When Pathology Turns Predatory

FEBRUARY 2019 # 51

Officialsociety partner of The Pathologist

Upfront In My View In Practice NextGen Better diagnosis How consolidation Color calibration for Spatial arrangements of Kaposi’s sarcoma helps laboratories slide scanners of immune cells

08 12 – 13 30 – 33 36 – 39

When Pathology Turns Predatory

… and how you can avoid becoming a victim

18 – 27

www.thepathologist.com Redefining Reference Standards www.horizondiscovery.com Case of the Month

A 49-year-old man presented with a testicular mass.

Based on your diagnosis, which of the following histologic findings incurs a worse prognosis?

a Anaplastic change b Anaplastic change and sarcomatous change

c Sarcomatous change

d Germ cell neoplasia in situ

Answer to last issue’s Case of the Month… B. Osseous choristoma Osseous choristoma, a well-circumscribed mass of viable lamellar bone surrounded by fibrous connective tissue, may occur as a sessile or pedunculated mass mostly on the posterior dorsum of the tongue, near the foramen cecum (1,2). Most develop in females in the second or third decade, and the treatment of choice is surgical excision.

References 1. BR Adhikari et al., “Osseous choristoma of the tongue: two case reports”, J Med Case Rep, 17 (2016). PMID: 26983573. 2. E Calonje et al., McKee’s Pathology of the Skin, 4th edition. Redefining Saunders: 2012. Submitted by Joana dos Santos, Anatomical Pathology Resident, Unidade Local de Saúde de Matosinhos, Hospital Reference Standards Pedro Hispano, Matosinhos, Portugal. www.horizondiscovery.com

To register your guess, please go to http://tp.txp.to/0219/case-of-the-month We will reveal the answer in next month’s issue!

www.thepathologist.com Contents

09 In My View

12 Using her own experience as an example, Bamidele Farinre emphasizes the benefits of 03 Case of the Month Upfront consolidation.

08 One TINY Step at a Time 13 A aron Schieving discusses the 07 Editorial dangers of prion contamination It’s a Dog-Eat-Dog 09 MDLUX2: Drawing a and how laboratory medicine World, by Michael Schubert Fuller Picture professionals can avoid it.

10 Monitoring the Microbiome

On The Cover 11 S teps Forward in From the ASCP Cancer Screening Like a shark after a swimmer, 15 Ac hieving Excellence Requires predatory groups pursue a Multifaceted Approach pathologists for profit To advance laboratory science and medicine, we need flexibility, innovation, and open-mindedness. ISSUE 51 – FEBRUARY 2019

Editor - Michael Schubert [email protected] Assistant Editor - Luke Turner [email protected] Content Director - Rich Whitworth [email protected] Publisher - Lee Noyes [email protected] Business Development Manager - Sally Loftus [email protected] Business Development Executive, America- Danny Crowe [email protected] Head of Design - Marc Bird [email protected]

Designer - Hannah Ennis [email protected] Junior Designer - Charlotte Brittain [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley [email protected] Audience Insight Manager & Data Protection Officer- Tracey Nicholls 50 NextGen [email protected] Traffic & Audience Database Coordinator - Hayley Atiz 36 W atch This Space! [email protected] Some lung cancers rapidly Project Manager - Webinars - Lindsey Vickers recur, whereas others never do. [email protected] Traffic Manager - Jody Fryett Report A new approach uses tumor- [email protected] infiltrating lymphocytes’ Traffic Assistant - Dan Marr 16 B uilding a Better Biopsy spatial arrangements to predict [email protected] Events Manager - Alice Daniels-Wright Using cfDNA synthetic plasma recurrence risk. [email protected] reference standards to improve Event Coordinator - Jessica Lines liquid biopsy. [email protected] Marketing Manager - Katy Pearson [email protected] Profession Social Media Manager - Joey Relton [email protected] Marketing Executive - Sarah Botha Feature 42 Lessons Learned, [email protected] with Andrew Feinberg Financial Controller - Phil Dale [email protected] 18 When Pathology We learn from one of the leaders Accounts Assistant - Kerri Benson Turns Predator y paving the way to a greater [email protected] Is our “publish (and present) understanding of epigenetics – Chief Executive Officer - Andy Davies [email protected] or perish” mindset causing what we can do, what we have Chief Operating Officer - Tracey Peers pathologists and laboratory yet to learn, and what we may [email protected] medicine professionals worldwide one day be able to do. Senior Vice President (North America) - Fedra Pavlou [email protected] to fall victim to predatory Change of address/ General enquiries journals and conferences? [email protected] Hayley Atiz, The Pathologist,Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK Sitting Down With www.texerepublishing.com +44 (0) 1565 745200 [email protected]

In Practice 50 Benjamin Garcia, Presidential Distribution: The Pathologist (ISSN 2055-8228), Professor of Biochemistry is published monthly by Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, 30 A Call for Color Calibration and Biophysics and Director WA16 8GS, UK Single copy sales £15 (plus postage, cost available on request Histopathology is increasingly of Quantitative Proteomics, [email protected]) Non-qualified annual subscription cost is moving toward digital imaging, Perelman School of Medicine, £110 plus postage

but Richard Salmon warns University of Pennsylvania, Reprints & Permissions – [email protected] The opinions presented within this publication are those of the authors and do users to make sure colors are Philadelphia, USA. not reflect the opinions of The Pathologist or its publishers, Texere Publishing. Authors are required to disclose any relevant financial arrangements, accurately represented. which are presented at the end of each article, where relevant. © 2018 Texere Publishing Limited. All rights reserved. Reproduction in whole or in parts is prohibited. Xpert® Breast Cancer STRAT4

one thing I can do…

deliver clear and objective molecular + test results in less than 2 hours.

Xpert Breast Cancer STRAT4 paves the way for standardized, fast, and reliable ER/PGR/HER2/Ki-67 mRNA assessment. Used in conjunction with GeneXpert® technology, Xpert Breast Cancer STRAT4 simplifies breast cancer biomarker assessment through semi-automated sample preparation, automated RNA isolation, reverse transcription, and amplification by real-time PCR and detection. The entire process happens within a patented cartridge-based system. Xpert Breast Cancer STRAT4: • Enables flexibility, simplicity, and random access for a streamlined workflow 24/7 • Offers a more objective solution compared to conventional IHC and FISH testing • Unequivocal and easy to interpret results • Delivers excellent concordance with recognized standards Visit http://info.cepheid.com/xpert-strat4 to learn more about Xpert Breast Cancer STRAT4 and Cepheid’s oncology products.

CE-IVD. In Vitro Diagnostic Medical Device. Not available in all countries. Not available in the United States.

Vira Solelh | Maurens-Scopont 81470, France | PHONE +33 563 82 53 00 | FAX +33 563 82 53 01 It’s a Dog-Eat-Dog World Editorial Xpert® Does the “publish or perish” mindset create a space Breast Cancer STRAT4 for predators to flourish?

one thing I can do… was recently invited to be a keynote speaker at a diagnostics conference. Shortly before that, I received an invitation to submit my thesis (or any other manuscripts II’d written since) to a prestigious science and medical publisher. And before that, I was asked if I would like to participate as an invited speaker at an ophthalmology-themed event. It seems my career as a leading scientist is taking off – or is it? Our cover feature this month deals with predatory journals and conferences (page 18). Although the piece addresses their effect on pathology and laboratory medicine, similar vultures circle above every field of scientific and medical advancement. Why? In part because many careers are built on prestige; having a range of publications can bring name recognition – valuable currency in an age when most research is built on collaboration. In part because academia is largely built upon the “publish or perish” mindset, which makes journal articles and conference appearances a key part of pay increases, promotion, and tenure. And perhaps in part because some researchers find it more difficult than others to make their voices heard – for instance, those who work in resource-limited settings; those not fluent in English, the language of most publications and events; or those whose work focuses on obscure or difficult-to-fund subjects. Given these pressures, it’s no surprise to find publishers and conferences who target these vulnerable academics. deliver clear and objective molecular For many, these predatory groups confer no real benefit. + test results in less than 2 hours. Articles published in for-profit journals often receive negative, rather than positive, attention. Speakers associated with predatory conferences may lose stature in academic circles – and may, in the future, find their identities used to promote further predatory events of which they have no knowledge! Xpert Breast Cancer STRAT4 paves the way for standardized, fast, and reliable We can all unhappily discuss the harm that such groups can ER/PGR/HER2/Ki-67 mRNA assessment. do to academic communities, and what each of us can do to avoid falling prey to them. But we must ask ourselves: are these ® Used in conjunction with GeneXpert technology, Xpert Breast Cancer STRAT4 simplifies breast predators the problem – or are they a symptom? If our academic cancer biomarker assessment through semi-automated sample preparation, automated RNA communities have built an environment where such publications isolation, reverse transcription, and amplification by real-time PCR and detection. The entire and conferences can flourish, is there something fundamental that must change? And if so… where do we begin? process happens within a patented cartridge-based system. Xpert Breast Cancer STRAT4: • Enables flexibility, simplicity, and random access for a streamlined workflow 24/7 Michael Schubert Editor • Offers a more objective solution compared to conventional IHC and FISH testing • Unequivocal and easy to interpret results • Delivers excellent concordance with recognized standards Visit http://info.cepheid.com/xpert-strat4 to learn more about Xpert Breast Cancer STRAT4 and Cepheid’s oncology products.

CE-IVD. In Vitro Diagnostic Medical Device. Not available in all countries. Not available in the United States. www.thepathologist.com Vira Solelh | Maurens-Scopont 81470, France | PHONE +33 563 82 53 00 | FAX +33 563 82 53 01 8 Upfront

Upfront Reporting on research, innovations, policies and personalities that are shaping pathology today. One TINY and tested a portable device that can Do you want to share be operated without electricity and may prove useful for KS diagnosis: the Tiny some interesting research Step at a Time Isothermal Nucleic acid quantification or an issue that will sYstem – TINY, for short (1). How to diagnose Kaposi’s impact pathology? In this system, a small biopsy of sarcoma in areas without the affected skin is taken under local reliable infrastructure anesthetic. DNA is then extracted from Email: the biopsy and tested for the presence of [email protected] Kaposi’s sarcoma (KS) presents a Kaposi’s sarcoma-associated herpesvirus diagnostic challenge even in optimal (KSHV) DNA via a reaction known as healthcare settings. This is because loop-mediated isothermal amplification presentation can be extremely (LAMP). Because LAMP does not heterogeneous, and there are many require the temperature cycling of the clinical entities which mimic KS polymerase chain reaction (PCR), it morphologically. Accurate diagnosis, can be performed via a variety of energy which conventionally requires sources and does not need the same stable experienced dermatopathologists, source of electricity required for PCR. is critical to avoid unwarranted Indeed, what makes TINY unique is its chemotherapy – and to ensure correct ability to collect and store energy from therapy for mimicking conditions. any source, including the sun – even in But histopathologic diagnosis is not the midst of intermittent cloud cover. always possible in resource-limited In preliminary testing, TINY is settings, such as sub-Saharan showing promise for its ability to diagnose Africa, where KS is one of the most KS. The multidisciplinary research team is common cancers among adults. In now working alongside Aggrey Semeere, these settings, clinicians must often a clinical researcher in Uganda, to test the diagnose KS only via macroscopic device in large numbers of patients with observation and, unfortunately, this is suspected KS. They are also seeking ways often incorrect. Even where pathology to keep its cost low. “Obviously, we need is available, lengthy turnaround times to make this as inexpensive as possible,” in interpretation often render the says Semeere. “There is little point on findings useless. working on such a project if we cannot To remedy this, a team led by make it affordable.” David Erickson, an engineer from Cornell University; Ethel Cesarman, a References pathologist from Weill Cornell Medical 1. R Snodgrass et al., “A portable device for School; and Jeffrey Martin, a medical nucleic acid quantification powered by epidemiologist from the University of sunlight, a flame or electricity”, Nat Biomed California, San Francisco designed Eng, 2, 657–665 (2018). Upfront 9

ensure sufficient funding and the successful genes linked to approved targeted therapies,” MDLUX2: implementation of such projects,” explains says Goncharenko – but because sequencing Nikolai Goncharenko, Coordinator of the analysis only partially reveals the identity of Drawing a Institut National du Cancer. Goncharenko is the tumor, proteins are also evaluated using enthusiastic about the new program because IHC, microsatellite instability (MSI), and Fuller Picture it will provide all patients with equal access tumor mutational burden (TMB) to assess to modern molecular cancer diagnostics. immunotherapy response. The testing even Luxembourg’s new molecular “The program will make cancer therapy in checks for unusual and damaging splicing diagnostics initiative seeks to Luxembourg more personalized. Knowing in mRNAs and measures the methylation better personalize cancer care the mutations and/or protein expression of of gene promoters. By combining all of these particular molecules will help the tumor analyses, investigators hope to establish a MDLUX2 has a bold overall mission: to boards and treating physicians select the complete genetic profile of the tumor that improve the treatment outcomes of cancer most appropriate treatment option for each can be used to predict response to targeted patients in Luxembourg, with a particular individual cancer patient.” Additionally, therapies, immunotherapies, and classic emphasis on rare and complex cancers (1). by bringing the program to the national chemotherapies. Patients can also allow their Continuing on from a previous initiative, the level with the support of private funding, samples and associated data to be biobanked program also aims to determine whether or the organizations involved – the Institut for future research projects, supporting not molecular diagnostics are feasible and National du Cancer, the Fondatioun further advances in cancer research in cost-effective as a routine part of cancer care; Kriibskrank Kanner, and the Integrated Luxembourg and around the world. at the moment, such tests are not paid for BioBank of Luxembourg – should be able by public health insurance, so MDLUX2 is to secure future public funding for further References vital in establishing their value to patients. initiatives. At least, that’s the hope of 1. European Society for Medical Oncology, “Bringing small-scale local healthcare Goncharenko and his colleagues. “Molecular diagnostic programme for better initiatives to the national level requires a The program’s diagnostic solution cancer treatment kicks off” (2018). lot of time, meticulous preparation, and the combines DNA and protein analyses. “It Available at: https://bit.ly/2sGZKux. engagement of all possible stakeholders to profiles solid tumor samples by sequencing 75 Accessed January 23, 2019. 10 Upfront

Monitoring the Microbiome

Can gut microbiota help improve the diagnosis and management of esophageal cancer?

Esophageal cancer is the sixth most common cause of cancer-related death worldwide despite the introduction of innovative surgical, chemotherapeutic, and radiological interventions. The high mortality rate is largely attributed to the large number of patients presenting with established disease, signaling a need for improved diagnostic tools to accurately dissect individual risk. To improve the odds, a research group led by Loris Lopetuso from Catholic University of Rome, Italy, delved into the pathogenesis of esophageal adenocarcinoma (EAC), asking: what drives the transition from normal esophageal epithelium to Barrett’s esophagus (BE) and EAC? And can we detect a unique signature that might allow us to spot the changes early (1)? Previous studies have demonstrated in the bacteria present separated the says Lopetuso. Identification of the that gut microbiota can play a crucial microbiota of patients with EAC and microbial communities associated with role in digestive tract health, including those with BE. carcinogenesis is of crucial importance in several gastrointestinal diseases “Taken together, our data indicate in terms of finding risk factors and and various types of cancer. Culture- that BE and EAC mucosal samples could potentially guide surveillance independent molecular techniques now can be differentiated by specific protocols. If coupled, genetic and facilitate the identification of bacterial characteristics of the gut microbiota; microbial markers may help detect actors that could represent significant changes to the gut microbiota could EAC at earlier, more treatable stages. markers of increased cancer risk. The represent a predisposing factor for BE Moreover, they could reduce the need researchers found a higher level of – making it the closest precursor of for repeated surveillance procedures on bacterial diversity in patients with EAC not only histologically, but also large numbers of patients who never EAC than those without (including microbially,” Lopetuso says. progress to cancer. a relative abundance of Bacterioidetes Genetic tests already exist to species but a relative paucity of characterize BE and EAC, and to Reference Firmicutes in the cancer patients) – predict the progression of disease. 1. LR Lopetuso et al., “Characterization of an unexpected finding, according to “Now, though, we have found that esophageal microbiota in patients with Lopetuso, who notes that intestinal specific microbial markers can further Barrett’s esophagus and esophageal diseases are typically linked to a lack of differentiate the two conditions, adenocarcinoma”. Presented at the 26th UEG bacterial diversity. Further differences increasing our powers of prediction,” Week; October 20-24, 2018; Vienna, Austria. Steps Forward in Cancer Screening

From an ultrathin fingertip blood flow monitor to falling cervical cancer screening rates, we round up the hottest news in pathology and laboratory medicine

Screening Shortages Cervical cancer screening rates in the US could be far lower than national data suggest hepatitis B, and 2.4 percent had hepatitis of patients treated for early-stage breast (1). A Mayo Clinic study found that fewer C. Although this reflects infection rates cancer between 2013 and 2015. Of the than two-thirds of women aged between 30 across the general US population, 87.3 1,063 women asked, 11 percent said that and 65 were on track with cervical cancer percent of those with acute hepatitis B, cancer worry had a high impact on their screening in 2016. Even more concerning 42.1 percent with chronic hepatitis B, life and 15 percent worried often or almost are the statistics for younger women; just and 31 percent with hepatitis C were always. Interestingly, the study found no over half of those between 21 and 29 were undiagnosed prior to the study screening. difference in the amount of worry patients up to date. Combined, the statistics suggest The study concludes that community experienced, regardless of whether they that true figures may be well below the 81 care clinics should universally screen for received the multigene panel test or an percent screening compliance rate self- hepatitis B and C to help cancer patients earlier version that only tested for BRCA1 reported in the 2015 National Health avoid liver failure, kidney disease, and and BRCA2 genes (5). Interview Survey. other complications (3). References The Eye of the Microneedle Fingertip Diagnostics 1. KL MacLaughlin et al., “Trends over time in Pap Despite the great diagnostic potential of An ultrathin, flexible plastic film can and Pap-HPV cotesting for cervical cancer interstitial fluid, our inability to gather act as a highly sensitive sensor of blood screening”, J Womens Health, [Epub ahead of sufficient quantities has hampered its use flow when attached to a fingertip (4). The print] (2019). PMID: 30614380. for clinical analysis – until now. A new wearable medical device is composed of 2. PR Miller et al., “Extraction and biomolecular technique that uses microneedles to draw conductive organic molecules and uses analysis of dermal interstitial fluid collected with relatively large amounts of the fluid opens infrared detectors to respond to blood hollow microneedles”, Commun Biol, 1, 173 new doors in the quest for rapid, painless, flow characteristics within milliseconds. (2018). PMID: 30374463. and minimally invasive draws. These So far, the device has been shown to 3. SD Ramsey et al., “Prevalence of hepatitis B virus, tiny, hollow needles could be effective for accurately measure heart rate; however, hepatitis C virus, and HIV infection among rapidly measuring exposure to chemical the development team believe that, with patients with newly diagnosed cancer from and biological warfare agents as well as increased sensitivity, it can serve as a academic and community oncology practices”, diagnosing disease (2). pulse oximeter. JAMA Oncol, [Epub ahead of print] (2019). PMID: 30653226. Under the Radar Don’t Worry About a Test 4. S Park et al., “Ultraflexible near-infrared organic An alarming number of cancer patients Genetic tests for breast cancer are photodetectors for conformal photoplethysmogram have acute or chronic hepatitis B or C that becoming increasingly complex – and sensors”, Adv Mater, [Epub ahead of print] (2018). goes undiagnosed, according to research multigene panel tests introduce a greater PMID: 29984437. from the SWOG Cancer Research degree of uncertainty when interpreting 5. SJ Katz et al., “Association of germline genetic test Network. In 3,051 cancer patients tested results. But does this ambiguity cause type and results with patient cancer worry after between 2013 and 2017, 6.5 percent had patients to worry about their risk of diagnosis of breast cancer”, JCO Precis Oncol, acute hepatitis B, 0.6 percent had chronic cancer? Not according to a new study [Epub ahead of print] (2018). PMID: 30656245.

www.thepathologist.com 12  In My View

Virology, and Infection Control – started A Win-Win-Win as two separate entities, but we have now In My consolidated our molecular diagnostics Situation into a single service. Within that service, our microbiology lab operates 24 hours a View Consolidation can improve day, seven days a week; the virology lab pathology services for operates during normal working hours, administrators, laboratory but also offers a weekend out-of-hours In this opinion section, staff, and patients service for the prevention, investigation, experts from across the and control of healthcare-associated world share a single infection in patients and staff. Why did we decide to consolidate? To enhance our strongly held view or turnaround times, increase our testing key idea. repertoire, and provide a more robust service to benefit our patient population. And we have achieved all of these Submissions are welcome. things. We have a variety of routine Articles should be short, tests available from broad-range 16S focused, personal and (bacterial) and 18S (fungal) sequencing to viral neurological PCR screening of passionate, and may cerebrospinal fluid. Moreover, we are deal with any aspect of constantly developing new methods laboratory medicine. of investigation to make best use of By Bamidele Farinre, Specialist diagnostic innovations. This year, for They can be up to 600 Biomedical Scientist in the Department instance, our virology department words in length and of Microbiology, Virology, and Infection researched the use of cutting-edge written in the first person. Control at Great Ormond Street RNAseq for deep sequencing of brain Hospital, London, UK tissue. We hope that this will help us pinpoint the exact viruses and bacteria Contact the editors at My hospital specializes in pediatric causing life-threatening brain infections [email protected] medicine, which means that our patients in children, ensuring that they receive – and thus our jobs – are unique. The rapid and appropriate treatment. The lab at Great Ormond Street Hospital success of this research will provide (GOSH) offers a wide range of us with a unique platform to review specialized clinical laboratory services samples from across Europe, and we to both support the tertiary services our hope it will revolutionize how doctors hospital provides and to act as a specialist treat encephalitis. referral center for institutions around the Pressure on pathology services to world. For me, that involves carrying out consolidate, reconfigure, or modernize routine and specialist analytical testing is nothing new. Lord Carter’s 2006 and on patient biological samples to help 2008 reports – independent reviews of clinicians diagnose, treat, and monitor NHS pathology services in England – recovery from infectious diseases. recommended consolidation of services My colleagues and I use tailor-made “to improve quality, patient safety and equipment and technologies to test a vast efficiency (1).” At the same time, it is range of biological samples, including important to recognize that pathology extraordinarily small sample volumes is a diverse group of clinical specialties; from some of our youngest patients. what works for one discipline may not Our department – Microbiology, work for another. Some pathology In My View  13

while reducing costs, consolidation was are now best located for effective the right decision. results; we can collaborate easily with “Because our But that’s not to say it was easy. subspecialty experts; we have research The consolidation of our molecular and development opportunities; we service is clinically microbiology services was a resource- can plan for training and succession; intensive project that required a dedicated overall, our service is larger and more led and our focus is team and the support of both management resilient than ever. I feel that, because and operations teams. It was a challenge our service is clinically led and our on providing to simultaneously change multiple aspects focus is on providing valuable services of our work (logistics, processes, facilities, to our patients, consolidation was valuable services to equipment, IT infrastructure, and staffing) a success – and it has improved our and we – the staff – were understandably turnaround times, allowing us to work our patients, somewhat hesitant. To that end, it was not just more, but better. The service important for our integration to have costs less to run, it’s easier to spread consolidation was a four main objectives: i) to maintain and workloads and share the burden, and improve customer service across networks, our patients receive accurate results success.” ii) to derive economies of scale and cost quickly: a win-win-win situation. benefits, iii) to control for and minimize risk during and after the transition process, References services must be located close to the and iv) to minimize the disruption and 1. Lord Carter of Coles, “Report of the Second patients and healthcare professionals impact on staff. Phase of the Independent Review of NHS who rely on them, whereas others can After a transition period, I can Pathology Services in England” (2008). be combined to serve larger areas. In comfortably say that the outcome has Available at: https://bit.ly/2zkXFZ3. our case, to ensure high-quality service been positive. Our clinical scientists Accessed November 21, 2018.

developing these products devote Protecting significant care and attention to the products they make, but contamination Patients can occur with any product at any time – even one manufactured under current from Prions Good Manufacturing Practice and a robust Quality Management System. We must ensure that Although this statement is true for all biological products are free from contamination – or we risk transmission of a fatal disease to a patient “Because these By Aaron Schieving, Director of Sales drugs, biologics, and devices come and Marketing at Lifecycle to market, the regulatory landscape products are used Biotechnologies, Fort Worth, USA evolves alongside them. Because these products are used on patients, it is on patients, it is With the evolution of science, the critical to ensure they are safe – which world is increasingly benefiting from can mean a number of different things, critical to ensure the amazing lifesaving and life- all of which should be built into the enhancing medical products developed design of these products well before they are safe.” and commercialized today. As new manufacturing begins. The companies

www.thepathologist.com 14  In My View

use of sodium heparin returned to the animal-derived products by avoiding usual figures. The next month, the FDA their use – but that simply isn’t possible; “It’s important for published the discovery that the heparin some materials either require, or are – which was highly contaminated cost-prohibitive without, such products. labs [...] to ensure – had been purchased from a single These may include proteins, enzymes, supplier, who in turn sourced the and amino acids; biotechnological that there’s no risk heparin from its Chinese factory. They products like serums, blood products, determined that the contaminant and vaccines; or even primary packaging of contamination was in the heparin material before materials like gelatin capsules (which it reached the supplier – but because are particularly susceptible to BSE/ when those the Chinese factory sourced its raw CJD). Even when a product involves heparin from small suppliers, it could no such materials, there may still be products are not be fully traced. The deficiency led to a risk of BSE/CJD contamination extensive revisions of the unfractioned if they share equipment or facilities provided to heparin monographs of both the US with biologically derived products. It’s and European pharmacopeias – and important for diagnosticians to bear this patients.” it provided a hard lesson that lead risk in mind when dealing with patients to much stricter control and better experiencing unexplained neurological understanding of how contamination symptoms – and it’s important for labs pharmaceutical products and medical risks can be mitigated. that produce such materials to ensure devices, it is especially true for biologics, Potential human donors of such that there’s no risk of contamination human cells, tissues, and cellular and products bear no lighter a burden. when those products are provided tissue-based products (HCT/Ps) due They must be screened to determine to patients. to their sources and/or the addition of their eligibility to donate, and to If the use of animal-derived products biologic components. ensure that the human cells and is at all avoidable, I suggest that It’s a matter of public record that, tissues to be transplanted are free from maintaining an animal-origin-free a few years ago, the pharmaceutical communicable disease agents. Once a facility is the best way to eliminate industry learned this the hard way person is deemed eligible to donate, the the risk of contamination entirely with an issue involving heparin (a tissues and cells consented for donation – and to hold suppliers to the same common, animal-derived product). are recovered to be transplanted and standard. To do otherwise is to In January 2008, the US health processed. If a potential donor is not welcome the risk of contamination into system authorities began to receive free from risk factors for – and clinical your laboratory. The pharmaceutical isolated reports of hypersensitivity evidence of – infection with a relevant industry is taking precautions to reactions in hemodialysis patients. communicable disease, they may be eliminate and mitigate this danger, Symptoms included hypotension, ineligible to donate their tissues and but academia and other industries have facial inflammation, tachycardia, cells. This is a critical step at the not followed suit. As consumers and hives, and nausea. Initially, inquiries beginning of the lifecycle of the HCT/ patients, we must educate ourselves were focused on the filters and lines Ps we use today. Why, then, after this on the risks associated with these used in dialysis; however, the research required screening and testing, would medical products – and, if necessary, carried out by the Centers for Disease you risk introducing one of these we must demand higher standards Control and Prevention proved that all communicable diseases back into your to ensure our patients’ safety. We known cases had in common the use tissues and cells? The question may must ask questions about the medical of sodium heparin. In February 2008, sound absurd; however, the risk is real, products we and our patients use and the manufacturer withdrew all batches especially for prion diseases like bovine demand that they be produced safely of the product – but there were still spongiform encephalopathy (BSE) and and with as little risk of contamination reports of allergic reactions, including its human variant, Creutzfeldt-Jakob as possible. Just think of the alternative some fatal cases. After monitoring by disease (CJD). if we don’t ask – patients may end up the US Food and Drug Administration In an ideal world, we would eliminate with a degenerative, ultimately fatal (FDA), fatalities associated with the the risk of contamination of human- and brain disorder. The choice is simple. From the ASCP  15

Achieving Excellence Requires a Multifaceted Approach

Laboratory professionals must be flexible, innovative, and open-minded

By E. Blair Holladay, CEO of the American Society for Clinical Pathology, Chicago, USA

When studying cytopathology in the another, especially in a discipline as broad early 1980s, we were taught that the as ours, requires flexibility, innovation, and causative agenda for cervical cancer was open-mindedness. You don’t have to be a “Advances in Chlamydia trachomatis, among other researcher to appreciate how important epidemiological factors. Of course, today, these concepts are to management and diagnostic we know that to be completely inaccurate administration in the clinical pathology – but it was a long road to acquire the laboratory. Achieving excellence in our techniques are only scientific evidence needed to finally link laboratories requires a multifaceted high-risk human papillomavirus (HPV) approach focusing on people, policies, and impactful if we are virotypes to cervical cancer. What tools practices. Laboratories need to be up-to- were missing? We needed advances in date on the regulations and accreditation trained in both the technology, such as Southern blot and bodies that govern our industry. PCR, to detect viral DNA integrated Pathologists and laboratory scientists theory behind the within host DNA. We needed that need to be aware of the latest clinical care data to correlate with cellular changes guidelines so they can implement changes tests and their indicating that malignant transformation in procedures if necessary. Laboratory was likely to occur. It was nearly 20 years administrators, managers, and staff need to practical use.” later that Harald zur Hauzen won the be proficient in conflict management and Nobel Prize for determining that HPV emotional intelligence to create a happy was the causative agent of cervical cancer. and productive workplace culture. And, on up with the current paradigm, but also Today, the virus can be detected by internal top of everything else, we must all continue commit to implementing the latest closed system PCR amplification and, to prioritize training, competencies, and innovations and anticipating new within hours of analyzing the epithelial continuing education. After all, advances gold standards of diagnostics. Our sample, we can determine if the patient is in diagnostic techniques are only impactful practice changes as our knowledge at high risk of cervical cancer. That gives if we are trained in both the theory behind base expands, and it’s up to us to make the clinician the information they need to the tests and their practical use. sure that knowledge base is as broad remove the precancerous lesion before it As laboratory professionals, it is our as it can be. It might feel impossible transforms into a malignancy – a clinical responsibility to constantly acquire new at times but, as practitioners dedicated game-changer for the patient. skills. Providing the very best care for to the highest level of patient care, we Moving from one consensus opinion to our patients means we must not only keep must be up for the challenge.

www.ascp.org 16  Sponsored Feature

Allelic Frequency Gene Variant Building a 5% 1% 0.1% 0% (WT) EGFR L858R 5.0 1.0 ND ND Better Biopsy EGFR ΔE746-A750 4.9 0.9 ND ND EGFR T790M 4.9 1.1 ND ND Combating the challenges of EGFR V769-D770ins 5.0 1.0 ND ND liquid biopsy with cfDNA synthetic KRAS G12D 5.1 1.0 ND ND plasma reference standards NRAS Q61K 4.9 0.9 ND ND NRAS A59T 5.2 1.1 0.7 0.7 By Lisa M. Wright, PhD PIKC3A E545K 5.0 1.0 ND ND

Medical professionals in the cancer sphere are all familiar with solid tumor testing for Human plasma Horizon’s synthetic plasma patients. And although valuable, these procedures are also painful, invasive, and Variable quantity and concentrations Defined volume and concentrations costly in multiple ways. Liquid biopsy – Lot-to-lot variability Lot-to-lot stability the approach of examining fluid samples, usually blood, for biomarkers – holds Irregular supply Reliable supply many advantages over solid tumor testing. Contamination with other analytes and/or No interfering analytes or genomic DNA It is less invasive for the patient and has genomic DNA improved levels of sensitivity to detect low-frequency somatic driver mutations. cfDNA degradation: time-limited storage Long-term cfDNA stability: over 24 months In oncology, pathologists often examine circulating free DNA (cfDNA) for markers Table 1. Comparing human and synthetic plasma as reference standards for cfDNA assays. that indicate the presence of cancer, its molecular characteristics, and the tumor’s been handling robust FFPE blocks for draw and immediate blood storage susceptibility to treatment. many decades are now faced with process, which can vary between The industry is pushing to make liquid processing blood samples, which phlebotomists and hospitals, can biopsy the go-to method of collecting have shorter shelf lives and require introduce further sample variation. clinical DNA samples for oncology multiple extraction steps. Each Controlling for this variation and genotyping. Liquid biopsies can be taken at step must be properly validated to introducing a consistent protocol is the point of diagnosis for routine monitoring ensure it does not introduce errors essential for the success of wide-scale during treatment, enabling practitioners to into the final results. liquid biopsy adoption. rapidly detect the appearance of resistance 2. Reliability of results mutations that might indicate the need for Liquid biopsy assays must The two big challenges a change of therapy. One day, liquid biopsy operate at much lower limits of 1. Limit of detection and false positive could even be used for preventative cancer detection than previous FFPE- error rates screening in the general population. The based sequencing. As a result, the A key challenge in using cfDNA to ultimate goal is to facilitate earlier diagnosis technology needs to be rigorously detect cancers early is the extremely and better treatment outcomes. tested to ensure it can accurately low quantities of cfDNA in patients’ As with any new technology, using call variants down to between 0.1– blood. So how can we be confident cfDNA for diagnosis via liquid biopsy 5 percent allele frequency without in our lower limit of detection and has its challenges. Common technical calling false positives. ensure that we’re not seeing false hurdles include: 3. Sample variability positives? The answer: an appropriate Human plasma naturally displays high reference standard. Using a reference 1. Sample handling lot-to-lot variability, making it difficult standard with a range of precisely Liquid biopsy workflows involve to control and implement a consistent defined allelic frequencies can help additional sample handling steps. protocol for your diagnostic assay. determine a true limit of detection For example, clinical labs that have Inconsistencies in the clinical blood and reduce the risk of false positives Sponsored Feature  17

Figure 1. cfDNA recovery (left) and ALK1 gene copy number deletion (right) in Horizon’s synthetic plasma reference standard.

In this example dataset, the reference (Qiagen); extraction efficiency was control the accuracy of new patient standard informs the user that i) measured with Qubit BR Reagents tests. These materials contain a range of the reliable limit of detection for (Molecular Probes). actionable variants in key cancer genes at this cfDNA assay is 1 percent allelic 3. Total AKT1 gene copies were well-characterized allele frequencies as frequency, and ii) they are calling a quantified by ddPCR (Biorad). determined by ddPCR. The variants are false positive for NRAS A59T. located within genomic DNA and have an When you run a reference standard Take control of your workflow average fragment size of 160 bp. before a patient sample, you can Having well-characterized cell line- Find out more at tp.txp.to/horizon/cfDNA be sure of the limit of detection for derived reference standards that closely your assay. It also allows pipeline mimic real patient samples, with clinically Our cfDNA material in synthetic plasma optimization; you can recalibrate relevant variants defined by a gold helps users to monitor the entire liquid and amend your workflow to standard mechanism like droplet digital biopsy workflow from DNA extraction counter any false results, which PCR (ddPCR), allows new liquid biopsy to interpretation of results, giving gives you confidence when handling assays to be properly validated. Users can: labs confidence in the accuracy of their test. real patient samples. • check that their workflows Find out more at tp.txp.to/synthplasma accurately detect all of the variants 2. The variability and instability of in the control material at the correct What’s next? human plasma allele frequencies without calling The ability to examine and support cancer Using human plasma as a control false positives patients using liquid biopsy is hugely exciting. for your cfDNA assay comes with • validate and control for the It promises to make genetic analysis more numerous challenges (see Table introduction of errors during the accessible with only a simple blood draw, 1). Yes, human plasma matches DNA extraction procedure and it encourages more frequent testing in all your patient sample behaviors, but • ensure that the design of their aspects of cancer management – pre-disease this does not always outweigh the liquid biopsy sequencing assay preventative monitoring, diagnosis, treatment, challenges that come with using it as a functions effectively with no tumor evolution, resistance management, reliable control for diagnosis. amplicon dropout (liquid biopsy and long-term remission surveillance and assays need to sequence from check-up. For both laboratory professionals Our approach to testing: smaller fragments of DNA than and the patients they serve, liquid biopsy with 1. 400 ng of cfDNA was spiked into 1 was previously required in fresh appropriate reference standards is the way mL of human or synthetic plasma and tissue or FFPE assays) to a brighter future. stored at -80˚C. Horizon has developed a range of cell 2. cfDNA was extracted using line-derived cfDNA reference standards Dr. Wright is Diagnostics Business Unit a Circulating Nucleic Acid kit to help develop, optimize, monitor, and Leader at Horizon Discovery plc.

www.horizondiscovery.com

Feature 19

When PATHOLOGY Turns PREDATORY

www.thepathologist.com predatory publishers to ensure your identity is not used ANATOMY OF without permission • This kind of predation is a symptom of a larger A PREDATOR problem; we need to reconsider how academic science and medicine are incentivized How to navigate the dangerous world of predatory journals and conferences in Academia’s “publish or perish” mindset is one that drives these “publish or perish” times productivity and competition. And that can be a good thing – inspiring hard work, broad collaboration, and rigorous scientific By Benjamin Mazer quality control. But sometimes, it can lead to the opposite – a sense of urgency in publishing and presenting that may make some look • Predatory journals and conferences often take less carefully at the journals and conferences accepting their work. advantage of academics pressured by the common This, in turn, opens the door to predatory organizations who take “publish or perish” mindset advantage of the perceived urgency. • These groups often overcharge those presenting or publishing without delivering the scientific rigor and What are predatory publishers? stature they promise • To avoid falling victim to predatory groups, always A predatory publisher is a for-profit company that uses minimal check journals’ and conferences’ credentials (ideally with to no traditional peer review (despite often advertising a rigorous respected researchers you know personally) and examine review process) and accepts nearly all submissions (for which it Feature 21

may charge exorbitant fees). Beyond simply lacking scientific “A P R E DATORY rigor, predatory publishers use deceptive practices meant to PUBLISHER IS increase the credibility of their offerings. They will use the names, biographies, and photographs of prominent scholars A FOR-PROFIT without permission, falsely claiming that they are journal editors or conference speakers. If a scholar has knowingly submitted C O M P A N Y an article to even one journal or spoken at even one conference THAT USES associated with these predatory publishing networks, their name and likeness may be – unbeknownst to them – disseminated MINIMAL TO NO throughout the network to advertise unrelated productions. The creation of “predatory” journals and conferences in TRADITIONAL science and medicine is raising new questions about the PEER REVIEW scholarly publishing process. What is the value of scholarly publication in the Internet era? How are scholarly publications AND ACCEPTS being used as secondary measures of influence and academic success? How effectively are we distributing the costs, labor, N E A R L Y A L L and profits associated with scholarly publishing? SUBMISSIONS.” Predatory publishers are also an unintended consequence of the rise of electronic journals and open-access publishing, two increasingly mainstream methods that are still dominated by legitimate players. Electronic publishing substantially lowers The FTC’s complaint alleges that the the barriers to entry into academic publishing due to its defendants do not tell authors lower costs. Open-access publishing also shifts the burden of submitting papers for paying for journals from large libraries to individual scholars. publication that, after Predatory publishers feel they can more easily manipulate these their online journals new consumers, who may have less experience with academic accept an article, the transactions than professional librarians. defendants charge the authors significant publishing fees and often do Predatory publishing networks not allow authors to withdraw their articles from submission, making Though there appears to be a seemingly endless supply of their research ineligible for publication in new open-access titles, each a slight variation on our sober other journals. academic vocabulary, most are actually part of a single Indian The FTC also alleges that, to promote their scientific predatory publishing network owned by Srinubabu Gedela conferences, the defendants deceptively use the names of (1). This network generated US$11.6 million in revenue in prominent researchers as conference presenters, when in fact many 2016, according to Bloomberg. Although profitable, this of those researchers had not agreed to participate in the events.” represents only a tiny fraction of the more than $24 billion According to the summary judgment motion (4) filed by (2) scholarly publishing market. the FTC last May, Gedela’s network of companies includes Gedela and related individuals and companies have been the OMICS Group, iMed Publications, Conference Series charged with fraud by the US Federal Trade Commission (FTC), LLC, Meetings International, Allied Academics, EuroSciCon, and a federal court has placed a preliminary injunction against and Pulsus Group. Hundreds of journals and conferences are the companies (3). The FTC charges make plain the risks these produced from this network of subsidiaries. Most are new publishers pose to researchers: publications; however, Gedela has also been purchasing older “The defendants deceptively claim that their journals provide publishers to gain credibility. The Pulsus Group and Andrew authors with rigorous peer review and have editorial boards made John Publishing, for example, were originally respected up of prominent academics when in fact, many articles are published Canadian publishers that are now part of this network, leaving with little to no peer review and many individuals represented to be Canadian scholars concerned (5) about academic “hijacking.” editors have not agreed to be affiliated with the journals. The OMICS group publishes multiple pathology-related

www.thepathologist.com 22 Feature

A recent spam email I received from the OMICS publishing group.

journals (6). Examining these journals, you will find publications by pathologists at many well-respected academic institutions. Each journal will list multiple editors, many of whom are prominent in our field. Some of these pathologists may not be aware at all that their names are being used for this purpose. Others may have consented to being listed as editors, but may not have been fully aware of the deceptive practices that these journals consider standard operating procedure. Predatory pathology conferences

Pathology is no more immune to predatory publishing practices than any other area of medicine or science. I was motivated to write about this topic for our community after seeing tweets by influential individuals and organizations about the “17th International Conference on Pathology & Cancer Epidemiology,” a conference run by OMICS subsidiary EuroSciCon. Among the sponsors listed for the conference was The Pathologist magazine – which, despite being a relatively new publication, has quickly gained respect within the pathology community and even formed a partnership with the American Society for Clinical Pathology. I contacted the editor of the magazine to learn more about their potential conference A spam message I received on Twitter about another predatory conference run sponsorship and learned that, by the OMICS group. although the magazine had knowingly made an agreement in the conference and had no prior knowledge that his likeness with the conference, they were not aware of its predatory nature was being used to advertise it. It’s clear from experiences like his and have discontinued the relationship. This pattern is a good that, despite FTC intervention, these predatory groups’ deceptive example of additive deception; a conference that advertises untrue practices continue unchecked. In 2013, University of New South affiliations with respected speakers and organizations may appear Wales biologist Richard Edwards memorably blogged about his falsely legitimate to further speakers and potential sponsors – negative experience at an OMICS-sponsored scientific conference who will then enter into genuine agreements, risking their own (9), describing an event “bordering on farce.” After examining reputations by accidentally liaising with predatory groups. these marketing materials and seeing similar practices still taking Examining the website and program brochure (7,8) for the place, I have no reason to believe his experience would be much conference, we can see some hallmarks of predatory conferences: different at a predatory pathology conference today.

• Sessions run the gamut of loosely related subdisciplines, with Not the victims’ fault topics ranging from dermatopathology to plant pathology to psychopathology – an absurd combination. The science presented in predatory journals and conferences is often • Past speakers at other conferences make up a large portion legitimate and high-quality – and that is exactly the pernicious of the promotional materials, a tactic meant to increase nature of these outfits. Predatory publishing’s deceptive perceived legitimacy and optimize search engine placement. practices can reduce scholars’ credibility, and that of their • Photos of related conferences show, at most, a few dozen scientific work by association. participants, despite so many purported topics and It is possible that a minority of people who publish in speakers listed on the website and in the program. predatory journals and speak at their conferences are aware • Content is disorganized, poorly edited, and clearly drawn of their true nature – and they wish to use the lack of rigorous from stock text. review to enhance their CVs. I do not intend to cast aspersions on even these behaviors. I have heard senior pathologists I reached out to one pathologist I know who was listed as a complain, over and over again, that in academic medicine there “renowned speaker” in the program brochure of this upcoming is increasing pressure to publish frequently, while protected predatory pathology conference. He was not, in fact, participating time for scholarly work is shrinking. Traditional publishing

www.thepathologist.com 24 Feature

also remains slow and cumbersome, and legitimate open-access how incentives are misaligned in science and medicine, leading journals often charge very high publication fees. to unintended consequences and sometimes outright fraud. If we want to avoid the knowing use of predatory publishing, When we use publication as a surrogate metric for scientific we must confront the misaligned incentives our system is creating. progress and quality, do we encourage scholars to game the system? Is the traditional, highly profitable scientific publishing Forensic implications industry stifling more innovative and affordable approaches? Is our over-reliance on peer review ironically driving down its In an editorial in the journal Forensic Science, Medicine, quality? I have no easy answers to these questions, but I hope and Pathology, forensic pathologist Roger Byard has raised the most experienced physicians and scientists will continue an important point about the risk predatory publishing to address these problems – and, eventually, embrace modern poses to forensic pathology in particular, due to its potential technology’s promise for scientific publishing. legal ramifications. “In forensic circles there has always been a problem in dealing Disclosures: I have been a member of the College of American with aberrant theories that are at odds with the mainstream Pathologists Residents Forum Executive Committee, which literature. In the past, this material was often introduced into court runs its own conferences for pathology residents. This article is without the imprimatur of peer-reviewed, or any, publication. It is written in my personal capacity, and is not affiliated with any now possible with the advent of predatory journals, however, that organization or my employer. even the most bizarre theories with inadequate or no scientific validation could be published. To the courts, these papers would Benjamin Mazer is Resident in Anatomic and Clinical Pathology in appear to be no different to those published in legitimate journals, the Departments of Pathology and Laboratory Medicine at Yale-New and without a clear knowledge of a particular journal’s reputation Haven Hospital and the Yale School of Medicine, New Haven, USA. and process, may be difficult to exclude. My concern is that predatory journals may be used in future to legitimize fringe References theories and to validate bogus experts (10).” 1. EE Deprez, C Chen, “Medical Journals Have a Fake News In this way, the use of predatory publishing in pathology Problem” (2017). Available at: https://bloom.bg/2wPmYTz. affects not only the scientific community, but also people facing Accessed September 12, 2018. criminal charges, if the falsely awarded credibility of peer 2. S Buranyi, “Is the staggeringly profitable business of scientific review means that unsubstantiated forensic pathology theories publishing bad for science?” (2017). Available at: https://bit.ly/2teqjJf. are used in legal proceedings. Accessed September 12, 2018. 3. Federal Trade Commission, “FTC Halts the Deceptive Practices of Academic Taking action Journal Publishers” (2017). Available at: https://bit.ly/2M1H6Fo. Accessed September 12, 2018. Unfortunately, the international nature and complex corporate 4. United States District Court, “FTC’S motion for summary judgment and structure of these predatory publishers, as well as an overall memorandum in support thereof ” (2018). Available at: https://bit. lax regulatory environment, virtually guarantees that these ly/2xa6MKg. Accessed September 12, 2018. problems will not be extinguished quickly. Many pathologists 5. MC Oved, “Canadian medical journals hijacked for junk science” (2016). are already familiar with the nature of such publishers, yet I still Available at https://bit.ly/2dnXAGB. Accessed September 12, 2018. see respected individuals and organizations in our community 6. OMICS International, “Pathology Journals” (2018). Available at: https:// inadvertently lending them credibility. bit.ly/2Qo0rnh. Accessed September 12, 2018. Pathologists should look for some of the telltale signs of deceptive 7. EuroSciCon, “17th International Conference on Pathology & Cancer practices described above, as well as consult their colleagues when Epidemiology: website” (2018). Available at: https://bit.ly/2C1fZdt. considering where to submit a paper or abstract. If a pathologist is Accessed September 12, 2018. considering submitting to a journal or conference that raises red 8. EuroSciCon, “17th International Conference on Pathology & Cancer flags, but is seeing respected scholars listed in association with it, Epidemiology: brochure” (2018). Available at: https://bit.ly/2QnXOSe. they should reach out to these scholars individually to determine Accessed September 12, 2018. whether or not their participation is legitimate. 9. R Edwards, “OMICS Group Conferences – Sham or Scam?” (2013). In my view, predatory publishers are not the problem; rather, Available at: https://bit.ly/2OfTuD8. Accessed September 12, 2018. they are a symptom of a larger one. Those who control the 10. RW Byard, “The forensic implications of predatory publishing”, Forensic Sci scholarly publication and promotion process should reflect on Med Pathol, 12, 391–393 (2016). PMID: 27038941. skills. On the other hand, these journals may also attract honest WHEN PROGRESS but inexperienced researchers who find their article “hijacked” after submission – no longer permitted to withdraw it, but BECOMES subject to pressure to pay the fee for publication. PREDATION How to spot a pseudojournal

Predatory publishing can lead to academic Predatory journals disguise themselves in different ways. ruin, especially for developing countries Some of them operate in the “borderline” zone, balancing legitimate and for-profit practice, but still consistently and By Yaman AlAhmad, Ibrahim Abdelhafez, notoriously publish low-quality or even fabricated articles Faruk Skenderi, and Semir Vranić without conducting any peer review. Unfortunately, there are no firmly established criteria to help distinguish a predatory “Pseudojournals” – predatory journals or publishers – abuse journal, particularly a “borderline” example, from a low-quality the academic system and community solely to gain profit. They but legitimate one. do so by charging for the publication of questionable scientific In more pronounced cases, it is easy to tell. At first sight, content, devoid of standard editorial procedures like peer these journals use titles similar to legitimate journals, or label review. These journals operate globally, but their deleterious themselves as American, British, or originating from another effects on the academic environment are felt most keenly in scientifically sound nation despite being based in a completely developing countries, where local researchers who publish in different location. At the same time, they display false, such journals build careers and gain tenure based on their misleading, or irrelevant scientific metric indices. Usually, publications, but fail to advance their scientific and medical information on the pseudojournals’ editorial policies is vague,

www.thepathologist.com 26 Feature

limited, incomplete, or altogether missing. The contents are especially where predatory journals come in to fill the gap. revelatory; such a journal publishes everything it gets, regardless of its This setting creates a vicious cycle leading to extreme detriment aims and scope, and sometimes even crossing the boundaries between of under-resourced academic communities. Inexperienced or branches of science, as with the Journal of Medicine, Radiology, incompetent researchers publish in pseudojournals, use those Pathology and Surgery. Published articles lack basic editing and the publications to rise through the ranks of academia, and train the layout is usually poorly done. These journals are almost never covered next generation of researchers in the same methods. Eventually, by PubMed/MEDLINE, Scopus, Web of Science, or the Directory the scientific potential of such a community could be devastated. of Open Access Journals (DOAJ). These journals also pose a significant challenge to individual In more discreet cases, it is not easy to recognize predatory laboratory professionals. In particular, young and inexperienced journals. They look deceptively like legitimate ones, with fitting researchers might be tricked into contributing to predatory titles, appropriate articles, and professional-looking layouts. Some publications. This can have a deleterious impact on their academic of these journals even manage to become members of authoritative and professional careers. Consider that the misfortune of publishing associations dealing with editorial and publishing best practices – in a predatory instead of a legitimate journal could result in a failure a fact they then misuse to improve their reputations. In addition, to fulfil the requirements for a doctoral thesis – or that relying some of them have their contents covered by PubMed or Scopus on results from an inadequately peer-reviewed publication could – which not only makes it more difficult to spot the fakes, but also mean a waste of months or even years of scientific work. For those creates “noise” in the literature and spreads irrelevant, trivial, or wrong whose academic work has a direct impact on patients, illegitimate information while making it more difficult to locate and identify true journals might even lead to a negative effect on patients’ health. science. Of note, in our research revealed that only one predatory Our research has shown that the number of predatory journals journal was listed in a reputable database (1). However, we do not in pathology is approaching the number of legitimate pathology know how many of them have applied and may be accepted for journals listed in Science Citation Index Expanded and the Web of inclusion in reputable databases. Science. If this trend continues, it is expected that pseudojournals Another common feature that should raise suspicion of a may outnumber the legitimate ones at some point in the future. predatory journal is its focus on authors – for instance, advertising Our next step is to look into the prevalence of predatory journals or overemphasizing rapid peer review, database coverage, journal in laboratory medicine to determine whether or not the threat is metrics, and emails with non-selective calls for papers. In contrast, equally great – and to help raise awareness and build reliable tools legitimate journals put emphasis on scientific content to attract for identifying these journals. readers. Nevertheless, sometimes a more detailed analysis of the journal is necessary to rule out its potentially predatory nature, Open access: a risk and a benefit including looking at the reputation of the editor-in-chief and the journal’s validation by databases or authoritative bodies. Sometimes, Like any other revolutionary development, open-access even a simple Google search for the journal can reveal other people’s publication can be – and has been – misused. However, we experiences that may assist determining its legitimacy. do not believe that open access itself is to blame for the rise of predatory journals. In fact, open access is definitely the way of The scope of the problem the future, especially in areas where researchers may not be able to afford multiple expensive subscriptions. The availability of The impact of predatory journals is astonishing – far more severe legitimate, peer-reviewed information facilitates research dynamics than it appears at first glance. They affect not only individual and the overall progress of science and medicine. The academic authors, but can have a negative or even ruinous impact on community widely recognizes the importance of open access, the academic environments of entire countries. Developing and many institutions support their researchers in publishing countries have limited scientific infrastructure and human with open-access journals. And the benefits extend to authors as resources. Unfortunately, without equivalent scientific well as to readers; many prefer open access because it means their resources, many researchers in these countries cannot reach papers are immediately available for reading and citation, the level of research quality and importance required to thus increasing the author’s reputation and disseminating publish extensively in reputable journals, so these countries knowledge faster. No wonder, then, that an increasing number usually have loose criteria for academic tenure. Nevertheless, of reputable publishers are offering open-access options to they have adopted the academic organizational structures of their contributors. Nevertheless, we believe that predatory developed countries, including the “publish or perish” mindset journals are damaging the open-access model – once again, that makes authorship essential for an academic career. This is with a more pronounced effect in developing countries. Feature 27

“AS THE ISSUE would any scientific result. Have I ever read an article from OF PREDATORY this journal? Have I seen it cited in other legitimate publications? Have any of my colleagues or collaborators published articles PUBLISHERS in this journal? If all of the answers are negative, or if any of the journal’s characteristics raise suspicion of a potential I S B R O U G H T predatory nature, you should definitely apply the criteria T O T H E used in our study (1) to ensure that your article is not being submitted to a pseudojournal. F O R E F R O N T , A plethora of excellent and legitimate open access journals enable the free and unrestricted sharing of scientific and T H E A C A D E M I C medical knowledge. Before deciding whether or not to submit C O M M U N I T Y your research to any of them, you should carefully evaluate the journal’s impact factor (as provided by Journal Citation WILL NEED TO Reports, Clarivate Analytics) and indexing status – especially given that even legitimate journals, if recently launched, may ADOPT QUALITY lack an impact factor and may not be indexed in the major CONTROL bibliographic databases. Notably, important information may be obtained from sources such as the World Association of Medical CRITERIA.” Editors (WAME) (2) and the Committee on Publication Ethics (COPE) (3), which are dedicated to promoting best principles and practices in publication ethics – including those related to research and publication misconduct. A coalition of scholars has also developed an online tool known as “Think. Check. Submit.” (thinkchecksubmit.org) to help scientists identify trusted journals in which to publish their research. When contributing to our collective knowledge, researchers would be well served to familiarize themselves with the basic principles of academic publishing and indexing using the above sources. Such knowledge is your best defense against academic predation! As the issue of predatory publishers is brought to the forefront, the academic community will need to adopt quality control criteria Yaman AlAhmad is a medical student at the College of Medicine, that can clearly differentiate between predatory and legitimate Qatar University, Doha, Qatar. journals – particularly in the countries that are most severely Ibrahim Abdelhafez is a medical student at the College of affected. Eventually, such precautions will improve the publishing Medicine, Qatar University, Doha, Qatar. landscape for both academia and legitimate publishers. Faruk Skenderi is an academic pathologist at the University of Sarajevo, Sarajevo, Bosnia and Herzegovina. In search of publication Semir Vranić is an Assistant Professor of Pathology and a Union for International Cancer Control Fellow at the College of Many researchers may find that they are pursued by predatory Medicine, Qatar University, Doha, Qatar. publishers, who ask them to submit manuscripts. And many more will likely come across these publishers online while References seeking appropriate venues for future articles. How can 1. YM AlAhmad et al., “A critical appraisal of predatory journals in legitimate academics protect themselves from danger? pathology” (2018). Available at: https://bit.ly/2CWxV7z. Accessed January In addition to the criteria mentioned earlier, they should 8, 2019. request the advice of senior colleagues and fellows – a task 2. World Association of Medical Editors, “Principles of Transparency and Best made much easier by social media; science and medical Practice in Scholarly Publishing” (2018). Available at: https://bit. professionals all over the world can share information ly/2ANXUfJ. Accessed January 18, 2019. about pseudojournals almost instantly. 3. Committee on Publication Ethics, “COPE” (2019). Available at: https:// It’s also important to question what you find, just as you bit.ly/2Ac6uHg. Accessed January 18, 2019. Advance Your Career and Improve Your Skills with ASCP Certificate Programs

ASCP offers a broad selection of online certificate programs that have been developed to support the ongoing professional needs of pathologists, laboratory professionals and residents. These programs are a convenient way to stay sharp and learn new skills. Review the certificate programs and see how they can help advance your career!

Comprehensive and Inclusive Leadership Training for the Laboratory Medicine Team Hone your leadership skills at your own pace with 12 on-demand courses offering CME/CMLE/SAMS credit! This program teaches participants to adapt their behavior, communication skills, and leadership styles to be effective in a variety of workplace situations.Through an advanced self-assessment program, participants gain insight into their current viewpoints on leadership topics, identify areas of growth and use the knowledge gained to develop advanced leadership skills.

The Best Training Resource in Laboratory Management Today Created for pathologists, residents and laboratory professionals, LMU is a customizable program for individuals planning on moving into management positions or seeking to advance their management skills.

A JOINT COLLABORATION BETWEEN ASCP AND APF

The Most Complete Pathology Informatics Education Program You Will Find Take the lead to improve lab productivity and move your lab to the next level with this unique self-paced online certificate program. The program is designed for individuals participating in laboratory informatics initiatives to enhance quality diagnosis, throughput and patient safety.

www.ascp.org/certificate-programs

5_190123_LS_Certificate Programs_FP Ad_The Pathologist.indd 1 2/4/19 9:40 AM In Advance Your Career and Practice Improve Your Skills with Technologies and techniques Quality and compliance ASCP Certificate Programs Workflow

A JOINT COLLABORATION BETWEEN ASCP AND APF

The Most Complete Pathology Informatics Education Program You Will Find 30-33 Take the lead to improve lab productivity and move your lab to the next level with A Call for Color Calibration this unique self-paced online certificate program. The program is designed for Digital imaging is the way of individuals participating in laboratory informatics initiatives to enhance quality the future, but those images are diagnosis, throughput and patient safety. of little use without accurate color representation. www.ascp.org/certificate-programs

5_190123_LS_Certificate Programs_FP Ad_The Pathologist.indd 1 2/4/19 9:40 AM 30 In Practice

FDA recognizes, and standardization A Call for of color can increase the validity, reliability and quality of WSI. Color Calibration Color calibration seeks to ensure color fidelity throughout the imaging Why digital slide scanners process. The goal? To provide the must be correctly calibrated pathologist – who may be looking at an to yield trustworthy results image scanned in their own lab or one scanned a lab across the globe – with By Richard Salmon the confidence that the colors they see are representative of the true colors of Many laboratories are moving into the tissue sample and are not altered digital imaging – scanning slides, by the scanning process. This gives viewing them on computer monitors, pathologists confidence that they are and using software-based tools to working from ground-truth data. assist with analysis. But there’s an But what exactly is color calibration – understandable hesitation from some and why should we trust it to provide a pathologists, who ask: “How can we true representation of tissue slides? be sure that the digital image we see is truly representative of the slide?” Bringing color fidelity to In particular, with histopathology’s biomedical imaging need for accurate staining, how can Digital pathology scanners (often practitioners be assured that nothing is referred to as WSI scanners) are being lost or inaccurately represented in computer imaging devices for the the digitization process? in vitro examination of biopsy, Guidance from the US Food and cytology, and tissue specimens. They Drug Administration (FDA) has are capable of all sorts of tasks – recommended color calibration for scanning, digitizing, compressing, whole slide imaging (WSI), just as it storing, retrieving, and even enabling does for many other digital systems. the viewing of high-resolution, high- “Histology There is substantial variation in color magnification digital medical images. between digital slide scanners, a fact the Most pathologists are aware that laboratories have digital pathology has only recently come into its own (go back 10 years shown reluctance to At a Glance and it was far less common than it is • For histopathologists, it is vital today). Histology laboratories have move away from to ensure that digital images shown reluctance to move away from of stained tissue accurately the age-old microscope and into the the age-old represent the original slides digital space. Why? At least in part, • Color calibration for whole slide their hesitance was due to the absence microscope imaging can verify accurate of color fidelity regulation and image color representation quality assurance in WSI systems. and into the • Calibration is a complex issue, Global transition to WSI systems especially given the variations has been gradual, with key regulatory digital space.” between different scanners and bodies, such as the FDA, requiring imaging software better color fidelity alongside other • A physical, slide-based device factors that determine diagnostic images from WSI systems will be may offer a good approach to reliability. In addition, the FDA very important in the future and has universal calibration believes that software analysis of therefore indicated that the analysis In Practice 31

www.thepathologist.com 32 In Practice

Original tissue as viewed Standard white balancing RGB standard values Scanner speci c ICC colour down the microscope by eye applied applied pro le applied

Figure 1. Different color representations of the same alcian blue-stained WSI scan. On the far left is the original image with no color correction; the three images to the right show the same scan with different color profiles applied. Images were captured on the same 12 MP camera, either from a calibrated monitor or down a microscope eyepiece. The act of digitally representing data such as this suffers from the paradoxical lack of color management for “truth” with the chosen digital medium; however, the use of the same camera for all figures is the closest available control. In Practice 33

software should be treated as a separate the output of a WSI device to identify corrected image is from a scanner with module in the medical approval process the device’s effect on color representation only standard white balancing applied (1). And that is only achievable if the through the digitization process. – a color correction that is likely to vary colors in the image being analyzed Creating a “truth” dataset is critical between scanner models in relation to are consistent and correct from one to the whole process and requires the differences in illumination source. The version of the same WSI system to use of specialist equipment calibrated to next is shown with only RGB standard another, and from one vendor’s WSI internationally accepted standards. Of values applied. The final image displays systems to those of another. equal importance is the precision of the the tissue with the scanner-specific ICC But color calibration and standardization color profile this calibrated equipment color profile applied. The color shows is complex. A significant degree of color generates, which is why color calibration clear variation in intensity across all variation exists between different WSI specialists work to International Color three images. Applying the RGB profile systems, and the method by which WSI Consortium (ICC), Commission improves the color representation of the systems observe color is different from Internationale de l’Eclairage (CIE), scan; however, it can’t compare with the the way the human eye does. All of this and ISO standards. improvement obtained by applying the means that images need to be processed ICC color profile, which most closely to interpret these differences. matches the original tissue as viewed through a microscope. The path to standardization Looking to the future, applying ICC How can we ensure that the colors of “How can we color profiles to WSI technology will also scanned specimens are the same when aid in the application and validation of digitally presented to a pathologist ensure that the artificial intelligence (AI) algorithms for as when viewed down a microscope? automated diagnostics. The algorithms And how can we ensure that those colors of scanned are then able to create, make decisions colors are the same regardless of the on, and work from data files to process systems on which they are scanned, specimens are the digital pathology images across disparate stored, and viewed? locations and scanner types. For AI To make sure WSI systems produce same when algorithms to be universally applicable images with an accurate replication of and medically reliable, we will need the stains used, one approach the FDA digitally presented rigorous validation and quality assurance suggests is color management using a of images fed into automated diagnostics unique slide-based device. The FDA’s to a pathologist as – including stringent control of color WSI guidelines (1) state, “The WSI management to ensure image fidelity. The system should be tested with a target when viewed application of color management using a slide. The target slide should contain a slide-based device has proven its potential set of measurable and representative color down a for ubiquity across WSI platforms and patches. Ideally the color patches should offers a subtle and integrable solution to have similar spectral characteristics to microscope?” this “pathology of digitization within stained tissue.” The document also digital pathology.” describes the need to create three datasets: truth, intended color, and Richard Salmon is Product Manager output color – a responsibility that I What difference does it actually make? – Life Sciences at FFEI, Hemel propose should lie with both the vendor Color calibration to device-specific Hempstead, UK. (to ensure that products are accurately ICC standards takes WSI scan fidelity calibrated prior to market) and the user to another level. Figure 1 shows an References (to ensure that systems remain calibrated alcian blue-stained tissue section as 1. N Anderson, A Badano, “Technical and validated for ongoing diagnostic viewed down the microscope alongside Performance Assessment of Digital Pathology accuracy). Essentially, this means three different representations of the Whole Slide Imaging Devices” (2015). obtaining a measure of the “true” color of same scanned image on the same Available at: https://bit.ly/2PUmsgQ. a stained sample and comparing it with calibrated display monitor. The first Accessed November 26, 2018.

www.thepathologist.com Virtual eSeminar Events Series On-Demand

1: NGS wet-lab workflow The future is now for NGS and guidelines Unlocking the FFPE block pathology. Are you ready? upstream and building confidence in downstream data 2: Demystifying big data in NGS cancer pathology Bringing state-of-art data As tumor profiling using DNA sequencing rapidly gains importance in interpretation and reporting within pathology, more laboratories are adopting NGS and more pathologists are reach of routine pathology labs looking to NGS data to deliver precision medicine in their clinical reports. 3: The next generation in However, adopting NGS is not easy. NGS Data Analysis Avoid the pitfalls. Know best practices. From data analysis basics to unleashing Attend our eSeminar Series: your inner informatician

Unlocking Precision Medicine: with NGS Tumor Profiling -From Sample to Report Register Free at: https://thepathologist.com/agilent/ NextGen

Research advances New technologies Future practice

36-39 Watch This Space! How can we predict which lung cancers may recur and which won’t? Examining the spatial arrangements of tumor-infiltrating lymphocytes may yield insight. 36 NextGen

Watch This Space!

Could the spatial arrangement of immune cells help reveal when aggressive chemotherapy is the right course of action for early-stage lung cancer patients?

By Anant Madabhushi

Patients with early-stage lung cancer have a head start from a diagnostic point of view. But once their disease has a name, it’s important to press that advantage by no such tests for lung giving them the right treatment as soon cancer – the most fatal as possible. However one of the critical cancer worldwide. My problems in early-stage lung cancer is colleagues and I recently predicting whether or not patients will discovered that the arrangement benefit from aggressive chemotherapy. of tumor-infiltrating lymphocytes In other cancers, predictive assays allow (TILs) is a prognostic signature of clinicians to identify which patients will early recurrence in early-stage lung receive added benefit of more aggressive cancer. Subsequently, we developed chemotherapy; unfortunately, there are an automated technique that uses their spatial architecture to predict patient outcomes. At a Glance • The number of tumor-infiltrating Looking into space lymphocytes (TILs) is associated Much of my career has involved linking with patient outcome in early- computer-aided diagnostics with digital “We developed stage lung cancer pathology, including the application of • A new automated method uses methodologies and algorithms for the an automated the spatial arrangement of TILs analysis of digital pathology slide images. to predict which early-stage Over the last 8–9 years, our focus has technique that patients will benefit most from shifted a little; we wanted to move away chemotherapy from using computational pathology uses [TIL] • The prognostic signature as a form of decision support for the separates patients by risk of pathologist, and instead explore how spatial disease recurrence and uses a deep computational pathology could play a direct learning approach to analyze role for the clinician. More specifically, architecture to digital pathology images we wanted to help oncologists modulate • Predicting the chance of disease therapy and manage patient treatment. predict patient recurrence is vital; up to 55 At the moment, we are attempting to use percent of patients relapse within computational algorithms in conjunction outcomes.” the first five years with digital pathology images to find NextGen 37

“It turned out that spatial arrangement was extremely important; in fact, significantly more so than the manual enumeration of TILs.”

technology for many aspects of digital pathology. We used targeted deep learning patterns that manual counting of TILs, the challenge to find the TILs and cancer nuclei initially, inform us about has always been trying to address issues but the subsequent spatial features and the aggressiveness with inter-reader variability. For that architecture were captured using a non- of disease. We hope reason, the first ambition of our project deep learning methodology known as a that these will ultimately was to use the spatial architecture of handcrafted feature approach (which we help us predict potential TILs to aid pathologists in counting. adopted to imbue some domain knowledge responses to therapy. In this In addition, we also wanted to use the into the process). One of the most critical respect, our goal has evolved from spatial arrangement of features to forecast aspects to me as a bioengineer is that there merely supporting the pathologist to prognosis and disease recurrence in early has to be feature and model interpretability; striving to develop companion diagnostic stage lung cancer patients. there has to be some degree of intuition tools for disease risk stratification and It turned out that spatial arrangement built into the classifier. That’s why, for me, treatment response assessment, making was extremely important; in fact, the most satisfying part of this research is decisions easier for the oncologist. significantly more so than the manual that it resonates with something we already I’ve been particularly interested in the enumeration of TILs. These features know about morphology of the disease: that concept of spatial nuclear architecture clearly separate the patients who are TILs are important. for a long time, especially in the context at high risk of disease recurrence (and I believe this combination of of grading breast and prostate cancer. who would therefore likely benefit from transparency and intuition is going to be The idea really took off when we started adjuvant chemotherapy following surgery) a critical facet of clinical adoption. One looking not only at the shape and number from those who are at a lower risk of of the challenges with deep learning is of immune cells, but also at how their recurrence and may not need adjuvant that, sometimes, it doesn’t quite provide spatial arrangement and architecture chemotherapy. The spatial architecture that transparency, and I have my concerns could be used to improve the grading of of TILs was prognostic in every one of that a lack of intuition and interpretability breast and prostate cancer, and therefore our data sets, providing good validation could potentially impede clinical adoption. benefit the pathologist. It’s already well of our initial hypothesis that arrangement Before clinicians make a call as to whether known in lung cancer that TIL number and architecture are critical. or not chemotherapy is needed, they are plays an important role in determining going to want to know exactly what’s prognosis and treatment response. But, Dipping into deep learning “under the hood.” And that’s why I find because there is a subjective element to the At the moment, deep learning is the go-to our approach so satisfying – because it

www.thepathologist.com 38 NextGen

resonates with what we know about the that will look at patients previously “We’re providing domain and has intuitive appeal. treated with surgery or surgery plus A vital aspect of the success of our test chemotherapy. Of those who were a risk score lies in making it simple for the end user – treated with surgery, we want to show the oncologist. In essence, we’re providing that we can identify which patients had a that gives a risk score that gives the oncologist easy higher risk of recurrence and would have access to clinically actionable information, benefited from adjuvant chemotherapy. the oncologist so we want to minimize the need for Additionally, of the patients treated training and learning. with surgery plus chemotherapy, we will easy access to attempt to identify the low-risk patients Space for progression who may not have needed chemotherapy. clinically We’ve already established that we have I think the signature also carries a prognostic signature, and we believe significant implications for other actionable that it will be validated in the future therapeutic modalities. There is currently as predictive of the potential added a great deal of excitement surrounding information.” benefit of adjuvant chemotherapy. We immunotherapy, and there has been are striving to begin clinical trials much interest in trying to understand NextGen 39

in clinics within 18–24 months. Once we have managed to prove that our prognostic signature is predictive, we must obtain “The TIL spatial regulatory approval from the US FDA. The beauty of our approach lies in the fact arrangement that we’re not destroying any tissue because we only use digital slides, so our validation signature from studies shouldn’t be too time-consuming. Indeed, we believe the technology can diagnostic biopsy be approved via a somewhat less onerous regulatory pathway. images also predicted Going global how well patients The fact that our concept potentially spans multiple different disease indications is would respond to very appealing. Joel Saltz and his group from Stony Brook recently wrote an immunotherapy.” excellent paper that looked at the spatial location of TILs within the tumor and stroma, and found that TIL position cancer anywhere in the world. The local was prognostic across multiple types pathologist or oncologist would simply of cancer. In cancers such as ovarian upload an image and analyze it with the cancer and triple negative breast cancer, algorithm to render a prediction – an the role of TILs has been linked with immediate change to the way cancers disease outcome and prognosis. Therefore, are diagnosed, staged, and treated although we’ve developed the signature throughout the world. using lung cancer, we absolutely intend to apply and validate it across multiple Anant Madabhushi is the F. Alex Nason disease stages and sites. For me, the Professor II of Biomedical Engineering most exciting part of this research is at Case Western Reserve University, and that it demonstrates the possibility for Director of the University’s Center for finding sub-visual signals and patterns Computational Imaging and Personalized whether patients who have more TILs in routinely acquired hematoxylin and Diagnostics, Cleveland, USA. will exhibit a better potential response to eosin (H&E) stain slides, which could immunotherapy than those with fewer help guide pathologists and oncologists References TILs. We have managed to show that in the future. 1. G Corredor et al., “Spatial architecture and the TIL spatial arrangement signature Although we’re working in a relatively arrangement of tumor-infiltrating lymphocytes from diagnostic biopsy images also new area of research, the impact that for predicting likelihood of recurrence in predicted how well patients would digital and computational pathology early-stage non-small cell lung cancer”, Clin respond to immunotherapy. Taken could have on global health is huge – and Cancer Res, [Epub ahead of print] (2018). together, these results suggest that our that’s very exciting. Expensive molecular PMID: 30201760. prognostic signature could help identify companion diagnostic tests have a big 2. X Wang et al., “Interaction of Tumor not only patients who stand to benefit market in Europe and North America, Infiltrating Lymphocytes and Cancer Nuclei from adjuvant chemotherapy, but also but large parts of the world are simply Predicts Response to Nivolumab in patients who stand to benefit from unable to afford these tests. Consider Non-Small Cell Lung Cancer (NSCLC)”. checkpoint inhibitor immunotherapy that, because our computational Presented at the International Association for for lung cancer. pathology approach can be carried out the Study of Lung Cancer’s (IASLC) 19th In terms of a timeframe for our vision, from an image alone, analysis can be World Conference; September 23-26, 2018; I believe we have a good shot at deploying performed for anyone with a specific Toronto, Canada.

www.thepathologist.com Meet… … the researchers overcoming the obstacles of bench-to-bedside research

Relauch.indd 1 29/01/2019 16:12 Profession

Your career Your business Your life

Meet… … the researchers overcoming the obstacles of bench-to-bedside research

Explore… … the technologies and techniques driving robust, cutting-edge life science Connect… … with the scientists, engineers and clinicians, who work together to improve global health Visit… … www.thetranslationalscientist.com 42-45 Lessons Learned, with Andrew Feinberg What has a decades-long career in epigenetics revealed about the nature, and the future, of the field?

Relauch.indd 1 29/01/2019 16:12 42 Profession

a medical degree after only two years of their future, which is an epigenetic Lessons Learned, of university. I applied on a whim and, trait, and this idea of epigenetic while working in France that summer plasticity stayed with me throughout with Andrew (for IBM again), I received a telegram my research career. That’s the idea that from my father saying that I had been eventually led me to conduct research Feinberg accepted at Hopkins and he had sent in into cancer epigenetics. a deposit. There weren’t any discussions From Cornell to Westminster about it, and he said I could change Abbey, Feinberg has traveled my mind. But I thought it sounded a compelling career path. good, and his judgment was probably “Throughout my Here, he describes his journey better than mine at 19 – so that’s how and offers his thoughts on the I became a teenaged medical student. career, I’ve always future of epigenetics Throughout my career, I’ve always had an instinct for finding really had an instinct for The importance of collaboration good teachers and collaborators, and I started out as a kid interested in I think that has been one of the most finding really mathematics and computers. I took important advantages I’ve had. I had a year of college math at Cornell the the good fortune of meeting eventual good teachers and summer after my junior year of high National Institutes of Health (NIH) school, then worked at IBM Research director Bernadine Healy when she collaborators, and after my senior year. I really thought was a resident and I was a second-year that was what I’d end up doing. I never medical student. She used to see me I think that has saw myself wanting to do biology in the pathology lab, trying to learn and absolutely never thought about to recognize tissues and diseases late been one of the medicine, but, during my sophomore at night, and she offered to tutor me year at Yale, I picked up a catalog out through it. I just about managed to pass most important of curiosity and noticed a five-year the course, which involved memorizing program at Johns Hopkins that led to slides and subtle differences in tissues advantages – a tough task for someone who can barely recognize peoples’ faces! I’ve had.” At a Glance Another great colleague of mine • Working alongside great mentors was Sam Barondes, and it was with and collaborators enables different him in the late 1970s, as a postdoc, perspectives to combine, helping that I first thought about epigenetics. After medical school and some solve complex problems Together we worked on Dictyostelium, clinical training, I did a second • Epigenetics is a relatively young the slime mold; we were trying to postdoc in the early 1980s with Bert but rapidly evolving field that solve the problem of differentiation Vogelstein. We specifically tested must be incorporated into the to understand the fate of its cells. the epigenetic hypothesis of cancer broader medical research picture There are two types of slime mold for the first time and discovered • The National Institutes of Health cells: vegetative and sporulating. I altered DNA methylation in human are one of the great triumphs of figured out a way to achieve density colorectal cancer compared with western civilization, but more separation of pre-spore and pre-stalk matched normal mucosa. As a funding should go to “high-risk, cells and label them differentially Howard Hughes Investigator at the high-reward” projects before reconstituting them into a University of Michigan, I continued • Because of the strong relationship vegetative state, or “slug.” When the these studies. I found another great between early life exposure and cells differentiated again, we were collaborator, Michael Debaun, a what happens to that person later amazed to see that they remembered pediatric hematologist at Washington in life, it is important to take an their former identity. It was clear to us University at the time, and we set up integrated view of the life cycle that they had some kind of “memory” a clinic for patients with Beckwith- Profession 43

www.thepathologist.com 44 Profession

Wiedemann syndrome (BWS), a My epiphany of missing heritability of disease – that congenital disorder that leads to Wilms I got a lot of skepticism for my early work is, that common variants do not explain tumor of the kidney. We showed that loss on epigenetics, especially by conventional most of the genetic risk. I couldn’t work of imprinting of IGF2 specifically causes “hardcore” transcription factor out how epigenetic traits were transmitted pre-malignant lesions in all BWS patients researchers. However, my persistence through many generations, which was with this abnormality, and half of them in epigenetics and a lot of evolutionary a common view at the time, but ran develop cancer – a 500-fold increase in biology study on my own resulted in what counter to my studies of the powerful risk. Without this epigenetic change, I like to facetiously call my “epiphany,” reprogramming in the genome we though, patients are not at increased risk. because it happened in Westminster see for imprinted genes. I was in It was the smoking gun that showed that Abbey. Prior to that, I had been trying London with my son enjoying some epigenetic changes can cause cancer even to understand how epigenetics could of the sights when it occurred to me: in the absence of genetic mutations. contribute to understanding the puzzle maybe there’s a role for stochasticity in Profession 45

human disease. It sounds like a scene injury. However, they also might will support your ideas. I understand from a movie, but I was standing in be aberrantly and constitutively why they take that approach and I front of Charles Darwin’s grave in reactivated in cancer, enabling the agree with it; they have to make sure November 2009 because a sign outside tumor to adapt epigenetically to a the money is well-spent and scientific Westminster Abbey announced that it changing environment. rigor is upheld. However, I’m constantly was the 150th anniversary of On the grateful that the NIH also supports Origin of Species. Next to Darwin’s innovative research. The NIH is, in grave is Isaac Newton’s grave, and my view, one of the great triumphs of you are not allowed to stand on it. our government, and its contributions Just above Newton’s grave is a plaque “Epigenetics stands to humankind are incalculable. In its in honor of Paul Dirac, one of the portfolio, I believe that “high-risk, founders of quantum theory in physics, right at the center high-reward” research is crucial; we which introduced stochasticity above should look for more ways to increase conventional Newtonian physics. of gene- it, particularly in areas where individual There was no such plaque in front institutes may not be able to fund some of Darwin’s grave, and the absence environment of the big trans-disciplinary ideas on caused me to realize that stochasticity their own and can collaborate with could be important if the environment interaction, and I other institutes to identify potential often changes. My idea was that breakthrough projects. multicellular, phenotypically complex believe it has a I also hope for epigenetics to be organisms that evolve in a sporadically incorporated more formally into big changing environment might develop huge role to play in human disease risk studies. Epigenetics genetic variants that themselves cause stands right at the center of gene- epigenetically mediated phenotypic predicting and environment interaction, and I believe variability. This would provide a it has a huge role to play in predicting selective advantage – for example, if mitigating human and mitigating human disease. In organisms have a growth advantage the future, we might be able to make in an environment with abundant disease.” epigenetic predictions about everyday nutrients, but then those nutrients life; for instance, by determining become scarce for many generations, what an individual’s diet should be to and then continue to switch back maximize health. Epigenetics is also and forth between the two extremes. High risk, high reward important in viewing the life cycle in It occurred to me at the same time Epigenetics is a branch of genetics an integrated way. There is a strong that this epigenetically mediated that I used to follow in its entirety, but relationship between prenatal and early stochasticity could also underlie now it has grown to the point where I life exposure and what happens to an tumor cell heterogeneity, which is what just can’t keep up with all of it. I think individual later in life, and it may had gotten me interested in cancer it’s wonderful to live in a state of some not be limited to a single generation. research years earlier in the first place. degree of ignorance, because it forces me Most importantly, epigenetic This idea would imply that there is to keep asking questions. My response diagnostics and therapy may be used a cellular mechanism for switching to that is to read widely and frequently, to tailor environmental exposure, epigenetic stochasticity on and off, but also to be prepared for unexpected and to deliver precision medicine to perhaps by the compartmentalization ideas to appear from nowhere, just both genetic and epigenetic targets to of large chromatin regions that waiting for me to grab them and start improve human health. contain varying degrees of intrinsic working through them – “How do I test noise. This stochasticity could be it out? What do I do?” I find this process Andrew Feinberg is Bloomberg helpful when cells need to change extremely exciting, but also a little Distinguished Professor of Medicine, their phenotypic state, such as in the scary – especially as grant reviewers Biomedical Engineering, and Mental epithelial-mesenchymal transition generally want you to have a substantial Health at the Johns Hopkins University in normal repair mechanisms after amount of preliminary data before they School of Medicine, Baltimore, USA.

www.thepathologist.com 46  Spotlight On...

Efficient specimen identification with the Signature Slide Printer

The Signature Slide Printer by Spotlight on... Primera Technology, designed for use in pathology and histology labs, Technology significantly increases the lab’s efficiency while helping to reduce the risk of specimen misidentification by directly printing onto slides, even in color. It can easily be integrated into existing LIS or can be purchased as a standalone system. http://dtm-medical.eu Sponsored Feature  47

LVEM 25 Low FioNA™– Fine Needle The Sapphire™ chip Voltage Transmission Aspiration Simulator Electron Microscope from Sawbones Crystal Digital PCR is Stilla’s next- generation technology for absolute The LVEM 25 is a perfectly suited Sawbones Fine Needle Aspiration Simulator quantification of nucleic acids. Using instrument when it comes to imaging (FioNA™) helps physicians, medical cutting-edge microfluidic innovations, this pathologic thin sections, providing students, cytotechnicians, and nurses practice technology integrates the Digital PCR well-contrasted and highly detailed and refine their fine needle aspiration skills. process in a single consumable. With Crystal images. The compact and easy-to- With FioNA™, users can now safely practice Digital PCR, the combination of powerful operate LVEM 25 is designed to be puncturing, aspirating material, and preparing image analysis and intuitive visual inspection installed where electron microscopy cytology smears: procedures that today offers an unmatched level of confidence in is needed most, creating seamless and are commonly practiced without previous the digital pcr measurement, yielding data efficient workflows. training experience and on live patients. you can truly trust. www.lv-em.com www.sawbones.com/fine-needle- www.stillatechnologies.com/naica-system/ aspiration-model-fiona.html

Milestone SealSafe - We listened. We learned. Faster decisions with Vacuum system for Now we lead. Olympus’ DP74 camera biospecimen management EKF Diagnostics has developed The DP74 brightfield and fluorescence Need a solution to improve your Quo-Lab, a semi-automated HbA1c camera: 60 fps live imaging, 20.7 MP diagnostic results due to unpredictable analyser, in conjunction with industry resolution, and faithful color reproduction. A pre-analytical? SealSafe is a vacuum experts to deliver a product that smart Position Navigator keeps track of your system that provides the flexibility to meets the requirements of NGSP location and returns to previous positions, receive specimens from the O.R. in fresh certification and CAP EQA criteria. an anti-whiteout function makes the live or in a monitored fixative condition. More Quo-Lab is setting new standards in image instantly available after every objective standardization with no more exposure HbA1c measurement. change, and automatic adjustment for low- to formalin fumes! To learn more visit www.ekfdiagnostics.com/ emitting fluorescent samples delivers rapid Milestone at USCAP. motion and clean still images. www.milestonemed.com www.olympus-lifescience.com 266x210 Immunology Ad-Print_Layout 1 06/02/2019 15:34 Page 1

Improve your awareness and stay up to date

Friday 29th March 2019 De Vere Colmore Gate, Birmingham

Immunology Diagnostic Service Update How to incorporate new tests and technology, improve quality and accuracy and nurture relationships

With immunology diagnostic service updates that you can’t afford to miss, this unique one day conference will bring you together with your peers to focus on how to incorporate new tests and technology, improve quality and accuracy in your immunology service plus how to nurture relationships and improve clinical practice.

Book your place today and benefit from the chance to investigate: • The practicalities of applying assays to new diabetes antibodies • Lupus (SLE) Extractable Nuclear Antigen (ENA) Antibodies assays • Should we stick with immunofluorescence or switch to new testing technologies? • ANCA testing guidelines for vasculitis • Ensuring accurate interpre tation and validation of results SPECIAL DISCOUNT • Driving forward quality assurance and best FOR practice in your immunology service The Pathologist • What makes paediatric immunology testing READERS: different to adult services? Quote AL1926 and receive Its time for Oncomine Dx Target Test— • What information and support do GPs need from immunology services? £110 OFF (This offer cannot be used the right choice for your patients in conjunction with any other offer.) For further details visit www.sbk-healthcare.co.uk Analyze all key biomarkers for EGFR, ALK, BRAF, and

Tel: 01732 89 77 88 | Twitter: @SBKevents | [email protected] | www.sbk-healthcare.co.uk ROS1 kinase inhibitors, and many more currently in clinical trials, from one sample, in one report, in 4 days Application Note  49

Among the biomarkers tested are not only EGFR,ALK,ROS1 Oncomine Dx Target and BRAF but also cMET, NTRK1/2/3, RET, ERBB2, and Test – an IVD NGS others, currently in clinical trials. Based on technology proven in many clinical oncology research solution for every lab trials, such as NCI MATCH, the Oncomine Dx Target Test can deliver results from a minimal FFPE tissue sample with a success rate over 93 percent, which makes With the ongoing development of precision it suitable for routine patient sample testing. oncology and more and more biomarkers It comes as part of a complete, end-to- entering routine clinical testing, a true end solution including bioinformatics end-to-end IVD solution, consolidating and application service, so even if your everything into one streamlined laboratory has no experience with NGS, workflow, is needed in more pathology you do not need to worry about additional laboratories. The Oncomine Dx Target expertise. Our clinical application Test, based on next-generation sequencing specialists team will take care of you. (NGS), is now available in Europe and offers just that – 46 gene targets, including Learn how your lab can enter the NGS biomarkers associated with approved and era. Now, NGS is here for everybody. investigative targeted therapies, all from https://www.oncomine.com/dx/testing- one test, in one workflow, and in four days. methods-eu

Its time for Oncomine Dx Target Test— the right choice for your patients

Analyze all key biomarkers for EGFR, ALK, BRAF, and ROS1 kinase inhibitors, and many more currently in clinical trials, from one sample, in one report, in 4 days The Epigenomic Explorer

Sitting Down With… Benjamin Garcia, Presidential Professor of Biochemistry and Biophysics and Director of Quantitative Proteomics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA Sitting Down With  51

Congratulations on receiving the 2018 amazing mentor – from the first day we expression was first suspected, we have Biemann Medal for your contributions met right up to the present. I came into certainly made progress, but there are to elucidating the histone code! his lab as part of a summer undergraduate still many unanswered questions. I’m It’s an amazing honor. Every person research program, knowing nothing about excited about taking our fundamental who has received this award has been analytical chemistry; he engaged with knowledge and applying it to health and an incredible pioneer in the field and me and held me accountable. I really disease by reprogramming a diseased has made significant contributions. I felt that I was part of the group. He also epigenome with small molecule inhibitors am overwhelmed to have my name on introduced me to several well-known or histone-modifying enzymes. I truly the same list as theirs, and to continue scientists who went on to become mentors believe that is a feasible long-term goal. deserving my place on that list, I feel that to me, such as Jack Beauchamp, for whom I use the analogy of a computer: the I must still achieve more! I worked at Caltech. In graduate school, computer hardware is your genome, but I worked with Donald Hunt, studying no computer works without the software When you said “it takes a society to tandem mass spectrometry of complex to control it, and the epigenome is that raise a scientist” in your acceptance biological mixtures. It was amazing to be software. If a virus infects your computer, speech, what did you mean? around a scientist of that caliber – very you can often combat it by resetting the In any field – and especially in science – few people have the vision he has. He is computer to its original state. I think we achieve very little alone. To become a great mentor and knows exactly how we’re going to be able to do that in independent, rigorous scientists with much flexibility and freedom to give you. human disease states. the vision to ask and answer important By that stage, more was becoming known questions, we must be trained and about histone modifications, but it was all mentored, supported and encouraged. bottom-up mass spectrometry looking at I definitely couldn’t have become the a few modifications at a time. I knew we scientist I am without that support. Even needed to take a broader approach, so I “The most creative now, I’m not doing it alone; I have a applied for a postdoc in Neil Kelleher’s fantastic research group with scientists group. Neil is an incredible, infectiously and productive at all levels and from all backgrounds. enthusiastic scientist, and it was the perfect training with him – both in top-down times in my group Many minority groups are proteomics and in running a group. Lastly, underrepresented in science. How can David Allis (Rockefeller University), who have been when we change that? won the Lasker Award for his chromatin As a young scientist, not seeing research, has been a collaborator, mentor, the lab has been at people like you at faculty level can and friend for a long time as well. be discouraging. It’s a catch-22. We its most diverse.” don’t have enough senior scientists Why did you choose to focus from underrepresented groups, so the on histones? next generation may not think it’s an Quite simply, because they are such achievable goal. I cannot change the amazing proteins. I’m fortunate that whole field, but I can work hard to bring the fields of proteomics and epigenetics What do you hope to achieve in diversity to my own lab. Diversity isn’t just have taken off and I’m at the crossroads your career? a worthy goal in its own right, but hugely of both. But I didn’t have a master plan; I won’t judge my ultimate success on beneficial to our work – the most creative I just kept studying what I was interested the scientific breakthroughs I make or and productive times in my group have in, without thinking too hard about what the awards I receive – gratifying as it is been when the lab was at its most diverse. would be “fundable” in future or whether to be recognized by my peers. Instead, I’d be able to build a career. when I look back on my career, I will Who have been your most judge myself on the impact I have had on influential mentors? What upcoming projects are you others. Seeing those I have trained and During my undergraduate studies at excited about? mentored take their place as leaders across the University of California, Davis, I Fifteen years or more since the role of multiple fields would be more satisfying met Carlito Lebrilla, who has been an histone modifications in controlling gene than any award I could ever receive.

www.thepathologist.com Experience The Power of Advanced Automation...

Designed to meet the needs of all IHC laboratories. VALENT is a uniquely open and flexible IHC staining platform that provides ease-of-use, full automation, high-throughput, and the quality staining results your lab requires.

Unmatched Open System Versatility High-Throughput Performance The open design of VALENT supports the transition of VALENT breaks the 30-slide barrier with true parallel your laboratory’s custom IHC protocols to fully automated, processing of 48 slides simultaneously, boosting walk-away workflows: saving valuable staff time. laboratory throughput with minimal user interaction.

Learn How VALENT Can Automate Your Lab: biocare.net/pathologist

Biocare Medical is a global leader in solutions for cancer research and diagnostics. We provide world-class reagents and a comprehensive suite of advanced instrumentation for IHC, molecular and histology testing. Our advanced platforms of semi and fully-automated instrumentation are designed to meet every need from high throughput clinical diagnostics to flexible research requirements.