. But ever undertaken for a mental health and synapse function, synaptic plasticity I do not think that genetic testing in condition (1). and cell signaling, although others were the general population will be accurate “This paper is a landmark. We have also active in the immune system. enough for diagnostic purposes. The role never before had such a profound and Despite the new information, one of the of other factors is important.” important look into the inner workings authors, Michael O’Donovan, (deputy As for next steps, O’Donovan explains of schizophrenia,” says study co-author director at the Institute of Psychological that even larger sample sizes should Patrick Sullivan, professor of genetics Medicine and Clinical Neurosciences, provide more information. Also, the and psychiatry at University of North Cardiff University, UK), cautions that current information needs to be used Carolina, USA, and director of the we shouldn’t get too ahead of ourselves to its full potential; “People need to Center for Psychiatric Genomics. and emphasizes that the study is only the figure out how genetic variation in the Genotype data was obtained and beginnings of understanding the biology. systems we identify is acting,” explains statistically analyzed from over 30,000 “Follow-up experiments will be needed O’Donovan, “We need to link genetic cases and more than 100,000 controls. to understand the impact of these genetic changes to changes in the function of So how will this benefit patients variations on the disease,” he says. the genes and cells and brain. That will with the condition? According to the According to O’Donovan, there is require a lot of non-genetic experiments authors, all current antipsychotics used already interest in genes encoding calcium from cell biologists, brain imagers, in schizophrenia are thought to target channels and glutamate signaling, but and psychologists.” RM the type 2 dopaminergic receptor – a he explains that it would be a “brave mechanism discovered over 60 years person” who expressed high confidence Reference ago. The SWG believe that a deeper that these will be successful treatment 1. Schizophrenia Working Group of the Psychiatric Upfront 13
Genomics Consortium, “Biological Insights from The team reviewed 19 studies that born at different times of year or in 108 Schizophrenia-Associated Genetic Loci”, examined the blood of a total of 2,804 different latitudes. Nature, 511, 421-27 (2014). participants. Apparently, the work Esmaillzadeh says that the next step represents the first comprehensive for his team will be to trial vitamin Team Two: Environmental Factors meta-analysis of its kind and yielded D supplementation in people with Low levels of vitamin D may be linked to unanticipated results. “We were very schizophrenia, as well as investigating schizophrenia risk surprised by the significant 2.16 maternal and neonatal serum vitamin times increased risk of schizophrenia D in relation to the condition in later A group of Iranian researchers took a in vitamin D deficient individuals,” life. RM different approach: delving further into the says Esmaillzadeh. proposed link between vitamin deficiency It has long been suspected that References and schizophrenia (1). “Vitamin D vitamin D levels may affect the 1. G. Valipour et al., “Serum Vitamin D Levels in deficiency is relatively prevalent across developing brain, and low levels Relation to Schizophrenia: a Systematic Review the world and is associated with several prenatally may predispose to and Meta-Analysis of Observational Studies”, disorders, including depression. So we schizophrenia (2). Deficiency during J. Clin. Endocrinol. Metab. (2014). [Epub ahead were interested in exploring its role in development has also been suggested of print]. psychiatric health further,” explains as a possible explanation for the 2. J. J. McGrath et al., “Developmental Vitamin Ahmad Esmaillzadeh, lead author of varying incidences of schizophrenia in D Deficiency and Risk of Schizophrenia: a 10 Year the study. different populations – such as people Update”, Schizophr. Bull., 36, 1073-78 (2010).
have profound effects on her child’s group; women who did not meet the Targeting physical and emotional development and criteria for full PPD, but who reported impact the entire family,” she explained. increased crying and sadness. This Postpartum Sacher believes that the discovery of group also showed elevated MAO-A the biomarker – elevated monoamine levels in brain regions important for Depression oxidase A (MAO-A) in the brain – balancing emotions and mood, such as could open up new directions to improve the prefrontal cortex and the anterior Could identification of a diagnosis, treatment and effective cingulate cortex. For the researchers, this new biomarker offer hope prevention strategies. was an interesting find. “Either these for mothers? The researchers used positron emission women will go on to develop PPD at tomography (PET), to measure some later time or they have some sort Postpartum depression (PPD) is the most MAO-A density in the prefrontal and of compensation mechanism protecting common complication of childbirth. It anterior cingulate cortex in the brain. them from developing the full-blown affects around 13 percent of mothers and They found that in women experiencing clinical disorder,” says Sacher. “Based is associated with over a ten-fold increase PPD, MAO-A values were 21 percent on our neurobiological model for PPD, in suicide risk compared with healthy higher than in healthy controls. promoting normalization of MAO-A individuals. Researchers from Canada “Our data argue for clinical trials of levels after the immediate postpartum and Germany now hope they can develop MAO-A inhibitors for PPD, and the period might reduce the probability of new treatment strategies through their development of new, well tolerated developing the full clinical disorder.” discovery of a new biomarker (1). MAO-A inhibitors that either rapidly RM Lead author of the study, Julia Sacher wash out of the periphery or which have from the Max-Planck Institute for human high brain to periphery concentrations,” Reference cognitive and brain sciences in Leipzig, says Sacher. 1. J. Sacher et al., “Relationship of Monoamine Germany, says PPD is an immense public According to the study, the biomarker Oxidase-A Distribution Volume to health issue. “It is often not diagnosed and doesn’t just identify depression; Portpartum Depression and Postpartum Crying”, in many cases not adequately treated. A substantial MAO-A binding changes Neuropsychopharmacology (2014). doi:10.1038/ mother’s mental health and well-being were also observed in the subclinical npp.2014.190 [Epub ahead of print]. 14 Upfront
The Survival Artists What motivated your research? Why would an obligate aerobe carry Mycobacteria are survival artists; they three of these enzymes? We learned that We know mycobacteria can need oxygen for growth, but they’re M. smegmatis uses these hydrogenases survive in the absence of oxygen. able to survive months or even years to produce hydrogen in the absence of But what is their secret? when it’s exhausted. M. tuberculosis can oxygen and is able to quickly recycle survive and persist in human lungs in the produced gas as soon as a suitable Mycobacterium tuberculosis is a pathogen granuloma, an environment known to electron acceptor (for example, oxygen known to survive in hostile conditions, be oxygen deprived. Likewise, many or fumarate) is available. This gives the but until recently, its ability to survive mycobacterial species isolated from the bacterium a high degree of metabolic without oxygen has not been well environment, such as the soil bacterium flexibility, as well as the ability to rapidly understood. A recent study from M. smegmatis, have been shown to adapt to changing conditions. researchers in New Zealand, Germany survive long-term oxygen deprivation. In addition, we could demonstrate and the US has managed to shed some Having an interest in mycobacterial fermentation in a mycobacterium, light on the subject (1). Up to a third of metabolism and energetics, I wanted to which suggests that M. smegmatis can the world’s population may have a latent pursue this metabolic conundrum: how switch between fermentation, anaerobic TB infection (2), and the researchers does an obligate aerobe – a bacterium respiration and aerobic respiration. hope that discovering mechanisms that that cannot grow without oxygen – allow mycobacteria to survive may lead survive hypoxia? What challenges did you face? to new drug targets for TB. The main challenge was to Michael Berney, assistant professor at Were there any surprises? experimentally dissect hydrogen Albert Einstein College of Medicine, We found that M. smegmatis encodes consumption and production by the NY, and one of the study’s lead authors, three different hydrogenases – enzymes bacterium. In order to determine tells us more. that are commonly found in anaerobic the contribution of each individual or facultative anaerobic organisms. enzyme to hydrogen metabolism, we Upfront 15
used genetic engineering to delete To Use pCR, We such, they propose that pCR is defined hydrogenases in the genome of M. as either ypT0/is or ypT0 ypN0 in future smegmatis and create single, double and Must First Define It studies; they found that ductal carcinoma triple mutants. had no effect on outcome in the studies With these strains in hand, we Pathological complete they analyzed. faced another challenge: measuring response can provide valuable A key objective for the team was hydrogen consumption and production information on survival in to establish pCR as a surrogate at extremely low concentrations breast cancer, but is a standard endpoint for assessing long-term (sub-atmospheric levels). We first definition within reach? breast cancer outcomes – namely EFS used a hydrogen sensor, but these and OS. Unfortunately, the trial was experiments were limited as we could A pooled analysis of the relationship unable to validate pCR as a surrogate only measure relatively high hydrogen between pathological complete response endpoint, which the authors admit was concentrations. There are only a (pCR) and breast cancer has highlighted disappointing. “This was also surprising handful of groups in the world who an important issue: different studies in view of the substantial improvements can measure hydrogen at such low are using different definitions of pCR, in survival for individual patients who concentrations, using ultrasensitive gas making it tough to compare results and attain pCR,” explains Patricia Cortazar, chromatography. Fortunately, we were to understand its prognostic value. lead author of the research. able to collaborate with Ralf Conrad of The analysis was conducted by However, Cortazar remains positive, the Max Plank Institute in Germany, Collaborative Trials In Neoadjuvant adding that the study does establish who has the necessary instrument Breast Cancer (CTNeoBC), an which pCR definitions best correlate and expertise. international breast cancer working to long-term outcomes – this may help group established by the US Food to address the lack of standardization of What’s next? and Drug Administration (FDA). The pCR. They also found that individual There are two main questions that we are study is believed to be the first to use patients who attain pCR have a 64 currently examining: primary source data to investigate the percent reduction in risk of death, relationship between pCR, event-free compared with patients with residual 1. Why are mycobacteria able to survival (EF) and overall survival (OS) tumor; the authors believe this confirms ferment and respire anaerobically in breast cancer patients. the prognostic value of pCR, which was yet are unable to grow without pCR refers to the eradication of cancer found to be greatest in patients with oxygen? It is very puzzling that in response to therapy, but its definition aggressive tumor subtypes. mycobacteria are equipped with remains unstandardized; an issue that Perhaps pCR will eventually be the tools to ferment and respire the CTNeoBC working group set out to established as a surrogate endpoint anaerobically, yet are unable to grow address (1). through further study. “We hypothesize under anoxic conditions. The study looked at 12 international that randomized trials of targeted agents 2. Do pathogenic mycobacteria, like breast cancer trials (a total of 11,955 in homogeneous tumor subtypes, with TB, also rely on hydrogen patients) and found several different larger differences in pCR rates, will likely metabolism or any other definitions of pCR were used. demonstrate a relationship between fermentative process to survive and CTNeoBC compared the most common pCR and long-term outcome,” says persist in their host? three: absence of cancer in breast tissue Cortazar. “Analyses of additional trials and lymph nodes (ypT0 ypN0); absence in a targeted population will be needed References of cancer in breast tissue and lymph to demonstrate whether or not there is 1. M. Berney et al., “An Obligately Eerobic Soil nodes regardless of the presence of ductal a relationship between pCR and long- Bacterium Activates Fermentative Hydrogen carcinoma (ypT0/is ypN0); and absence term outcome at a trial level.” RM Production to Survive Reductive Stress of cancer in breast tissue alone (ypT0/is). During Hypoxia”, PNAS (2014). doi: 10.1073/ The study revealed that eradication References pnas.1407034111. of tumor from both breast tissue and 1. P. Cortazar et al., “Pathological Complete 2. World Health Organization – Tuberculosis fact lymph nodes had a stronger association Response and Long-Term Clinical Benefit in sheet (2014). http://www.who.int/mediacentre/ with improved EFS and OS than did Breast Cancer: the CTNeoBC Pooled Analysis”, factsheets/fs104/en/. eradication from breast tissue alone. As Lancet, 384, 164-72 (2014).
Feature 17
Digital pathology is pushing the boundaries of convention and dividing the community. Uptake of the technology is growing, but only slowly. Can its adoption be resisted forever? Here, we look at the benefits – and challenges – of implementing this inevitable technology.
By Iestyn Armstrong-Smith
igital pathology is making its presence felt The plus points all over the world. For some pathologists, You can do a lot more with digital pathology than you can it’s becoming a part of everyday working with manual microscopy: instant sharing of results with life; for others it is something to be viewed multiple departments and colleagues; being able to include with skepticism. digital images with your pathology report; using computerized DEarlier this year England’s National Health Service (NHS) quantitative analysis for prognostic scores; removing the published an overview of its National Pathology Program: “Digital danger of breaking glass slides in transit; remotely interpreting First: Clinical Transformation through Pathology Innovation”(1). frozen sections and so on. These advantages can all help speed The document sets out how healthcare could apply new technology up diagnostic accuracy or turnaround times. to help meet increasing demand, which is particularly pertinent for a It goes without saying that quality assurance (QA) is health system that is financially stressed. Jo Martin (national clinical much improved with the technology – manual errors are director of pathology for NHS England, and professor of pathology reduced through its ability to perform automatic case reviews at Queen Mary University of London) prefaces by stating, and tracking of slide assessments for completeness. Image “Pathology is leading the way in the use of digital technology, with analysis efficiency, precision and reproducibility are also much the automated disciplines at the leading edge.” Martin highlights improved compared with manual microscopy (2, 3). how, in her own practice, technology has had a huge impact on But, it’s not only those of you who work in the clinical setting improving communications, procedures, workload and quality. who have gained. For example, the inherent robustness and The document is full of examples and references that support longevity of digital slide teaching sets are a big advancement use of the technology, but it is clear that bridges must be crossed on glass slides, which can fade, break or be misplaced. Other before we witness widespread adoption. advantages include the ability to scan a single tissue sample 18 Feature
to provide slides for numerous teaching classes; it also enables different from digital resolution, so correct equipment setup students to experience a wider range of cases. is a priority. The benefit of using a monitor, however, is a better Whichever way you look at it, digital pathology technology field of view and the ability to view more slides at once, as well is significant and the market for it is growing (see “The Digital as being readily able to move them around to see more of the Pathology Market” on page 25). The big question: why is there tissue directly on screen. an apparent reluctance to implement it in every hospital? It seems there is no single, clear-cut answer. Indeed, The Pathologist welcomes your comments, which we hope you will be happy to share with the whole pathology community. “In practical terms, one of the Problems and challenges first hurdles to overcome is the Pulmonary pathologist Timothy Craig Allen goes some way to explaining the apparent reluctance by highlighting a amount of bench space needed to number of challenges that face digital pathology, including legal, privacy, security, confidentiality, and standard of care site a system. ” issues, in a recent article (4). In practical terms, however, one of the first hurdles to overcome is the amount of bench space needed to site a The strain on a lab’s IT system – and the other systems it system. Also, the workflow is something quite different; it isn’t connects with – is another area of concern, with reliable simply a matter of scanning slides, digitizing them, adding network and Internet bandwidth being important factors. meta data and sending them to a computerized library to share with others. The very high resolution, highly detailed images Burgeoning patents result in huge files (think gigabytes rather than megabytes), Patents have created unwanted obstacles too. As new so storage is also a real challenge. And because most files are in technologies emerge, inventors and developers scramble to proprietary formats, you can’t open them using standard software. protect intellectual property. Even now, digital pathology In addition, you have to consider how you make the files viewable patents run into several hundred according to research by to others and whether or not another pathologist will see the slides Ioan. Cucoranu et al. (5). The group’s investigation shows that in exactly the same way, if they are using different monitors. the number of patents has quadrupled over the last 10 years, Perhaps more fundamentally, the quality of the image may which goes hand in hand with developments in the field. not be assured. For example, the scale of an image displayed Telepathology and whole slide imaging (WSI) account for on a computer monitor is different to the same image viewed the majority and there is a growth in digital image analysis through a path lab microscope. And optical resolution is and CAD. The researchers found that although the process of
Vendors’ Viewpoints What is pathologists’ biggest concern a digital image can be as fast as viewing about digital pathology adoption? using a microscope. However, computers Matthew Burke (MB), Sales Engineer are getting faster and networking from Hamamatsu Photonics UK MB: The scarcity of time! Because technology is providing more bandwidth Limited, Perry van Rijsingen (PvR), of increased workloads – including for transferring large image files, so the gap General Manager Philips Digital identifying new markers needed for is closing as the pixilation of large images Pathology Solutions from Philips diagnosis – pathologists are short of time associated with digital pathology is now Healthcare, and Olga Colgan (OC), to commit to new training and to consider becoming a thing of the past. Director of Commercial Marketing testing a digital solution compared with Also, the lack of clear guidance from Aperio ePathology from Leica their current procedure. regulatory authorities about the validity Biosystems, offer their perspectives Pathologists still need convincing of of using digital slides to report cases is on digital pathology adoption and the the benefits of sharing images and the fact an issue. Pathologists are very concerned future of the field. that the time needed to view a case from about their legal position if they Telepathology Networking
What? EURO-TELEPATH – Telepathology Network in Europe securing a patent can be lengthy, the abandonment rate was When? Established in 2007, ended 2011 10.6 percent, which is relatively low. The problem is the potential conflict between patents Why? To consolidate the best research references and standards that may arise when the implementation of in informatics applied to anatomic pathology so standards necessitates use of technology protected by patents. that standards could be developed for representing, As the market expands, we should expect to see growth in the interpreting, browsing and retrieving digital medical number of patents too, and that will not help the problem. On a images while preserving their diagnostic quality positive note, some manufacturers have recognized the need for necessary for clinical, learning and research purposes an open playing field in terms of standards. Leica, for example, is helping to clear the way by making its Aperio technology Who? Participants included COST (European patents, which cover technology included within international Cooperation in the field of Scientific and Technical standards, available free of charge to other manufacturers. Research) Agency, with representatives from 16 European countries The need for standardization In general, pathologists are very good at implementing How? EURO-TELEPATH participants took part in standardized technology, and a lot of what is already done meetings, working groups, training schools in the path lab is automated. For example, barcoding helps with accurate labeling and identification of samples and with The end result? Collaboration with international workflow. Laboratory information management systems health informatics standardization bodies to foster the (LIMS) are the norm and allow primary and secondary care development of standards for digital pathology. Also gave clinicians to order tests, and view the results, electronically. rise to the AIDPATH initiative. In terms of standards for digital medical images and related information, DICOM (Digital Imaging and Communications in Medicine) is the recognized international standard and is identical to ISO 12052. Published in 1993, the standard is implemented in almost every radiology, cardiology imaging, which systems communicate with each other. and radiotherapy device and increasingly in devices in other Though some progress is being made in the development medical domains (for example, ophthalmology and dentistry). of standards, an open digital image format standard is yet DICOM Supplement 145 is applied to WSI and defines the to emerge, with vendors locked into proprietary imaging archiving and storing of image files. Integrating the Healthcare technologies. This creates problems with compatibility both Enterprise (IHE) is an anatomic pathology group initiative backwards and forwards, which is something that Marcial that has also defined a standard that covers the manner in Garcia Rojo discusses in “The Digital Pathologist’s View”.
misdiagnose a case using a digital slide they need help to make the full shift to were a factor preventing implementation. displayed on a computer screen. digital. High image quality and system The total-cost-of-ownership can be performance are a prerequisite for them, higher than expected too. PvR: There are concerns over clinical so the real discussion is about integration Also, as pathologists tend to be (regulatory), technology and system with their existing workflow, connectivity, traditionalists and there is limited integration and financial issues. In IT infrastructure and scalability. regulatory approval in some regions of general, we hear from customers using the world, institutions are wary of it. our solution for high volume pathology OC: Although there are a number of good While it makes collaborating quicker, laboratories and integrated pathology reasons for adopting digital pathology, compared with shipping slides or needing networks that digital pathology is there are also obstacles. a pathologist to travel to different sites, the important for moving their businesses Historically, the cost of systems user experience when viewing slides can be forward. Most have some experience combined with few research papers slower than that of a microscope (if wide with digital pathology and know that validating the return on investment (ROI) area networking is limited or if users need 20 Feature
address the need, which would hopefully and ultimately encourage the use of digital imaging. Two main standards have been developed. DICOM Supplement 145, defines how we archive and store the very large image files. The second comes from the IHE initiative, which defines how different systems communicate with each other.
What about validation? In the USA, the Food and Drug Administration (FDA) insists on validation studies before pathologists can use digital images for diagnosis. We don’t have this problem in Europe because we have sufficient validation studies. Here, it is the norm The Digital Pathologist’s View to perform validation studies once a lab buys a scanner and before using it for the first time. All the validation studies that Marcial Garcia Rojo of the Hospital de Jerez de la Frontera, I am aware of have demonstrated that these technologies are Cadiz, Spain, is a key proponent and early adopter of digital suitable for performing diagnoses. pathology, having used the approach for more than seven years. However, we do need to perform further studies on Here, he shares his experiences so far. efficiency; for example, we need to know that we are working efficiently with DICOM standard images. We also need to Can you tell us why there is a need for standardization? know the impact of using standards within our pathology About seven years ago, digital scanners were appearing and workflows and that is something we are working on with the pathologists were taking an interest in what they could offer. AIDPATH initiative (see sidebar “Collaborative Clout” on At the same time the EURO-TELEPATH initiative was page 21). investigating how we could automate many of the manual processes in the laboratory (see sidebar, “Telepathology How can we address the patent problem? Networking” on page 19). We concluded that digital imaging Patent problems are slowly being resolved. Various was something that needed developing as it could offer manufacturers were concerned about whether they could use pathologists the opportunity to perform a complete scan of technologies covered by DICOM because of patent concerns. a digital slide or scans of sets of slides. However, we couldn’t Leica, for example, is allowing DICOM certified companies recommend digital imaging without a standard. So, we set to use its technology, which is a step in the right direction. about collaborating with various international standardization I bought my first scanner about seven years ago, which organizations – DICOM, IHE and SNOMED CT – to used a specific file format and a specific viewer. Since
training or if they lack familiarity with the pathology for the EQA (External Quality the results of these trials will encourage system, for example). Assessment) scheme. The tipping point pathologists to accept that this is the future will come when the training norm will be of pathology. What is being done to address to use digital images and pathologists will However, clear guidelines on reporting the concerns? progress onto reporting from scans of their from a digital image and whether a routine cases. standard process is required to integrate MB: There is more exposure to digital There are a number of ongoing tests and the workflow are needed. The FDA, EU images these days, so greater familiarity trials to show side-by-side comparisons and others must provide leadership and with the technology is important. New between standard reporting and reporting discuss with slide scanning companies trainee pathologists, for example, are from a digital image. These tests look how to optimize the process so that taught how to work with digital images at what is limiting the uptake of digital pathologists can benefit fully from this from an early stage of their career; also, pathology – reporting time, image quality new technology. there is more interest and use of digital and the effect on workflow. We believe Collaborative Clout
What? AIDPATH – Academia and Industry Collaboration for Digital Pathology then I have used several different file formats that are not When? Established 2013 interchangeable. Really, you should be able to use any format; if I can see any slide through my microscope then the same Why? To exploit the new and emerging digital should be possible with viewing digitized images. So that’s pathology technologies effectively in order to process why we need technology companies to adopt a uniform and model all data. The initiative aims to help with standard, which should be possible now that patent problems developing efficient and innovative products to fulfil are being addressed. Standardized technology will enable the needs of digital pathology. Through training it will pathologists to scan images with the confidence that in 10 help professionals to develop novel image analysis years’ time they will be able to read those images without solutions for future pathology diagnosis and solutions any problems. for biomarker evaluation and quantification
Could you tell us about the technological hurdles? Who? Participants include universities across Spain, Five years ago, we were debating whether or not this the UK, Italy, Romania and Lithuania, the European technology would be quick enough and produce high quality Commission, as well as technology manufacturers, such images. We’ve proven that it does and that it is suitable for as AstraZeneca, Leica, Barco and Tissue Gnostics performing on-screen diagnoses. However, the lack of standardized technology and the difficulty in implementing How? AIDPATH participants engage in focused and using it needs to be addressed, if we expect to see wider research and training. Activities include networking, adoption. In addition, we need to be able to provide adequate workshops, summer schools and conferences standardized training to users. Scanning speed has reached a plateau and I doubt that it will get much faster before new technology emerges that captures the slide in one go. Feedback from the pathology community will play a big part in bringing forward the technological improvements we seek. The AIDPATH initiative, for example, is enabling us to What about file compatibility? work with industry to drive such improvements. We are able to As long as we have different technologies that use proprietary test new equipment and tell the manufacturers what they need file formats and specific viewing software, we will always have to change. Also, the industry is working with university groups compatibility problems. I don’t think we should compress to improve imaging algorithms. Any successful work will be images using proprietary file formats because we may need patented and distributed so that everyone will have access to to refer to them in the future. It’s so important that new standard algorithms. technologies take backwards compatibility into account.
PvR: Pathology is very demanding and OC: As an increasing number of The global trend towards big data, cloud- digitization can provide great benefits if institutions adopt digital pathology for based solutions, reduced costs for server implemented correctly. But we recognize routine diagnostics and second opinions space and storage, and improvements in that this differs per lab, so together with (outside the USA), there is documented data security are also helping to reduce the the pathologist we define a solution evidence of diagnostic equivalence with uncertainty felt by some institutions and that works for them – whether it be conventional light microscopy. Also, individuals around digital pathology. In workflow, IT, or finance, for example. more use of the technology is providing addition, the clearance of certain digital Providing the technology is half of the independent and true total-cost-of- pathology image analysis systems by service, the rest is provided in support ownership evaluations. In addition, the US Food and Drug Administration, to ensure that the right steps are taken improved connectivity coupled with combined with its adoption for primary towards effective digitization. improvements in system throughput diagnosis in Canada and Europe, is and performance provides a better user helping to increase overall confidence in, experience when reviewing digital slides. and exposure to, the technology. 22 Feature
Pathology Informatics Timeline
Early 1980s: US National Library of Medicine (NLM) 2000: Association sponsored informatics of Pathology Infor- 1962: College of fellowships become 1990s: Hospital matics receives its American Pathologists available (USA) Information charter (USA) 2003: First US establishes the first 1980s: Introduction Systems adopted FDA clearance computer education 1970 onwards: of computerized increasingly for quantitative programme for Laboratory tomography (Europe) image analysis of pathologists (USA) Information Systems technology results in Mid to late immunohistochemi- 1965: Systematized (LIS) in use in decrease in number of 1990s: Imple- cal cancer markers. HL7 creates a Early 1950s: Hans Nomenclature of clinical labs (USA) autopsies (Europe) mentation of genomics working Elias analyzes Pathology published 1976: SNOMED 1986: First calls PACS (picture group (USA) the structure of (USA) first edition for pathologists as archiving and 2005: DICOM cre- mammalian liver 1968: National published. First medical information communication ates Working Group using stereology Committee for Clinical online surgical specialists (USA) systems) and DI- 26 for Pathology (USA) (Europe) Laboratory Standards pathology system 1989: First book on COM standards 2009: Digital Pa- 1952: First founded. First system – Massachusetts pathology informatics (Europe) thology Association computers used in for remote pathologic General Hospital published (ABCs of 1996: First formed (USA) clinical labs (USA) diagnosis demonstrated (USA) LIS) (USA) virtual microscope (USA) system developed (USA)
1950's 1960's 1970's 1980's 1990's 2000's
Source: S. Park, et al., “The history of pathology informatics: a global perspective”, J. Pathol. Inform., 1(7), (2013).
Which innovations are most widely We believe that new research and which can be reduced by using digital adopted? Where is research and development will improve features such pathology. New algorithms are being development heading? as multi-level scanning of whole slides produced that can extract more to replicate the z-axis focus function of a information from a whole slide image or MB: We have found that there are a large microscope. Also, extended focus imaging multiple slides to provide more numerical number of pathologists who are willing will enable us to merge multilevel images data. These improvements should progress to use and diagnose from a digital image together so that a whole section is in patient diagnosis by reducing the number instead of a microscope, especially with focus at every point. This will take us to a of possible mistakes and decreasing the regard to cellular pathology. For instance, point where an image from a slide scanner time for a diagnosis. it is now possible to scan a section in under provides a new perspective that cannot be one minute and therefore we are moving achieved on a microscope. PvR: Now, pathologists can interact with on from simply accepting the ability to Current methods of evaluating slides a digital image in an intuitive way and scan and share a whole slide. lead to a degree of observer variation, they can collaborate with others using Feature 23
Are there any issues with LIS products? Yes. The LIS companies are not evolving their products quickly “The LIS companies are not enough to keep up with other areas of the market. Picture archiving and communication systems (PACS) and scanner evolving their products quickly companies are moving ahead but LIS vendors are trailing behind. It takes about five years to develop a LIS to ensure that enough to keep up with other a product is robust and reliable; the vendors need to speed up development. That said, I don’t think we need other companies areas of the market.” to get involved and flood the market with competing products – that’s not the way to go. We do try to involve LIS companies in AIDPATH by defining a project in which they can help. For example, seven What has changed since you began using digital pathology? years ago, we told the LIS vendors that they ought to produce We are now much more selective about scanning. We select web-based systems – at that time, there were no web-based cases that could be problematic, need quantitative analysis solutions in Spain. We have learned that vendors only tend to and image analysis to measure the width of infiltration of a respond when you ask them for something new; we need them melanoma, for example. We also use it for making second to be more proactive. opinions. This amounts to about 15 to 20 percent of my cases. Only when we reach the point that everything is standardized Do you think that digital technology integration is moving will I decide it is time to digitize everything. too slowly? On one hand, it is slower than I’d like it to be, but on the Despite the challenges, do you feel digital pathology has other, I think it is going as fast as the technology allows it to. benefitted your practice? For example, until about three years ago, scanners were slow Yes. I actually think my digital pathology images are becoming and there were too many out of focus areas in an image. That as popular as X-ray film! has changed, but scanners remain difficult to implement, The main benefit is that I am more confident with image the images are very large and a PACS struggles with storing analysis and measuring. For example, I can use it to measure everything we’d like to archive. Ki-67 protein levels or the size of melanomas. It also reduces Therefore, we need to get everything right with the the time my colleagues need to wait for a second opinion – I technology so that we aren’t worrying about it and so that we might get the request first thing, and I can email my assessment can concentrate on doing our jobs as pathologists. to them in the same morning. In addition, I am able to share my images with the other medical specialists in the hospital – I really feel this has made
this technology. However, innovation for different phenotypes and expression More recently, the use of automated in healthcare is not just about technical for high-throughput assessment has been image analysis in a clinical setting, such developments. New ways of working particularly popular in biomarker discovery. as a companion diagnostic HER2 assay, are helping to achieve improved Image sharing and collaboration for enables reproducible and objective health outcomes in a cost effective a variety of cases is another of the most stratification of patients into cohorts way. Digitization, therefore, provides widely recognized uses of the technology; of likely responses to drug therapies a backdrop for looking at new ways to this is validated by a number of studies and helps to eliminate inter- and intra- improve the patient experience. across a broad range of providers. The observer interpretation variability. technology is also enabling efficiencies With increased subspecialization of OC: Digital pathology emerged primarily in tumor boards, second opinions, and pathologists, the ability to engage with in the education sector. It was then adopted other applications requiring access to experts in a given field is greatly enhanced by researchers. Its ability to capture whole subspecialty expertise, which provides by digital pathology. This is helping with slide scans and automatically analyze them objectively verifiable ROI. difficult evaluations, streamlining access to 24 Feature
pathology more respected by other departments. You can see it in the faces of the dermatologist and hematologists, for “I think it will take longer example; they are impressed when you show them digital slides. They really appreciate being able to see whether their markers than 10 years to see digital are correctly excised in a tumor or whether morphological features in a leukemia case correspond with those in their own pathology fully embraced specimens, for example. Collaborating with other specialists is much easier with digital pathology. across Europe.” Where do you see your lab in 10 years? In 10 years’ time, I think I’ll be fully digital. That’s not to say I’ll What do you say to the cynics? be getting rid of my microscope! I’ll still need it, for example, All patients need the same opportunity and no one should to deal with polarized light or fluorescence, or to counter get in the way of progress. Doing it your own way may not be compatibility issues. the best way and, in the future, the best diagnosis will come with advances in digital pathology. You have to think of the What is the general attitude to digital pathology in Europe? patient and how to provide the best service and outcome I would say that the attitude is changing. Pathologists now for them. view digital pathology more positively. They see that the technology is much more accessible and affordable; however, References it needs to be easier to use and the pathology workflow it has 1. NHS England, National Pathology Programme, “Digital First: Clinical introduced needs simplifying. We’ve been working on some Transformation through Pathology Innovation” (2014) of these issues at the hospital and have completely remodeled http://www.england. our processes, which has improved our workflow and made it nhs.uk/wp-content/uploads/2014/02/pathol-dig-first.pdf easier to manage. 2. J. Webster, R. Dunstan, “Whole-Slide Imaging and Automated Image Analysis: Considerations and Opportunities in the Practice of Pathology”, And in the next decade? Vet. Pathol., 51(1), 211-23 (2014). doi:10.1177/0300985813503570 I think it will take longer than 10 years to see digital pathology 3. Insight Pharma Reports, “Digital Pathology Insights: Imaging Technologies, fully embraced across Europe. Pathologists in private labs may Expert Perspectives, Standardization, and Current Outlooks” (2014). not see the need, for example. However, I expect more hospitals 4. T. C. Allen, “Digital Pathology and Federalism”, Arch. Pathol .Lab. Med., to be using it. Also, as time passes, the pathology community 138(2), 162-5 (2014). will have access to the results of numerous validation studies, 5. I.C. Cucoranu, et al., “Digital pathology: A systematic evaluation of the which should encourage wider adoption. patent landscape”. J. Pathol. Inform. 5, 16 (2014).
the right experts, and ultimately improving helping us to appreciate how those image analysis will allow them to turnaround time for decision support genetic differences affect tissue we will provide responses rapidly and accurately, to the benefit of researchers, health care never truly understand disease. So, with especially with routine cases, which providers and patients. advances in personalized medicine will give more time for dealing with we believe that the workload and difficult cases. What is your prediction for the role of importance of pathologists will increase. the pathologist in the next 10 years; how Digital pathology will enable PvR: First, there will be an intensified will digital pathology affect the way pathologists and pathology departments collaboration between pathologists as they work? to become more efficient. The ability well as within cross-disciplinary teams. to view images from any location in This opens up new opportunities for MB: Although there has been significant the world will allow them to be more pathology labs, for example, to offer investment into genomic research flexible and to provide specialist or their expertise to regions beyond their in recent years, without pathologists second opinions quickly. In addition, current scope, where experienced or Digital Pathology Market European pathologists are the second largest users of digital pathology technology behind North America. Some European countries have witnessed successful pathology projects, which are likely to lead to higher adoption of digital pathology in these countries (1).
North America dominates the digital pathology market, key reasons include favorable reimbursement The Asian market, though it currently trails behind North America scenario in the USA and Europe in its use of digital pathology, is expected to experience the and the use of digital highest growth in the next five years. This is attributed to the rise in pathology to improve awareness of digital pathology and its benefits, collaborative efforts by the quality of cancer manufacturers, and federal health departments encouraging the use of diagnosis in Canada digital pathology to improve the quality of cancer diagnosis (1). (1).
1. Markets and Markets, “Digital Pathology Market by Slide Scanners (Whole Global Digital Slide Imaging), Analytics (Image Analysis Software), Delivery Modes (Web $2.2 billion ~ $4.5 billion Pathology Market Based/Cloud Based) & by Whole Slide Image Storage - Global Forecasts & in 2013 in 2018 Size (2) Trends to 2018”, (2014). www.marketsandmarkets.com 2. BCC Research, “Digital Pathology: Technologies and Global Market”, (2014). www.bccresearch.com
specialized pathologists are scarce. often separated from colleagues companion diagnostics, is driving the Second, the role of the pathologist in and laboratory facilities, so digital use of multiplexing several markers on a taking clinical decisions will increase pathology will help to improve single sample, which is best interpreted based on their central role in extracting efficiency in sharing slides and cases. using automated image analysis. more data from tissue. Digital pathology Also, the implementation of electronic In the end, digital pathology will will complement the increasing need health records is optimized by lead to greater efficiencies in laboratory to develop quantitative data sets to digital images. workflow, provide decision support tools, help develop predictive algorithms for In addition, early detection and and transform the interaction between personalizing cancer care. screening programs, combined with oncologists, pathologists and patients, minimally invasive biopsy and surgery, as well as researchers, instructors and OC: With the consolidation of often results in less tissue to analyze. students. In 10 years’ time, we predict healthcare resources, pathologists are This, coupled with the emergence of new that, digital pathology will be known working in distributed environments, biomarkers and increased trend towards simply as “pathology.” MASS SPECTROMETRY SOLUTIONS FOR IN VITRO DIAGNOSTICS
You’re not the only one who needs to trust the test results
ACCURACY THE FIRST TIME
Clinicians and patients count on the most reliable diagnostic answers. We want you to be confident that results are as timely and accurate as possible. SCIEX Diagnostics offers an in vitro diagnostics solution with exceptional assay performance that helps overcome the limitations of current testing methods. Our newly introduced assays for Vitamin D, Newborn Screening and Immunosuppressants accurately measure multiple analytes in a single run, and virtually eliminate the need for re-runs and send-outs. And not only are SCIEX Diagnostics solutions backed by over 25 years of leadership in mass spectrometry, they are surprisingly affordable, too.
Find out how SCIEX Diagnostics can help improve your accuracy, turnaround and confidence at www.sciexdiagnostics.com
Diagnostics
For In Vitro Diagnostic Use. Not available in all countries. © 2014 AB SCIEX. SCIEX is part of AB SCIEX. The trademarks mentioned herein are the property of AB Sciex Pte. Ltd., or their respective owners. AB SCIEX™ is being used under license. IVD-MKT-13-1360-A NextGen
Research advances New technologies Future practice
28-30 Human Proteome Maps – Two Perspectives With most of the proteome now mapped, information being unraveled could be crucial for medical research. So why is it under scrutiny?
31-32 Operating Within Molecular Margins Clinical mass spectrometry has the potential to transform surgical resection and histopathology procedures. 28 NextGen
Human Proteome Maps – Two Perspectives
Now more than 90 percent complete, this project could prove invaluable for medical research.
By Roisin McGuigan
The sequencing of the human genome represented a game changing moment for science, but it didn’t provide the whole story. The human proteome, which is still not fully explored, represents a wealth of information. Identifying which proteins are being expressed at a given time, in what tissues and in what volume, could provide completely new insights into disease conditions and aid drug discovery. It’s not hard to see why so many would with Bernhard Kuster, lead author of the see sidebar, “The Human Protein Atlas”], want to be involved in this important Munich team, about the progress of their our hope is to eventually provide as research challenge. research and the most important findings. broad coverage as possible of the human In May of this year, two teams published Michael Tress of the Spanish Cancer proteome,” says Kuster. drafts of the human proteome in Nature; Research Center queries the quality of the Clearly, the research efforts so far have researchers at Johns Hopkins University data and offers a counter opinion. generated huge amounts of data – data and the Technische Universität München which needs to be accessed and used by (TUM) (1, 2). The Pathologist spoke the scientific community at large. Both proteome maps are available online We’ve Come a Long (through the ProteomicsDB and Johns At a Glance Way Together Hopkins Human Protein Map) and • Two maps identifying over 90 percent application programming interface (API) of the human proteome were published In an interview with The Pathologist, access has been enabled for the TUM this year in Nature. Bernhard Kuster, whose team has so far database, which allows computers to “talk” • The information gathered from this cataloged over 18,000 proteins, explained the to the database. research could crucially support the next important steps for the mapping project. advancement of medical research, some “Non-coding” coding regions results are also surprising. “We have now joined forces with the One of the most interesting findings • Several groups are collaborating to Johns Hopkins team to take the research from Kuster’s work so far (mirrored by integrate all of the information one stage further. By compiling all of the findings of the Johns Hopkins group) available into online, free-to-access our data into one central source, the was the discovery that some regions of the databases. ProteomicsDB, and partnering with genome previously thought to be non- • Not everyone is convinced by the others, such as the Human Protein coding do actually code for protein. “This value of these projects, and question Atlas [a Swedish team that is working to is especially significant as it implies that their accuracy. develop antibodies against all proteins; we don’t yet fully understand which DNA NextGen 29
regions encode for proteins. I believe our the proteome is now mapped, the last 10 The Human findings are only the beginning; I suspect percent is still missing, and it may transpire we will find a lot more ‘non-coding’ regions that getting that last 10 percent turns out Protein Atlas that have functions we aren’t yet aware to be ten times harder than getting the first of. We do not yet know what biological 90! It is very difficult to say when, or if ever, • Established in 2003 significance these proteins will have, but we will be able to claim to have a complete • Set up by a Swedish team, headed uncovering their functions is an interesting map.” He admits the idea of a ‘complete by Mathias Uhlén future task for us,” explains Kuster. human proteome’ is rather a philosophical • Key aim is to generate an antibody one: “We have currently set out to find one against every human protein Missing proteins and our diminishing protein product per gene. But we all know • Information on over 21,000 sense of smell that a single gene can have many protein antibodies has been collected to On the flip side are the so called “missing” products, perhaps even hundreds or date, targeting proteins from proteins, that is, proteins thought to exist thousands. We are still very far away from more than 16,600 genes that weren’t found during the course of covering every variant of every protein. • Overall objective is to have a first the study. “There are several explanations Despite this, we have come a long way and version of the proteome by 2015, for this,” Kuster says, “the first is that we are learning more than ever before.” and a curated version by 2020 the current technology simply isn’t able to detect them. Another is that they Next steps are expressed in tissues we haven’t yet As well as continuing their current work looked at. The third, and possibly most on the human proteome, Kuster and his interesting, is the hypothesis of “obsolete” team also want to work with diseased the donation of data from fellow scientists. genes. During the course of our work, tissues (most of their data is currently One of the best aspects of the scientific we discovered that many olfactory G taken from healthy tissue) in order to gain community is the spirit of collaboration. protein-coupled receptors (GPCRs) were more information on protein expression Many people are willing to share their missing, and in much higher proportions in different contexts. They hope to begin discoveries to provide different pieces of in comparison to other protein families. similar efforts for the mouse (an important the puzzle, and by doing this we are able This pointed to the possibility that it was disease model), the rat (an important to do so much more than we could alone. more than a technical problem or a case toxicological model), other animal species, It is this emphasis on collaboration and of examining the wrong tissue type.” and plants (which could prove valuable for this willingness to freely share information Added to this theory is the work of other the food industry). that I find truly heartening in scientific geneticists who have proposed that many Working to map the human proteome research; without it, we wouldn’t be where olfactory GPCRs are no longer functional is important in and of itself, but Kuster we are today,” he concludes. (4). We also know that humans have lost a predicts that it will also help to progress lot of their sense of smell compared with clinical research and development by References other animals in which these proteins supporting the discovery of new molecular 1. M. S. Kim et al., “A Draft Map of the Human are active (dogs and truffle pigs being disease markers, or by tracking the Proteome”, Nature, 509, 575–81 (2014). two good examples). “Even though this progress of drug treatment. “There’s a clear 2. M. Wilhelm et al., “Mass-Spectrometry-Based finding may not have far reaching clinical translational aspect to our work, although Draft of the Human Proteome”, Nature, 509, implications, it is nonetheless extremely these developments will obviously arrive 582–87 (2014). interesting from a scientific perspective, further in the future,” he adds. 3. F. Ponten et al., “The Human Protein Atlas – a and will also help in the annotation of the Despite the volume of work ahead, Tool for Pathology”, J. Path., 216, 387-93 (2008). human genome,” adds Kuster. Kuster is happy with the progress made so 4. D. Pierron et al., “Current Relaxation of Selection far. “In terms of my hopes for this project, on the Human Genome: Tolerance of Deleterious The quest for 100 percent I’m pleased to say that we are already Mutations on Olfactory Receptors”, Mol. Phylo. It is clear that mapping over 90 percent of ahead of expectations, mainly because Evol., 66, 558-64 (2013). the proteome is a significant advancement of the excellent technology that we have for proteomics and biomedical research in at our disposal (and its ability to analyze Professor Bernhard Kuster is the chair of general, but Kuster believes there is still huge volumes of data), collaborations with proteomics and bioanalytics at the Technische some way to go: “While the majority of our academic partners, and also because of Universität München (TUM), Germany. 30 NextGen
reanalysis of the spectra from previously they analyzed a wide range of human A Word of Caution published large-scale experiments. tissues, rather than cell lines. It’s possible However, they did not provide the results that research groups carrying out tissue- By Michael Tress of their re-analyses, meaning we could specific experiments will use this data as a only analyze the CellZome data, which is gold standard, and even now will be writing When the two proteome maps appeared in 25 percent (roughly 4,500 peptides) of the proposals based on it. This concerns me Nature, the numbers certainly raised some Kuster data (although the CellZome data because I think, at best, this data will not eyebrows. My colleagues and I are part of alone identifies genes for 36 ORs). aid good scientific research. At worst, I the GENCODE consortium, which is suspect using this data could be a poor use annotating the human genome, so we are of time and resources. In situations like very interested in large-scale proteomics these, the onus is on the authors to provide information. We were also in the process “I think, at best, information that is as accurate as possible. of publishing our own analysis (1), and we Large-scale evidence for cross-tissue were surprised by what these papers were this data will not peptide expression would be a real step reporting. How had they managed to find forward for proteomics. However, the more protein products from genes than any aid good scientific information provided by these draft previous experiment of this kind, finding proteome maps cannot be used without several thousand more genes than the entire research.” first filtering out large amounts of possibly combined efforts of the worldwide human unreliable data. genome project, all without any kind of technological breakthrough? The Pandey group reported 17,296 Michael Tress is a staff scientist at the When we looked at our data, we noticed genes and the Kuster group over 18,000. Spanish Cancer Research Centre (CNIO), we had not identified any peptides for I personally believe that the Mann Group Madrid, Spain. olfactory receptors (ORs). Further, other (4, 5) identified as many if not more protein databases, such as PeptideAtlas and coding genes than the Pandey group Have an opinion on this topic? PRIDE-Q (2), which I consider to contain and Kuster’s CellZome experiments. Please feel free to join the debate, high quality data, also identified very few We carried out a comparable analysis of email [email protected] ORs. We therefore reasoned that a study these experiments at the same time as the which identifies multiple ORs (Pandey’s proteome map data, and after filtering References group found 108, Kuster’s 200) is likely to the peptides we found that the various 1. I. Ezkurdia et al., “Multiple Evidence Strands be unreliable. We decided to investigate. studies had identified 8,050 (Nagaraj et Suggest That There May Be As Few As We carried out a quality test on the ORs al), 8,929 (Geiger et al), 7,972 (Kuster 19,000 Human Protein-Coding Genes”, the groups had found, and this produced CellZome) and 7,458 (Pandey). This led Human. Mol. Genet. (2014) [Epub ahead some concerning results. For example, the us to conclude that the two proteome of print]. Pandey data shows that ORs are most maps contained questionable data. 2. J.A. Vizcaino et al., “The Proteomics Identifications highly expressed in the liver (3). For us, Our analysis identified many factors (PRIDE) Database and Associated Tools: Status this confirmed what we had suspected – which I think contributed to this data in 2013”, Nucleic Acids Res., 41 (D1), the data was not reliable. inflation: the inclusion of poor quality D1063-D1069 (2013). We carried out a reanalysis of the spectra, using a single peptide to identify 3. I. Ezkurdia et al., “Analyzing the First Drafts peptides detected in both experiments, multiple genes, confusion between leucine of the Human Proteome”, J. Prot. Res., 13, 3854- and found reliable evidence for between and isoleucine, the use of two search engines 55 (2014). 7,500 and 8,000 of the genes they to increase the peptide coverage rather than 4. T. Geiger et al., “Comparative Proteomic Analysis identified. The Pandey group’s data was to increase the reliability of the peptide of Eleven Common Cell Lines Reveals Ubiquitous entirely their own, published previously spectrum matches, and the combination but Varying Expression of most Proteins”, Mol. in the Journal of Proteomics Research. of multiple experiments (which ratchets up Cell. Prot., 11(3), 1-11 (2012) doi: 10.1074/mcp. The Kuster group carried out comparable false positive rates). Some of the problems M111.014050. experiments on a similar number of tissues we identified only affected one of the two 5. N. Nagaraj et al., “Deep Proteome and (using CellZome technology), but in their data sets and some affected both (3). Transcriptome Mapping of a Human Cancer Cell paper they also included results from a These two studies stand out because Line”, Mol. Syst. Biol., 7, 548 (2011). Operating Within Molecular Margins
Is the accurate identification of tumor types during surgery – in real-time – a realistic possibility or a pipe dream?
By Sandro Santagata and Nathalie Agar
Today, we still rely on a century-old technique – microscopic review of H&E stained frozen sections – to analyze tissue in an intraoperative setting. And while the value and diagnostic expertise provided by the pathologists who use such traditional techniques are unquestionable, knowledge is advancing around us. Despite progress in other fields, we lack advanced tools in pathology that allow us to quickly assess the molecular make-up of biopsy specimens during a tumor resection. Consequently, molecular information remains hidden in the tissue until later diagnostic evaluation with immunohistochemistry, genetic analyses or other molecular techniques. The ability to conduct molecular analysis during surgery would offer big advantages to pathologists from a cost and workflow perspective, but more importantly, it could have a life-saving impact on the patient.
At a Glance Stepping away from tradition DESI MS in action • Frozen section still remains the In the operating theatre, time is of the Desorption electrospray ionization cornerstone of intraoperative diagnostics. essence; there is a real need for creative (DESI) targets the tissue surface with • New tools, such as desorption new approaches that allow pathologists a stream of charged solvent droplets, electrospray ionization mass and surgeons to make diagnostic which extract molecules from the spectrometry (DESI MS) may decisions based on detailed molecular sample and introduce them into the provide ‘real-time’ diagnostic information. Using mass spectrometry mass spectrometer. An MS profile information during tumor resections. (MS), we have been able to rapidly is quickly acquired in a line scan or • Using DESI MS to define molecular detect molecules and distinguish tumor a more detailed two-dimensional margins of a tumor marks a new from normal tissue during surgical molecular image, a fact that extends paradigm in surgical thinking. procedures in real-time (1). its use to tissue sectioned on a slide. 32 NextGen
Corporate Backing Like many, we are encouraged by molecules, such as lipids and the early research with DESI and metabolites, with masses below Waters Corporation recently announced REIMS techniques. While still in 1,000 Daltons an exclusive agreement with US-based their conceptual stages of development, • It can acquire useful molecular instrument manufacturer Prosolia the technologies must continue to information in a matter of seconds. for DESI technology for clinical demonstrate application benefits to mass spectrometry applications ( June a range of diseased tissues in much It’s important to note that this 2014). One month later, it announced larger patient populations. There is two-dimensional molecular imaging its acquisition of rapid evaporative also ongoing development work to be approach allows us to validate MS ionization mass spectrometry (REIMS) completed to make the instruments data against the gold standard of technology from MediMass. Clearly, more feasible for routine surgical use in histopathology, which also offers real the company sees real potential in the terms of installation, maintenance and value in research. technology. Here, Jeff Mazzeo, Senior use. Lastly, regulatory strategies must be By using lipid profiles acquired Director, Health Science Business, discussed and agreed in order to develop by DESI MS, we have been able to Waters Division tells us why. solutions that can meet regulatory discriminate different types of brain requirements so that clinical trials can tumors (for example, meningioma from What promise have you seen so far with be performed. glioma), different gliomas subtypes use of ambient ionization mass spec (for example, astrocytoma from technology in surgical applications? The advantages for the surgeon and oligodendroglioma) and different grades During an operation to remove patient are obvious, but what do you think of tumor (for example, WHO grade II cancerous tissue, surgeons can be this would mean for the histopathologist? glioma from WHO grade IV glioma). unsure of exactly where the diseased Just as we believe that MS has the In our latest study, we used DESI MS to tissue ends and healthy tissue begins. potential to transform surgery, we detect a single metabolite that is generated The result is that healthy issue is also believe that imaging MS has the by gliomas with mutations in isocitrate sometimes excised, or worse, parts potential to transform histopathology. dehydrogenase (IDH) 1 and 2 genes (1), of a tumor are missed and a follow While more work is needed to correlate found in the high majority of low grade up operation must be scheduled to the results of MS investigations with gliomas. These mutated enzymes generate remove the remaining malignant traditional histopathology techniques, an oncometabolite – 2-hydroxyglutarate tissue. I believe the work conducted by objective chemical information will (2-HG) – which accumulates to high Santagata, Agar and team, as well as hopefully add to the understanding of levels in these gliomas and can be used to work by Zoltan Takats (1), have shown the morphology of tissue sections. trace tumor cells. that ambient ionization MS has the potential to one day transform surgical Reference DESI MS approach, step-by-step resection procedures. 1. J. Balog et al., “Intraoperative Tissue The full clinical protocol is described in Identification Using Rapid Evaporative our recent paper (1); however, we can Do you foresee any immediate challenges Ionization Mass Spectrometry”,Sci. Transl. summarize the DESI MS process in to more routine use of MS in this setting? Med., 5, 194ra93 (2013). three key steps: 1) Smear or touch prep from tissue on glass slide; 2) Place glass slide on the instrument; 3) Acquire data in single points analysis intraoperatively; The spatially resolved data can then be molecular information on the tissue (2D imaging in the lab). overlaid on top of a histology image at stake. We believe this approach has We have been able to reproducibly for validation of the methodology several advantages over traditional detect 2-HG in regions containing outside of the operating room, which molecular evaluation: tumor, but not in normal tissue or allows correlation of histology with regions of hemorrhage, which supports signatures (multiple peaks) or specific • It requires minimal to no sample the use of DESI MS in defining the single peaks that target one molecule. preparation, and can be performed margins of a tumor and, therefore, Intraoperatively, single point analyses in ambient air conditions guiding surgery. The high sensitivity are performed in seconds, providing • It can reliably measure small and specificity was exciting to see, “ As the expertise using these approaches increases, validation studies will be required to determine the elements of pathology practice that might be redundant and those where complementary information is added to existing modalities.” as was the ability to detect tumor of these technologies will require a cell concentration down to under 5 long period of rigorous testing and percent. We have validated our findings validation. As the expertise using using a complete DESI MS analysis these approaches increases, validation system installed in the Advanced studies will be required to determine Multimodality Image Guided Operating the elements of pathology practice (AMIGO) suite at the Brigham and that might be redundant and those Women’s Hospital (BWH) in Boston, where complementary information MA, USA (see Figure). is added to existing modalities. Mutations in IDH1 and IDH2 are Indeed, it seems likely that the new not only found in gliomas but also in intraoperative approaches being intrahepatic cholangiocarcinomas, developed by us and other groups Texere Publishing has acute myelogenous leukemias (AML) around the world will provide truly expertise in science, technology and chondrosarcomas, so we believe complementary tools – based on mass and medicine publishing and the detection of 2-HG or other spectrometry and other analytical marketing. Now you can tap metabolites with DESI MS could be tools – for the pathologists and useful in other clinical applications. surgeons of tomorrow. into our expertise to meet your Moreover, DESI MS could have communication needs. applications in the diagnosis of a Sandro Santagata is an assistant We offer customized print, digital, broad range of tumor types and could professor in pathology at Harvard audio and multimedia services that also provide a good alternative to Medical School and practices will enable you to engage with intraoperative MRIs – without the neuropathology at Brigham and customers, colleagues/employees, and associated high cost and disruption to Women’s Hospital and Children’s the wider public. standard operative workflows. Hospital, Boston, USA. Use our skills to help you to achieve Tools of the future? Nathalie Agar is the founding director your business goals. We hope that our work will pave the of the Surgical Molecular Imaging way for further development and Laboratory (SMIL) in the Department For more information contact clinical trial testing of metabolite of Neurosurgery at Brigham and Tracey Peers guided surgical approaches; we have Women’s Hospital, and an assistant [email protected] proof of principal studies underway professor of neurosurgery and of both in the area of brain tumors as radiology at Harvard Medical School. 01565 752883 well as for resection of breast cancer (our manuscript on this study will Reference soon by published in PNAS). These 1. S. Santagata et al., “Intraoperative MS are the first steps in what could be Mapping of an Onco-metabolite to Guide a revolution in the way we conduct Brain Tumor Surger”, Proc. Natl. Acad. Sci. surgery. Admittedly, implementation USA, 111 (30), 10906-07 (2014). Publishers of
Custom Pubishing third.indd 1 14/02/2014 10:41 5
In Practice
Staff training SOPs Checklists
Barcoding Accreditation LIMS
Specimen type and origin Sample Tracking processing Internal QC Labeling Sample handling & receipt Fixation Temperature requirements Labeling Micro- / macro- Timely? dissection In Practice 4 Continuous audit Validation Transport Cross time and Centrifugation There are many good reasons to subscribe and it’s free to you! temperature contamination Necessary? Cross contamination System Reason #1: Usefulness trials Cross Best practice Fluorometry Request Spectrophotometry contamination guidance for molecular PCR / NGS Labeling analysis Turnaround / Sanger, Automated / time? PCR Manual molecular pyrosequencing
pathology labs Quantification Temperature Appropriate The PathologistProcesses features: and key test? Storage considerations when Labeling • Informed discussion of emerging conducting a molecular Analytical technologies and techniques pathology test for cancer methods • Troubleshooting of real lab problems DNA / RNA patients. Errors introduced extraction • Profiles of the people driving the Responsibility % mutations at any stage along this to be tested for sector forward pathway is likely to impact • Business perspectives from those working Clarity of negatively on the overall results in the field Reporting process, and the outcome style & Single • Tips on training, lab management, could be an inaccurate result content best practice, career development gene assay / and a molecular pathology and budgeting. Panel testing report that fails to guide on the # samples Length most appropriate diagnosis or treatment for the patient. Conflictingdata # genestested to be
Appropriate Interpretation diagnosis / Relevant treatment for advice Reason patient Reason #1: Reason #2: Reason #3: Reason #5: Reason #6: #4: Personal Usefulness Credibility Style Relevance Community Development Molecular Accurately pathology interpreted report molecular Integrated pathology reporting report Subscribe free to the print, online, tablet and smartphone versions at www.thepathologist.com/subscribe
Patient Accurate identification molecular pathology report 5
In Practice
Staff training SOPs Checklists
Barcoding Accreditation LIMS
Specimen type and origin Sample Tracking processing Internal QC Labeling Sample handling & receipt Fixation Temperature requirements Labeling In Micro- / macro- Timely? dissection In Practice Practice 4 Continuous audit Validation Technologies and techniques Transport Cross time and Centrifugation Quality and Compliance temperature contamination Workflow Necessary? Cross contamination System trials Cross Best practice Fluorometry Request Spectrophotometry contamination guidance for molecular PCR / NGS Labeling analysis Turnaround / Sanger, Automated / time? PCR Manual molecular pyrosequencing pathology labs Quantification Temperature Appropriate Processes and key test? Storage considerations when Labeling conducting a molecular Analytical pathology test for cancer methods DNA / RNA patients. Errors introduced extraction Responsibility % mutations at any stage along this to be tested for pathway is likely to impact Clarity of negatively on the overall results Reporting process, and the outcome style & Single content could be an inaccurate result gene assay / and a molecular pathology Panel testing report that fails to guide on the # samples Length most appropriate diagnosis or treatment for the patient. Conflictingdata # genestested to be
36-39 Appropriate Interpretation Minimize Errors, Report diagnosis / with Accuracy Relevant With molecular testing growing in treatmentpatient for advice importance, it’s vital that standard procedures are followed.
Molecular 40-41 Accurately pathology Lab Turnaround Time Study Sets interpreted report Alarm Bells Ringing molecular Integrated Study of turnaround times reveals pathology reporting some startling statistics. So where report do we go from here?
Patient Accurate identification molecular pathology report 36 In Practice
The new drugs require new testing we must be clear about our responsibilities Minimize Errors, processes and have challenging at every stage of the molecular pathology requirements for both equipment and process – from requesting molecular Report with staff. Inevitably, pathology laboratories analysis to pre-analytical sample handling are faced with greater workloads, greater to nucleic acid extraction and analysis to Accuracy resource requirements, greater training the reporting of results. Furthermore, the needs – and greater room for error. requirements for the laboratories offering Best practice guidance to ensure Given the large number of processes those services need to be clearly outlined. that molecular pathology labs and people involved – from the The infographic on page 38 summarizes get the best possible result moment a molecular pathology report all of the individual steps (and key is first requested to its finalization – the considerations) involved in the molecular By Ian Cree importance of standardizing procedures pathology process, which are discussed in and implementing guidelines is obvious. more detail in the guidance (2). All steps Molecular pathology is growing at an Progress is certainly being made in (and factors or technologies related to astonishing rate. It’s an area of medicine this regard. For example, in the US, the them) share the risk that any deviation that continues to generate excitement, not College of American Pathologists (CAP) from standard operating procedures only amongst health care professionals, in collaboration with the International is likely to have a negative, knock-on but also the public. Rarely a week passes Association for the Study of Lung impact on the overall process, leading to by without an announcement from the Cancer and the Association for Molecular an inaccurate result. If this guidance is press about a medical ‘breakthrough’ and Pathology (AMP) have recently issued followed as a minimum precaution, we everyone appears to be sold on the merits guidance for laboratories operating lung believe the resulting molecular pathology and promise of personalized therapy. cancer molecular pathology services (1). report will not only be accurate, but it will Often, these breakthroughs are the result Recognizing the need to develop also provide the optimal treatment for the of molecular research and many targeted a more general guideline – or a best patient. With multiple stages and people drugs are now reaching the clinic. practice document – for laboratories involved, the catch is getting everyone on This is an exciting time for medical performing molecular pathology tests the same page. research, but what does it mean for in Europe, a large team made up of those involved in performing molecular pathologists, geneticists, scientists, Request or reflex pathology tests for cancer patients? industry representatives, oncologists, For those requesting a molecular quality assurance experts, and others, was pathology test, it’s very important to assembled from across Europe. We focused consider what type of test is needed; when At a Glance our initial efforts on developing a guideline the result is required and, perhaps most • Molecular testing is becoming an for those involved in performing tests for importantly, whether a test is needed at all. increasingly important part of the patients with cancer since the majority of Currently, not everyone who would benefit diagnosis of any patient with cancer. advances in personalized medicine have from a cancer test is getting one. There • The molecular pathology process been made in this therapy area. will always be workload and budgetary consists of many stages, each of which We are now one year on and have concerns within pathology, but these can can be a source of error. produced a consensus document (2), be better balanced through integration • A European, multidisciplinary team which has been recognized and is of molecular pathology with other has developed guidelines for supported by the European Society of departments. And while this is already laboratories that aim to minimize the Pathologists (ESP) and the UK Royal happening (there are improvements occurrence of errors and to facilitate an College of Pathologists (RCPath). across Europe), it is still very challenging. accurate report on which to base Our ultimate goal is to ensure that those cancer treatment. Beyond the obvious in need have access to testing. A standard • The SPE and RCPath are now The modern challenge to pathologists operating procedure that supports the recommending this guidance as best is to think beyond the diagnosis and multidisciplinary team (MDT) requesting practice to laboratories performing classification of a disease, and to produce process can help, but much comes down to molecular pathology tests for information that guides treatment more good communication between the clinic cancer patients. efficiently and accurately. To be effective, and the laboratory. In Practice 37
Another way of tackling the problem is convinces pathologists, but also – and Just the beginning to consider reflex testing. In other words, more importantly – helps gain backing Here, we have only touched on a small pathologists are made directly responsible from national health care regulators. number of points included within the for the molecular analysis request based on Aside from processes, one very overall guidance. The figure provides an a patient’s diagnosis and tissue availability. important aspect that is discussed overview of the critical considerations Given that more than 10 percent of throughout the guidance is the need for when conducting a molecular pathology patients with any particular diagnosis accreditation of laboratories in accordance test. The authors of the guidance certainly need molecular analysis, reflex testing has with the External Quality Assessment acknowledge that further guidance and great potential. For example, we routinely (EQA) scheme, which is applicable to standards can and should be developed do HER2 testing for all breast cancer, and all laboratories in Europe. It is extremely for each of the separate elements of the a similar approach to EGFR mutation important for laboratories offering process, but we’ve made a good start by testing in lung cancer can save time in molecular testing to participate. For those covering all of the core processes. deciding treatment in patients who are who do, I would advise that you look at the While the new guidance is specific for often very ill at diagnosis. There are many results of EQA schemes, and the mistakes cancer, there are many elements that are circumstances where a pathologist should made by others, which may help highlight applicable to other facets of molecular exercise his or her clinical judgment and areas where you might be introducing pathology. Our scientific understanding simply order the test. errors in your own lab. and technology are evolving all the time, For the laboratory, reflex testing has a lot Those laboratories who believe they can so we acknowledge that revisions will be to offer in terms of speeding up the process. perform molecular pathology tests without needed in the future. It is also financially attractive to hospitals the sort of oversight that accompanies Where next? Well, work is ongoing to in some instances, because it can reduce EQA participation are taking big risks and develop the guidance even further, and the number of MDT discussions and the should be aware of that fact. is currently focusing on internal quality number of outpatient appointments. It assessment. In the meantime, the ESP and does, however, need to be balanced against Clearing clinician confusion RCPath are disseminating the guidance as unnecessary testing in patients who do not With the high (and growing) number best practice for laboratories performing need further treatment. With that in mind, of processes involved in performing a molecular pathology tests for cancer the RCPath and ABPI (Association of the molecular test, it’s no surprise that the patients. Our ultimate goal is to support British Pharmaceutical Industry) are in final complex report can result in clinicians everyone working in molecular pathology the process of developing planning tools scratching their heads in puzzlement. We laboratories to provide the right diagnosis that should help departments decide when must aim to produce coherent reports and treatment for patients accurately and reflex testing might be beneficial. and accurate advice that guides treatment efficiently. If you share that goal, we hope in the clearest possible way. We have you will join us on the journey. Common blunders provided recommendations in this area, As you move along the pathway outlined but we will increasingly need to provide Ian Cree is the Yvonne Carter Professor of in the infographic on page 38, you will tools that will allow clinicians to easily and Pathology at Warwick Medical School, UK. all see potential problem areas. From accurately interpret and act upon reports. experience, the majority of issues that The US is making a lot of headway in this References lead to inaccurate results occur during the regard. The CAP Cancer Committee has 1. N. I. Lindeman et al., “Molecular Testing pre-analytical stage, starting as early as the launched 70 cancer protocols in total that Guideline for Selection of Lung Cancer Patients discussion about which biopsy to take. aim to standardize pathology reporting for EGFR and ALK Tyrosine Kinase Inhibitors: Thereafter, DNA or RNA extraction across a large range of cancers; these are Guideline from the College of American can often be prone to errors. Many people now an integral part of routine pathology Pathologists, International Association for the still use manual processes, but there are practice across the country. The RCPath Study of Lung Cancer, and Association for good automated systems available that and ICCR (International Collaboration Molecular Pathology”, Arch. Pathol. Lab. Med, help eliminate some errors and help to on Cancer Reporting) minimum datasets 137, 828-60 (2013). achieve better consistency of extraction. are another part of the solution, but much 2. I. A. Cree et al., “Guidance for Laboratories Analytical methods vary, and comparative depends on their implementation by Performing Molecular Pathology for Cancer studies of these are needed. Such studies the commercial providers of laboratory Patients”, J. Clin. Pathol. (2014) doi:10.1136/ can generate economic data that not only information systems. jclinpath-2014-202404. 38 In Practice
Best practice guidance for Continuous audit Validation Internal QC molecular pathology labs
Processes and key Timely? considerations when conducting a molecular pathology test for cancer patients. Errors introduced at any stage along this pathway are likely to impact Request Necessary? negatively on the overall molecular process, and the outcome analysis could be an inaccurate result and a molecular pathology report that fails to guide on the most appropriate diagnosis or Turnaround treatment for the patient. time? Appropriate test?
Appropriate diagnosis / Clarity of treatment for results patient Conflicting Reporting data style & Responsibility Length content
Accurately Relevant interpreted advice Interpretation molecular pathology report
Integrated reporting Molecular Accurate pathology molecular report pathology report Patient identification In Practice 39
Accreditation Staff training SOPs Checklists
LIMS Specimen Barcoding type and Labeling origin
Tracking Sample handling & receipt
Transport time and Fixation temperature requirements Sample processing
Micro- / macro- dissection Cross contamination PCR / Labeling NGS / Sanger, pyrosequencing Temperature
Spectrophotometry
Centrifugation Fluorometry
Cross Analytical contamination methods Quantification System PCR trials Automated / Manual Cross contamination % Mutations to Single be tested for gene assay / Panel testing DNA / RNA Labeling extraction Storage Temperature # Genes to be tested # Samples Labeling 40 In Practice
Lab Turnaround Time Study Sets Alarm Bells Ringing
Pathologists in high- throughput laboratories are working as fast as they can to return results as quickly as possible. But are clinicians actually looking at them?
By Enrique Rodríguez-Borja
In any fast paced pathology laboratory, turnaround time (TAT) of results is extremely important. As laboratory pathologists, we may imagine our clinical colleagues sitting anxiously in front of their computers waiting for our reports. But actually this often isn’t the case. Sometimes they don’t access our results for days. And in a few cases, they aren’t accessed at all.
Why is TAT important? clinicians – and various models are used in Spain (1). Some of the results were As pathologists, we’re consistently to assess our performance in this regard. surprising – and alarming. expected to work efficiently – so too are But total TAT (defined here as the time In many of today’s labs, the majority from the clinician requesting a test to of results from pathologists are “in the receiving and interpreting the results) is cloud”, so not only do we no longer At a Glance very rarely studied. Last year at our clinic print hard copies, but we can see when • Investigation into turnaround times we established a maximum TAT for our our results are accessed by clinicians. For (TAT) reveals alarming statistics – outpatient day hospitals. But even if my two months we collected two specific 27 percent of “priority requests” are not laboratory meets these standards and times concerning each request: the looked at for several days; seven percent validates results within this timeframe, time the results were made available on are not consulted at all. the information still needs to be accessed the intranet, and the time the results • TAT is no longer just a problem for by the clinician in order to be of any were first accessed by a clinician. We the laboratory, everyone involved in value to the patient. I know how efficient also established that the latest time for the process – from requesting and my lab is, but I was curious about my consulting results on the day in process taking a sample to consulting the result clinician colleagues. Could I find out (the time limit) would be 3 pm. – must take responsibility for efficiency. when my results were consulted? This Based on the advice of clinicians, we • Total TAT needs to be defined and motivated my investigation into post established a maximum TAT of two agreed by all clinical services. analytical TAT, in other words, how long hours for processing requests from our • Measuring total TAT will be a it takes for a clinician to access patient day hospitals. This means that from challenge and new methods must test results, once they left my lab at the receiving samples in the laboratory to be established. University of Valencia Hospital Clinic reporting basic biochemistry results on In Practice 41
our intranet, no more than two hours there is no system in place to do so; there As pathologists, we must be able to should elapse. are huge variations in lab workflows and prioritize our work. If all requests are there is no standardized method for equally urgent, then in reality, none of Good news, bad news measuring TAT. For example, TAT for them are deemed urgent. So clinicians Let’s start with the positive results our lab would usually only include the must make us aware of those requests from our study, which included 945 intra-laboratory tests or “pure analytical that are high priority. requests; the vast majority (73 percent) phase” part of the work, but why? Most But to be truly effective as a laboratory, of clinicians accessed our results the laboratory errors occur before and after we must agree with the rest of the day they became available, which is the lab testing (2), and these two phases may clinical services (such as clinicians and ideal scenario. However, one-fifth were also be responsible for up to 96 percent phlebotomists) a total TAT for the requests not accessed for between one and eight of total TAT (3,4). we receive. We must also define what we days (despite the results being available). mean by those TATs – what specific stages Surprisingly, 27 percent of the tests we in the process do they include? carried out were consulted late or not Once TATs are agreed and defined we at all (see Chart). It’s a shockingly high “No matter must continue to measure the degree of number, which implies that the initial compliance with them. requests were perhaps less crucial than how capable the clinicians initially thought. Were What needs to change? these results just unimportant from the your laboratory The information from our study start or had there been a failure to follow demonstrates the value of measuring up? After discussing this with them is, a failure to TATs. In this case it has also served to it seemed that they were largely made highlight a serious issue: the volume of because of oncological protocols attached communicate and requests that are not consulted. to treatments and “just in case” scenarios. As pathologists, we must always aim Finally, a small number of cases were establish standards to improve our TATs by lowering our consulted before the complete results delivery non-performance rate (found were available. This was our fault because with other clinical to be four percent in this particular our laboratory failed to provide the study). But, improvement has to come results within the two-hour timeframe, services will result in from both sides. Communication with but I was pleased to note that after clinicians is essential – our colleagues this initial enquiry by the clinician, full inefficient practices” must be aware of when our reports will results were made available fairly quickly be available in order to encourage them (between 13 minutes to an hour after the to consult results earlier. clinician initially accessed them), so the The majority of laboratory LIS could play an important role. We waiting time for results in these cases information systems (LIS) do not would recommend that LIS developers was not too long. measure total TAT (the time from implement a software function, which Our study turned up some interesting initial clinician request through to their allows us to measure TAT both during findings about what happens to our consultation of the results) or even the the time the specimen is in our laboratory, results once they’ve left the lab. But individual TATs for the pre and post but also before it arrives and after it using TAT as a measure of efficiency is analytical phases in the testing process. leaves, giving us important information not always straightforward. In effect, our laboratory is operating on the pre and post analytical stages. blind. How do we know exactly how This would result in much closer No measurement, no improvement much time has lapsed since the sample collaboration and transparency between “If you cannot measure it, you cannot was obtained to when it arrives in our various groups within the healthcare improve it”. Lord Kelvin’s quote laboratory? How do we define the time system. As an example, the phlebotomist perfectly illustrates the dilemma we are the sample is in the laboratory? Before could record the initial venipuncture currently facing in our pathology labs: or after centrifugation? And which step and collection of the sample, our how can we possibly improve TAT if we machine or device is recording the time? laboratory could then record arrival cannot measure it accurately? Currently, And how? and analysis of the sample, the time we 42 In Practice
Clinician consultation of picture and will not optimize delivery of a test result from initial request. The lab results in an fact is, no matter how capable your laboratory is, a failure to communicate outpatient hospital and establish standards with other clinical services will result in inefficient practices. To tackle the challenge 4% of results (39 requests) presented, a new method has to be were consulted before the created, established and controlled by time limit, but the results of results (61 requests) were never both laboratories, clinicians, and other 7% weren’t yet available. Results looked at, as of 31 December 2013 health professionals working in close were made available between (6 months after the initial request). collaboration. 13-66 mins after If we have no information on TATs rst attempted at all phases of the testing process, we access. 20% of results (191 requests) can’t detect inefficiencies and potential were looked at after the time drawbacks, making it very difficult limit. Results were accessed anywhere between 1 and to introduce strategies to improve. If 8 days after being my laboratory is analyzing samples made available. it receives at lightning speed but the samples arrive very slowly or doctors consult my results very late, then what am I actually achieving? Total TAT is a crucial, bottom-line measurement of the efficiency of all the 69% of results (645 requests) were looked at before the time services involved in testing a patient limit (3 pm on the day in process) – the ideal situation. Results were and one which deserves much more consulted between 30 minutes to two hours after being made available. scrutiny as we strive to continually streamline and improve our services.
Enrique Rodríguez-Borja is a pathologist in charge of the pre analytical and LIS department at the University of Valencia validate it and make it accessible to the are not. We’ve also urged them to Hospital Clinic, Spain. clinician. Finally, the time the clinician consult available results earlier since we accesses the result could be recorded, have demonstrated that our lab meets References giving us a full and clear picture of the its TAT targets 96 percent of the time. 1. E. Rodríguez-Borja et al., “Enquiry Time as Part sample’s journey from the moment it of Turnaround Time: When do our Clinicians was taken. Ideally, all of these times Think outside of your lab Really Consult our Results?”, J. Clin. Pathol., 67, would be monitored by software, using The most important thing we have 642-4 (2014) doi:10.1136/jclinpath-2013-202102 a completely computerized physician learned from our study is that 2. M. Plebani, “The Detection and Prevention of order entry system. improving TAT is no longer just a Errors in Laboratory Medicine”, Ann. Clin. Pathologists, clinicians and patients “laboratory problem”. The time it takes Biochem., 47(2), 101-10 (2010). would all see benefits if our processes to obtain a sample, the length of its 3. P. G. Manor, “Turnaround Times in the are optimized. In our case, these results journey to your laboratory, the hour at Laboratory: a Review of the Literature”, Clin. have led us to implement several which the clinician consults your report Lab. Sci., 12, 85-9 (1999). improvement measures. Importantly, – all of these things have an impact 4. J. I. Rollo, B. A. Fauser, “Computers in Total we have encouraged clinicians to on your efficiency and your workflow. Quality Management. Statistical Process Control consider which of their requests are To focus simply on speed within the to Expedite Stats”, Arch. Pathol. Lab. Med., 117, really in need of prioritizing, and which laboratory does not provide the full 900-5 (1993). $25,000 prize
Recognizing Altruism and Innovation in the Analytical Sciences
HUMANITY IN SCIENCE AWARD October 12-16, 2014 Hyatt at Olive 8 Seattle, WA
CE in the Biotechnology & Pharmaceutical Industries 16th Symposium on the Practical Applications for the Analysis of Proteins, Nucleotides and Small Molecules
Abstract Submission Deadline July 18, 2014 for oral presentation September 12, 2014 for poster presentation
Symposium Co-chairs: Tim Blanc, ImClone Systems, a wholly-owned subsidiary of Eli Lilly & Company Oscar Salas-Solano, Seattle Genetics, Inc.
SCAN to browse CASSS for program updates at casss.org Profession
Your career Your business Your life
46-49 Where is the Next Generation of Pathologists? With fewer students choosing to study pathology, could the future of this vital field be a bleak one? RCPath President Elect Suzy Lishman discusses the importance of education and public awareness initiatives. 46 Profession
But that‘s easier said than done. affects the patient and how they can Where is the Television programs, such as CSI and care for them,” she says. Right now, she Quincy, M.E., have led to the public thinks a lot of work is needed to boost Next Generation thinking that pathology is solely about the understanding of the importance of performing complicated analyses to pathology, but first and foremost, actually of Pathologists? help cops catch criminals. For most getting students to recognize it as an pathologists, this couldn’t be further independent subject is even a challenge. Inadequacy of course from the truth. This misapprehension is Lishman believes the demise of content, lack of awareness, causing problems for the profession, and the hospital autopsy hasn’t helped. poor perception, changing it needs to be tackled in two key ways. “The number of consented autopsies healthcare priorities – it’s The first: pathology’s profile in general performed in the UK has plummeted no wonder pathology is needs to be raised – we need to show in recent years. This, I believe, is a struggling to attract new that it goes well beyond the autopsy slab global phenomenon and means that talent. Can the UK’s Royal and a quizzical detective. The second: the students don’t have the opportunity College of Pathologists help way that pathology teaching is delivered to see autopsies on patients for whom buck the trend? needs to be improved in a way that they’ve cared so they don’t have the reflects the true value of the field. With chance to see how valuable they can be,” By Fedra Pavlou medical students being under increasing she says. Although she believes that pressure to learn non-clinical skills, such medical students have a huge appetite You’re a pathologist. Obviously something as communication and leadership, the for pathology, with other subjects happened during your academic studies teaching of other disciplines is being competing for crucial curriculum that made you think: I’d like to get squeezed. Pathology, sadly, is one of those. airtime, something’s got to give. involved in that! Now that you work in Having spoken with many pathologists the profession, you understand the crucial Returning to form around this subject recently, it’s apparent role that pathology plays in supporting “I do think there’s a lack of knowledge that the issues described by Lishman high standards in patient care and in and understanding about the range of extend into Europe and beyond. In the advancement of scientific research. career options in pathology. Students fact, a Canadian research team felt So why aren’t more medical students don’t have the sort of exposure that they compelled to look into the factors that choosing the profession of pathology? do to other specialties and therefore it lead to a career choice in pathology, Certainly, numbers are dwindling, and means they often don’t consider it as a citing manpower shortage as their given that a large portion of pathologists career choice,” admits Suzy Lishman, reason for conducting the study (2). are nearing retirement age (1), it’s now Royal College of Pathologists’ (RCPath) While they highlighted the importance more important than ever to reinvigorate President Elect. of good course content and access to interest in this field of medicine. Reflecting on her experience in the pathologists as key factors to attract UK, Lishman believes the move away students to the profession, also made from solid blocks of didactic pathology some interesting observations around At a Glance teaching, and towards its integration the influence of rumors and negative • Fewer medical students are choosing into a systems-based approach is not perception amongst students. Hearsay, pathology today. helping. “It’s great for putting the perception and stereotype were actually • Course content must provide more patient at the center of care, which is three of the six key factors that they extensive coverage of pathology if its where they should be. But it’s not so found influenced career choice (see “Six value is to be recognized. good for students learning the basic Factors Influencing the Career Choice • Ever-expanding curricula, economic science that underpins diagnosis and of Pathology”). Raising awareness of pressures and healthcare reforms are treatment,” she explains. “I believe pathology more generally, ensuring negatively impacting pathology teaching. we’ve possibly gone too far in the wrong good course content, but also providing • Profile-raising public awareness direction. We need to bring it back. students with access to pathologists, initiatives demonstrate the value, Students need a basic understanding should improve the appeal of the and increase the attractiveness, of pathology, physiology, anatomy, etc., profession. In other words it all starts of the profession. before they can understand how disease with education. Profession 47
Figure 1: Suzy Lishman performing a “virtual autopsy”.
the undergraduate medical student of pathology or helping to deliver events curriculum, to ensure that every student for schools or the public. “Training doctors of has a basic grounding in the science of However, one potentially huge hurdle pathology, irrespective of where they to progression is the planned overhaul the future who are study. The second was to introduce an to the way in which junior doctors undergraduate membership category are trained in the UK. The emphasis fit to practice and of the College, encouraging students is being firmly placed on flexibility, to learn more about the specialty by with doctors becoming generalists for understand and value providing careers advice, talks, bursaries, several years after qualification, before competitions and awards. Increased deciding on a specialism. The main pathology is one of our collaboration with other medical and reason? To make a much larger resource pathological societies formed the third pool available to over-stretched accident biggest challenges.” step, particularly with the introduction & emergency departments. “It could this year of the Pathology Summer go one way or the other; this overhaul School, attended by 80 students from could encourage more people to come around the UK. Finally, the College into pathology because we have well- Overhaul obstacles encourages medical students to get developed curricula and clear career In the UK, the RCPath is taking an active involved in its public engagement paths that are attractive to trainees. Or role in tackling these issues. The first program – either attending an event it may put people off because they’ll step is working towards standardizing aimed at increasing their understanding think it’s too general and takes too long 48 Profession
Six Factors Influencing the Career Choice of Pathology
1 Medical students’ perceptions (accurate and inaccurate) regarding the role of pathologists in medical care
2 The oler of the course as a career choice. The course was most important in medical student and pathologist group. Non- content related factors such as teaching style or personality more important than content for 5 The influences of clinical medical students. experience and role models. generation of pathologists, but it’s crucial All groups agreed that these in raising the profile of the profession 3 Lifestyle of students, residents and were important influences, both in more generally – the work you do affects pathologists. Most prominent discovering or confirming everyone. As pathology services continue factor in the resident group. pathology as a career as well as to be financially squeezed, a positive (but a excluding other specialty choices. realistic) public profile helps. 4 The influence of rumor among In the UK, the I Love Pathology brand medical students. Students 6 Overcoming the negative and website, and National Pathology expressed that many career stereotype of the pathologist. Week are making some real headway. decisions were based on Negative stereotype known to even First launched by Lishman in 2008, class rumors. junior medical students. National Pathology Week is a unique initiative that aims to build the profile of Source: T. Hung et al., “Residency Choices by Graduating Medical Students: pathology amongst the public through Why Not Pathology?”, Hum. Pathol., 42, 802-7 (2011). simultaneously-run events across the UK. “The original plan for the first National Pathology Week in 2008 was for 40 events to be held around the country where pathologists would either go out into – if you do three or five years of general Depending on the outcome of planned communities and hold events, or invite medical training, you’re probably not overhauls, they may need to revise the the public into their labs. In the end, 320 going to want to do another five years curricula for every one of those 19; no events actually took place – which is far of pathology training. So I think the enviable task. Lishman acknowledges that more than we expected!” says Lishman. reconfiguration of training is probably “training doctors of the future who are National Pathology Week takes place going to be one of the factors that fit to practice and understand and value in the first week of November and the determines how pathology evolves over pathology is one of our biggest challenges.” number of events is growing year on year. the next decade,” says Lishman. The I Love Pathology website was born The RCPath’s work on postgraduate I love pathology out of the annual initiative and is the curricula is particularly important; over A second key challenge is raising awareness RCPath’s year-round public engagement 50 different exams are already developed of the value of pathology. Not only is program. It hosts information about for the 19 pathology subspecialties. this important for attracting the next past events and provides educational Profession 49
autopsy” (Figure 1) is by far the most Certainly, National Pathology Week has “It’s no good popular event amongst attendees. “It’s been great for encouraging pathologists to important to remind people that the step outside of their labs and to get closer doing all the hard majority of the work that pathologists to the public that they serve. This needs do is with, or for, the living, but this to happen more often. Pathology is at the work and then event has always been the most well- forefront of the molecular revolution that received. I’ve given it many times now, is transforming the way that diseases are letting somebody to rooms of 30 to 500, aged from eight diagnosed and treated; indeed there are to 80 years, and at venues ranging from very few news stories about innovations else make the medical institutions and schools to in medicine today that aren’t underpinned music and arts festivals. I always get the by pathology. But how many people are announcement; we same level of enthusiasm,” she says. Now aware of that fact? pathologists up and down the country “It’s no good doing all the hard work need to be out there are perfecting their own virtual autopsy and then letting somebody else make events. Not only have these sessions the announcement; we need to be out communicating it been important in raising the profile of there communicating it to the public pathology, but they’ve also educated the and to policy makers so that they value to the public and public on the dignified and respectful pathology,” concludes Lishman. way in which autopsies are performed. The exceptional achievements already to policy makers “One of the things I’ve been made by pathologists can only be built particularly keen to highlight is the upon if a healthy pipeline of new talent so that they value cross over between arts and science and can be secured – and that means attracting to work with less traditional audiences,” government and public support for your pathology.” explains Lishman. One such event endeavors. Admittedly, it’s not going to focused on the heart, where attendees be easy. Hurdles will continue to present were invited to view striking images of themselves, but by working together, we and branded materials, the aim being the organ and to admire its beauty and can make a difference. Promoting the to allow pathologists to select a tried symmetry. “When you step back, you amazing work that you do, for example, and tested off-the-shelf event that see that pathology really is beautiful,” by giving talks to students at your old they can just deliver. “One of the most reflects Lishman. University department or by speaking heartening statistics we gained from This year sees the very first with the press, will help make your vital feedback was that over half of the people International Pathology Day on field more attractive to everyone. You’re who have attended National Pathology Wednesday, November 5th. Working shaping the future of medicine – why not Week events had never attended any with more than 40 international shout about it? sort of science related event in the past,” organizations, the aim will be to raise remarks Lishman. the profile of pathology on a global References And it’s not just the public who have scale. “We’re hoping that there will be 1. T. Hung et al., “Residency Choices by benefited. “The initiative has a real feel- hundreds of events happening all around Graduating Medical Students: Why Not good factor. Many event organizers have the world on that day, all focusing on Pathology?”, Hum. Pathol., 42, 802-7 (2011). said that it has been great for teamwork pathology,” says Lishman. 2. S. Raphael, L. Lingard, “Choosing Pathology: A in their departments. It has also allowed Qualitative Analysis of the Changing Factors them to get together with different Communication is key Affecting Medical Career Choice”, J. Intl. Assoc. disciplines with whom they rarely speak. These initiatives have so far proven to Med. Sci. Edu., 15, 81-91 (2005). Some said that it has reignited their be a hit in the UK; given their relative passion for the subject because teaching infancy, the overall impact on the future If you’d like to tell us about awareness- it, or communicating it to members of of pathology remains to be seen. It will building initiatives that you’re involved the public, reminded them of exactly why certainly be interesting to see how the in, or give us your thoughts on the issues they liked it in the first place,” she says. international community responds once discussed in this article, I’d love to hear from According to Lishman, the “virtual events are rolled out globally. you: [email protected] Always Pushing the Boundaries Sitting Down With… Stephen Minger, Chief Scientist, Cellular Sciences – Life Sciences, GE Healthcare, London, UK Sitting Down With 51
What initially attracted you to at UCSD where we developed some of the neuropathology? first fetal-derived neural stem cells during “We lobbied I got interested in the human brain the 1990s. When I moved to the UK from in the 1980s working at a leading the US I brought that technology with me parliament, overcame diagnostic neuroepilpsy clinic at the to Guys Hospital, London. University of Minnesota – I thought When I started my lab in London, slammed doors, and it possessed tremendous complexity, I planned to use human stem cells to but its susceptibility to diseases such as develop therapies for brain diseases. It was one day in 2002 I Alzheimer’s disease (AD) also fascinated a frustrating process; I could make the cells me. A fantastic talk by Peter Davies inspired I wanted, but very quickly I’d lose them, heard the lead story me further, and he actually ended up being because they’d change state. That’s why my PhD mentor at Albert Einstein College neural transplantation never really took on BBC Radio 4” of Medicine in New York. Everything I off. And then – boom – human embryonic know about neuroscience I learned there. It stem cells arrive. was an amazing place. top of the list, but they’re actually more like And that was your next tricky step… five to ten years away. You’re disappointed with lack of progress Right. What started out as an email to My CEO, John Dineen, is not your in AD. Why? Peter Braude – board member of the typical CEO of a Fortune 500 company. Significant advances have been made Human Fertilization and Embryology He’s a visionary. I was on the phone with in the diagnosis of AD. But, if you look Authority (HFEA) and Head of the him recently and he said, “Any company at the therapeutic advances, they still Assisted Conception Unit at Guys – led can make stuff that makes money, we’re unfortunately amount to very little. Thirty to the creation of a small group at Kings making stuff that changes the world”. years on from starting my PhD there’s College London that consisted of me, Peter, not a single drug on the market that does and Susan Pickering. We had one goal: to Are you still following AD? anything to really impact on the disease. produce human embryonic stem cells. We Yes. I read an interesting paper the other There are some medicines that can help lobbied parliament, overcame slammed day. Researchers are tracking thousands slow it down or help with symptoms, but doors, and one day in 2002 I heard the lead of patients who are double ApoE4 these only work on a subset of people and story on BBC Radio 4: the HFEA had positive; apparently, these people have only provide some benefit. granted the first license in the world for a roughly 80% chance of developing Back in 1990, my then boss said to me, human embryonic stem cell research. We AD, independently of other amyloid “Once you get AD, it’s all over. You need did it! That was a really seminal event in my mutations. Why haven’t others been doing to understand what happens 50 years life. It categorically changed everything. this? We’ve known about the ApoE4 gene before it gets to that.” He was absolutely for 20 years! I’m going to follow up on it. right. Looking at postmortem tissue from What tempted you to join GE? people with AD tells you very little. Disease At that time they were exploring some Do you ever regret moving away susceptibility and factors that impact AD pretty cool areas related to stem cells. I’d from academia? development happened long before you see never linked GE with cells or cell therapy, When I washed up in the UK in 1996 I the clinical features. I felt really despondent but they think way out of the box. And had nothing. When I got my own lab, it and thought, “I’m in a dead-end field – how I’m not a conventional scientist; I push was pretty much empty, aside from a rusty am I going to make an impact?” boundaries. So when GE asked me to water bath. But things turned around for join them, I was astonished. The first time me and though I loved academia, I would What ignited your interest in stem cells? I met my manager, he said, “You’re the never go back. I never thought I’d work for I read a study by a Swedish group who, kind of guy that’s going to keep me awake a big company, I always thought I would in the 1980s, transplanted human fetal at night.” have to give things up, but that’s not true. In tissue into the brain of Parkinson’s patients I’m now responsible for what we call fact, I’ve accomplished more in the last five – their long-term clinical recovery was “blue skies”, a tactic that explores where years than in the last 20. I receive comments phenomenal. I thought that was very we might want to be in 20 years. It could from people who think I’ve “sold out”, but cool! But would it work in AD? So I did be tissue printing, nano-neural prosthetics, what we do makes a huge impact. So, I’d a post-doc in a neural transplantation lab microbiomic diagnostics, which are at the unabashedly say, “No, I haven’t.” The Pathology Company
Aperio ePathology – Leading the way in Digital Pathology
We know your work changes lives. Aperio ePathology offers world-class solutions for creating and working with digital slides, allowing you to consult, collaborate and analyze with ease. Our fl exible scanning and software platforms provide tailored applications for clinical, pharmaceutical and research professionals, scalable to grow with your needs, and designed with data security to the forefront.
With over a decade of experience in digital pathology, and an in-depth understanding of the histopathology laboratory workfl ow, Leica Biosystems Aperio ePathology solutions put digital pathology into practice. www2.LeicaBiosystems.com/Aperio
Certain products are FDA-cleared and labeled for specifi c clinical applications. Unless otherwise labeled, all other products are intended to be made commercially available “For Research Use Only. Not for use in diagnostic procedures.” Copyright Notice: © 2001 - 2014 Aperio. All Rights Reserved. LEICA and the Leica logo are registered trademarks of Leica Microsystems IR GmbH. Aperio is a registered trademark of Leica Biosystems Imaging, Inc. in the USA and other countries. IMC 3021-REV-A. 95.12625 REV A