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12 Rapid biomarker testing for improved clinical decision-making in non-small cell lung cancerBy Edward H. Kaplan, MD

18 CE TestTests can be taken online or by mail. See page 18 for testing and payment details.

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DEPARTMENTS

4 From the editor

10 The observatory

44 Tips from the clinical experts

Testing for vaginitis and group A strep

PRODUCTS

46 Product focus: analyzers

49 New products

MARKETPLACE

49 Spotlights

51 Advertiser index

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52 Providing innovative solutions to serve the chemistry and toxicology markets

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20 Clinical labs streamline GI testing with MDxBy Sherry Dunbar, PhD

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22 How MALDI-TOF MS has changed the microbiology labBy Mary Valdez, MS, MT

CLINICAL ISSUES

24 Emerging strategies for optimizing clinical chemistry performanceBy Jeffrey Hill, MLS(ASCP), MS, LSSBB(ASQ), PPM

THE PRIMER

28 Special sample types: CSFBy John Brunstein, PhD

FUTURE BUZZ

32 Protein biomarker discovery By Scott Peterman, PhD, and Lisa Thomas, BS, MBA

LAB MANAGEMENT

36 Keeping clinical lab errors to a minimumBy Jeff Osborne

MANAGEMENT MATTERS

38 The human side of lab automationBy Sophie Dochez Belin

SPECIAL REPORT

42 Humanitarian endeavor brings rapid cancer diagnostics to sub-Saharan Africa and HaitiBy Dan A. Milner, Jr., MD, MSc(Epi), FASCP

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References: 1. Carr PL et al. “Shotgun” versus sequential testing. Cost-eff ectiveness of diagnostic strategies for vaginitis. JGIM. 2005;793-799. 2. BD MAX Vaginal Panel Package Insert/Clinical Trial Data.

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MLO - MEDICAL LABORATORY OBSERVER(ISSN: 0580-7247). Published monthly, with an additional issue in August, by NP Communications, LLC., 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231 (941) 388-7050. Subscription rates: $127.60/year in the U.S.; $154.88 Canada/Mexico; Intl. subscriptions are $221.43/year. All issues of MLO are available on microfilm from University Microfi lms International, Box 78, 300 N. Zeeb Rd., Ann Arbor, MI 48106. Current single copies (if available) $15.40 each (U.S); and $19.80 each (Intl.). Back issues (if available) $17.60 each (U.S.); $22.00 each (Intl.). Payment must be made in U.S. funds on a U.S. bank/branch within the continental U.S. and accompany request. Subscrip-tion inquiries: [email protected]. MLO is indexed in the Cumulative Index for Nursing and Allied Health Literature and Lexis-Nexis. MLO Cover/CE, Clinical Issues, and Lab Management features are peer reviewed. Title® registered U.S. Patent Offi ce. Copyright© 2017 by NP Communications, LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage-and-retrieval system, without written permission from the publisher. Offi ce of publication: Periodicals Postage Paid at Sarasota, FL 34276 and at additional mailing offi ces. Postmaster: Send address changes to MLO MEDICAL LABORATORY OBSERVER, 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231.Printed in U.S.A.

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MEDICAL LABORATORY OBSERVER Vol.49, No.6Publisher/Executive Editor/PresidentKristine [email protected]

EditorAlan [email protected]

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MLO EDITORIAL ADVISORY BOARD

John Brunstein, PhD, Biochemistry (Molecular Virology)President & CSOPathoID, Inc., British Columbia, Canada

John A. Gerlach, PhD, D(ABHI)Laboratory DirectorMichigan State University, East Lansing, MI

Barbara Strain, MADirector, Supply Chain AnalyticsUniversity of Virginia Health System, Charlottesville, VA

Jeffrey D. Klausner, MD, MPHAssociate Clinical Professor of Medicine Divisions of AIDS and Infectious Diseases University of California, San Francisco, CA

Susan McQuiston, JD, MT(ASCP)Instructor, Biomedical Laboratory Diagnostics ProgramMichigan State University, East Lansing, MI

Donna Beasley, DLM(ASCP)ManagerHuron Healthcare, Chicago, IL

Anthony Kurec, MS, H(ASCP)DLMClinical Associate ProfessorSUNY Upstate Medical University, Syracuse, NY

Suzanne Butch, MLS(ASCP)CM, SBBCM, DLMCM

Administrative Manager, Blood Bank and Transfusion Service, University of Michigan Health System Department of Pathology, Ann Arbor, MI

Paul R. Eden, Jr., MT(ASCP), PhDLt. Col., United States Air ForceChief, Laboratory Services88th Diagnostics/Therapeutics SquadronWright-Patterson AFB, OH


On May 9, the U.S. Senate voted on President Trump’s nomination of Scott Gottlieb, MD, to be the new com-missioner of the U.S. Food and Drug Administration

(FDA). By a vote of 57 to 42, Dr. Gottlieb was confi rmed.The vote was, as news reports say “largely” along party

lines. But it was not as much so as some of the president’s other nominees, who had virtually no support from Sen-ate Democrats. Five Democrats joined with the Senate’s 52 Republicans to confi rm Gottlieb.

What will Scott Gottlieb as FDA commissioner mean for the clinical lab? Will approval of new diagnostics be accel-erated or delayed? Will there be more stringent oversight of laboratory-developed tests (LDTs)?

To answer that, it’s useful to look at the new commissioner’s professional history. He is 44 years old, and he is a physician. (He is also a cancer survivor.) Unlike many of President Trump’s nominees for government posts, he is some-thing of a “Washington insider”: He served in George W. Bush’s second admin-istration as an FDA deputy commissioner, spent a year as a senior adviser to the administrator at the Centers for Medicare and Medicaid Services, and has been serving on the federal Health IT Policy Committee.

In the private sphere, he has been a fellow in the conservative American Enterprise Institute think tank. He has had success as a venture capitalist. He has had fi nancial relationships with large pharmaceutical companies—a point that worried some senators who voted “no” on his confi rmation. Reportedly, he has served on the boards of directors for American Pathology Partners, MedAvante, Glytec, Daiichi Sankyo, Aptiv Solutions, Gradalis, Tolero Pharma-ceuticals, Molecular Insight Pharmaceuticals, and Bravo Health. Dr. Gottlieb promised senators that he would sever his ties to Big Pharma and the biotech industry, and divest himself from healthcare companies.

There is no question that as FDA head he will work toward creating a faster-track for drug approval, perhaps particularly for cancer drugs and “orphan” drugs for rare diseases. He wrote in 2012: “In so heavily prioritizing one of its obligations—the protection of consumers—the FDA has sometimes subordi-nated and neglected its other key obligation, which is to guide new medical innovations to market. Ultimately, the only way to change the threshold for approval of these sorts of drugs is to change the FDA review culture itself.”

That tells you what he thinks and what he plans to do. He affi rms that part of the FDA’s mission is to protect consumers. But he thinks that the other part is to help bring new products to the market, and he believes that has gotten short shrift, so he will restore the balance by making changes in the FDA review process. That is, the fast-track.

In the public mind, the FDA is mostly associated with drug approval. Of course, we know that it also approves medical devices and, most important I assume to the readers of MLO, diagnostics. So back to my original question: what does this mean for the clinical lab? Well, apart from the issue of compan-ion diagnostics, it probably means that diagnostic assays will also be on a faster track, and that should be, in a broad sense, good for business. It may mean that the controversial topic of proposed tighter regulation of LDTs, which has been discussed in these pages and many other places for years now (e.g., my “From the Editor” in the January and March 2017 issues), will recede as the FDA backs further away from changing the status quo. That could be good for labs too—as long as suffi cient (not duplicative) regulation remains in place to protect the public.

Everyone loses if that fi rst “obligation” is lost. But if Dr. Gottlieb can thread the needle between public safety and industrial development, maybe everyone wins.

New man to head the FDAWhat will Dr. Scott Gottlieb mean for labs?

FROM THE EDITOR By A lan Lenhof f, Edi tor

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Patients testing positive for the EGFR T790M mutation may be eligible for TAGRISSO• Nearly 2 out of 3 cases (98/155) of progression with first-generation EGFR TKIs are related to the acquired EGFR T790M mutation1

• The cobas® EGFR Mutation Test v2 can identify the EGFR T790M mutation via tissue or plasma testing2

• In a Phase III, randomized, open-label, head-to-head clinical trial of 419 patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease had progressed on or after EGFR TKI therapy, TAGRISSO outperformed doublet chemotherapy (pemetrexed plus carboplatin or cisplatin)3

Median progression-free survival was more than twice as long with TAGRISSO than with doublet chemotherapy*3

*As determined by investigator assessment (IA).

To identify patients for therapy

TEST FOR THE EGFR T790M MUTATION WITH EITHER TISSUE OR PLASMA

(95% CI: 8.3, 12.3)

(95% CI: 4.2, 5.6)

MONTHS

1.0

0.8

0.6

0.4

0.2

0.0

0

No. at Risk

TAGRISSO

Doubletchemotherapy

279

140

240

93

162

44

88

17

50

7

13

1

0

0

3 6 9 12 15 18

HR=0.30 (95% CI: 0.23, 0.41) p<0.001

Platinum-based doublet chemotherapy

4.4 MONTHS

10.1 MONTHS

TAGRISSO

PRO

BABI

LITY

OF

PRO

GRE

SSIO

N-F

REE

SURV

IVA

L

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Testing for the presence of the EGFR T790M mutation in plasma specimens is recommended only in patients where tumor tissue is not available3

IMPORTANT SAFETY INFORMATION

• There are no contraindications for TAGRISSO

• Interstitial Lung Disease (ILD)/Pneumonitis occurred in 3.5% and was fatal in 0.6% of 833 TAGRISSO-treated patients. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms indicative of ILD (eg, dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD is confi rmed

• Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 833 TAGRISSO-treated patients, 0.7% of patients were found to have a QTc > 500 msec, and 2.9% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia

• Cardiomyopathy occurred in 1.9% and was fatal in 0.1% of 833 TAGRISSO-treated patients. Left Ventricular Ejection Fraction (LVEF) decline ≥ 10% and a drop to < 50% occurred in 4% of 655 TAGRISSO-treated patients. Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO

• Keratitis was reported in 0.7% of 833 TAGRISSO-treated patients in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye infl ammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) to an ophthalmologist

• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during TAGRISSO treatment and for 6 weeks after the fi nal dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the fi nal dose

• The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%)

INDICATION

TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy.

Please see Brief Summary of complete Prescribing Information on adjacent pages.

References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. cobas® EGFR Mutation Test v2 [package insert]. Indianapolis, IN: Roche Molecular Systems, Inc.; 2016. 3. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

For more information about testing to identify patients eligible for TAGRISSO, visit TAGRISSOhcp.com

TAGRISSO is a registered trademark of the AstraZeneca group of companies.COBAS is a registered trademark of Roche.

©2017 AstraZeneca. All rights reserved. 3322513 4/17

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TAGRISSO® (osimertinib) tablets, for oral useBrief Summary of Prescribing Information.For complete prescribing information consult official package insert.INDICATIONS AND USAGETAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.DOSAGE AND ADMINISTRATIONPatient SelectionConfirm the presence of a T790M EGFR mutation in tumor or plasma specimens prior to initiation of treatment with TAGRISSO [see Indications and Usage (1) and Clinical Studies (14) in full Prescribing Information]. Testing for the presence of the mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. Information on FDA-approved tests for the detection of T790M mutations is available at http://www.fda.gov/companiondiagnostics.Recommended Dosage RegimenThe recommended dose of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food.If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.Administration to Patients Who Have Difficulty Swallowing SolidsDisperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces of) water and immediately drink.If administration via nasogastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL).Dosage ModificationAdverse ReactionsTable 1. Recommended Dose Modifications for TAGRISSO

TargetOrgan Adverse Reactiona Dose Modification

Pulmonary Interstitial lung disease (ILD)/Pneumonitis

Permanently discontinue TAGRISSO.

Cardiac

QTc† interval greater than 500 msec on at least 2 separate ECGsb

Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose.

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia


Symptomatic congestive heart failure or asymptomatic left ventricular dysfunction that persists ≥ 4 weeks


Other

Adverse reaction of Grade 3 or greater severity

Withhold TAGRISSO for up to 3 weeks.

If improvement to Grade 0-2 within 3 weeks

Resume at 80 mg or 40 mg daily.

If no improvement within 3 weeks Permanently discontinue TAGRISSO.a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).b ECGs = Electrocardiograms† QTc = QT interval corrected for heart rate

Drug InteractionsStrong CYP3A4 InducersIf concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when coadministering with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7), and Clinical Pharmacology (12.3) in full Prescribing Information].CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSThe following information for ILD/ Pneumonitis, QTc Interval Prolongation, Cardiomyopathy and Keratitis reflects exposure to TAGRISSO in 833 patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who received TAGRISSO at the recommended dose of 80 mg once daily in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143).Interstitial Lung Disease/PneumonitisInterstitial lung disease (ILD)/pneumonitis occurred in 3.5% (n=29) of TAGRISSO-treated patients (n=833); 0.6% (n=5) of cases were fatal.Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6) in full Prescribing Information].

QTc Interval ProlongationHeart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 833 patients treated with TAGRISSO in clinical trials, 0.7% (n=6) were found to have a QTc greater than 500 msec, and 2.9% of patients (n=24) had an increase from baseline QTc greater than 60 msec [see Clinical Pharmacology (12.2) in full Prescribing Information]. No QTc-related arrhythmias were reported.Clinical trials of TAGRISSO did not enroll patients with baseline QTc of greater than 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4) in full Prescribing Information].CardiomyopathyAcross clinical trials, cardiomyopathy (defined as cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 1.9% (n=16) of 833 TAGRISSO-treated patients: 0.1% (n=1) of cases were fatal.Left Ventricular Ejection Fraction (LVEF) decline greater than or equal to 10% and a drop to less than 50% occurred in 4.0% (26/655) of patients who had baseline and at least one follow-up LVEF assessment.Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO [see Dosage and Administration (2.4) in full Prescribing Information].KeratitisKeratitis was reported in 0.7% (n=6) of 833 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.Embryo-Fetal ToxicityBased on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended human dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5-times those observed in patients at the 80 mg dose level.Advise pregnant women of the potential risk to a fetus.Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.3) in full Prescribing Information].ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) in full Prescribing Information]QTc Interval Prolongation [see Warnings and Precautions (5.2) in full Prescribing Information]Cardiomyopathy [see Warnings and Precautions (5.3) in full Prescribing Information]Keratitis [see Warnings and Precautions (5.4) in full Prescribing Information] Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described below reflect exposure to TAGRISSO (80 mg daily) in patients with EGFR T790M mutation-positive metastatic NSCLC in an open-label, randomized, active-controlled trial (AURA3, n=279) and in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required: steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from trial enrollment.AURA3 TrialThe safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized(2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%). Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. AURA3 was not designed to demonstrate a

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2TAGRISSO® (osimertinib) tablets, for oral use

statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 2 and 3.Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3

Adverse Reaction TAGRISSO (N=279)

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)

(N=136)All Gradesa

(%)Grade 3/4a

(%)All Gradesa

(%)Grade 3/4a

(%)Gastrointestinal disordersDiarrhea 41 1.1 11 1.5Nausea 16 0.7 49 3.7Stomatitis 15 0 15 1.5Constipation 14 0 35 0Vomiting 11 0.4 20 2.2Skin disordersRashb 34 0.7 5.9 0Dry skinc 23 0 4.4 0Nail toxicityd 22 0 1.5 0Prurituse 13 0 5.1 0Metabolism and Nutrition DisordersDecreased appetite 18 1.1 36 2.9Respiratory, Thoracic and Mediastinal DisordersCough 17 0 14 0Musculoskeletal and Connective Tissue DisordersBack pain 10 0.4 9 0.7General Disorders and Administration Site ConditionsFatiguef 22 1.8 40 5.1

* NCI CTCAE v4.0.a No grade 4 events were reported.b Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash

pustular, erythema, folliculitis, acne, dermatitis and acneform dermatitis.c Includes dry skin, eczema, skin fissures, xerosis.d Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail

disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia.

e Includes pruritus, pruritus generalized, eyelid pruritus.f Includes fatigue, asthenia.

Table 3. Common Laboratory Abnormalities (>20% for all NCI CTCAE Grades) in AURA3

Laboratory Abnormality

TAGRISSO(N=279)

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)

(N=131a)Change from

BaselineAll Grades

(%)

Change from Baseline to

Grade 3 or Grade 4 (%)

Change from Baseline

All Grades(%)

Change from Baseline to Grade 3 or

Grade 4(%)

Leukopenia 61 1.1 75 5.3Lymphopenia 63 8.2 61 9.9Thrombocytopenia 46 0.7 48 7.4Neutropenia 27 2.2 49 12

a Based on the number of patients with available follow-up laboratory dataAURA Extension and AURA2 TrialsThe safety of TAGRISSO was evaluated in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). A total of 411 patients with EGFR 790M mutation-positive NSLC who received one or more prior EGFR therapies including an EGFR TKI were treated with TAGRISSO (80 mg daily). The majority of patients were heavily pretreated. Prior to enrollment, 68% of patients had received at least 2 prior treatment regimens, 46% had received 3 or more prior lines of therapy, and 63% had received prior platinum-based chemotherapy.Median duration of exposure to TAGRISSO was 7.7 months (range: <0.1 to 11.6 months). The toxicity profile of TAGRISSO observed in the AURA Extension and AURA2 trials was generally consistent with the toxicity profile observed in the AURA3 trial. Four patients (1%) treated with TAGRISSO developed fatal adverse reactions of ILD/pneumonitis. Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with TAGRISSO. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis.DRUG INTERACTIONSEffect of Other Drugs on OsimertinibStrong CYP3A InducersCoadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Decreased osimertinib exposure may lead to reduced efficacy.Avoid coadministering TAGRISSO with strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) [note: effect of St. John’s Wort varies widely and is preparation-dependent]. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.4) in full Prescribing Information]. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.

Effect of Osimertinib on Other DrugsCoadministering TAGRISSO with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Increased BCRP substrate exposure may increase the risk of exposure-related toxicity.Monitor for adverse reactions of the BCRP substrate (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO.USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryBased on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataWhen administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1-times the AUC observed in patients at the recommended dose of 80 mg), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.LactationRisk SummaryThere are no data on the presence of osimertinib in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1) in full Prescribing Information]. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise a lactating woman not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.Females and Males of Reproductive PotentialContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1) in full Prescribing Information].MalesAdvise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1) in full Prescribing Information].InfertilityBased on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible [see Nonclinical Toxicology (13.1) in full Prescribing Information].Pediatric UseThe safety and effectiveness of TAGRISSO in pediatric patients have not been established.Geriatric UseThree hundred and forty-six (42%) of the 833 patients in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (9.8% versus 6.8%) and more frequent dose modifications for adverse reactions (10.1% versus 6.0%) in patients 65 years or older as compared to those younger than 65 years.Renal ImpairmentNo dose adjustment is recommended in patients with mild, [creatinine clearance (CLcr) 60-89 mL/min, as estimated by the Cockcroft Gault method (C-G)] moderate, (CLcr 30-59 mL/min, as estimated by C-G) or severe (CLcr 15-29 mL/min) renal impairment. There is no recommended dose of TAGRISSO for patients with end-stage renal disease [see Clinical Pharmacology (12.3) in full Prescribing Information].Hepatic ImpairmentNo dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST] or moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850TAGRISSO is a registered trademark of the AstraZeneca group of companies.©AstraZeneca 2017Iss. 03/17 3338004 4/17

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NE WS T RENDS A N A LYSIS

Lung cancer in America

158,080Is the approximate number of

Americans who died from lung cancer in 2016.

27 percentIs the proportion of all cancer deaths

attributed to lung cancer in the U.S. in 2016.

51.7Per 100,000 is the age-adjusted

death rate from lung cancer for American men.

34.7Per 100,000 is the age-adjusted

death rate from lung cancer for American women.

415,000Is the approximate number of

Americans living today who have been diagnosed with lung cancer at some

point in their life.

83 percentIs the proportion of Americans living with lung cancer who are age 60 or

older (2013 fi gures).

17.7 percentIs the fi ve-year survival rate for

lung cancer overall.

55 percent Is the fi ve-year survival rate for

lung cancer that is diagnosed whenit is still localized.

>50%Is the proportion of lung cancer

patients who die within one year of diagnosis.

~80%Is the proportion of small cell and

non-small cell lung cancer in women in which smoking is a contributing factor.

~90%Is the proportion of small cell and

non-small cell lung cancer in men in which smoking is a contributing factor.

• Source: American Lung Association “Lung Cancer Fact Sheet.” http://www.lung.org/lung-health-and-diseases/lung-disease-lookup/lung-cancer/resource-library/lung-cancer-fact-sheet.html

Zika Virus

Researchers identify potential ZIKV target. New research provides insights

into why infection with ZIKV after birth

generally causes only mild symptoms,

whereas devastating fetal malformations

can develop when infection occurs dur-

ing pregnancy.

Healthy people are protected by antivi-

ral factors of the innate immune system.

Investigators have now shown that re-

ducing levels of one antiviral factor called

interferon-induced transmembrane pro-

tein 3 (IFITM3) makes cultured cells high-

ly sensitive to ZIKV infection.

The research team found that IFITM3

normally stops multiplication of the virus

in human cells at an early step, prevent-

ing the infected cells from “implosive”

cell death. Therefore, drugs that block this

cell death pathway might be helpful for

preventing the effects of ZIKV infection

during pregnancy.

“We describe a striking succession

of events that may lead to the death of

cells infected with Zika virus. Hopefully,

the cells are equipped with antiviral gate-

keepers that allow the host to control the

infection,” says Dr. Olivier Schwartz of In-

stitut Pasteur, senior author of The EMBO

Journal study.

A speedy, sensitive, and low-cost detec-tion test for ZIKV. A fast, highly sensitive,

and inexpensive new test not only detects

ZIKV in mosquitoes and human bodily

fl uids, but can also distinguish between

African and Asian strains. That could im-

prove efforts to more effectively track the

virus’s spread.

Colorado State University researcher

Nunya Chotiwan and colleagues de-

vised an assay to directly detect ZIKV

from mosquitoes and several different

types of unprocessed clinical samples

(including human blood, saliva, and se-

men). They amplifi ed ZIKV genomes us-

ing a molecular technique called loop-

mediated isothermal amplifi cation

(LAMP), an approach that proved compa-

rably sensitive to the current gold-stan-

dard detection method, qRT-PCR. Unlike

qRT-PCR, however, LAMP does not re-

quire costly reagents. Importantly, LAMP

did not yield false-positives for closely-

related pathogens such as dengue virus

and chikungunya virus.

The researchers validated the LAMP

test using virus artifi cially spiked into ma-

terials obtained from healthy individuals,

and also in clinical specimens collected

from confi rmed cases of ZIKV infection.

LAMP was also suffi ciently sensitive to

identify one single infected mosquito

from a collection pool of 50 uninfected in-

sects. The authors say that LAMP’s mini-

mal processing requirements and accel-

erated turnaround time will be valuable

for ZIKV surveillance and control.

New Studies

Displaying EHR lab test costs doesn’t deter doctors from ordering them. Patients are stuck for a blood draw

almost every day they are admitted to a

hospital. Lab tests are one of the most

common orders placed by doctors, but

research indicates that nearly one-third of

those tests are not needed.

Hospitals nationwide are seek-

ing ways to use price transparency—

displaying the price of lab tests at the

time when doctors are placing the

order—to nudge doctors to consider

whether the benefi ts are worth the cost.

Results of a new study, however, show

that simply displaying the Medicare al-

lowable fees did not have an overall im-

pact on how clinicians ordered the tests.

In the new study, researchers randomly

assigned 60 groups of inpatient lab tests

to either display Medicare allowable fees

in the patient’s EHR (intervention arm), or

not (control arm). The randomized clini-

cal trial was conducted at three hospitals

within the University of Pennsylvania

Health System over a one-year period

and compared changes in the number

of tests ordered per patient per day, and

associated fees, for more than 98,000 pa-

tients (totaling over 142,000 admissions).

Results of the study showed that in the

year prior to the study, when cost infor-

mation was not displayed, the average

number of tests and associated fees or-

dered per patient per day was 2.31 tests

totaling $27.77 in the control group, and

3.93 tests totaling $37.84 in the interven-

tion group. After the intervention, when

cost information was displayed for the

intervention group, researchers noted

the average number of tests and associ-

ated fees ordered per patient per day did

not change signifi cantly: they were 2.34

tests totaling $27.59 in the control group,

and 4.01 tests totaling $38.85 in the

intervention group.

Though the study found no overall

effect, the authors noted important fi nd-

ings in specifi c patient groups that have

implications for how to improve price

transparency in the future. For exam-

ple, there was a slight decrease in test

ordering for patients admitted to the

ICU—an environment in which doctors

are making rapid decisions and may be

more exposed to the price transparency

intervention. The authors also found that

the most expensive tests were ordered

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11JUNE 2017 M L O - O N L I N E .C O M

NE WS T RENDS A N A LYSIS THE OBSERVATORY

less and the cheaper tests were ordered

more, suggesting that future interven-

tions might be more successful if they

are better designed to framed relative

pricing.

Saliva test predicts prolonged concus-sion symptoms in children. Although

most of the three million concussions

diagnosed in the U.S. each year occur in

children, the bulk of clinical guidelines

are based on adults. Because of this, pe-

diatricians are limited in how accurately

they can advise families about how long

a child may suffer symptoms such as

headaches, fatigue, and trouble concen-

trating that can interfere with school and

other activities.

New research presented at the 2017

Pediatric Academic Societies Meeting

last month, however, suggests a simple

saliva test may yield more answers. In-

vestigators from Penn State College of

Medicine presented an abstract of the

study “Peripheral microRNA patterns

predict prolonged concussion symptoms

in pediatric patients” at the conference.

Micro ribonucleic acids (miRNAs) are

genetic molecules, chiefl y found within

cells, that help regulate protein produc-

tion. Previous studies have found altered

miRNA levels in the saliva of children

with mild concussions. This mirrored

similar miRNA changes in cerebrospinal

fl uid of patients with severe brain injury.

The researchers studied 50 children

between the ages of 7 and 18 years with

mild traumatic brain injury. Spit samples

were collected and tested for miRNA lev-

els. In addition, concussion symptoms

were evaluated through parent and child

Sports Concussion Assessment Tool

(SCAT-3) surveys, a standardized tool

commonly used to evaluate injured chil-

dren for concussion and to guide clini-

cal decision-making. The surveys were

taken within 14 days of injury and again

four weeks post-concussion. The 29 chil-

dren with prolonged concussion symp-

toms had higher scores for headaches,

fatigue, and diffi culties concentrating.

Steven Hicks, MD, PhD, FAAP, lead

study author, says the salivary miRNA

levels were signifi cantly more effective

than evaluations using SCAT-3 survey

in predicting which children would con-

tinue to experience headaches, fatigue,

concentration diffi culties, and other

concussion symptoms that lasted lon-

ger than four weeks. Results showed

the standard survey to be less than 70

percent accurate in identifying children

who would have prolonged concussion

symptoms, he says. In comparison, he

reports, miRNA in saliva correctly pre-

dicted whether concussion symptoms

would remain present for at least a

month nearly 90 percent of the time.

“We believe that saliva-based RNA

testing holds great promise as an ac-

curate and non-invasive method for

evaluating pediatric concussions and

giving patients and families a more solid

prognosis,” Dr. Hicks says.

Cancer

Women should continue cervical can-cer screening as they approach age 65. Cervical cancer is often thought of as

a disease that primarily affects young

women. Because of this, many older

women fail to keep up with appropri-

ate screening as they age. While cur-

rent guidelines indicate that screening

can be stopped for average-risk patients

after age 65, many women lack the ap-

propriate amount of screening history to

accurately assess their risk.

A new study in the American Jour-

nal of Preventive Medicine found that

incidence rates of cervical cancer do not

begin to decline until 85 years of age

among women without a hysterectomy

and that women over 65 who have not

been recently screened may benefi t from

continued surveillance.

“An older woman who has not had her

cervix surgically removed has the same

or even higher risk of developing cervical

cancer compared to a younger woman,”

says lead investigator Mary C. White,

ScD, Chief of the Epidemiology and Ap-

plied Research Branch, Division of Can-

cer Prevention and Control, Centers for

Disease Control and Prevention (CDC).

“Women who have not had a hysterec-

tomy need to continue to be screened

until age 65, and possibly later if they

have not been screened for many years

or are at special risk, consistent with cur-

rent U.S. Preventive Services Task Force

recommendations.”

In 2013, one-fi fth of cervical cancer cas-

es and one-third of cervical cancer deaths

occurred among women 65 years of age

and older. Current recommendations say

that screening can be stopped at age 65

if an adequate testing history indicates

consistently negative results. Three con-

secutive negative cytology results or two

consecutive negative co-test results with-

in the last 10 years, with the most recent

test within the last fi ve years, are consid-

ered suffi cient reason to stop screening

average-risk women after age 65.

Using data from the 2013 and 2015

National Health Interview Survey, investi-

gators looked at the use of screening tests

and rates of cervical cancer for women 65

and older. The data revealed that many

women approaching the “stopping” age

of 65 were not getting suffi cient screen-

ing. Researchers established that the pro-

portion of women not recently screened

increases with age. While only 12 per-

cent of women in their 40s had no recent

screening history, that number progres-

sively increased for women in their 50s

and 60s. Nearly 850,000 women aged 61

to 65 years had not been screened within

the last fi ve years.

Higher prostate cancer risks for black men may warrant new approach to screening. A new study indicates that higher prostate

cancer death rates among black men in

the United States may be due to a higher

risk of developing preclinical prostate can-

cer as well as a higher risk of that cancer

progressing more quickly to advanced

stages. Published early online in CANCER,

the study suggests that screening policies

may need to be tailored to the higher-risk

status of this population.

Among black men in the U.S., the in-

cidence of prostate cancer is 60 percent

higher than that of white men, and their

mortality rate from prostate cancer is

more than twice as high. To understand

why, researchers used three models of

prostate cancer incidence and prostate

specifi c antigen (PSA) screening in the

U.S. to estimate disease onset and pro-

gression based on prostate cancer data

from 1975 to 2000 reported by the Sur-

veillance, Epidemiology, and End Results

program of the National Cancer Institute.

The investigators estimated that 30 per-

cent to 43 percent of black men develop

preclinical prostate cancer by age 85, a risk

that is 28 percent to 56 percent higher than

that among men of any race.

Among men with preclinical disease,

black men have a similar risk of being di-

agnosed (35 percent to 49 percent) com-

pared with the general population (32

percent to 44 percent) in the absence of

screening. Their risk of progression to ad-

vanced disease by the time they’re diag-

nosed is 44 percent to 75 percent higher

than in the general population, however (a

12 to 13 percent risk in black men versus

a seven to nine percent risk in the general

population).

“We found that the interval from getting

preclinical cancer to being diagnosed is

long—10 years or more on average—and

is similar in black and white men. But dur-

ing that interval, cancers in black men tend

to progress faster,” says Ruth Etzioni, PhD,

a senior study author. “What this means

is that in developing screening policies for

black men, it will be important to consider

beginning screening them at an earlier

age and potentially screening them more

frequently than would be recommended

by general population guidelines.”

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To earn CEUs, see test on page 18 or online at

www.mlo-online.com under the CE Tests tab

LEARNING OBJECTIVESUpon completion of this article, the reader will be able to:1. Discuss the statistics on lung cancer in terms of diagnosis

time, prognosis, and therapies.2. Identify the importance of effi cient and timely diagnosis and

treatment of lung cancer.3. List the new types of biomarker tests that are accelerating in

the fi eld of lung cancer diagnostics.4. Discuss the capabilities that the biomarker tests provide and

the information they can give to physicians.

Continuing Education

ONCOLOGY

One devastating aspect of lung cancer is that it can de-velop slowly and remain undetected for years before becoming symptomatic. By the time lung cancers are

discovered and diagnosed, a high proportion (>66 percent) of them have reached an advanced, malignant, and aggres-sively metastatic stage that is not amenable to surgical inter-vention.1 Many patients with newly diagnosed lung cancer face a poor prognosis and a fi ve-year survival rate of approx-imately 16 percent, according to the American Cancer Society (2012), despite the increasing range of systemic and targeted therapies that have become available.

The demand from clinicians and patients for clinically rel-evant real-time biomarkers that guide treatment decisions and prognosticate and monitor for response to therapy and/or disease progression, therefore, is high. The objective of this article is to review the newest developments in the fi eld of biomarker testing for non-small cell lung cancer (NSCLC), and to demonstrate its emerging role as a standard of care in clinical management.

Biomarker testing in diagnosis and treatmentThe mainstays of treatment for advanced NSCLC include generalized therapies (platinum-based or single-agent che-motherapies and radiation), immunotherapies (checkpoint inhibitors), second line without biomarker, Keytruda (check-point inhibitor) in frontline patients with high PD-L1 stain-ing, and targeted tyrosine kinase inhibitor (TKI) drugs, which are directed at specifi c mutations in the epidermal growth-factor receptor (EGFR).2 However, several new developments are shaping changes in the NSCLC treatment landscape. For one, the number and breadth of targeted therapies for NSCLC continue to grow as new drugs are being brought to market. At the same time, it has become well understood that the presence of certain tumor biomarkers is highly pre-dictive of an individual’s response to both generalized and

By Edward H. Kaplan, MD

Rapid biomarker testing for improved clinical decision-making in non-small cell lung cancer

targeted treatments, and this understanding is supported by new diagnostic tools capable of providing actionable infor-mation with which to make critical decisions about clinical management.

The profi les now provided by some commercially avail-able biomarker tests can give physicians the opportunity to improve patient quality of life by reducing ineffective treat-ment. Such information can be used to customize the treat-ment plan, helping to avoid wasting precious time, causing debilitating therapeutic side effects, and dedicating fi nan-cial resources to therapies that are not likely to work. Ad-ditionally, this information may suggest a benefi t in pursu-ing subsequent broad molecular profi ling which can identify rare mutations that might present options for therapeutic alternatives or clinical trials. Biomarker testing may help en-able physicians to provide their patients with an objective, realistic assessment of prognosis and life expectancy to fa-cilitate planning together for appropriate palliative care and end-of-life decisions.3,4

Basic research efforts into gene-expression profi ling and genome-wide association studies continue to uncover poten-tial correlations between the presence of genetic mutations and the aggressiveness of NSCLC and other cancers. A hand-ful of these genetic aberrations—including point mutations, deletions, and fusions—have been proven to have direct predictive value with respect to treatment effi cacy and prog-nosis in NSCLC. These so-called “driver” mutations some-times perform a direct, mechanistic role in driving malignant transformation and cancer progression, and are often targets for current drug therapies. Some of these mutations include:• EGFR sensitizing mutations (del19; (E746-A750); L858R): Muta-tions in the EGFR gene that render NSCLC cells sensitive to fi rst- and second-generation EGFR-TKIs. Patients may benefi t from treatment with afatinib, erlotinib, or gefi tinib.• EGFR resistance-conferring mutations (T790M): A second-site mutation associated with acquired resistance to gefi tinib and erlotinib. Patients with this mutation may benefi t from treatment with third-generation EGFR-TKIs osimertinib.• ALK fusion variants (EML4 (E6:A20, E13-A20, E20-A20)): A translocation mutation that results in overexpression of the ALK kinase gene, resulting in dysregulation of critical down-stream signaling pathways. Patients may benefi t from treatment with crizotinib, ceritinib, or alectinib, depending on previous therapies.• ROS1 fusion variants CD74 (C6:R34, C6:R32); SDC4 (S2:R32, S2:R34); SLC34A2 (S13del2046:R32, S13del2046:R34); EZR (E10:R34); TPM3 (T8:R35): Another genetic translocation that re-sults in aberrant receptor tyrosine kinase activity. Patients may benefi t from treatment with crizotinib.• RET fusion variants KIF5B (K15:R12, K16:R12, K22:R12, K23:R12, K24:R11, K24:R8); CCDC6 (C1:R12); TRIM33 (T14:R12): Patients with mutations in this oncogene may benefi t from treatment with cabozantinib or vandetinib.

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ONCOLOGY CE

• KRAS mutations (G12C, G12D, G12V): Mutations in this critical oncogene lead to constitutive activation of intracellular signaling cascades that normally regulate cell growth and differentiation. Prognosis is generally poorer in patients with these mutations.

• BRAF mutant V600E: Mutations in this serine/threonine-protein kinase adversely affect cell division and differentia-tion. Patients may benefi t from vemurafenib, dabrafenib, or dabrafenib+trametinib.

Genetic and/or genomic testing panels that include these mutations (Table 1, pg. 14) are those that are most likely to provide actionable information to guide treatment strategies.

Turnaround time in biomarker testingThe clinical course of newly diagnosed, advanced NSCLC can be rapid, with prognoses typically measured in months. Early intervention with appropriately targeted therapies can increase the overall chance of survival, and therefore speed is critical when obtaining biomarker information that might infl uence the design and initiation of a therapeutic strategy. However, the results from tumor biopsies generally take three weeks or more, and inadequate sampling at the initial biopsy can lead to even longer wait times. According to a recent study, nearly 80 percent of patients diagnosed with NSCLC did not receive the results of biomarker testing in time for the initial consultation with their oncologist, and the median time to receive those results was 21 days after the initial consultation.5 When biomarker profi les were available at the initial consultation, patients experienced markedly shorter median times from consultation to decision (0 vs. 22

days, p = 0.0008), and to initiation of treatment (16 vs. 29 days, p = 0.004), compared to patients whose biomarker data were not yet available.

Timely availability of biomarker profi les is likely to im-prove due to the recent advent of so-called liquid biopsy for use in NSCLC biomarker testing.6 Liquid biopsy exploits the presence, in blood or other body fl uids, of intact circulat-ing tumor cells (CTCs) or cell-free, circulating tumor DNA (ctDNA) that is shed when tumor cells undergo apoptosis or necrosis. These cells and nucleic acids represent a read-ily available, easily accessible, and virtually limitless source of analytical material compared to tissue biopsy. In the last fi ve years or so, the testing platforms that have been devel-oped to analyze them have improved in sensitivity, speed, and cost to the point where they can achieve results much faster than techniques that begin with tissue as a starting ma-terial. With this technology, blood samples can be acquired on the same day as a tissue biopsy to yield rapid biomarker genotyping results.

Liquid biopsy is unlikely to replace the need for tissue bi-opsy in the near-term because information from tissue his-tology remains essential to diagnosing and subtyping the cancer.7 Liquid biopsy technologies are also limited in their ability to detect small, early-stage tumors that are not ac-tively shedding material. However, due to its rapid time to results, biomarker testing of liquid biopsies represents such a powerful companion technique that the Cleveland Clinic included in its list of top ten medical innovations projected to impact patient care in 2017.8

Figure 1. The “refl ex strategy” for NSCLC diagnostics.

continued on page 14



ONCOLOGY

Newer detection platforms Liquid biopsy and other improvements in biomarker testing for NSCLC have been enabled by new diagnostic platforms that are faster and more sensitive than traditional immuno-histochemistry, fl uorescence in situ hybridization (FISH), and traditional rtPCR.

Droplet digital PCR (ddPCR) is a newly developed tech-nique that uses water-oil emulsion droplet technology for highly sensitive, quantitative, reproducible detection of rare target mutations in ctDNA as well as cDNA copied from ctRNA.9–12 With this technique, processed nucleic acids from blood samples are diluted and partitioned into thousands of tiny droplets, each of which acts as an independent PCR amplifi cation chamber. The results of amplifi cation and de-tection yield absolute information regarding the quantity of mutations in the sample, independent of the amplifi cation reference curves required for quantitative rtPCR experi-ments. Biomarker test platforms using ddPCR technology are very fast and highly sensitive (Table 1); median turn-around time for ddPCR testing in advanced stage NSCLC is three days, compared to 12 to 27 days for tissue genotyping assays.6 A recent study assessing performance of a ddPCR-based biomarker-testing platform demonstrated a sensitivity of 88 percent, specifi city of 99 percent, and overall concor-dance with tissue biopsy of 96 percent. Thus, ddPCR is well suited for the sensitive analysis of small, defi ned panels of validated target biomarkers that yield clinically actionable information.

Next-generation sequencing (NGS) is a general term encompassing a variety of high-throughput, highly parallel DNA sequencing technologies that have replaced simple dye terminator sequencing methods.13 NGS enables relatively rapid, massively parallel analysis of large DNA segments or complex samples, including entire genomes. Originally developed to reduce the time and costs of genome sequenc-ing, NGS technologies can analyze broad panels of genes for multiple mutations, all at the same time. In biomarker test-ing, NGS is well suited for liquid biopsy analysis and faster than more traditional methods, and it generally allows for analysis of larger gene panels than can be conducted with ddPCR (Table 1). However, much of the additional informa-tion currently yielded by NGS-based genomic panels is not actionable for NSCLC. Large panels have the potential to confuse clinical decision-making, because many of the genes and mutations are less well characterized, have not yet been validated, and are not yet part of recommended diagnostic guidelines.

Proteomic biomarkers provide complementary informationAnother promising new direction for NSCLC biomarker test-ing is the availability of clinically validated tests that measure a patient’s response to a growing tumor using blood-derived proteomic information. Such tests take advantage of the com-plex biological interactions that occur as tumor cells begin to break free of normal growth control pathways, and the

Table 1. Currently available genetic biomarker testing for NSCLC.

Source Mutations/Fusions PlatformPerformance

Sensitivity Specifi cityTurnaround

TimeMedicare

ReimbursedSource

material

Company 1 *EGFR, *T790M, *ALK, ROS1, RET, *KRAS, BRAF ddPCR 91%1 100%1 72 hours Yes Blood

(ctRNA)

Company 2ALK, hENT1, MET, PD-L1, PTEN, ROS1, TOPO1, TP, TRKpan, TUBB3

NGS, IHC N/A2 N/A2 4-5 days Yes Tissue

Company 3 *EGFR, *T790M, *ALK rtPCR w/NGS

EGFR: 86%3T790M: 64.7%3

ALK: 88%4

EGFR: NAALK: NA

ALK: 100%45 days Yes Blood

Company 4 *EGFR, T790M, ALK, ROS1, RET, KRAS, BRAF, MET, HER2 rtPCR 90%5 100%5 5-7 days Yes Blood

(CTCs)

Company 5 EGFR1, EGFR T790M, ALK1, ROS11, KRAS1, PD-L11 ddPCR N/A2 N/A2 5-9 days Yes Not

specifi ed

Company 6 *EGFR, *T790M, KRAS, BRAF ddPCR w/ NGS

URINE:EGFR Exon 19: 67%6

EGFR L858R: 75%6

T790M: 72%6

BLOOD:EGFR Exon 19: 100%6

EGFR L858R: 87%6T790M: 93%6

URINE:EGFR Exon 19: 94%6EGFR L858R: 100%6

T790M: 96%6

BLOOD:EGFR Exon 19: 96%6EGFR L858R: 100%6

T790M: 94%6

2 weeks Yes Blood or urine

Abbreviations: ddPCR, droplet digital PCR; FISH, fl uorescent in situ hybridization; IHC, immunohistochemistry; NGS, next-generation (high-throughput) DNA sequencing; rtPCR, reverse transcriptase PCR. Refer to text for detailed description of biomarkers.*Clinical validation data available. N/A indicates no validation data was found online.1. Mellert H, et al. J Mol Diagn. 2017 May;19(3):404-416.2. No published data could be located.3. Krug AK, et al. EGFR activating and T790M resistance mutation in plasma exoRNA and cfDNA, detected with single-step isolation columns and targeted resequencing. Presented at: 2015 IASLC 16th World Conference on Lung Cancer, (Denver, Colorado; September 2015).4. Brinkmann K, et al. Exosomal RNA-based liquid biopsy detection of EML4-ALK in plasma from NSCLC patients. Presented at: 2015 IASLC 16th World Conference on Lung Cancer, (Denver, Colorado; September 2015).5. Barrera L, et al. Clinical evaluation of the utility of a liquid biopsy (Circulating tumoral cells and ctDNA) to determine the mutational profi le (EGFR, KRAS, ALK, ROS1 and BRAF) in advanced NSCLC patients. Presented at: ESMO 2016 Congress, (Copenhagen, Denmark; October 2016).6. Reckamp KL. J Thorac Oncol. 2016 Oct;11(10):1690-700.


continued from page 13


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ONCOLOGY

patient’s immune system responds with attempts to regulate and shut down this uncontrolled growth. This biological inter-play between tumor and host releases a variety of acute-phase reactant proteins into the bloodstream. These can be detected and quantifi ed, yielding important insights into the aggressive-ness of the cancer and its susceptibility to available treatments.

So far, there is just one proteomic test that is commercially available for NSCLC. This proprietary test uses an advanced form of mass spectrometry, called matrix-assisted laser desorp-tion/ionization-time of fl ight (MALDI-ToF), to detect and mea-sure the chronic expression proteins associated with patient responses to aggressive cancer.14 The information yielded by this test can identify which patients are likely to benefi t from fi rst-line, standard-of-care platinum doublet therapy, and it is also predictive of therapeutic benefi t from EGFR-TKIs.15,16 The results of the test have also been shown to be highly predictive of overall prognosis.14-16

Putting it all together: the refl ex strategy Tissue histology, genetic/genomic tests, and proteomic tests yield complementary information. Combining their results us-ing what is termed a “refl ex strategy” can be a powerful tool to help guide clinical management (Figure 1, pg. 13).

For example, a patient presenting with newly diagnosed NSCLC can undergo tissue and blood biopsy on the same day. Tissue histology confi rms the diagnosis and aids in sub-typing the disease. Meanwhile, in as few as 72 hours

after the blood draw, rapid genetic profi ling from the liquid biopsy provides information regarding sensitizing EGFR mutations, as well as the presence of EML4-ALK, ROS1, or RET positive results, which indicate candidates for specifi c EGFR-TKIs and other targeted therapies.

For patients treated with EGFR-TKI therapy whose disease subsequently progresses, genetic profi le testing can be per-formed again, without need for additional tissue biopsy, to detect EGFR mutations that confer resistance to EGFR-TKI, and to predict whether or not the tumor may be susceptible to third-generation EGFR-TKI inhibitors.

Patients whose initial genetic profi le indicates the presence of wild-type EGFR, or whose EGFR status is unknown,15,16 can be refl exed to proteomic profi ling to determine how aggressively their tumor is growing. A predicted prognosis of “good” indi-cates that a patient’s tumor is likely to respond to platinum-based therapy, single-agent chemotherapy, or EGFR-TKI-based therapies. A “poor” prognosis identifi es aggressive cancer that is unlikely to respond to EGFR-TKI therapies and may also not respond to standard of care.

Availability of this information has been shown to change pa-tient and physician decisions about treatment and supportive care in positive ways. They can preserve valuable time by shift-ing their focus from ineffective therapies to investigating broad genetic profi ling, clinical trial options, or alternative treatments, thereby avoiding overtreatment that negatively impacts quality of life in terminally ill patients.



ONCOLOGY CE

Edward H. Kaplan, MD, is a medical

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In conclusion, the adoption curve for biomarker testing for NSCLC is accelerating, driven by rapid improvements in analytical technologies, drug development, and evidence-based translational research. For clinicians, understanding the relevance and utility of the current state of biomarker testing is essential for optimizing outcomes and provid-ing quality patient care. Laboratorians play a vital role in performing such testing and disseminating its results to oncologists.

REFERENCES

1. Hurria A, Kris MG. Management of lung cancer in older adults. CA Cancer J Clin. 2003;53(6):325-341.

2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): non-small cell lung cancer. NCCN website. https://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Published 2017.

3. Enzinger AC, Zhang B, Schrag D, Prigerson HG. Outcomes of prognostic disclosure: associations with prognostic understanding, distress, and relationship with physician among patients with advanced cancer. J Clin Oncol. 2015;33(32):3809-3816.

4. Epstein AS, Prigerson HG, O’Reilly EM, Maciejewski PK. Discussions of life expec-tancy and changes in illness understanding in patients with advanced cancer. J Clin Oncol. 2016;34(20):2398-2403.

5. Lim C, Tsao MS, Le LW, et al. Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol. 2015;26(7):1415-1421.

6. Bowling M, Mattingley J, Bhadra K, Pritchett M, Skibo S, Walker PR. PS01.16: Short-ening time from diagnosis to treatment in NSCLC: are blood-based biopsies the answer? Topic: Pulmonology. J Thorac Oncol. 2016;11(11S):S278-S279.

7. Mino-Kenudson M. Cons: Can liquid biopsy replace tissue biopsy?—the US experi-ence. Transl Lung Cancer Res. 2016;5(4):424-427.

8. Cleveland Clinic Newsroom. Cleveland Clinic unveils top 10 medical innovations most likely to be game changers. https://newsroom.clevelandclinic.org/2016/10/26/cleveland-clinic-unveils-top-10-medical-innovations-likley-game-changers/. Published 2016.

9. Beck J, Bierau S, Balzer S et al. Digital droplet PCR for rapid quantifi cation of donor DNA in the circulation of transplant recipients as a potential universal biomarker of graft injury. Clin Chem. 2013;59(12):1732-1741.

10. Watanabe M, Kawaguchi T, Isa S, et al. Ultra-sensitive detection of the pretreat-ment egfr t790m mutation in non-small cell lung cancer patients with an egfr-activating mutation using droplet digital PCR. Clin Cancer Res. 2015;21(15):3552-3560.

11. Whale AS, Devonshire AS, Karlin-Neumann G, et al. International interlaboratory digital pcr study demonstrating high reproducibility for the measurement of a rare se-quence variant. Anal Chem. 2017;89(3):1724-1733.

12. Zhang BO, Xu CW, Shao Y, et al. Comparison of droplet digital PCR and conventional quantitative PCR for measuring EGFR gene mutation. Exp Ther Med. 2015;9(4):1383-1388.

13. Metzker ML. Sequencing technologies—the next generation. Nat Rev Genet. 2010;11(1):31-46.

14. Taguchi F, Solomon B, Gregorc V, et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst. 2007;99(11):838-846.

15. Gregorc V, Novello S, Lazzari C, et al. Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or che-motherapy (PROSE): a biomarker-stratifi ed, randomised phase 3 trial. Lancet Oncol. 2014;15(7):713-721.

16. Carbone DP, Ding K, Roder H, et al. Prognostic and predictive role of the VeriStrat plasma test in patients with advanced non-small-cell lung cancer treated with erlotinib or placebo in the NCIC Clinical Trials Group BR.21 trial. J Thorac Oncol. 2012;7(11):1653-1660.



MLO and Northern Illinois University (NIU), DeKalb, IL, are co-sponsors in offering continuing education units (CEUs) for this issue’s CE article. CEUs or contact hours are granted by the College of Health and Human Sciences at Northern Illinois University, which has been approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E.® program. Approval as a provider of continuing education programs has been granted by the state of Florida (Provider No. JP0000496). Continuing education credits awarded for successful completion of this test are acceptable for the ASCP Board of Registry Continuing Competence Recognition Program. Readers who pass the test successfully (scoring 70% or higher) will receive a certifi cate for 1 contact hour of P.A.C.E.® credit. Participants should allow three to fi ve weeks for receipt of certifi cate. The fee for this continuing education test is $20. This test was prepared by Amanda Voelker, MPH, MT(ASCP), MLS, Clinical Education Coordinator, School of HealthStudies, Northern Illinois University, DeKalb, IL.

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RAPID BIOMARKER TESTING FOR IMPROVED CLINICAL DECISION-MAKING IN NON-SMALL CELL LUNG CANCER

June 2017 [This form may be photocopied. It is no longer valid for CEUs after December 31, 2018.)

1. What proportion of lung cancers have reached a metastatic stage by the time they are discovered and diagnosed?

a. >66 percent b. >76 percent c. >86 percent d. >96 percent

2. According to the American Cancer Society (2012), the fi ve-year survival rate of lung cancer patients is

a. 5 percent. b. 16 percent. c. 48 percent. d. 66 percent.

3. Traditional therapies for the treatment of advanced non-small cell lung cancer (NSCLC) include generalized therapies, immunotherapies, second line without biomarker, Keytruda, and targeted tyrosine inhibitor drugs.

a. True b. False

4. New biomarker tests are showing promise in treating NSCLC because the presence of the biomarker is predictive of the patient’s response to

a. generalized treatments. b. targeted treatments. c. both a and b. d. neither a nor b.

5. Profi les of biomarker tests can be used by physicians to customize a treatment plan, which helps to

a. avoid wasted treatment time. b. avoid causing debilitating side effects. c. avoid the spending of fi nancial

resources on therapies that aren’t likely to work. d. all of the above

6. The gene mutations noted in the article that have been found to have a direct role in treatment effi cacy and prognosis in NSCLC are

a. EGFR, ALK, ROS1, RET, KRAS, and BRAF. b. EGFR, ALK, and BRAF. c. ASK, ROS1, KRAS, and BRAF. d. ALK, ROS1, RET, KRAS, and BRAF.

7. Obtaining timely results in biomarker and biopsy information is crucial to the overall chance of survival.

a. True b. False

8. Typical results from tumor biopsies generally take

a. 1 week or more. b. 3 weeks or more. c. 4 weeks or more. d. 8 weeks or more.

9. According to the article, a recent study showed that the percentage of patients who did not have biomarker results by the time of their initial consultation was

a. 55 percent. b. 70 percent. c. 80 percent. d. 95 percent.

10. This type of biopsy exploits the presence of cells or DNA in blood or other body fl uids that can be measured in a testing system.

a. tissue b. droplet c. liquid d. none of the above

11. Liquid biopsy shows promise to replace the need for tissue biopsy because it can also subtype the cancer.

a. True b. False

12. Which type of technology uses a water-oil emulsion that is very fast and highly sensitive?

a. ddPCR b. rtPCR c. FISH d. MALDI-ToF

13. The median turnaround time for ddPCR technology in advanced stage NSCLC is

a. 1 day. b. 3 days. c. 5 days. d. 7 days.

14. This type of technology has the capability to analyze broad panels of genes for multiple mutations.

a. PCT b. PCR c. NFS d. NGS

15. Proteomic tests measure the chronic infl ammatory proteins associated with patient responses to aggressive cancer and are highly predictive of overall prognosis.

a. True b. False

16. The one proteomic test that is commercially available for NSCLC uses which type of methodology?

a. rtPCR b. ddPCR c. MALDI-ToF d. NGS

17. The term “refl ex strategy” refers to a powerful tool that helps guide clinical management of NSCLC and uses which combination of tests?

a. tissue histology and proteomic tests b. tissue histology and genetic/genomic

tests c. proteomic tests and genetic/genomic

tests d. tissue histology, proteomic tests, and

genetic/genomic tests

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With flexible sample requirement, clinically proven broad and sensitive mutation coverage, and speed to result, the cobas® EGFR Mutation Test v2 removes barriers to testing and gives physicians the information needed to make confident treatment decisions for their critically ill patients.

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SPECIAL FEATURE

Clinical labs streamline GI testing with MDxBy Sherry Dunbar, PhD

The standard approach for determin-ing the cause of diarrheal disease in a patient is tedious and time-consum-

ing. The series of tests required for each case—representing a range of different assay types, each of which can take days to generate results—doesn’t serve the best interests of patients, physicians, or clinical labs, largely because they do not generate results quickly. The traditional approach was shaped by decades of adding tests for different bacteria, parasites, or other causes as the community’s understanding of these diseases expanded.

Surely if we could invent a new pro-tocol from scratch, knowing everything we now know about these diseases and their causes, it would look nothing like the piecemeal, step-by-laborious-step ap-proach currently used in labs. Today, with the rise of outcomes-based medicine, we have a rare opportunity to do exactly that: rethink how we manage testing for diar-rheal diseases. Any effort to rein in costs while improving patient care must in-volve generating answers more promptly, subjecting patients to fewer tests, and ac-celerating decisions about treatment.

Molecular testing offers the stream-lined process that could meet all of those requirements. There are several options available now, from panel tests that cover the vast majority of infectious causes of diarrheal diseases to “pick-and-choose” assays that allow physicians and lab ex-perts to select the most likely agents. These diagnostics produce results rapidly, with higher accuracy and less hands-on time than conventional tests. They are cost-effective and, most importantly, they get actionable information into the hands of physicians so patients can be treated (or deliberately not treated) sooner.

Diagnostic complexityDiarrheal disease occurs frequently and has a remarkably high burden, leading to approximately 760,000 deaths in children under the age of fi ve each year world-wide.1 Globally, there are an estimated 1.7 billion cases annually.

What makes these illnesses so diffi cult to diagnose is the vast array of poten-tial causes and the tremendous overlap in symptoms. Diarrheal disease can be brought on by viruses, bacteria, and para-sites, often through foodborne illness or unsanitary water. But there are also many non-infectious causes of diarrheal disease, such as medications, food allergies, and infl ammatory bowel disease. Physicians trying to determine the cause of a pa-tient’s diarrhea must become detectives, hunting for clues to help track down the culprit.

The process begins with a complicated fl ow chart, which recommends certain tests based on symptoms, travel history, duration of illness, and other pertinent factors. Those tests are run in various clin-ical labs; microbiology, virology, and mo-lecular testing facilities are each respon-sible for certain assays. Tests that involve culturing are particularly time-intensive, requiring many different steps and a sig-nifi cant amount of hands-on time. Para-site tests require daily stool collection for three days followed by microscopy, which suffers low sensitivity because it is easy to miss the parasite by choosing the wrong bit of sample to examine.

Usually, these tests are run one at a time; with each negative result, the phy-sician chooses another potential cause to test. Defi nitive results can take a week or more to generate, during which time the patient is likely either going without

needed treatment or being given treat-ment that is not relevant to his or her specifi c condition.

Molecular testingIn recent years, new molecular tests have become available for various causes of di-arrheal disease.2,3 These assays cover po-tentially responsible infectious agents—viral, bacterial, and parasitic—with some methods including more than 90 percent of potential culprits in a single panel. Other types of molecular tests allow us-ers to select the most likely causes and test only for them, but if subsequent rounds of testing are needed, the existing sample can be used; it is not necessary to return to the patient to start the process all over again. Labs that have adopted molecular testing for diarrheal disease can eliminate the vast majority of culturing, enabling their staff to run tests for more patients in less time.

Some payers have expressed concern that panel-based molecular approaches constitute unnecessary testing because they assay for such a broad range of pos-sible causes. The reality is that these tests dramatically improve patient care while reducing the time and costs associated with multiple rounds of conventional test-ing. Unlike the standard techniques, they produce useful diagnostic results for the vast majority of cases. For most patients, these tests replace a tedious, frustrating process with a “one and done” approach, in many cases getting them on the road to recovery faster. Molecular tests can simplify the diagnostic path for patients, physicians, and clinical labs teams alike.

Numerous studies of molecular tests for diarrheal disease have been conducted in patient populations around the world.

GAS T ROEN T EROLOGY

This illustration depicts a three-dimensional (3D) computer-generated image of a cluster of drug-resistant, curly-cue shaped Campylobacter sp. bacteria. The artistic recreation was based upon scanning electron microscopic (SEM) imagery.

MLO201706_SpecFeature_MECH_AL.indd 20MLO201706_SpecFeature_MECH_AL.indd 20 5/11/2017 4:16:40 PM5/11/2017 4:16:40 PM


Sherry Dunbar, PhD,

serves as Senior

Director of Global

Scientifi c Affairs for

Luminex.

Results from studies in Asia, Africa, the United States, and elsewhere consistently show that these assays are highly accu-rate, in some cases detecting pathogens missed by conventional tests that have long been considered the standard.4-7 They also detect cases of coinfection that would likely go undetected with a serial testing strategy. With such strong clinical utility, molecular testing offers the chance to streamline the diagnostic process for diarrheal disease, potentially reduc-ing the morbidity and mortality burden associated with these illnesses.

Moving forwardAs more clinical labs adopt molecular assays as the primary test for cases of di-arrheal disease, we can expect defi nitive diagnoses for more patients, as well as shorter hospital stays. A signifi cant reduc-tion in the use of laborious conventional tests will also ease the burden on clini-cal labs, making it possible to generate answers for more patients in less time.

REFERENCES

1. Diarrhoeal Disease, Fact sheet N°330. World Health Organization. http://www.who.int/mediacentre/fact-sheets/fs330/en. 2. Dunbar S. Molecular revolution entering GI diagnos-tic testing. MLO. 2013;45(8):28.https://www.mlo-online.com/molecular-revolution-entering-gi-diagnostic-test-ing.php.3. Binnicker MJ. Multiplex molecular panels for di-agnosis of gastrointestinal infection: performance, result interpretation, and cost-effectiveness. J Clin Mi-crobiol. 2015;53(12):3723-3728. http://jcm.asm.org/con-tent/53/12/3723.long.4. Deng J, Luo X, et al. A comparison of Luminex xTAG® Gastrointestinal Pathogen Panel (xTAG GPP) and routine tests for the detection of enteropathogens cir-culating in Southern China. Diagn Microbiol Infect Dis. 2015;83(3):325-330. http://www.dmidjournal.com/article/S0732-8893(15)00288-6/abstract.5. Duong VT, Phat VV, Tuyen HT, et al. Evaluation of Lu-minex xTAG Gastrointestinal Pathogen Panel Assay for detection of multiple diarrheal pathogens in fecal sam-ples in Vietnam. J Clin Microbiol. 2016;54(4):1094-1100. http://jcm.asm.org/content/54/4/1094.full.6. Gu Z, Zhu H, Rodriguez A, et al. Comparative evalua-tion of broad-panel PCR assays for the detection of gas-trointestinal pathogens in pediatric oncology patients. J Mol Diagn. 2015;17(6):715-721. http://jmd.amjpathol.org/article/S1525-1578(15)00146-4/abstract.7. Albert MJ, Rotimi VO, Iqbal J, Chehadeh W. Evalua-tion of the xTAG Gastrointestinal Pathogen Panel Assay for the detection of enteric pathogens in Kuwait. Med Princ Pract. 2016;25:472-476. https://www.karger.com/Article/FullText/447698.

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EDUCATION M ASS SPEC T ROME T RY

Mary Valdez, MS, MT, serves as product manager of ID/

AST Systems at bioMerieux. Inc. She joined the company

in early 2016 after spending 16 years as a Section

Coordinator in the Microbiology Lab at Integrated

Regional Laboratories in Fort Lauderdale, FL.

How MALDI-TOF MS has changed the microbiology labBy Mary Valdez, MS, MT

Four years ago in this space, my colleague Anne Beall wrote about the introduction of mass spectrometry into the mi-crobiology laboratory.1 Her column was forward-looking,

because it came just two months after the U.S. Food and Drug Administration (FDA) granted 510(k) de novo clearance to the fi rst matrix-assisted laser desorption ionization time of fl ight (MALDI-TOF) mass spectrometer for clinical use in the identifi cation of disease-causing bacteria and yeast.2

There was a great deal of enthusiasm about this approval because it was the fi rst fundamentally new technology intro-duced to clinical microbiology labs in many years. The Cleve-land Clinic named MALDI-TOF MS as one of the “Top Ten Breakthrough Medical Technologies of 2013.3

At the time of the FDA clearance of this technology, I was working for a large, full-service provider for clinical labora-tory and anatomic pathology services in southern Florida. We served as the core lab for 13 hospitals, providing all routine microbiology testing for them as well as specialty testing for hospitals throughout Florida.

Our lab director was quick to acquire MALDI-TOF MS be-cause we were eager to adopt technology that would reduce the turnaround-time of our results. We immediately realized several key benefi ts from MALDI-TOF MS. While mass spec-based methods for pathogen identifi cation still require culture, MALDI-TOF can effectively identify a pathogen from signifi -cantly less culture growth compared to standard biochemi-cal methods, which require clearly developed and well dis-tinguished colony development.4 MALDI-TOF MS can often make an accurate identifi cation based on the fi rst signs of growth.

This is vitally important and a key benefi t of MALDI-TOF that leads to multiple other advantages. Most bacterial organ-isms begin to grow at 18 to 24 hours, but it can be another day, if not 48 hours or more, before suffi cient isolated growth is seen to perform biochemical identifi cation. Because of this, we imme-diately cut our identifi cation times by six hours to several days. At the fi rst signs of culture growth, we would run the isolate on MALDI-TOF MS, and we had a positive identifi cation within minutes.

The benefi ts of rapid infection identifi cation are well docu-mented. When clinicians can intervene quickly with optimal antimicrobial therapy, patients recover faster and have reduced length of hospital stay, and hospitals can save dramatically on pharmacy expenditures. Our clinicians noticed this almost immediately after adopting MALDI-TOF MS.

Of course, positive identifi cation is just one part of the puz-zle. Rapid identifi cation also provides very useful information regarding pathogens with intrinsic resistance.

Anaerobic organisms provide an excellent example of this benefi t. Anaerobes are high-maintenance pathogens that re-quire a much more manual and time-intensive process to get a positive identifi cation. They must be protected from oxy-gen exposure and typically need at least 48 hours of oxygen-free incubation to see visible growth. However, because of poor methodology during specimen collection, transporta-tion, and preparation for anaerobic culture, delayed iden-tifi cation of anaerobes and the need for a second sample

collection and repeated culture are not uncommon. The delays prolong proper treatment and can contribute to the deterioration of a patient’s condition.

One example is Bacteroides, an anaerobic gram-negative bacilli. Bacteroides species are a common cause of infections that can develop in all body sites including the central nervous sys-tem, head, neck, and abdomen, as well as skin and soft tissue infections. They are often diffi cult to isolate and identify, and treatment is complicated by the slow growth of the organism and the increasing resistance to antimicrobial agents.

One member of the Bacteroides family, B. fragilis group, in-cludes several species including B. fragilis, which is the cause of many clinical infections. The bacteria in this group are resistant to penicillins, usually through the production of beta lactamase.

When an organism such as Bacteroides can be rapidly identi-fi ed, this provides physicians with information they can use—along with antibiogram data and patient assessment—to make treatment decisions. We found that for certain organisms, es-pecially anaerobes, we could provide physicians with useable data before the susceptibility results were available.

Of course, having a positive identifi cation is critical to select-ing the right susceptibility test. So by generating results quickly from colony growth, MALDI-TOF MS also helps in speeding the process of antimicrobial susceptibility testing by guiding the laboratorian to choose the correct susceptibility testing to perform.

Another benefi t was that with only two reagents, a pipette tip and a MS slide, MALDI-TOF MS signifi cantly reduces the use of the reagents required and waste generated compared to routine biochemical identifi cation.

For the core lab I worked at, MALDI-TOF MS was an ideal tool that provided many benefi ts, improved our workfl ow, and provided clinicians with faster results. For this reason, a growing number of labs are investing in this technology.

Microbiology is never black and white, but when you can provide positive pathogen identifi cations after only 18 to 24 hours—even if the culture is mixed—the benefi ts to the lab, clinicians and patients are signifi cant.

REFERENCES

1. Beall A, Automated mass spectrometry. MLO. 2013;45(10):50-51. https://www.mlo-online.com/automated-mass-spectrometry.php.2. U.S. Food and Drug Administration. New test system identifi es 193 different yeasts and bacteria known to cause illness. Aug. 21, 2013; www.fda.gov/NewsEvents/News-room/PressAnnouncements/ucm365907.htm.3. MedCity New. Bariatric surgery for diabetes deemed Cleveland Clinic’s top medical innovation for 2013. Oct 31, 2012. http://medcitynews.com/2012/10/cleveland-clinic-deems-bariatric-surgery-for-diabetes-the-top-medical-innovation-for-2013/[Mass spec was #3 of 10.]4. Wunschel DS, Hill EA, McLean JS, et al. Effects of varied pH, growth rate and tem-perature using controlled fermentation and batch culture on matrix assisted laser desorp-tion/ionization whole cell protein fi ngerprints. J Microbiol Methods. 2005;62(3):259-271.

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CLINICAL ISSUES CHEMIS T RY

Emerging strategies for optimizing clinical chemistry performancePerformance partnerships are playing an increasingly important roleBy Jeffrey Hill, MLS(ASCP), MS, LSSBB(ASQ), PPM

In the realm of diagnostics, clinical chemistry has been at the forefront of the technological revolution to create automated environments that enable fast, cost‐effi cient, high‐quality test-

ing. In 1978, the industry was changed with the introduction of an automated system that allowed a number of critical routine chemistry tests to be performed using one consolidated unit.1 This initial system made it possible to complete these tests, com-monly ordered as a STAT, in less than one minute using a sin-gle small sample. This technology became a foundation for the future of automated chemistry testing.

While great strides have been made in chemistry testing tech-nology, today’s clinical laboratories continue to face emerging complexities, owing largely to industry growth, an ever‐chang-ing healthcare landscape, and network consolidations. Effective and advancing rapidly, innovation has succeeded in bringing sig-nifi cant relief to over‐burdened laboratories carrying the weight of increasing test volumes, stricter cost controls, labor shortages, and multifaceted network operations. In the fast‐paced labora-tory environment, however, the benefi ts of technology are not always fully realized. For this reason, many laboratory profes-sionals are looking beyond technology for solutions that will help them achieve their effi ciency, cost, and care goals.

Industry advancements have enabled most manufacturers to produce high‐quality products with Six‐Sigma assay perfor-mance. But the availability of these products may be only part of the equation. For laboratories seeking to improve turnaround times (TATs), lower cost of ownership, and address the need for standardization throughout the organization, the other part of the equation may be to optimize available technology by building robust business systems.

Performance partnerships as a total solutionSince the 1980s, industrial companies, faced with the competi-tive pressures of globalization, have embraced Lean principles, Six Sigma techniques, and continuous process improvement practices to create business systems that offer a sustained com-petitive advantage.2 Many laboratories have sought similar so-lutions that would help them achieve performance goals unat-tainable via technology alone. This has led corporations with successful business systems to partner with their lab customers to help them apply proven continuous improvement method-ologies to healthcare. These partnerships are strategic alliances formed for the purpose of elevating a laboratory’s ability to meet increasing industry demands and achieve care and ef-fi ciency goals. An established performance partner addresses laboratory operations beyond chemistry instrumentation, con-sidering the strategic use of those instruments, workfl ow, re-source management, and the day‐to‐day execution of tasks by personnel.

Improving TATs One of the roles of a strategic partner is to help laboratories optimize operations to improve TATs. This involves design-ing a laboratory with Lean concepts, measuring performance, and using problem‐solving techniques that drive continu-ous improvement. Many times, lab leaders discover that the lab was not designed in a truly strategic manner. Instead,

instrumentation has been acquired somewhat haphazardly, in response to specifi c needs at specifi c times. This as‐needed ap-proach to purchasing instruments can create redundancies in equipment and wasteful workfl ow. It also puts a strain on al-ready‐stretched resources, as each system has its own training protocol, reagent requirements, maintenance schedule, trouble-shooting steps, and service contract.

An instrument vendor that understands Lean processes can help identify waste in a laboratory process and can recommend changes that will provide both quality testing and operational effi ciency. Process mapping is one tool that enables a laboratory to analyze its entire testing process—from sample collection to results interpretation. This exercise often enlightens laboratory personnel about areas where their current workfl ow is frag-mented and ineffi cient, and enables them to implement process improvements.

Once equipment and workfl ow are optimized, vendors may help laboratories build a culture that supports regular measure-ment of key performance indicators (KPIs) and the use of tools that guide laboratory team members to action. Problem‐solving processes are an important part of continuous process improve-ment. They help teams identify the root causes of problems and then implement meaningful and actionable countermeasures. This step involves full‐team engagement, cross‐functionality, action‐driven response, and the input of a knowledgeable part-ner who can help to problem‐solve areas that need attention.

Lowering cost of ownership Cost containment is presently a major concern in all areas of healthcare, including clinical chemistry. Lowering testing‐re-lated costs involves a clear understanding of a laboratory’s current operational practices around expenditures and rev-enue. Looking merely at costs per test gives only a portion of the profi tability picture. Finding and reducing hidden costs is important to maintaining a laboratory’s economic health.

One area in which hidden costs often lurk is the execution of routine tasks. These include system calibration and qual-ity control functions, both of which are vital for ensuring that equipment performs as intended. Simplifying these activities through automation can promote testing accuracy, reduce workload, and decrease those hidden costs.

Reagent management is also time‐consuming. Storing, re-placing, and thawing reagents slows down the workfl ow by requiring staff time and attention. Selecting concentrated re-agents allows for fewer replacements, saving on both costs and time. Their smaller packages are also more easily stored. Refrigerated storage space is surprisingly expensive, and it is often not considered when evaluating new instrumentation. Thus improving reagent management can contribute greatly to a laboratory’s overall savings.

To lessen system maintenance burden, requiring precious staff-hours, many laboratories choose instruments with simpler designs that require less cleaning and troubleshooting. Reduc-ing consumables is another way to save on overall costs. This includes using permanent glass cuvettes to minimize resources allocated for their replacements, biohazardous waste disposal, and maintenance of plastic cuvettes.


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CLINICAL ISSUES CHEMIS T RY

Jeffrey Hill, MLS(ASCP), MS, LSSBB(ASQ), PPM, has more than 20

years’ experience in laboratory

science within the clinical, research,

and academic spheres. He has served

as a Lean consultant in a variety of

fi elds including clinical/research

laboratory, allied health services,

manufacturing, customer service, and logistics. He has

earned the level of Master Black Belt within the Danaher

Business System and master facilitator in Lean,

Leadership and Growth.

System uptime is vitally important to laboratory perfor-mance. While costs are surely impacted by a lag in uptime, there also are far‐reaching consequences. Emergency rooms and op-erating rooms may become impacted with patients waiting for test results. Physicians may be unable to provide patients with information in a timely manner, which could affect patient care and compromise the doctor-patient relationship. Finding sys-tems and services designed to maximize uptime is crucial when considering costs and performance.

Standardizing operations As it is in many industries, consolidation is a prominent theme in healthcare. Network consolidations often introduce new chal-lenges, however, including duplication of efforts, multiplication of systems, and non‐standardization of processes. Standardizing laboratory operations across a network can improve quality, re-duce costs, and maximize labor resources. Standardizing consum-ables simplifi es inventory management tasks and allows kits to be shared across the network, saving costs, creating process effi -ciencies, and reducing needed storage space. Standardizing work-fl ow means that in all areas of the network, there is consistency in systems and processes. Because of this, laboratory personnel can be cross‐trained to work in multiple areas. That is a factor that may be increasingly important as laboratories are faced with continuing labor shortages.

Beyond laboratory optimization, standardization plays an im-portant role in patient care. With standardized processes, tests are processed the same way across a network. Result ranges are the same, so interpretation of results is consistent, not only for the laboratorians but also for the physicians. This can greatly improve laboratory performance and reduce variables that can cause error.

Despite technological advancements, today’s laboratories con-tinue to feel the pressure to deliver accurate and timely results, manage costs, and address the challenges of network consolida-tions. While high‐quality products can greatly improve the effi -ciency and effectiveness of laboratory operations, these systems can be further optimized through superior business systems. The value of a knowledgeable partner with the ability to implement ef-fi ciencies through laboratory design, process mapping, KPI mea-surement, and problem‐solving processes will enable laboratories to enhance the quality of patient care through improved TATs, reduced cost of ownership, and standardization of systems and processes.

REFERENCES

1. Kricka LJ, Savory J. A guide to the history of clinical chemistry. Clin Chem. 2011;57 (8):1118‐1126. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.851.7382&rep=rep1&type=pdf.2. iSix Sigma. The history of Six Sigma. https://www.isixsigma.com/new-to-six-sigma/history/history-six-sigma/.


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A GUIDE TO MOL ECUL A R DIAGNOS TICS

Many infectious agents of clinical signifi cance infect the central nervous system (CNS) and are

thus of interest to the diagnostic labora-tory. Examples can be found from every imaginable pathogen type; some of the better known suspects include viruses such enteroviruses, various herpesvirus-es, and JC virus; bacteria such as C. pneu-monia, N. meningitidis, T. pallidum, and H. infl uenzae; yeast and fungi including C. neoformans and Candida spp.; and para-sites like Acanthamoeba spp., Balamuthiaspp., and T. gondii.

Many tests for infectious agents can make use of relatively easily obtained sample types, from direct swabs of acces-sible surfaces to expelled samples (urine, stool, sputum) to peripheral blood sam-ples. Access to the CNS compartment is signifi cantly more challenging, as direct tissue biopsy isn’t a simple option, and the presence of the blood-brain barrier negates any possible use of peripheral blood as a reliable sample type.

The best option left is cerebrospinal fl uid (CSF), a protein-rich liquid which serves functions including cushioning of the brain, nutrient diffusion, and mainte-nance of intracranial pressure. An aver-age adult CNS total volume is estimated at approximately 150 ml; however, only relatively small volumes (1-2 ml) are generally available for safe collection via lumbar puncture. CSF is an intrinsically sterile sample type, meaning that almost any pathogen detection is both pathogenic and signifi cant, although exceptions can occur due to contamination during sample collection or may result in context of a systemic, non-CNS infection if there are transient breakdowns in the blood-brain barrier.

Challenges of CSF Two challenges are common in the use of CSF as a diagnostic sample. The fi rst is that titers of organisms may be quite low, which is one of the reasons why highly sensitive molecular methods may be the test modality of choice in this sample type. (By comparison, one study of CSF viral culture for HSV showed only a four percent positive detec-tion rate in biopsy proven cases of

HSV encephalitis).1 Unfortunately, the second problem is that CSF may often contain numerous substances inhibi-tory to nucleic acid amplifi cation tests (NAATs) such as polymerase chain re-action (PCR) and in particular is rich in RNases, which can be problematic for effi cient recovery of RNA targets such as enteroviruses. Optimal use of CSF as an MDx diagnostic specimen type thus requires both effi cient recovery of low titer nucleic acids present and ef-fective removal of a range of possible inhibitors, possibly along with RNase inactivation.

While rapid, crude sample prepara-tion methods can work well for provid-ing PCR template in some settings, this does not appear to hold true when the specimen is CSF. One representative study of this by Alfonso and cowork-ers2 reported on the relative effi cacy of four CSF sample preparation methods in context of recovery of T. gondii DNA. In this example, all four approaches began by obtaining a cell pellet from the CSF by a brief low speed centrifugation. The least effective method was to digest this pellet with proteinase K followed by phenol-chloroform extraction, al-cohol precipitation, and resuspension; the authors report a limit of detection (LOD) of 117 tachyzoites. Direct boiling of the cell pellet in sterile water was a better approach, with an estimated LOD

Special sample types: CSFBy John Brunstein, PhD

of 16 tachyzoites. This was still signifi -cantly improved upon by an approach of proteinase K digestion in a cell lysis buf-fer followed by centrifugation to remove debris and testing of supernatant, with a reported LOD of two tachyzoites. Finally (and reassuringly, if your lab has invest-ed in commercial nucleic acid extraction systems), a commercial extraction meth-od based on the now common chaotropic lysis/silica adsorption/wash/elute ap-proach was the clear winner, with a re-ported LOD of a single tachyzoite.

Two further observations might be made with regard to these results. First, it’s sometimes suggested that PCR in-hibition observed with CSF samples is likely due to high protein content. That the poorest results of this study were ob-tained with phenol–chloroform extrac-tion (a potent protein removal approach) casts some doubt onto this claim and suggests that CSF inhibition likely arises from non-protein constituents, at least in the context studied here. A second indi-rect observation is that three of the sam-ple preparation approaches described here would likely have little effect on inactivating endogenous RNases; they are notoriously robust against proteinase digestion and extended boiling. Only the fourth (commercial) method, with use of a chaotropic lysis agent, would have much effectiveness at inactivating RNas-es. Thus, if the assay target were an RNA

species such as an enterovirus, an even bigger bias in favor of the fourth method would likely have been observed. In fact, it’s notable that one of the early references for the use of guanidine thiocyanate (chaotrope)-based extraction meth-ods3 was expressly in the context of CSF samples.

Two takeawaysA takeaway from this, then, is that CSF extraction is probably best done by commercially available, chaotropic lysis-based methods (which include most of the com-mon paramagnetic particle-based methods and common spin-column methods). As another takeaway, recall that we observed above that target organism titers can be low in CSF. This suggests


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THE PRIMER A GUIDE TO MOL ECUL A R DIAGNOS TICS

John Brunstein, PhD, is

a member of the MLO

Editorial Advisory

Board. He serves as

President and Chief

Science Offi cer for

British Columbia-based

PathoID, Inc., which

provides consulting for development and

validation of molecular assays.

that inclusion of a carrier or coprecipi-tant molecule such as tRNA during the extraction process is also likely a wise choice. (Briefl y, these act as a sacrifi cial material to intrinsic losses in the process; that is, if X ng of nucleic acid is normally lost in the protocol through adherence to plasticware, escape in aqueous waste phase, and other reasons, and all your in-put is meaningful target nucleic acid but on the order of X ng, you may lose all of it. If, however, you add in 9X ng of a car-rier at the start for a total of 10X ng input, now the X ng lost consists of 0.9X ng car-rier and 0.1X ng target material, mean-ing you still have 0.9X ng target material coming out, or 90 percent of your input.) This second point—frequently low target content—is also why functional removal of NAAT inhibitors by simple dilution of extracts may not be a viable option for CSF-derived samples, even though it often works with other, more target-rich specimen types.

As with most other MDx speci-men types, fresh samples are ideal; however, freshly frozen CSF samples have been successfully extracted with


recovery of at least some intact nucleic acids following prolonged storage. DNA targets are generally more stable than RNA ones for recovery after fro-zen storage, and in either case use of a sample which has been through mul-tiple freeze-thaw cycles is highly un-desirable.4 Post extraction, the eluted nucleic acids can be stored equivalently to any other MDx extracts (i.e., -20 °C for DNA, or RNA short term; -80 °C recommended for RNA longer term).

While the invasive collection nature of CSF can be outweighed by its ability to sample the otherwise hidden CNS compartment, this value proposition in its collection only holds true when it can be extracted and analyzed in a man-ner that maximizes its diagnostic utility. Less than ideal laboratory practices that may allow acceptable diagnostic accura-cy on less demanding sample types can-not always be expected to perform well when CSF is being examined. Starting with the largest possible input volume of fresh sample and using best practic-es in extraction methods are crucial in making the most of this sample type.

REFERENCES

1. Nahmias AJ, Whitley RJ, Visintine AN, Takei Y, Alford CA Jr. Herpes simplex virus encephalitis: labo-ratory evaluations and their diagnostic signifi cance. Collaborative Antiviral Study Group. J Infect Dis. 1982;145(6):829-836.2. Alfonso Y, Fraga J, Cox R, et.al. Comparison of four DNA extraction methods from cerebrospinal fl uid for the detection of Toxoplasma gondii by polymerase chain reaction in AIDS patients. Med Sci Monit.2008;14(3):MT1-6. 3. Casas I, Powell L, Klapper PE, Cleator GM. New method for the extraction of viral RNA and DNA from cerebrospinal fl uid for use in the polymerase chain re-action assay. J Virol Meth. 1995;53(1):25-36.4. DeBiasi RL, Tyler KL. Molecular methods for diagnosis of viral encephalitis. Clin Microbiol Rev. 2004;17(4):903–925.

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FUTURE BUZZ PROT EOMICS

Protein biomarker discoveryResearchers are bridging the gap between discovery and validation for clinical useBy Scott Peterman, PhD, and Lisa Thomas, BS, MBA

Diagnostic testing plays a vital role in modern medicine, helping clinicians make informed decisions regard-

ing disease identifi cation and treatment. The majority of routine chemistry tests are currently based on spectrophotomet-ric or immunologic analysis.1 There has been a growing realization, however, that effective diagnostic assays will require screening for multiple (rather than indi-vidual) markers using in vitro diagnostic multivariate index assays (IVDMIAs) and the inherent ability of mass spectrometry (MS) to multiplex analytes effi ciently and precisely. This has put MS-based protein biomarker discovery at the forefront of molecular diagnostics research.

And much progress has been made over the past two decades. The latest ad-vances in proteomics technologies, from advances in MS technology and tandem mass tag reagents to the creation of power-ful bioinformatics software, spectral librar-ies, and peptide databases, are creating new opportunities for the development of protein biomarkers for disease diagnosis, prognosis, and prediction of response to therapeutic treatment.

However, despite the large number of candidate protein biomarkers reported, there is a well-documented shortfall be-tween the number of candidate biomark-ers identifi ed and those cleared or ap-proved by the FDA for clinical use.1-5 Here, we consider whether the use of robust quality control (QC) measures and ro-bust experimental design can help bridge this gap and accelerate the translation of biomarkers from bench to bedside.

Protein biomarkers Proteins are particularly useful molecules to use as biomarkers as they are often the effectors of diseases and the targets of ther-apeutic treatments. Using panels of protein biomarkers, healthcare experts can per-form accurate disease diagnosis through convenient non-invasive testing. Such screening enables early disease diagnosis in donor samples from individuals who otherwise present no unusual symptoms.

But protein biomarkers offer more than just early disease diagnosis; they also pres-ent signifi cant opportunities in terms of personalized medicine. In the treatment of cancer, for instance, protein biomark-ers are now being used to guide treatment

choices. The detection of proteins associ-ated with tumor drug resistance or sen-sitivity toward chemotherapy, hormone therapy, or immunotherapy is already be-ing used to predict the type of treatment that may be most effective. Used in com-bination with genome and transcriptome sequencing, targeted proteomics can help healthcare experts deliver more effec-tive treatment tailored to an individual’s condition.

Bridging the gapThe past two decades have witnessed signifi cant advances in the proteomics technologies used to identify new pro-tein biomarkers.1 Research has resulted in the identifi cation of many thousands of candidate protein biomarkers.6,7 How-ever, relatively few of these candidates have successfully translated into FDA-approved clinical diagnostic tests. Too of-ten, biomarkers identifi ed in initial discov-ery studies have not shown reproducible activity during subsequent validation.

A key consideration when developing clinical diagnostics is defi ning the clini-cal intended use.2 For example, when de-veloping cancer protein biomarkers, it is important to establish whether they will be used for screening, diagnosis, or prog-nosis. The intended use will determine the target population used to progress the biomarkers from the discovery stage to ap-proval, and will have a signifi cant impact on the overall clinical performance of the diagnostic test.

Careful study design is also essential to reduce the potential for systematic bias and ensure that conclusions are meaningful. Some of the most common sources of bias involve systematic differences in subject selection or specimen collection between donors and control subjects. This bias can be minimized by adopting uniform collec-tion protocols with accurate knowledge of donor history and, for example, ensuring that not all disease samples are from one institution while healthy samples are from another.8

It is also important to ensure that pro-teomics experiments at the discovery stage are designed appropriately to reduce ana-lytical variability, which can increase the likelihood of false positives when identi-fying biomarkers. Factors associated with poor sample handling, such as storage du-


ration and temperature, can impact repro-ducibility in proteomics investigations.9,10

Challenges associated with proteomicsOne way to improve confi dence in the clinical viability of candidate biomark-ers and increase statistical signifi cance is the use of larger population sizes.6 And, thanks to advances in the analyti-cal performance of mass spectrometry (MS) instrumentation and ultra-high performance liquid chromatography (UHPLC) technologies, as well as rapid improvements in the capability of bio-informatics software, proteomics inves-tigations can now be performed on an unprecedented scale, with exceptional analytical precision and workfl ow robustness.

Though the ability to study thousands of donor samples in a single proteomics study offers signifi cant advantages in terms of investigational capability, it also presents a number of challenges around the design of analytical work-fl ows. While the acquisition time re-quired for initial discovery stage pro-teomics investigations may be a matter of days, for large-scale studies involving several hundred or thousands of donor samples this can be several weeks. With a longer analytical run comes the great-er likelihood of workfl ow disruption; this is a factor that is often underesti-mated and even overlooked completely.

Understanding how factors such as the gradual decline in chromatographic performance caused by the impurities present in biological samples, and the need to recalibrate MS instruments mid-investigation, affect the reliability of experimental data over the duration of an analytical investigation is therefore of increased importance for large-scale studies. Even using the most rugged and robust MS and UHPLC technolo-gies, analytical workfl ows will need to be interrupted for recalibration and closely monitored for performance issues.

To draw meaningful conclusions from large-scale proteomics studies, it is therefore essential to deploy robust QC and system suitability strategies to separate biological differences from analytical variance.

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FUTURE BUZZ PROT EOMICS

biomarkers from the research laboratory into the clinic.

The latest comprehensive proteome profi ling approaches are helping to meet this challenge by facilitating biomarker discovery on an unprecedented scale.

REFERENCES

1. Crutchfi eld CA, Thomas SN, Sokoll LJ, Chan DW. Ad-vances in mass spectrometry-based clinical biomarker discovery. Clin Proteomics. 2016;13:1. DOI: 10.1186/s12014-015-9102-9.2. Li D, Chan DW. Proteomic cancer biomark-ers from discovery to approval: it’s worth the ef-fort. Expert Rev Proteomics. 2014;11(2):135-136. DOI: 10.1586/14789450.2014.897614.3. Goossens N, Nakagawa S, Sun X, Hoshida Y. Cancer biomarker discovery and validation. Transl. Cancer Res. 2015;4(3):256-269. DOI: 10.3978/j.issn.2218-676X.2015.06.04.4. Füzéry AK, Levin J, Chan MM, Chan DW. Transla-tion of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges. Clin Proteomics. 2013;10(1):13. DOI: 10.1186/1559-0275-10-13.5. Diamandis EP. The failure of protein cancer bio-markers to reach the clinic: why, and what can be done to address the problem? BMC Med. 2012;10:87. DOI: 10.1186/1741-7015-10-87.6. Hernández B, Parnell A, Pennington SR. Why have so few proteomic biomarkers “survived” validation? (sample size and independent validation considerations). Advanced Biosystems. 2014;14(13-14):1587-1592. DOI: 10.1002/pmic.201300377.7. Paulovich AG, Whiteaker JR, Hoofnagle AN, Wang P. The interface between biomarker discovery and clini-cal validation: The tar pit of the protein biomarker pipe-line. Proteomics Clin Appl. 2008;2(10-11):1386-1402. DOI: 10.1002/prca.200780174.8. Petri AL, Høgdall C. Marchiori E, et al. Sample han-dling for mass spectrometric proteomic investigations of human urine. Proteomics Clin Appl. 2005;77(16):5114–5123. DOI: 10.1002/prca.200780010.9. Hu J, Coombes KR, Morris JS, Baggerly KA. The importance of experimental design in proteomic mass spectrometry experiments: Some cautionary tales. Brief Funct Genomics Proteomics. 2005;3(4):322-331.10. Pepe MS, Feng Z et al. Pivotal evaluation of the accuracy of a biomarker used for classifi cation or pre-diction: standards for study design. J. Natl Cancer Inst. 2008;100(20):1432-1438. DOI: 10.1093/jnci/djn326.

Scott Peterman, PhD,

serves as marketing

manager and senior

scientist at the BRIMS

(Biomarkers Research

Initiatives in Mass

Spectrometry) Center,

Thermo Fisher Scientifi c. He has been involved in

targeted protein quantitation research

since 2007.

Lisa Thomas, BS, MBA,

serves as senior direc-

tor of marketing for the

clinical and forensic

markets in the chro-

matography and mass

spectrometry division

of Thermo Fisher Scientifi c. She has developed and mar-

keted scientifi c solutions, medical devices,

software, and professional services.

Analytical vs. biological varianceEstablishing statistical signifi cance in proteomics studies requires hard metrics based on robust analytical controls. There are two approaches that are often adopted for the assessment of analytical variance in these types of studies.

The fi rst approach involves spiking do-nor samples with one or more non-human proteins that act as internal controls. Pro-teins such as alcohol dehydrogenase from yeast or beta-galatosidase from E. coli are often used for this purpose, although a wide variety of others are also available. To ensure that these controls are representa-tive of the entire sample preparation and analysis workfl ow, these control proteins should undergo the same protocols that donor samples are subjected to, including sample handling, digestion, and recovery. Proteins should also be chosen to avoid overlap with endogenous peptides where possible.

A parallel approach involves creation of a pooled sample containing all of the do-nor samples, analyzed at regular intervals throughout the analytical run. This global QC sample would be injected every fi ve to ten injections, thus providing a real-time system suitability check for the full set of donor samples. Using the same sample

with exactly the same molecular complex-ity, and analyzed via the same method, this replicate can be used to determine the statistical variance of the method.

While the QC protein provides sys-tem suitability for each individual donor sample, the pooled sample provides a global QC metric at well-defi ned time points to assess the statistical signifi cance of the overall acquisition workfl ow. Used in combination, these QC measures en-able an assessment of statistical signifi -cance of results to be made, and therefore the contribution of analytical variance to experimental variance.

Many software packages exist that can help automate this process and simplify the statistical analysis required. And as the use of certain controls become estab-lished, it is likely that software packages will incorporate these more commonly used protocols as default options, further simplifying analysis.

The broader use of biomarker panels in clinical diagnostics promises more person-alized and effective treatment of diseases. However, the translational gap that ex-ists between proteomic biomarker dis-covery and validation is a signifi cant one that must be closed if we are to accelerate the progression of sensitive and selective


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LAB MANAGEMENT REDUCING L AB ERRORS

Jeff Osborne is the Chief Executive

Offi cer and President of Accumen, Inc. (and its subsidiary, Chi Solutions,

Inc.), which provides clinical laboratory

consulting, outreach, comprehensive

patient blood management (cPBM),

and laboratory excellence solutions for

hospitals and health systems.

Keeping clinical lab errors to a minimumBy Jeff Osborne

Today’s healthcare climate challenges the clinical laboratory to offer improved patient care while reducing costs and increas-ing effi ciencies. There is no room for error, however small.

Seventy percent of all medical decisions are made based on high-volume laboratory testing and the corresponding results.1 Critical information in the clinical laboratory directly impacts patient care and must be delivered with excellence. Performance improvement initiatives to optimize the lab are integral to achieve key quality benchmarks. Methodologies must be put in place that safeguard against lab errors at all stages, and a culture must be developed in which staff will not hesitate to report defi ciencies. Leadership also must be engaged and provide oversight at all lev-els within the health system to be effective. While the frequency of errors in the clinical lab is generally lower than other departments across a health system, any error that impacts quality patient care is too many.

The impact of error Errors are a lab’s worst enemy because they increase waste—wasted time, resources, and supplies. These wastes cost the lab money, decrease its effi ciency, and ultimately pose increased risks for the patient.

Clinical labs perform billions of tests each year. The results rep-resent the bulk of a patient’s electronic medical record, and they are a key driver of medical decisions. Given the volume of tests performed, even if only a small fraction have errors, large num-bers of patients can be affected. While the impact on patient care is not something we can easily apply a value or a dollar amount to, the bottom line is that every test matters, and labs need to consis-tently deliver the right results for the right patient at the right time.

Phase by phaseTesting presents challenges across the phases—pre-analytical, analytical, and post-analytical—so all three should be reviewed and addressed.

The majority, probably the large majority, of errors are associ-ated with the pre-analytical phase. Mislabeled specimens are the most costly. Whether specimens are collected by phlebotomists or nurses, the laboratory has a major role in identifying, tracking, and correcting errors. Larger hospitals and health systems have accelerated their use of positive patient ID barcoding and hand-held printers to print patient labels at the bedside as one method of addressing the problem. In facilities where this has been imple-mented, a drop to almost zero patient ID errors during patient specimen collection has been observed.

To further tighten up the patient identifi cation process, the next step in achieving quality excellence is to track “near misses.” Un-der-reporting can be an issue in this context. To empower staff to report near misses, there often needs to be a culture shift in which potential errors are de-personalized and the entire organization looks at the process that resulted in the error. Health systems that have a strong Lean program or have adopted the practice of “Just Cause” typically approach errors in a manner that empowers staff to speak up about potential errors.

For the analytical phase, emergency department (ED) test turnaround time (TAT) is one of the most common metrics. Labs use this metric to evaluate how well they perform some of their most critical tests. Delays in delivering the test results can lead to delayed patient care and extend length of stay in the ED. When evaluating how a lab is performing on ED TAT, multisite hospital laboratories often have the added challenge of disparate criteria for evaluating what constitutes good performance. To address

this, all stakeholders should be involved to defi ne TAT acceptance criteria and measure their performance against internal and ex-ternal benchmarks. Being able to identify where there are gaps in performance and making them visible allow the laboratory team to take steps to close those gaps.

As the quality process matures, the lab can move from mea-suring the outcome metrics (ED TAT) to focusing on the leading indicators that drive the TAT (for example, non-barcoded tubes, QNS samples). Implementation of quality-leading indicator met-rics and a robust program to review and act quickly on the results are staples of laboratories that successfully eliminate errors at this stage.

The post-analytical process is the fi nal step. The sample was successfully collected, and the lab has completed the ordered tests. Now all that is left is to tell the physician. Errors at this stage in the process range from sending results to the wrong physician, to hav-ing to resend the results because they didn’t arrive, to failing to call physicians with critical value results in a timely manner.

Technology can play an important role in reducing errors in this stage. In the outreach environment, non-affi liated physi-cian groups can be connected directly to their laboratory results through a portal, so the right physician receives his or her patients’ results (usually the same day). This saves signifi cant non-value added time for laboratory staff, who no longer need to manually mail/call results to physicians—a process that is in itself suscep-tible to errors. Being able to reduce the number of errors and im-prove the consistency of result delivery helps a lab demonstrate an improved quality maturity level. This in turn leads to increased physician satisfaction and the lab becoming the physician’s “lab of choice.”

Maintaining improvementsOnce a process change has been put into place, the only way to maintain that change is through ongoing, proper monitoring of the process. This requires regularly tracking and displaying the performance of the leading indicators and differentiating between normal and special cause variation in results (control charts are especially helpful with this). Successfully sustaining a positive process change also requires a culture where staff work together to identify problems. When the entire team takes ownership of its performance and is supported in its goal to achieve zero defects, the impossible goal of “perfect” quality becomes approachable.

The next 20 years will see advanced clinical labs taking on a more signifi cant role in healthcare delivery. Using advances in technology and analytics and developing a culture of excellence will allow laboratories to improve their quality and service and mature into powerhouses for positive patient care. The success of the lab of the future depends on the work we do today to increase effi ciency, utilization, and quality.

REFERENCE

1. Hallworth MJ. The ‘70% claim’: what is the evidence base? Ann Clin Biochem. 2011;48(6):487–488; doi: 10.1258/acb.2011.011177.

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MANAGEMENT MATTERS

Sophie Dochez Belin serves as Global

Marketing Manager for Services for

Siemens Healthineers Laboratory Diagnostics. In her role, Sophie is

responsible for identifying new service

offerings to enhance customer satis-

faction, from lab design services to

performance management services.

The human side of lab automationHere are some best practices to break down the “silos”By Sophie Dochez Belin

Breaking down silos in your organization is the fi rst step to a smooth automation transition, and it should happen be-fore equipment installation even begins. If thinking about

how to do this makes you feel uneasy or confused, you are not alone. But it can be done, with advanced planning, and maybe a little help from a friend.

The human side of the automation process often is over-looked, but it is as important as addressing the physical and technical aspects of the transition. The most successful lab transformations occur as a result of staff input, alignment and adaptability—all of which require communication.

The more a laboratory automation solution project is fully in-tegrated, through IT and multi-disciplinary analyzers, the more complex the change is for an organization that, like most do, had been operating in silos. This is because traditional process-es and muscle memory are interrupted when an automation project is underway, but the workload does not stop. Strong col-laboration among laboratory staff and stakeholders, however, preserves productivity during the temporary disruption.

While every project is unique, deploying the following best practices throughout implementation will improve alignment among colleagues and positively affect the outcome.

Identifying stakeholdersUpon deciding to initiate an automation project, identify each stakeholder who will support or feel the effect of the project. This is an opportunity both to gain crucial buy-in through staff involvement and to excite staff by demonstrating how their in-put will make their roles and the laboratory’s offerings better. Stakeholders range from lab directors and purchasing decision makers to vendor project managers and many others—such as IT specialists, quality managers, lab technicians, disciplines managers, and others who can offer insight into the hospital or health system’s protocols for upgrades or modifi cations. Each stakeholder will bring to the table different experiences, backgrounds, and skill sets as part of the planning process.

Give them a voice Once you have identifi ed stakeholders, meet with them to de-velop a list of needs and desirable outcomes, and to discuss their anticipated roles and responsibilities during planning and execution. Discuss all possible goals versus what is feasible against the project budget, to ensure that everyone is aligned on the outcomes. Goals should be specifi c, measurable, and, most important of all, achievable. Expand thinking beyond one or two years ahead to consider expansions and updates that may happen fi ve or 10 years from now. All of these variables will contribute to developing the most effective project plan. Discussion points should include:

• strategic, fi nancial, operational, clinical, and organizational goals

• current service capabilities and expansion opportunities • health system or hospital protocols for upgrades or modifi ca-

tions (for example, infection, electrical, ventilation, plumbing, IT, staff training)

• internal and external factors, opportunities, and risks that may infl uence the outcome of the project

• the budget • specifi c objectives and project scope (and importantly, what

may be considered outside the scope) • a realistic and achievable timeline with specifi c milestones • measurable success criteria for each milestone • defi ned return on investment so stakeholders can easily

recognize the value • frequency and forms of communication to keep stakeholders

apprised.

Consider outside helpHow to navigate these decisions—or where to begin—may seem overwhelming. Consider enlisting the aid of a workfl ow consultant and a project manager.

A workfl ow consultant is an expert trained to methodically analyze a laboratory’s productivity objectively and offer so-lutions for improvement. He or she adds value to the project team by conveying to decision makers cost justifi cations for modifi cations based on process improvement methodologies and offering case studies from other projects with similar goals. The early planning stage is the optimal time to add a workfl ow consultant to the project team

A project manager is an expert certifi ed to coordinate the technical and physical aspects of implementation, resources management, and third-party management. The project man-ager works hand-in-hand with the workfl ow consultant and is responsible for validating project milestones and timing, and for adhering to budget compliance.

Maintain stakeholder involvement Deliver regular progress updates. Use the predetermined chan-nels to communicate to all stakeholders. There is no such thing as over-communication. Take advantage of the opportunities to celebrate milestones and to highlight the success criteria estab-lished during the planning phase. When the project is complete, showcase the ROI the laboratory is contributing to the greater hospital or health system.

In closing, automation success hinges on detailed plan-ning and cross-collaboration, which requires input from and communication with stakeholders from the beginning. Communication and involvement throughout every imple-mentation phase will avoid common obstacles resulting from miscommunication or ambiguity.


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MANAGEMENT MATTERS

An example of the value that a workfl ow consultant and proj-

ect manager can bring to an automation project is provided

by the experience of the North Memorial Health Care (NMHC)

reference laboratory in Minnesota.1 NMHC serves the Twin Cit-

ies metropolitan area with a Level I trauma center, community-

based primary and urgent care, and a 24/7 reference laboratory

that provides vital services to area physician offi ces, clinics,

nursing homes, and other organizations. Its reference labora-

tory was among the fi rst in the area to implement automation,

but as the system aged and healthcare reform challenged the

NMHC to run lean, the laboratory could no longer meet goals

to improve quality, effi ciency, and productivity while reducing

costs. Too many processes remained manual and therefore

prone to error, leading to workfl ow ineffi ciency and inconsis-

tent turnaround times, which in turn forced some testing to be

sent offsite.

NMHC aimed to generate revenue by expanding its reference

laboratory but was constrained by a system that could accom-

modate neither growing demand nor changing test menus.

Defi ning its upgrade requirements, NMHC wanted total auto-

mation, from pre-analytic to post-analytic processes, with the

ability to prioritize STAT testing on the track. It sought a consoli-

dated solution that would enable the lab to cross-train staff to

work where they were most needed. A smaller-footprint solu-

tion would occupy less space and also take less time for people

and tubes to traverse.

The consultation team performed a workfl ow analysis that

identifi ed opportunities to optimize track design, menu balance,

and load balance. For example, to streamline workfl ows, the

laboratory deployed automation modules for tube input/output,

centrifugation, decapping, sealing, desealing, and refrigerated

storage and retrieval. With guidance, NMHC designed its track

with a “T” at one end to accommodate more instruments for

a seamless transition when the lab integrates additional test

disciplines in the future.

At pre-implementation meetings, the workfl ow consultant

and project manager set expectations, answered questions,

and provided a timeline. Further, they project-managed the in-

stallation to ensure everything was in place to support smooth

implementation and trained NMHC staff on the new system.

The NMHC laboratory automation example demonstrates

the advantages of deploying a strategic vendor relationship to

help navigate the process. NMHC now has increased capacity,

faster and more-consistent turnaround times (TAT), and staff-

ing effi ciencies. After implementing automation, the laboratory

was able to increase its annual reference lab sample volumes 12

percent. Additionally, the lab was able to decrease turnaround

times for BNP and troponin tests to benefi t trauma, stroke, and

cardiac patients. BNP turnaround times were reduced by 19 per-

cent and troponin turnaround times were reduced by 17 per-

cent.1 These improvements were critical in extending NMHC’s

leadership as both a community care provider and a revenue-

producing reference lab.

REFERENCE

1. White Paper. Automation upgrade helps improve effi ciency and grow outpatient business. https://static.healthcare.siemens.com/siemens_hwem-hwem_ssxa_websites-context-root/wcm/idc/groups/public/@global/@lab/@corelab/documents/download/mda1/njez/~edisp/151032-gc2_global_aptio_case_study_n_memor_web-02581851.pdf.

North Memorial Health Carecontinued from page 38

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SPECIAL REPORT

Humanitarian endeavor brings rapid cancer diagnostics to sub-Saharan Africa and HaitiBy Dan A. Milner, Jr., MD, MSc(Epi), FASCP

More than 18 months ago, the American Society for Clinical Pa-thology (ASCP) set out to design

a humanitarian program of major pro-portion. At the time, ASCP CEO E. Blair Holladay, PhD, SCT(ASCP)CM, called it “herculean.” The endeavor was to bring rapid cancer diagnostics to severely re-source-limited countries in sub-Saharan Africa and the Caribbean nation of Haiti.

Approximately 650,000 people in Af-rica develop cancer annually, and about 510,000 cancer deaths occur annually due to limited treatment. More than one-third of the cancer deaths in Africa are from cancers that are easily preventable and/or treatable, if detected early. His-totechnology laboratories are a major gap in many African countries, which prevents many people from getting the diagnosis and treatment they need.

Since it was announced in October 2015 by the administration of former President Obama, Partners for Cancer Diagnosis and Treatment in Africa has achieved several major milestones. Last fall, it introduced advance histotechnol-ogy and telepathology to the Butaro Dis-trict Hospital, in Butaro, Rwanda. The telepathology connection is enhanced by the simultaneous installation of a fully automated tissue processing system, which has transformed the capacity of the laboratory toward 1,000 blocks per day and allows for same day turnaround on biopsies. The Partners Initiative has also entered into an agreement with Rwanda’s Minister of Health to move forward with augmenting a second labo-ratory site and providing cancer diagno-sis and treatment education to clinicians in 47 different hospitals.

Partnership with MutomboIn December 2016, ASCP announced a partnership with NBA Hall of Famer and philanthropist Dikembe Mutombo to provide patients in his homeland, the Democratic Republic of Congo (DRC), access to rapid cancer diagnostics and appropriate care and treatment. Plans call for building a new histopathology lab, which will be used by Biamba Ma-rie Mutombo Hospital in Kinshasa, DRC, and will add to the existing histopathol-ogy laboratory capacity in the DRC.

In March 2017, ASCP leaders visited Kenya, Uganda, Tanzania, Rwanda, and the DRC to meet with the stakeholders and conduct assessments to determine country readiness to open more telepa-thology laboratories. As a result:

• ASCP has completed planning for tele-pathology services at the Rwanda Mili-tary Hospital (RMH) to serve RMH, Ki-gali Central Teaching Hospital, and King Faisel Hospital in Rwanda. Deployment began in May 2017. • The Uganda Cancer Institute (UCI) is planning implementation for telepathol-ogy with ASCP in Kampala to serve UCI, Mulago Hospital, and Makere University in Uganda, with deployment scheduled for August 2017.• The Kenyan National Public Health Lab-oratories is installing a national anatomic pathology reference lab in Nairobi, which will serve all patients in Kenya through re-ferral networks and hubs and which ASCP plans to support with telepathology. • The Kilimanjaro Christian Medical Cen-ter is planning implementation for telepa-thology with ASCP in Moshi, Tanzania, to serve the 15 million-plus catchment area of patients for diagnostics of cancer.

The rapid pace at which the Partners Initiative has been moving forward would not have been possible without three key elements: partnerships, country assessments, and funding. The process it-self began by connecting with partner countries to understand the perceived needs, assessing the situation on the ground to determine the actual needs and what is most feasible and plausible within that location, and then creating an implementation plan.

In-country assessmentsASCP hopes that observers do not look at the second element of the Initiative, the country assessment, and consider it to be patronizing—affl uent folks in the United States responding in a conde-scending way to people in “underprivi-leged” countries. That’s not what ASCP and its partners are doing, and to say otherwise would be a bad rap. The fact is, it is common for people of any nation who ask for help in pathology not to—well, not to be pathologists. Therefore, some mutual discussion and education about pathology is often required to get a team all on the same page. The real

KenyaRwanda

Democratic Republic

of Congo

Uganda

Tanzania

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SPECIAL REPORT

Dan A. Milner, Jr., MD, MSc(Epi), FASCP, is

chief medical offi cer of

the American Society for Clinical Pathology (ASCP) and oversees

the Society’s global

healthcare initiatives.

He came to ASCP in September 2016 from

Harvard Medical School, Boston, where

he held the positions of Associate Profes-

sor of Pathology and Associate Professor

in the Department of Immunology and

Infectious Disease at the Harvard T. H.

Chan School of Public Health.

challenge then comes in the implemen-tation that follows. This is where part-ners come in—so challenges can be met and unforeseen issues can be dealt with.

It’s important to keep in mind that ASCP can’t do it alone, and it’s critical to have buy-in from the country part-ners, including the Minister of Health, the pathologists, the hospitals/health centers, and the fi nancial backers for the effort. Each country is unique regarding who these partners are.

The Partners for Cancer Diagnos-tics and Treatment in Africa Initiative includes a medical education steer-ing committee as well as partners who have education as their mission. Part of the process includes an assessment of a country’s current and future needs. Initiative leaders work with in-country schools and partners to insure that there is a plan in motion to create the sus-tained workforce needed to do the work going forward.

Meeting fi nancial challengesThen there is the issue of funding, the third element in the Initiative. Whether through donations of equipment or money, there must be fi scal support for a project because pathology is expen-sive in terms of personnel, reagents, equipment, and time. The Initiative has reached out to establish critical indus-try partnerships, as well as with lead-ers in several countries in sub-Saharan Africa and in Haiti. Sakura Finetek provided histopathology instruments to the laboratory for preparing biop-sies. Pfi zer provided funding support. Global health expert Paul Farmer, MD, and his team from Partners in Health (PIH) make care and treatment avail-able for patients post-diagnosis. Other prestigious partners include Roche Di-agnostics, GE Healthcare, the National Cancer Institute, and the Union for International Cancer Control (UICC).

The Partners Initiative is also sup-ported by more than 600 ASCP mem-bers who have volunteered their time to review slides and make diagnoses, via cloud technology. A team of ASCP volunteer pathologists in the U.S. will use the telepathology equipment to perform rapid diagnostics and review patient specimens for therapy in con-junction with the one pathologist sta-tioned in Butaro. The system has multi-ple uses, including primary diagnostics (when pathologist is absent), secondary consultation, clinical correlation confer-ence, and teaching Rwandan pathology residents.

Recruiting new partnersAll the solutions for cancer in Africa ex-ist. We just have to get them to Africa in an effi cient and timely manner to start seeing impact. We need everything for standard pathology including grossing hoods, tissue processors, embedding stations, microtomes, slide stainers, and coverslippers. We need microscopes. We need storage equipment for blocks and slides. We need computers and software to manage the laboratory. We need re-porting systems to get the diagnoses back to the patients and care givers.

We have identifi ed partners who are helping or can help us with these items, but no single partner can provide suf-fi cient numbers of any one item to meet all of the needs. We need clinicians in-country to be trained to identify cancer; surgeons to be able to biopsy/remove lesions; oncologists to be able to act on our diagnoses; and a cadre of ancillary health workers to support and care for our patients. Again, we have identifi ed partners, but do not have enough to cover what we could do. So, our major challenge is to either recruit duplicate

partners to expand what we can do or publish what we are doing in a “how to” manner so that others can create and execute similar approaches. This is not a competition and not a process to seek glory. This is providing care for people who need it—a moral obligation in a time when cancer does not have to be a death sentence.

MLO201706_SpecReport_MECH_AL.indd 43MLO201706_SpecReport_MECH_AL.indd 43 5/12/2017 11:11:57 AM5/12/2017 11:11:57 AM


TIPS F ROM T HE CL INICA L E XPER TS

This month, we introduce our newest “Tips” expert: Nicholas M. Moore, MS, MLS(ASCP)CM. Mr. Moore serves as As-sistant Director of Clinical Microbiology and Assistant Professor at Rush University Medical Center in Chicago. He is respon-sible for the education of medical stu-dents, pathology residents, and infectious disease fellows related to clinical micro-biology. He is actively engaged in clinical research funded through the Centers for Disease Control and Prevention (CDC) re-lated to the rapid identifi cation of multidrug resistant organisms and controlling the spread of these organisms in healthcare settings.

Q I have just moved to a new hos-pital. On the vaginal wet prep, we have only three reportable

parameters: yeast cells, clue cells, and trichomonas vaginalis—but not white blood cells (WBCs). Do you think that in not reporting WBCs we are leav-ing out an important parameter for diagnosing vaginitis?

A Vaginitis is a general term that refers to a myriad of disorders of the vagina that may be due to in-

fection, infl ammation, or other causes that lead to changes of the vaginal mi-crobiota. The most common symptoms include a malodorous discharge, itch-ing, changes in urinary frequency, and general discomfort. Commonly, vagini-tis is due to infection with Candida spp. or Trichomonas vaginalis, which when combined account for more than 90 percent of cases.1

Because these symptoms are non-specifi c, women who develop these symptoms should be evaluated by a clinician. The evaluation should in-clude a pelvic examination and some limited diagnostic studies to determine the cause. Saline wet mounts are often used in approaches to provide diag-nostic evidence for vaginitis in symp-tomatic women. A sample of vaginal discharge is collected with a vaginal/cervical scraper or a cotton-tipped swab. The sample is mixed with a few drops of 0.9 percent saline on a slide, coverslipped and examined using light microscopy. Normal vaginal discharge should reveal a predominance of squa-mous epithelial cells, rare polymor-phonuclear leukocytes (PMNs), and Lactobacillus spp. The laboratorian is checking for the appearance of bud-ding Candida spp. hyphae, T. vagina-lis, clue cells, or increased PMNs, as

Testing for vaginitis and group A strepthese are characteristics of bacterial vaginosis (BV).

In my laboratory, we report the Nugent score, which takes into account the average number of morphotypes of bacteria, including Lactobacillus, Gard-nerella/Bacteroides, and curved Gram-negative bacilli. We report and semi-quantitate the presence of PMNs, yeast, and clue cells as rare, few, moderate, or many. We perform a separate Tricho-monas antigen test; for the majority of our patients both tests are ordered.

I think the presence of WBC may be helpful, but if your laboratory is using only the Amsel criteria, reporting WBC is not one of the parameters. The Amsel criteria includes production of a grey-white discharge, increased vaginal pH >4.5, positive whiff-amine test, and/or >20 percent of observed epithelial cells seen are clue cells.2 In one study of 640 women evaluated for BV, observa-tion of clue cells was the most reliable diagnostic fi nding to predict BV.3

REFERENCES1. Sobel JD. Vulvovaginitis in healthy women. Compr Ther. 1999;25(6-7):335-346.2. Landers DV, Wiesenfeld HC, Weine RP, Krohn MA, Hiller SL. Predictive value of the clinical diagnosis of lower genital tract infection in women. Am J Obstet Gy-necol. 2004; 190(4):1004-1010.3. Eschenbach DA, Hillier S, Critchlow C, Stevens C, DeRouen T, Holmes KK. Diagnosis and clinical mani-festations of bacterial vaginosis. Am J Obstet Gynecol. 1988;158(40)819-828.

Q Our doctors request strep group A culture on throat specimens which are negative for rapid

strep group A testing. On culture workup, if we have beta hemolytic strep, we perform latex grouping only for GAS and report negative for GAS if latex is negative and positive if latex is positive. I think we should confirm all GAS with PYR, and also should group and report other non-GAS. What is your take on this?

A Throat culture continues to be the recommended standard to diagnose exudative pharyngitis caused by

group A strep (Streptococcus pyogenes).1 Throat cultures have a reported sensi-tivity between 90 percent and 95 per-cent.2,3 However, most labs fi rst rely on a rapid test directly from a throat swab. Many commercial rapid antigen tests have specifi cities ≥95 percent, but sen-sitivities can vary from 65 percent to 90 percent.2-6 Because of this decreased sensitivity, it is recommended and best

Streptococcus pyogenes (group A strep)

Streptococcus spp. (groups C and G)

Neisseria gonorrhoeae

Fusobacterium necrophorum

Arcanobacterium haemolyticum

Corynebacterium diphtheriae

Francisella tularemia

Mycoplasma pneumoniae

Epstein-Barr virus

Cytomegalovirus

Human Immunodefi ciency Virus

Herpes Simplex virus (types 1 and 2)

Table 1. Differential diagnosis of organisms that can cause an exudative pharyngitis.

practice to perform a culture on all nega-tive rapid strep tests. A variety of other organisms can also cause pharyngitis in children and adults (Table 1). For ex-ample, pharyngitis caused by Arcanobac-terium haemolyticum can have a similar clinical syndrome as group A strep, in-cluding fever, exudative pharyngitis, and accompanying rash.7

Because of the high specifi city of most commercial latex kits, I don’t think it is necessary to confi rm PYR on a beta he-molytic strep isolate. I do think it is im-portant, though, that other beta hemolytic strep colonies that grow but test negative for group A be tested with reagents to groups C and G, as these have also been reported to cause pharyngitis. Depending on the local epidemiology or in certain scenarios, the presence of other organ-isms could be responsible for a patient’s condition and should not be ignored.

REFERENCES

1. Bisno AL. Acute pharyngitis. N Engl J Med. 2001;344(3):205-211.2. Shulman ST, Bisno AL, Clegg HW, et al. Clin Infect Dis. 2012;15(55):e86-102.3. Gerber MA. Comparison of throat cultures and rapid strep tests for diagnosis of streptococcal pharyngitis. Pediatr Infect Dis J. 1989;8(11):820-824.4. Dagnelie CF, Bartelink ML, van der Graaf Y, Gossens W, de Melker RA. Towards a better diagnosis of throat infections (with group A beta-haemolytic streptococcus) in general practice. Br J Gen Pract.1998;48(427):959-962.5. Gerber MA, Shulman ST. Rapid diagnosis of pharyn-gitis caused by group A streptococci Clin Microbiol Rev. 2004;17(3):571-580.6. Tanz RR, Gerber MA, Kabat W, Rippe J, Seshadri R, Shulman ST. Performance of a rapid antigen-detection test and throat culture in community pediatric offi ces: implications for management of pharyngitis. Pediatrics. 2009;123(2):437-444.7. Carlson P, Renkonen OV, Kontiainen S. Arcanobac-terium haemolyticum and streptococcal pharyngitis. Scand J Infect Dis. 1994; 26(3): 283-287.

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Cell counter for CSFThe GloCyte Automat-

ed Cell Counter for CSF

is an FDA-approved ana-

lyzer that delivers consis-

tent TNC and RBC counts

and timely turnaround

with just 30 μL of sam-

ple per test. It uses a nov-

el combination of fl uores-

cence imaging technology

and a one-of-a-kind sample cartridge. It is linear down to 0

cells/μL for both TNC and RBC and reduces manual mistakes. AI Companies, www.rsleads.com/706ml-150

Automated ESR analyzerThe iSED is a fully-automated ESR analyzer

that is capable of analyzing samples in 20

seconds, using just 100μl of blood directly

from the primary EDTA collection tube. The

20-position iSED has a continuous, random

access feed and is also compatible with BD

Microtainer MAP Microtubes without any

additional sample manipulation, making it

effective for pediatric testing and avoiding

QNS issues. No batching, pipetting, sample

splitting, or duplicate primary tubes are

necessary. The analyzer interfaces with any LIS, measures 14.3

x 10.5 x 13.4 inches, and is manufactured in the United States. ALCOR, www.rsleads.com/706ml-151

Clinical chemistry systemThe ACE Axcel Clinical Chemistry

System offers advances that en-

hance in-offi ce laboratory testing. Its

comprehensive menu of routine and

specialized assays provides an effec-

tive tool in the diagnosis and man-

agement of diabetes, heart disease,

metabolic syndrome, and anemia,

as well as other diseases. Processing

up to 285 tests/hour, the ACE Axcel

offers touch screen functionality, an

intuitive user interface, and Internet

connectivity, with no external water or waste supply required.

Alfa Wassermann, www.rsleads.com/706ml-152

Simplifi ed urinalysis testingThe AUTION HYBRID

AU-4050 is a fully au-

tomated and integrat-

ed urine analyzer that

consolidates two tech-

nologies to perform

urine chemistry and

sediment analysis. The

compact analyzer mea-

sures 31.5 inches wide.

This provides the ability to standardize technology throughout

a healthcare network. The hybrid analyzer employs fl ow cytom-

etry technology to reduce subjective sediment interpretations.

Superior bacteria detection is achieved with a dedicated reac-

tion chamber, specifi c stain, and amorphous interference re-

moval. Along with reduced subjectivity, a reduction in hands-on

time can be seen with auto-verifi cation rates up to 92 percent. ARKRAY, www.rsleads.com/706ml-153

Helicobacter pylori testAutoGenomics Inc. has

developed a test to de-

tect Helicobacter pylori

and mutations at 2142G

and 2143G on the 23S

Ribosomal RNA. Sev-

eral publications indicate

that these mutations are

responsible for caus-

ing resistance to clar-

ithromycin, the fi rst line drug prescribed for eradicating H. py-

lori. The INFINITI H. pylori QUAD Assay can be performed on

AutoGenomics’ INFINITI Plus and INFINITI High Throughput Sys-

tem (HTS), which utilize a proprietary multiplexing microarray

technology. The INFINITI H. pylori Assay is for Research Use Only

and not for use in diagnostic procedures. AutoGenomics is cur-

rently conducting clinical studies for 510K submission for this

assay to the FDA. AutoGenomics, www.rsleads.com/706ml-154

Multiplex testing includes QCThe BioPlex 2200 Sys-

tem combines pro-

prietary random ac-

cess multiplex testing

with innovative soft-

ware and QC features

to maximize workfl ow

and ensure result ac-

curacy. Fully automat-

ed, it eliminates batch

testing, providing reproducible results with fast turn-

around times. This System supports a variety of autoim-

mune, infectious disease, and specialty assays, such as the

fi fth-generation HIV Ag-Ab assay and the Vitamin D assay.

BioPlex immunoassays use magnetic beads infused with fl uo-

rescent dyes and coated with Ag/Ab ligands, allowing simultane-

ous detection of multiple analytes from a single sample. The Bio-

Plex 2200 can process a minimum of 150 individual bead results

per assay. BioRad, www.rsleads.com/706ml-155

Immunoassay instrument based on CLEIAThe LUMIPULSE G1200 is a robust,

mid-sized, fully automated immu-

noassay instrument based on CLEIA

(chemiluminescent enzyme immu-

noassay) technology. This unique

and user-friendly system includes

features to simplify workfl ow with

continuous access loading and un-

loading of samples. Other features

include disposable tips to eliminate

contamination and sample carry

over, a unitized test cartridge to

reduce waste of reagent and eliminate cross contamination, 120

tests/hour, 30 minute time to result for all assays, stand alone


A N A LY Z ERSPRODUCT FOCUS

MLO201706_ProdFocus_MECH_AL.indd 46MLO201706_ProdFocus_MECH_AL.indd 46 5/12/2017 11:13:00 AM5/12/2017 11:13:00 AM

Optilite® is a special protein analyzer designed to bring simplicity to complex analytical processes.

Key features include

Enhance your efficiency Optimize your workflow Trust your results

Automatic re-dilution to end result

Continuous loading and unloading of samples, reagents and cuvettes

Three methods of antigen excess protection

Optimized assay protocols for Freelite®,

subclasses, and many other special protein assays with wide measuring ranges and large dilution steps

Contact us to learn more.Binding Site Inc.Tel: [email protected]

Optilite and Freelite are registered trademarks of The Binding Site Group Ltd (Birmingham, UK) in certain countries.

The Specialist Protein Company

THE FUTURE OF

SPECIAL PROTEINANALYSIS

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or capable of connecting to track systems, and faster calibra-

tion using less reagent (most assays use 2-3 point calibration). Fujirebio, www.rsleads.com/706ml-156

Blood lead analyzerThese FDA-approved

blood lead analyzers

use electrochemistry

to provide quantita-

tive results in three

minutes, using just 50

μL of blood. LeadCare

Ultra offers through-

put and convenience

for high-volume clini-

cal labs, while Lead-

Care Plus makes it cost-effective for labs to bring lead testing in

house at virtually any volume. These compact systems feature

electronic calibration, require no set-up or routine maintenance,

and don’t need highly trained staff to operate them. LeadCare II

is a CLIA-waived blood lead analyzer for use at the point of care.

Magellan Diagnostics, www.rsleads.com/706ml-157

800 photometric tests per hourThe BA-800M Chemistry

Analyzer was launched

in early 2017. The ana-

lyzer offers a through-

put of 800 photometric

test results per hour and

an overall throughput

of 1,200 tests per hour

with ISE. The Sample

Delivery Module of-

fers 440 sample posi-

tions, providing large

volume laboratories hours of unmanned operational time.

The design of this analyzer minimizes reagent usage per test,

insuring that the laboratory is recognizing the lowest operat-

ing cost per test. The BA-800M can be twinned to increase the

capacity for labs with expanding test volumes. The advanced

features of the BA-800M Analyzer provide the laboratory with

smooth and enhanced operational and workfl ow effi ciencies. MedTest, www.rsleads.com/706ml-158

Cardiac biomarker analyzerThis cardiac biomarker analyzer

is available in the U.S. with a 5.1

percent CV for Troponin I at the

99th percentile cutoff. With the

fl exibility to run whole blood or

plasma samples, PATHFAST al-

lows for up to six simultaneous

tests in under 17 minutes. The

test menu includes Troponin I, CK-

MB, NTproBNP, D-Dimer, hsCRP,

and Myoglobin. With measure-

ment unaffected by hemolysis (up

to 1000 mg/dL), results can

be obtained quickly and with accuracy and precision.

PATHFAST, www.rsleads.com/706ml-159

Chemiluminescence-based immunoassayThe FastPack IP is a chemi-

luminescence-based im-

munoassay analyzer that

is designed for the physi-

cian’s offi ce laboratory.

With its simple three-step

operation (pipette sample,

load the pack, press RUN)

and its rapid turnaround

time (7-12 minutes depend-

ing on assay), the FastPack

IP will fi t into any workfl ow.

The system’s menu consists of Vitamin D, Testosterone, PSA,

TSH, T4, and hCG. The FastPack IP minimizes the need for callback

of patients as it allows diagnosis and treatment in a single visit.

Sekisui Diagnostics, www.rsleads.com/706ml-160

POC PT/INR coagulation analyzerThe Xprecia Stride Coagula-

tion Analyzer is a POC PT/INR

device cleared by FDA based

on the new rules published in

March 2016. It delivers fast, re-

liable Prothrombin Time/Inter-

national Normalized Ratio (PT/

INR) testing for POC monitor-

ing and management of oral

anticoagulation therapy with

warfarin, a vitamin K antago-

nist. No bigger than a smart-

phone and weighing just 10.5

oz., the Xprecia Stride Coagu-

lation Analyzer can be brought

directly to the patient’s fi nger for effi cient and comfortable blood

sample application. The analyzer uses fresh capillary whole

blood, and results are expressed as INR. It utilizes the same

Dade Innovin reagent used by Siemens Healthineers central lab

analyzers to minimize any potential for variability. Studies have

shown the performance to be equivalent to a reference labora-

tory hemostasis system, with results available within minutes.

Siemens Healthineers, www.rsleads.com/706ml-161

Compact chemistry analyzersThe Indiko se-

ries, Indiko and

Indiko Plus, are

fully automated

random access

bench-top ana-

lyzers. Analyzer,

system reagents

and consumables form a fully supported system for therapeu-

tic drug monitoring and drugs of abuse testing. The user menu

is intuitive, and the continuous way of working, adding sam-

ples, reagents, and cuvettes without interrupting the ongo-

ing analysis, gives walk-away freedom. The low-volume cu-

vette design enables small sample and reagent volumes and

minimal water consumption. On-board sample capacity is

up to 108, and any mix of sample cups or tubes can be used.

Thermo Fisher Scientifi c, www.rsleads.com/706ml-162


A N A LY Z ERSPRODUCT FOCUS

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Robotics and lab automation enclosures

SHEMCO enclosures are designed to enclose robots and other

lab automated processes by providing exhaust air systems or

HEPA fi ltered clean workstations. Robots are benefi cial in many

applications, and are proven to increase effi ciency and produc-

tivity. Robots integrated into existing facilities are shown to

increase output and improve quality, while providing additional

fl exibility in the production process. Enclosures are built to

protect robotic processes from contamination and person-

nel from hazardous fumes. Utilizing a fl exible, modular de-

sign, HEMCO Enclosures are engineered and built to exact customer size and design

requirements. HEMCO offers a wide selection of standard sizes in vented or HEPA fi ltered

models.

HEMCOwww.rsleads.com/706ml-202

Centrifuge cell windows

A line of sapphire UV cell windows for Beckman centrifuges that

simplify fi eld replacement and are impervious to acids, alkalis,

plasma, and body fl uids are available from Meller Optics, Inc.

of Providence, RI. These Sapphire Centrifuge Windows are re-

sistant to most acids, alkalis, plasma, and body fl uids, making

them ideal for use where chemical-, scratch-, and high-pressure

resistance are required. Ideally suited for Beckman centrifuges

and similar instruments, they feature a scribed arrow on their

edges to project the optic axis and simplify installation align-

ment. Available for OEMs and end-users, they measure 19.03 mm

dia. ±0.03 mm by 5 mm thick ±0.10 mm and are offered wedged one or two degrees and

plano; with chambers 0.35 mm x 45 degrees in two places; and have a 30-5 scratch-dig

surface fi nish. For less demanding applications, windows made from quartz are offered

with a 10-5 scratch-dig surface fi nish and a 16.00 mm central clear aperture.

Meller Optics, Inc.www.rsleads.com/706ml-203

Forensic DNA grade consumables

A new product line sealed with the new purity grade

“Eppendorf Forensic DNA Grade” complies with the

stringent requirements of the recently released ISO18385.

This standard specifi es the demands on manufacturers

of products which are used in forensic DNA laboratories

to further minimize the risk of contamination. Eppendorf

confi rms the compliance for every production lot and

provides lot-specifi c certifi cates. The comprehensive

approach of this product line assures an excellent purity

and performance level as well as optimized packaging that supports contamination and

error-free handling. The Forensic DNA grade products encompass consumables for DNA

extraction, sample processing, and PCR setup as well as for sample storage.

Eppendorfwww.rsleads.com/706ml-200

Tissue cassette printer

The Signature Cassette Printer is designed for use in pathology and his-

tology labs to print high-resolution text, graphics and bar codes directly

onto tissue cassettes. The increasing use of 2D bar codes for accurate

specimen identifi cation also requires the use of a latest-generation

direct-to-cassette printer. The Signature Cassette Printer utilizes thermal

transfer ink ribbons. Advantages include: 1) virtual silence while print-

ing; 2) no smell or smoke; 3) does not require proprietary cassettes and

no fume removal system is required; 4) no ink tanks or print heads that

dry out, need maintenance, and have short expiration dates; 5) crisp,

clear text, graphics, and bar codes that won’t smear or rub off during

or after processing; and 6) the ability to print color on white cassettes,

eliminating the need for colored cassettes. An exclusive feature of the Signature Cassette

Printer is that a smaller lab can start with the manual-feed SCP-M. When processing vol-

umes increase, it can add the robotics module later. The same SCP-M printer is simply

placed on top of the robotics module and connected via a USB communications cable.

Primerawww.rsleads.com/706ml-201

CLINICAL SPOTLIGHTS

Get to the next-level of HIV testingI n t r o d u c i n g t h e

BioPlex® 2200 HIV Ag-

Ab diagnostic test. The

fi rst and only test that

s i m u l t a n e o u s l y

detects, differentiates,

and reports HIV-1 p24

antigen and antibodies

to HIV-1 (Groups M

and O) and HIV-2.

Bio-Rad Laboratorieswww.rsleads.com/706ml-400

BioFire FilmArray TorchFilmArray Torch is the latest

advancement in molecular infectious

disease diagnostics. The high-

throughput FilmArray Torch is a

ful ly-integrated, random and

continuous access system designed

to meet your laboratory’s syndromic

infectious disease testing needs.

BioFire Diagnosticswww.rsleads.com/706ml-402

Simplify POCT Administration, Management, & EHR Integration

Orchard® Trellis™ offers POCT

m a n a g e m e n t a n d E H R

integration tools to ease the

workload of POC coordinators.

Results are captured real-time

in your LIS and EHR, and

Trellis supports user certifi cation, remote handling of

QC for POC instruments, and automated billing.

Orchard Softwarewww.rsleads.com/706ml-401

3-Screen Islet Cell Autoantibody Test KitKRONUS® is

p l e a s e d t o

offer the fi rst

commercially

a v a i l a b l e

3-Screen Islet Cell Autoantibody (GAD/IA-2/ZnT8Ab)

Test Kit†, provided in a simple, highly-robust and user-

friendly ELISA assay format.

†For Research Use Only. Not for Use in Diagnostic Procedures.

KRONUS, Inc.www.rsleads.com/706ml-403

NEW PRODUCTS

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CLINICAL SPOTLIGHTS

New automated HDL3-C assay from RandoxIntroducing a new automated assay

for quantitative determination of

HDL3-C in human serum or plasma,

which can be applied to most

biochemistry analyzers. Randox

HDL3-C is for research use only, and

not for diagnostic use in USA.

Contact-Tel: (+1) 866 4 RANDOX or

Fax: (+1) 866 RANDOX 1.

Randox Laboratories-US, Ltd.www.rsleads.com/706ml-404

Optilite® – The Future of Special Protein Testing

Optilite is the perfect solution for

your modern protein laboratory.

It’s fully optimized to create

simplicity from complex analytical

processes. The analyzer and

assays work together, giving you

the freedom to allocate your time

more effectively.

Binding Sitewww.rsleads.com/706ml-408

Introducing the BD MAX™ Vaginal PanelElevate the standard of care

with the fi rst FDA-authorized,

microbiome-based assay that

detects the 3 most common

infectious causes of vaginitis.

Consistent, accurate results

that surpass t radi t ional

methods for vaginitis detection.

BD Diagnosticswww.rsleads.com/706ml-405

The Next Dimension in Blood CultureFirst FDA-cleared system

with fully automated load

& go, automated blood

l e v e l d e t e c t i o n , &

automated unloading.

Biomerieuxwww.rsleads.com/706ml-409

Accelerating Lab Effi ciencyReliable products create

effi ciency and confi dence

in your results. From

standards to sample

prep and separation,

MilliporeSigma provides

p r o d u c t s t h a t a r e

rigorously tested and documented to ensure the

highest level of quality in the industry.

Millipore-Sigmawww.rsleads.com/706ml-406

Thermo Scientifi c™ CEDIA® Buprenorphine II Drugs of Abuse Assay

The new, CEDIA Buprenorphine II Assay

is the only one on the market that

detects all major metabolites,

minimizing potential false-negatives.

This next-gen assay also has no

significant cross-reactivity to other

opioids (including morphine), making

it suitable for testing urine samples from patients on

slow-release morphine therapy.Thermo Fisher Scientifi c

www.rsleads.com/706ml-410

Quick turnaround time for CSF counts GloCyte del ivers highly

accurate and precise TNC and

RBC counts, with just 30 μL of

sample per test, using a novel

combination of fl uorescence

and imaging technology with

linearity down to 0 cells/μL.

Advanced Instrumentswww.rsleads.com/706ml-407

Explore how we can take your lab BEYOND A BETTER BOX

S y s m e x ® X N -

Series Hematology

Analyzers enable

laboratories of any

size to implement

advanced clinical

and operational capabilities.

SYSMEXwww.rsleads.com/706ml-411

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cobas® EGFR Mutation Test v2Designed to provide clear,

act ionable results, the

cobas® EGFR Mutation Test

v2 is a real-time PCR assay

approved as an aid in fi rst-

line and subsequent therapy

decisions for patients with

non-small cell lung cancer

(NSCLC).

Roche Diagnosticswww.rsleads.com/706ml-412

cobas Liat PCR SystemWhether your fl u A/B, RSV or strep

A result is positive or negative, you

can confi dently treat patients at the

time of visit without confi rmation –

when they need it most. CLIA-

waived test results in 20 minutes or

less.


Blood Glucose Linearity and Daily QCIntroducing Linearity DROP

LQ Blood Glucose (Item

#K736M-5) and Control

DROP LQ Blood Glucose

(Item #K078M-8).These

ready-to-use liquid products are intended to be used

with quantitative assays on clinical laboratory

analyzers, simulating human patient samples. For

more information please visit: www.auditmicro.com

AUDIT MicroControlswww.rsleads.com/706ml-414

Deliver defi nitive CT/NG resultsThe cobas® CT/NG v2.0 Test is the

only third-generation chlamydia/

gonorrhea test with dual targets

for CT and NG and an internal

c o n t r o l , p r ov i d i n g h i g h

sensitivity and specificity for

defi nitive results.


INDEX OF ADVERTISERS

This index is provided as a service. The publisher does not assume liability for errors or omissions.

Advanced Instruments, Inc. ..........aicompanies.com/OsmoPRO ....................IBC

AstraZeneca ....................................TAGRISSOhcp.com .................................... 6-7

AstraZeneca ....................................TAGRISSOhcp.com ........................................8

AstraZeneca ....................................TAGRISSOhcp.com ........................................9

AUDIT MicroControls, Inc..............www.auditmicro.com ..................................35

BD Diagnostics (MAX) ...................BD.com/DS ......................................................3

Beckman Coulter, Inc .....................www.beckmancoulter.com/DxC700AU ......29

Binding Site ....................................www.bindingsite.com ..................................47

Bio-Rad Laboratories .....................bio-rad.com/diagnostics ................................5

BioFire Diagnostics ........................biofi reDX.com............................................. IFC

BioMerieux Inc................................biomerieux-usa.com/virtuo .........................39

CLSI/Clinical Laboratory Standards Institute .........................http.shop.clsi.org ..........................................30

DiaSorin Molecular (formerly Focus Diagnostics) ........www.focusdx.com .......................................17

DRG International ...........................www.drg-international.com ........................34

ITL Biomedical ................................www.ITLBioMedical.com ............................16



Kamiya Biomedical Co...................www.k-assay.com/MLO.php .......................33

KRONUS ..........................................www.kronus.com .........................................41

Millipore Sigma ..............................emdmillipore.com/milliq-iqsystem ............37

Orchard Software ...........................www.orchardsoft.com .................................23

Puritan Medical Products ..............www.puritanmedproducts.com .................21

Quest Diagnostics ..........................QuestDiagnostics.com ................................BC

Randox Laboratories ......................randox.com/clinical-chemistry-analysers ..25

Roche Diagnostics ..........................www.cobasEGFRtest.com ...........................19

Roche Tissue Diagnostics ..............usdiagnostics.roche.com .............................15

Streck ...............................................streck.com .....................................................31

Sysmex America Inc ......................www.sysmex.com/beyond_mlo ...................1

Thermo Fisher Scientifi c - Clinical Diagnostics ........................www.thermofi sher.com/MLO/spice............27

Vista Technology, Inc. .....................www.vistatechnology.com ..........................43

ADVERTISER WEB PAGE

CLASSIFIED

Mercy Medical CenterNorth Iowa

Medical Technologist: Mercy Medical Center – North Iowa, New Hampton, IA; Bachelor’s Degree in Chemical, Physical, or Biological Sci-ence, or Medical Technology as well as Medi-cal Technology certifi cation; MLS/MT (ASCP) registry required.

Mail CV to: Heidi Willrett, Employee Relations Coordinator | HR, Mercy Medical Center – North Iowa, 1000 4th ST SW, Mason City, IA 50401.

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EXECUTIVE SNAPSHOT By A lan Lenhof f, Edi tor

HANJOON RYU

CEO

MedTest Dx

ProfessionalI have been the CEO at MedTest for four

years. Prior to that, I served as a Senior Vice

President at Siemens Healthcare Diagnos-

tics from 2007 to 2012, and was respon-

sible for strategy, business development,

strategic partnership, and innovation. I

was head of Siemens Healthcare Diagnos-

tics’ Point of Care business and Molecu-

lar business unit. Prior to Dade Behring’s

acquisition by Siemens AG, from 1999 to

2007, I held various leadership positions

with Dade Behring, and was responsible

for global and strategic marketing, com-

mercial marketing, and strategic corpo-

rate projects. Before joining Dade Behring

in 1999, I was a consultant with Bain &

Company, a management consulting fi rm.

EducationI hold an MBA degree from The Wharton

School, University of Pennsylvania, as well

as a Master’s degree in Marketing and a

Bachelor’s degree in Business Adminis-

tration from Yonsei University, in Seoul,

Republic of Korea.

PersonalI love reading, eating, playing sports, and

traveling with my family. The latest trip I

took with my wife was amazing. We went

to Croatia and fell in love with Adriatic Sea

and coastal towns.

Providing innovative solutions to serve the chemistry and toxicology marketsIf you were explaining MedTest Dx to someone who is not familiar with the organization, how would you characterize its primary areas of expertise? When it comes to the clinical chemistry and toxicology mar-kets, MedTest is uniquely positioned to deliver cost-effective and comprehensive solutions for laboratories as well as for regional and local IVD companies who have missing pieces in their total solution. In addition, what I really want MedTest to

be known for is that we are the “customer excellence freaks.” Customers come fi rst for everyone at MedTest.

What are the major categories of so-lutions that the company provides for the clinical lab? We have two types of customers: laboratory customers and business customers. The laboratory cus-tomers are the ones who are performing the tests. We provide them with reagents, instruments, installation, customer train-ing, technical phone support, and fi eld service when needed. But more impor-tantly, we provide them with full imple-mentation support so that they can get their operation up and running quickly and smoothly.

The business customers are the global IVD companies who put together their solutions for their laboratory custom-ers. They can outsource reagents, instru-ments, and service from MedTest in any way they need. We are very fl exible in customizing the solutions to help them be successful.

How and when did the MedTest Dx brand of products come into being? MedTest has more than 30 years’ history of quality products and services in the industry. Many readers might be familiar with our product brands, such as MedTest DX, Pointe Scientifi c, Medical Laboratory Solutions (MLS), and Clinitox Diagnostix. Each brand brings its own in-depth expertise and innovative ideas.

• The MedTest DX brand provides the lat-est technology in chemistry and hematol-ogy instrumentation, along with reagents for general chemistry and drugs-of-abuse screening testing.

• The Pointe brand is well known globally for its high-quality reagent development and manufacturing, with more than 75 products approved by the FDA. Pointe’s fl agship product, an immunoturbidimet-ric direct HbA1c reagent, is innovative in measuring HbA1c directly, providing the best sensitivity and specifi city results. Many well-known IVD companies use our HbA1c reagents.

• The MLS brand is well known in the United States for its high-quality instru-ment refurbishment program as well as nationwide fi eld service coverage. This enables MedTest to deliver the “best in class” responsiveness and customer ex-cellence to the laboratory. Many IVD business customers who lack a service infrastructure contract with us to provide service to their customers.

• The Clinitox Diagnostix brand brings

innovation to the LCMS testing segment. We work with laboratories and help them implement their customized LCMS test-ing and maintain the quality of opera-tions by providing them with necessary equipment, reagents, and consumables.

And MedTest brings all four of those brands together? Yes. We can be a “single source supplier” for toxicology laboratories who are performing both drug screening and confi rmation testing. We can be a project manager for those who are establishing a new laboratory in chemistry and toxicology, since we pro-vide them with full implementation sup-port above and beyond selling the sup-plies and equipment. We can be a partner for many IVD companies who need out-sourcing options to keep their resource utilization effi cient. We can provide them with our reagents, instruments, and service individually or collectively.

People sometimes think there’s “nothing new under the sun” in Chemistry. Why are they wrong? As I think about our health delivery system, disease diagnosis should be accurate and available in a timely manner—that will never change. Many laboratories, outside of the big teaching hospitals and the big commercial laboratories, have been ig-nored by the big IVD companies. Those laboratories are the ones who are most vulnerable to the consequences of health-care reform and reimbursement reduc-tion. They need a partner who can bring true cost savings, timely responsiveness, and support. MedTest can be that partner. From that point of view, our strategy and what we are doing is very innovative and new.

As CEO, how do you view the cul-ture and potential of the organiza-tion you lead? I am proud of my team and their faith in the company roadmap we’ve created. The roadmap has expe-rienced many turns and changes that have transformed the company into an exciting platform for delivering real value to clinical laboratories worldwide. I have been very fortunate to have met many great minds and hearts who have provided me with the opportunities to experience innovative and strategic de-velopment of products, businesses, and customer relationships. Together we have made MedTest a forward-looking company with the vision to become a leading solution company for clinical chemistry and toxicology laboratories.

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Go with the PRO…OsmoPRO.

There’s a lot to get excited about with OsmoPRO®, the newest multi-sample osmometer from Advanced Instruments.

With OsmoPro, you can deliver the most accurate test results, streamline your workflow and do it all with the greatest of ease.

Intuitive touch screen operation

Integrated 2D barcode scanner

20-sample capacity

Small 20μL sample volume

Convenient LIS interface and data management capabilities

Learn more about the latest innovations in multi-sample osmometry.Visit aicompanies.com/OsmoPRO | +1 781.320.9000

MP21070 rev0 PCN3701

MLO201706_AD AdvancedInstruments.indd COVERIIIMLO201706_AD AdvancedInstruments.indd COVERIII 5/12/2017 12:02:31 PM5/12/2017 12:02:31 PM

Address outcomes and cost with MTB/rifampin testingOne or two negative M tuberculosis/rifampin

resistance assay results support the release of

TB patients from airborne infection isolation.1

Less subjective than the AFB smear and with a

24-hour turnaround time, MTB/RIF is an excellent

add-on to an AFB culture for more accurate

diagnosis, insight into antibiotic choice, and

earlier patient release when appropriate.

That’s a win for everyone.

Test Name Test Code

M tuberculosis Complex and

Rifampin Resistance, Culture

and PCR, Sputum

94578(X)

M tuberculosis Complex

and Rifampin Resistance,

PCR, Sputum

94577(X)

For more information about MTB/rifampin testing, contact your

Quest Diagnostics sales representative.

Reference1. Consensus statement of the Association of Public Health Laboratories and National Tuberculosis Controllers Association, April 2016.

© 2017 Quest Diagnostics Incorporated. All rights reserved.

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mlo201706 cover final - medical laboratory observer · sysmex has a decades-long legacy of...

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