PATHOLOGY ◆ LABORATORY MEDICINE ◆ LABORATORY MANAGEMENT APRIL 2019

Next act in genomics: the consumer orders

Karen Titus testing. Others prefer consumer- access testing, placing them both in or rather, a digital screen—even the
For years, laboratories have chafed facing testing. the category of consumer genomics. phrase “test menu” takes on a differ-
against testing being, literally and Jill Hagenkord, MD, adds a few Whatever the phrase, the shift is ent tone. Menus aren’t being handed
figuratively, an out-of-sight, out-of- more to the mix. Dr. Hagenkord, chief striking. Patient-centered care sounds only to clinicians who order for them-
mind transaction. Now a new, highly medical officer at Color Genomics, almost quaint. With consumers pull- selves and patients, like a well-heeled
visible era in genetics may be pushing refers to direct-to-consumer and easy- ing up their own chairs to the table— gentleman —continued on 20
testing the other way, into the hands
Cindy Charles

of consumers who value entertain-

ment as well as medical information.
Study gauges impact
Anyone who wants to write a book of genotyping on
about this shift has a ready-made title:
From Basement to Big Top. gonorrhea treatment
It’s not that clinical testing is be- Amy Carpenter Aquino
coming an actual circus. But ever Genotypic testing for ciprofloxacin
since the first consumer genetic tests susceptibility in Neisseria gonor-
entered the market in 2007—in a non- rhoeae has been proved to be effective
physician-ordered, SNP array tech- in guiding physician treatment in a
nology way—labs, physicians, and single-center study at UCLA Health.
regulatory agencies have had plenty Jeffrey D. Klausner, MD, MPH, a
to juggle. Today that includes rela- clinical professor in the Department
tively affordable sequencing, DNA of Medicine, Division of Infectious
ancestry searches, and patient em- Diseases, and the Department of
powerment. Throw in a little Silicon Epidemiology, David Geffen School
Valley verve, and we arrive at the of Medicine and the Fielding School
present: presumably healthy consum- of Public Health, University of Cali-
ers who want a peek at their own fornia, shared the details of the
genetic profiles. study at last year’s Association for
Some call this consumer-directed Molecular Pathology meeting and in
a recent interview.
Dr. Jill Hagenkord (right) with Wendy McKennon, vice pres- “The overall concept is that with
ident of product and user experience, at Color Genomics. rapid detection of Neisseria gonor-
“We’re all part of this first group of clinical pathologists rhoeae, and detection of key antimi-
and laboratories that are actually doing real consumer crobial resistant genes, we can en-
genetics,” Dr. Hagenkord says. able doctors to do —continued on 32
MICROSCOPY’S DANGERS:

From wear and tear to disabling injury

Anne Paxton Ewaskow, of Pacific Pathology Part- people in any immobile, static posi-
When pathologist Sandra Ewaskow, ners in Seattle. “I said I would write a tion all day are likely to encounter
MD, was asked at a recent medical book on pathology and ergonomics.” problems. From the standpoint of
conference what topic she would The idea touched a nerve. “The ergonomics, it’s not only the micro-
choose if she were to write a book in rest of the meeting, for days, different scope but also other elements of pa-
address with corrections to CAP TODAY: 847-832-8153.
Vol. 33, No. 4 Moving? Fax a copy of the below

her field, she thought of her own expe- specialists in pathology, primary care, thology work that are hard on the
rience with musculoskeletal pain and orthopedics, and surgery kept com- body. “Practitioners are spending so
of her mother, who had recently been ing up and saying, ‘You’ve got to much time at the —continued on 42
hospitalized for occupational therapy write that book. We sit
after a hip fracture. “It was very much at a computer all day
on my mind, the kinds of things she and we have those is- Too few
had to do to get comfortable and re- sues in our practice.’”
train her body to move,” says Dr. In fact, she notes,
technologists
Labs finding new solutions
Head tk Page 14
Subhead tk
subhead tk Page xx
Melissa Pessin, MD, PhD

0419_1-46_Genomic-Ergonomics-Ngonorrhea_v4.indd 1
APRIL 2019 4/9/19 3:11 PM
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 APRIL 2019 | CAP TODAY 5
QUANTITATIVE IMAGE ANALYSIS

In guideline, preliminary rules for pathology’s third revolution

Anne Paxton to detect and quantify HER2 membranous IHC as opposed to information provided by inference.
With the release in January of a new guideline for staining of invasive breast cancer cells, and to pro- Developing the recommendations was difficult,
quantitative image analysis of HER2 immunohisto- vide an accurate, precise, and reproducible quantita- he says. But it won’t be the last word by any
chemistry for breast cancer, the CAP believes it is tive HER2 result. After conducting a systematic re- means. Continuing work on QIA standards will
filling a gap and blazing a trail for the profession. In view of the literature and choosing eight published be needed. “It wasn’t one protocol that fits all. We
setting evidence-based standards, the guideline studies for its evidentiary base, the QIA expert panel did a very small slice of what will have to happen
provides background and details about the quantita- produced seven recommendations and four expert in the future. And that will not happen easily be-
tive image analysis (QIA) process and the data and consensus opinions for improving accuracy, preci- cause there are way too many pieces of technology
metadata it generates. The guideline will help facili- sion, and reproducibility of HER2 IHC results for in this pipeline.”
tate pathology’s increasing use of not only digital breast cancer (Bui MM, et al. Arch Pathol Lab Med.
pathology but also artificial intelligence, says Mari-
lyn Bui, MD, PhD, chair of the CAP expert panel for
QIA of HER2 IHC. “This is not just another guide-
Published online ahead of print Jan. 15, 2019).
The panel’s strongest recommendations: Labora-
tories should require validation of their QIA systems
S tudies have shown, Dr. Bui says, that digital
image analysis correlates better with pinpoint-
ing the correct molecular subtype of tumor than
line. It is a milestone for pathologists.” and procedures before implementation and must manual biomarker assessments in breast cancer,
The CAP and the American Society of Clinical ensure regular maintenance and evaluation of qual- including HER2. Nevertheless, “Quantitative image
Oncology have issued clinical practice guidelines for ity control and quality assurance. Pathologists with analysis has not yet gained widespread acceptance,”
testing, interpreting, and reporting of HER2, but expertise in HER2 QIA should supervise perfor- she says. A 2016 CAP survey revealed that 22.15
those guidelines do not address QIA standards. The mance, interpretation, and reporting, the guideline percent of 826 laboratories enrolled
new QIA guideline picks up where those guidelines recommends. in the CAP Histology Quality Im-
left off. When used for HER2 IHC, QIA’s purpose is The expert panel chose a breast cancer biomarker provement Survey were using QIA
for this initial QIA guideline because breast cancer tools. “The majority were still do-
CAP TODAY APRIL 2019 Vol. 33, No. 4 is a common cancer with a broad impact and every ing manual reading.”
Copyright 2019 by the College of American Pathologists. All rights reserved. breast cancer patient needs to be tested for HER2 All members of the QIA expert
None of the contents of this publication may be reproduced, stored in a
retrieval system, or transmitted in any form or by any means (electronic,
and ER/PR, says Dr. Bui, senior member of pathol- panel strongly believed in the
mechanical, photocopying, recording, or otherwise) without prior writ- ogy and president of the medical staff, Moffitt Can- merit of HER2 QIA, Dr. Bui re-
ten permission of the publisher. Views and opinions expressed in CAP
TODAY are not necessarily endorsed by the CAP. cer Center, Tampa, Fla., and president of the Digital ports. “But the general sense from Dr.Bui
President: R. Bruce Williams, MD Pathology Association. “We decided on HER2 be- pathologists in the field varies.
President-Elect: Patrick E. Godbey, MD
Secretary-Treasurer: Richard R. Gomez, MD cause it is a more difficult stain to read than nuclear Some may feel that if you use QIA, that means a new
Governors: Timothy Craig Allen, MD, JD; Alfred Wray Campbell, MD, stains. We narrowed our focus to IHC only for now, set of guidelines to follow as well as a new set of
MBA; Rajesh C. Dash, MD; Eric F. Glassy, MD; Jennifer L. Hunt, MD, MEd;
Bharati S. Jhaveri, MD; Donald Steven Karcher, MD; Jonathan Louis Myles, not FISH or ISH yet.” checklists.” With the guideline, “We’re saying if you
MD; Raouf E. Nakhleh, MD; Richard M. Scanlan, MD; Emily E. Volk, MD;
Nancy A. Young, MD
The need to validate the QIA system, algorithm, are practicing QIA, and believe these are the best
President, CAP Foundation Board: Guillermo G. Martinez-Torres, MD and procedure was a key concern of the expert panel. ways, we hope you will find the guidelines are ev-
Speaker, House of Delegates: Kathryn T. Knight, MD “The Food and Drug Administration only regulates idence-based and practical.”
Vice Speaker: Sang Wu, MD
Residents Forum Chair: Adam Lee Booth, MD the manufacturer to ensure that the product is safe The most important guideline among the 11 state-
Chief Executive Officer: Stephen Myers
and does what it claims to do,” Dr. Bui says. “We ments, in her view, is No. 10: The pathologist who
Medical Editorial Board to CAP TODAY: Marilyn M. Bui, MD, PhD, chair;
Dorothy M. Adcock, MD; Philip T. Cagle, MD; Sarah Amelia Donnell, MD; need to evaluate it in our laboratory with real patient oversees the entire HER2 QIA process used for clini-
Donna E. Hansel, MD, PhD; Frederick L. Kiechle, MD, PhD; Samuel McCash,
MD; Deborah Ann Sesok-Pizzini, MD, MBA; Gene P. Siegal, MD, PhD; Mary
samples used in similar practice sessions and con- cal practice should have the appropriate expertise in
K. Washington, MD, PhD; Shi Wei, MD, PhD; Thomas L. Williams, MD; Carla tinue to watch the system to make sure it is doing this area. For laboratories already conducting the
S. Wilson, MD, PhD
Contributing Editors: Raymond D. Aller, MD; Nancy E. Cornish, MD;
the right thing.” types of QIA in the guideline, she says, this recom-
Robert P. DeCresce, MD; Donna E. Hansel, MD, PhD; Shaomin Hu, MD, In writing the guideline, the panel had two objec- mendation should pose no additional burden.
PhD; Rouzan Karabakhtsian, MD, PhD; Mark S. Lifshitz, MD; Frederick L.
Kiechle, MD, PhD; Nicole C. Panarelli, MD; Deborah Ann Sesok-Pizzini, tives, says panel member John E. Tomaszewski, MD, “Pathologists are in the front and center of preci-
MD, MBA; James Solomon, MD, PhD; Rachel Stewart, DO, PhD; Hal Weiner;
Richard Wong, MD, PhD
chair of pathology and anatomical sciences at the sion medicine. We are practicing pathology in a
Editorial Office: College of American Pathologists University of Buffalo Jacobs School of Medicine. historical moment. Some call it the ‘third revolu-
325 Waukegan Road, Northfield, IL 60093
847-832-7000; fax 847-832-8153; Subscriptions fax 847-832-8153
“We reviewed the literature of image analytics ap- tion’ in pathology. The first was when IHC was
Publisher: Bob McGonnagle, 847-832-7476 plied to pathology data, especially in reference to introduced; the second was when molecular diag-
Editor: Sherrie L. Rice, 847-832-7504, srice@cap.org
Managing Editors: Kimberly Carey, 847-832-7249, kcarey@cap.org;
HER2, and we then grappled with the different nostics was incorporated into pathology. The third
Karen Titus aspects of those image analytics vis á vis what is is whole slide imaging, which gives rise to compu-
Senior Editor: Amy Carpenter Aquino, 847-832-7245, aaquino@cap.org
Associate Editor: Kristen Eberhard, 847-832-7649, keberha@cap.org considered ‘ground truth’”—that is, empirical evi- tational pathology and artificial intelligence.”
Circulation Director: Kimberly Gilfillan, 847-832-7456, fax 847-832-8153,
subscription@cap.org
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APRIL 2019 page 5 4/8/19 2:42 PM
 6 CAP TODAY | APRIL 2019

Quantitative image analysis
continued from 5
shown that artificial intelligence has great potential
to assist pathologists in providing better care, Dr. Bui
notes. “The federal government reported in 2016 that
a top artificial intelligence system has an error rate
of 7.5 percent while a top pathologist has an error
rate of 3.5 percent in identifying metastatic breast
cancer in lymph nodes. But when you combine AI
with the pathologist’s skills in practice, you get an
error rate of only 0.5 percent. That’s one reason why
the government is interested in ‘deep learning’ in
medicine,” she adds (referring to a method of ma-
chine learning based on learning data representa-
tions, as opposed to task-specific algorithms).
Some pathologists have greeted this revolution
with wariness or resistance. “Some refuse to accept
it. They say, ‘It cannot do better than I can; I don’t
trust it.’ But when the evidence is proving that the
machine can do better in certain tasks, then many
get scared they will be replaced.” Similar reactions
were seen in 1848, she says, when microscopes were
a disruptive technology and there were warnings
that it could never become employed in ordinary
practice. “For people who are hesitating to adopt
digital pathology, that puts things in perspective.
Digital pathology and artificial intelligence are here
to stay and will continuously transform the delivery
of precision medicine.” But pathologists should not
worry that AI is going to replace them anytime soon,
she says, urging pathologists “to prepare and find a
way to control the direction in which this is going so
it will come out better for patients and
the profession.”
“With conventional pathology, we
have a microscope and we read glass
slides. We are limited by location and

P P
time, and if you want to share, the per-
son can only view it through another

Save More Lives.

head connected to the scope,” Dr. Bui
notes. “The data is analog, which is dif-
ficult to share, analyze, compare, search,
retrieve, and integrate. With whole slide
imaging, the analog data is transformed

P by screening for colorectal cancer. to digital data, which can be shared

without limitation of space or time. It is

P
permanent, searchable, manageable,
and integrable.” Most important now,
she says, is that this digital information
can be analyzed by algorithms or more
sophisticated artificial intelligence such
as deep learning.
Dr. Bui says artificial intelligence can
Automated FIT Blood Test for Colorectal be a formidable ally to pathology. “It
can detect and find things, including
(Fecal Immunochemical Test) Cancer Screening rare events that are tedious for patholo-
gists to look for like acid-fast bacilli to
Only FDA approved automated FIT FDA Approved for colorectal diagnose tuberculosis. It can quantify.
cancer screening for people who If you want to count stains, infiltrating
Recommended FIT by the USPSTF are unwilling or unable to be lymphocytes, or percentage of tumor
- “The OC-Light and the OC screened by recommended necrosis, we believe the AI will do bet-
FIT-CHEK (OC-Auto) family of methods. ter. And classification is the third thing.
FITs (Polymedco, Inc., Cortlandt It can decide, for example, is this a tu-
Manor, NY) have the best test Epi proColon is a molecular test mor or not? Is it a low-grade or high-
performance characteristics that detects methylated Septin 9 grade tumor?” There are also algo-
(i.e., highest sensitivity and DNA in blood. rithms to improve workflow and effi-
specificity).” 1 ciency, and published data showing the
DNA methylation of the SEPT9 prognostic and predictive value of AI.
1 patient sample gene is increased in colorectal “It lets us improve quality and effi-
cancer. ciency with new ways of looking at
Completely closed sampling pathology data to make clinically ac-
bottle Methylated Septin 9 DNA can be tionable knowledge and present it to
found in tumor DNA that has been clinicians to help with decision-mak-
Convenient patient take home shed into the bloodstream from ing,” Dr. Bui says.
packs and absence of dietary proximal and distal colon and Given all the pathology information
restrictions for maximum patient rectal sites, making it a differential available, “we feel right now we have
compliance biomarker for the early detection only scratched the surface of the infor-
of colorectal cancer. mation and data from the samples we
study. With immunohistochemistry we
can now get into the cellular level, with
molecular information we get to the
genome level, and at the digital pathol-
“Increasing screening rates to 80% by 2018 would prevent 277,000 new
cases of colon cancer and 203,000 deaths within 20 years.”2

P
P ogy level we will be able to combine
all this together with clinical, radiologi-
cal, and longitudinal information on
prognosis to predict what will hap-
pen—that’s the power of digital pa-
thology in the era of precision medi-
www.polymedco.com cine,” Dr. Bui says.
info@polymedco.com Although it took about three years
1. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/colorectal-cancer-screening2
2. http://www.cancer.org/cancer/news/news/impact-of-achieving-80-by-2018-screening-goal 800-431-2123
to develop the QIA —continued on 8

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 8 CAP TODAY | APRIL 2019
Quantitative image analysis
continued from 6
guideline, it is only the tip of the iceberg, Dr. To-
maszewski agrees. He believes the field must pre-
pare for a complete change in how anatomic patholo-
gists conduct diagnostics. “It will be based on digital
pathology and computational pathology skills. The
digital pathology part is how you get an image, how
you do a scan, the quality of the scan, basically what
is the information in the pixels.”
“The ability to get a high-resolution image and
know where a pixel is and its resolution as an image
has drastically changed over the past 15 years,” he
says. “The cameras and sensors are way better than
they were.” Similarly, the speed of computer process-
ing has soared. “Maybe eight years ago, if I took an
algorithm we had and ran it on a case it might take
Screen shot of an invasive ductal carcinoma of the breast with brown membranous immunohistochemical
staining of HER2. An FDA-approved quantitative image analysis algorithm was applied to the whole slide image
to render the HER2 score. The areas selected by the responsible pathologist within the green lines are scored. of making the guideline we
weeks; it took a whole Linux cluster to run the thing.
Now we can do it in seconds on a desktop with a
GPU chip in it.”
The third and biggest advance is the algorithmic
approach to computing on an image, Dr. Tomasze-
wski says. “The computational pathology world is
how you use an algorithm on those pixels. With the
whole artificial intelligence explosion, computational
pathology is getting real big, real quick.”
Because AI involves an algorithm that learns, it
is an algorithm that constantly changes, he ex-
plains. “In a laboratory view of the world, we will
have to grapple with that probabilistic aspect of
data, as opposed to a deterministic approach to
data. As laboratories, we don’t know how to deal
with that probabilistic approach to data in applica-
tion, and our clinical colleagues certainly don’t
understand it.”
In this decade, there has been a surge in use of
neural networking (information processing modeled
after the human brain and the way it learns) and
deep learning, which can delve deeper into data to
develop predictions. These testing modalities allow
image analytics devices to handle massive amounts
of data and learn on their own. To address the im-
plications of deep learning, “We have to come to-
gether with a quality management system or sys-
tems that meet the needs of safety, and we don’t
know how to do it yet,” Dr. Tomaszewski says.
Down the line, “We’ll need to have a very robust
discussion. This guideline is a very targeted pre-
amble of a much bigger issue.”
“Stay tuned” is his message, he says—not “Be
afraid.” People should pay more attention to this
0419_5-11_QIA-PrezDesk-4.indd 8
new technology, but they should not fear it be-
cause it will allow pathologists to capitalize on
their strengths, he says. “Pathologists think in
very systematic ways because we have to. We
need to be early adopters, because we’re better
positioned than anybody else in medicine to do
this leap into the new machine learning environ-
ment with all our data.”
A s the only non-pathologist on the QIA expert
   panel, Anant Madabhushi, PhD, director of the
Center for Computational Imaging and Personalized
Diagnostics at Case Western Reserve University, saw
part of his role as clarifying the algorithms behind
computational imaging. “For a lot of pathologists,
it hasn’t been immediately clear how these algo-
rithms work. Many people think of AI as one box
or one algorithm, but it is not. So in the discussions
we needed to understand
the spectrum of algorithms.”
That included understanding
the two main types of ma-
chine learning: “supervised”
algorithms—where the out-
put values are known and
the algorithm discovers how
the input data lead to those
values—and “unsupervised”
algorithms, which are left to
their own devices to discover
useful patterns within unla-
beled data.
“What was refreshing to
me is that through this process
made a meticulous effort to
understand the variety of algorithms,” Dr. Madab-
hushi says. But narrowing the scope of the guideline
was also important. “The plans for setting standards
for image analysis were originally more grand. But
we realized we couldn’t boil the ocean. There were
too many ways and directions we could go. So ulti-
mately we decided to just look at quantification.”
For him, one of the guideline’s most important
recommendations is No. 5: Laboratories should
monitor and document the performance of their QIA
system. “The commonality among many algorithms
is that they need to be calibrated or validated from
time to time,” Dr. Madabhushi says. “No matter how
good your algorithm is, if there are preanalytic or
other factors that affect parameters like the appear-
ance and color of the image, the parameters start to
‘drift,’ and it is going to affect the image analysis
algorithm.”
For example, “Say you have an approach that is
focused on quantifying HER2 and requires a number
to do that. If the value of a stain is above some thresh-
old, then you identify it as HER2-positive; otherwise
it’s negative. The problem is if your scanner or other
preanalytic variables suffer from a drift effect, they
can have dramatic effects on your results.”
“That was the basis for the guideline’s emphasis
on continued assessment of systems: to ensure, fairly
rigorously, that there is a system in place to assess
the drift of the algorithm for consistency and us-
ability. We stressed the need to go back and revisit
and recalculate and reassess whether the approach
is providing consistent, useful results,” he says.
The capability to conduct QIA potentially allows
for improving efficiency and workflow, removing
bottlenecks, and empowering pathologists to pro-
vide more precise diagnoses that will help manage
treatment, and the guideline will help achieve that,
in his view. But the broader hope of the expert panel
is that the guideline will serve as a
template for guidelines put for-
ward for other quantifications as
well, as AI makes its way into
other areas—for example, the mi-
totic count as an indicator of tumor
cell proliferation. “There is a huge
amount of variability there be-
Dr.Madabhushi
cause normally mitotic count is
done manually. We have a number
of different folks working on algorithms,” he says,
but “there are grand challenges” left to meet in the
quantification of mitosis.
The expert panel did not opt to make the guide-
line on AI because it would have been too large an
undertaking at this point, Dr. Madabhushi explains.
But he believes the need for continued assessment
of the system cannot be overstated. “It’s not just
about the image analysis factors. In my mind, con-
tinuously monitoring and calibrating the system is
a core message for AI in general.”
A number of published papers have reported the
troubling finding that AI is not necessarily translat-
ing from site to site, he says. “Our own group has a
lot of examples where we have found if we train the
AI on data from one site, it didn’t work on data from
another site. So carefully evaluated consistency and
reproducibility of results is a critical consideration,
not just in the context of guidelines but in the bigger
picture in pathology.” The QIA expert panel hopes
the guideline will contribute to greater consistency
in identifying HER2 as positive or negative. “We
know there is still a huge amount of variability from
manual reading, and even with the image analysis
algorithms there tend to be variations.”
Because of the potential sensitivity of these algo-
rithms to the data they are trained on, he says,
changes in a scanner or other preanalytics may keep
the algorithms from performing correctly, which
means recalibration may require retraining of the
neural network. For that reason, it is crucial to con-
stantly evaluate the output of the QIA algorithm.
“Don’t assume those results that the IA algorithm
produces are going to consistently perform exactly
the way you envisioned.”
As deep learning algorithms for QIA of digital
pathology images evolve, they might lead to further
recommendations, the guideline notes. “I can envi-
sion in the future, if deep learning algorithms be-
come more prevalent, we may have to revisit the
standards and think about how to evaluate the
consistency and reproducibility of these QIA ap-
proaches,” Dr. Madabhushi says.
F urther QIA standards development is already
  on the calendar. The QIA guideline is slated for
review every four years or more often if substantive
and high-quality evidence is published that could
potentially alter the recommendations. Quality as-
surance in whole slide images will be the next target
of the CAP’s image analysis standard-setting, Dr. To-
maszewski says. That includes scanning platforms
and the quality of data that come out of scanning,
plus the human perception of images based off
those data.
All of those need separate sets —continued on 11
APRIL 2019 page 8 4/8/19 2:42 PM
 Sebia FILE— NEW
0419_TABs-Sebia-Hse-8.indd 9 APRIL 2019 page 9 4/2/19 4:14 PM
 Agena Bioscience
0419_TABs-Abbott-ComputerTrust-9.indd 10 FILE— NEW APRIL 2019 page 10 4/2/19 3:35 PM

from the
President’s Desk
R. Bruce Williams, MD
CAP Learning: building on feedback
As Dr. Seuss famously wrote, “It is fun to have fun,
but you have to know how.” CAP Council on Edu-
cation chair Jennifer Hunt, MD, MEd, agrees. Learn-
ing styles evolve as we mature, she says; grownups
are not just tall children. We know what we want
to do and are drawn to knowledge we can use.
Most pathologists are born educa-
tors; we can’t help ourselves. We like
to think about how we learn. I think
that’s why the CAP Learning team
does such an outstanding job—they
know what to ask, how to listen, and
when to act. Participant evaluations
are scrutinized and what we learn
from them is applied quickly.
CAP education is unique because
it is so tightly targeted to pathologists,
but that’s not the whole story. CAP
Learning set out in 2016 to update
our education design strategy, which
considers tools and educational
methods we use, parameters we set,
and goals we agree to pursue. Con-
currently, they launched a needs ana­
lysis via one-on-one member inter-
views that shaped agendas for focus groups whose
feedback uncovered problems and opportunities.
The new tools and methods to achieve the strategy
are now emerging in live and online workshops and
courses. These robust and dynamic options are spon-
taneous, challenging, and, importantly, respectful of
the learner’s time. Modular formats, sometimes called
bite-size learning, allow participants to complete
coursework in one or several sessions as convenient.
For example, “Creating a Culture of Patient Safety”
covers epidemiology, systems-based thinking, human
factors and cultural aspects, communication, error, and
quality improvement across seven individual modules.
“Managing Your Revenue Cycle for Success” takes the
learner to where the rubber hits the road in practice
management. Nine lessons cover everything from how
pathology practices monitor their revenue streams to
which management choices will most affect the bottom
line. What calculations need to be made and how of-
ten? Which functions can be outsourced? Where do
you start? “Negotiation Strategies for Pathologists” is
another example. Participants learn the skills they need
to gather and organize the right information for suc-
cessful negotiation, including how to separate the
person from the problem and find common ground.
Quantitative image analysis
continued from 8
of guidelines, he says. “The algorithms themselves,
plus the codes used to calculate all the pixels in the
images, will have to be quality controlled.” The task
of “shedding light on the black box” is a responsi-
bility of the pathology profession, he says. “We
cannot, as domain knowledge experts, just say,
‘That algorithm has output x and that’s all I need
to know about it.’”
0419_5-11_QIA-PrezDesk-4.indd 11
Our education is becoming more flexible, allow-
ing learners to find the content they need easily,
when and where they need it. You’ll be accessing
more courses from your mobile devices and partici-
pating in more audience response from your phones.
There will be more interactive videos, where pa-
thologist actors present case exam-
ples, learners are asked to comment,
and their answers determine whether
the next frame is a deep dive into new
territory or a detour around already
familiar material.
“Feedback and You: Give it. Seek
it. Use it.” is framed on a popular an-
nual meeting program that CAP Cur-
riculum Committee chair Sarah Bean,
MD, and her colleague Sara Jiang,
MD, both of Duke University School
of Medicine, Department of Pathol-
ogy, have presented for years. This
self-assessment module activity in-
cludes six podcast episodes that are
no longer than 16 minutes each. My
personal favorite episode, on the basis
of the title alone, is called “Ask-Tell-
Ask: Beyond the Feedback Sandwich.”
Online learning is a fine option, but most of us
enjoy “live” learning as well. CAP19 (Sept. 21–25,
at the Gaylord Palms Resort and Convention Center
in Orlando, Fla.) will be my first choice for that this
fall. The meeting is engaging on so many levels,
and it’s over in a blink. This year, pathologists will
choose from more than 80 CME courses, more than
half of which are new. Seven pathology and clinical
societies will cosponsor courses. Several hot topics
will be added closer to the meeting date. And in
order to accommodate more of those who cannot
join us during the week, a full cadre of courses are
planned for the weekend. Counting your self-
assessment module credits? CAP19 will provide
ample opportunity to complete SAMs with courses.
The annual meeting is an ideal place to grow your
competence in public policy, too. We may come for
the cutting-edge pathology education, but most of us
can spare an hour for the CAP advocacy town hall late
Monday afternoon—and those who do are always
glad they did. A panel on the future of the pathology
workforce, talks on the Pathologists Quality Registry,
and an update on value-based payment are also on
the agenda. Speaking of medical citizenship, I hope
Dr. Bui says patients need to know that patholo-
gists are their advocates, doing their best to provide
the diagnosis and biomarker report. “By develop-
ing guidelines for QIA, we’re showing another way
we can deliver tests, using HER2 as an example,”
she says. “So patients should rest assured we are
taking the quality of the work we do very seriously.
If they want to ask their medical oncologist or
pathologist to read their slides digitally, I think
that’s a good thing. Pathologists are in control of
the process, and if the algorithm gives a ridiculous
APRIL 2019 | CAP TODAY 11
many members will spend time in the House of Del-
egates meeting on Saturday morning, where we’ll be
talking about the best ways to support our state pa-
thology societies. The CAP Residents Forum also
meets on Saturday; I wouldn’t miss it for the world.
As always, the learning options will be outstand-
ing; I’ll mention just a few. The Sunday morning
scientific plenary will focus on microbiome therapy—
its applications, risks, benefits, and potential impact
in the laboratory. On Tuesday afternoon, Carl T.
Wittwer, MD, PhD, will give a not-to-be missed spe-
cial lecture, sharing insights from a lifetime at the
cutting edge of molecular diagnostics and his pioneer-
ing work in PCR. And on Wednesday, three full-day
tracks will offer immersive learning in genitourinary
pathology and deep dives into proficiency testing and
laboratory inspector training. I’m looking forward to
hearing from participants as they conduct their first
inspections and discover how rewarding it is.
The CAP19 Abstract Program received the second
highest number of submissions ever for the CAP an-
nual meeting. Abstracts and case studies selected by
members of the Archives of Pathology & Laboratory
Medicine editorial board will be available for viewing
during four poster sessions Sunday through Tuesday.
I hope everyone will stop in during at least one of the
one-hour poster focus sessions to meet the authors
and talk about their research. Focus sessions take
place during the first hour of each poster session.
The exhibit hall hosts cutting-edge equipment
demonstrated by people trained in its use. Remark-
able learning and tremendous friendships have
been known to come out of standing in line for
coffee or while jostling to see over the heads of two
dozen pathologists in the exhibit hall. Check out
the exhibit hall Sunday through Tuesday and con-
sider attending the reception at 7:15 Sunday night.
So, yes, it is fun to have fun, but you have to know
how. Which brings another appealing opportunity
to mind.
Registration opens this summer for the CAP’s
2020 Pathology in the Park program, to be held June
22–25 at the Tenaya Lodge, two miles outside of
Yosemite National Park. This four-day CME confer-
ence will feature breast pathology, gastrointestinal
pathology, and hematopathology presentations by
internationally known faculty who have insight
into challenges encountered in everyday pathology
practice. The format will be half-day sessions offer-
ing CME credits with afternoons free to explore
Yosemite with your family and fellow participants.
More details are coming soon, so stay tuned.
Yosemite is an amazing place. So is Orlando. We
have a lot to look forward to.
Dr. Williams welcomes communication from CAP mem-
bers. Write to him at president@cap.org.
result, they can detect and override it.”
QIA has been available for a long time, and it is
showing high reproducibility and accuracy, Dr. Bui
adds. “We are encouraging you to use it, and while
you do use it, we hope you find this guideline help-
ful and practical.”
Anne Paxton is a writer and attorney in Seattle. The
guideline was endorsed by the ASCP Commission on
Science, Technology, and Public Policy and the Associa-
tion for Pathology Informatics Council.
APRIL 2019 page 11 4/8/19 2:42 PM
 12 CAP TODAY | APRIL 2019
In memoriam
Harold E. Bowman, MD Hospital, now Sparrow Hospital, in
1925–2019 Lansing, Mich., and as associate chair,
Harold E. Bowman, MD, a member of Department of Pathology, Michigan
the CAP Board of Governors from State University College of Human
1979 to 1985, died on Feb. 1 at age 93. Medicine.
Dr. Bowman retired in 1994 as di- Dr. Bowman was a member of the
rector of laboratories at St. Lawrence CAP Foundation Board of Directors
Thank you for going above and beyond
The following healthcare providers brought hope and peace of mind to women who need it most
by hosting a See, Test & Treat® program.
In 2018, more than 700 women in underserved communities received free cervical and breast cancer
screenings through the CAP Foundation’s See, Test & Treat program. They also received same-day results,
education about healthy lifestyle choices, and connections to regular medical care because of you.
These women and their families are deeply appreciative of the gifts of your dedication, time and expertise.
Thank you for making See, Test & Treat® possible.
Cambridge Health Alliance Cambridge, Massachusetts
Charles Drew Family Health Center Omaha, Nebraska
Hampton Roads Community Health Center Portsmouth, Virginia
IVFMD Center Arlington, Texas
Liberty-Dayton Regional Medical Center Liberty, Texas
Loyola University Medical Center Maywood Illinois
Montefiore Medical Center Bronx, New York
NorthPoint Health & Wellness Center Minneapolis, Minnesota
Rutgers Cancer Institute of New Jersey at University Hospital Rutgers, New Jersey
St. Joseph Mercy Health System Ann Arbor, Michigan
University of Mississippi Medical Center Jackson, Mississippi
Your continued support will help expand the
CAP Foundation and the See, Test & Treat program.
325 Waukegan Road, Northfield, IL 60093
© 2019 College of American Pathologists. All rights reserved.
27339.0419
27339_Foundation_STT_ThankYou_Ad_Final.indd 1
0419_12_Memoriam.indd 12
and treasurer and president of the
CAP Foundation from 1980 to 1990.
He was also chair of the Council on
Education and of the Commission on
Anatomic Pathology.
“He was a very nice gentleman
who was committed to the founda-
tion,” says Paul Bachner, MD, who
joined the CAP Foundation Board of
Directors when Dr. Bowman was
president. “He was key in developing
foundation.cap.org
800-323-4040 ext. 7718
APRIL 2019 page 12
3/7/19 10:54 AM
some of their programs.”
“I remember that he went out of his
way to acclimate me to the foundation
board, despite the fact that we didn’t
always agree on certain things,” says
Dr. Bachner, a professor and immedi-
ate past chairman of the Department
of Pathology and Laboratory Medi-
cine, University of Kentucky, where
he served as director of laboratories
from 1993 to 2015. “He was always
very collegial.”
Joseph Leverone, MD, who also
served with Dr. Bowman on the CAP
Foundation Board of Directors, re-
members him as someone who “had
a ready smile and
was very concerned
about the future of
the CAP, especially
in terms of the
younger patholo-
gists.” Dr. Leverone
is medical director
of laboratory ser- Dr.Bowman
vices, HealthEast
Care System in St. Paul, Minn., and
president of Central Regional Pathol-
ogy Laboratories, Maplewood, Minn.
“At that time there wasn’t the orga-
nizational concern for younger pa-
thologists that there is today, so he
was a little ahead of his day in that
regard. We have the New in Practice
Committee now,” Dr. Leverone says.
While Dr. Bowman was not directly
involved in creating the New in Prac-
tice Committee, he was devoted to
promoting organizational education
for residents and newly practicing
pathologists. “He kept the subject in
front of us all the time.”
One of Dr. Bowman’s most signifi-
cant initiatives during his term on the
foundation board was organizing a
series of educational conferences on
strategic, mission-related topics on
pathology and medicine, Dr. Bachner
says. Between 1980 and 1989, the
foundation held five conferences,
with titles such as “The Autopsy:
Revitalizing the Ultimate Medical
Consultation” and “Pathology in a
World of Changing Technology.”
Summaries of each conference ap-
peared in CAP publications.
“He was a community-oriented
person and a pillar of whatever he be­
longed to—the CAP, his community,
his practice, his hospital,” Dr. Leverone
says. “He was forward-looking and
didn’t rest on the status quo.”
“He was a very hale and hearty fel-
low, the kind of individual you enjoyed
spending an evening with,” he adds.
Dr. Bowman, of Muskegon, Mich.,
is survived by two sons, a daughter,
10 grandchildren, and four great-
grandchildren. His wife, Sally, pre-
ceded him in death in 2005.
—Amy Carpenter Aquino
4/3/19 12:34 PM
 What do you need
from your anatomic
pathology computer
system?
Intuitive Functionality

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Quality Imaging
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14 CAP TODAY | APRIL 2019
Too few technologists: labs take inventive steps
Valerie Neff Newitt
The tight supply of technologists to
fill open positions is pushing labora-
tories to be creative in finding an-
swers. Memorial Sloan Kettering
Cancer Center and TriCore Reference
Laboratories found their answers by
looking not just outward but also—
and largely—inward.
MSK has created an innovative
Laboratory Scholars Program that
draws employees from other parts of
the cancer center, places them in an
education program in coordination
with a partnering college, and re-
trains them to become laboratory
technologists.
TriCore Laboratories in Albuquer-
que, NM, designed a Histology Ap-
prenticeship Program that recruits
candidates from among TriCore em-
ployees to participate in targeted his-
totechnology training. Those who
complete the training successfully can
apply for an HT level-one position
within the laboratory.
New York City proves to be a tough
recruitment locale for laboratory tech-
nologists, says Melissa S. Pessin, MD,
PhD, chair of the MSK Department of
Laboratory Medicine. “It is worse than
in other parts of the country for a few
reasons. First, many clinical laboratory
scientist training programs had closed
in New York State. Second, it is very
expensive to live in the New York City
metro area, so many lab technologists
have worked two jobs. Those reaching
retirement age just can’t handle the
strain of that anymore; as a result,
many of the technologists are retir-
ing,” she says.
In addition, anyone from outside
the state has to take the full ASCP
Board of Certification exam and un-
dergo a transcript and clinical educa-
tion review, in accordance with New
York State licensure law. “So we can’t
easily bring in a specialist—for ex-
ample, someone who has been doing
just micro for 20 years—because that
person would have to pass the full
board, which presents a challenge.”
Not unique to New York is the
general lack of knowledge about the
profession, “which certainly doesn’t
help any of us.”
With a number of new sites open-
ing over the next few years in the MSK
network, Dr. Pessin and others wor-
ried there would be far too few labora-
tory technologists to staff them. In
2013 Dr. Pessin, working with the
human resources department and
Cynthia McCollum, senior vice presi-
dent of hospital operations, started to
explore solutions. Dr. Pessin suggested
the creation of a scholars program that
would include MSK employees, rather
than students drawn strictly from
outside, in hopes of attracting some of
their own employees to the field.
“We don’t have our own medical
laboratory technology school, and to
create one would have been too diffi-
cult,” Dr. Pessin says. There was no
place to house it, and an administra-
tive structure and New York State
approval would have been needed. clinical rotations.
“So we devised an option that no one “Scholars must rotate through all of
else had considered. We partnered the general labs. They do blood bank,
with another organization in an in- chemistry, hematology which includes
novative way.” coagulation, urinary analysis and
Tomya Watt, MSK’s VP of talent body fluids, and microbiology,” Dr.
acquisition, working with the non- Pessin says. “We also give them extra
profit Council for Adult and Experi- experiences: phlebotomy, time in our
ential Learning, identified several outpatient site, time in our flow cy-
potential partners. Marist College in tometry/cell immunology area, and
Poughkeepsie, NY, about two hours time in cell therapy where we process
away by train, was the potential part- stem cells for transplants.” Molecular
ner school with the greatest flexibility pathology is being added to the
to create a customized program. “To- program.
‘We devised an option that no one else had
considered. We partnered with another
organization in an innovative way.’
Melissa Pessin, MD, PhD
gether,” Dr. Pessin says, “we came up When the scholars complete the
with a plan that would allow our program, they sit for the ASCP BOC
students the shortest amount of time exam for the medical laboratory scien-
for retraining, and which in turn tist. Successful completion of the
would allow us to fill these positions exam, along with the degree from
as fast as possible.” Marist College, is recognized by the
The yearlong program, which got state, qualifying scholars to apply for
underway in 2014, runs from July to the New York State license.
July. From July to December the
scholars attend lectures at MSK two
days a week and participate in study
groups on a third day. On alternative
J oann C. Rittersbach, BS, MT(ASCP),
educational liaison manager for
laboratory medicine at MSK, is confi-
days, twice weekly, they travel to dent there is no other program like this
Marist College for their student lab in the United States. “And I suspect
experience. From January to February there is not another program like this
they are in level-two didactic courses, outside of the U.S. as well,” she says.
and from March to July they are in Rittersbach meets —continued on 16
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 16 CAP TODAY | APRIL 2019
Technologists
continued from 14
with educators often and says she has
yet to come across anyone who has
developed a similar program. “There
is a lot of interest in it because it’s the
right thing for the right reasons.”
Recruitment for the program
started in 2014 on MSK’s internet site
where information about the program
is available. Email, informational ses-
sions, referrals, and posted notices
help get the word out. Candidates
must be full-time MSK employees in
good standing and employed for at
least a year by the time they apply for
the program, and they must hold a
bachelor’s degree or higher in a life
science or a two-year MLT degree.
They have to submit an essay about
why they want to work in the lab, be
interviewed, and complete prerequi-
site courses required by Marist College
(general biology I and II, general
chemistry I and II, introduction to or-
ganic chemistry or organic chemistry
I and II, microbiology, all with labs;
immunology, parasitology, statistics,
and a computer class).
Ultimately, Marist College holds
the curriculum for the program and
grants the degree.
“Many of the people we get are
working as research assistants, physi-
cian office assistants, or in animal tech
jobs,” Dr. Pessin says. “Often they
hope to get into medical school and
then realize it may not work out for
them. They want to stay in medicine
and want to do something more pa-
tient-care-related than what they have
been doing.”
“We also pay,” Dr. Pessin says. “By
redirecting part of the tuition reim-
bursement budget, the HR depart-
ment covers their salary while they are
students in the program throughout
the year, the cost of prerequisite
courses, the tuition, their books, their
train travels to Marist and back, re-
view courses for them, and the cost of
their exam. It’s a good deal.” If partici-
pants put in the effort, she says, “they
don’t take a financial hit doing it.” It’s
an opportunity for MSK employees to
change careers at the cancer center’s
expense. Scholars pay only for the
resulting license, and graduates of the
program must commit three years to
laboratory medicine once they receive
their New York State license and it can
be verified by MSK.
Says Rittersbach: “Graduates are
technically clinical laboratory tech-
nologists, and are considered LT1, our
entry-level medical technologist posi-
tion. Managers with open positions
offer interviews to the graduates. The
scholars and the managers rank their
0419_14-18_Retention.indd 16
preferences, and then we do a match-
ing system to find the best fit for both.”
Eight scholars have been accepted
into the program each year from 2014
to 2019. Thirty have graduated.
D r. Pessin says the program has
  been a success by all accounts.
“We are very satisfied. The scholars
have worked at various parts of the
institution; they bring new perspec-
tives from other departments. And
they tend to be very motivated. We are
at 100 percent exam pass rate, which is
terrific, for our first four cohorts.” All
are still employed at MSK.
The scholars now make up about
12 percent of the laboratory technolo-
gist/technician workforce.
“But we’ve been expanding at a
fairly rapid rate, so it is not enough,”
Dr. Pessin says. “We remain chal-
lenged. We always have openings, but
I know for a fact that we are doing
better at recruitment than most of the
other New York City hospitals.”
The Laboratory Scholars Program
itself is expanding. “For the 2019–2020
cohort,” Rittersbach says, “we will
expand to 10 scholars in the program,
collaborate with pathology, and in-
clude a molecular component to meet
the pathology experience.” Dr. Pessin
explains: “Anatomic pathology is
completely separate from lab medi-
cine here at MSK. We have been so
successful that AP would like us to
recruit for them as well and train for
molecular technologists.”
‘The scholars and the managers rank their
preferences, and then we do a matching
system to find the best fit for both.’
Joann Rittersbach, BS, MT(ASCP)
Dr. Pessin has not overlooked the
related challenge of retaining talent.
“Something that has been a challenge
in most institutions is there are very
few places to promote medical tech-
nologists. Traditionally we have LT1,
2, and 3 positions. After LT3 you pos-
sibly could become a supervisor or a
manager. But obviously there are not
many supervisors or managers. Fur-
thermore, not every great tech should,
or wants to, supervise. So we came up
with a lab technologist 4, or LT4,
which is the same salary level as a
supervisor and allows technologists
to be experts in their area or other
areas—for example, a quality expert,
lab information system expert, or edu-
cation expert.” It has provided op-
portunities to promote people so they
do not feel they have to go to other
institutions to advance. “This is a
creative way to value people in each
of our service areas.”
The HR department handles the
program’s funding matters. “HR is
accountable for financials; we are not
involved,” Dr. Pessin says. “But they
have done the numbers and found this
is more cost efficient than other forms
of recruitment. Based on how much it
costs them for the level of recruiting
they have to do for us, they felt this
was a good investment. And because
MSK is traditionally so supportive of
advancing its own employees, they
felt this was the right thing to do.”
Rittersbach adds, “That MSK is
financially supporting the Lab Schol-
ars Program—salaries, tuition, ex-
penses—shows a commitment of
administration, the lab management
team, and technologists who all rec-
ognize the value of having highly
trained and qualified employees
working at the bench.”
W hen TriCore Reference Lab-
 oratories experienced a more
than 20 percent vacancy rate in histo-
technologist positions in its pathology
department, it was clear it was time to
take action.
“We just could not find experienced
HTs to fill all the positions,” says Chris
Goodwin, MBA, PA(ASCP), CT(ASCP),
anatomic pathology core lab manager.
“My director, Eric Carbonneau, and I
sat down to do our staffing plan and
knew we had to get creative. We came
up with the Histology Apprenticeship
Program.”
They crafted job descriptions, after
consulting with their human capital
management department, “and set the
program up correctly, so we could
fulfill the business need for TriCore as
well as attract the right candidates for
the lab,” Goodwin says.
The apprenticeship program was
launched in 2017 to recruit candidates
for histotechnology training from
within and outside TriCore. When the
apprentices complete the program and
graduate, they are encouraged to ap-
ply to TriCore’s open HT1 positions
and take the ASCP BOC exam.
“In our AP areas we employ many
great individuals who have experience
in pathology in terms of accessioning,
processing, slide distribution, and all
the other things that make AP work,”
Goodwin says. “This program pro-
vides them with a defined career path.
They can go from a lab assistant to a
APRIL 2019 page 16
histotechnologist. In fact, we have been
able to recruit great people into our AP
lab assistant program, based on our
having this apprenticeship program
open to them. They see a future.”
Laura Enriquez, HT(ASCP), Tri-
Core’s technical supervisor of histol-
ogy, says program participants must
have completed 60 semester hours of
academic coursework from an accred-
ited college or university, and it has to
include 12 hours of biology and chem-
istry. “All lab assistants with that col-
lege coursework can apply for an ap-
prentice position. They will then go
through a routine interview process,
and we make a selection.”
The program begins with basic
embedding, which is a four- to six-
week process during which partici-
pants do little else. At the end of that
period they must demonstrate 50 per-
cent productivity, which is 20 blocks
per hour, with a variety of tissues.
Once they achieve that benchmark,
they move on to microtomy for six to
eight weeks. “Again, they have a
benchmark,” Enriquez says, “where
they must meet a minimum of 10
blocks per hour of cutting. Once they
master that, they spend the next 12
weeks rotating between embedding
and cutting. They also learn to cut the
recuts, to cut from a special stain,
IHCs.” At the end of the six-month
period, they are encouraged to ap-
ply—“I hold my breath and hope they
do,” Enriquez says—for a full-time
HT1 position. “That provides a pay
increase for them.”
While the program is still in its in-
fancy, “and evolving as we evolve,”
she says, “we already have one ap-
prentice who became an HT1 in July
2018, two who became HT1s in Febru-
ary, and two more who completed the
program in March who also plan to
jump into full-time positions.”
TriCore had been down seven his-
totechnologists, but with the recent
apprentices added to the mix, it is now
short two.
“There is a shortage of histotech-
nologists across the country, so basi-
cally we just had to grow our own,”
Enriquez says. “The positions wouldn’t
be filled otherwise. I feel great that we
are drawing great people into the field.
I am proud of my apprentices; they are
all wonderful.”
Histotechnologists who are already
on staff mentor the apprentices, Good-
win says. “We are taking full advan-
tage of their experience and knowl-
edge. At first there were a few people
who were a tad reluctant to step in and
help train the apprentices. They may
have doubted their teaching ability,
but that changed in a hurry,” he says.
“Once they tried it —continued on 18
4/8/19 3:15 PM
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 18 CAP TODAY | APRIL 2019

Technologists Apprentices receive a salary while

they train. At the program’s end, they
continued from 16
are not constrained in any way, nor
and got adjusted to the idea, it im- must they make a time commitment
proved their lives and job satisfac- to the lab.
tion.” Some now enjoy being a mentor. Because the apprenticeship is open
“I don’t think there is a single person to everyone who meets the educa-
in our lab who has not helped the ap- tional criteria, many have wanted to
prentices along their journey. The pro- take advantage of it. “We post the
gram has increased overall engage- apprenticeships as positions,” En-
ment and has been great for morale.” riquez says. “On my first two postings
there were roughly 90 applicants. So
while we were having trouble getting
histotechnologists, we had no trouble
getting apprentices.” TriCore’s human
capital management recruitment team
uses social media to spread the word.
Enrollment is on a rolling basis.
“Whenever we have good candi-
dates,” Goodwin says, “we bring
them in, as long as we are ready for
them. We don’t want too many at any
given time because we have to have
an experienced HT to provide one-on-
one training for each apprentice.” Af-
ter two apprentices complete the pro-
gram, two more are brought in. “We
just want to keep the cycle going—le-
veraging our knowledge and growing
our own.”
Valerie Neff Newitt is a writer in
Audubon, Pa.

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 20 CAP TODAY | APRIL 2019
Consumer genomics
continued from 1
announcing “The lady will have. . . .” The lady can
do her own ordering, thank you very much.
W hen she gives talks on the subject, Dr.
  Hagenkord makes a point of differentiat-
ing between nonclinically valid information—
“ancestry, eye color, fun stuff”—and tests that are
clinically valid. She notes that with their ability to
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sequence a genome or exome, consumer labs have
the option of including “infotainment” genetic
information as well as clinically valid information.
The infotainment piece, she says, engages consum-
ers and can increase their genetic literacy, as well as review. PWN Health may reach out to patients and
drive family health discussions.
Matthew Ferber, PhD, agrees. He’s the director
of Mayo Clinic GeneGuide, a genetic testing experi-
ence that lets consumers initiate the test; Mayo’s
hook, so to speak, is education.
Mayo has partnered with PWN Health, a physi-
cian provider and genetic counseling network
licensed in all 50 states, and Helix, which per-
forms the actual sequencing. Dr. Ferber, a clini-
cal molecular geneticist who is also co-director
of Mayo’s clinical genomics laboratory and
founder of the institution’s clinical genome se-
quencing center, uses the term near-consumer
testing to describe the service.
GeneGuide launched at the end of last Sep-
tember, after a roughly two-year development
period. “We felt there was an opportunity for
Mayo to do it in a very responsible way,” says
Dr. Ferber.
It’s crucial, he says, for
consumers to know exactly
what they will and won’t get
‘The only thing
out of the experience (a word really left in our lives
that pops up a lot in these
conversations). GeneGuide that is analog and not
is not aimed at people look- consumer-friendly,
ing for a diagnosis, but
rather at increasing genomic and very 20th century,
literacy; it does so by includ-
ing topics such as autosomal
is health care.’
recessive diseases, pharma- Jill Hagenkord, MD
cogenomics, and complex
disease. “It’s purely educa-
tional,” Dr. Ferber says. The goal is to get
people excited about learning, starting with
their own DNA. This in turn should lead to
deeper conversations about health with family
members and physicians, he says.
Mayo advertises on social media and online
radio stations but has taken steps to prevent a
floodgates-have-opened scenario that many
fear. When a consumer purchases a kit online
($199.99, plus $9.95 standard shipping), that
triggers a qualification questionnaire that is
reviewed by PWN Health. Just because a con-
sumer orders a test doesn’t mean it’s appropri-
ate—you can probably order sushi at a truck
stop, too, but that doesn’t make it right.
A pregnant woman can order the Gene-
Guide test, for example, but will need to ac-
knowledge she understands that the test is not
diagnostic and that comprehensive carrier
screening is available elsewhere. If a consumer
says they are affected by any of the conditions
covered by GeneGuide (including as part of
their family history), they can’t order the test;
instead, they are directed to see their personal
physician and pursue diagnostic testing. Like-
wise, the test is not deemed appropriate for
someone who has had a bone marrow trans-
plant or a liver transplant.
Once they’re collected, samples are sent di-
rectly to Helix for sequencing.
Mayo receives an alert when sequencing has
been completed and will download the portion
APRIL 2019 page 20
of data required to drive the GeneGuide interpreta-
tion engine. Dr. Ferber reviews the results and in-
terpretations and signs out the reports. These re-
sults go first to PWN Health, which does its own
schedule a genetic counseling session in the event
of a troubling finding—two cystic fibrosis altera-
tions, say, or a positive malignant hyperthermia
variant. Only after everyone is comfortable will
Mayo release the data to the consumer on its app,
says Dr. Ferber.
G eneGuide is not meant to compete with clinical
  diagnostics, Dr. Ferber says. Its limited menu
is meant to whet the appetite of consumers. Testing
is divided into four categories:
g Carrier screening: cystic fibrosis, GJB2-related
hearing loss, MCAD deficiency, and sickle cell
disease.
g Medication response: over-the-counter ibupro-
fen and omeprazole metabolism, and pseudocho-
linesterase deficiency and malignant hyperthermia
susceptibility. The latter two were chosen after
discussions with Mayo anes-
thesiologists. Says Dr. Ferber:
“They felt like having that data
was as good as having a piece
of family history data in a pre-
op visit. That level of informa-
tion, coming from an educa-
tional experience like this,
would be of value to consum-
ers as well.”
g Disease risk: age-related
macular degeneration, atrial
fibrillation, coronary artery dis-
ease, and venous thrombo­-
embolism.
All four entail genetic risk but are also influ-
enced by environment, gender, and lifestyle, Dr.
Ferber says. Mayo portrays individual risks using
a beaker analogy that shows consumers the chang-
ing water levels as risks are added/reduced. In
many cases, the genetic risks are relatively minor
compared with other factors, he notes. With CAD,
for example, “If you’re a smoker, that’s a bigger risk
than the independent genetic factors that are in-
cluded within the test. People need to know that.”
He and his fellow “nerds are quite happy with how
we did this,” he says with a laugh. “I’m eager to
see post-market surveys to see if consumers are
enjoying this as much as we did in the lab as we
built it.”
g Health traits: alcohol flush reaction, atopic
dermatitis, and lactase persistence.
These are not Mayo’s “sweet spots,” Dr. Ferber
concedes, but these common traits were included
to potentially provide consumers with an a-ha!
moment.
Once it completes the sequencing, Helix stores
the data on its secure server. “This is important,”
says Dr. Ferber. Even though Helix is doing whole
exome sequencing, Mayo Clinic GeneGuide has
access only to the data being tested for in the Gene-
Guide kit.
Down the road, the additional data might prove
important. And since the test started with the
consumer, later follow-up might be easier when,
say, a new variant is reclassified—the consumer
can be reached directly and —continued on 22
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4/2/19 3:18 PM
22 CAP TODAY | APRIL 2019
Consumer genomics
continued from 20
quickly. Or, as Dr. Ferber puts it, “The report isn’t
just for the physician anymore.”
While waiting for results, users can peruse edu-
cation modules that cover a range of topics, includ-
ing genetic fundamentals, heredity, precision medi-
cine, and common familial diseases. Clearly Mayo
deems this information important, but Dr. Ferber
admits the material continues to be tweaked—
based on early returns, he says, consumers appear
to be quite focused on their test results, and perhaps
a little less so on education.
And for a dose of fun and learning (Dr. Ferber’s
words), GeneGuide also offers an interactive pedi-
gree drawing tool, similar to what’s used in profes-
sional medical settings, but in a simpler version.
Consumers can fill out and edit an electronic sur-
vey; users can toggle between a consumer view and
a physician view. Dr. Ferber sees several advan-
tages to this flexible approach. First, it keeps the
language consistent, without overwhelming pa-
tients or oversimplifying matters for professionals.
It also helps with accuracy. His clinical colleagues,
he says, tell him that patients often inadvertently
provide inaccurate information during an office
visit. It also encourages patients to include other
relatives. “It’s not just you and your doctor and
maybe a significant other in the room, trying to
recall all this stuff. This allows you to fill out this
information while sitting on your couch, in the
comfort of your own home.” Ideally, he adds, it will
be possible to link individual pedigrees to patients’
EHRs, though this goal is a ways off. “It’s a great
idea, but a complex one,” he says.
D avid Bick, MD, chief medical officer and a
  faculty investigator at HudsonAlpha, has
been keeping a close watch on the field. He’s a
coauthor (as are Drs. Hagenkord and Ferber) of an
article (Lu JT, et al. J Mol Diagn. 2019;21[1]:3–12)
that looked at consumer genomics, including a
framework for evaluating analytical and interpre-
tive components of the tests. “The concept for the
article was hatched maybe two years ago, when
we all realized that elective genomic testing”—Dr.
Bick’s preferred phrase—“was becoming extremely
widespread. We were saying this is clearly happen-
ing—there’s no doubt about that. Let’s do it in a
responsible way.”
Adds Dr. Hagenkord: “We’re all part of this first
group of clinical pathologists and laboratories that
are actually doing real consumer genetics. None of
this is hypothetical to us. We run into expected and
unexpected problems every day, and we’re starting
to amass enough of a knowledge base to help” with
future guidelines. The authors noted, for example,
that testing in elective settings, in a low-risk popula-
tion, needs to control false-positive rates in a way
that’s different from the diagnostic setting.
Dr. Bick is also associate laboratory director of
HudsonAlpha’s Clinical Services Laboratory, which
provides a fee-for-service whole genome sequenc-
ing and pharmacogenetics test called Insight.
About three years ago the company started the
Smith Family Clinic for Genomic Medicine (Dr.
Bick is the medical director), which uses genomics
in regular patient care for those with rare and un-
diagnosed diseases. When the standard practice of
medicine didn’t return an answer, Dr. Bick explains,
the next step would entail using whole genome
sequencing. Medical history, family history, physi-
cal exam results, and medical records from the
patient’s personal physician are all sent to the labo-
ratory with the sample. “The laboratory has a lot
of clinical information to help them look at the
genome and personalize the results to the indi-
vidual,” he says, adding, “This is what patients/
consumers want: a test result that reflects their
personal medical situation.”
When he gave talks about this approach, he says,
he would invariably be approached by someone
who expressed interest in having their own genome
sequenced, even though they had no known ge-
netic condition.
For a long time, says Dr. Bick, “We said no—
that’s not what we’re focused on. But liter-
ally, we got so many requests for this, we
said, ‘Why are we telling people that they
can’t have their genome analyzed? Why is
that? If they want to pay for their own test-
ing, then it should be possible.’”
The ultimate goal, he says, is to identify
risk in people who are ostensibly healthy.
“What’s happening over and over again,”
Dr. Bick says, “is the realization that re-
stricting genetics to people who have some
obvious, in-your-face problem leaves out a
lot of people who could benefit.”
Of the approximately 50 patients who’ve ‘ Labs need to step up and be involved in doing this
had their sequencing done, several have
been found to have an unexpected variant
that suggested a different approach to, say,
colorectal cancer screening. Dr. Bick calls
ones who should be directing elective genomics.
this a primary result, related to the indi-
vidual’s medical problem(s).
Sequencing also yields secondary results, which
may lead to disease in the future. One patient was
interested in a possible genetic clue to his Parkin-
son’s disease; no link was found, but he did have a
pathogenic variant in BRCA2, which prompted
discussions with his sons and granddaughters
about possible inheritance.
The clinic also offers carrier status testing. In this good experience for physicians as well as patients,
case, says Dr. Bick, consumers see the information
as a gift of sorts for their children and grandchil-
dren. (The self-pay approach tends to self-select
older clients, he says.)
In the case of the pharmacogenetics testing, the
clinic tests for 89 different drugs with pharmacoge-
netic variants. Patients may not currently be on any
of the drugs, but having the information available
may be useful if they’re prescribed one, he says.
“The time you need a pharmacogenetics test is the
day before the doctor orders the drug for you.” In
one case, an individual who was on Plavix (clopi-
dogrel) was found to have a DNA variant that in-
terfered with his ability to convert the drug into its
active form; he subsequently switched to a different
platelet inhibitor.
A t Color, Dr. Hagenkord says, the focus is on
  using genetics for population health manage-
ment. Though consumers can purchase the test
online ($208.95, including shipping and handling),
the company’s business model is broader—she calls
it business-to-business-to-consumer, versus the
business-to-consumer model used by companies
such as 23andMe. Color partners with large institu-
tions that are responsible for the health care of an
entire population—a health care institution, say, or
a large, self-insured employer—and offers whole
genome sequencing as a health benefit.
Color has started by optimizing for a gene set
based on a National Academy of Medicine paper
(Murray MF, et al. “A Proposed Approach for
Implementing Genomics-Based Screening Pro-
grams for Healthy Adults.” Dec. 3, 2018). The
physician-ordered test covers hereditary breast and
ovarian cancer syndrome (BRCA1, BRCA2),
Lynch syndrome (MLH1, MSH2, MSH6, PMS2,
EPCAM), and familial hypercholesterolemia
(LDLR, APOB, PCSK9). All three conditions have
high penetrance and effective interventions for
prevention or reducing risk, yet most people at risk
are unaware of their status.
from the get-go. They’re the experts. They’re the
David Bick, MD
’
The panel not only has the academy’s imprima-
tur, she says, but it’s the perfect size, at least for
now. “People go too much, too far, too fast with
genes,” she says. “It’s completely overwhelming
to the primary care physician—really, to all physi-
cians except geneticists. But starting with these
three conditions makes it just a little bit easier of a
starting base.” Consumer genomics needs to be a
she says.
“We also have to convince our buyers that our
product is going to have beneficial health out-
comes,” Dr. Hagenkord says. “So we can’t optimize
it for junky ‘trinkets’ or fun stuff.” Once the health
hurdle has been cleared, however, it makes sense
to “use whatever other levers we can with genet-
ics—because people find it so interesting—to create
continued engagement around health actions you
want them to take.”
“Genetics has been shown to be an activator,”
she continues. “People have this health awareness
moment when they get the genetics,” which, ide-
ally, can be used to nudge them into the programs
that would be most beneficial. Color also offers a
collaborative health history and personal health
history app, which Dr. Hagenkord characterizes as
“a learning system that tracks its own effectiveness
as we go along.” Participants can have the results
sent to physician(s) of their choice; for health care
clients, results are integrated into the EHR.
Says Dr. Hagenkord: “Patient-reported out-
comes turns out to be pretty reliable for certain
types of information.” She suggests that answering
a survey while sitting on the —continued on 24
 The advertising that appeared in this space
in the printed edition has been removed here from
the digital edition, as requested by the advertiser.
 24 CAP TODAY | APRIL 2019
Consumer genomics
continued from 22
couch—in the consumer genomics world, patients
seem to enjoy filling out forms while sitting on their
couches—is less stressful than sitting in a physi-
cian’s office “and being judged by the white coat.”
The app allows family members to share family
health history and build information “that’s much
richer and more reliable than the health history you
‘I’m eager to see post-market surveys to see
if consumers are enjoying this as much as
we did in the lab as we built it.
Matthew Ferber, PhD
’ he says.
give in 60 seconds during your doctor’s visit,” she
says. “You can actually ask your Uncle Mark in
Green Bay, Wis., if he ever had a blood clot, or what
kind of cancer he had, and how old was he? And
then we can share that in a structured way with our
health system partners.”
Several studies have demonstrated this engage-
ment also translates to compliance, she says. One
study showed that patients who were prescribed
a statin and received genetic information were up
to 43 percent more compliant with their drug, up
to 18 months out, than a group that received no
such information at the time of prescription. Yet
traditional medicine has never considered using
genetics to motivate patients, she says.
D r. Hagenkord doesn’t mince words when she
  peers into the future. Labs “will have to get
on board eventually.”
Drawing on her years in Silicon Valley, Dr.
Hagenkord says, “If you look at the way we do
everything else in our lives right now, everything
is app-based, convenient, frictionless. The only
thing really left in our lives that is analog and not
consumer-friendly, and very 20th century, is health
care. Ten years from now, that’s going to be com-
pletely different,” she says. Case in point: 10 years
ago, the roads were Uber-free and smartphones
were a novelty. “You can see how that completely
changed our expectations on how to live our daily
lives. I think that’s going to happen in health care.”
In the relatively near future, Dr. Hagenkord
predicts, sequencing will be within-rounding error-
free and become a commodity. “So the value of
genomic sequencing isn’t having the sequence it-
self; the value is in what you do with it.”
Different companies are placing different bets on
what that value is. Color, obviously, is “making a
population health play. Some of us are going to be
more focused on health outcomes,” she says. “Some
of us are going to be more focused on fun and de-
0419_1-46_Genomic-Ergonomics-Ngonorrhea_v4.indd 24
light. Some of us are going to be more focused on
ancestry.” Trying to understand the field as it un-
folds will be futile without understanding the un-
derlying business models.
She worries, however, that the various models
are making matters needlessly complicated. A test
designed for research and ancestry, using older
technologies, won’t detect pathogenic rare vari-
ants and novel variants. “It’s confusing the mar-
ketplace,” Dr. Hagenkord says, even with clear
FDA labeling that indicates the limitations
of such genetic testing. That in turn could
sow doubt among physicians just when
they need to become more involved.
Dr. Ferber says he himself was a skeptic
early on. “I used to look at these consumer-
focused genomics companies and quite
honestly, I didn’t agree with the direction
they were going. And some of them, I still
don’t.” But done right, he says, everyone
can benefit.
Even so, he says, “The vast majority of
physicians aren’t comfortable talking about
genetics.” So it wouldn’t surprise him, he
says, if many of them dismissed consumer
genomics tests out of hand. “I totally get it,”
But the move toward digital and auto-
mation is inevitable, he says, echoing, Dr.
Hagenkord. “So it’s going to be even more impor-
tant, as this happens, to make sure that people
know that consumer tests are for an otherwise well
population,” Dr. Ferber says. “If somebody is sick,
or suspects themselves of having a disease, that, to
me, is off limits. That, to me, is a physician visit. We
have to work hard to not confuse people. That’s not
safe, and that’s not good for any of us.”
Companies that got an early start in consumer
genetic testing have played their cards differently
than clinical labs—a game of Go Fish versus con-
tract bridge. By focusing on consumers, not the test
per se, “They’ve always been a bit more Silicon
Valley,” Dr. Ferber says, “a little bit more, Don’t
confuse people with the details—just keep them
engaged, keep them excited. But the details are im-
portant. How do you communicate—without los-
ing them?” He’s confident clinical labs will find the
answer. “It may seem like we’re behind, but this is
a pretty long race to run. It’s not too late.”
D r. Ferber also foresees a time when consumer
  genomics will become the norm. At a low
enough price, he says, widespread genetic testing
will be as valuable as newborn screening. “I see a
time when everybody gets this. I don’t know what
the appropriate age would be. But there comes a
time when healthy people should just know this
type of stuff.”
Using his own experience as a guide, Dr. Ferber
would like physicians at least to start thinking
and talking about it. “My knee-jerk reaction was,
This is bad. And it’s met with a lot of cautionary
tales about the demands it will place on the health
care system.” Done correctly, however, the right
people will receive the right tests, he insists, and
labs will be educating an important group of
patients about genetics much faster than they ever
could before.
Dr. Bick thinks he sees an easier road. Many labs
are already running clinical tests that could transfer
APRIL 2019 page 24
to the elective realm. “That’s an immediate way to
get into offering elective testing without a huge
financial commitment.” He agrees physicians
might push back—but not all of them. “Not to be
too mean to the oldsters,” he says (noting that he’s
in his 60s), “but younger physicians are more likely
to look at regular diagnostic genetic testing as part
of regular care—and by the same token, elective
genetic testing.”
Labs that do become involved can help head off
the horror stories that emerge when people receive
confusing results. “Having raw data doesn’t help
you; it could, in fact, confuse you,” Dr. Bick says. A
sophisticated laboratory can tell patients and physi-
cians if the data are good, and what they mean.
“Labs need to step up and be involved in doing this
from the get-go. They’re the experts. They’re the
ones who should be directing elective genomics.
And they should be doing it tomorrow.”
S ome of the pushback Dr. Hagenkord has seen
  from physician colleagues is tied to outdated
information. “Most people aren’t up to date on how
consumer genomics has evolved,” she says. When
polygenic risk scores came on the scene as part of
the first wave of DTC genomic testing, “no one was
talking about consumers. And the entire complaint
by the entire medical professional community was
almost exclusively on the fact that there was no
established clinical validity for the polygenic risk
scores that these companies were providing.” That
has changed, she says. Old technology was SNP-
based, but virtually everyone has moved to clinical-
quality sequencing and uses board-certified experts
to interpret/report results, she says. Nevertheless,
colleagues are still reciting the old mantra about
lack of clinical validity.
The debate needs to change, she says. “It’s not
about, is this test accurate or not? It’s the same test
that you would get at any clinical lab,” but cheaper
and easier to get.
Since Color launched in 2015, Dr. Hagenkord has
learned a few things about the consumer perspec-
tive. Chief among her findings: “People love to
learn about themselves, and they love to talk about
themselves.” Combining the two leads to a “virtu-
ous cycle, an exchange of information that both
parties seem to benefit from.”
Consumers want to know, among other
things, their APOE-related Alzheimer’s risk, she
says. Even though they can’t act on this informa-
tion, “Consumers find it interesting and engag-
ing. People are declaring what they find to have
personal utility as opposed to this very strict
clinical utility model that we have in the noncon-
sumer world.”
Need more proof? Dr. Hagenkord recounts
23andMe’s voluntary research efforts, which she
says attracts a very high percentage of the test’s
buyers. As part of those efforts, the company asks
its users what topics they’re interested in. One ex-
ample in particular makes Dr. Hagenkord laugh.
“23andMe was able to, with a few clicks of a button,
do the world’s largest genomewide association
study on stretch marks.
“Trust me: The NIH is never going to fund a $5
million, five-year stretch marks project.”
Karen Titus is CAP TODAY contributing editor and co-
managing editor.
4/9/19 3:11 PM
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0419_TABs-IL-Randox-8.indd 25 FILE— NEW APRIL 2019 page 25 4/2/19 3:18 PM
26 CAP TODAY | APRIL 2019

Acute promyelocytic leukemia with ules are not apparent as they are sub-
microscopic. Cytochemical stains such
as myeloperoxidase and Sudan black
cryptic t(15;17) identified by RT-PCR are strongly positive in both variants,
often to the point that the cytoplasmic
CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY granules obscure the nucleus.
readers. AMP members write the reports using clinical cases from their own practices that show molecular testing’s important Case. A 16-year-old male presented
role in diagnosis, prognosis, and treatment. The following report comes from the University of New Mexico. If you would with a one-week history of fatigue
like to submit a case report, please send an email to the AMP at amp@amp.org. For more information about the AMP and all and easy bruising. Complete blood
previously published case reports, visit www.amp.org. count revealed a white count of 4.8 ×
different locations, resulting in differ- decreased appetite, and/or weight 103/mm3 with left shift of the myeloid
ent transcript sizes with similar func- loss; however, a subset may also pre- lineage with 50 percent blasts, hema-
tions (Fig. 1).4 sent with bleeding due to dissemi- tocrit of 31 percent, hemoglobin of
The most common breakpoint sub- nated intravascular coagulation (DIC), 10.8 g/dL, and a platelet count of 29
case report type of PML, bcr-1 (breakpoint cluster which is associated with APL.5 Rapid × 103/mm3. Review of the peripheral
region) or long form, is at intron 6, diagnosis is imperative in cases of blood smear showed numerous blasts
Brittany Coffman, MD which occurs in 45 to 55 percent of APL due to the increased risk of death with increased nuclear-cytoplasmic
Brian Menkhaus, MD APL cases.4 The second most common secondary to DIC in this patient popu- ratio and bilobed nuclei with sliding
Devon Chabot-Richards, MD is the short form, or bcr-3, which oc- lation. Most patients demonstrate plate morphology (Fig. 2). Myeloper-
Acute promyelocytic leukemia (APL) curs in 35 to 45 percent of cases and pancytopenia on complete blood oxidase stain performed on the pe-
is a subtype of acute myeloid leuke- occurs at intron 3 of PML. Finally, the count, though some patients present ripheral blood was strongly positive
mia (AML) in which promyelocytes least common subtype is the variable with leukocytosis. Leukocytosis is (Fig. 3). The morphologic and clinical
predominate. APL accounts for about form, or bcr-2, which occurs in five to more common in the microgranular findings were concerning for APL and
10 percent of AML cases, and although 10 percent of cases and occurs at exon variant of APL. thus the clinical team started ATRA
APL can be diagnosed at any age, it is (all-trans-retinoic acid) while awaiting
most common among young adults final diagnosis. Flow cytometry re-
B (long
bcr-1 FM
form)
with a slight male predominance.1    
 

 

 vealed the blast population to be dim



45 to 55 percent
APL is defined by the balanced recip- CD45, bright CD33, subset CD34, dim
rocal translocation (15;17)(q22;q21) HLA-DR, dim CD13, CD117, subset
between PML and RARA, although CD56, and cytoplasmic MPO positive
B
FM
bcr-3 (short form)
variant translocations involving 
 

 

 

 (Fig. 4). Dual color dual fusion fluo-




35 to 45 percent
RARA and other partner genes can rescence in situ hybridization was
occur. The fusion results in uncon- negative for t(15;17) (Fig. 5).6
trolled cell proliferation and inhibition A bone marrow biopsy was then
B
EFM
of cell differentiation.
 

 

 performed and revealed a hypercel-


The PML gene, or promyelocytic
leukemia gene, is located on chromo-
some 15.2 Its gene product is a tumor
suppressor protein that blocks cell
proliferation and regulates apoptosis
via FAS ligand and tumor necrosis
factor-alpha. The RARA gene, or
retinoic acid receptor-alpha, is lo-
cated on chromosome 17. 3 The
RARA gene codes for a nuclear re-
ceptor that regulates gene transcrip-
tion, including genes involved in
differentiation, apoptosis, and granu-
lopoiesis. The translocation between
PML and RARA occurs between the
long arms of both chromosomes 15
and 17, respectively. The breakpoint
of RARA occurs at intron 2, but the
breakpoint of PML can occur at three
Fig. 2. Peripheral blood smear demonstrating blasts with “sliding plate” morphology (right) and bilobed nuclei (left) with coarse cytoplasmic granules.
bcr-2 (variable form)
  
5 to 10 percent
lular marrow with left shifted matura-
tion in the myeloid lineage with 77
Fig. 1. The breakpoint of RARA occurs at intron 2, but the breakpoint of PML can occur at different locations, percent blasts (Fig. 6). Blast morphol-
resulting in three different fusion transcripts termed bcr-1, bcr-2, and bcr-3. Bcr-1 (long form) PML breakpoint ogy was similar to the peripheral
occurs at intron 6, resulting in a fusion between PML exon 6 and RARA exon 3. The bcr-3 (short form) PML blood. Flow cytometry performed on
breakpoint occurs at intron 3, resulting in a fusion between PML exon 3 and RARA exon 3. The PML breakpoint
of bcr-2 (variable form) occurs within variable regions of exon 6, resulting in a fusion between PML exon 6 and
the bone marrow was identical to the
RARA exon 3. (Image courtesy of Dr. Evelyn Lockhart) peripheral blood. Conventional
karyotype performed on the bone
6 of PML. The bcr-2 form is termed Two morphologic forms of APL are marrow revealed a normal male chro-
variable form because the breakpoints recognized including hypergranular mosome complement with no abnor-
can occur at different sites within exon (or typical) and microgranular vari- malities identified. Due to the clinical
6. The resulting PML-RARA fusion ants. The blasts of typical APL have suspicion of APL along with blast
gene product prevents normal tran- irregular large nuclei that can be bi- morphology and immunophenotype,
scription, which ultimately leads to lobed and may have a “sliding plate” despite negative FISH and karyotype,
lack of differentiation of myeloid cells morphology. The cytoplasm is densely reverse transcription-polymerase
and provides cells with a survival packed with large granules and oc- chain reaction (RT-PCR) testing was
advantage. casional Auer rods. Microgranular obtained.7 Testing revealed a cryptic
Patients may present with nonspe- variant blasts mostly have a bilobed t(15;17) with the bcr-3 transcript, and
cific symptoms such as fever, fatigue, morphology, and cytoplasmic gran- the patient was formally diagnosed
Fig. 3. Peripheral blood smear stained with myeloperoxidase (MPO) dem-
onstrating a blast with MPO-positive granules, which obscure the nucleus.
 APRIL 2019 | CAP TODAY 27

and other genes can occur.
Variant translocations
may require additional
FISH probes as they may
not be recognized by usual
t(15;17) dual color probes;
it is important to recog-
nize, however, that these
are not cryptic transloca-
tions but variant transloca-
tions. Furthermore, all
cryptic and variant altera-
tions involve RARA but
may not involve PML,
highlighting the impor-
tance of RARA gene al-
Fig. 4. Flow cytometry performed on the peripheral blood revealed blasts
terations in the develop-
(highlighted red) that are positive for CD33, subset CD34 (top right plot), ment of APL.
dim HLA-DR, dim CD13 (bottom left plot), CD117, and cytoplasmic Of note, cases of variant
myeloperoxidase (MPO) (bottom right plot). translocations involving
RARA but not PML may
with APL (Fig. 7). Despite starting have blasts morphologically resem-
ATRA, the patient developed DIC, bling APL but with a worse prognosis,
which was effectively treated with specifically t(11;17)(q23;q21), which
transfusion. The patient was dis- may also be resistant to ATRA. These
charged home one month later and cases are best classified as APL with a
remains in remission more than three variant RARA translocation per the
PCR testing primarily, each testing type, with a longer turnaround time of
modality has its own advantages. five to 10 days, can identify the usual
FISH carries the advantage of there t(15;17) and may also —continued on 28
being specific probes to de-
tect the translocation and
can often be completed
within 24 hours. In addition,
break-apart probes can be
used to identify fusions with
other partners, an advantage
when dealing with variant
translocations. The disad-
vantages of FISH are its in-
sensitivity for minimal re-
sidual disease monitoring
and the possibility of miss-
ing cryptic cases, such as this Fig. 6. Bone marrow biopsy demonstrated hypercellular marrow with
case. Conventional karyo- increased blasts.
Delta Rn vs Cycle
1.0e+001
1.0e+000
Delta Rn

years later. 2016 WHO.8 The majority of cryptic

Discussion. APL is an acute leuke-
mia that is defined by t(15;17) and re-
quires prompt diagnosis because it is
associated with DIC. Review of blast
morphology and cytochemical stains
can aid the pathologist in narrowing
the differential diagnosis, but the final
cases of APL have similar morphol-
ogy, immunophenotype, and cyto- 1.0e-001
chemical staining patterns, which
should raise clinical concern for APL.
In these cases, RT-PCR, microarray,
and gene sequencing can identify the
cryptic translocation and definitively 1.0e-002
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

diagnosis of APL often requires ad- establish the proper diagnosis. Cycle Number
ditional testing. It is common for rapid Although it may seem that the ini- Fig. 7. RT-PCR for PML-RARA (blue) along with internal control ABL (black): This shows high copy number of
turnaround FISH to be performed to tial best option would be to use RT- PML-RARA, which crosses the cycle threshold (green line).
identify the t(15;17), thus securing the
diagnosis. However, in cases such as
this one, FISH and karyotype will fail NEW Fentanyl Assay (also detects Norfentanyl)
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to identify the cryptic translocation. NEW Oxcarbazepine Metabolite Assay
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be detrimental and even lead to death NEXT GENERATION ASSAYS NEW Ethyl Glucuronide Assay
if ATRA therapy is not begun. NEW Linezolid Assay
Cryptic translocations of APL ac- NEW EDDP Assay
count for about two percent to four NEW Tramadol Assay

percent of all APL cases. The majority THERAPEUTIC DRUG MONITORING ASSAYS & URINE DRUG TESTS
of cryptic translocations result from ARK introduces its homogeneous enzyme immunoassay
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automated clinical chemistry analyzers.
variant translocations between RARA
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28 CAP TODAY | APRIL 2019
Case report
continued from 27
identify other genetic abnormalities
that have prognostic significance.
Karyotype may also miss cryptic trans-
locations and it too is insensitive to
monitoring for minimal residual dis-
ease. RT-PCR is by far the most sensi-
tive testing modality and is frequently
used for minimal residual disease
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monitoring and to identify cryptic
translocations. Turnaround time, how-
ever, is typically longer than for FISH.
RT-PCR has the added advantage that
it can identify the specific translocation
subtype, including bcr-1, -2, or -3.
A final option for identifying genetic
abnormalities in such cases is next-
generation sequencing. It is by far the
most sensitive method of identifying
genetic abnormalities because it can
Simple, easy-to-use kit
Fast 15-15-15 protocol
Highly sensitive
GSDM-0110.B
identify numerous abnormalities, not
limited to cryptic translocations.9 His-
torically, the clinical use of next-gener-
ation sequencing has been limited due
to high cost and long turnaround time;
however, with technology advances
the cost and turnaround time have
been significantly decreased. Even
with these advances, next-generation
sequencing is not readily available in
every laboratory.
In cases where APL is suspected it
is important to obtain rapid turn-
around FISH and to alert the clinical
team of the suspected diagnosis so
ATRA therapy can be initiated
promptly to prevent DIC. If FISH is
demonstrated to be negative in a case
with typical APL morphology and
immunophenotype, it is important to
perform additional molecular testing
to rule out cryptic translocation before
assigning a diagnosis other than APL.
With appropriate diagnosis and treat-
ment, patients with APL have an ex-
cellent prognosis.
1. Paulson K, Serebrin A, Lambert P, et al. Acute
promyelocytic leukaemia is characterized by
stable incidence and improved survival that
is restricted to patients managed in leukaemia
referral centres: a pan-Canadian epidemiologi-
cal study. Br J Haematol. 2014;166(5):660–666.
2. Salomoni P, Dvorkina M, Michod D. Role
of the promyelocytic leukaemia protein in cell
death regulation. Cell Death Dis. 2012;3:e247.
3. Pandolfi PP. Oncogenes and tumor suppres-
sors in the molecular pathogenesis of acute
promyelocytic leukemia. Hum Mol Genet.
2001;10(7):769–775.
Test yourself
Here are three questions taken from the case
report. Answers are online now at www.amp.
org/casereports and will be published next
month in CAP TODAY.
1. Which of the following is true regarding
acute promyelocytic leukemia?
a. Patients are always older.
b. Patients may present in DIC.
c. Diagnosis requires identification of t(8;21).
d. Patients always present with leukocytosis.
2. The long form, or bcr-1, breakpoint ac-
counts for what percentage of acute promy-
elocytic leukemia cases?
a. 15–20 percent
b. 80–90 percent
c. 45–55 percent
d. 35–45 percent
3. What is an advantage of performing fluo-
rescence in situ hybridization over reverse
transcription-polymerase chain reaction?
a. Rapid turnaround time
b. Ability to detect cryptic translocations
c. More sensitive for minimal residual disease
d. Allows for subtyping of breakpoint
Test yourself answers
In the March 2019 issue was a case report
(page 34), “FDA-approved DNA blood test
for colorectal cancer prompts patient to un-
4. Choppa PC, Gomez J, Vall HG, Owens M,
Rappaport H, Lopategui JR. A novel method
for the detection, quantitation, and breakpoint
cluster region determination of t(15;17) fusion
transcripts using a one-step real-time multiplex
RT-PCR. Am J Clin Pathol. 2003;119(1):137–144.
5. Adams J, Nassiri M. Acute promyelocytic
leukemia: a review and discussion of vari-
ant translocations. Arch Pathol Lab Med.
2015;139(10):1308–1313.
6. Campbell LJ, Oei P, Brookwell R, et al. FISH
detection of PML-RARA fusion in ins(15;17)
acute promyelocytic leukaemia depends on
probe size. Biomed Res Int. Epub March 28,
2013. doi:10.1155/2013/164501.
7. Gabert J, Beillard E, van der Velden VH, et
al. Standardization and quality control studies
of ‘real-time’ quantitative reverse transcriptase
polymerase chain reaction of fusion gene
transcripts for residual disease detection in
leukemia—a Europe Against Cancer program.
Leukemia. 2003;17(12):2318–2357.
8. Swerdlow SH, Campo E, Harris NL, et al.,
eds. WHO Classification of Tumours of Hae-
matopoietic and Lymphoid Tissues. Vol 2. Re-
vised 4th ed. Lyon, France: WHO Press; 2017.
9. Welch JS, Westervelt P, Ding L, et al.
Use of whole-genome sequencing to di-
agnose a cryptic fusion oncogene. JAMA.
2011;305(15):1577–1584.
Dr. Coffman is a pathology resident and
Dr. Chabot-Richards is associate professor
of hematopathology and molecular patholo-
gy—both in the Department of Pathology,
University of New Mexico, Albuquerque.
Dr. Chabot-Richards is also medical di-
rector, TriCore Reference Laboratories,
Albuquerque. Dr. Menkhaus, formerly a
pathology resident at UNM, is in the De-
partment of Pathology, Memorial Hospital
of Sheridan County, Sheridan, Wyo.
dergo colonoscopy,” written by members of
the Association for Molecular Pathology. Here
are answers (in bold) to the three “test your-
self ” questions that followed that case report.
1. The five-year survival for patients diag-
nosed with stage I CRC is closest to:
a. 10 percent
b. 35 percent
c. 50 percent
d. 90 percent
2. In the United States, the number of age-
eligible individuals who are not compliant
with guideline-recommended CRC screen-
ing is closest to:
a. 1 million
b. 10 million
c. 20 million
d. 100 million
3. The FDA-approved SEPT9 test is indi-
cated for:
a. Symptomatic patients who refuse other CRC
screening methods.
b. Postoperative surveillance in patients with stage
II CRC.
c. Asymptomatic, average-risk, age-eligible
patients who have refused other screening
methods.
d. Predictive testing in asymptomatic patients with
a family history of CRC.
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32 CAP TODAY | APRIL 2019
Neisseria gonorrhoeae
continued from 1
targeted treatment, which will re-
duce antibiotic selection pressure
and decrease the emergence of resis-
tance,” Dr. Klausner said.
The British Association for Sexual
Health and HIV endorsed this ap-
proach when it issued a gonorrhea
guideline update in January, Dr.
Klausner says. “They specifically
recommend the use of molecular
tests to predict susceptibility of anti-
biotics in Neisseria gonorrhoeae in-
fections.” The new guideline re-
moves the recommendation for dual
therapy with azithromycin and en-
courages the use of ciprofloxacin in
certain cases when a molecular test
predicts susceptibility.
Dr. Klausner describes the “wake-
up case” as that of a heterosexual
man who presented to a sexual
health clinic in the United Kingdom
in December 2014 with a two-week
history of urogenital symptoms (Fi-
fer H, et al. N Engl J Med. 2016;374
[25]:2504–2506). The patient had re-
turned 10 days earlier from a trip to
Japan, where his Japanese female
partner had been treated for
gonorrhea.
The patient’s nucleic acid ampli-
fication tests were positive for
N. gonorrhoeae in a urine specimen
and pharyngeal swab, and he had an
N. gonorrhoeae-positive urethral
culture. He received the standard
dual treatment for N. gonorrhoeae
infection in the U.K. at the time,
which was a 500-mg injection of
ceftriaxone plus one gram orally of
azithromycin. (The Centers for Dis-
ease Control and Prevention cur-
rently recommends a similar dual
therapy of a 250-mg injection of
ceftriaxone with one gram orally of
azithromycin.)
Phenotypic testing revealed that
the patient’s N. gonorrhoeae strain
was resistant to cefuroxime, cipro-
floxacin, and tetracycline. The pa-
tient had follow-up pharyngeal
NAATs on days 15, 79, and 98; all
tested positive for N. gonorrhoeae. A
culture taken on day 98 was also
positive.
The patient was then treated with
double doses of the initial treatment:
a one-gram injection of ceftriaxone
and two grams orally of azithromy-
cin. “Finally, nearly four months
later, his pharyngeal swab tested
negative,” Dr. Klausner said.
Antimicrobial susceptibility test-
ing by Etest of the pharyngeal isolate
found resistance to ceftriaxone, ce-
fixime, cefotaxime, azithromycin,
penicillin, tetracycline, and cipro-
APRIL 2019 page 32
floxacin. It was susceptible only to
spectinomycin (which is not avail-
able in the United States).
Whole genome and conventional
sequencing of the organism found
multiple gene alterations. “They
found what we call a mosaic penA
gene, which has been classified as X,”
Dr. Klausner said. “People have clas-
sified about three dozen different
mosaic penA types associated with an
altered penicillin-binding protein 2,
with a decreased target affinity to
ceftriaxone.” Other
gene alterations
were an mtrR pro-
moter deletion of
one adenine (which
increases MtrCDE
efflux of ceftriax-
one and azithromy-
Dr.Klausner
cin) and a change
in penB (which de-
creases the PorB influx of ceftriaxone
and azithromycin).
Third-generation cephalosporin
resistance in N. gonorrhoeae is rising
in the U.S., as noted by CDC data
published in the New England Jour-
nal of Medicine in 2012 (Bolan GA,
et al. 366[6]:485–487). In 2011, Dr.
Klausner said referring to the data,
isolates from states in the West, from
five percent of men who have sex
with men, had higher levels of ele-
vated MICs for decreased suscepti-
bility to cefixime.
Drug-resistant N. gonorrhoeae has
been declared one of the three most
urgent infectious public health
threats. “That’s a critical thing be-
cause it alerts funders and policy-
makers to this issue,” Dr. Klausner
said. He was in Washington, DC, last
summer, and “the one thing politi-
cians knew about STDs,” he said,
“was that there is untreatable gonor-
rhea out there,” which has resulted
in more funding and research
opportunities.
N. gonorrhoeae antibiotic resis-
tance is a pattern that has persisted
for decades, since the sulphon-
amides of the 1930s. But because the
return on investment for a single-
dose antibiotic for the infection has
not been “particularly motivating”
for drug developers, Dr. Klausner
said, new strategies are needed. He
has pursued one such strategy for
the past decade.
I n N. gonorrhoeae, there are multiple
targets for different antimicro-
bials and multiple mechanisms of
resistance. Dr. Klausner zeroes in
on where fluoroquinolones work
on the gyrA enzyme, which is coded
by the gyrA gene. “As we develop
better tools and —continued on 34
4/9/19 2:07 PM
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4/2/19 3:35 PM
 34 CAP TODAY | APRIL 2019
Neisseria gonorrhoeae
continued from 32
understanding, we can learn more about how we
can use the prediction from sequencing to look at
antimicrobial susceptibility.”
N. gonorrhoeae is notorious for its promiscuity
and ability to collect DNA elements, either plas-
mids or chromosomal genes from neighboring
organisms, he said. “The oropharynx normally has
a high level of Neisseria commensals. It’s normal
0419_1-46_Genomic-Ergonomics-Ngonorrhea_v4.indd 34
in the throat to have a Neisseria cinerea, Neisseria
subflava, other Neisseria species, and the thought
is that by taking antibiotics, those other species
may develop resistance.” When a patient acquires
a gonococcal infection, there is easy transforma-
tion of those resistant elements to the new
N. gonorrhoeae that have just landed in the throat,
“a particularly good place for growth and the pas-
sage of resistant elements.”
CDC data from 2016 on antimicrobial suscep-
tibility of N. gonorrhoeae isolates showed that 73
APRIL 2019 page 34
percent of isolates are ciprofloxacin susceptible,
with 27 percent resistant. “I began thinking, we
treat this bug with a sledgehammer by treating
every infection with ceftriaxone plus azithromy-
cin,” Dr. Klausner said. “If we actually knew the
susceptibility profile of the organism at the time
of treatment, we could probably be smarter. We
could reduce the selection pressure on the organ-
ism by the use of different antibiotics.”
DNA gyrase A is the target of ciprofloxacin. “In
a wild-type gyrase, the ciprofloxacin binds to that
enzyme, inhibits the enzymatic activ-
ity, prevents a normal development of
DNA, and the organism is nonviable,”
Dr. Klausner said. In the mutated
enzyme, the ciprofloxacin cannot bind
‘It is a laboratory-developed
method that is widely
available, and any
laboratory can follow
the published protocol
and replicate it.’
Jeffrey Klausner, MD, MPH
or act and the organism is resistant.
Different work has shown that a sin-
gle point mutation at Ser-91 is associ-
ated with this mutation. “We’re lucky
that one single point mutation was
both necessary and sufficient,” he
said. “While there are other muta-
tions, such as in par C and gyrB, the
singular presence of the alteration in
Ser-91 can predict both sensitivity and
resistance.”
His researcher’s review of more
than 1,000 isolates and about 10 dif-
ferent studies found that the sum-
mary of the wild-type gyrA to predict
fluoroquinolone susceptibility was 98
percent sensitive and nearly 99 per-
cent specific.
Dr. Klausner’s group and Mark
Pandori, PhD, formerly of the San
Francisco Public Health Laboratory,
developed in 2006 a reverse transcrip-
tion PCR assay to study fluoroquino-
lone susceptibility. Using different
probes and melting points generated
from that process, “we were able to
clearly differentiate a resistant isolate
from a susceptible isolate.”
Their early data looked at the MIC
of about 100 different N. gonorrhoeae
isolates to ciprofloxacin, and the ex-
cellent differentiation by their gyrA
assay, Dr. Klausner said, showed a
very high range of MICs in the wild-
type and mutant isolates (Siedner MJ,
et al. J Clin Microbiol. 2007;45[4]:
1250–1254). “We had one missed call
where the organism was determined
to be wild type but actually was resis-
tant,” he said.
Phase one of the study Dr. Klaus-
ner reported on at —continued on 36
4/8/19 2:38 PM
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 36 CAP TODAY | APRIL 2019
Neisseria gonorrhoeae
continued from 34
the AMP meeting was assay verification. They
used urine triplicates seeded with wild-type or
mutant gyrA isolates at a concentration of 1,000
CFU/mL, from the CDC and the University of
Washington. “We found no difference in the per-
formance across the different triplicates,” Dr.
Klausner said. This phase included cross-reactivity
studies because of a primer concern that there
could be cross-reaction with other common Neis-
seria species in the throat. “We did not see that.
The primers were developed to be targeted toward
Neisseria gonorrhoeae, not other Neisseria species”
(Hemarajata P, et al. J Clin Microbiol. 2016;54[3]:
805–808).
In phase two of the study, Dr. Klausner and
colleagues introduced the assay for routine clinical
use at UCLA Health, which serves more than
500,000 patients at two hospitals and in more than
150 primary care clinics and other outpatient set-
tings. “In November 2015, we began to do reflex
gyrA genotyping on all Neisseria gonorrhoeae
nucleic-acid–positive clinical specimens at the
UCLA Health microbiology laboratory.” GyrA
results were reported to providers in the electronic
health record within 24 to 48 hours of receipt of
the specimen. The report showed the positive N.
gonorrhoeae result and the presence or absence of
the wild-type gyrA gene. A standard disclaimer
said the gyrA assay was not FDA approved but
had good performance results in accordance with
CLIA requirements.
The study’s objectives were to examine the
impact of gyrA genotyping on N. gonorrhoeae
treatment at UCLA Health and to evaluate patient
outcomes among those with a wild-type gyrA
genotype. In a retrospective review portion of the
study, Dr. Klausner’s team examined records for
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0419_1-46_Genomic-Ergonomics-Ngonorrhea_v4.indd 36
all laboratory-confirmed cases of N. gonorrhoeae
between Jan. 1, 2015 and Sept. 8, 2017. They also
collected test-of-cure data among patients with
wild-type N. gonorrhoeae infections treated with
ciprofloxacin.
“During this 32-month study, there were more
than 500 Neisseria gonorrhoeae infected patients,”
Dr. Klausner said. Some patients had multiple ana-
tomic site-specific infections or repeat infections.
Forty percent of infected patients were
treated empirically on about the same Neisseria
day. “That is one limitation to the assay,”
he said, since standard practice is to treat
gonorrhea immediately before obtaining 100%
test results if a patient is symptomatic.
For patients who were not empirically 80%
treated, the average time from specimen
collection to treatment was up to five 60%
days, which provides a good window for
Percent of
performing reflex testing and sending
Percent
40%
results to the provider to inform treat-
ment choices, he said. 20%
“When we looked at 655 infections
that underwent gyrA genotyping, we 0%
had results for 43 percent that were wild
type, 27 percent were mutant, and about
30 percent were indeterminate,” Dr.
Klausner said. The reason for the high number of
indeterminate infections is complicated, he added,
and may have to do with the site of specimen
source, either the rectum or pharynx. “We still see
that difficulty,” he tells CAP TODAY. “Newer as-
says are somewhat better, but because of lower
bacterial burden in the pharynx, or competition
from other Neisseria species in the pharynx, the
ability of the assay to characterize the gyrA gene
is decreased.” Research is underway on the mo-
lecular assays’ performance to predict susceptibil-
ity so that they are equally successful, indepen-
dent of anatomic site, “because we know that
Neisseria gonorrhoeae infections in the throat
can be spread to sex partners, and we also
know that Neisseria gonorrhoeae infections in
the throat serve as an important reservoir
where drug resistance is acquired.”
O ne of the study’s primary outcomes
showed a decline in ceftriaxone use for
treatment of N. gonorrhoeae infections from
94 percent before gyrA genotyping to 76 per-
cent after gyrA genotyping. “What replaced
that ceftriaxone treatment, surprisingly, was
ciprofloxacin,” Dr. Klausner said. “Over time,
we had a nice increase in the use of ciprofloxa-
cin among those who were nonempirically
treated.”
A retrospective test-of-cure study of 25 pa-
tients with gyrA wild-type infections treated
with ciprofloxacin showed a 100 percent cure
rate, regardless of anatomic site. “The sample
size is small but quite encouraging.”
To sum up, the study found that routine
gyrA genotyping can be implemented in a
large health system and that gyrA results can
have an impact on the treatment of patients
with N. gonorrhoeae. Ceftriaxone use declined
with a rise in ciprofloxacin use, and the test of
cure was 100 percent (Allan-Blitz LT, et al. Clin
Infect Dis. 2017;64[9]: 1268–1270). It was a
single-center study, further implementation
and replicaton of the gyrA assay are needed, and
there was no measure of the ecologic impact of the
reduction in ceftriaxone use on Neisseria gonor-
rhoeae in the population, Dr. Klausner said, citing
the study’s limitations.
“For me, it was important to show that this
could be done,” he tells CAP TODAY. He isn’t cer-
tain his team’s assay is the best. “But it is a labora-
tory-developed method that is widely available,
Neisseria gonorrhoeae
gonorrhoeae gyrA Genotypes
gyrAgenotypes by by
anatomic site, UCLA Health,
anatomic site, UCLA Health, 2015–2016 2015-2016
Gyrase
GyraseAAwild
Wildtype
Type Gyrase AAmutant
Gyrase Mutant Unable to genotype
Unable Genotype
infections
ofInfections
Vaginal (n=5) Pharyngeal (n=37) Rectal (n=26) Urine (n=41)
Anatomic location
Anatomic Location
and any laboratory can follow the published
protocol and replicate it.”
Final clinical validation is underway as phase
three. It’s an NIH-funded clinical study of the as-
say with 240 N. gonorrhoeae gyrA wild-type cul-
ture-positive patients treated with 500 mg of cip-
rofloxacin. “We completed enrollment at the end
of December. The results look promising,” Dr.
Klausner says. “We will be able to produce a pre-
cise estimate of the efficacy of ciprofloxacin in the
treatment of Neisseria gonorrhoeae infections, with
predicted susceptibility as determined by the gyrA
molecular assay.”
He expects genotypic testing to be a topic of
discussion among groups updating gonorrhea
treatment guidelines. “This is an important topic
for which now there is new evidence. Molecular
susceptibility testing can enable physicians to
select specific antibiotics,” he says.
SpeeDx (Sydney, Australia) received the CE
mark and the Australian Therapeutic Goods Ad-
ministration approval for its assay to predict cip-
rofloxacin susceptibility in N. gonorrhoeae, Dr.
Klausner says. Shield Diagnostics (San José, Calif.)
announced in March the launch of its Target-NG,
a rapid molecular test for antibiotic susceptibility
in N. gonorrhoeae. The company says Target-NG
can determine if a given gonorrhea infection is
susceptible to ciprofloxacin with the same turn-
around time as gonorrhea screening tests. (Dr.
Klausner has advised various test manufacturers,
among them Shield Diagnostics, SpeeDx, Cepheid,
Hologic, and Click Diagnostics.)
Advances in molecular testing are key to stem-
ming the growth of antimicrobial resistance, Dr.
Klausner said. “New genotypic Neisseria gonor-
rhoeae diagnostics are here—highly accurate and
predictive of susceptibility and treatment out-
comes. And better, multi-targeted tests integrated
with Neisseria gonorrhoeae detection and addi-
tional antibiotics are forthcoming.”
Amy Carpenter Aquino is CAP TODAY senior editor.
APRIL 2019 page 36 4/8/19 2:38 PM
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 38 CAP TODAY | APRIL 2019
Peripheral blood evaluation: B12 deficiency, anemia, ET, CMML
Amy Carpenter Aquino
Diagnoses of essential thrombocythe-
mia and chronic myelomonocytic
leukemia were among those covered
in four cases in a CAP18 session on
practical challenges in peripheral
blood evaluation.
Second of two parts
Carla S. Wilson, MD, PhD, profes-
sor of hematopathology, and Devon
S. Chabot-Richards, MD, associate
professor of hematopathology and
molecular pathology, Department of
Pathology, University of New Mexico
School of Medicine, walked attend-
ees through seven cases illustrating
the benefits of peripheral blood
smear evaluation, four of which are
reported here. Drs. Wilson and
Fig. 1. Severe vitamin B12 deficiency mimicking thrombotic thrombocytopenic purpura
■ ↓ RBC survival
■ Pancytopenia
(↓↓ platelets)
■ ↓ MCV if concurrent
microcytic anemia
(Fe deficiency,
thalassemia trait)
Chabot-Richards are medical direc-
tors at TriCore Reference Laborato-
ries, Albuquerque, NM.
The first case was that of a 58-year-
old man who presented with a three-
month history of weakness, palpita-
tions, and shortness of breath. He
complained of bleeding gums, epi-
staxis, and a tingling sensation
throughout his body. His CBC with
differential counts revealed marked
anemia (Hb 5.6 gm/dL), high RDW
(21.2 percent), mild leukopenia (WBC
2.7 × 109/L), lymphopenia, adequate
neutrophils, and moderate thrombo-
cytopenia (platelet 68 × 109/L).
Review of the peripheral blood
smear was remarkable for prominent
red cell anisopoikilocytosis with
schistocytes, oval macrocytes, rare
spherocytes, and nonspecific poikilo-
cytes. Polychromasia was not in-
creased and the reticulocyte count
was normal, Dr. Wilson said.
Additional studies revealed that
the patient had low haptoglobin (<8
mg/dL), elevated LDH (1023 U/L),
and elevated indirect bilirubin (3.5;
normal range 0.2–1.0) consistent with
hemolysis, she said. “We recom-
0419_38-41_SmearEval2.indd 38
mended additional testing which
showed a serum vitamin B12 level of
<60 pg/mL [normal 193–986], normal
RBC folate level, methylmalonic acid
of 3.08 µmol/L [normal 0–0.4], and
positive intrinsic factor and parietal
cell antibodies. The clinicians were
worried about thrombotic thrombo-
cytopenic purpura because of all the
schistocytes,” Dr. Wilson said. They
sent out for an ADAMTS13 activity
assay; results were normal.
“This is a case of severe vitamin
B12 deficiency that can mimic micro-
angiopathic hemolytic anemia,” or
MAHA, she said. “The key is that
you can see a lot of fragmented red
cells in vitamin B12 deficiency due to
increased red cell fragility causing
decreased survival in circulation.”
(Fig. 1)
Severe vitamin B12 deficiency af-
fects DNA synthesis in all hematopoi-
etic lineages, and the CBC often
shows pancytopenia.
Hypersegmented neutrophils are
an important clue to vitamin B12 de-
ficiency, as shown in Fig. 1. Hyperseg-
mentation is defined as the presence
of six or more lobes in a neutrophil or
five lobes in at least five percent of
neutrophils. This abnormality is
quickly reversed and may not be
recognized in smears after initiation
of vitamin B12 supplementation. Hy-
persegmented neutrophils are not
specific to vitamin B12 deficiency.
“You can see hypersegmented neu-
trophils and macrocytic anemia in
association with myelodysplastic
syndromes or in individuals receiv-
ing certain drugs such as hydroxy-
urea,” Dr. Wilson said.
“How do we distinguish vitamin
B12 deficiency from microangiopathic
hemolytic anemia?” she asked.
 A high reticulocyte count can be a
reliable indicator of MAHA, she said.
The reticulocyte percentage may be
elevated in B12 deficiency but the
absolute reticulocyte number is low
wa
di
bin
due to ineffective hematopoiesis. notably when the HTC results fall
 Pancytopenia is rare in MAHA. into an indeterminate range of 25 to he
The degree of anemia is not as severe 70 pmol/L (depending on the assay). va
in MAHA and platelet counts are typi- Similar to serum B12 assays, results in bin
cally lower than in B12 deficiency. the intermediate range should be fol- Bo
 The MCV in vitamin B12 deficiency lowed up with tests for methylmalo- ric
is usually high and often exceeds 120 nic acid (MMA) preferentially or se
fl, although it may be normal in cases homocysteine.
of severe hemolysis or with concur- MMA is an imperfect test for some an
rent iron deficiency or thalassemia. individuals, Dr. Wilson said, and m
Reticulocytosis associated with particularly for patients with renal sic
MAHA only causes a slightly elevated disease who do not excrete serum as
MCV, if at all. The MCV was 114 fl in metabolites of MMA. The elevated ce
this case. metabolites can make the patient ap- ha
 Neutrophil hypersegmentation or pear to be B12 deficient. “MMA is
neutropenia is not a feature of MAHA. better than homocysteine because it’s F
“The problem with making a diag- usually not elevated in folate defi-
nosis of vitamin B12 deficiency in less ciency and homocysteine is also af-
severe cases is that no single marker fected by renal disease,” she said.
detects deficiency in all patients,” she Automated tests for MMA can detect
said, and serum vitamin B12 testing is subtle disturbances in vitamin B12
neither sensitive nor specific. metabolic pathways and should be
Reference ranges for serum vita- combined with serum B12 or HTC
min B12 are based on population testing for complete interpretation,
studies and may not be adequate for Dr. Wilson said.
individuals. Another problem is that If faced with discordant vitamin
serum B12 assays measure the total B12 laboratory results in a patient
B12 bound to both transcobalamin (20 with strong clinical features of defi-
percent) and haptocorrin (80 percent). ciency, “just tell the clinicians to
Only the 20 percent of B12 bound to treat,” she advises, to avoid neuro-
transcobalamin is available to tissues logical impairment. “Vitamin B12
through CD320 cell receptors. The 80 deficiency is easily corrected.” an
percent bound to haptocorrin is meta- wh
bolically unavailable; serum B12 mea-
surements are significantly affected
by changes in the haptocorrin protein
O
“
ur next case is a case of anemia,”
said Dr. Chabot-Richards as
she described test results from a
gl
he
ne
level. Increased haptocorrin is pro-
12-year-old African-American girl fa
duced by the liver in some malignan-
who presented to the emergency wi
cies, and about 15 percent of people
department with acute hip pain. A sic
normally have decreased levels. CT scan and CT angiogram revealed all
The metabolically active B12-trans-
a bony infarction in the femoral neck,
cobalamin complex is called holo- and the girl’s CBC and peripheral ha
transcobalamin (HTC), and some blood smear showed evidence of bin
laboratories, particularly those out-
anemia. Her blood smear was clearly sa
side the United States, are testing for
abnormal, with numerous classic “In
HTC rather than total serum B12 as a
sickle cells with pointed ends, as ga
measure of B12 deficiency. well as other elongated red blood Cl
cells with blunt ends. cre
‘
The key is that you can see a lot of Howell-Jolly bodies
and target cells were ce
fragmented red cells in vitamin B12 present. The patient on
deficiency due to increased red cell also had an elevated wo
reticulocyte count at glo
fragility causing decreased survival 3.7 percent. he
in circulation.
Carla Wilson, MD, PhD
’ “This was sent
out for hemoglobin
ce
wi
electrophoresis. Al- no
“With decreased vitamin B12, you kaline electrophoresis is the classic pe
see decreased HTC,” Dr. Wilson said. screening test we do to evaluate for “T
“There is less uptake of B12 into tis- abnormal hemoglobins,” Dr. Chabot- of
sues, and it starts affecting the B12 Richards said. “It often reflexes to th
dependent pathways.” acid depending on our results.” sic
The immunoassay for HTC is be- The patient had 42 percent abnor-
ing marketed as an active B12 assay, mal hemoglobin running in the m
and preliminary studies suggest it S/D/G lane and 46 percent running tro
may have some of the same problems in the C/E/O/A2 lane. Hemoglobin 80
as the existing serum B12 assays, most F was two percent. A Sickledex test tie
APRIL 2019 page 38 4/9/19 5:05 PM
 APRIL 2019 | CAP TODAY 39

was positive, and the patient was
diagnosed with sickle cell/hemoglo-
bin C disease.
“This is a patient who has co-in-
heritance of two different β-chain
variants: hemoglobin S and hemoglo-
bin C,” Dr. Chabot-Richards said.
Both are common variants in the Af-
rican population, so it’s possible to
see them combined.
The girl had no normal β-chain
and was unable to make normal he-
moglobin A. The combination of
sickle cell and hemoglobin C causes
a sickling disorder similar to sickle
cell anemia. These patients typically
have a slightly milder clinical picture
and their cells sickle in low-oxygen
environments. “These patients are
typically hyposplenic, so their spleens
infarct at a fairly young age,” Dr.
Chabot-Richards said. Sickle cell ane-
mia patients are also at risk for death
from infection, stroke, or respiratory
failure due to lung infarction.
Peripheral blood smear findings of
a sickle cell anemia patient show
numerous elongated cells, much
more pointed on the ends than what
was seen in the 12-year-old girl
(Fig. 2). “There is a lot of anisopoikilo-
cytosis, so the cells have a higher red
cell distribution width,” Dr. Chabot-
Richards said.
to have sickle hemoglobin and
α-thalassemia co-inherited. These
patients have decreased hemolysis
and soft tissue damage, so the com-
bination is slightly protective for
them, though they have increased
bone infarction and osteonecrosis.
Overall survival rates are not very
different.
If the sickle cell anemia is hetero-
zygous and diagnosed along with an
QuickSlide™
α-chain variant, typically the electro-
phoresis will show a decreased per-
centage of hemoglobin S.
Sickle hemoglobin with β-thal-
assemia is also not uncommon. Pa-
tients who have a sickle cell β-chain
with severe β-thalassemia leading to
complete loss of protein function are
unable to make normal hemoglobin
A. They have less hemolysis than
sickle cell anemia —continued on 40

Fig. 2. Sickle cell anemia blood smear findings

Automated Hematology Slide Stainer

and longer red blood cell survival, In a comparison of findings of

which leads to having a higher hemo-
globin. Patients also have chronic
hemolysis and are at risk for femoral
neck necrosis and bone marrow in-
farction. Compared with patients
with sickle cell anemia, patients with
sickle cell hemoglobin C disease usu-
ally have delayed hyposplenism.
“These patients don’t typically
have true sickle cells or true hemoglo-
bin C crystals,” Dr. Chabot-Richards
said of the blood smear findings.
“Instead, you see more unusual, elon-
gated cells with rounded ends.”
Clam- or boat-shaped cells are in-
creased, as are target cells.
In comparison, patients with sickle
cell trait have one normal β-chain and
one sickle β-chain. Electrophoresis
would show 35 to 45 percent hemo-
globin S, with the remainder normal
hemoglobin A. The majority of sickle
cell trait patients are asymptomatic
sickle cell anemia patients and sickle
C disease patients, she pointed out
that while both patients have anemia,
it is typically more severe in those
with sickle cell anemia. Sickle cell
anemia patients also typically have
higher reticulocyte counts, higher
WBC counts owing to the inflamma-
tory process, higher bilirubin, and
higher LDH because of increased
hemolysis.
Sickle cell trait is fairly common
and can be seen in combination with
other hemoglobinopathies, which
have different clinical manifestations,
such as sickle cell/hemoglobin D.
These patients have milder disease
and usually a stable hemoglobin
level. Sickle cell/hemoglobin O-Arab
is a severe sickle disease; patients
have one O-Arab β-chain and one
Standardization at the
sickle β-chain. “Usually, the hemoglo-
bin S is at a slightly higher percentage

with cells that rarely sickle, and have
normal CBC parameters and normal
peripheral blood cell appearance.
“They do have an increased incidence
of renal medullary carcinoma, a risk
they share with people who have
sickle cell anemia,” she said.
Sickle cell anemia patients are ho-
mozygous for the S β-chain, and elec-
trophoresis results show greater than
80 percent hemoglobin S. These pa-
tients have chronic hemolytic anemia,
touch of a button.
than the O because the O is such a
deleterious mutation,” Dr. Chabot-
Richards said.
Another variation is sickle cell C- Stain blood smears in as little as 90 seconds!
Harlem, which usually is present at a
slightly higher percentage than the S
on electrophoresis.
“If you have sickle cell trait to-
gether with an α-chain variant, it’s
usually clinically silent,” Dr. Chabot-
Richards said.
It is not uncommon for patients Contact us for a free demonstration at
HardyDiagnostics.com/HemaPRO
40 CAP TODAY | APRIL 2019

Peripheral smear
continued from 39
patients, and their hemoglobin pa-
rameters are typically higher. A pe-
ripheral blood smear from a patient
with β-thalassemia shows a scattering
of nucleated red blood cells at low
power; sickle cells with pointed ends
and numerous target cells are appar-
ent at a higher power.
“Similar to B12 deficiency, some-
times there can be confusion with
microangiopathic hemolytic anemia,”
especially if the patient has very high
anisopoikilocytosis, Dr. Chabot-Rich-
ards said. With insufficient experience,
“it can be hard to distinguish between
a sickle cell and a schistocyte.”
Sickle cells typically are larger and
more uniform in size than schisto-
cytes. The clinical presentations of
sickle cell anemia and microangio-
pathic hemolytic anemia should be
distinct.
Hemolysis is associated with
thrombocytopenia, increased biliru-
bin and LDH, and decreased hapto-
globin, so it is helpful to use ancillary
tests to help determine the degree of
hemolysis.
“Inheritance of any sickle cell he-
moglobin will cause a positive Sickle-
dex, so it’s important to realize that a
positive Sickledex does not necessarily
equal sickle cell disease in the patient,
or even that the patient will sickle
clinically,” Dr. Chabot-Richards said.
Fig. 3. ET diagnostic criteria phase can be similar to ET, and bone
marrow is required for diagnosis.
Major criteria Platelets > 450 “We usually do reflex testing for
BM biopsy these myeloproliferative-associated
Q Proliferation of mainly megakaryocytes with increased large, mature forms with
hyperlobulated nuclei mutations,” Dr. Chabot-Richards
Q No increase in granulopoiesis or erythropoiesis said. “We will start with a JAK2
Q Fibrosis MF-0 or very rarely MF-1 V617F. It’s the most common muta-
Not meeting criteria for another diagnosis tion we see in a polycythemia vera,
Presence of JAK2, CALR, or MPL mutation but it is also seen in 60 percent of
cases of ET and primary myelofibro-
Minor criterion Presence of a clonal marker or rule out reactive
sis.” If the results are negative, they
reflex to additional testing based on
PV diagnostic criteria the clinical picture.
Major criteria Increased RBC parameters “Typically, we would either go to
Q Hb >16.5 or Hct > 49% in men JAK2 exon 12, if it looked more con-
Q Hb >16 or Hct > 48% in women sistent with polycythemia vera; that’s
Q Or increased red cell mass
positive in an additional four percent
Bone marrow biopsy findings of those cases and is not seen in ET
Q Hypercellularity, panmyelosis including prominent erythroid, granulocytic and
megakaryocytic proliferation, pleomorphic, mature megakaryocytes with differences in size and primary myelofibrosis. If it
Presence of JAK2 mutation looked more like ET or primary my-
elofibrosis, we would do CALR and
Minor criterion Subnormal serum erythropoietin level MPL.” Rarely do they do all such tests
Diagnosis requires either all three major or first two major and the minor on any one patient, she said, and ini-
or
tial molecular testing typically con-
Sustained erythrocytosis, major three, and the minor
sists only of JAK2, CALR, and MPL.
If additional prognostic testing is
cause of the sustained thrombocyto- platelets (“we think of that as a dys- requested, it can be done on blood,
sis. The patient wanted to avoid a plastic finding, but it can be seen in though it is more typically done on
biopsy and requested additional pre- these cases”), possibly circulating bone marrow, and it would be sent
procedure workup. megakaryocytic nuclei appearing as for next-generation sequencing using
“In this patient, we could do muta- dark, very condensed nuclei, and a myeloid gene panel. ASXL1 and
tion testing on the peripheral blood neutrophilia without significant left SRSF2 are associated with inferior
before going to bone biopsy,” Dr. shift. “They should not have signifi- overall and leukemia-free survival.
Chabot-Richards said. “We sent this cant dysplastic features, you shouldn’t EZH2 mutations are associated with
for JAK2, CALR, and MPL testing.” be seeing any increase in blasts, and inferior overall survival. IDH1/2 mu-
The JAK2 V617F testing was nega- basophils and the red blood cells tations are associated with inferior
tive, and reflex testing for CALR and should be fairly unremarkable,” Dr. leukemia-free survival.
MPL revealed the patient had a Chabot-Richards said. “The significance of these is mostly
CALR 52 base pair insertion. The 2016 WHO update sets forth known in primary myelofibrosis. It’s

A 44-year-old woman returned

to her doctor six months after
a routine CBC that showed increased
“Given what we were seeing in the
peripheral blood, the sustained
thrombocytosis, the CALR mutation,
the major and minor diagnostic crite-
ria for ET (Fig. 3).
Essential thrombocythemia diag-
not clear in ET and PV, but it seems
reasonable that it would be similar,
and preliminary studies have shown
platelets. The blood smear at follow- we said it’s likely essential thrombo- nosis requires either all four major that,” she said.
up showed increased platelets with cythemia, but you cannot make that criteria, or the first three major and the National Comprehensive Cancer
a range in size but normal granula- diagnosis without a bone marrow minor criteria. “If you can’t find muta- Network guidelines recommend that
tion. The woman had no history of biopsy to confirm the morphology.” tion in JAK2, MPL, or CALR, but you cytogenetic testing be performed on
thrombotic or hemorrhagic events Essential thrombocythemia is a can find some other clonal marker, a bone marrow specimen, but periph-
and no medication history, and she myeloproliferative neoplasm associ- you can still make this diagnosis.” eral blood testing is acceptable. “This
had normal coagulation and iron ated with increased platelets. The It’s important to distinguish ET is used to detect clonal abnormalities,
studies, LDH, and liver function tests. blood findings usually consist of from polycythemia vera, which is and you can see prognostic abnor-
The patient’s hematologist recom- platelet anisocytosis with small and commonly associated with increased malities,” Dr. Chabot-Richards said.
mended a bone marrow biopsy be- large forms, possibly hypogranular RBCs as opposed to high platelet “Most of the abnormalities here are
count (Fig. 3). Diagnosis requires ei- similar to those we see in any my-
ther all three of the major criteria or eloid neoplasm, such as MDS.”
the first two and the minor, or a pa- Chronic myeloid leukemia must
FROM CAP PRESS tient with sustained erythrocytosis, also be considered with essential
Ensure quality specimens for testing in your JAK2 mutation, and the minor crite- thrombocythemia. Patients may
lab. So You’re Going to Collect a Blood Speci- ria. “You can make this diagnosis show thrombocytosis but should also
men is a basic instructional text and functional without the bone marrow biopsy,” have absolute basophilia, a leukocy-
reference guide for phlebotomy, now in its 15th Dr. Chabot-Richards said, but “I tosis with a left shift, and are positive
edition. This well-illustrated manual provides would not recommend it because the for t(9;22) BCR-ABL1.
step-by-step instructions for obtaining blood by assessment of myelofibrosis is very Reactive thrombocytosis can have
venipuncture and skin puncture from adult and important for prognosis.” many causes. A patient who has
pediatric patients. Routine collections and those Primary myelofibrosis is a third thrombocytosis post-surgery or
with special circumstances are covered. Safety and quality assurance are myeloproliferative neoplasm, one trauma will resolve quickly, in con-
emphasized throughout. Edited by Frederick L. Kiechle, MD, PhD. For associated with leukocytosis with trast to patients who have, for ex-
CAP members, $28; for others, $35. To order, go to www.cap.org, “Shop” tab; ultimate progression to cytopenias ample, iron deficiency anemia,
or call 800-323-4040 option 1. Also available as an ebook ($25 at ebooks.cap.org). due to fibrosis. There are two stages: chronic inflammation, or post sple-
pre-fibrotic and overt. The early nectomy. “It’s important to figure
 APRIL 2019 | CAP TODAY 41

ne that out,” she said. CD13, and CD14.” There was aber- count can be much higher in the bone normalities and mutations in ASXL1,
The initial molecular testing can be rant expression of CD56 and abnor- marrow than it is in the peripheral JAK2, and CBL. Dysplastic type
or performed on peripheral blood speci- mally dim HLA-DR. blood,” she said (Fig. 5). (WBC <13 × 109/L) has lower mono-
ed mens, though the NCCN recom- The diagnosis: chronic myelo- Flow cytometry can help to quan- cyte and blast counts, lower LDH,
ds mends bone marrow, Dr. Chabot- monocytic leukemia (CMML), an tify the immature cells. Most of the and normal cytogenetics, and is more
K2 Richards said. Peripheral blood test- overlap myelodysplastic/myelopro- monocytes in CMML show classical likely to have a mutation in SF3B1.
ta- ing results may convince the patient liferative neoplasm. These neoplasms immunophenotype: CD14 positive Myelodysplastic syndromes,
ra, and oncologist that bone marrow typically have dysplastic features and and CD16 negative. An aberrant phe- which share the same cytogenetic
of testing is necessary. “Bone marrow is a combination of cytopenias and cy- notype, such as increased CD56 or abnormalities and mutations with
ro- required for the ultimate diagnosis toses. “In this disease, patients often aberrant expression of CD2, is also CMML, can be distinguished by a
ey because the presence of fibrosis is so have thrombocytopenia. A monocy- common. predominance of cytopenias and a
on important.” tosis is required for diagnosis,” she The morphologic blast count takes lack of monocytosis. “These patients
said. The WHO criteria consist of a priority, she said. “No matter what have dysplastic findings in one or
to
n-
t’s
A 68-year-old man with myas-
  thenia gravis was being fol-
lowed for anemia. His CBC showed a
persistent peripheral blood monocy-
tosis of >1 × 109/L and >10 percent of
the WBC count. Patients should have
your immature blast count is on flow,
if it doesn’t correlate with your mor-
phology, you should trust your
more of the lineages, in greater than
10 percent of cells of that lineage,” she
said. Promonocytes should not be
ent white blood cell count of 7.6 × 109/L, less than 20 percent blasts and equiv- morphology.” used as blast equivalents in MDS.
ET with neutrophils slightly decreased alents in the blood and bone marrow; Most cases of CMML will have a Of the myeloproliferative neo-
it for his age and monocytes slightly in- a higher percentage would give them normal karyotype; when abnormali- plasms, chronic myeloid leukemia
my- creased. His peripheral blood smear a diagnosis of leukemia. ties are seen they’re similar to those must be excluded, and FISH or mo-
nd revealed only 57 percent neutrophils “One thing that can trip people up seen in MDS. BCR-ABL1 should be lecular testing is recommended. “In
sts and many large, mononuclear cells. is this idea of blast equivalents,” Dr. excluded in all cases, and PDGFRA, particular, CML-P190 variant is as-
ni- PDGFRB, FGFR1, and PCM1-JAK2 sociated with a monocytosis, so these
n- Fig. 4. Blast equivalents in CMML should be excluded if eosinophilia is patients can have similar peripheral
PL. present. “The new WHO update blood findings,” Dr. Chabot-Richards
is recommends that if you have a pa- said. Dysplasia or thrombocytopenia
od, tient you think has chronic myelo- is not typically seen in CML.
on monocytic leukemia, you should do Other myeloproliferative syn-
nt FISH or molecular testing for t(9;22) dromes may present with monocyto-
ng to completely exclude chronic my- sis. JAK2, CALR, and MPL muta-
nd eloid leukemia, because it is impor- tions may support a diagnosis of
or tant to treat those patients with tyro- MPN. “They’re not specific, so you
al. sine kinase inhibitors,” Dr. Chabot- can see JAK2 mutations in CMML.
th Richards said. But if you find them, it might be good
u- Most cases of CMML have muta- to take another look to see if there’s
or tions on gene panel testing, com- anything else abnormal about the
monly TET2, SRSF2, and ASXL1 patient presentation,” Dr. Chabot-
tly Monoblasts: Fine, open chromatin, Promonocytes: Stippled chromatin, (the latter is predictive of aggressive Richards said.
t’s round or minimally irregular nuclei, variable nucleoli, delicate nuclear folds, disease). SETBP1 is strongly associ- All MPNs require bone marrow
ms prominent nucleoli light gray cytoplasm ated with a CMML diagnosis but is for correct classification and assess-
ar, less common. “If you do find it, it can ment of fibrosis. “This can help you
wn be strongly supportive of this specific distinguish between MPN and
A review of the chart found that Chabot-Richards said. While in most diagnosis,” she said. CMML based on the bone marrow
cer the patient’s WBC had fluctuated diseases, a myeloblast is a blast, “in Other mutations seen are RUNX1, morphology.”
hat between normal and elevated, and this disease, we’re going to include NRAS/KRAS, CBL, and EZH2. The Other MDS/MPN overlap syn-
on his monocyte count ranged between some other things.” NPM1 mutation is rare but associ- dromes may be confused with
h- one and 2.2. His anemia fluctuated Promonocytes are blast equiva- ated with increased progression to CMML. Atypical chronic myeloid
his between mild and moderate. The lents in CMML. “It’s important to acute leukemia. “Finding a mutation leukemia usually has more promi-
es, patient also had thrombocytopenia, recognize these because while they in any gene is not sufficient for diag- nent dysplasia, marked left shift, a
or- ranging from mild to moderate. are blast equivalents, atypical mono- nosis of CMML.” lack of significant monocytosis, and
id. Dr. Chabot-Richards took another cytes that are mature are not. It can be CMML is subdivided into prolif- SETBP1 mutations. There is some
are look at the blood smear and saw difficult to distinguish between the erative and dysplastic types. A WBC overlap in diagnostic criteria with
my- many large cells with convoluted two,” she said (Fig. 4). Dr. Chabot- >13 × 109/L is proliferative, which juvenile myelomonocytic leukemia,
nuclei, consistent with monocytes, Richards typically performs her dif- has a higher monocyte count, higher which is rare and usually fairly dis-
ust and a few neutrophils with nuclear ferential twice in these cases. circulating immature myeloid cells tinct clinically because most patients
ial irregularities, including neutrophils “You need to do bone marrows on and blasts, and higher LDH, and is are under age three.
ay with Pelger-Huet-like nuclei. In the these patients because often the blast more likely to have cytogenetic ab- In summarizing this case, Dr.
so lateral edges of the blood smear, there Chabot-Richards said, “We always
cy- were larger cells with smooth nuclear Fig. 5. Blast-based classification of CMML (WHO 2016) suspect CMML in an adult with
ve contours and delicate folds, account- monocytosis.” The accurate blast
% Peripheral % Bone marrow
ing for less than one percent of cells. Other count is key for CMML classification,
blood blasts blasts
ve She also discovered rare large cells and bone marrow biopsy is required
as consistent with blasts. CMML-0 <2 <5 for final classification. Gene muta-
or The patient’s blood was sent for CMML-1 2–4 5–9
tions are helpful but not sufficient in
n- flow cytometry. “Based on our side the absence of other criteria.
ex- scatter and CD45, we were able to get CMML-2 5–19 10–19 Auer rods present
ia, 23.4 percent monocytes,” Dr. Chabot- Amy Carpenter Aquino is CAP TODAY
Bone marrow biopsy is required for final classification—many cases show significantly higher
le- Richards said. “Monocytes showed senior editor. Part one was published in
blast counts in marrow.
re normal expression of CD36, CD64, the March issue of CAP TODAY.

0 0419_38-41_SmearEval2.indd 41
APRIL 2019 page 41 4/9/19 5:05 PM
 42 CAP TODAY | APRIL 2019

Microscopy dangers
continued from 1
computer now—much more than a
few years ago. We can now access
surgical reports and imaging at our
desk where in the old days, we would
have to get up and could stretch. Now
there is less need for us to move from
our workstations.”
Prolonged microscope use has
been known for almost four decades
to be associated with developing
chronic pain syndromes, says Evan
George, MD, clinical associate profes-
sor in the Department of Anatomic
Pathology, University of Washington.
He published an article in 2010 that
addressed microscopy as an occupa-
tional hazard of pathology practice
(Am J Clin Pathol. 2010;133[4]:543–
548), but he believes the knowledge
gap remains sizable. “It’s a subject
that pathologists don’t talk about a
lot,” Dr. George says.
Ergonomics caught his attention
because of pain he experienced dur-
ing his anatomic pathology work.
When he began to have problems
while practicing in a community
hospital setting, he noticed that
symptoms were most intense when
he was working at the microscope—
to the extent that it was difficult to
concentrate and complete his daily
work. “There wasn’t a specific event,
and because I used to lift weights for
exercise, I first consulted an orthope-
dist. Symptoms did not improve with
anti-inflammatory medications, and
there were no radiographic abnor-
malities. The orthopedic physician
was puzzled, and I hadn’t made the
connection that the pain might be
from the microscope work.”
After confiding his symptoms to

SAFE SOLUTIONS
other pathologists in his group, sev-
eral of them told him they too had
experienced musculoskeletal symp-
toms at some point in their careers,
which improved with physical ther-
apy or workstation modifications, or
both. One colleague had herniated
Even with minimal tube volumes, discs in the cervical spine that re-
quired surgery and a month or two
the potential for injury from manual away from work.

DECAPPING
decapping or manual Luckily, Dr. George happened to
mention his symptoms to a physical
recapping is a medicine doctor at his hospital who
offered to visit his office. “He made
real possibility You have an almost instantaneous diagnosis of
known about repetitive stress syndrome.” After Dr.
George obtained an ergonomically
our Pluggo™ designed microscope, allowing him
to gaze straight ahead, as one would
decappers do with a periscope, “My symptoms
diminished a lot.”
Now The neck and upper back are the
available; areas most intensely affected by mi-

KapSafe™
croscope use, Dr. George has found.
Surface electromyography has con-
firmed that “the neck and back mus-
Recappers cles truly are working when we are
sitting down viewing slides at the
in several microscope or staring at a computer,”
models he writes in his 2010 article. But since
microscope work includes repetitive
to fit any movement of the arms and hands

RE volume needs and because the body’s joints and

C AP
muscles are connected in such com-

PI N G
plex ways, pain in the shoulders,
arms, wrists, hands, and lower back
can also result. For example, “I notice
that if you’re a short stature patholo-
gist and your feet don’t reach the

Make your goal ZERO

floor when you are sitting, it brings a
lot of excess stress to the shoulders.”
Repetitive stress syndrome, also
known as cumulative trauma disor-

repetitive stress injuries der, refers to wear and tear on ten-

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 44 CAP TODAY | APRIL 2019
Microscopy dangers
continued from 42
time, he says, muscle fiber shortening
and fibrosis may lead to postural im-
balances, which, if uncorrected, cause
additional strain on affected tissue or
injury at previously uninvolved ana-
tomic sites.
The risk factors for symptoms in
pathology and cytotechnology prac-
tice are better known: hours of micro-
scope work, duration of work without
breaks, fast work pace, and poor
workstation ergonomic conditions.
Over the years, these can steadily add
up, leading to disabling injury. “There
are a variety of types of medical prob-
lems or injuries, probably resulting
from recurrent microtrauma to myo-
fascial tissue that occurs so gradually
most people don’t realize it until a
critical threshold is reached and symp-
toms become severe,” he explains.
M arilyn Bui, MD, PhD, was one
  such person. On her first job in
pathology, she routinely put in 10- to
12-hour days and exercised regularly
after work. “You feel young and in-
vincible. You just keep working until
you are exhausted,” says Dr. Bui, who
is now senior member of pathology
and president of the medical staff,
Moffitt Cancer Center, Tampa, Fla.
But one day, after three years on
the job, she discovered she couldn’t
get out of bed. “My back muscle was
frozen. I couldn’t walk.” As radiology
testing confirmed, “It was a very bad
back muscle spasm.” She saw a chi-
ropractor who surmised that her
work on the microscope was creating
a posture problem and advised her to
stop wearing high heels, to correct the
bad postures, and to start walking
every hour. She complied with most
of that advice and started getting back
adjustments and deep muscle mas-
sages. “It went well for one or two
years with treatment, then it hap-
pened again. My back was completely
frozen one day when I was trying to
pick up something very light.”
One provider explained to her that
the repetitive stress of her working
environment was like a million small
paper cuts on the body, and the body
was defending itself, in her case with
back pain. The advice she received this
time was sobering: “As long as you are
doing your job,” the provider told her,
“if you don’t change your behavior,
this pain will not go away. And when
you get older, it will get worse.”
In anatomic pathology, there can
be considerable repetitive motion
beyond the microscopy arena, Dr.
Ewaskow points out. “The typical
workflow will consistently go from
0419_1-46_Genomic-Ergonomics-Ngonorrhea_v4.indd 44
one side to another. Pathologists will
have a specific place to set up slides,
they’ll pick them up the same way,
put them on the scope in the same
way, and move the slides with the
same hand.”
The effects of repetitive motion
may not become apparent for years,
but then they can make themselves
known in subtle or unexpected ways.
“I remember a con-
versation with an-
other pathologist
who found after
seven years of this
kind of practice full
time that he noticed
a change when
Dr.Ewaskow
looking at a rear-
view mirror while
driving. He perceived just looking
over his shoulder as being difficult,”
Dr. Ewaskow says.
Kay Ballen, OTR/L, is an occupa-
tional therapist and ergonomic spe-
cialist for employees at Evergreen-
Health, Kirkland, Wash. Her job is
not to diagnose musculoskeletal
disorders but to evaluate office set-
ups and provide recommendations
to improve postures, positioning,
and comfort, and to overall reduce
the risk for musculoskeletal disor-
ders. “Generally, when we have a
request for an evaluation, it is be-
cause someone is reporting discom-
fort or pain or a new employee is
making sure their workstation is set
up properly,” Ballen says. “There are
several laboratories within our hos-
pital, and most often those employ-
ees using a microscope during the
majority of their shift request an er-
gonomic evaluation due to having
neck, back, and shoulder discomfort
or pain.”
When a chair is not properly ad-
justed or a desk, table, monitor, or
microscope is not at
the proper height,
Ballen finds that the
faulty positioning
may induce leaning
or flexing of the
neck. But a behavior
pattern with possi-
Ballen
bly even greater im-
pact is the increased
amount of sitting that people are
doing during the day. “Sitting has
increased tenfold in the last four years
because people are going paperless,
and people are working more 10-
hour or 12-hour shifts at a computer
instead of five eight-hour shifts. As
their day progresses, their body be-
comes more fatigued the longer they
are sitting. We start to see a lot of
postural issues and upper body or
neck pain.”
Ballen’s professional focus when
conducting ergonomic in-service
training for clinics and departments
at EvergreenHealth is on prevention.
New employees receive information
regarding proper sitting postures
and positioning and ergonomic con-
tact information as part of their one-
week orientation.
When employees request an ergo-
nomic evaluation, “we evaluate their
desk height and the need for chair
adjustments, including seat depth
and armrests. We evaluate the com-
puter screen viewing distance, screen
height, keyboard and mouse types
and their placement, microscope
height, positioning of the scope, and
how a person’s arms are placed on
the table or desk.” In addition, they
evaluate tasks that are done repeti-
tively during the work shift that
could contribute to discomfort or
pain, including the length of time a
person is sitting. “Would they benefit
from a certain kind of workstation or
elevated desk? Do they need im-
proved lighting?”
These considerations reflect a cen-
tral idea: Work has to move with the
human body, not vice versa. “Instead
of us adjusting to a camera or an an-
gle of a desk or a chair, somehow the
design has to be more fluid. It has to
coordinate more with the natural in-
clination or movement of our body,”
Dr. Ewaskow says.
F or Donna Hansel, MD, PhD, inter-
  est in ergonomics also stemmed
from an injury: a massive lumbar
disc herniation she experienced after
surgery when she worked as an assis-
tant professor of anatomic pathology
at Cleveland Clinic, leading to two
years of rehabilitation. “It became
difficult just to walk, I lost a lot of
range of motion with my leg, and it
was almost impossible to sit.”
When she approached a friend in
ergonomics for help, it led to several
changes in her office layout. “He
photographed me while I was sitting
and made a range of modifications.
We raised the desk an inch, got some-
thing to put my feet on and a place to
rest my elbow, changed the way the
microscope was positioned, and
changed the type of chair and how I
sat in it. He prescribed all of that, set
it up, and said, ‘Do not change it.’”
Despite initial discomfort, the setup
brought relief, and she was sold on
ergonomics as a solution. “I became
a believer,” she says.
Later, as chief of the Division of
Anatomic Pathology at UC San Diego
Health, Dr. Hansel negotiated for
space in La Jolla for a new faculty
office and made sure ergonomic de-
APRIL 2019 page 44
sign was a priority. Although some
faculty were wedded to their tradi-
tional wooden desks and insisted on
keeping them through the move, the
majority went along with new tables
where microscopy and the computer
could go from fully standing to sit-
ting, with experts advising on the
optimal heights. “The style that had
arm supports was by far the most
popular, and they put these in all the
faculty offices,” Dr. Hansel says. In
the end, “no one ever wanted their
old desk back.”
“About half of the faculty will do
sign-outs standing up and half will
do them sitting down but with the
option to adjust to proper heights.
The ergonomics experts come in to
make final adjustments, including
appropriate ancillary items such as
foot and elbow
rests, and to make
sure all the resi-
dents and attend-
ings have adjustable
eyepieces for the
microscopes, elimi-
nating the need to
Dr.Hansel
bend. With the cut-
out we did in the
table surface, you can sit straight up
in your chair and be close enough to
the scope to see through it. That was
part of the design of the table.” A
large sign-out space with several six-
headed scopes and projection capabil-
ity for group consults also has an
adjustable table.
The perils of using a scope are only
a few of the potential ergonomics is-
sues, she says. “Another is how you
position your arms when moving
slides. Many times, people develop
shoulder problems because of having
to use slides without proper arm sup-
port.” In fact, she has had a few
friends who ended up retiring early
because their shoulders were such a
problem. “This is really where an
expert in ergonomics can come in
and make adjustments if you need
them. That’s made a big difference
for me. I feel if I have shoulder pain,
it’s because I haven’t positioned
things correctly.”
One faculty member, Dr. Hansel
adds, had severe sciatica, causing
great difficulty with sitting for sign-
outs. “She is one who often uses the
desk standing up, and that helps a lot.
She does physical therapy, stretches,
and massage, and she has expressed
interest in teaching other faculty and
trainees stretches that can help with
some of the muscles that are over-
used during sign-out.”
Protecting the body from muscu-
loskeletal pain caused by pathology
and laboratory —continued on 46
4/8/19 3:28 PM
 NCCN Guidelines® iwCLL Guidelines

The NCCN Clinical Practice Guidelines in

Oncology (NCCN Guidelines®) and iwCLL
Guidelines recommend FISH and molecular
genetic testing before CLL treatment1,2

The majority (>50%) of CLL patients Tests for Prognostic Factors1

have at least one high-risk factor.3-5 Molecular Analysis

IGHV mutation status

FISH
The iwCLL Guidelines now recommend del 17p
always testing for these important, high-risk del 11q
prognostic factors2: Genetic Sequencing
IGHV unmutated, del 17p/TP53 mutation, del 11q TP53 mutation status

iwCLL recommends testing before you treat

CLL=chronic lymphocytic leukemia, del=deletion, FISH=fluorescent in situ hybridization, IGHV=immunoglobulin heavy-chain variable region gene, iwCLL=International Workshop on CLL,
NCCN=National Comprehensive Cancer Network, PFS=progression-free survival.
References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed October 30, 2018. To view the most recent and complete version of the guideline, go online to
NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2. Hallek M,
Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
3. Fischer K, Bahlo J, Finket AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood.
2016;127(2):208-215. 4. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab
in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928-942.
5. Kröber A, Seiler T, Benner A, et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410-1416.

© Pharmacyclics LLC 2019 © Janssen Biotech, Inc. 2019 01/19 PRC-04991

 46 CAP TODAY | APRIL 2019
Microscopy dangers
continued from 44
technology work requires taking pro-
active steps, and that involves more
than appropriate equipment, Dr.
Hansel says. “It’s also making sure
you have an expert who evaluates
how you are using the equipment,
whether it’s the proper height, and
so on. It involves personal care,
stretching exercises, and making
those a priority.”
A sk people what they do to stay
   healthy and they’re likely to
mention diet and exercise, not body
position and posture. That voice
from childhood reminding us to
sit up straight might have seemed
more related to comportment than
to health. But Elizabeth DeMarse, PT,
DPT, MTC, rehabilitation specialist
at Moffitt Cancer Center, considers
that a mistake (though she advises
that people aim for a “neutral spine”
with a concave curve in the lumbar
spine when they are seated). From
her standpoint, the spine is central
to overall health. Work in the labo-
ratory can insidiously, gradually,
often without notice, take a toll on
the spine, she says, and from there,
a toll on many other structures of
the body.
Dr. DeMarse specializes in manual
therapy, a physical treatment that in-
volves manipulation of muscles, fas-
cia, and joints. Her practice includes
work, geared to Moffitt’s cancer pa-
tients and employees, on posture,
breath, and preservation of structures
of the body. Where the employees’
problems are concerned, ergonomics
is often integral to treatment.
Her colleague Dr. Bui has been
open about her experience with
myofascial pain caused by her work
and about the treatment Dr. DeMarse
provided. “In addition to her chronic
back pain, Dr. Bui was having con-
stant pain in her scapular area, and
it was related to her positioning with
occupational tasks because she was
looking into a microscope and typ-
ing on a computer on a regular ba-
sis,” Dr. DeMarse says. She worked
with Dr. Bui by using specialized
manual treatment to mobilize the
scapular area and surrounding mus-
cles and by giving her supplemental
exercises.
Dr. DeMarse and Nancy Keating,
Moffitt’s injury prevention supervisor,
also evaluated Dr. Bui’s workspace
and how it could be reconfigured to
prevent it from exacerbating her con-
dition. Changes based on ergonomics
were essential. “When I saw her over
a two-month period of time, we were
0419_1-46_Genomic-Ergonomics-Ngonorrhea_v4.indd 46
able to keep her pain managed so she
did not have to miss work because of
the pain,” Dr. DeMarse says.
Usually the employees she sees for
physical therapy have back problems,
but the hips and shoulders can also
be a main source of pain, she says. “It
might be something that has started
outside of work but because their
work requires them to be sitting at a
desk all day, we would want to inter-
vene and address both areas.” Com-
monly, it is the sitting posture that
perpetuates the problem, whether it
involves shoulders, hips, or back.
“The spine is meant to move dynami-
cally with the arms and legs. But
when you aren’t moving the arms
and legs and are sitting for extended
periods of time, that is where the
downfall begins.”
Making sure the employees are
aware of how their sitting position
relates to spine mechanics and how
they can reduce the amount of strain
on the spine and its related structures
is an important part
of preventing and
treating ergonomic
problems. “Some-
times when they
have a back prob-
lem and get to work,
they are on the
phone and their Dr.DeMarse
phone is off to the
left and their computer is in front of
them. Always moving to one side will
alter the balance between the right and
left sides, which will ultimately affect
the spine.”
“You may want to move it to the
center so that you are not twisting to
use it,” Dr. DeMarse says of the
phone, “making sure that repetitive
motions are balanced out and not
focused on one side or the other.” For
the same reason, she encourages
people who are right-handed to use
the left hand occasionally.
Pathologists may need a certain
position to get close to the micro-
scope. In the case of Dr. Bui, “She was
leaning forward and using her arm
to adjust the microscope, so we made
certain adjustments to her workspace.
She was able to get an extension on
the eyepiece of the microscope,
changing the screen position so she
did not have to turn so far from place
to place. And we adjusted her com-
puter because she was going from her
microscope to her computer and they
were at different heights.” She also
got an additional monitor to reduce
the head turning motions, Dr.
DeMarse says. Keating gave Dr. Bui
an ergo chair, which Dr. Bui says
made a big difference in her muscu-
loskeletal health.
Reinforcing and keeping posture
awareness at the forefront of employ-
ees’ activities are priorities. “Bending
forward is one of the worst things
they can do,” Dr. DeMarse says. “It is
usually the thing that causes them
pain. Sometimes they don’t realize
that is what is causing the pain be-
cause it comes a little bit after the
activity, so they don’t put it together
with stress on their spine structures.”
For example, disc issues are common,
and forward bending will make them
worse because of where the disc pro-
trudes, causing a herniation. With
some of the younger patients, she
says—and that includes people in
their 30s—“that ergonomic assess-
ment is huge over the long term. If
they are not aware of this at a young
age, it is the kind of thing that could
debilitate them later in life.”
Without the necessary awareness,
people can perpetuate a problem year
after year with poor posture habits,
which can weaken the back and the
ligaments that support the lower
back—one reason why people chroni-
cally throw their back out. It’s similar
to what happens after the first time a
person sprains an ankle; they often
have chronic sprains of the same an-
kle. “Once you have sprained your
ankle, you have changed the integrity
of the ligaments in the ankle, especially
if you have not strengthened the mus-
cles around the ankle. The same is true
of the ligaments around the spine. But
someone with an ankle sprain can
wear a brace and stay off the ankle.
You cannot stay off your back.”
In addition, the wrong posture can
increase the likelihood of arthritis,
which is essentially an irregularity in
the joint surface, she explains. “As we
age, the ligaments get even tighter
because of the dehydration that hap-
pens in our body over time. The sy-
novial fluid is not as viscous after
people are in their 30s or 40s, and the
ligaments aren’t as supportive. There
are 96 joints in the spine and 96 op-
portunities for them to have arthritis.
Having some knowledge of how to
maintain spinal health will help pre-
vent people from having back prob-
lems in their future.”
It’s easy to see how manual labor-
ers doing heavy lifting could de-
grade their spine, but over time,
occupational tasks from a sedentary
position can result in the same dam-
age, Dr. DeMarse says. “Joints have
to move to stay healthy,” she says.
“The synovial fluid lubricates the
bone surfaces with movement.” To
encourage this lubrication, she ad-
vocates use of standing desks and
mobile workstations such as com-
puters on wheels that are not too
APRIL 2019 page 46
heavy. “Even just standing in front
of a computer and shifting your
weight from one leg to the other is
excellent.” Eliminating trash cans
under desks is another way to get
people to stand up and walk, further
facilitating lubricated joints.
W hen Dr. George wrote his arti-
  cle almost 10 years ago on mi-
croscopy as an occupational hazard
of pathology, there was little more
than a few anecdotal accounts of
stress injury in the pathology litera-
ture, plus some surveys of industry
workers and cytotechnologists who
use microscopes. “But there wasn’t
really a global discussion of the
issues in the pathology literature,
and that’s why I thought it would
be helpful.” He finds conference
planners are still approaching him
about appearing as a speaker based
on the article, which he takes as a
sign that not enough other research
has been conducted over the past
decade and more voices are needed
to raise the alarm.
Dr. George gives new residents a
talk every year on the topic of repeti-
tive stress syndrome as part of their
orientation. “And if I see someone
doing something that definitely looks
awkward in terms of posture, I’ll offer
suggestions. If they have sustained
problems, I’ll recommend they go to
the residency director and employee
health office and probably get an er-
gonomics evaluation or a physical
therapy evaluation.” In addition to
the ergonomics adaptations, physical
therapy, including sustained gentle
stretching over time, has brought him
relief from some of his symptoms
and, he believes, has helped prevent
new problems.
As a warning not to delay attend-
ing to ergonomics issues, Dr. George
says that for some problems he has
experienced, the opportunity for pre-
vention or cure is gone for good. “I’ve
never returned to a painless life,” he
says. For Dr. Bui, the work-related
musculoskeletal issue may never go
away. But after three acute episodes,
she says, it became clear she needs to
be “mindful about prevention,” every
day and in every activity.
Anne Paxton is a writer and attorney
in Seattle. For prevention of repetitive
stress syndrome or cumulative trauma
disorder from microscopy, Dr. George
lists modified suggestions of the Cen-
ters for Disease Control and Prevention
in his article “Occupational hazard for
pathologists: microscope use and muscu-
loskeletal disorders” (Am J Clin Pathol.
2010;133[4]:543–548). Other sugges-
tions of medical providers for easing and
preventing symptoms are also included.
4/8/19 3:28 PM
 APRIL 2019 | CAP TODAY 47

Clinical Pathology quire antifibrinolytics. This study

Selected Abstracts
Editor: Deborah Sesok-Pizzini, MD, MBA, professor, Department of Clinical Pathol-
ogy and Laboratory Medicine, Perelman School of Medicine, University of Pennsyl-
vania, Philadelphia, and chief, Division of Transfusion Medicine, Children’s Hospital
of Philadelphia.
Trauma resuscitation
considerations: gender
as a biological variable
Sex dimorphisms in coagulation
are well established, with females
manifesting a more hypercoagulable
profile, but the relationship between
sex dimorphism in coagulation and
trauma outcomes has not been inves-
tigated. Trauma-induced hemorrhage
remains a leading cause of early post-
injury death. While several studies
have reported decreased morbidity
and mortality among females fol-
lowing trauma, other studies found
increased mortality or no gender-
related differences. None of these
studies have accounted for the whole
blood hemostatic state. The authors
conducted this study to determine
the differences between males and fe-
males following trauma and to exam-
ine how differences in gender-specific
coagulation affect clinical outcomes,
specifically massive transfusion and
death. The authors hypothesized that
severely injured females are more
hypercoagulable and, therefore, have
lower rates of massive transfusion
and mortality. They prospectively
examined the hemostatic profiles,
using thrombelastography (TEG),
and clinical outcomes from all trauma
activation patients from two level one
trauma centers, with gender as an
experimental variable. The authors
compared coagulation profiles be-
tween genders and examined their
association with massive transfusion
and mortality. Of the 464 patients,
23 percent were female. By TEG, the
female patients had a more hyperco-
agulable profile, with a higher angle
(clot propagation) and maximum
amplitude (clot strength). In addi-
tion, the females were less likely than
the males to present with hyperfi-
brinolysis or prolonged activating
clotting time. Furthermore, female
gender was a survival benefit in the
setting of depressed clot strength,
and hyperfibrinolysis was associ-
ated with a higher case-fatality rate
in males. The authors concluded that
severely injured females have a more
hypercoagulable profile than males
and this protects against mortality
in the setting of trauma-induced co-
agulopathy. They noted that this may
challenge the clinical bias of a unified
transfusion strategy and suggest that
females require less blood product
transfusion and are less likely to re-
further highlights the need to inves-
tigate gender as a biological variable
in trauma populations.
Coleman JR, Moore EE, Samuels JM, et al. Trau-
ma resuscitation considerations: sex matters. J
Am Coll Surg. 2019. doi:10.1016/j.jamcollsurg.​
2019.01.009.
Correspondence: Dr. Erik D. Peltz at erik.peltz@
ucdenver.edu
Vitamin D toxicity: a 16-year
retrospective study at an
academic medical center
Interest in vitamin D supplementa-
tion has increased, in part, because
of studies that link the vitamin to
improved immunity, cardiovascular
health, and prevention of cancer and
osteoporosis. Supplementation may
be recommended by physicians or
patient driven. Most patients’ test
results for 25-hydroxyvitamin D
[25(OH)D] show normal or deficient
levels, but the incidence of 25(OH)D
toxicity has risen. Vitamin D toxicity
has been reported in multiple age
groups, and toxic levels correlate
poorly with symptoms. Among the
causes of vitamin D toxicity is ingest-
ing megadoses, such as 50,000 IU, of
vitamin D supplements and incorrect
dosing of supplements in children.
The authors performed a retrospec-
tive review of elevated 25(OH)D
levels during a 16-year period at the
University of Iowa Hospitals and
Clinics to describe the causes of hy-
pervitaminosis D and determine the
extent to which vitamin D levels
correlate with serum calcium levels
and clinical symptoms. All serum/
plasma 25(OH)D levels derived from
clinical testing were retrieved from
the electronic medical record. Ele­
vated 25(OH)D was defined as levels
higher than 80 ng/mL, although
toxicity was considered unlikely
unless levels exceeded 120 ng/mL.
During the study period, there were
127,932 measurements of 25(OH)D
performed on 73,779 unique patients.
The authors also identified 1,068
samples from 780 unique patients
with 25(OH)D levels greater than 80
ng/mL, which comprised 0.8 per-
cent of total 25(OH)D measurements
and 1.1 percent of all patients tested.
Eighty-nine (0.12 percent) patients
had results that exceeded 120 ng/
mL, and four of them showed symp-
toms of vitamin D toxicity at the
time of blood draw. The toxicity in
three of the patients resulted from
misdosing of liquid formulations.
Statistical analysis showed a weak
correlation between vitamin D con-
centrations and total serum/plasma
calcium concentrations. The authors
concluded that vitamin D toxicity is
uncommon, and elevated levels of
25(OH)D did not correlate strongly
with calcium levels or clinical symp-
toms. The findings highlight the po-
tential risk of misdosing vitamin D
using liquid formulations.
Lee JP, Tansey M, Jetton JG, et al. Vitamin D
toxicity: a 16-year retrospective study at an
academic medical center. Lab Med. 2018;49:​
123–129.
Correspondence: Dr. John P. Lee at john-p-lee@
uiowa.edu

Anatomic Pathology
Known pathogenic mutations were not identified
in any of the six cavernous hemangiomas. These
data suggest that HSVNs share a similar molecular
Selected Abstracts biology to several other vascular lesions—congenital
hemangioma, tufted angioma, anastomosing hem-
Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology angioma, lobular capillary hemangioma, and kapo-
Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, siform hemangioendothelioma—recently reported to
assistant professor, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington; Nicole have GNAQ, GNA11, or GNA14 mutations.
Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center;
and Shaomin Hu, MD, PhD, pathology resident, Albert Einstein College of Medicine, Montefiore Medical Center. Joseph NM, Brunt EM, Marginean C, et al. Frequent GNAQ
and GNA14 mutations in hepatic small vessel neoplasm. Am
J Surg Pathol. 2018;42(9):1201–1207.
liver, including eight HSVNs, six classic cavernous
Frequent GNAQ and GNA14 mutations hemangiomas, and four variant lesions with overlap-
Correspondence: Dr. Nancy M. Joseph at nancy.joseph@ucsf.edu
in hepatic small vessel neoplasm ping features between HSVN and cavernous heman-
Hepatic small vessel neoplasm is a recently described gioma. All 18 lesions had simple genomes without
infiltrative vascular neoplasm of the liver composed copy number alterations. Seventy-five percent (six of
Relevance of tumor grade among
of small vessels. Although its infiltrative nature can eight) of the HSVNs demonstrated known activating MMR-deficient colorectal carcinomas
mimic angiosarcoma, hepatic small vessel neoplasms hotspot mutations in GNAQ (two of eight, p.Q209H) Intestinal-type colorectal adenocarcinomas are
(HSVNs) are thought to be benign or low-grade or GNA14 (four of eight, p.Q205L), and the remain- graded based on extent of glandular differen-
neoplasms because they lack cytologic atypia and ing two had the same missense mutation in GNAQ, tiation, although mucinous, signet-ring cell, and
increased proliferation. To characterize the molecular p.G48L, which has not been previously described. solid cancers are, by convention, classified as high
pathogenesis of HSVN, the authors performed tar- Twenty-five percent (one of four) of variant lesions grade. Mismatch repair (MMR)-deficient tumors
geted panel sequencing and exome sequencing on had a hotspot GNAQ p.Q209H mutation and an- frequently show high-grade histologic features, yet
18 benign or low-grade vascular neoplasms of the other variant lesion had a GNAQ p.G48L mutation. the World Health Organization —continued on 48

0419_47-49_Abstracts.indd 47
APRIL 2019 page 47 4/3/19 12:41 PM
 48 CAP TODAY | APRIL 2019

Molecular Pathology ing whole exome sequencing. When

comparing patients affected with TIM
and those who were unaffected, the
levels were available for 75 percent
of patients with exome analysis. All
(10 of 10) patients with no TPMT
Mo
NU
me
Selected Abstracts authors found no significant differ- activity and 73 percent of patients
Ge
Co
ences in gender, type of IBD, behavior (80 of 109) with low TPMT activity
stju
Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and of IBD, or extent of disease. Affected carried various variant TPMT haplo-
professor, Department of Pathology, University of California, San Diego; James Re
patients were noted to be younger types. Overall, 4.9 percent (16 of 328) al.
Solomon, MD, PhD, resident, Department of Pathology, UCSD; Richard Wong, at the time of IBD diagnosis and re- of affected patients and 0.2 percent Co
MD, PhD, molecular pathology fellow, Department of Pathology, UCSD; and ceived a higher weight-adjusted thio- (one of 633) of unaffected patients bas
Sounak Gupta, MBBS, PhD, molecular pathology fellow, Memorial Sloan Kettering
purine dose than unaffected patients. had two TIM-associated TPMT vari- 201
Cancer Center, New York. 10.
GWAS analysis confirmed the prior ant haplotypes. The median time to
reported association of TIM with TIM was shorter for affected patients Co
Variants in NUDT15: association rines, reducing their conversion to TPMT (variant rs11969064), seen in who carried NUDT15 and double stju

with thiopurine–induced
myelosuppression
The thiopurines mercaptopurine,
thioguanine, and azathioprine are
purine antimetabolites widely used
as anticancer and immunosuppres-
sive agents. Commonly prescribed
in patients with inflammatory bowel
diseases (IBD), such as Crohn’s dis-
ease and ulcerative colitis, they are
valuable steroid-sparing treatment
options. Unfortunately, approxi-
mately 15 percent of IBD patients
develop adverse drug reactions, such
as thiopurine-induced myelosup-
pression (TIM), that necessitate drug
withdrawal. TIM has a cumulative
incidence of seven percent in IBD
patients and an estimated mortality of
one percent. A similar phenomenon is
also described when this class of drug
is used in antineoplastic protocols.
The enzyme thiopurine methyltrans-
ferase (TPMT) metabolizes thiopu-
active drug. Genetic variation in the
TPMT gene can result in decreased
enzyme activity, increased active
drug concentrations, and subsequent
bone marrow suppression. TPMT
variants are found in 25 percent of
patients of European ancestry affect-
ed by TIM, suggesting the presence
of other genetic and environmental
determinants. Studies in patients of
East Asian ancestry and other popu-
lations have identified variants in
nudix hydrolase 15 (NUDT15) as
risk factors for TIM. The authors of
this study used genome-wide asso-
ciation studies (GWAS) and whole
exome sequencing on a large case
control cohort of patients to identify
genetic variants associated with TIM
in a population of European ancestry.
Recruiting from 89 international sites
during a four-year period, they tested
311 TIM-affected and 608 unaffected
IBD patients using GWAS and 328 af-
fected and 633 unaffected patients us-
30.5 percent (95 of 311) of affected TPMT variants than for affected pa-
patients compared with 16.4 percent tients who did not carry risk variants. Us
(100 of 608) of unaffected patients in With the ubiquitous use of thiopu-
this study. No other genetic associa- rines across multiple diseases, the
es
tions with TIM exceeded the a priori authors’ findings are likely to have to
threshold for statistical significance. significance beyond IBD patients. Es
Exome sequencing to investigate the According to population studies, co
role of rare coding variants revealed a variant NUDT15 haplotypes can be six
TIM association with a 6–base pair in- found in 29.2 percent of East Asian, re
frame deletion in exon 1 of NUDT15 20.7 percent of Latin American, and ca
(p.Gly17_Val18del) for 5.8 percent (19 13.4 percent of South Asian ancestry su
of 328) of the affected patients com- populations. In line with these find- gr
pared with 0.2 percent (one of 633) of ings, recent recommendations by the ch
the unaffected patients. Variants in Clinical Pharmacogenetics Imple- fiv
NUDT15 or TPMT, or both in some mentation Consortium advocate for 15
patients, were enriched in patients pretreatment TMPT and NUDT15 ca
affected with early-onset TIM, which genotyping in patients slated to start ve
occurs no more than eight weeks after thiopurine drugs. do
starting the maximum thiopurine Walker GJ, Harrison JW, Heap GA, et al.
m
dose. The only other variant outside Association of genetic variants in NUDT15 ge
of NUDT15 that was significantly with thiopurine-induced myelosuppression of
associated with TIM in the exome in patients with inflammatory bowel disease. ar
sequencing data was within TPMT. JAMA. 2019;321(8):773–785. pr
Correlating functional assays with Correspondence: Dr. Tariq Ahmad at tariq. stu
genetic data, TPMT enzyme activity ahmad1@nhs.net ac

Anatomic abstracts ated with pathologic stage or outcome. The authors

continued from 47
classifies them as low grade to reflect their favor-
able prognosis compared with MMR-proficient
cancers. Although some MMR-deficient colorectal
cancers behave aggressively, few authors have
identified features that predict their behavior.
The authors of this study sought to determine
which histologic features, if any, predict outcome
among MMR-deficient colorectal carcinomas. They
identified 116 MMR-deficient colorectal carcino-
mas, including 77 localized (stage I to II) and 39
advanced (stage III to IV) tumors, and evaluated
them for extent of gland formation, extracellular
mucin, signet-ring cell differentiation, solid growth,
nuclear grade, tumor-infiltrating lymphocytes, and
tumor budding. The authors assessed relation-
ships between these features, pathologic stage,
and disease-free survival. They found that high-
grade MMR-deficient tumors were more often of
advanced stage than low-grade tumors (46 percent
versus 23 percent; P = .01). Disease-free survival
was inversely associated with a dominant high-
grade component and tumor budding (P = .01 and
0.04, respectively). Predominantly solid tumors,
in particular, were significantly associated with
decreased disease-free survival compared with
low-grade tumors (P = .001). Nuclear grade and
tumor-infiltrating lymphocytes were not associ-
concluded that low-grade MMR-deficient carcino-
mas present at an earlier stage and pursue a more
favorable course than those primarily composed of
high-grade elements. These findings suggest that
MMR status should not supplant histologic grade
in the assessment of colorectal carcinomas.
Johncilla M, Chen Z, Sweeney J, et al. Tumor grade is prog-
nostically relevant among mismatch repair deficient colorectal
carcinomas. Am J Surg Pathol. 2018;42(12):1686–1692.
Correspondence: Dr. Melanie Johncilla at mej9041@med.cornell.edu
Histopathologic findings in breast
tissue from female-to-male gender
reassignment surgery
Breast-reduction surgery or mastectomy follow-
ing administration of androgen therapy is part of
the female-to-male gender reassignment process.
Details regarding the histopathologic findings in
breast tissue from patients undergoing female-to-
male gender reassignment surgery are limited. The
authors reviewed hematoxylin-and-eosin–stained
sections of breast tissue from 148 patients who un-
derwent breast-reduction surgery or mastectomy
as part of the female-to-male gender reassignment
process at their institution between January 2014
and May 2017. The spectrum of histologic features
in each case was cataloged. The median patient
age was 27 years (range, 18–60 years). Lobular
atrophy was seen to some degree in 73 percent
Ga
of cases and was prominent in 42 percent. A pre- cl
dominantly fibrotic stroma was seen in 45 percent Cr
of cases, and areas resembling the fibrous stage of rec
gynecomastia were seen in 41 percent. Other fea- wi
tures included variably ectatic ducts in 96 percent ty
of cases, cysts in 42 percent, apocrine metaplasia sto
in 32 percent, fibroadenomatous change in 27 all
percent, usual ductal hyperplasia in 26 percent, sp
and pseudoangiomatous stromal hyperplasia in Jan
19 percent. Five cases (three percent) demonstrated 66
atypical hyperplasia—atypical ductal hyperplasia we
in two, atypical lobular hyperplasia in two, and sto
both atypical ductal hyperplasia and atypical an
lobular hyperplasia in one. One case demon­ 56
strated high-grade ductal carcinoma in situ. No we
invasive carcinomas were identified. The authors di
concluded that the majority of breast specimens m
from patients undergoing female-to-male gender ad
reassignment demonstrate at least some degree di
of lobular atrophy as well as ectatic ducts, fibrous pr
stroma, and areas resembling the fibrous stage of tor
gynecomastia. Cases rarely showed atypical le- hig
sions, for which clinical significance is uncertain. of
Torous VF, Schnitt SJ. Histopathologic findings in breast top
surgical specimens from patients undergoing female-to-male fib
gender reassignment surgery. Mod Pathol. 2018. doi: 10.1038/ pa
s41379-018-0117-4. Published October 11, 2018. on
Correspondence: Dr. Stuart J. Schnitt at sschnitt@bwh.harvard.edu ha

0419_47-49_Abstracts.indd 48
APRIL 2019 page 48 4/3/19 12:41 PM

 APRIL 2019 | CAP TODAY 49

nt Moriyama T, Nishii R, Perez-Andreu V, et al. previously characterized EACs. Cases a selective advantage, the authors with TP53 mutation, suggesting that
All NUDT15 polymorphisms alter thiopurine had high quality clinical annotation, correlated cases with matched RNA- its degradation can functionally sub-
MT metabolism and hematopoietic toxicity. Nat associated whole genome sequenc- seq to detect changes in expression. stitute for the effect of TP53 mutation.
Genet. 2016;48(4):367–373.
nts ing (WGS), and RNA sequencing Although the study may have been Mutually exclusive relationships were
Correspondence: Dr. Jun J. Yang at jun.yang@
ity (RNA-seq) data. From these 551 sam- underpowered to detect small ex- observed among KRAS and ERBB2,
stjude.org
lo- ples, the authors identified 11,813,333 pression changes, the authors were GATA4 and GATA6, and cyclin genes
Relling MV, Schwab M, Whirl-Carrillo M, et
28) al. Clinical Pharmocogenetics Implementation
single-nucleotide variants (SNVs) able to identify significant changes in (CCNE1, CCND1, and CCND3).
nt Consortium guideline for thiopurine dosing and small insertions or deletions (in- 17 cancer genes, including ERBB2, The authors also identified co-occur-
nts based on TPMT and NUDT15 genotypes: dels), 286,965 copy number alterations KRAS, and SMAD4. Some loci also ring relationships between TP53 and
ri- 2018 update. Clin Pharmacol Ther. 2018. doi:​ (CNAs), and 134,697 structural vari- showed extremely high copy number MYC, GATA6 and SMAD4, and Wnt
to 10.1002/cpt.1304. ants. They used an armamentarium of amplification, commonly more than and immune pathways. In univariate
nts Correspondence: Dr. Jun J. Yang at jun.yang@ bioinformatic tools to assess recurrent 100 copies. In one example, circu- analysis, events in two genes were
stjude.org
ble mutations within a gene (dNdScv, larization and amplification initially associated with significantly poorer
pa- ActivedriverWGS, and MutSigCV2), occurred around MYC but subse- prognosis after multiple-hypothesis
ts. Use of genomic landscape of high-functional-impact mutations quently incorporated ERBB2 from a correction—GATA4 amplification
u- (OncodriveFM and Activedriver- different chromosome. Such a pattern and SMAD4 mutation or homozy-
he
esophageal adenocarcinoma WGS), mutation clustering (Onco- of extrachromosomal amplification gous deletion. The authors presented
ve to define biomarkers driveClust, eDriver, and eDriver3D), via double minutes has been previ- a detailed catalog of genomic events
ts. Esophageal cancer is the eighth most and recurrent amplification or de- ously noted in EAC. The authors also that have been selected for during
es, common cancer worldwide and the letions of genes (GISTIC; genomic detected several cases of overexpres- the evolution of EAC. This catalog of
be sixth most common cause of cancer- identification of significant targets sion or complete expression loss with- biologically important gene altera-
an, related death. Esophageal adeno- in cancer) undergoing concurrent out associated copy number changes, tions was used to identify prognostic
nd carcinoma (EAC), the predominant over- or underexpression. Seventy-six reflecting nongenetic mechanisms for biomarkers and actionable genomic
ry subtype in the West, is highly ag- EAC driver genes were discovered, driver dysregulation. Novel drivers events. This study should help pave
d- gressive and generally resistant to 71 percent of which had not been of particular interest included B2M, the way for evidence-based clinical
he chemotherapy, and it has an overall detected in EAC and 69 percent of which encodes a core component trials for esophageal adenocarcinoma.
le- five-year survival rate of less than which are known drivers based on of the MHC class I complex and is Frankell AM, Jammula S, Li X, et al. The
or 15 percent. In comparison to other published pancancer analyses. The a marker of acquired resistance to landscape of selection in 551 esophageal ad-
15 cancer types, EAC is characterized by authors discovered 21 noncoding immunotherapy, and ABCB1, which enocarcinomas defines genomic biomarkers
art very high mutation rates but, para- driver elements in the study cohort, encodes a channel pump protein as- for the clinic. Nat Genet. 2019;51(3):506–516.
doxically, a paucity of recurrently including known elements, such sociated with multiple instances of Correspondence: Dr. Rebecca C. Fitzgerald at
rcf29@mrc-cu.cam.ac.uk
al.
mutated genes. Knowledge of which as the enhancer on chromosome 7, drug resistance. TP53 was found
genetic events drive the development which is linked to TP53TG1, and new to be a critical tumor suppressor in Secrier M, Li X, de Silva N, et al. Mutational
15 signatures in esophageal adenocarcinoma
on of EAC is limited. Consequently, there elements found in the 5′ untranslated EAC, although 28 percent of cases define etiologically distinct subgroups with
se. are few molecular biomarkers for region of MMP24. Using GISTIC, remain TP53 wild type. Amplification therapeutic relevance. Nat Genet. 2016;48(10):​
prognosis or targeted therapeutics. A they identified 149 recurrently de- and overexpression of MDM2, an E3 1131–1141.
riq. study by Frankell, et al., accumulated leted or amplified loci. To determine ubiquitin ligase that targets p53 for Correspondence: Dr. Rebecca C. Fitzgerald at
a cohort of 551 newly sequenced and which genes within these loci confer degradation, is mutually exclusive rcf29@mrc-cu.cam.ac.uk

ar available up to 228 weeks. All four patients had carcinomas (HCCs) and compared the results
nt
Gastric crystal-storing histiocytosis: a persistent/recurrent lymphoma, and two patients with corresponding histological and prognostic
re- clue to hematolymphoid malignancies died of lymphoma-related complications. None data. They classified the immune microenviron-
nt Crystal-storing histiocytosis is an under- of the CSH cases were prospectively recognized ment of HCC into three distinct immunosubtypes:
of recognized entity that has a striking association as CSH, and one case was initially misdiagnosed immune high, immune mid, and immune low.
ea- with lymphoproliferative disorders. To study the as a xanthoma. Because CSH can be so florid as to The immune-high subtype was characterized by
nt typical morphologic features of gastric crystal- obscure the concomitant lymphoma, awareness is increased B-/plasma-cell and T-cell infiltration,
sia storing histiocytosis (CSH), the authors retrieved crucial for accurate diagnosis. and the immune-high subtype and B-cell infil-
27 all lymphomas diagnosed using in-house gastric Arnold CA, Frankel WL, Guo L, et al. Crystal-storing histiocyto-
tration were identified as independent positive
nt, specimens at the Ohio State University between sis in the stomach: A clue to subtle hematolymphoid malignan- prognostic factors. Varying degrees of intratumor
in Jan. 1, 2008 and Jan. 1, 2017. This search yielded cies. Am J Surg Pathol. 2018;42(10):1317–1324. heterogeneity of the immune microenvironment
ed 66 specimens from 51 unique patients. All cases were observed, some of which reflected the mul-
Correspondence: Dr. Christina A. Arnold at christina.arnold@osumc.edu
sia were reviewed, and CSH was identified in seven tistep nature of HCC carcinogenesis. However,
nd stomach biopsies from four patients (two men the predominant pattern of immunosubtype and
cal and two women; average age, 69 years; range, immune cell infiltration of each tumor was prog-
n­ 56–82 years). The patients’ endoscopic findings
Landscape of immune microenvironment nostically important. Of note, the immune-high
No were abnormal—diffuse nodularity and white in hepatocellular carcinoma subtype was associated with poorly differentiated
ors discoloration (n = 1), patchy nodularity (n = 1), and Immune cells constitute an important element of HCC, cytokeratin 19+ (CK19+), Sal-like protein 4+
ns malignant-appearing fundic mass with lymph- tumor tissue. Accumulating evidence indicates (SALL4+) high-grade HCC, and Hoshida’s S1/
der adenopathy (n = 2). The typical gastric CSH lesion their clinicopathological significance in predicting Boyault’s G2 subclasses. Patients with high-grade
ee displays full-thickness expansion of the lamina prognosis and therapeutic efficacy. Nonetheless, HCC of the predominant immune-high subtype
us propria by a lymphohistiocytic infiltrate that dis- the combinations of immune cells forming the had significantly better prognosis. These results
of torts the usual gastric glandular architecture. On immune microenvironment and their association provide a rationale for evaluating the immune
le- high power, all cases were defined by the presence with histological findings remain largely un- microenvironment in addition to the usual histo-
n. of macrophages with abundant eosinophilic cy- known. Moreover, it is unclear which immune logical and molecular classification of HCC.
ast toplasm containing nonrefractile, nonpolarizable cells or immune microenvironments are the most Kurebayashi Y, Ojima H, Tsujikawa H, et al. Landscape of im-
ale fibrillary cytoplasmic inclusions. Three of the four prognostically significant. The authors conducted mune microenvironment in hepatocellular carcinoma and its
8/ patients had a kappa-restricted lymphoma; the a study in which they comprehensively analyzed additional impact on histological and molecular classification.
one patient with a lambda-restricted lymphoma the immune microenvironment and its intratumor Hepatology. 2018;68(3):1025–1041.
u had the fewest macrophages. Follow-up data were heterogeneity in 919 regions of 158 hepatocellular Correspondence: Dr. M. Sakamoto at msakamot@z5.keio.jp

8 0419_47-49_Abstracts.indd 49
APRIL 2019 page 49 4/3/19 12:41 PM
 50 CAP TODAY | APRIL 2019
Q&A
Editor: Frederick L. Kiechle, MD, PhD
Dr. Kiechle is consultant, clinical pathology, Cooper City, Fla. Submit your inquiries
to Sherrie Rice, srice@cap.org. Questions that are of general interest will be answered.
Q. Please describe the contemporary
significance and use of osmolality
testing in the clinical laboratory.
A.
Osmolality testing aims to
quantify the number of osmoti-
cally active particles per unit mass
of solution, often reported in milli-
osmoles per kilogram. In biological
fluids, it is reported in millimoles
per liter. Freezing point depression
osmometry is the preferred method
8”
4”
0419_50_Q&A.indd 50
for measuring osmolality in the clini-
cal laboratory since, unlike vapor
pressure osmometry, its results are
not influenced by atmospheric tem-
perature.1 There are clinical applica-
tions for measuring the osmolality
of serum, urine, and stool. The prin-
cipal osmotically active solutes are
sodium, chloride, potassium urea,
and glucose. In nondisease states,
urine osmolality corresponds to
urine specific gravity. The ratio of
urine to serum osmolality is nor-
mally about 1:3.
Serum and urine osmolality are
used for the diagnostic workup of
sodium disturbances and polyuria,
while stool osmolality can help dis-
tinguish etiologies for chronic diar-
rhea. Serum osmolality also has
some utility in testing for intoxica-
tion. In the context of hyponatremia,
urine osmolality distinguishes be-
tween primary polydipsia and other
entities, such as the syndrome of
inappropriate antidiuretic hormone
secretion.2 When correcting hypona-
tremia using isotonic saline or a
similar infusate, frequent monitoring
of plasma and urine osmolality is
critical to ensuring that the rate of
correction is appropriate and the risk
of osmotic demyelination syndrome
is minimized.2 In the workup of
polyuria, after excluding diabetes
mellitus, urine and serum osmolality
guide the differential diagnosis be-
tween diabetes insipidus and other
entities.1 Urine osmolality aids in the
distinction between water diuresis,
which is seen in diabetes insipidus,
and osmotic diuresis. If it is equivo-
cal, the water deprivation test can be
used to increase serum osmolality
and facilitate more definitive test
results.2 Urine and plasma osmolal-
ity are measured every few hours
during the water deprivation test to
clarify the diagnostic picture and
monitor for potentially clinically
detrimental fluid imbalances. Stool
osmolality is occasionally directly
measured when factitious diarrhea
(created by adding water or other
hypotonic fluids to a stool sample)
is suspected. In the case of factitious
diarrhea, stool osmolality is lower
than serum osmolality.1
In the context of toxicology test-
ing, an increased serum osmol gap
(the difference between calculated
and measured osmolality) may sug-
gest the presence of otherwise un-
measured osmotically active sub-
stances, including volatile alcohols.
While direct testing for the more
common alcohols is generally read-
ily available, the osmol gap may
support a clinical suspicion for in-
toxication while more definitive
laboratory workup is pending.
Measurement of serum, urine,
and stool osmolality plays a key role
in the diagnostic workup and moni-
toring of several clinical conditions.
Although in some settings its utility
and practicality are limited by the
availability of alternative testing,
such as direct ethanol testing in the
setting of suspected intoxication or
urine specific gravity to estimate
APRIL 2019 page 50
renal concentrating ability, osmolal-
ity measurement remains the best
test in certain clinical scenarios.
1. Rifai N. Tietz Textbook of Clinical Chem-
istry and Molecular Diagnostics, 6th ed. St.
Louis, Mo.: Elsevier; 2018.
2. Goldman L, Schafer AI. Goldman-Cecil
Medicine, 25th ed. Philadelphia: Elsevier
Saunders; 2016.
Sammie Roberts, MD
Department of Pathology
University of Colorado School of Medicine
Aurora, Colo.
Former member, CAP Clinical
Chemistry Committee
Sridevi Devaraj, PhD, D(ABCC)
Professor, Pathology and Immunology
Baylor College of Medicine
Director, Clinical Chemistry and
Point of Care Testing
Associate Director, Microbiome Center
Texas Children’s Hospital
Houston
Member, CAP Clinical Chemistry
Committee
Q. When a result is outside the analyti-
cal measurement range, the sample
is processed by dilution. If the result of
that dilution is found within the AMR, it is
then multiplied by the dilution factor and
reported. Should we include a comment on
the report saying the result was obtained
after dilution?
A. For results greater than or less
than the analytical measure-
ment range, a numeric result must
not be reported unless the sample is
processed by dilution, a mixing pro-
cedure, or concentration to obtain
a value that falls within the AMR.
The result must be within the AMR
before it is mathematically corrected
by the concentration or dilution fac-
tor to obtain a reportable numeric
result. Although the laboratory is
required to retain testing records,
including mathematical corrections,
there is no requirement to include
a comment on the patient report
indicating that a result was obtained
after dilution.
1. Medicare, Medicaid, and CLIA programs;
laboratory requirements relating to quality
systems and certain personnel qualifications.
Fed Regist. 2003;68(16):3712. To be codified at
42 CFR § 493.1282(b)(1)(ii).
2. College of American Pathologists. CHM.
13710 Diluted or concentrated samples. In:
Chemistry and toxicology checklist. Aug.
22, 2018.
Joel Graff, MBA, MT(ASCP)
Senior Technical Specialist
Laboratory Accreditation Program
College of American Pathologists
Northfield, Ill.
4/3/19 1:33 PM
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0419_TABs-Sebia-Hse-8.indd 51 APRIL 2019 page 51 4/2/19 4:14 PM
 52 CAP TODAY | APRIL 2019
Newsbytes
Editors: Raymond D. Aller, MD, & Hal Weiner
NYU adapting VR technology
to tell a pathology ‘story’
The R&B classic “Time Is on My
Side” may be an anthem for rejected
lovers, but a new virtual reality
teaching tool that allows students to
“visit” the pathology lab without
leaving the classroom may soon have
NYU medical students humming the
song’s refrain.
The experiential learning content,
being developed collaboratively by
multimedia specialists and patholo-
gists, is designed to “maximize stu-
dents’ time by condensing complex
information,” says Greg Dorsainville,
Greg Dorsainville, senior multimedia developer at NYU’s Institute for
Innovations in Medical Education, experiments with virtual reality
technology for pathology.
senior multimedia developer for
NYU’s Institute for Innovations in
Medical Education. Case in point: He
took an hour of footage for the proj-
ect’s pilot video, which shows a pa-
thologist demonstrating a colorectal
cancer staging. The final product
clocks in at six minutes.
But the content isn’t merely in-
tended as a timesaver for over-
stretched students. Dorsainville and
Amy Rapkiewicz, MD, vice chair of
pathology at NYU Winthrop Hospi-
tal, hope it will help teach pathology
concepts—and how decisions made
at the grossing table affect patient
care—to medical students who have
limited access to the pathology lab
and no preclinical standalone courses
in the specialty.
In the 1970s, says Dr. Rapkiewicz,
who is also director of the integrated
anatomy, histology, and pathology
course at the NYU Long Island
School of Medicine, medical schools
began revising their preclinical cur-
riculums to follow a systems-based
approach in which traditional sci-
ences like pathology are taught as a
component of courses on the organ
systems. “This was spurred on by
the finding that students seemed to
0419_52-53_Newsbytes_2.indd 52
do better contextualizing the basic
sciences when they’re learning
about clinical sciences at the same
time,” she explains. Consequently,
educators have had to determine not
only what to teach students in their
preclinical years but how to teach it
to them.
This led to a eureka moment of
sorts that developed organically from
a long collaborative partnership be-
tween Dorsainville and Dr. Rapkie-
wicz, who initially worked together
to create a digital catalog of pathol-
ogy specimens. The two moved
away from that project, Dr. Rapkie-
wicz says, after realizing students
were unlikely to benefit
Photos courtesy of NYU Langone Health
from the library with-
out a structured didac-
tic approach.
But Dr. Rapkiewicz,
a forensic pathologist
and autopsy director,
had repeatedly seen
material click for stu-
dents who visited the
autopsy suite and inter-
acted directly with spec-
imens. When she shared
this insight with Dorsa-
inville, he suggested
immersive content, giv-
ing students “a feeling of presence, as
if they’re standing next to the profes-
sor in the lab.”
Dorsainville, an experienced vid-
eographer who’s been working with
immersive technologies for three
years, uses a 360-degree wide-angle
camera to film the video content. The
camera, which captures a much larger
field of vision than a traditional video
camera, “gets as much of the view as
possible but also gives a stereo feel,”
he says.
The videos, which can be viewed
from a virtual reality headset or a
desktop computer, aren’t difficult to
develop from a technical stand-
point. What’s tricky, Dorsainville
says, is “creating a viable educa-
tional experience.”
The example video of the colorectal
cancer staging is in usability testing
with a group of preclinical students at
the NYU School of Medicine. All con-
tent will be pilot tested before becom-
ing part of the curriculum. Because
crafting an effective pedagogical strat-
egy is challenging, Dr. Rapkiewicz is
working with colleague Margret
Magid, MD, pathology content direc-
tor, on how best to implement the
videos in integrated coursework.
In the meantime, the development
team is focused on creating content
that has what Dr. Rapkiewicz calls “a
robust pathology story.” A post-che-
motherapeutic osteosarcoma, for ex-
ample, has a clean narrative with an
illustrative surgical specimen. A les-
son featuring an osteosarcoma might
show the x-ray, chemotherapeutic
effect, and surgical amputation, cul-
minating with the oncologic targets
and revealing the extensive role pa-
thologists play in a patient’s down-
stream clinical management. A sar-
coma of the soft tissue, which “kind
of looks like a blob,” would not be a
good candidate, she notes.
“A lot of times I see people make
wonderful simulations or innovative
VR content and it’s something I may
be able to explain to students [by
drawing] on a napkin,” Dr. Rapkie-
wicz says with a laugh. “We’re really
trying to use it to fit the technology
with the problem.”
For preclinical instruction, this
means using the content to augment
areas of the curriculum for which
students might need “extra context to
understand how pathology and dis-
ease are represented in the body,” Dr.
Rapkiewicz says. For clinical instruc-
tion, she envisions directing students
to supplementary pathology mate-
rial—for example,
students on a sur-
gery rotation might
be given a list of im-
mersive videos to
view after observing
a gallbladder sur-
gery. This “just-in-
time learning” will Dr.Rapkiewicz
be essential for stu-
dents who don’t have time to “follow
their specimen to the pathology lab,”
she adds.
The first project of Dorsainville
and Dr. Rapkiewicz to be incorpo-
rated into the preclinical curriculum
is tangential to pathology. Beginning
this fall, students in the general anat-
omy course at the NYU Long Island
School of Medicine will use virtual
prosection modules, in lieu of cadav-
ers, in the introductory anatomy
course. “Our strategy right now is to
follow responsive design—for all this
content to be accessible in some for-
mat, regardless of whether students
have a headset, computer, or mobile
device,” explains Dorsainville. “All
experiences will be available via the
Web. For true immersion, students
will have access to devices loaned by
the school.”
Dorsainville, meanwhile, hopes to
further develop other virtual reality
pathology content by adding an in-
teractive component that allows stu-
APRIL 2019 page 52
dents to manipulate digital models of
the tissue, similar to what he’s done
with the prosection modules.
eff
life
tat
“The only thing really lacking,” he ter
says, “is that you can’t walk around no
and pick things up.”—Charna Albert
No
Xifin adds functionality im
to LIS and RCM system bi
Xifin has announced a strategic part- Li
nership with Glidian under which an
Glidian will integrate its automated Be
prior authorization capabilities with us
the Xifin RPM revenue cycle manage- en
ment solution and Xifin’s laboratory
information system. vid
“By integrating our electronic prior gr
authorization submissions with Xifin inc
RPM and Xifin LIS, we’re able to help og
providers streamline their workflows,
prevent denials, and help expedite rea
decisions to make sure patients receive ing
the important diagnostic information op
they need,” said Ashish Dua, CEO of sis
Glidian, in a press statement. The ap- be
plication works with the existing prior pa
authorization workflow, logic, and as
document storage in Xifin RPM. di
Xifin has also introduced a patient sta
responsibility estimator for Xifin RPM, ch
which is designed to enhance patients’ um
understanding of out-of-pocket costs
for ordered tests. The estimator, which
is available to physicians and patients
through Xifin’s multi-portal infra-
Cy
structure, also offers patients a prepay- sm
ment option. Th
Xifin, 866-934-6364 ter
cy
me
Paige.AI receives FDA
breakthrough designation tor
The FDA has awarded Paige.AI break- ma
through device designation for its use fac
of computational pathology to build da
artificial intelligence tools for cancer ru
diagnosis and treatment. an
“We are thrilled to receive break- tom
through designation and look for-
ward to collaborating with the FDA
to bring our products to market, start-
ing with prostate cancer and expand-
ing from there,” said Leo Grady, PhD,
CEO of Paige.AI, in a company press
release.
Paige.AI has received more than
1 million deidentified images of digi-
tized slides from Memorial Sloan
Kettering Cancer Center under a li-
cense agreement with that institution.
The company is funding the digitiza-
tion of an additional 4 million slides
from MSK’s archives to develop a
portfolio of artificial intelligence
products across cancer subtypes for
use by pathologists.
The FDA grants breakthrough de-
vice designation for technologies that
have the potential to provide more
4/3/19 12:47 PM
 APRIL 2019 | CAP TODAY 53

of effective diagnosis or treatment for ance Cybersecurity Toolkit apart is pects the center, a project of Cleve- Researchers are also undertaking
ne life-threatening or irreversibly debili- that it is an action kit,” said Philip land Clinic Enterprise Analytics, to cancer-focused projects to predict
tating diseases or conditions than al- Reitinger, president and CEO of the have global reach and include col- patient outcomes.
he ternative approved products or where Global Cyber Alliance, in a press state- laborations between industry and
nd no alternative exists. ment. “Our focus is on producing a academia.
Dr. Aller teaches informatics in the
ert dynamic clearinghouse of operational Already underway are projects to Department of Pathology, University
Northwest Pathology tools that help small and medium build machine learning models that of Southern California, Los Angeles.
[sized] businesses address risk and identify patients who have a high
implements LigoLab improve their cybersecurity posture, risk of death within 48 to 72 hours of
He can be reached at raller@usc.edu. Hal
Weiner is president of Weiner Consult-
billing/RCM system leveraging the deep expertise of our admission and predict inpatient ing Services LLC, Eugene, Ore. He can
rt- LigoLab Information Systems has network of global partners, such as length of stay and readmission risk. be reached at hal@weinerconsulting.com.
ch announced that Northwest Pathology, Mastercard, and the experiences of
ed Bellingham, Wash., recently began actual GCA toolkit users.”
ith using its comprehensive billing/rev- The Global Cyber Alliance part-
ge- enue cycle management solution. nered with several organizations to
ry The billing/RCM module is pro-
vided as part of the LigoLab inte-
develop the toolkit, including the Cen-
ter for Internet Security, Cyber Readi- If your fentanyl assay is not
or
fin
grated information system, which also
includes anatomic and clinical pathol-
ness Institute, and cities of London
and New York. The guide will be up- detecting norfentanyl...
elp ogy and molecular diagnostics. dated regularly with input from users,
ws, The billing/RCM system offers industry experts, and public and pri-
ite real-time patient demographic check- vate partners worldwide.
ve ing and patient insurance eligibility The toolkit is available at https://gca
True positive samples could be
on options, automatic CPT and diagno- toolkit.org/smallbusiness. slipping through your fingers.
of sis coding, claim scrubbing, advance
p- beneficiary notice generation, and
or patient and client billing. It includes Cleveland Clinic launches
nd a screen for patient encounters that AI innovation center
displays the billing record and claim The Cleveland Clinic has established
ent status, corresponding codes and the Center for Clinical Artificial Intel-
M, charges, scans of associated case doc- ligence to develop clinical applica-
ts’ uments, and reports. tions for AI.
sts LigoLab, 800-544-6522 The innovation hub will bring
ch together specialists from several de-
nts partments, including pathology, im-
ra-
Cybersecurity toolkit for aging, information technology, on-
The opioid epidemic is a serious global crisis affecting public health as well as
small to midsize companies social and economic welfare. Fentanyl abuse, misuse and diversion is a major
ay- cology, genomics, and quantitative contributor to this crisis.
The Global Cyber Alliance and Mas- health sciences.
64 tercard have released a free online “The center will serve as a plat- Fentanyl is metabolized to norfentanyl and other metabolites. About 90% of
cybersecurity toolkit for small and form for collaboration and commu- the dose is excreted in urine as norfentanyl, while parent fentanyl accounts for
medium-sized businesses. nication between physicians and data less than 7%. Detection of both parent and this major metabolite is essential
The toolkit helps users take inven- scientists; provide programmatic and to determine fentanyl use and is an integral part of combating the opioid
epidemic.
tory of cyber-related assets, create and technology support for AI initiatives;
ak- maintain strong passwords, use multi- and conduct research in several areas
use factor authentication, back up critical of medicine that can solve clinical
ARK Diagnostics, Inc. now offers an FDA 510(k) cleared,
ild data, and prevent phishing and vi- problems using machine learning,
CE-marked immunoassay that detects fentanyl in urine.
cer ruses. It provides templates of policies deep learning, and other AI technolo-
and forms, training videos, and cus- gies,” according to an announcement Exceptional analytical sensitivity at a 1ng/mL cutoff level
ak- tomizable documents. from the Cleveland Clinic.
or- “What sets the Global Cyber Alli- The health care institution ex- Detection of both the parent and major metabolite to identify more true
positives
DA
rt- Crossreactivity to norfentanyl extends the window of detection
d-
D, Liquid, ready-to-use convenience improves lab efficiency
ess FROM CAP PRESS Three suitable kit sizes for low, moderate and high volume laboratories
More than a new edition, Autopsy Performance &
an Reporting has been overhauled and now contains Application protocols for most general chemistry analyzers
gi- hundreds of full-color images that both seasoned
an autopsy pathologists and those who don’t regu-
li- larly perform autopsies will find valuable. The If your fentanyl assay does not detect the major compounds that
on. book is organized into seven sections: introduc- are present in urine, your facility may already be losing
za- tion to the autopsy, preautopsy and administra- the fight against fentanyl abuse.
des tion, autopsy safety, autopsy performance, special
a studies, autopsy reporting, and quality assurance. Included are approaches
ce to specialized autopsies, procedures for specific organ systems and patient
or populations, and standardized reporting formats. Edited by Kim A. Collins,
MD. For CAP members, $128; for others, $160. To order, go to www.cap.org,
de- “Shop” tab; or call 800-323-4040 option 1. Also available as an ebook ($112
NEXT GENERATION ASSAYS
hat at ebooks.cap.org).
48089 Fremont Blvd Fremont, CA 94538
ore
877.869.2320
www.ark-tdm.com

2 0419_52-53_Newsbytes_2.indd 53
APRIL 2019 page 53 4/3/19 12:47 PM
Executive War College
Conference On Laboratory & Pathology Management
April 30-May 1, 2019 • Sheraton Hotel, New Orleans, LA

SPACE IS LIMITED

REGISTER TODAY!
executivewarcollege.com

PAMA Reporting for Hospital Labs • Tougher Compliance Hottest Topics!

Finding New Revenue Sources • Clinical Lab 2.0 Successes Essential Insights!
I f you believe 2019 is the
year that a “perfect storm of
disruption” brings major, unwel-
come changes to the entire clinical
laboratory industry, then our 24th
annual Executive War College on
April 30-May 1 is the must-attend
event for you.
Both clinical labs and
anatomic pathology groups face
unprecedented financial and
compliance pressures in coming
months. Executive War College
connects you with the experts
and insights you need to protect
and preserve your lab’s financial
stability.
Two factors differentiate 2019
from earlier years. First, govern-
ment and private payers are slash-
ing prices they pay for lab tests.
Every lab in the U.S. is feeling
immediate financial pain from
these actions. Second, stricter
compliance with new federal and
private payer requirements raises
the stakes for labs slow to comply.
That means big penalties and loss
of access to patients for labs that
fail with a timely response.
Yes! These are tough times for
labs. But, for 23 years, Executive
War College has earned the repu-
tation as the one place where the
best minds in lab strategy, oper-
ations, compliance, and revenue
management come together and
share insights, best practices, and
what’s working in the current
market. It’s why you and your lab
team need to attend, network, and
participate.
For many labs, 2019 may be
the make-or-break year for sur-
vival. The same market forces
causing disruption today are fac-
tors in why such labs as PAML,
PeaceHealth Laboratories, and
Boyce & Bynum Pathology Labs
ended decades of independence
by selling. Equally true for ana-
tomic pathology, every year more
private practices disappear—with
the volume of case referrals they
handled now being performed by
more nimble pathology groups of-
fering the right mix of pricing and
service.
The key message to you is
that 2019 and beyond will not
be “business as usual.” With 100
speakers, 60 sessions, and two
full-day workshops, Executive
War College is the only time and
place where you get access to the
experts who can help you succeed.
Reserve your place now to
attend this year’s Executive War
College. It’s the best investment
you will make to ensure the
success of your lab and your loyal
staff. Register today!
Top Speakers!
• New ways your lab can be paid and how
to tap different sources of revenue
• Defending your lab as a vital resource to
your hospital/health network
• What every lab must know about PAMA
reporting: doing it right at lowest cost
• New compliance landmines: what they
are and how to avoid penalties, fines
• What payers want from labs and how to
get paid for those lab services
• Real-time analytics to support lowering
costs, deliver value, boost revenue
• How to gain and retain network access
with major health insurers
• Advances in core lab automation that
deliver lower costs and shorter TATs
• Essential molecular testing innovations
for hospital/health system labs
• Lab/Pathology Mergers & Acquisitions
Panel to assess lab valuation trends

Plus Choose from 2 Full-Day Workshops Thursday, May 2 (separate registration required)
Help Your Lab Report PAMA Test Prices Lessons from Clinical Lab 2.0 Innovators:
Correctly and Accurately: Creating new Revenue Streams for Your Lab,
What All Hospital and Independent Labs Must Ways to Add Value, How to Engage Payers
Know to Meet the Law and Avoid Penalties of Includes a special “Shark Tank” Session involving real
$10,000 per Day Clinical Lab 2.0 projects with physicians and payers!

Many more hospital and other labs must now report their
PAMA private payer price data to Medicare. This is the
must-attend event for everyone in your hospital and lab team
responsible for gathering, analyzing, and reporting this data
to CMS. You’ll get answers to your toughest problems, learn
about potential pitfalls, and master knowledge needed to report
accurate and complete data on time!
Your lab needs new streams of revenue to offset ongoing
deep cuts to lab test prices. Join this workshop and learn
from lab leaders now being paid for helping physicians
and payers achieve better patient outcomes. Hear how
to leverage your informatics and which specific diseases
generate the biggest patient care improvements. Bring
your team to jump start your lab’s added value programs!

For details and to register, visit executivewarcollege.com • 512.264.7103

FN-CapToday-10.875x13.indd 1
zzz-Executive War College
0419_TABs-Sebia-Hse-8.indd 54 FILE— 0219-51 APRIL 2019 page 54 1/18/19 4:08 PM
4/2/19 4:14 PM
 APRIL 2019 | CAP TODAY 55

Classified Marketplace
Advertising Luminex acquires and integrated imaging to maximize
FLORIDA case-handling efficiency,” the company
MilliporeSigma’s flow reports. Digital imaging integration is
cytometry portfolio offered in partnership with Virtus Imag-
Luminex has completed its acquisition of ing; integrated imaging provides high-
MilliporeSigma’s flow cytometry portfo- output case management and touch-free
lio for $75 million. The flow cytometry image processing.
portfolio includes the Amnis family of
Full-time Academic Associate or imaging flow cytometry products for cell-
Professor Faculty Position in Breast Pathology based analysis and the Guava portfolio of
microcapillary flow cytometry systems.
MIAMI, FLORIDA (USA). The Department of Pathology and Laboratory Medicine of the University
of Miami Miller School of Medicine invites applicants with an M.D. or D.O. degree to apply for a “The Amnis and Guava products
full-time academic oriented Associate Professor or Professor Faculty position in Breast pathology. complement our wide range of existing
Academic rank, compensation, and appointment type will be commensurate with qualifications and flow-based offerings, further differenti-
experience. The applicant should have board certification in Anatomic Pathology and preferably
completed a breast pathology fellowship program. The candidate should be accomplished in ating our portfolio and ensuring we are
providing excellent diagnostic service, possess strong communication skills, committed to teaching well positioned to support customers
and training of residents, fellows, and medical students, and have a strong record of participation in today and into the future,” Homi Shamir,
peer- reviewed clinical and translational research. Depending on the qualifications of the candidate
the position will be constructed as breast pathology, breast pathology/funded research or breast president and CEO of Luminex, said in a
pathology/subspecialty surgical pathology (Gyn, Cyto, Pulmonary, Head and Neck, GU, Bone and press release. “With this acquisition, we
Soft Tissue pathology). Responsibilities for the position are with the University of Miami network now have expanded our installed base
of hospitals and clinics (UHealth System) and the flagship county hospitals of Miami-Dade County
(Jackson Health System). to include more than 5,000 flow cytom-
etry systems worldwide, adding to our
The Department of Pathology and Laboratory Medicine is subspecialized and works closely with
the University of Miami Sylvester Cancer Center in providing excellent patient care and is an impressive footprint and creating the po-
important member of the multidisciplinary Breast Site Disease Group. The service handles more tential for additional meaningful growth.”
than 4000 breast specimens annually and the diverse spectrum of surgical pathology is remarkable The buyout is expected to contribute
and challenging. The service has two ACGME combined fellowship positions in Breast and GYN
pathology that attract excellent candidates. Opportunities to collaborate with funded researchers $40–$50 million in revenue to Luminex
are numerous. The successful candidate will be joining an excellent family of subspecialized faculty this year. The company’s formalin dispensing
that is caring, committed, and dedicated. In addition to a competitive salary and excellent benefits Luminex, 512-381-4397 system, Forma-Flow, is compatible with
package, this is an outstanding opportunity to practice in Miami, a highly desired area with rich
culture, diversity, weather, vegetation, and opportunities for outdoor activities. its grossing station and has a patent-
pending design. Forma-Flow is designed
Interested candidates should apply online https://umiami.wd1.myworkdayjobs.com/ FDA approves Herceptin to eliminate formalin bubbling and splat-
UMFaculty/job/Miami-FL/Professor_R100030225
for subcutaneous use ter, evacuate fumes from stored formalin,
For questions regarding the position, please contact: Carmen Gomez-Fernandez, MD The Food and Drug Administration ap- provide ergonomic formalin transfer
Email: cgomez3@med.miami.edu
proved trastuzumab and hyaluronidase- from carboys, and eliminate the need for
The University of Miami is an Equal Opportunity Employer oysk (Herceptin Hylecta, Genentech) for pump priming.
subcutaneous injection for the treatment PMT Scientific is headed by business
of certain people with HER2-positive ear- partners Max Corona and Jane VanDusen,
ly breast cancer in combination with che- who both have more than 25 years of pa-
motherapy and HER2-positive metastatic thology equipment design, manufactur-
breast cancer in combination with pacli- ing, and installation experience.
taxel or alone in people who have received PMT Scientific, 888-519-2286
one or more chemotherapy regimens
for metastatic disease. This treatment
includes the same monoclonal antibody
Bio-Rad quality control
as intravenous Herceptin (trastuzumab) for urinalysis testing
in combination with recombinant human Bio-Rad Laboratories announced the
hyaluronidase PH20, an enzyme that launch of Quantify Advance Control, an in-
helps to deliver trastuzumab under the dependent quality control used to monitor
ARE YOU LOOKING TO skin. Herceptin Hylecta is a ready-to-use
formulation that can be administered in
the precision of laboratory
urinalysis test procedures.
two to five minutes, compared with 30 The control contains hu-
PROMOTE YOUR PRODUCTS to 90 minutes for intravenous Herceptin.
Genentech, 650-225-1000
man urine solution and
offers 31 days of open vial

OR SERVICES? PMT Scientific

begins operations
PMT Scientific, a company that designs
Place Your Ad Here! morgue, pathology, histology, and vi-
varium medical equipment, is now op-
Reach Lab Professionals erating in Redford, Mich. PMT Scientific
focuses on providing custom grossing
stations along with a complete array of
pathology equipment.
Its grossing stations incorporate
To place a classified ad: height-adjustable actuators, high-color-
rendering lighting, and durable and easy-
Toll free: 888-489-1555 to-maintain plumbing fixtures, and can
come equipped with air quality monitor-
Email: sales@kerhgroup.com ing devices.
“With customer input, PMT Scientific
has developed state-of-the-art lighting
To place a classified ad, please call 888-489-1555
stability for all analytes,
including ketones, at room
temperature. The Unity in-
terlaboratory program and
Unity QC data manage-
ment solutions, designed
to improve the effectiveness of the
laboratory’s statistical process control, are
available for use with Quantify Advance.
Bio-Rad, 510-724-7000
Tissue dissociation guide
Worthington Biomedical Corp. has re-
leased the 18th edition of its Tissue Dis-
sociation Guide for biochemistry, cell
biology, molecular biology, preclinical
research, and bioprocessing applications.
The guide covers —continued on 56
56 CAP TODAY | APRIL 2019
Marketplace
continued from 55
cell isolation theory
and techniques, opti-
mization techniques
and strategy, and tis-
sue culture and stem
cell glossaries. Also
featured are a new
applications table,
updated references,
expanded tissue less than 115 minutes. The system can pro-
tables, and a techni- vide 300 results in about eight hours and
cal wall poster that can have up to 20 assays onboard at one
features a primary cell isolation enzyme time. Alinity m may also reduce the lab
digestion scale for troubleshooting a dis- equipment footprint of four to six instru-
sociation and planning isolation strategy. ments down to one, the company reports.
Worthington Biomedical Corp., 732-942-1660 Alinity m STI assays include virologic
testing for HIV 1, hepatitis B virus, and
Abbott gains CE mark for hepatitis C virus; sexual health-related
testing for Chlamydia trachomatis, Neis-
Alinity m system, assays seria gonorrhoeae, Trichomonas vaginalis,
Abbott announced it has received the and Mycoplasma genitalium, or CT/NG/
CE mark for its Alinity m automated TV/MG panel; and high-risk human
molecular diagnostics system and assays. papillomavirus testing.
Alinity m features ReadiFlex technol- In the United States, Alinity m is in de-
ogy, the company’s proprietary technol- velopment and not commercially avail-
ogy for true random access, a universal able for diagnostic use.
sample rack, and a time to first result of Abbott, 224-667-6100
Audit MicroControls
linearity, quality controls
Audit MicroControls announced several
additions to its line of calibration verifica-
tion/linearity and daily quality control
products. The company’s galectin-3 lineari-
ty and control kits are for use with quantita-
tive assays on clinical laboratory analyzers,
simulating human patient samples.
The Linearity LQ Galectin-3 is a ready-
to-use liquid and consists of five levels
that demonstrate a linear relationship to
one another when assayed for galectin-3.
The Control LQ Galectin-3 is a ready-to-
use liquid intended to simulate human
patient samples for use as assayed qual-
ity control materials for galectin-3.
The Linearity Drop LQ Fructosamine
for Roche systems is intended to simu-
late human patient serum samples for
determining linearity, calibration veri-
fication, and verification of reportable
range for the fructosamine analyte. It is
a ready-to-use liquid product consisting
of five levels that demonstrate a linear re-
lationship to one another when assayed
for fructosamine.
These products have an open vial sta-
bility of seven days when stored at 2°–8°C.
The company provides Auditor QC, a
free, online real-time data reduction pro-
gram that offers Levey-Jennings charts,
graphs, statistics, and peer group data.
Report results are given immediately and
are stored on the Auditor QC website for
future reference.
Audit MicroControls, 866-252-8348
FDA proposes 510(k)
exemption for certain
flow cytometers
The U.S. Food and Drug Administration
is issuing a proposed order to exempt cer-
tain class II flow cytometry instruments
from premarket notification (510[k]) re-
quirements, subject to limitations and con-
ditions. The FDA will continue to review
the relevant functionality of these devices
when they are used clinically with an in
vitro diagnostic device reagent or test kit
that is subject to FDA premarket review.
The proposed exemption applies only
to cytometry instruments used for count-
ing or characterizing cells. The comment
period will be open until May 5 in the
Federal Register under docket number
2019-03967.

GenePOC group A
strep test cleared
GenePOC announced its GenePOC Strep
A assay has been cleared by the FDA for
use with the Revogene device. The assay
is a qualitative in vitro diagnostic test for
the detection of Streptococcus pyogenes
nucleic acids from throat swab speci-
mens. It can provide results in 42 minutes
for positive specimens and in about 70
minutes for negative specimens, without
the need for culture confirmation.
Revogene is an automated, standalone
device that enables testing of single-use
microfluidic cartridges using fluores-
cence-based, real-time polymerase chain
reaction technology.
GenePOC, 418-650-3535
NeoGenomics launches
CDx test for TNBC
NeoGenomics announced availability of
the Ventana PD-L1 (SP142) Assay for tu-
mor tissue from patients with the triple
negative subtype of breast cancer. This
PD-L1 assay is a companion diagnostic test
recently approved by the FDA to identify
advanced, metastatic triple negative breast
carcinoma cancer patients who may re-
spond to the immune checkpoint inhibitor
therapy Tecentriq (atezolizumab) used in
combination with chemotherapy.
NeoGenomics, 239-768-0600
Qiagen, Tecan collaboration
Qiagen and Tecan Group announced a
collaboration to improve the processing
of Qiagen’s QuantiFeron-TB Gold Plus
diagnostic test. The companies are work-
ing together to optimize a solution that
standardizes and automates the manual
steps in liquid handling for the aliquot-
ing of samples. Customers will be able to
use Tecan’s Fluent laboratory automation
workstation for the aliquoting of samples
for the optional lithium heparin single-
tube workflow. The Fluent instruments
will be supplied to laboratories through
Tecan’s Life Sciences Business division.
Qiagen announced in a separate release
a partnership with Ares Genetics to de-
velop bioinformatics and assay solutions to
Abbott Molecular, page 60
Accelerate Diagnostics, page 34
Agena Bioscience, page 10
ARK Diagnostics, pages 27, 53
BD Diagnostics, pages 15, 37
Binding Site, page 43
Bio-Rad Laboratories, page 33
Biocare Medical, page 19
BioFire Diagnostics, page 4
Computer Trust, page 13
DiaSorin Molecular, page 32
accelerate research targeting the health chal-
lenges posed by antibiotic-resistant bacteria.
Qiagen has acquired an exclusive license to
leverage Ares Genetics’ proprietary anti-
microbial resistance database, ARESdb, as
well as bioinformatics tools and workflows
from the Ares technology platform, ARES-
tools, in Qiagen’s bioinformatics products
and services for researchers. Qiagen also
obtained a nonexclusive worldwide license
to develop and commercialize molecular
research assays using ARESdb content
with Qiagen next-generation sequencing
and polymerase chain reaction solutions.
Qiagen, 800-426-8157
Validate CSF total
protein kit
LGC Maine Stan-
dards has added
Cerebrospinal Fluid
Total Protein to its
Validate Body Fluids
kit for laboratory-
developed test validation, documentation
of linearity, calibration verification, and
verification of the reportable range.
LGC Maine Standards, 207-892-1300
EKF, McKesson
distribution agreement
EKF Diagnostics has signed a private label
distribution agreement with McKesson
Medical-Surgical for the company’s hand-
held, reagent-free hemoglobin analyzer,
the DiaSpect. The DiaSpect will be sold
by McKesson under its own branded line
as the McKesson Consult Hb analyzer.
The analyzer provides accurate hemo-
globin measurements (precision: CV ≤1 per-
cent) within two seconds of when the whole
blood–filled cuvette is inserted for analysis.
EKF Diagnostics, 830-249-0772
RML selects Alinity
Abbott announced that Regional Medical
Laboratory, of Tulsa, Okla., will use Ab-
bott’s Alinity ci-series. RML, part of the
Ascension network, performs diagnostics
testing for more than 2.4 million patients
through hospital systems in Texas, Wis-
consin, Oklahoma, Kansas, and Tennessee.
INDEX TO ADVERTISERS
Elitech Group, page 50
Executive War College, page 54
Gold Standard Diagnostics, page 28
Hardy Diagnostics, page 39
Instrumentation Laboratory,
pages 17, 59
Janssen Biotech, page 45
Kronus, page 14
LGP Consulting, page 42
LOXO Oncology, page 29
Luminex, page 18
Nova Biomedical, page 25
The installation of Alinity in RML fa-
cilities will include a custom automation
line. “Alinity’s innovative technology
and our new custom automation allows
us to provide faster, more accurate pa-
tient care while increasing the capacity
of our laboratory staff and driving down
costs,” C. Terrence Dolan, MD, president
of RML, said in a statement.
Abbott, 224-667-6100
Ortho Clinical, Leadman
introduce assays in China
Ortho Clinical Diagnostics, in collabora-
tion with Beijing Leadman Biochemistry,
launched four MicroTip partnership as-
says in China. The assays, for renal, liver,
and cardiac testing, include cystatin C,
α-hydroxybutyrate dehydrogenase, ho-
mocysteine, and total bile acid.
Leadman will offer these reagents in
prefilled packages to be used on the Vit-
ros 4600 chemistry system and the Vitros
5600 integrated system in China.
Ortho Clinical Diagnostics, 800-828-6316
Hardy Diagnostics,
EliTech partnership
Hardy Diagnostics is now an authorized
distributor of EliTech’s Mycofast US, a
rapid system to detect, enumerate, and
identify genital Mycoplasma hominis and
Ureaplasma urealyticum.
The Mycofast US system takes 24 hours
for a positive result and an additional 24
hours to confirm a negative result. This
is a streamlined version, with enhanced
sensitivity, of the traditional culture media
method, the company says, and aims to be
a cost-effective alternative to traditional
culture media and PCR methods.
Hardy Diagnostics, 805-346-2766
CAP TODAY (ISSN 0891-1525) is published monthly
by the College of American Pathologists, 325 Wau-
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Printed in U.S.A. ISSN 0891-1525
Olympus Life Science, page 20
Orchard Software, page 21
Polymedco, page 6
Qiagen, page 23
Randox Laboratories, page 35
Roche Diagnostics, pages 2–3
Sebia, page 9
Siemens Healthineers, page 7
Streck, page 51
Sysmex, pages 30–31
Techlab, page 36
Voicebrook, page 56
APRIL 2019 | CAP TODAY 57
Put It on the Board
continued from 58
all randomized patients, and further
data will be shared with the FDA
and presented at an upcoming medi-
cal meeting.
The Ventana PD-L1 (SP142) Assay,
launched in 2016, is the primary di-
agnostic assay within the Tecentriq
clinical development program and
was used to enroll and stratify pa-
tients in the Tecentriq clinical trials.
It was previously approved by the
FDA and CE marked for use as a
companion diagnostic in urothelial
carcinoma and as a predictive assay
in second-line non-small cell lung
cancer with Tecentriq.
Advanced Biological, Mayo
collaborate on test for
CMV patients
Advanced Biological Laboratories, a
Luxembourg-based diagnostics com-
pany, and Mayo Clinic Laboratories
are working together to develop a
clinical test that will detect mutations
associated with antiviral resistance in
human cytomegalovirus.
Based on a next-generation se-
quencing method, the assay sequenc-
es PCR amplicons of the specific genes
UL54 and UL97 of CMV. The test is
coupled with Advanced Biological
Laboratories’ software called Deep-
Chek-CMV, which is used to analyze
sequencing data and provide an inter-
pretation of potential drug resistance
in cytomegalovirus.
Roche launches Navify
Mutation Profiler, Navify
Therapy Matcher
Roche announced the CE-IVD mark
and launch of its Navify Mutation
Profiler, clinical software that pro-
vides annotation, interpretation, and
clinical reporting of next-generation
sequencing tests. Roche launched
also its Navify Therapy Matcher, an
optional clinical decision support app
that further aids clinicians in linking
clinically actionable mutations to
relevant therapy options.
Navify Mutation Profiler simpli-
fies how labs report on their NGS
tests, according to Roche.
Navify Mutation Profiler and
Navify Therapy Matcher together
offer a “clinical decision support
solution that addresses a major
workflow challenge for NGS labs,
synthesizing large amounts of medi-
cal and scientific data into action-
able insights,” Neil Gunn, head of
Roche Sequencing Solutions, said in
a statement.
 58 CAP TODAY | APRIL 2019
Put It on the Board
Shield launches test
for antibiotic susceptibility
in N. gonorrhoeae
Shield Diagnostics launched Target-
NG, a rapid molecular test for antibiotic
susceptibility in Neisseria gonorrhoeae.
THE BEST OF
E M E R G I N G T E C H N O L O GY
D I S T I N G U I S H E D FAC U LT Y
I N F O R M AT I C S E XC E L L E N C E
GAT H E R H E R E .
For more info, contact Nova Smith,
nova.smith@pathologyinformatics.org or
Beth Gibson, bethgibs@med.umich.edu
Brought to you by
the Association for
Pathology Informatics.
treating gonorrhea with a sledgeham-
mer; we’re treating everything with
the same exact regimen. And it’s not
rather than the current injectable
treatment, clinicians can prescribe
antibiotics for the patient to give to
a surprise that the organism will be- their partners.
“Rapid molecular testing for cip- come resistant to what we’re cur- “Shield has launched Target-NG
rofloxacin resistance allows for smart- rently using.” (See story, page 1.) to help clinicians adopt a precision
er medicine,” Jeffrey D. Klausner, Ciprofloxacin can be used to treat medicine approach to gonorrhea
MD, MPH, a professor of infectious 80 percent of infections and is 99.8 treatment,” said Nidhi Gupta, PhD,
disease medicine at the University of percent effective when susceptibility lead scientist on the project.
California, Los Angeles, said in a has been determined. Because it is “Target-NG can determine if a
Shield statement. “Right now we’re administered as a single oral dose, given gonorrhea infection is suscep-
tible to ciprofloxacin with the same
turnaround time as regular gonor-
rhea screening tests,” Fred Turner, the
company’s CEO, said in a statement.
“This is enabling prescription of a
single-dose pill as an effective treat-
ment for gonorrhea.” The test is
available from urine, rectal, and pha-
ryngeal samples.
FDA grants accelerated
approval to Tecentriq in
combination with Abraxane
The Food and Drug Administration
has granted accelerated approval to
Genentech’s Tecentriq (atezolizu-
mab) plus chemotherapy (Abraxane)
for the treatment of adults with un-
resectable locally advanced or meta-
static triple-negative breast cancer
whose tumors express PD-L1 as de-
termined by an FDA-approved test.
This indication is approved under
accelerated approval based on
progression-free survival. Continued
approval may be contingent upon
verification and description of clinical
benefit in a confirmatory trial or trials.
The FDA also approved Roche’s
Ventana PD-L1 (SP142) Assay as the
R E G I S T R AT I O N N O W O P E N first companion diagnostic to aid in
identifying triple-negative breast
M AY 6 - 9 , 2 0 1 9 • P I T T S B U R G H , P A cancer patients who are eligible for
PAT H O L O GY I N F O R M AT I C S . C O M the treatment.
“The FDA approval of this Tecen-
triq combination is an important treat-
ment advance for people with PD-L1-
P I S U M M I T 2 0 1 9 F E AT U R E S positive, metastatic triple-negative
breast cancer, a disease with high un-
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strated that Tecentriq plus nab-
analysis using the R statistical programming language. When mastered, R is a powerful tool paclitaxel reduced the risk of disease
for machine learning, image analysis, business intelligence, and much more! Limited to 30 worsening or death (PFS) by 40 per-
people, pre-registration required (available online when you register for the Summit). Workshop cent compared with nab-paclitaxel
Cost: WITH Summit 2019 registration: $200; WITHOUT Summit 2019 registration: $300. alone (median PFS=7.4 versus 4.8
months) in PD-L1-positive patients
S A V E T H E D AT E S with unresectable locally advanced
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or metastatic TNBC who had not
PI-SUMMIT 2020:4H`7P[[ZI\YNO7(࠮3rd API DPAI Workshop: Dec. 13-14, 2019, Pittsburgh, PA
received prior chemotherapy for
metastatic disease. Overall survival
R E G I S T E R O N L I N E T O D AY
results were immature with 43 per-
PathologyInformatics.com
cent of events in —continued on 57
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