001 013 cli dec - Clinlabint.com › fileadmin › user_upload › 7._CLI... · 2017-06-06 · NGS...

Also in this issue :

TSH receptor ABs inGraves disease diagnosis Pg. 6

CgA as biomarker ofneuroendocrine tumours Pg. 10

Molecular differentiatorsof uterine sarcomaPg. 18

Mutation assay for MPN diagnosis

Pg.33

Using the microbiome forcolorectal cancer screening Pg.14

News updates on www.cli-online.com | Dec 2016/Jan 2017 | Volume 40

by Qiagen

Component-based test for precise diagnosis of peanut allergy

Pg.32by Euroimmun

High-volume specialty hemostasis analyser

Pg.31by Siemens Healthineers

001_013_cli_dec 1 14/12/16 19:34

001_013_cli_dec 2 14/12/16 19:34

Frances Bushrod, Ph.D.

Mild hypothyroidism, where plasma levels of thyroid stimulating hor-mone (TSH) are above the ‘normal’ upper limit but where there is no equivalent change in circulating levels of the thyroid hormones tetra-iodothyronine (T4) and triiodothy-ronine (T3), is common in women of childbearing age; the condition is found in up to 3 % of pregnant women. While normally asymp-tomatic, in pregnant women mild hypothyroidism has been associated with miscarriage, perinatal death and preterm delivery, the major cause of neonatal death. Several studies have investigated whether treatment with levothyroxine, a synthetic thy-roid hormone, would improve the obstetric outcome in women with borderline thyroid function, and results from the most recent study were reported at the Society for Endocrinology (BES) conference in November.In this study, 645 women out of more than 13 000 tested at the end of the fi rst trimester of pregnancy were found to have sub-clinical hypo-thyroidism (340) or isolated hypo-thyroxinemia (305). In the latter condition TSH levels are normal but T4 levels are below the lower refer-ence limit. Five hundred and eight-een women with abnormal thyroid function took part in a randomized trial, with half being prescribed levo-thyroxine and half acting as control. Rates of stillbirth, neonatal death and delivery before 34 weeks were com-pared, as well as delivery between 34 and 37 weeks and cesarean sec-tions carried out before 37 weeks. It was found that untreated women with abnormal thyroid function had an increased risk of stillbirth, delivery before 37 weeks and hav-ing an early cesarean section when compared with women with normal thyroid function and those treated with the synthetic thyroid hormone. Although the authors emphasize that larger trials are needed to con-fi rm their fi ndings, it seems likely that this cheap and safe drug could have a signifi cant impact on obstet-ric outcome.

In the more developed coun-tries thyroid autoimmunity is the main cause of hypothyroidism, with iodine defi ciency being less frequent. Th yroid autoantibod-ies, particularly thyroid peroxi-dase antibodies (TPO), can be measurable even in women with

biochemically normal thyroid function, and are a risk factor for miscarriage and preterm deliv-ery. Elevated levels are found in up to 20 % of women, but also in as many as 31 % of sub-fertile women. Th ere is a dearth of robust studies to assess the eff ect

of levothyroxine on pregnancy outcomes in these women but it could be that measuring TPO in both sub-fertile as well as preg-nant women, followed by treat-ment with levothyroxine if indi-cated, could result in many more healthy, full-term babies.

Accurate results quickly

Over 70 ready-to-use system reagents in volumeoptimized kit sizes

Thermo Scientific™ Indiko™, compact clinical and specialty chemistry analyzer

Thermo Scientific™ Indiko™ Plus, compact clinical and specialty chemistry analyzer

Find out more at thermofisher.com/indiko

© 2016 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher

Scientific and its subsidiaries unless otherwise specified. 1216

In the Middle East:

tel: 009714 4398 117

[email protected]

In Europe:

tel: +358 10 329 200

[email protected]

In the United States:

tel: 1 510 979 5000

[email protected]

Easy to use automation with validated applications offer excellent solution for patient monitoring.

Analyzer, system reagents and consumables form a fully supported system for clinical chemistry,

specific proteins and drug of abuse testing as well as for therapeutic drug monitoring.

Confidence in patient

testing

www.cli-online.com & search 27374

Improving obstetric outcome: antenatal thyroid screening

– Dec 2016/Jan 20173EDITOR’S LETTER

001_013_cli_dec 3 14/12/16 19:34

ContentsFRONT COVERFRONT COVER

FEATURESFEATURES

[6 - 13] ENDOCRINOLOGY[6 - 8] Role of TSH receptor antibodies in the diagnosis of Graves’ disease

[10 - 13] Chromogranin A as a biomarker for the detection of neuroendocrine tumours

[14 - 17] COLORECTAL CANCER The potential of the microbiome for colorectal cancer screening

[18 - 21] UTERINE SARCOMA Molecular differentiators of uterine leiomyosarcoma and endometrial stromal sarcoma

[22 - 27] NEWS IN BRIEF

[28] SCIENTIFIC LITERATURE REVIEW Colorectal cancer

REGULARSREGULARS

[3] Editor’s letter

[29 - 30] Industry news

[31 - 34] Product news

[34] Calendar of events

Alterations of the microbiome are associated with colorectal cancer. Research suggests that microbi-ome data could improve colorectal cancer screen-ing. Analysis of the microbiome directly from existing screening methods offers the opportunity to rapidly translate this research into practice, with the potential to develop a multifactorial colorectal cancer screening tool.

Also in this issue :

TSH receptor ABs inGraves disease diagnosis Pg. 6

CgA as biomarker ofneuroendocrine tumours Pg. 10

Molecular differentiatorsof uterine sarcomaPg. 18

Mutation assay for MPN diagnosis

Pg.33

Using the microbiome forcolorectal cancer screening Pg.14

News updates on www.cli-online.com | Dec 2016/Jan 2017 | Volume 40

by Qiagen


Pg.32by Euroimmun

High-volume specialty hemostasis analyser

Pg.31by Siemens Healthineers

For submission of editorial material, contact the editors at [email protected]

For advertising information, go online to www.cli-online.com, simply click on ‘Magazine’

and ‘Media Information’ or contact Astrid Wydouw at [email protected]

Clinical lab professionals are entitled to receive the digital edition of CLI for the next 12 months com-pletely free of charge. To begin a new subscription or to continue your existing free subscription go to

www.cli-online.comClick on Free Subscription and follow instructions

COMING UP IN CLI FEB/MARCH 2017

NGS in microbiiology diagnostics

Infectious respiratory diseases

Free Subscription for Clinical lab professionals

ISSN 1373-1580

Av. Princesse Elisabeth 176 • B1030 Brussels, BelgiumTel. +32-2-240 26 11 • Fax: +32-2-240 26 18

www.cli-online.com

Managing EditorAlison Sleigh, Ph.D.

Contributing EditorFrances Bushrod, Ph.D.

News EditorTony Spit, Ph.D.

Editorial CoordinatorShirley Waring

Editor in Chief/PublisherBernard Léger, M.D.

Advertising Coordinator

Jennifer Christophers

Circulation ManagerArthur Léger

Publishing Executive / Advertising ManagerAstrid Wydouw

[email protected]

WebmasterJennifer Christophers

©2016 by PanGlobal Media bvba-sprl. Production & Lay-out by Studiopress Communication, Brussels.

Circulation Controlled by Business of Performing Audits, Shelton, CT, USA.

The publisher assumes no responsibility for opinions or state-ments expressed in advertisements or product news items. The opinions expressed in by-lined articles are those of the author and do not necessarily refl ect those of the publisher. No conclusion can be drawn from the use of trade marks in this publication as to whether they are registered or not.

SINCE 1977

001_013_cli_dec 4 14/12/16 19:34


001_013_cli_dec 5 14/12/16 19:35

IntroductionHyperthyroidism is relatively common, with a prevalence of between 0.5 and 2 % [1]. A range of symptoms and signs are associated with hyperthyroidism because of the influence of thyroid hor-mones on multiple organ systems. Many of the most important manifestations are related to effects on the cardiovascu-lar system, which may include tachycar-dia and arrhythmias. Untreated, hyper-thyroidism is associated with significant morbidity and mortality. Hyperthyroid-ism can usually be diagnosed through the measurement of thyroid stimulat-ing hormone (TSH) and free thyroxine (FT4), with TSH usually suppressed and FT4 raised [occasionally free triiodo-thyronine (FT3) is raised in the absence of elevated FT4].

The major causes of hyperthyroidism are Graves’ disease and toxic multi-nodular goitre. Other etiologies include solitary toxic adenoma and thyroiditis (Table 1). Graves’ disease is the most

common cause of hyperthyroidism with most other cases due to either toxic multinodular goitre or solitary toxic nodules, which result from autonomous secretion of thyroid hormones (T4 and T3) by one or more nodules. Transient thyrotoxicosis can occur as the result of thyroiditis, secondary to viral infection or autoimmunity. Graves’ disease is an autoimmune dis-ease characterized by stimulation of the thyroid by TSH receptor stimulating antibodies (TRAbs). This leads to the clinical features typical of hyperthy-roidism such as weight loss, heat intol-erance, palpitations, anxiety, tremor and tiredness. These autoantibodies may also recognize antigens in other tissues, notably fibroblasts in the eye muscles. This can lead to growth and inflam-mation of fat cells and muscles around the eye leading to Graves’ orbitopathy, characterized by upper eyelid retrac-tion, lid lag, swelling, conjunctivitis and exophthalmos.

It is important to differentiate between Graves’ disease and other causes of hyperthyroidism as the approach to treatment may depend on etiology. Current guidelines recommend that all cases of hyperthyroidism are referred to an endocrinologist for further investiga-tion to determine the cause and a treat-ment plan [2, 3]. This article focuses on the role of TRAb measurements in the diagnosis of Graves’ although TRAbs also provide prognostic information [4] and have a role in assessing the risk of neonatal hyperthyroidism in pregnan-cies involving maternal Graves’ [5].

Diagnosis of Graves’ diseaseDetermining the underlying cause of hyperthyroidism relies on a combina-tion of clinical history, physical exami-nation, biochemical testing and imaging. Certain findings are highly suggestive of Graves’ disease such as a symmetri-cally enlarged, non-nodular thyroid and evidence of orbitopathy. The most com-monly used imaging tests are radiolabel uptake scans, which allow visualization of a thyroid radiolabel uptake pattern. In Graves’ disease there is homog-enous, increased uptake of label across the thyroid, whereas in multinodu-lar goitre there is patchy uptake with increased uptake at the sites of the over-active nodules. Radioactive iodine has largely been replaced with technetium pertechnetate (99mTc), which mimics

Role of TSH receptor antibodies in the diagnosis of Graves’ diseaseHyperthyroidism can result from a number of different disorders including Graves’ disease. The diagnostic gold standard is based on radiological tests but measurement of thyroid stimulating hormone receptor antibodies plays an important role in the diagnosis of Graves’. It is important to understand the diagnostic strengths and limitations of these measurements.

by Dr Christopher Boot

– Dec 2016/Jan 2017 Endocrinology6

Cause of thyrotoxicosis Pathogenesis

Graves’ disease Circulating TSH receptor stimulating antibody

Toxic multinodular goitre Nodular thyroid gland with areas functioning autonomously

Toxic nodule Solitary autonomously functioning nodule

Thyroiditis Inflammation of thyroid gland causes release of stored thyroid hormone (transient)

Amiodarone High iodine content of medication disrupts thyroid hormone metabolism

TSHoma Autonomous production of TSH by a pituitary tumour

Factitious thyrotoxicosis Exogenous thyroid hormone

TSH, thyroid stimulatin g hormoneTable 1. Etiologies of thyrotoxicosis.

001_013_cli_dec 6 14/12/16 19:35

the behaviour of iodine but exposes patients to lower radiation doses. The recommended role for TRAbs in the diagnosis of Graves’ varies. One recom-mended approach is to measure TRAbs in new cases of primary hyperthyroid-ism and where TRAb results are posi-tive to diagnose Graves’ disease (Fig. 1). Where TRAb results are negative, uptake scans can then be used to distin-guish Graves’, toxic nodule(s) and thy-roiditis [6]. However, some guidelines have recommended an uptake scan as the first-line test, with TRAbs only used in certain situations [7].

TRAb assaysThere are two main categories of TRAb assays. The majority of assays in clini-cal use detect TRAbs in patient sam-ples through their competition with an added TSH receptor ligand for binding of the TSH receptor. These competition-based assays are sometimes referred to as thyrotropin-binding inhibitory immunoglobulin (TBII) assays. Com-petition-based assays do not discrimi-nate between stimulatory TRAbs (as found in Graves’) or non-stimulating (inhibiting or neutral) TRAbs. In cases

of hyperthyroidism it is assumed that any detected TRAbs are stimulating. The second category of TRAb assay is bioassays, which detect only stimulating TRAbs.

Competition-based assays have evolved over the years. Early assays used por-cine thyroid membrane extracts and detected the inhibition of binding of radiolabelled TSH to these extracts. Liq-uid-phase assays were developed when recombinant human TSH receptor became available and the inhibition of radiolabelled TSH to recombinant TSH receptor was detected. Further evolu-tion of competition assays involved replacement of labelled TSH with mon-oclonal anti-TSH receptor antibod-ies as the competing ligand. Modern TRAb assays typically use fluorescent or chemiluminescent labels and can be automated allowing high throughput.

Bioassays for stimulating TRAbs detect the production of cAMP in cells incu-bated with patient serum. Current bioas-says use Chinese hamster ovary (CHO) cells transfected with human TSH receptor. These cells produce cAMP in

response to TSH receptor stimulation. cAMP can be measured by immunoas-say or a luciferase reporter gene may be used to generate a chemiluminescent signal in response to increasing cAMP. TRAb bioassays are more complex and expensive than competition-based assays and less commonly used in clini-cal practice.

Diagnostic performance of TRAb assaysThe current generation of competi-tion-based TRAb assays are gener-ally reported to offer a high degree of diagnostic specificity and sensitivity for Graves’ disease. A meta-analysis of clinical studies using current assays indicated a pooled specificity of 99 % and sensitivity of 97 % [8]. This high diagnostic performance has led some authors to recommend TRAbs as a first-line test to distinguish Graves’ disease from other causes of hyperthyroidism. This may lead to a quicker and more cost effective diagnosis in many cases com-pared to initial use of imaging tests [9]. In particular, the high diagnostic speci-ficity achieved means that untreated, hyperthyroid patients with positive TRAbs are highly likely to have Graves’ disease so that uptake scans may not be necessary in this scenario, particularly when the clinical presentation suggests Graves’. However, a recent study that compared the diagnostic sensitivity of a number of competition-based TRAb assays found significant variability with sensitivity varying from 65 to 100 % depending on the TRAb assay used [10]. Therefore, a negative TRAb result may not always rule out Graves’ disease with a high degree of certainty.

Assessment of the diagnostic performance of TRAbs in a UK tertiary referral centreIn view of the variability in reported diagnostic sensitivity and the identifi-cation of a number of cases of appar-ent TRAb-negative Graves’ disease in our centre, a retrospective study of the performance of TRAbs in the diag-nosis of Graves’ was carried out. The Kryptor (ThermoFisher) TRAb assay was used throughout the period of the study. Results from all TRAb requests for patients referred with a new pres-entation of thyrotoxicosis were gath-ered over 18 months. Routine diagno-sis of the etiology of hyperthyroidism was based on the uptake pattern on 99mTc scintigraphy, clinical course and

– Dec 2016/Jan 20177

Figure 1. Example algorithm illustrating the potential use of TRAbs as a fi rst-line test in the investigation of thyrotoxicosis.

001_013_cli_dec 7 14/12/16 19:35

other features in addition to TRAb concentrations. Ninety-nine cases of Grave’s disease were identified and 131 cases where an alternative cause of thyrotoxicosis was diagnosed. There was some overlap in TRAb concentra-tions between patients with Graves’ and patients with other etiologies (Fig. 2). Using the diagnostic cut-off of >1.8 IU/L suggested by the manu-facturers of the assay, diagnostic sen-sitivity was 81.8 % (18 of 99 cases of Grave’s were TRAb-negative), whereas diagnostic specificity was 99.2 %. Applying a lower cut-off of >1.2 IU/L resulted in an improved sensitivity of 88.9 % but slightly lower specificity of 97.7 %.

This data from our centre demon-strated a significant number of cases of TRAb-negative Graves’ disease among patients referred with a new presenta-tion of thyrotoxicosis. The diagnostic sensitivity of the Kryptor TRAb assay, therefore, appears to be lower than that suggested by the manufacturer’s data (96.3 %). This could possibly be as a result of more stringent classification of Graves’ in other studies, whereas this data represents the range of patients investigated in practice, which includes cases of borderline/mild hyperthyroid-ism. Of the 99 cases of Graves’ disease in this study, 40 patients had a FT4 of less than 30 pmol/L. Twenty percent of patients in this group had a TRAb level of <1.0 IU/L (the lower limit of

quantification for the assay). Of the remaining 59 cases of Graves’ disease with a FT4 of ≥30 pmol/L, only 5 % had a TRAb level of < 1.0 IU/L. This suggests that cases of Graves’ with milder bio-chemical thyrotoxicosis on presentation are more likely to be TRAb-negative.

Applying a lower diagnostic cut-off than that recommended by the manu-facturer may improve the sensitivity of the Kryptor TRAb assay in the diagno-sis of Grave’s disease. Practice in our laboratory is now to report an ‘equivo-cal’ range of 1.0–1.8 IU/L in addition to a cut-off for positivity of >1.8 IU/L. This better reflects the overlap in TRAb concentrations between Graves’ and other causes of thyrotoxicosis observed in our study than a binary positive/negative threshold. However, no cut-off provided 100 % diagnostic sensitivity for Graves’ disease.

SummaryTRAb assays are useful in the differ-entiation of Graves’ disease from other causes of thyrotoxicosis. In particular, TRAbs appear to provide a high degree of diagnostic specificity so that hyper-thyroid patients with positive TRAb results are highly likely to have Graves’. Radioactive uptake scans may, there-fore, not be necessary in all cases of TRAb-positive hyperthyroidism. How-ever, some studies (including our local data) suggest that the diagnostic sensi-tivity of a negative TRAb result alone is

not sufficient to reliably rule out Graves’ disease. Diagnostic performance is likely to vary between TRAb assays, so assay-specific reference data should be used for interpretation.

References1. Vanderpump MPJ. The epidemiology of thyroid

disease. Br Med Bull. 2011; 99: 39–51.2. Ross DS, Burch HB, Cooper DS, Greenlee MC,

Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, et al. 2016 American Thyroid Associa-tion guidelines for diagnosis and management of hyperthyroidism and other causes of thyro-toxicosis. Thyroid 2016; 26: 1343–1421.

3. UK Guidelines for the use of thyroid function tests. Association of Clinical Biochemistry, British Thyroid Association and British Thy-roid Foundation 2006.

4. Vos XG, Endert E, Zwinderman AH, Tijs-sen JG, Wiersinga WM. Predicting the risk of recurrence before the start of antithyroid drug therapy in patients with Graves’ hyper-thyroidism. J Clin Endocrinol Metab. 2016; 101(4):1381–1389.

5. Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi J. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence-based symposium organized by the European Thyroid Association. Eur J Endo-crinol. 1998; 139: 584–586.

6. Vaidya B, Pearce SHS. Diagnosis and manage-ment of thyrotoxicosis. BMJ 2014; 349: g5128.

7. Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Associa-tion of Clinical Endocrinologists. Endocr Pract 2011; 17: 457–520.

8. Tozzoli R, Bagnasco M, Giavarina D, Bizzaro N. TSH receptor autoantibody immunoassay in patients with Graves’ disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analy-sis. Autoimmun Rev. 2012; 12: 107–113.

9. McKee A, Peryerl F. TSI assay utilization: impact on costs of Graves’ hyperthyroidism diagnosis. Am J Manag Care 2012; 18: e1–14.

10. Diana T, Wüster C, Kanitz M, Kahaly GJ. Highly variable sensitivity of five binding and two bio-assays for TSH-receptor antibodies. J Endocrinol Invest. 2016; 39: 1159–1165.

The authorChristopher Boot PhD, FRCPathDepartment of Blood Sciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

*Corresponding authorE-mail: [email protected]


Figure 2. Kryptor TRAb results in patients with Graves’ and hyperthyroidism of other etiology. TRAb results are on a logarithmic scale. The horizontal dashed line indicates a TRAb concentration of 1.8 IU/L.

001_013_cli_dec 8 14/12/16 19:35

STart Max

- ©

2015

Dia

gnos

tica

Stag

o - A

ll rig

hts

rese

rved

- N

on-c

ontr

actu

al p

hoto

s - 0

2/20

16

Simplicity born from ExpertiseDiscover the STart Max, the new semi-automated instrument from the Max Generation.Designed by Stago, the expert in Coagulation, the STart Max remains simple to use but with true innovation to achieve a maximum performance.

Start with Max, stay with Max!

MaxInnovation

MaxAccuracy

MaxReliability

MaxPracticality


001_013_cli_dec 9 14/12/16 19:35

IntroductionNeuroendocrine tumours (NETs) are a group of tumours that are usually derived from the cells of the nervous and endocrine systems. Th e tumours are characterized by being rare, heterogeneous and may aff ect diff erent tissues and organs with neuroen-docrine elements including the gastroenter-opancreatic system, lungs, thyroid, parathy-roid, pituitary, sympathoadrenals, and other tissues [1]. Th e NETs are distinctive in that their structural components of cells have the ability to synthesize, store, and secret bioactive amines and peptide hormones, a phenomenon termed ‘amine precursor uptake and decarboxylation’ (APUD) [2].

Although NETs may be considered rare, there is, however, increasing interest in their diagnosis, reported incidence and increased survival duration over time, suggesting that NETs are more prevalent than were previ-ously reported.

Th e US Surveillance, Epidemiology, and End Results (SEER) Program registries in their search from 1973 to 2004, identifi ed 35 618 patients with NETs with a signifi cant increase in the reported annual age-adjusted incidence of NETs from 1973 (1.09/100 000) to 2004 (5.25/100 000). Using the SEER reg-istry data, the estimated 29-year limited-duration prevalence of NETs in January

2004, was found to be 9263 and the esti-mated 29-year limited-duration prevalence in the United States on that date was 103 312 cases (35/100 000) [3]. Th e clinical presen-tations in patients with NETs vary accord-ing to the site where the tumour develops, which can be anywhere in the body and can range from a silent tumour, to one that is associated with an overproduction of the hormone/peptide (with their pathophysi-ological and clinical sequels) known to be produced by that tissue, or to a metastatic tumour. Th e growing interest in NETs in recent years is attributed to the increasing medical awareness, availability of laboratory markers for the detection of NETs particu-larly the chromogranins and the wide use of radiological imaging that have increased the diagnostic yields of these tumours.

Physiology of the granin family including chromogranin ATh e secretory granules of the neuroendo-crine and endocrine cells contain a fam-ily of highly acidic proteins, the granins. Th e most abundant forms of granins are chromogranin A (CgA), chromogranin B (CgB), secretogranin II (SgII), whereas granins the other forms that include SgIII, VGF, 7B2, and proSAAS are much less dis-tributed in these granules. Th e granins are involved in the granulogenesis of the secre-tory granule biogenesis, with some being processed to form numerous peptides that

Chromogranin A as a biomarker for the detection of neuroendocrine tumoursNeuroendocrine tumours (NETs) are a heterogeneous group of tumours that vary depending on their anatomical sites, functionality and hormones produced. They are often silent clinically, and diagnosis is usually delayed. Chromogranin A (CgA) is the best-known general biomarker which is used for the diagnosis and management of NETs. It can be measured in serum or plasma using different analytical methods that include RIA, IRMA or ELISA. Raised circulating CgA is considered to be a relatively sensitive marker for the diagnosis of NET. As the test is rather non-specifi c, the diagnostic yield can be improved if other non-NET related conditions with raised CgA including renal failure, cardiac, hepatic and infl ammatory diseases and use of proton pump inhibitor (PPI) are excluded.

by Dr Elham AlRisi and Prof. Waad-Allah S. Mula-Abed


001_013_cli_dec 10 14/12/16 19:35


We are exhibiting at

Arab Lab 20-23 March, 2017 in Dubai

001_013_cli_dec 11 14/12/16 19:35

have diff erent physiological activities. CgA, the most studied chromogranin, was fi rst isolated from the chromaffi n cells of the adrenal medulla. It is a single polypeptide chain of 439 amino acids and 10 dibasic cleavage sites; the CgA gene is localized on chromosome 14q32 [4, 5].

Chromogranins contribute intracellularly to the overall vesicle biogenesis and facilitate the processing and regulation of other secre-tory proteins. Processing of chromogranins gives rise to multiple bioactive peptides that include the vasodilator vasostatin (human CgA 1–76), catecholamine release inhibitor catestatin (human CgA 352–372) and dys-glycemic peptide pancreastatin (human CgA 250–301) [6]. Pancreastatin regulates glucose metabolism in cells and certain organs by inhibiting glucose-mediated insulin release from pancreatic islet cells, and inhibiting glu-cose uptake by adipocytes and hepatocytes. Other contributing functions of CgA include its involvement in regulating endothelial barrier, tumour angiogenesis, anti-apoptosis, and vascular structure and permeability [7].

Laboratory methods for the measurement of chromogranin ATh ere are diff erent approaches for the determination of circulating CgA. Th e cur-rently available methods include radioim-munoassay (RIA), immunoradiometric assay (IRMA) and enzyme-linked immu-nosorbent assay (ELISA). Th e introduction of commercially available ELISA kits for CgA assay (with their advantages of hav-ing long shelf life, technical ease, safety of use, and reported reasonable validity) has greatly improved the measurement of CgA in the diagnosis and clinical management of patients with of NETS. Currently there is increasing availability of these kits for meas-uring CgA in many hospital laboratories.

CgA can be measured using plasma or serum specimens. Although plasma CgA has been reported in a few studies to be higher than in serum, the diff erence may not aff ect clinical interpretation, particu-larly if there is consistent use of a single specimen type [6]. Diff erent results might be reported by the diff erent techniques, which might aff ect the validity indicators using these techniques. Th ere are no uni-versal standards for the techniques used and no universally accepted technique. Th ere are reports that favour RIA over other methods; however, the practical advantages of ELISA techniques, especially the long shelf life, might make them attractive methods for use by many laboratories and might explain their widespread use in today’s practice [8].

Nevertheless, the selection of the analytical method to be used depends on the technical feasibility and convenience in the laboratory.

Chromogranin A and neuroendocrine tumoursCgA and its fragments are usually present in the circulation in equimolar concentra-tion with the secretory activity of the secret-ing neuroendocrine tissue of both normal subjects and patients with diff erent NETs; hence, CgA concentration in the circulation can be measured to provide information on the diagnosis, prognosis and monitoring of patients with these tumours, if other non-NET related physiological, pathological and pharmacological causes are excluded.

CgA is usually secreted by a variety of NETs, which include: carcinoids, pheochromo-cytoma, paraganglioma, medullary carci-noma of thyroid, parathyroid adenomas, pulmonary NETs including small cell lung cancer, gastroenteropancreatic (GEP-NETs) including functioning and nonfunctioning pancreatic islet cell tumours, some pituitary adenomas and other APUD tumours. Th e highest CgA values are observed in small intestine NETs and GEP-NETs associated with MEN1. Moderate-to-high CgA values are noted in pancreatic NETs, Zollinger-Ellison syndrome and gastrinomas. CgA is more frequently elevated in well-diff erenti-ated tumours compared to poorly diff eren-tiated NETs [9]. Diff erent clinical validity indicators for CgA have been reported by diff erent workers in the diff erent patient cohorts. Yang et al. through their search of 13 studies that included 1260 patients with NETs and 967 healthy controls, reported an overall sensitivity, specifi city and diag-nostic odds ratio (DOR) of 0.73, 0.95 and 56.3, respectively, while the summary posi-tive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 14.56 and 0.26, respectively [10]. In addition, the area under the curve (AUC) of the circulating CgA in the diagnosis of NETs was 0.896. Th e pooled sensitivity and specifi city values of CgA were 0.73 and 0.95, respectively, whereas the pooled PLR and NLR values were 14.56 and 0.26, respectively for the diagnosis of NETs. All these data suggested a higher diagnostic accuracy of CgA for the diagnosis of NETs. Among the included studies, three diff erent assays were used to measure the circulating CgA, the sensitivity was both 0.74 by ELISA and RIA assays, and 0.69 by IRMA assay. Th e specifi city was 0.93, 0.95 and 1.00 for ELISA, RIA and IRMA assays, respectively.

CgA values also have a prognostic role, as their high levels correlate with poor

prognosis and short survival in certain NETS [11]. Th is relationship is usually lim-ited in patients with gastrinomas, who have high CgA values despite the small primary tumour size and absence of metastases, pos-sibly due to CgA secretion from G cells. Also, CgA values refl ect the tumour burden, and monitoring the disease by CgA usually helps in detecting tumour recurrence or progression following treatment by surgery or radiotherapy. In patients with midgut NET, serum CgA level was the fi rst marker to refl ect tumour recurrence compared with urinary 5HIAA and radiological measure-ments [12]. Also, in pheochromocytoma, especially when large and lacking the proper hormonal characterization, CgA may be the only laboratory guide in the diagnosis and management of patients with such tumours [13].

Pitfalls in the interpretation of chromogranin A valuesAlthough CgA is a useful general marker for the diagnosis and management of NETs, its universal secretion by almost all neuroen-docrine cells makes its use confounded by its co-elevation in a variety of non-NET conditions including non-NET malignan-cies [14–16]. Hence, interpretation of CgA results must be done in the context of the overall confounding factors, whether physi-ological, pharmacological or pathological. Such conditions include the use of pro-ton pump inhibitors (PPIs) or H2-recep-tor blockers, chronic atrophic gastritis, impaired renal function, cardiac failure, hepatic insuffi ciency, infl ammatory bowel disease, benign prostatic hypertrophy or malignancy, rheumatoid arthritis, untreated essential hypertension, and some non-NET neoplasms. Th e pattern of elevation in serum CgA in certain non-NET conditions has been suggested recently to be utilized as a biomarker and prognostic marker in the stratifi cation of some chronic diseases. Th is is particularly the case for heart failure where CgA might have a role in identifying those at higher risk of short- or long-term mortality [17]. Th e role of CgA in diabetes is not clear. However, CgA and its cleavage fragments, including WE-14, might play a part in the pathogenesis of type 1 diabetes mellitus, possibly as a T-cell autoantigen in pancreatic β-cell destruction [18]. Th ere-fore, CgA might have a potential use as a biomarker in the future [18].

ConclusionChromogranin A is a secretory protein of neuroendocrine origin that is usually pre-sent with its fragments in the circulation as a result of the secretory activity of the


001_013_cli_dec 12 14/12/16 19:35

secreting neuroendocrine cells of both normal subjects and patients with diff erent NETs. It is the best-known general biomarker which is increasingly used for the diagnosis and management of NETs. It can be measured in plasma or serum using diff erent analytical methods that include RIA, IRMA or ELISA. Raised circulating CgA is considered to be a relatively sensitive marker for the diagnosis of NET particularly if there is clinical suspicion and other work-up investigations that are in plan. Its measurement is also of value in monitoring the progress of treatment and prognosis of the disease. Th e diagnostic yield is improved if other non-NET related diseases or conditions are considered and excluded prior to the interpre-tation of CgA values. Th ese conditions include the use of PPIs or H2-receptor blockers, chronic atrophic gastritis, impaired renal, cardiac, or hepatic insuffi ciency, infl ammatory bowel disease, rheu-matoid arthritis, and some non-NET neoplasms.

References1. Kaltsas GA, Besser GM, Grossman AB. Th e diagnosis and medical management of

advanced neuroendocrine tumors. Endocr Rev. 2004; 25(3): 458–511.2. Pearse AG. Common cytochemical and ultrastructural characteristics of cells

producing polypeptide hormones (the APUD series) and their relevance to thy-roid and ultimobranchial C cells and calcitonin. Proc R Soc Lond B Biol Sci. 1968; 170(1018): 71–80.

3. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years aft er “carcinoid”: epidemiol-ogy of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26(18): 3063–3072.

4. Banks P, Helle K. Th e release of protein from the stimulated adrenal medulla. Bio-chem J 1965; 97(3): 40C–41C.

5. Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SR. Th e extended granin family: structure, function, and biomedical implications. Endocr Rev. 2011; 32(6): 755–797.

6. Bech PR, Martin NM, Ramachandran R, Bloom SR. Th e biochemical utility of chromogranin A, chromogranin B and cocaine- and amphetamine-regulated tran-script for neuroendocrine neoplasia. Ann Clin Biochem. 2014; 51(1): 8–21.

7. Taupenot L, Harper KL, O’Connor DT. Th e chromogranin-secretogranin family. N Engl J Med. 2003; 348(12): 1134–1149.

8. Stridsberg M, Eriksson B, Oberg K, Janson ET. A comparison between three commercial kits for chromogranin a measurements. J Endocrinol. 2003; 177(2): 337–341.

9. Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M. Chromogranin A- biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol. 2010; 17(9): 2427–2443.

10. Yang X, Yang Y, Li Z, Cheng C, Yang T, Wang C, Liu L, Liu S. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS One 2015; 10(4): e0124884.

11. Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumours treated at a single institution. Clin Cancer Res. 2008; 14(23): 7789–7803.

12. Welin S, Strisberg M, Cunningham J, Granberg D, Skogseid B, Oberg K, Eriksson B, Janson ET. Elevated plasma chromogranin A is the fi rst indication of recur-rence in radically operated midgut carcinoid tumors. Neuroendocrinology 2009; 89(3): 302–307.

13. Mula-Abed WA, Ahmed R, Ramadhan FA, Al-Kindi MK, Al-Busaidi NB, Al-Mus-lahi HN, Al-Lamki MA. A rare case of adrenal pheochromocytoma with unusual clinical and biochemical presentation: A case report and literature review. Oman Med J. 2015; 30(5): 382–390.

14. Gut P, Czarnywojtek A, Fischbach J, Bączyk M, Ziemnicka K, Wrotkowska E, Gryczyńska M, Ruchała M. Chromogranin A – unspecifi c neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci. 2016; 12(1): 1–9.

15. Glinicki P, Jeske W. Chromogranin A (CgA) – the infl uence of various factors in vivo and in vitro, and existing disorders on its concentration in blood. Endokrynol

Pol. 2011; 62(Suppl 1): 25–28 (in Polish).16. Capellino S, Lowin T, Angele P, Falk W, Grifk a J, Straub RH. Increased chro-

mogranin A levels indicate sympathetic hyperactivity in patients with rheuma-toid arthritis and systemic lupus erythematosus. J Rheumatol. 2008; 35(1): 91–99.

17. Goetze JP, Hilsted LM, Rehfeld JF, Alehagen U. Plasma chromogranin A is a marker of death in elderly patients presenting with symptoms of heart failure. Endocr Connect. 2014; 3(1): 47–56.

18. Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, Piganelli JD, Barbour G, Bradley B, Crawford F, Marrack P, Mahata SK, Kappler JW, Haskins K. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immu-nol. 2010; 11(3): 225–231.

The authorsElham AlRisi MD; Waad-Allah S. Mula-Abed* MBChB MSc FRCPathDirectorate of Laboratory Medicine and Pathology, Royal Hospital, Muscat, Oman


– Dec 2016/Jan 201713

77 Elektronika Kft.Budapest, Hungary E-mail: [email protected] Web: www.e77.hu

New PHASE with CONTRAST

• Throughput: up to 120 tests/hour• Zoomable LPF-like images• 3x more investigated sample volume compared to UriSed 2 • Revolutionary particle visualization utilizing both bright-field and phase contrast microscopy• UriSed 3 and LabUMat 2 together make a Complete Urine Laboratory System

New category in urine sediment analysis

UriSed 3

• Based on the patented UriSed Technology• Manual sample injection and fully automatic measurement process within 1 minute• Highly effective tool in small laboratories, emergency departments or as a back-up system for automated sediment analyzers

UriSed mini Semi-automated Urine Microscopy Analyzer

Automated Urine Sediment Analyzer

Booth no.: Z4E30Meet Us at Medlab Middle East 2017!

92x178_CLI_LMI_2016_MEDLAB.ai 1 2016.11.23. 10:15:32


001_013_cli_dec 13 14/12/16 19:35

Current colorectal cancer screening methodsDifferent countries have adopted vari-ous approaches to colorectal cancer screening. They share a common goal: detection of asymptomatic adenomas or early stage carcinomas, as detection and treatment at an earlier stage is associated with improved survival [1]. Two main screening methods are in use: detec-tion of fecal occult blood and visualiza-tion of the colon. Stool DNA testing has recently been approved but is currently prohibitively expensive.

Detection of fecal occult blood can be achieved using the guaiac fecal occult blood test (gFOBT) or an immunochem-ical method, fecal immunochemical test (FIT). The gFOBT method requires participants to apply stool to a gFOBT

card on three occasions and return this to a screening centre through the post. Hydrogen peroxide is applied and if heme is present, blue discolouration occurs. This method has been shown to reduce mortality by 16 % [2]. The FIT method requires participants to insert a FIT probe into stool and return this to a screening centre through the post. An antibody-based assay is used to detect globin. FIT is more sensitive and specific, can be analysed quantitatively and has improved acceptability [3]. Participants in whom fecal occult blood is detected above a threshold, by either method, are referred for colonoscopy.

Alternatively, direct visualization of the colon by colonoscopy/sigmoidoscopy can be undertaken as first-line screen-ing. Limitations include procedural

risks, associated costs, workforce capac-ity and reduced acceptability [4].

The microbiome and colorectal cancerThe microbiome can be characterized using a number of technologies: next generation sequencing (NGS) of bacte-rial 16SrRNA, whole genome shotgun metagenomics of bacterial communi-ties or the analysis of fecal metabolites (metabolomics). These techniques have enabled an appreciation of the diver-sity and function of the microbiome in health and disease.

Epidemiological studies demonstrate that the incidence of colorectal cancer is highest in countries with a Western cul-ture, which encompasses Western diet, sanitation and hygiene, medication use, urbanization, etc. [5]. Migrant popu-lations to such countries acquire the increased risk, suggesting an environ-mental risk factor. African Americans, who typically have a high incidence of colorectal cancer, have been shown to have different microbiomes to Native Africans, who have a low incidence of colorectal cancer [6] and the diets typi-cal of these two groups have been shown to differentially influence the microbi-ome [7].

Numerous studies have found differ-ences in the microbiome, ‘dysbiosis’, of patients with colorectal adenomas or carcinomas compared to healthy con-trols [8]. In general, dysbiosis is charac-terized by a decrease of short chain fatty acid-producing bacteria, an increase of bacteria that produce bile salts or hydro-gen sulphide, an increase of pathogenic bacteria and inflammation [9]. In par-ticular, the species Fusobacterium nucle-atum, a Gram-negative oral commensal, has been associated with colorectal car-cinoma in many studies.

Animal models have explored poten-tial mechanisms [10] and interestingly show that risk is transferable with trans-plant of dysbiotic microbiomes. This suggests that dysbiosis may be causa-tive or promotional of the development

The potential of the microbiome for colorectal cancer screeningAlterations of the microbiome are associated with colorectal cancer. Research suggests that microbiome data could improve colorectal cancer screening. Analysis of the microbiome directly from existing screening methods offers the opportunity to rapidly translate this research into practice, with the potential to develop a multifactorial colorectal cancer screening tool.

by Dr Caroline Young and Professor Philip Quirke

– Dec 2016/Jan 2017 Colorectal cancer14

Those who have spent their lives in the diagnostics industry know that delivering quality results

everyday requires science and art, blended with a passion for excellence and patient care. At

Sekisui, we are focused on developing products and providing great service and support to

help you master the challenges. For more information about our assays and systems, please visit

us at www.sekisuidiagnostics.com or email us at [email protected]

H E L P I N G Y O U M A S T E R T H E A R T O F D I A G N O S T I C S

C L I N I C A L C H E M I S T R Y / C O A G U L AT I O N / E N Z Y M E S / I N F E C T I O U S D I S E A S E / P O I N T - O F - C A R E

© 2016 Sekisui Diagnostics, LLC. All rights reserved.


of colorectal cancer, rather than merely associative.

Given the association between dysbiosis and colorectal cancer, researchers have considered whether the microbiome could be used as a screening tool.

The microbiome compared to gFOBTSeveral studies have compared the accu-racy of the microbiome as a screening tool to gFOBT. Amiot et al. showed that a screening model combining age plus microbiome (typed by qPCR) was no better than a model combining age plus gFOBT [11]. However, metabolomic analysis [by 1(H)-NMR spectroscopy] was more accu-rate than gFOBT [12]. Zeller et al. created a screening model that combined metagen-omic data with gFOBT results, which lead to an increase in sensitivity compared to gFOBT alone. This model was subse-quently validated in a cohort of a different nationality. It showed some ability to dis-tinguish colorectal cancer from a distinct bowel condition (inflammatory bowel dis-ease) and could be extrapolated to NGS of 16SrRNA (a cheaper method) [13].

Zackular et al. used 16SrRNA analysis of the microbiome to create models combin-ing microbiome data and patient metadata that were more accurate than models based on metadata alone [14]. A model compris-ing BMI, microbiome data and gFOBT was more accurate at distinguishing adenoma from carcinoma than gFOBT alone. Yu et al. used metagenomics to identify two discriminatory bacterial genes that they

then validated as biomarkers by qPCR (a cheaper method) in a cohort of a differ-ent nationality. The area under the receiver operating characteristic (ROC) curve for discriminating carcinoma from controls was 0.84, although gFOBT or FIT screening was not performed for comparison [15].

The microbiome compared to FITAs FIT is replacing gFOBT in many screening programmes and has a higher sensitivity, comparing the accuracy of the microbiome as a screening tool with FIT is more appropriate.

Baxter et al. used 16SrRNA to create a screening model that combined microbi-ome data and FIT to discriminate healthy controls from cases with either adenoma or carcinoma [16]. This model was more sensitive but less specific than FIT alone; it detected 70% of cancers and 37% of adeno-mas which were missed by FIT. Liang et al. [17] identified four bacterial species (one being F. nucleatum) by qPCR that could distinguish colorectal carcinoma from healthy controls with greater accuracy than FIT. Combining microbiome and FIT data afforded greater accuracy still.

Goedert et al. [18] analysed the micro-biome by 16SrRNA in patients with a positive FIT result at baseline. The microbiome data gave an area under the ROC curve for discriminating between healthy controls and colorectal adenoma of 0.767.

Limitations of current researchThe studies mentioned above show prom-ise for the microbiome as a potential colo-rectal cancer screening tool. However, they should be interpreted with a degree of caution, owing to a number of limita-tions which mean that aspects of the stud-ies do not realistically reflect screening conditions. Several of the studies assessed participants at increased risk of colorectal cancer or who were symptomatic. Some collected stool samples following bowel preparation and colonoscopy; one study found that this did not affect the signifi-cance of results [16], whereas another found that it did [15]. Several studies included adenomas <10 mm within their control groups. Many of the studies cre-ated models that distinguished adenomas from carcinomas or carcinomas from healthy controls; few designed models to discriminate between healthy con-trols and participants with any colorectal lesion (i.e. either adenoma or carcinoma).

All of the studies used whole stool sam-ples that were refrigerated or frozen by participants at home or delivered within a limited time window to research centres. This method of sample collection would not translate to national screening pro-grammes, which already struggle with poor participant uptake. In light of this, research-ers have, therefore, investigated whether the microbiome can be analysed directly from the existing screening tools, gFOBT or FIT.

Analysing the microbiome directly from existing screening toolsSinha et al. emphasize the need to assess reproducibility, stability over time and how accurately results reflect the gold standard (fresh or immediately frozen stool) when analysing different meth-ods of microbiome sample collection [19]. They found that 16SrRNA microbi-ome results were similar when analysed from unprocessed or processed gFOBT cards and, in addition to Dominianni et al. [20], showed stability after storage at room temperature for several days. This work was extended by Taylor et al. [21] who demonstrated that the microbiome is stable when analysed by 16SrRNA

– Dec 2016/Jan 2017 Colorectal cancer16

“Numerous studies have found differences in the microbiome, ‘dysbiosis’,

of patients with colorectal adenomas or carcinomas

compared to healthy controls”

Examples of methods of stool collection. From bottom to top: gFOBT card, FIT, specimen collection pot. (NB alternative brands exist).

from processed gFOBT cards stored at room temperature for up to 3 years.

Lotfield et al. showed that metabolomic assessment of the microbiome by ultra-performance liquid chromatography and high resolution/tandem mass spectrom-etry was stable and accurate (albeit with a degree of bias affecting certain metab-olite groups) when analysed directly from gFOBT samples but not from FIT samples [22]. This suggests that differ-ent methods of sample collection may be more or less appropriate dependent upon the method of microbiome analysis.

These studies have assessed methods of microbiome sample collection from healthy volunteers. Baxter et al. [23] have analysed the microbiome directly from processed FIT from subjects with normal bowels, colorectal adenomas or carcinomas. Their study comes with the caveat that some of the stool samples were collected after bowel preparation and colonoscopy; samples were stored at −80 °C before being thawed and trans-ferred to FIT; FIT was refrigerated for up to 2 days, processed, then stored at −20 °C before being thawed for micro-biome analysis. The study demonstrated that a screening model to discriminate between healthy controls and subjects with any colonic lesion had a simi-lar area under the ROC curve whether microbiome analysis was performed directly from FIT samples or whole stool samples.

As an alternative to stool, Westenbrink et al. analysed microbiome-related volatile organic compounds from urine [24] and described a similar sensitivity for the detection of colorectal cancer as gFOBT or FIT.

ConclusionResearch suggests that there is potential for microbiome analysis to both aug-ment and to be integrated with existing screening methods. The landscape of colorectal cancer screening is changing [25]; it seems likely that a more sophis-ticated, multifactorial screening tool will be adopted. Microbiome analysis is likely to contribute and may even offer information beyond that of screen-ing, e.g. prevention or treatment targets [26]. Furthermore, collection of longi-tudinal, population-based microbiome data via national screening programmes will transform the field of microbiome research.

References1. Cancer Research UK (http://www.cancerresearchuk.

org).2. Hewitson P, Glasziou PP, Irwig L, Towler B, Watson

E. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2007; DOI: 10.1002/14651858.CD001216.pub2

3. Schreuders EH, Grobbee EJ, Spaander MC, Kui-pers EJ. Advances in fecal tests for colorectal cancer screening. Curr Treat Options Gastroenterol. 2016; 14(1): 152–162.

4. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, García FA, Gillman MW, Harper DM, et al. Screening for colorectal cancer: US preven-tive services task force recommendation statement. JAMA 2016; 315(23): 2564–2575.

5. Haggar FA, Boushey RP. colorectal cancer epidemiol-ogy: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009; 22(4): 191–197.

6. Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, Gaskins HR, O’Keefe SJ. Diet, micro-biota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013; 98(1): 111–120.

7. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505(7484): 559–563.

8. Borges-Canha M, Portela-Cidade JP, Dinis-Ribeiro M, Leite-Moreira AF, Pimentel- Nunes P. Role of colonic microbiota in colorectal carcinogen-esis: a systematic review. Rev Esp Enferm Dig. 2015; 107(11): 659–671.

9. Sun J, Kato I. Gut microbiota, inflammation and colorectal cancer. Genes Dis. 2016; 3(2): 130–143.

10. Keku TO, Dulal S, Deveaux A, Jovov B, Han X. The gastrointestinal microbiota and colorectal can-cer. Am J Physiol Gastrointest Liver Physiol. 2015; 308(5): G351–363.

11. Amiot A, Mansour H, Baumgaertner I, Delchier JC, Tournigand C, Furet JP, Carrau JP, Canoui-Poitrine F, Sobhani I; CRC group of Val De Marne. The detection of the methylated Wif-1 gene is more accurate than a fecal occult blood test for colorectal cancer screening. PLoS One 2014; 9(7): e99233.

12. Amiot A, Dona AC, Wijeyesekera A, Tournigand C, Baumgaertner I, Lebaleur Y, Sobhani I, Holmes E. (1)H NMR spectroscopy of fecal extracts enables detection of advanced colorectal neoplasia. J Prot Res. 2015; 14(9): 3871–3881.

13. Zeller G, Tap J, Voigt AY, Sunagawa S, Kultima JR, Costea PI, Amiot A, Böhm J, Brunetti F, et al. Poten-tial of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol. 2014; 10: 766.

14. Zackular JP, Rogers MA, Ruffin MT 4th, Schloss PD. The human gut microbiome as a screening tool for colorectal cancer. Cancer Prev Res (Phila). 2014; 7(11): 1112–1121.

15. Yu J, Feng Q, Wong SH, Zhang D, yi Liang Q, Qin Y, et al. Metagenomic analysis of faecal microbiome

as a tool towards targeted non-invasive biomark-ers for colorectal cancer. Gut 2015; DOI: 10.1136/gutjnl-2015-309800.

16. Baxter NT, Ruffin MT 4th, Rogers MA, Schloss PD. Microbiota-based model improves the sensitivity of fecal immunochemical test for detecting colonic lesions. Genome Med. 2016; 8(1): 37.

17. Liang JQ, Chiu J, Chen Y, Huang Y, Higashimori A, Fang JY, Brim H, Ashktorab H, Ng SC, et al. Fecal bacteria act as novel biomarkers for non-invasive diagnosis of colorectal cancer. Clin Cancer Res. 2016; DOI: 10.1158/1078-0432.CCR-16-1599.

18. Goedert JJ, Gong Y, Hua X, Zhong H, He Y, Peng P, Yu G, Wang W, Ravel J, et al. Fecal microbiota characteristics of patients with colorectal adenoma detected by screening: a population-based study. EBioMedicine 2015; 2(6): 597–603.

19. Sinha R, Chen J, Amir A, Vogtmann E, Shi J, Inman KS, Flores R, Sampson J, Knight R, Chia N. Collect-ing fecal samples for microbiome analyses in epi-demiology studies. Cancer Epidemiol Biomarkers Prev. 2016; 25(2): 407–416.

20. Dominianni C, Wu J, Hayes RB, Ahn J. Comparison of methods for fecal microbiome biospecimen col-lection. BMC Microbiol. 2014; 14: 103.

21. Taylor M, Wood H, Halloran S, Quirke P. Exam-ining the potential use and long term stability of guaiac faecal occult blood test cards for microbial DNA 16srRNA sequencing. J Clin Pathol. Accepted for publication.

22. Loftfield E, Vogtmann E, Sampson JN, Moore SC, Nelson H, Knight R, Chia N, Sinha R. Compari-son of collection methods for fecal samples for discovery metabolomics in epidemiologic studies. Cancer Epidemiol Biomarkers Prev. 2016; 25(11): 1483–1490.

23. Baxter NT, Koumpouras CC, Rogers MA, Ruffin MT 4th, Schloss P. DNA from fecal immunochemi-cal test can replace stool for microbiota-based colo-rectal cancer screening. Microbiome 2016; 4(1): 59.

24. Westenbrink E, Arasaradnam RP, O’Connell N, Bailey C, Nwokolo C, Bardhan KD, Covington JA. Development and application of a new electronic nose instrument for the detection of colorectal cancer. Biosens Bioelectron. 2015; 67: 733–738.

25. Nguyen MT, Weinberg DS. Biomarkers in colo-rectal cancer screening. J Natl Compr Canc Netw. 2016; 14(8): 1033–1040.

26. Pitt JM, Vetizou M, Waldschmitt N, Kraemer G, Chamaillard M, Boneca IG, Zitvogel L. Fine-tuning cancer immunotherapy: optimizing the gut microbiome. Cancer Research 2016; 76(16): 4602–4607.

The authorsCaroline Young* MA, BMBCh; Philip Quirke BM, PhD, FRCPath, FMedSciWellcome Trust Brenner Building, St James University Hospital, Leeds LS9 7TF, UK


– Dec 2016/Jan 201717

IntroductionThe majority of cancers affecting the uterine corpus are carcinomas, i.e. tumours of epithelial origin. Uterine sarcomas, tumours that are of mesen-chymal origin, are a group of rare and clinically aggressive tumours constitut-ing 7 % of all soft tissue sarcomas and 3 % of malignant uterine tumours [1, 2]. The most common entities within this group are leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS) [2, 3]. Although LMS and ESS are readily diagnosed based on morphology and a limited immunohistochemistry (IHC) panel in many cases, some tumours may pose diagnostic difficulty, and currently used antibodies are not 100 % sensitive or specific [4]. Improved understand-ing of the molecular make-up of these tumours may lead to more accurate diag-nosis and better understanding of their biology, eventually improving our ability to design targeted therapy approaches

with the objective of improving patient outcome.

The genetic make-up of ESS and LMSLow-grade ESS, the more common type of ESS, is characterized by several gene rearrangements creating fusion genes, of which the first described was fusion of the zinc finger gene 1 JAZF1, located at 7p15, and JJAZ1, also termed SUZ12, at 17q21 through a 7;17-translocation. Other fusions in low-grade ESS include the one between JAZF1 and the PHD finger protein 1 gene (PHF1) in 6p21, as well as between PHF1 and enhancer of polycomb homologue 1 (EPC1) gene at 10p11 and the MYST/Esa1 associated factor 6 gene (MEAF6) at 1p34. X chro-mosome rearrangements include fusion of the open reading frame CXorf67 and the BCL-6 interacting corepressor (BCOR) gene, both at Xp11, with the MBT domain-containing protein 1 gene

(MBTD1) at 17q21 and with the zinc finger CCCH-type containing 7B gene (ZC3H7B) at 22q13, respectively.

High-grade ESS is characterized by a fusion between the tyrosine 3/trypto-phan 5 monooxygenase gene (YWHAE) gene at 17p13 and the NUT family mem-ber gene (NUTM2; previously known as FAM22) at 10q22, creating YWHAE-NUTM fusion through a 10;17-translo-cation (reviewed by Davidson and Micci, invited review submitted to Expert Rev Mol Diagn). These alterations were recently confirmed by analysis of the ESS transcriptome and/or whole-exome sequencing, including the application of next generation sequencing [5–7].

The body of data with respect to the molecular characteristics of LMS is more limited. An observation found in several studies is the presence of exon 2 mutations in the mediator complex sub-unit 12 (MED12) gene on chromosome band Xq13.1 in some LMS. MED12 protein forms complex with MED13, cyclin-dependent kinase 8 (CDK8), and cyclin C, termed the CDK8 submodule of the Mediator, the mediator being a large multiprotein complex regulating transcription [8]. Though less frequent in LMS compared to leiomyomas, the benign counterpart of LMS, this finding appears to be absent in other malignant soft tissue sarcomas, and is rare in car-cinomas, and is thus potentially relevant in the diagnostic setting (reviewed by Croce & Chibon [9]).

RNA sequencing of 99 LMS, of which 49 were uterine, identified 3 distinct molec-ular subtypes. Leiomodin (LMOD1) and ADP-ribosylation factor-like 4C (ARL4C) were found to be markers for type I and II tumours, respectively, and the latter group was associated with poor prognosis when located in the uterus [10].

Comparative molecular analysis of ESS and LMSOur group performed two studies of uterine LMS and ESS with the aim of

Molecular differentiators of uterine leiomyosarcoma and endometrial stromal sarcomaLeiomyosarcoma and endometrial stromal sarcoma are the most common types of uterine sarcoma, a group of rare and clinically aggressive mesenchymal cancers. These two sarcomas may have overlapping clinical presentation, morphology and protein expression profiles, making their diagnosis occasionally difficult. This article discusses molecular approaches that may be applied to the diagnosis of these two cancers and may generate data expanding our therapeutic options and patient outcome.

by Professor Ben Davidson

– Dec 2016/Jan 2017 Uterine sarcoma18

Are you still diagnosing Trichomonas with a microscope or waiting forlab results? Trixie here is an amazing swimmer and is a very tricky bug todetect, and treatment is important.

The OSOM® Trichomonas Test is the only CLIA waived rapid diagnosticdesigned for labs or decentralized testing. It does not rely on the detection of a live organism and can be completed in 10 minutes!

What does this mean to you and your patients? Far more accurate detection and the ability to test and treat in onevisit which helps improve patient care and reduce costs.

Answers for Healthcare. Awesome...yes, OSOM®.Call +44-1622-607800 or email [email protected].

TRICH OR TREAT?

© 2016 Sekisui Diagnostics, LLC. All rights reserved. OSOM® is a registered U.S. trademark of Sekisui Diagnostics, LLC.MADE IN THE USA


identifying novel biomarkers that may expand the arsenal of markers currently used in diagnosing these tumours, as well as improving our understanding of their unique biology.

In the first study, the gene expression profiles of 7 ESS and 13 LMS were com-pared using the HumanRef-8 BeadChip from Illumina. We identified 549 unique probes that were significantly differen-tially expressed in the two tumour enti-ties, of which 336 and 213 were overex-pressed in ESS and LMS, respectively. Genes found to be overexpressed in ESS included CCND2, ECEL1, ITM2A, NPW, SLC7A10, EFNB3, PLAG1 and GCGR, whereas genes overexpressed in LMS included FABP3, TAGLN, CDKN2A, JPH2, GEM, NAV2 and RAB23. qPCR analysis confirmed these differences for 14 of 16 genes selected for validation. Five protein products were selected for validation by IHC, including the LMS markers fatty acid binding pro-tein (FABP3), transgelin (TAGLN) and neuron navigator 2 (NAV2) and the ESS markers cyclin D2 (CCND2) and inte-gral membrane protein 2A (ITM2A). All were found to be significantly

differentially expressed in LMS vs ESS (Fig. 1) [11]. Data for FABP3, TAGLN, NAV2 and CCND2 were recently con-firmed in a large (approx. 350 tumours) uterine sarcoma series [Davidson et al., manuscript submitted].

Recently, we compared the microRNA (miRNA) profiles of primary ESS (n=9), primary LMS (n=8) and metastatic LMS (n=8) using Taqman Human miRNA Array Cards. Ninety-four miRNAs were significantly differentially expressed in ESS vs LMS, of which 76 and 18 were overexpressed in ESS and LMS, respec-tively. Forty-nine miRNAs were differ-entially expressed in primary and meta-static LMS, among which 45 and 4 were overexpressed in primary and metastatic LMS, respectively. Twenty miRNAs found to be most significantly differen-tially expressed in primary ESS vs LMS or in primary vs metastatic LMS were further studied in a validation series of 44 tumours using qPCR. Of these, 10 were confirmed to be differentially expressed in these groups, including overexpression of 7 miRNAs (mir-15b, mir-21, mir-23b, mir-25, mir-145, mir-148b and mir-195) in ESS compared

to primary LMS. The remaining 3 dif-ferentially expressed miRNAs were in comparative analysis of primary and metastatic LMS (lower mir-15a and mir-92a levels and higher mir-31 levels in primary LMS). Differentially expressed miRNA regulated the mitogen-activated protein kinase (MAPK) signaling path-way, Wnt signaling, focal adhesion, the mTOR signaling pathway and the trans-forming growth factor-β (TGF-β) sign-aling pathway. As Wnt signaling pathway genes are controlled by miRNAs 15a, 31 and 92a in LMS, we looked at the biolog-ical role of Frizzled-6 in LMS cells and found that Frizzled-6 silencing by siRNA significantly inhibited cellular invasion, wound closure and matrix metallopro-teinase (MMP-2) activity [12]

Conclusion and future perspectivesRecent years have brought about con-siderable progress in our understand-ing of the molecular events occurring in ESS and LMS. Our studies and data from other groups may aid in the diag-nosis and classification of these cancers, hopefully providing rationale for tar-geted therapy. Uterine sarcomas express different cancer-related molecules that may be targeted (reviewed by Cuppens et al. [13]). Anti-hormonal treatment is used in patients with hormone receptor-positive tumours, and expression of pro-gesterone receptor was recently shown to be a prognostic marker in stage I LMS [14]. In two studies, targeting of mTOR, Aurora kinases and other mitotic check-point regulators has been suggested as therapeutic modality in LMS [15,16]. Additional studies are likely to identify new relevant targets in the future, hope-fully improving the outcome of uterine sarcoma patients.

AcknowledgementThe work of Dr Davidson is supported by the National Sarcoma Foundation at the Norwegian Radium Hospital.

References1. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD,

Devesa SS. Incidence patterns of soft tissue sar-comas, regardless of primary site, in the surveil-lance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer 2006; 119: 2922–2930.

2. D’Angelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol. 2010; 116: 131–139.

3. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (Eds.). WHO classification of tumours of female reproductive organs. IARC 2014.

– Dec 2016/Jan 2017 Uterine sarcoma20

Figure 1. (A) Leiomyosarcoma (LMS; H&E stain); (B) Endometrial stromal sarcoma (ESS; H&E stain); (C) ITM2A immunostain in ESS; (D) CCND2 immunostain in ESS; (E) TGLN immunostain in LMS; (F) NAV2 immunostain in LMS.

4. Abeler VM, Nenodovic M. Diagnostic immu-nohistochemistry in uterine sarcomas: a study of 397 cases. Int J Gynecol Pathol. 2011; 30: 236–243.

5. Micci F, Gorunova L, Agostini A, Johannessen LE, Brunetti M, Davidson B, Heim S, Panago-poulos I. Cytogenetic and molecular profile of endometrial stromal sarcoma. Genes Chromo-somes Cancer 2016; 55: 834–846.

6. Choi YJ, Jung SH, Kim MS, Baek IP, Rhee JK, Lee SH, Hur SY, Kim TM, Chung YJ, Lee SH. Genomic landscape of endometrial stro-mal sarcoma of uterus. Oncotarget 2015; 6: 33319–33328.

7. Li X, Anand M, Haimes JD, Manoj N, Berlin AM, Kudlow BA, Nucci MR, Ng TL, Stewart CJ, Lee CH. The appli-cation of next-generation sequenc-ing-based molecular diagnostics in endometrial stromal sarcoma. Histo-pathology 2016; 69: 551–559.

8. Clark AD, Oldenbroek M, Boyer TG. Mediator kinase module and human tumorigenesis. Crit Rev Bio-chem Mol Biol. 2015; 50: 393–426.

9. Croce S, Chibon F. MED12 and uterine smooth muscle oncogene-sis: state of the art and perspectives. Eur J Cancer 2015; 51: 1603–1610.

10. Guo X, Jo VY, Mills AM, Zhu SX, Lee CH, Espinosa I, Nucci MR, Varma S, Forgó E, Hastie T, Anderson S, Ganjoo K, Beck AH, West RB, Fletcher CD, van de Rijn M. Clinically relevant molecular subtypes in leiomyosarcoma. Clin Cancer Res. 2015; 21: 3501–3511.

11. Davidson B, Abeler VM, Hel-lesylt E, Holth A, Shih IeM, Skeie-Jensen T, Chen L, Yang Y, Wang TL. Gene expression signatures differentiate uterine endometrial stromal sarcoma from leiomyosar-coma. Gynecol Oncol. 2013; 128: 349–355.

12. Ravid Y, Formanski M, Smith Y, Reich R, Davidson B. Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures. Gynecol Oncol. 2016; 140: 512–517.

13. Cuppens T, Tuyaerts S, Amant F. Potential therapeutic targets in uterine sarcomas. Sarcoma 2015; 2015: 243298.

14. Davidson B, Kjæreng ML, Førsund M, Danielsen HE, Kristensen GB, Abeler VM.. Progesterone recep-tor expression is an independent prognosticator in FIGO stage I uterine leiomyosarcoma. Am J Clin Pathol. 2016; 145: 449–458.

15. Brewer Savannah KJ, Demicco EG,

Lusby K, Ghadimi MP, Belousov R, Young E, Zhang Y, Huang KL, Lazar AJ, Hunt KK, Pol-lock RE, Creighton CJ, Anderson ML, Lev D.. Dual targeting of mTOR and aurora-A kinase for the treatment of uterine leiomyosarcoma. Clin Cancer Res. 2012; 18: 4633–4645.

16. Shan W, Akinfenwa PY, Savannah KB, Kolomeyevskaya N, Laucirica R, Thomas DG, Odunsi K, Creighton CJ, Lev DC, Anderson ML. A small-molecule inhibitor targeting the mitotic spindle checkpoint impairs the growth of uterine leiomyosarcoma. Clin Cancer Res. 2012; 18: 3352–3365.

The authorBen Davidson1,2 MD, PhD1Department of Pathology, Norwegian Radium Hospital, Oslo University Hospi-tal, N-0310 Oslo, Norway2University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316 Oslo, Norway


– Dec 2016/Jan 201721

Greiner Bio-One GmbH | Bad Haller Straße 32 | A-4550 KremsmünsterPhone: (+43) 75 83 67 91-0 | Fax: (+43) 75 83 63 18 | E-mail: [email protected] www.gbo.com/preanalytics

� Simple sampling for different patient groups

� Easy sample transfer with integrated blood collection scoop

� No accessories necessary, such as capillaries or funnels

� Leakproof caps for safe transport

� Tubes with fill volume ranges for more flexibility

Capillary Blood Collection System*

Every Drop Counts

*System is currently just available on the European market


Strength test for plateletsBleeding disor-ders could one day be diagnosed by putting platelets through strength tests, researchers have proposed.Biomedical engi-neers from Emory University and the

Georgia Institute of Technology have devised a microfluidic testing ground where platelets can demonstrate their strength by squeezing two protein dots together. Imagine rows and rows of strength testing machines from a carnival, but very tiny. A platelet is capable of exert-ing forces that are several times larger, in relation to its size, than a muscle cells.After a blood clot forms, it contracts, pro-moting wound closure and restoration of normal blood flow. This process can be deficient in a variety of blood clotting disorders. Previously, it was difficult to measure an individual platelet’s contribu-tions to contraction, because clots’ various components got in the way.“We discovered that platelets from some patients with bleeding disorders are ‘wimpier’ than platelets from healthy peo-ple,” says Wilbur Lam, an assistant pro-fessor in the Department of Pediatrics at Emory University School of Medicine and in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Our device may function as a new physics-based method to test for bleeding disorders, complemen-tary to current methods.”The first author of the paper is David Myers, an instructor at Emory’s medical school. Lam is also a physician in the Aflac Cancer and Blood Disorders Center, Chil-dren’s Healthcare of Atlanta. The scientists infer how strong or wimpy someone’s platelets are by measuring how far the protein dots move, taking a picture of the rows of dots, and then analysing the picture on a computer.The dots are made of fibrinogen, a sticky protein that is the precursor for fibrin, which forms a mesh of insoluble strands in a blood clot.In addition to detecting problems with platelet contraction in patients with known inherited disorders such as Wiskott Aldrich syndrome, Myers, Lam and colleagues could also see differences in some patients who had bleeding symp-toms, but who performed normally on standard diagnostic tests.The researchers also used chemical tools

to dissect the process of platelet contrac-tion. They showed that inhibitors of Rho/ROCK enzymes shut down platelet con-traction, but inhibitors of a related path-way, MLCK (myosin light chain kinase), did not. Individual platelet contraction could become an assay for development or refinement of blood thinning drugs, Lam says.Georgia Techhttp://tinyurl.com/j8byzzg

Aggressive form of leukemia linked to defective ‘protein factory’

Twenty to forty percent of the patients with the type of leukemia known as multiple myeloma have a defect in the ‘pro-tein factory’ of the

cell: the ribosome. These patients have a poorer prognosis than patients with intact ribosomes. At the same time, they respond better to a drug that already exists. These are the findings of a study by the KU Leuven Laboratory for Disease Mecha-nisms in Cancer, led by Professor Kim De Keersmaecker.Multiple myeloma (MM, also known as Kahler’s disease) is a blood cancer whereby the plasma cells in the bone marrow start proliferating malignantly. MM cannot be cured and is most common among older people. Various treatments exist to tempo-rarily suppress the disease, but the chal-lenge is determining to which treatment the patient will respond best.Doctoral student Isabel Hofman dis-covered defects in the ribosome of MM patients. “The ribosome is the protein fac-tory of a cell. In MM patients, one part of the ribosome is produced less in 20 to 40 percent of the patients, depending on how aggressive the cancer is. We suspect that their cells are still producing protein, but that the balance is somewhat disrupted. In any case, we found that these people have a poorer prognosis than MM patients with an intact ribosome,” explains Professor De Keersmaecker.One possible treatment for MM is the use of proteasome inhibitors. “The proteasome is the protein demolition machine in a cell. There’s a type of drugs, including Bort-ezomib, that inhibits its functioning. How the defects in the ribosome influence the proteasome is not quite clear yet. But we discovered that patients with a defective ribosome respond better to Bortezomib. In other words, their poorer prognosis can

be offset by this treatment. On the basis of these findings, we can now develop tests to identify defects in the ribosome and thus determine which therapy will have most effect in a specific patient.”The notion that cancer is related to ribo-some defects is a relatively new concept in science. “A few years ago, we discovered defects in the ribosome of patients with acute lymphatic leukemia. Now we know that the same applies to MM. In all like-lihood, this will also hold true for other types of cancer. KU Leuvenhttp://tinyurl.com/jnubnm7

Key regulator of bone development identified

Loss of a key protein leads to defects in skel-etal develop-ment including reduced bone density and a shortening of

the fingers and toes -- a condition known as brachydactyly. The discovery was made by researchers at Penn State University who knocked out the Speckle-type POZ Protein (Spop) in the mouse and charac-terized the impact on bone development. The research redefines the role of Spop during bone development and provides a new potential target for the diagnosis and treatment of bone diseases such as osteoporosis.“The Spop protein is involved in Hedge-hog signalling -- a well-studied cell-to-cell communication pathway that plays multiple roles during development,” said Aimin Liu, associate professor of biol-ogy at Penn State and the corresponding author of the study. “Previous studies done in cell culture suggested that Spop nega-tively regulates or ‘turns down’ Hedgehog signalling. However, in our study, we show that Spop positively regulates the pathway downstream of a member of the Hedge-hog family, a protein called Indian Hedge-hog, during bone development. This new understanding adds to our knowledge of the genetic basis of bone development and could open new avenues to study bone disease.”Indian Hedgehog (Ihh) plays an essen-tial role in bone development. It is near the top of a hierarchical cascade of genes that program cells to produce cartilage and bone. Ihh controls gene expression by regulating the activity of the transcrip-tion factors -- proteins that control the

NEWS IN BRIEF – Dec 2016/Jan 2017 22

expression of other genes -- Gli2 and Gli3. Gli2 acts mainly as an activator of gene expression and Gli3 acts mainly to repress gene expression. The Spop protein tags the Gli proteins to be degraded in the cell.“Previous studies led to a hypothesis that a loss of Spop function would increase Hedgehog signalling because the Gli acti-vators were no longer being degraded,” said Hongchen Cai, a graduate student at Penn State and an author of the paper. “We were surprised to see in our study the repressor of gene expression, Gli3, built up in developing bone, but not the activator of gene expression, Gli2. This imbalance led to an overall decrease in Hedgehog signalling.”In order to study the role of Spop in bone development more closely, the research-ers knocked the gene out specifically in the limb. Limbs that lacked Spop had less dense bone, mimicking osteopenia -- a human condition characterized by low bone density, but not as severe as osteo-porosis. The limbs also had shorter than normal fingers and toes. The researchers also showed that the effects of losing Spop could be mitigated by simultaneously reducing the amount of Gli3 in the limbs.Penn State http://tinyurl.com/jx3y6nj

For invasive breast cancer, researchers identify biomarkers of treatment response

Why do some breast cancers respond to treatment while others resist it? A study led by researchers at the Univer-

sity of North Carolina Lineberger Com-prehensive Cancer Center may provide insight into this important question.The researchers report at the San Antonio Breast Cancer Symposium they have iden-tified biomarkers they believe can be used as part of a larger model to predict how patients with HER2-positive operative breast cancer will respond to the targeted treatment trastuzumab, commercially known as Herceptin, and chemotherapy.“We’re trying to find biomarkers for resist-ance to trastuzumab treatment and chem-otherapy,” said the study’s first author Maki Tanioka, MD, PhD, a postdoctoral research associate at UNC Lineberger. “What’s the cause of response? What’s the cause of resistance? That’s what we are try-ing to identify in this genomic study.”Tanioka and his colleagues analysed

multiple biologic features of cancer cells from 213 patients treated for HER2-pos-itive breast cancer through a National Cancer Institute cooperative group clini-cal trial, CALGB 40601. The biologic fea-tures included multiple kinds of genetic information such as DNA mutations, DNA copy number and RNA gene expres-sion data. The researchers found that cer-tain gene signatures, and either having too many, or too few, of certain genes were pre-dictive of whether patients responded to treatment, and that combining those two features was the most effective method of predicting response.Examining features like mutations, ampli-fications or deletions of genes in tumour cells, the overall subtype of the tumour, as well as indicators of immune responses helped the researchers predict response. The researchers also determined that amplification of a specific chromosome, and a particular gene called MAPK14 on that chromosome, may be a predictor of sensitivity to treatment, while deletions of other genes predicted resistance.The researchers say the next step is to identify another set of data to validate and broaden their findings.“HER2-positive breast cancer is genomi-cally heterogeneous,” Tanioka said.

– Dec 2016/Jan 201723NEWS IN BRIEF


“Therefore, we need a model that incor-porates all these different features. We are actively seeking a set of patient data that we can use to validate the biomarkers we have identified so we can create a compre-hensive predictive model of response to allow us to better tailor treatment.”University of North Carolina Lineberger Comprehensive Cancer Centerhttp://tinyurl.com/grk84cg

Rapid test identifies disease pathogens

Researchers at the Fraunhofer Institute for Interfacial Engineering and Biotech-nology IGB in Stuttgart are developing a test which rapidly and cost-effectively identifies bacteria, fungi or viruses. It can be carried out directly in situ with-out laboratory equipment and specialist knowledge. “The ImmuStick can even detect pathogens outside the body – on medical devices or in hospital rooms for example. However, the technology would certainly also be of interest for testing human blood for germs or allergies“, says Dr. Anke Burger-Kentischer.The method works as simply as a preg-nancy test. The ImmuStick is a test strip onto which a few drops of fluid are applied. If the fluid contains pyrogens, fragments of pathogens, this is shown by a coloured strip in a viewing window. First of all, human immune receptors sensitive to certain pyrogens are applied to the surface of the stick. These are laboratory-produced immune receptors which are synthesized on the basis of the biological model. During production, at the docking point of the immune recep-tors to which the pyrogens normally bind, a type of placeholder is mounted which is marked with a dye. When drops of a fluid containing pyrogens are then applied to the test strip, the pyrogens rush to the docking point on the immune receptor. The placeholders marked with the dye migrate with the fluid through the test strip until they are visible in the viewing window. The colour signal thus indicates that pyrogens that have docked on the immune receptors are present.The ImmuStick project was financed with money from the Discover programme. In

this way the Fraunhofer-Gesellschaft is supporting projects for the duration of one year in order to demonstrate the fea-sibility of a technology. The ImmuStick has passed this test. “We were able to show that it works very well for the bac-terial pyrogen LPS. Together with indus-trial partners, we now want to develop it into a product“, says project manager Burger-Kentischer. “We are currently testing further immune receptors that are specific for other pyrogens.“Currently envisaged are applications in the food and pharmaceuticals sector or in medical technology, as a complete absence of germs or pyrogens is required there. In principle, the ImmuStick would also be of interest for blood analysis. Pyrogens in the blood often lead to blood poisoning, sepsis, from which many peo-ple still die today, especially weakened intensive care patients. “However, blood is a special challenge as it is complex and contains many constituent parts. But in the medium term we are aiming at blood analysis“, says Burger-Kentischer.As pyrogens also include certain allergy trigger factors, an application here would also be conceivable. In the food and pharmaceutical industries, for example, it is important that products are free of allergens. With the ImmuStick these could be detected quickly, cost-effectively and simply. Costly and laborious labora-tory tests would therefore no longer be needed or could be supplemented. At present the IGB researchers are seeking cooperation partners who want to fur-ther develop the ImmuStick to make it ready for the market.Pyrogens become a problem when hygiene is of particular importance – in the food and pharmaceutical indus-tries for example, or on intensive care wards in hospitals. Especially people with weakened immune systems can become severely ill. For this reason, tests are frequently carried out and the surfaces of machines or medical devices are tested for pyrogens using swabs. However, to date these tests have been costly and laborious as pyrogens can only be detected with laboratory equipment. A widely used standard test is the detection of LPS, a structure that is present in the membrane of cer-tain bacteria. At present this test takes up around two hours. Other pyrogens can even only be detected in animal experiment.Fraunhofer Institute for Interfacial Engineering and Biotechnology IGBhttp://tinyurl.com/jyrlqct

Blood-borne HPV antibodies indi-cate head, neck cancer prognosis

People with head and neck cancers with evidence of human papilloma-virus (HPV) infec-tion generally have a better prognosis than people with-out evidence of infection. A new study suggests

that to produce a strong, reliable prog-nostic signal, all that’s needed is a blood serum test for two specific HPV antibodies, rather than lab work on a biopsy. Further, the researchers said, the study shows that this blood-based biomarker is predictive of outcome for all types of head and neck cancer.“What this adds is that it helps us know how best to measure clinically the HPV contribution to this disease,” said study sen-ior author Karl Kelsey, a professor of epide-miology and of pathology and laboratory medicine at Brown University. Kelsey col-laborated with lead author Heather Nelson of the University of Minnesota Masonic Cancer Center in making the findings.Moreover, Nelson, Kelsey and their col-leagues wrote, referring to the common HPV16 strain of the virus: “These data are among the first to demonstrate a con-vincing relationship between HPV16 and improved patient survival for tumours of the larynx and oral cavity.”The study examined blood serum samples and five-year survival rates among more than 1,000 Boston-area head and neck can-cer patients diagnosed between 1999 and 2011. Overall, those who tested positive for antibodies to the oncogenic HPV proteins E6 or E7 were less likely to die during the five year follow-up period after diagnosis compared to those who tested negative for the antibodies. Based on the analysis, the researchers estimated that those with evi-dence of an immune response to HPV were 25% less likely to die during the course of follow-up compared to those with no immune response to HPV.The study’s purpose was to determine whether the antibodies provide a reliable indication of prognosis. In ongoing trials, doctors are testing whether patients with HPV-associated cancers can be treated less aggressively — and hopefully with fewer negative side effects — than people with non-HPV-associated cancers, Kelsey said. If trials prove successful, then it will be par-ticularly important to determine whether cancers are HPV-associated.


“The assessment of a patient’s HPV status likely will affect treatment,” he said. “That’s why there’s real interest in getting it right; for instance, how do you test?”Prior studies have focused primarily on the role of HPV in the oropharynx — the area of the throat right behind the mouth. An important contribution of the current study, Nelson said, is demonstration that an immune response to HPV is important for all forms of head and neck cancer, although the benefit does show some variance based on the exact cancer location. Those patients with an HPV immune response with tumours located in the oropharynx and lar-ynx had a similar risk of dying during the follow-up period, though the reduced risk was slightly attenuated for those patients with tumours located in the oral cavity.The results didn’t depend significantly on whether people had high or low levels of the antibodies, so long as they had some, the researchers found, though testing posi-tive for both E6 and E7 was better than for just one.The reduced chance of dying by five years carried through for people who tested positive for the antibodies even if they consumed tobacco and alcohol. But the worst prognoses in the study were among

smokers whose cancers could not be traced to HPV.In all, the findings controlled for the sta-tistical influences not only of tobacco and alcohol exposure, but also of age, race, gen-der, education and how far advanced the cancer was.Kelsey said the findings could help bring head and neck cancer treatment closer into line with two emerging practices of fight-ing the disease: personalized medicine and immunotherapy.Brown Universityhttp://tinyurl.com/z3n94a4

Scientists can now better diagnose diseases with multiple genetic causesScientists at Baylor College of Medicine, Baylor Genetics, the University of Texas Health Science Center at Houston and Texas Children’s Hospital are combining descriptions of patients’ clinical features with their complex genetic information in a unified analysis to obtain more pre-cise diagnoses of complex diseases, par-ticularly those that involve more than one gene causing the condition.The researchers anticipate that improved

clinical and genetic diagnoses could lead to patients receiving more effective treat-ments and families benefiting from needed counselling. “One of the main interests of our lab is to better understand the impact of genetic variation on human health and disease,” said co-first author Dr. Jennifer Posey, assistant professor of molecular and human genetics at Baylor.“Traditionally, physicians have spoken of a unifying diagnosis, meaning that genetic conditions are due to mutations in only one gene,” said co-first author Dr. Tamar Harel, who was a genetics fel-low at Baylor when she was working on this study and currently is a geneticist at Hadassah Medical Center in Israel. “Yet, we see here that two or more genes can be involved in a disease and produce a complex clinical picture. For many in the field, this is a revolutionary idea.”


CoagS Coag2D

Coag4D

CoagM*CoagL

HAEMOSTASIS TESTING SOLUTIONBeauty in simplicity, safety and support

CoagXL

advanced automation and qualitymanagement for speciality

testing

customizedPoint of Care solution simplicity and efficiency for

low volumes

CoagSYSTEM

Diagon Ltd. - Hungary1047 Budapest, Baross u. 48 - 52.tel.: (+36 1) 369 6500e-mail: [email protected]

*available from mid 2017


The challenge of diagnosing diseases with multiple genetic causesThe researchers used whole exome sequenc-ing to analyse all the genes in the genomes of nearly 7,400 unrelated patients with the goal of identifying the genetic cause of their conditions. They found a genetic cause in 2,076 of the 7,374 patients (28 percent); among these patients, 101 (approximately 5 percent) had two or more disease genes involved. If an individual has multiple defective genes, he or she may present with a complex set of clinical features that may lead to an imprecise diagnosis.“Clinically, multiple genetic causes can be missed because a patient may present with characteristics that overlap those of two different conditions, so the patient can be diagnosed with one or the other,” said Posey. “Alternatively, a patient’s clinical characteristics may not match those of any described condition, so the patient may be diagnosed with what is thought to be a new condition.”“In these situations, we, as physicians, have to think of the possibility that more than one gene might be involved in the patient’s disease,” said senior author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. “Our study shows the limitations of defining a disease according to what we see in the clinic alone. Our work shows the need to consider that a patient may have two or more genetic dis-eases, not one, and to send for a genomic test to help sort out the patient’s condition and causes of it.”

Paving a future toward more precise multiple genetic diagnoses“One of the contributions of our work involves utilization of a structured pheno-type ontology,” said Posey. “This computa-tional tool allows us to model complex clin-ical features (phenotypes) that can result when more than one gene is involved, in order to better understand, from the per-spective of the physician, how such cases may present in the clinic.”Furthermore, Dr. Regis James, now at Regeneron Pharmaceuticals, previously created OMIM Explorer while training as a graduate student at BCM. OMIM Explorer is a tool that helps analyse genomic data in the context of the clinical characteristics of the patient. Both James and his thesis advi-sor and mentor, Dr. Chad Shaw, director of bioinformatics at Baylor Genetics and asso-ciate professor of molecular and human genetics at Baylor, were contributors to this work.“It provides a more complete perspective of how genes and physical traits relate to each

other,” said Lupski.“My colleagues and I anticipate that in the future, geneticists, clinicians and mathema-ticians will work together using genetic and clinical information to make diagnostic and therapeutic decisions,” said Harel.Baylor College of Medicinehttp://tinyurl.com/jm44mr5

Copeptin levels associated with renal and cardiac disease

Type 1 diabetes patients with elevated albu-min in their urine had three times the risk of

life-threatening kidney and cardiac disease as those with normal levels, according to researchers at the University of Colorado Anschutz Medical Campus.The study, led by Dr. Petter Bjornstad, MD, of the Barbara Davis Center for Child-hood Diabetes at CU Anschutz, looked at 38 males with type 1 diabetes and albumin in their urine and 38 diabetic males with normal albumin levels. The subjects were recruited across the country from the Type 1 Diabetes Exchange Biobank.Albuminuria, or the presence of elevated albumin in the urine, is a marker for kid-ney disease. Bjornstad found that the copeptin was more than three times higher in patients with albuminuria. Copeptin is secreted along with arginine vasopressin or AVP from the pituitary gland and elevated levels appear to predict risk of cardiovas-cular mortality.AVP is a hormone that regulates urina-tion, though chronically high levels may cause kidney and vascular damage. But measuring AVP is extremely difficult due to its small size and short half-life. So researchers use copeptin as a surrogate. It is more stable, derived from the same molecule as AVP and can be more easily measured.In this study, researchers found that the men with type 1 diabetes and albuminuria had significantly greater concentrations of copeptin compared to diabetic males with normal albumin levels.“High levels of copeptin were associated with greater odds of albuminuria and impaired glomerular filtration rate which measures kidney function and stages of kidney disease,” Bjornstad said.The findings, he said, could open the door to new ways of treating diabetic kidney dis-ease and other illnesses. Specifically, a fam-ily of drugs called vaptans could be used to block excess vasopressin in these patients.“We think that vaptans or therapies

targeting vasopressin can delay or stop the development of diabetic kidney disease,” Bjornstad said. “There are clinical trials undergoing with vaptans in polycystic kid-ney disease, but to our knowledge no one is looking at vaptans and diabetic kidney disease yet.”The study has important limitations. The sample size was small and its design prevents determination of causality. It also focused on men and may not apply to young people or women. But the findings support earlier research done by Bjornstad in the Coronary Artery Calcification in Type 1 Diabetes Study (CACTI.)“We think these findings may have life-saving implications for those with diabetic kidney and heart disease,” Bjornstad said.University of Colorado Anschutz Medical Campushttp://tinyurl.com/jfsnggz

Gene discovered to cause rare, severe neurological disease

The scientists from the Montreal Neuro-logical Institute and Hospital at McGill University, led by Peter McPherson,

along with collaborators in Saudi Arabia, Jordan, Germany, and at SickKids Hos-pital and the University of Toronto, have discovered that a severe form of epilep-tic encephalopathy is caused by recessive loss-of-function mutations in the gene DENND5A. Epileptic encephalopathy is a rare but dev-astating sub-form of epilepsy that results in severe mental and physical disabilities in children from birth. It is often caused by improper development of the brain. Individuals with epileptic encephalopathy caused by mutations in DENND5A pre-sent with serious anomalies in brain struc-ture along with calcifications in the brain and altered facial features. Researchers performed whole exome sequencing on three children with epilep-tic encephalopathy from two families, one from Saudi Arabia and another from Jordan. Both families were consanguineous, mean-ing the parents were related to each other. This greatly increases the chance that rare mutations that are recessive and that cause no harm to the parents are expressed in the children. The whole exome sequencing, along with extensive and complex genetic analysis, revealed that recessive mutations in DENND5A were responsible for the dis-ease, with the Saudi family and the Jorda-nian family having different mutations but


in the same DENND5A gene. They found that mutations in DENND5A lead to a lack of the DENND5A protein, resulting in underdevelopment of the central nerv-ous system. The protein expressed from the DENND5A gene is present at highest lev-els in the nervous system especially while the brain is developing, corroborating the evidence that mutations in the gene cause epileptic encephalopathy. The researchers discovered that the DENND5A protein controls the move-ment of receptors for key developmental factors called neurotrophins. Disruption of DENND5A function leads to altered levels of these receptors, which could explain why loss of DENND5A leads to the severe neurologi-cal developmental defects in the patients. Epilepsy affects approximately three per cent of the world population, and epilep-tic encephalopathy is a rare sub-form of the disease. It is difficult to say how many children with epileptic encephalopathy have the DENND5A mutations, but now that the gene has been identified as a cause, researchers around the world can begin to test patients for mutations in this gene. This finding also improves our understand-ing of neuronal development. The obser-vation that loss-of-function mutations in DENND5A causes epileptic encepha-lopathy suggests that DENND5A protein controls membrane trafficking pathways critical for normal neuronal development and strengthens the argument that pro-tein trafficking processes in cells are criti-cal for normal neuronal development and function.“Our study demonstrates the impor-tance of membrane trafficking in neu-ronal development and it provides a new

pathophysiological mechanism for this disease type. This will allow physicians around the world to test if mutations in DENND5A are causing the disease in their patients, and also to provide genetic coun-selling for affected families,” says Dr. Chan-shuai Han, the lead author on the study.The Montreal Neurological Institute and Hospital http://tinyurl.com/jfb7aho

Biochemical test for the diagnosis of Parkinson’s disease

Misfolded proteins associated with Parkinson’s disease were detected in cer-ebrospinal fluid by scientists at McGov-

ern Medical School at The University of Texas Health Science Center at Houston (UTHealth), paving the way to develop-ment of a biochemical test for the diagno-sis of the disease.The research was led by Claudio Soto, Ph.D., professor in the Department of Neurology and the director of the George and Cynthia Mitchell Center for Alzheimer’s disease and Related Brain Disorders at UTHealth.Parkinson’s disease (PD) is a degenerative disorder of the brain that initially affects motor skills, causing tremors, stiffness, slowness of movement and impaired bal-ance. As it progresses, patients may develop cognitive problems, psychiatric alterations and dementia. There are no current labora-tory or blood tests that have been proven to help in diagnosis. Because the disease can be difficult to diagnose accurately, diagno-sis is sometimes made by ruling out other neurological diseases.

Using a technology developed by Soto that was shown in previous studies to detect misfolded proteins associated with diseases such as Creutzfeld-Jacob and Alzheimer’s disease, researchers targeted misfolded alpha-synuclein (aSyn) aggregates as a way of developing a sensitive biochemical diagnosis for PD. The Protein Misfolding Cyclic Amplification (PMCA) technology was able to detect very small amounts of the misfolded protein circulating in cer-ebrospinal fluid.“Of significant interest is that the amount of aSyn detected correlates with the sever-ity of the disease and in two of the control samples, aSyn was detected and those peo-ple later developed clinical symptoms of PD,” Soto said.The research included blind screenings of cerebrospinal fluid of two cohorts of 76 PD patients, as well as controls of 65 peo-ple who were healthy or affected by other neurological disorders, 18 affected by neu-rodegenerative diseases and 14 affected by Alzheimer’s disease.Since cerebrospinal fluid is removed through spinal taps, which are invasive and painful, the hope is that future research would enable optimization of the PMCA assay to detect aSyn in blood or urine.“The hope is that we could use aSyn-PMCA to detect PD in patients before they develop symptoms, and those patients could be entered into clinical trials for novel treatments that might prevent, cure or delay the progression of the disease before substantial and irreversible damage of the brain,” Soto said.The University of Texas Health Science Center at Houstonhttp://tinyurl.com/j98zslw



Highly sensitive stool DNA testing of Fusobacterium nucleatum as a marker for detection of colorectal tumours in a Japanese populationSuehiro Y, Sakai K, Nishioka M, Hashimoto S, Takami T, Higaki S, Shindo Y, Hazama S, Oka M, Nagano H, Sakaida I, Yamasaki T. Ann Clin Biochem. 2016; pii: 0004563216643970. [Epub ahead of print]BACKGROUND: Accumulating evidence shows an over-abun-dance of Fusobacterium nucleatum in colorectal tumour tissues. Although stool DNA testing of Fusobacterium nucleatum might be a potential marker for the detection of colorectal tumours, the diffi-culty in detecting Fusobacterium nucleatum in stool by conventional methods prevented further explorations. Therefore, we developed a droplet digital polymerase chain reaction (PCR) assay for detecting Fusobacterium nucleatum in stool and investigated its clinical utility in the management of colorectal tumours in a Japanese population.METHODS: Feces were collected from 60 healthy subjects (control group) and from 11 patients with colorectal non-advanced adeno-mas (non-advanced adenoma group), 19 patients with colorectal advanced adenoma/carcinoma in situ (advanced adenoma/carci-noma in situ (CIS) group) and 158 patients with colorectal cancer of stages I to IV (colorectal cancer group). Absolute copy numbers of Fusobacterium nucleatum were measured by droplet digital PCR.RESULTS: The median copy number of Fusobacterium nucleatum was 17.5 in the control group, 311 in the non-advanced adenoma group, 122 in the advanced adenoma/CIS group, and 317 in the colo-rectal cancer group. In comparison with that in the control group, the Fusobacterium nucleatum level was significantly higher in the non-advanced adenoma group, the advanced adenoma/CIS group and the colorectal cancer group.CONCLUSIONS: This study illustrates the potential of stool DNA testing of Fusobacterium nucleatum by droplet digital PCR to detect individuals with colorectal tumours in a Japanese population.

A genome-wide assessment of variations of primary colorectal cancer maintained in metastasesCai Z, Han S, Li Z, He L, Zhou J, Huang W, Xu Y. Gene 2016; 595(1): 18–24.Colorectal cancer (CRC) is a highly heterogeneous disease that is the third leading cause of cancer-related deaths worldwide. This study presents a genome-wide assessment of variations in primary colorectal cancer maintained in metastases, even in distant metas-tases. The purpose of this study was to determine whether intratu-mor heterogeneity is related to disease progression and metastasis in CRC. The results showed that 882 single nucleotide polymor-phism (SNP) associated genes and 473 copy number variant (CNV) associated genes specific to metastasis were found. In addition, 57 SNPs mapped to miRNAs showed significant differences between primary tumours and metastases. Functional annotation of metas-tasis-specific genes suggested that adhesion and immune regula-tion may be essential in the development of tumours. Moreover, the locus rs12881063 in the fourteenth chromosome was found to have a high rate of the G/C type in metastases. The rate of the G/C type in nearby lymph node metastases was 66.7%, while the rate of the G/C type in distance lymph node metastases was 83.3%. These results indicate that rs12881063 may be the basis for clinical diagnosis of CRC metastasis.

High tumour mast cell density is associated with longer survival of colon cancer patientsMehdawi L, Osman J, Topi G, Sjölander A. Acta Oncol. 2016; 55(12): 1434–1442.BACKGROUND: Inflammatory cells and inflammatory mediators play an important role in colorectal cancer (CRC). Previous studies have shown that CRC patients with increased expression of cysteinyl leukotriene receptor 1 (CysLTR1) have a poorer prognosis, and

Cysltr1-/- mice display fewer intestinal polyps. However, the role of mast cells (MCs) in colon cancer progression remains unclear. The aim of the present study was to explore the relevance of MCs in CRC.MATERIAL AND METHODS: A tissue microarray from 72 CRC patients was stained with MC anti-tryptase and -chymase antibod-ies. Mouse colon tissue was stained with MC anti-tryptase antibody. Immunohistochemistry was used to identify MCs in patients and mice.RESULTS: Patient colon cancer tissue had in comparison with normal colon tissue a reduced number of MCs, predominantly of chymase-positive cells. Further analysis revealed that patients with a relative high MCD in their cancer tissues showed significantly longer overall survival compared to those with a low MCD [hazard ratio (HR) 0.539; 95% confidence interval (CI), 0.302–0.961]. Similar results were observed in subgroups of patients with either no distant metastasis (p = 0.004), or <75 years (p = 0.015) at time of diagnosis. Multivariate Cox analysis showed that MCD independently corre-lated with reduced risk of death in colon cancer patients (HR 0.380; 95% CI 0.202-0.713). Additionally, a negative correlation was found between cytoplasmic CysLTR1 expression and number of MCs. In agreement, in the CAC mouse model, Cysltr1-/- mice showed signifi-cantly higher MCs in their polyp/tumor areas compared with wild-type mice.CONCLUSION: A high MCD in cancer tissue correlated with longer patient survival independently from other risk factors for CRC. The concept that MCs have an anti-tumor effect in CRC is further supported by the findings of a negative correlation with CysLTR1 expression in patients and a high MCD in colon polyps/tumors from CysLTR1-/- mice.

Are hemorrhoids associated with false-positive fecal immunochemical test results?Kim NH, Park JH, Park DI, Sohn CI, Choi K, Jung YS. Yonsei Med J. 2016; 58(1):150–157.PURPOSE: False-positive (FP) results of fecal immunochemical tests (FITs) conducted in colorectal cancer (CRC) screening could lead to performing unnecessary colonoscopies. Hemorrhoids are a possible cause of FP FIT results; however, studies on this topic are extremely rare. We investigated whether hemorrhoids are associated with FP FIT results.MATERIALS AND METHODS: A retrospective study was con-ducted at a university hospital in Korea from June 2013 to May 2015. Of the 34,547 individuals who underwent FITs, 3946 aged ≥50 years who underwent colonoscopies were analysed. Logistic regression analysis was performed to determine factors associated with FP FIT results.RESULTS: Among 3946 participants, 704 (17.8%) showed posi-tive FIT results and 1303 (33.0%) had hemorrhoids. Of the 704 participants with positive FIT results, 165 had advanced colorectal neoplasia (ACRN) and 539 had no ACRN (FP results). Of the 1303 participants with hemorrhoids, 291 showed FP results, of whom 81 showed FP results because of hemorrhoids only. Participants with hemorrhoids had a higher rate of FP results than those without hem-orrhoids (291/1176, 24.7% vs. 248/2361, 10.5%; p<0.001). Addition-ally, the participants with hemorrhoids as the only abnormality had a higher rate of FP results than those experiencing no such abnor-malities (81/531, 15.3% vs. 38/1173, 3.2%; p<0.001). In multivariate analysis, the presence of hemorrhoids was identified as an independ-ent predictor of FP results (adjusted odds ratio, 2.76; 95% confidence interval, 2.24-3.40; p<0.001).CONCLUSION: Hemorrhoids are significantly associated with FP FIT results. Their presence seemed to be a non-negligible contribu-tor of FP results in FIT-based CRC screening programmes.

– Dec 2016/Jan 2017 SCIENTIFIC LITERATURE REVIEW: Colorectal cancer

Beckman Coulter Life Sciences has launched an international HIV/AIDS award at the 2016 conference for the African Society for Laboratory Medicine (ASLM) recently held in Cape Town, South Africa (December 3 to 8).The annual award is part of the company’s

global CARES Initiative dedicated to helping people who are living with HIV/AIDS. Beckman Coulter’s CARES award is designed to recognize individuals who have shown ‘care, dedication and commit-ment’ in their communities as part of the fight against HIV/AIDS. The winner will receive a $5,000 (€4,700) donation in their name to one of the selected causes, with the three individual stories that receive the most nominations publicized around the world on the CARES Initiative website.Potential winners can be nurses, healthcare workers, national coordi-nators, lab scientists and even clinicians; or lay people who are active in community outreach work. This could include a social worker pro-viding AIDS counselling.CARES supports the UNAIDS 90-90-90 target to ensure that by the year 2020, 90% of people living with HIV will know their status, 90% of those with diagnosed HIV infection will receive sustained antiret-roviral therapy, and 90% of all people receiving antiretroviral therapy will have viral suppression.It focuses on providing innovative solutions for the monitoring of HIV and AIDS treatment. CARES was inspired by the work of Pro-fessor Debbie Glencross, a South African laboratory pathologist, who found a different and less expensive way to measure a patient’s CD4 count. While this is intended as an international award, in its first year, the award will focus on recognizing the dedication of people in Africa, one of the areas in the world most affected by HIV/AIDS. The 2017 award will be launched at the annual meeting of the African Society for Laboratory Medicine (ASLM), a pan-African professional body aiming to improve laboratory services.

Recognition for unsung heroes Samuel Boova, Beckman Coulter’s Director Alliance Development, High Burden HIV Markets, said: “The award is to give a platform to the work and stories of those we see as the unsung heroes of indi-vidual communities. These are people who have shown individual dedication, commitment and courage or who have made a difference in the battle against HIV/AIDS. “However, it is not just the final winner we want to publicaly recog-nize. We hope the award will encourage communities to learn about and honour the work of every nominee, so that more people will come forward to help and support those living with HIV/AIDS.”Nominations must first be made via the CARES website. Once a name has been nominated, the local community will be given the opportu-nity to vote in support. People with the greatest number of votes will be put forward for the final assessment panel. Rules of entry and full details are available in full from http://www.beckman.com/cares.Mr Boova gave the following examples of ordinary people who sup-port their local communities in the field of HIV/AIDS. “We are look-ing for dedicated and committed individuals like these who work in the community helping others to live with, and manage, the disease,” he added.

Potential NomineesThe first example is how a young HIV positive woman in Uganda was inspired and empowered by a community charity, PINA (People In Need Agency), to rebuild her life and become an advocate herself for young people living with HIV. This was the objective of PINA when it was first set up by a local case worker – to work with young people, helping them overcome the stigma of living with HIV and rebuild their self-esteem. Mr Boova also pointed out that there are many women in rural Africa who walk miles every day to see patients to ensure they are compliant with their medications. Medication alone does not help without the commitment of these women – and they have to walk many miles between patients each day and every day, whatever the conditions.www.beckman.com/cares

– Dec 2016/Jan 201729INDUSTRY NEWS

www.oriondiagnostica.com

Orion GenRead®

CampylobacterWhen prompt diagnosis matters

Orion GenRead Campylobacter is a molecular

test for detection of Campylobacter species

C. jejuni, C. coli and C. lari. This ready-to-use

kit offers fast and sensitive results and is used

with the Orion GenRead instrument.

Orion GenRead product portfolio:

» Available tests:

Campylobacter, C. diffi cile

» Next analytes:

Infl uenza A & B, RSV


Beckman Coulter launches annual CARES award as part of initiative to help people living with HIV/AIDS

DiaSys celebrates 25th anniversary with essential product launches

New enzymatic test for HbA1c The worldwide rapid rise in diabetes is a challenge for treatment as well as for diagnosis and monitoring. With the new test HbA1c net FS, DiaSys Diagnostics System has introduced an innovative product with highest accu-

racy setting new standards for reliable results in diagnosing and monitoring diabetes. Based on enzymatic measurement Hba1c net FS ensures highest specificity without interferences by hemoglobin variants as well as outstanding precision. Using the fully automated process including on-board hemolysis on the DiaSys analysers, BioMajesty® and respons®910, labs of every size can optimize their workflow for HbA1c. Several other major product launches were made in time for DiaSys’ 25th anniversary. Under the trademark QDx DiaSys announced a point-of-care product line comprising test strips and devices for various diagnostic fields such as cardiac, vita-min D, allergy, anemia, lipids and urinalysis. Furthermore, respons®910UP was presented offering improved handling and performance for the small to medium lab (up to 150 tests/hour).25 years of success as a mid-size company in the challeng-ing and ever changing market of in-vitro diagnostics - DiaSys takes this opportunity to thank all employees, customers and partners for their contribution and confidence and looks for-ward to a common prospering future.www.diasys-diagnostics.com

Can genetic testing determine antimicrobial susceptibility? EUCAST experts say not yet…

Experts at the European Com-mittee on Anti-microbial Sus-

ceptibility Testing (EUCAST), who define the optimal drug concentrations to inhibit the growth of pathogens, have found that genetic methods cannot yet be used to test for suscepti-bility in a number of important bacterial species. Although there have been advances in whole genome sequencing (WGS), which allows to determine the DNA sequence of an organism’s genome at a single time, there are still several hurdles to over-come before this type of genetic testing can be used in clinical laboratories, they concluded.A EUCAST subcommittee dedicated to reviewing the role of WGS in antimicrobial susceptibility testing (AST) consid-ered the most recent published evidence on the use of whole genome sequencing as a tool for susceptibility testing. The group – comprising of over a dozen leading experts and led by Prof. Neil Woodford, Head of Public Health England’s Antimi-crobial Resistance and Healthcare Associated Infections Refer-ence Unit – did not rule out that it will one day be possible for a single assay to predict how a species of bacteria will respond to a specific antimicrobial drug, but there is little evidence to suggest we will reach this point in the near future. EUCAST’s technical data coordinator, Prof. Gunnar Kahlmeter of the Central Hospital, Växjö, Sweden, said that it is premature to suggest that breakpoints and recommendations for pheno-typic susceptibility testing will no longer be required as genetic methods will supersede them any time soon. “To be of use in a clinical situation, WGS will need to predict antimicrobial resist-ance and also antimicrobial susceptibility, which are two quite different things. It will also be necessary for WGS to quantify the degree of resistance for an organism, something which is currently not possible.” The group has chosen to compare how WGS can predict whether or not the organism belongs to the wild type (is with-out resistance mechanisms) with the same prediction per-formed through the use of the epidemiological cut-off values (ECOFFs) developed by EUCAST. Whether or not and in that case how this can be extended to clinical breakpoints is dis-cussed in the paper.The EUCAST subcommittee also highlighted that there is cur-rently no way to assess how accurate different WGS laboratories are, and that there is an urgent need to establish a single public database of all known resistance genes within different bacterial species so that data can be shared and compared more easily.The EUCAST experts also note that WGS technology is currently limited because it cannot be used to analyse specimens directly – bacteria can only be sequenced once they have been cultured. This inevitably leads to significant time delays and additional financial costs, which is usually prohibitive for most laboratories.EUCAST recommends that whole-genome sequencing should be made a research and funding priority in the future to expand on our current knowledge and to develop more sophis-ticated prediction tools. As bacteria continue to develop mul-tiple resistance mechanisms, unravelling the genetics of their interaction with antimicrobials will become even more chal-lenging and even more necessary, particularly as we face the spectre of extreme drug resistance and global failure of some antimicrobials.www.escmid.org

INDUSTRY NEWS – Dec 2016/Jan 2017 30

FREE 25OH VITAMIN D ELISAThe only available Kit on the Market

Better marker for Vitamin D activity than total 25OH Vitamin D in case of :

Cancer

Obesity and Pregnancy

Hormone replacement therapy

Liver- and Renal Failure

Proteinuria

Cystic fibrosis

Better reflects Vitamin D deficiency in African Americans and in Asian Ethnicities.

Key assay features :

Direct measurement of free 25OH Vitamin D

No sample Pre-treatment

Calibrated against Rate Dialysis

Low 10μl sample volume

MEET US AT MEDLAB DUBAI

AT OUR BOOTH Z2.G51

ManManManMananannnnannnufufufaufafaufaufuufuufau ctctctuctuctuctuctuctuctucctctctuctucturedredredredddddddd bbbbbybybbyby

DIADIAIAIAsousououuuuuourrrcrcrcrceceerceee ImImmmmmImImmmI munmunmunmmmunmunmunmumumunnmumunooooAoAoAsoAsooooAsoAoAsAsAsA sayasaysaysayysays Ss SSs Ss Ss S.A..A..A..A --- RuRueRueRueR dududuu BoBoBoBoBosqusquuuet et t 22 -2 -2 -2 - 11313131 448448 48 LouLouuvaivvaivaiiainn-Ln-Ln-LLa-Na-a-Neueuvve e -e - BeBeeB llglgil umum mumTTelTelTele +3+3+3+333222 12 12 12 1122 10 80 80 80 80 80 80 84 94 94 94 94 94 9999 19 19 19 1 -1 - FaFax +x +32 32 2 10 10 84884844 99 99 9999 96 96 696 9 - w- www.ww.www ddiadiadidid sousourcercrcee-d--dididi-diagnagnagngnnagnosossttooo icsics.coommmm


Manual pipettes Unlike traditional pipettes which utilize a single rotating plunger to set volumes, the new EVOLVE manual pipette range from INTEGRA features

an innovative approach that allows users to set volumes more than ten times faster. Available in single, eight and twelve chan-nel formats, covering a volume range of 0.2 – 5,000 μl, the ultra-lightweight, well balanced design of the EVOLVE enhances pro-ductivity and comfort even during prolonged pipetting sessions.

INTEGRA www.cli-online.com & search 27310

New generation POC test for stomach-specifi c biomarkers

Different from the previous test ver-sions, the new Gas-troPanel Quick test is designed for the point-of-care (POC) measure-ment of four stom-

ach-specific biomarkers in the blood: pepsinogen I (PGI), pepsinogen II (PGII), gastrin-17 (G-17) and Helicobacter pylori IgG antibodies. In the new test version, sample pro-cessing is based on a lateral flow (LF) principle, with quan-titative marker detection by double Ab (Ag) sandwich tech-nique. The results are immediately read by the LF reader, which increases the test acceptance among clinicians, who are now capable of making the diagnosis onsite. The main indications of use for the GastroPanel remain unchanged. The test is designed for the diagnosis of (1) H. pylori infec-tion (2) atrophic gastritis (AG), and (3) functional disor-ders among symptomatic (dyspeptic) patients as well as for screening of asymptomatic subjects for gastric cancer risk. Also the recently introduced interpretation algorithm remains valid, based on eight distinct biomarker profiles, five of which reflecting morphological abnormalities while the other three reflect a functional disorder.

BIOHIT OY www.cli-online.com & search 27402

PRODUCT NEWS – Dec 2016/Jan 2017 31

Clinical Chemistry Anti-CCPAnti-CCP testing in your chemistry workflow

www.axis-shield.com

Proven Clinical Performance• Excellent specificity for Rheumatoid Arthritis

Convenience• For the first time Anti-CCP can be consolidated with other

serology markers into your routine chemistry workflow

• Simple direct assay with only two reagents

Flexibility• Applicable to many different clinical chemistry analysers


High-volume specialty hemostasis analyser Siemens Healthineers has recently launched the CE-marked Atellica COAG 360 System, a fully automated high-volume coagulation analyser designed to streamline and unify hemo-stasis testing. Th e Atellica COAG 360 System is the fi rst analyser to unify fi ve methodologies on one testing platform

- clotting (optical and optomechanical), chromogenic, immunologic, high-sensitivity luminescence based immunoassay (LOCI) technol-ogy, and platelet aggregation testing. Th is unifi cation enables labo-ratories to potentially replace up to three stand-alone systems with just one analyser, saving space, simplifying inventory management, reducing maintenance - reducing the overall cost of ownership. Th e system also provides intelligent reagent and consumable manage-ment - including true continuous loading and unloading, and real-time monitoring - extending walkaway time, providing uninter-rupted sample measurement, and enabling faster availability of test results. PSI checks and advanced preanalytics detect underfi lled or overfi lled samples and accurately identify assay-specifi c hemolytic, icteric, and lipemic (HIL) interferences using nine pre-defi ned levels. Th e dedicated, automated module for the detection of HIL interfer-ences improves consistency and reproducibility of results compared to a visual check of samples. Th is helps to advance preanalytical pro-tocols and improve the quality of hemostasis test results. By integrat-ing high-sensitivity immunoassay using LOCI technology and plate-let aggregation testing, Atellica COAG 360 System provides faster test results for all samples and increases insight into hemostatic disorders. Patented LOCI technology from Siemens Healthineers enables labs to test small volume samples with a high level of precision, while reducing the risk of interference. Additionally using LOCI technol-ogy, determination of F1+2 (a coagulation factor that aids in risk assessment of thrombosis and anticoagulant therapy monitoring) is automated with an assay turnaround time of less than 15 minutes - four times faster than the current testing protocol. To support labs in need of fully automated multidisciplinary testing, the Atellica COAG 360 System connects with Aptio Automation. With a rapid through-put on samples requiring multiple specialty tests, the Atellica COAG 360 System complements the fast routine testing throughput of the Sysmex CS-5100 System. Th e system is now available in Europe.

SIEMENS HEALTHINEERSMEDLAB DUBAI Z4. E10 www.cli-online.com & search 27412

031_036_cli_dec.indd 31 14/12/16 19:37

New connectivity for point-of-care HbA1c analysersA new connectivity package for EKF’s Quo-Test and Quo-Lab HbA1c analysers enables secure bi-directional communication between these POC analysers and a multitude of central data management sys-tems. Using the industry recognized

POCT1-A2 communication protocol, EKF’s connectivity solution unlocks a host of new features aimed at improving security and qual-ity control (QC) for diabetic HbA1c testing. Th e new connectivity package includes a proprietary connector interface box, cables and a soft ware upgrade. Th is enables EKF’s HbA1c analysers to automati-cally transmit patient data to the majority of Lab Information Man-agement Systems (LIMS) or Hospital Information Systems (HIS). Traceability and results recall speed are improved by use of patient ID and increased demographic data (such as family name and date of birth). Th ese can now be recorded through either selecting from a pre-approved list or via the barcode scanner and keyboard. Also ensuring the integrity of results generated at the POC, security and QC are enhanced on Quo-Lab and Quo-Test through user ID and QC lockout functions which are included in the connectivity pack-age. By restricting access to trained users only, the lockout functions minimize the chances of user error and adhere to security protocols in many institutions. Furthermore, unauthorized users will be pre-vented from accessing patient information. Multiple user-defi ned QC lockout options are also available to POCT coordinators in order to enforce regular testing of QC materials and ensure compliance. HbA1c, or glycated hemoglobin, is well recognized as a reliable meas-ure for glycemic control and managing patients with diabetes. As HbA1c levels refl ect average circulating glucose concentration over a

two to three month period, this means that it can off er greater clini-cal information than a single glucose measurement. Quo-Lab and Quo-Test analysers deliver lab-quality results for HbA1c from 4μL of blood within 4 minutes, enabling the consulting clinician to give immediate feedback to a patient. In addition to ensuring the reliabil-ity of results, the new connectivity package also allows the clinician to add commentary to any test result, further enhancing the monitoring and management of diabetes in a point-of-care setting.

EKF DIAGNOSTICS www.cli-online.com & search 27413


IMMUVIEW® S. PNEUMONIAE AND L. PNEUMOPHILA URINARY ANTIGEN TEST

The first lateral flow strip test for detection of both Pneumococcus and Legionella in one test!

Results in 15 minutes

Reduce health care costs

Improve diagnostics

SSI DiagnosticaRapid tests • ELISA • PCR • AntiseraW ssidiagnostica.com @ [email protected]



Th e multiparameter component-based test EUROLINE DPA-Dx Peanut allows diff erentiation of primary peanut allergy from pollen-associated cross reactions, enabling assessment of the patient’s risk for severe reactions. In the test, specifi c IgE antibodies against seven defi ned components from peanut and the major birch pollen allergen Bet v 1 are analysed in parallel using immunoblot technology. Patients who show IgE antibod-ies to the peanut seed storage proteins Ara h 1, h 2, h 3, h 6 and h 7 or the lipid transfer protein h 9 are likely to have a primary sensitization to peanut and a higher risk of a severe reaction. Th e severity of the allergy is, moreover, greater when multiple high-risk components are involved. Reactions with the PR 10 protein Bet v 1 (homologue of Ara h 8 from peanut) or the pro-fi lin Ara h 5 indicate a pollen-associated cross reaction and are associated with milder symptoms and a lower risk of a severe reaction. Th e EUROLINE DPA-Dx provides an extremely wide ranging screening in one assay. In suspected cases of peanut allergy, the test identifi es reactions arising from a pollen-asso-ciated food allergy, which present a lower risk for the patient. Th e assay requires only a small amount of serum (100 to 400 μl), making it ideal for pediatrics. Automated processing and evaluation are available. Peanut allergy can be one of the most severe forms of allergy, with patients at a high risk of life-threat-ening systemic reactions, including anaphylactic shock. Even small amounts of peanut can trigger a severe reaction. Classic diagnostics based on allergen extracts cannot, however, dif-ferentiate between a primary sensitization against peanut and a pollen-associated food allergy due to a cross reaction. Only component-based diagnostics can deliver this decisive infor-mation. Establishing a precise diagnosis facilitates decision-making on treatment and disease management. Patients with a sensitization to high-risk components should strictly avoid the allergen source and always carry an emergency set. Patients with only a birch pollen-associated food allergy do not nor-mally have to follow a strict peanut-free diet. If the patient also suff ers from birch allergy related symptoms, specifi c immuno-therapy for the birch pollen allergy can be undertaken, which is likely to additionally relieve the peanut-induced symptoms.

EUROIMMUN www.cli-online.com & search 27400

031_036_cli_dec.indd 32 14/12/16 19:37

Ethanol test in serum, plasma and urine

BioSystems launches a new reagent for measurement of etha-nol in serum, plasma and urine. Ethanol is a small molecule found mainly in alcoholic beverages, medical preparation and food. Their consumption is widespread but often abusive. Therefore, ethanol determination is one of the most common diagnostic tests in the toxicology and forensic laboratory and it is used for both medical and legal purposes. Ethanol acts as a central nervous system (CNS) depressant and can cause loss of attention, stupor, coma and possible death. BioSystems introduces this test in dedicated presentation for the A15 and A25 analysers (code 12789: 1 x 10mL + 1 x 7 mL) and for the BA400 analyser (21789: 2 x 20mL + 2 x 7mL). It is calibrated using Ammonia/Ethanol/CO2 Calibrator (BioSystems cod. 18065). The reagent offers an improved detection limit (8 mg/dL) and is optimized to work with the company’s analys-ers although it can also be adapted to other models. It is rec-ommended to use the Ammonia/Ethanol/CO2 Control level I (cod. 18063) and II (cod. 18064) to verify the accuracy of the measurement procedure.

BIOSYSTEMS MEDLAB DUBAI Z5. C39 www.cli-online.com & search 27399

– Dec 2016/Jan 201733PRODUCT NEWS

Tailor made solutions for individual customer needs!

www.diasys-diagnostics.com

DiaSys Diagnostic Systems and

Tosoh Bioscience present consolidation

of clinical chemistry and immunoassay

analysis; either simply with a middle ware

or fully automated with a track system.

Next Level of Laboratory Automation


Mutation assay for MPN diagnosis Launched in Europe, the CE-IVD marked calreticulin (CALR) mutation assay aids in establishing the diagno-sis of myeloproliferative neoplasms (MPN). Th e new ipsogen CALR RGQ PCR Kit (ipsogen CALR assay) is

intended for the detection of CALR mutations in genomic DNA from subjects suspected of MPN. It enables identifi cation of the two majors CALR mutations, Type 1 and Type 2, and detects additional mutations in the CALR exon 9 region. Th e ipsogen CALR assay simplifi es CALR testing by covering various relevant mutations in a real-time PCR-based assay to deliver multiple clinical results in less than a working day. Th e test runs on QIAGEN’s QIAsymphony and Rotor-Gene (RGQ) platforms, employing the CE-IVD marked Rotor-Gene Q MDx 5Plex HRM Platform real-time cycler with auto-mated analysis and interpretation using the Rotor Gene AssayMan-ager soft ware. Maximum throughput fl exibility is achieved by DNA sample processing from peripheral blood using either the manual QIAamp DSP DNA Blood Mini Kit or the fully automated sample processing on the QIAsymphony SP instrument. Th e new ipsogen CALR RGQ PCR Kit is highly synergistic with the CE-IVD marked ipsogen JAK2 RGQ PCR Kit, for detecting the V617F mutation in the janus kinase 2 (JAK2) gene, as CALR mutations can be detected from the same patient sample. Th e ipsogen CALR assay is the latest addi-tion to QIAGEN’s ipsogen portfolio of assays for both common and rare leukemia types. MPN are a group of blood cancers character-ized by signifi cant symptoms and complications such as thrombosis

(blood clots) and a high risk of transformation into acute leukemia. MPN include polycythemia vera (PV), essential thrombocythemia (ET) and various forms of (primary) myelofi brosis (PMF), and aff ect nearly 250,000 patients in Europe and 300,000 patients in the US. Th e combined annual incidence rate for MPN worldwide is roughly 2.5 in every 100,000. Th e importance of CALR mutations in MPN was fi rst described in December 2013 in two important papers published in the New England Journal of Medicine (Klampfl T. et al. and Nanga-lia J. et al). In April 2014 QIAGEN obtained the exclusive worldwide license rights to intellectual property covering specifi c mutant alleles of the CALR gene from the Research Centre for Molecular Medicine of the Austrian Academy of Sciences, whose scientists led the team that discovered the presence of CALR mutations in MPN. Earlier this year, mutations in CALR were included in addition to JAK2 mutations as a major diagnostic criterion for MPN in the updated WHO guide-lines for the classifi cation of myeloid neoplasms and acute leukemia. Both CALR and JAK2 V617F mutations were recently described in clinical guidelines to have prognostic signifi cance. Th is emphasizes the outstanding importance of CALR mutations, together with JAK2 mutations, in the diagnosis and prognosis of MPN. QIAGEN also has an exclusive license to intellectual property rights for the detec-tion of the V617F specifi c mutation in the JAK2 gene for diagnostic purposes. Th e company’s ipsogen product line includes more than 20 assays in hemato-oncology testing.

QIAGENMEDLAB DUBAI Z5. G10 www.cli-online.com & search 27411

031_036_cli_dec.indd 33 14/12/16 19:37

Compact automated coagulometerTh e new CoagL autoanalyser from DIAGON is the last-est addition to its portfolio of specially designed high qual-ity hemostasis testing systems. Coag systems off er advanced, fl exible and effi cient automa-tion for routine and specialty

testing coagulation labs and is supported by the same test technolo-gies, reagents, cuvettes and consumables with low operation and maintenance costs. CoagL is a compact 4 channel coagulometer designed to include everything that could be improved in its category: it has extremely user friendly soft ware with a high level of customi-zation, off ers real-time and post-run curve analysis, random access, refl ex testing, and fi rst tube preanalytical optical interference check. Th e company’s product range also includes a convenient and sensitive photo-optical CoagS POC INR test using recombinant technology, high tech Coag2D and Coag4D multichannel manual coagulometers and the 300 PT test/hour CoagXL fully automated coagulometer. All systems come with a complete reagent system, controls and calibra-tors both in liquid and lyophilyzed formats. Diagon off ers Coag Sys-tems for distribution and for customized OEM cooperation.

DIAGON MEDLAB DUBAI Z5. G30 www.cli-online.com & search 27367


Over 6000 senior trade visitors from Asia's fastest growing markets.

Covers the entire industry spectrum.

Healthcare - Pharma - Wellness and CleanRoomTech.

i

A YEAR’S WORK IN

3 DAYS - IN ASIA’S BEST

VENUE.

www.abcex.com

tttttttttttttttrrrrrrrrrrrrrrraaaaaaaaaaaaaaddddddddddddddeeeeeeeeeeeeeee vvvvvvvvvvvvvvviiiiiiiiiiiiissssssssssssssiiiiiiiiiiiiiitttttttttttttttoooooooooooooorrrrrrrrrrrrrrrssssssssssssss fffffffffffffffrrrrrrrrrrrrrrroooooooooooooommmmmmmmmmmmmmm AAAAAAAAAAAAAAAssssssssssssssiiiiiiiiiiiiiiaaaaaaaaaaaaaa''''''''ssssssssssssss fffffffffffffffaaaaaaaaaaaaaassssssssssssssttttttttttttttteeeeeeeeeeeeeessssssssssssssttttttttttttttt ggrroowwiiiiiiiiiinnnnnnngg mmaarrkkkkkkkkkkkkkkeettttttttttsssggggggggggggggrrrrrrrrrrrrrrroooooooooooooowwwwwwwwwwwwwwwiiiiiiiiiiiiiinnnnnnnnnnnnnnngggggggggggggg mmmmmmmmmmmmmmmaaaaaaaaaaaaaarrrrrrrrrrrrrrrkkkkkkkkkkkkkkeeeeeeeeeeeeeeetttttttttttttttssssssssssssss.............

CCCCCCCCCCCCCCoooooooooooooovvvvvvvvvvvvvvveeeeeeeeeeeeeerrrrrrrrrrrrrrrssssssssssssss ttttttttttttttthhhhhhhhhhhhhhheeeeeeeeeeeeeee eeeeeeeeeeeeeeennnnnnnnnnnnnnntttttttttttttttiiiiiiiiiiirrrrrrrrrrrrrreeeeeeeeeeeeeeiiiiiiiiiiiiiinnnnnnnnnnnnnnndddddddddddddduuuuuuuuuuuuuusssssssssssssstttttttttttttttrrrrrrrrrrrrrrryyyyyyyyyyyyyyy sssssssssssssspppppppppppppppeeeeeeeeeeeeeecccccccccccccctttttttttttttttrrrrrrrrrrrrrrruuuuuuuuuuuuuummmmmmmmmmmmmmm..........

HHHHHHHHHHHHHHHeeeeeeeeeeeeeeaaaaaaaaaaaaaallllllllllllllttttttttttttttthhhhhhhhhhhhhhhccccccccccccccaaaaaaaaaaaaaarrrrrrrrrrrrrrreeeeeeeeeeeeee ----- PPPPPPPPPPPPPPPhhhhhhhhhhhhhhhaaaaaaaaaaaaaarrrrrrrrrrrrrrrmmmmmmmmmmmmmmmaaaaaaaaaaaaaa ----- WWWWWWWWWWWWWWWeeeeeeeeeeeeeellllllllllllllllllllllllllllnnnnnnnnnnnnnneeeeeeeeeeeeeeessssssssssssssssssssssssssssaaaaaaaaaaaaaannnnnnnnnnnnnnndddddddddddddd CCCCCCCCCCCCCClllllllllllllleeeeeeeeeeeeeeeaaaaaaaaaaaaaannnnnnnnnnnnnnnRRRRRRRRRRRRRRoooooooooooooooooooooooooooommmmmmmmmmmmmmmTTTTTTTTTTTTTTTeeeeeeeeeeeeeeecccccccccccccchhhhhhhhhhhhhhh.........

OOOOOOOOOOOOOOvvvvvvvvvvvvvvveeeeeeeeeeeeeeerrrrrrrrrrrrrrr 666666666666666000000000000000000000000000000000000000000 sssssssssssssseeeeeeeeeeeeeeennnnnnnnnnnnnniiiiiiiiiiiiiioooooooooooooorrrrrrrrrrrrrrr A YEAWORK

3 DAYSS ’SASIA’S B

VENUVENU

Over 6000 senior trade visitors from Asia's fastest growing markets.

Covers the entire industry spectrum.

Healthcare - Pharma - Wellness and CleanRoomTech.

Please contact us

UBC Rapid - The first Quantitative POC–test for the detection of Bladder Cancer!

STILL COUNTRIES OPEN FOR DISTRIBUTION

®

www.idlbiotech.com [email protected] www.cli-online.com & search 27337

CALENDAR OF EVENTSFebruary 6-9, 2017MEDLAB Dubai, UAEwww.medlabme.com

February 9-10, 2017Labquality days 2017International congress on quality in laboratory medicineHelsinki, Finlandwww.labqualitydays.com

April 3-5, 2017Medlab Asia Pacifi cSingaporewww.medlabasia.com

April 11-13, 2017SEACare 2017Kuala Lumpur, Malaysiawww.abcex.com

April 22-25, 2017ECCMIDVienna, Austriawww.eccmid.org

May 3-5, 2017FocusLeeds, UKwww.focus-acb.org.uk

May 15-18, 2017CMEF SpringShanghaiwww.cmef.com.cn/g1250.aspx

June 11-15, 2017EuromedlabAthenswww.athens2017.org

July 30-August 3, 2017AACCSan Diego, CAwww.aacc.org

September 2-6, 2017European Congress of PathologyAmsterdam, The Netherlandswww.esp-congress.org/

September 11-14, 2017MSACL EUSalzburgwww.msacl.org

October 22-25, 2017IFCC WorldLab Durban 2017Durban, South Africawww.durban2017.org

November 13-16, 2017MEDICADusseldorf, Germanywww.medica.de

Dates and descriptions of future events have been obtained from offi cial industrial sources. CLi cannot be held responsible for errors, changes or cancellations.

For more events see:www.cli-online.com/events/

031_036_cli_dec.indd 34 14/12/16 19:37

031_036_cli_dec.indd 35 14/12/16 19:37

OUR IN VITRO DIAGNOSTICS IDENTITY

CLINICAL CHEMISTRY SEROLOGY

COAGULATION SPECIFIC PROTEINS

IMMUNOASSAY AND AUTOMATION

AUTOIMMUNITY

Sclavo KOS 1 & KOS 2 Semi-automated Coagulation System. Compact, 1 or 2

channels, high reliability. Fully

optical measurement. Complete

panel of Sclavo reagents.

SkyLAB™ 752 Fully automated ELISA and IFA platform. Able to process EIA microplates

and IFA slides simultaneously.

New feature: full automation

of BLOT assays available soon.

Sclavo Palio™ 200N

Fully automated Clinical Chemistry and Specific Proteins System. Compact, benchtop,

random access, throughput up

to 360 tests/hour.

[email protected] [email protected] Via R. Merendi 22 - 20010 Cornaredo MI ITALY

VISIT US AT BOOTH HALL Z4.J39


031_036_cli_dec.indd 36 14/12/16 19:37

001 013 cli dec - Clinlabint.com › fileadmin › user_upload › 7._CLI... · 2017-06-06 · NGS...

Documents

Transcript of 001 013 cli dec - Clinlabint.com › fileadmin › user_upload › 7._CLI... · 2017-06-06 · NGS...