This document discusses innovation in clinical laboratory medicine in France and immunology. It notes that historically, university hospital professors were expected to excel in teaching, medical duties, and research to quickly transfer innovations from research to patient care. However, recent regulations and cost-cutting have made this triple mission difficult by increasing administrative burdens and prioritizing reducing healthcare costs over quality. This threatens clinical research initiatives by medical laboratory scientists and reduces training opportunities for future professionals. Nonetheless, there is hope in increasing public awareness of the importance of laboratory medicine and engaging in networking and knowledge-sharing to support innovation.

1. Innovation in France
and Immunology
• Innovation in « Laboratory Medicine
at the clinical interface »?
– Historical french context in university
hospitals
– Examples of disruptive innovations
using flow cytometry
• Is there still room for innovation?
– « It's difficult not to be pessimistic »
• But, there are hopes

2. Once upon a time.... 1958
Ordonnances Debré Triple threat
La ministre a indiqué que les professeurs universitaires-praticiens hospitaliers doivent être en mesure
d'exercer leurs trois missions à un même niveau d'excellence afin de transférer le plus tôt possible
l'innovation liée à la recherche vers les soins aux patients.
Teaching, Medical duties, Research...
and administration

3. Recherche clinique/Clinical research
Laws Huriet 1988-2004-2009
Laws HPST
• Claude Bernard
• Clinical Research
– Physiopathology
– Classification
– DIAGNOSTICS
– THERAPEUTICS (Clinical trials)
– ETHICS

4. Non-interventional
Clinical trials = Interventionals
Different from research where medical strategy is not defined
by a protocol but is based on current medical practice
Ce terme marque bien la distinction avec la recherche ou les études dites « non interventionnelles » qui sont « de
s recherches pour lesquelles la stratégie médicale destinée à une personne qui se prête à la
recherche n'est pas fixée à l'avance par un protocole et relève de la pratique courante » (Code
de la santé publique)

5. Autoimmunity
• Individual patients
– Sm (anti-Smith)
• Follow-up of individuals, of groups
of patients
• Collection of sera, cells..
• Analysis of molecular specificities
– Journal of Case Reports, BMJ...
• Autoantibody markers in
neurobiology (A Vincent)

6. Flow Cytometry developments
• From Ig/rosettes in the 80's to
inumerable MoAbs (363 CDs)
• Development technologics
– From a full room to benchtop and
POCT?
– From oligoparametric to
multiparametric flow cytometry

7. Clinical Research
• GEIL/GOELAMS/EGIL/ELN/ESF
– Publications, Communications, meetings
– Network structuration of national and
european groups
– WP10 diagnosis
– International Immunological Leukemia
classifications
– GEIL particpation in HLDA 2010 (Mutual
benefits of B-ALL and HLDA/HDCM
Immunology Letters 2011)

8. Multiparametric flow cytometry
MC Béné, on behalf of GEIL, GTLLF, GOELAMS
Normal Bone marrow
Minimal Residual Disease
Rare events: detection and quantification
in « bermudes »
CD13 SSC
CD34 CD45

9. With patients'help
From immune deficiencies (congenital,
acquired) to every medical specialty?
Rheumatology, Oncology, Neurology..
Haematology
From phenotypes to rare events detection
and quantification and cytokine
signatures

10. Marqueurs phénotypiques et signatures fonctionnelles
Diversités fonctionnelles associées
• migration vers les tissus lymphoïdes et non
lymphoïdes
• prolifération, sécrétion cytokinique et cytotoxicité
(cellules trop différentiées vs TCM)
Pantaleo et al. Nature Reviews Immunology 6, 417–42

11. Identification and quantification of malignant cells
(CSFTCs) in cerebrospinal fluid :
GC Faure, Q Tu (Nancytomique- Nancy),
E Le Rhun (Lille)
Diagnosis of leptomeningeal metastases (LM)
in patients with solid tumors (breast, lung,
prostate...) and melanomas remains difficult.
Usual diagnostic methods of cytomorphological
assessment of cerebro-spinal fluid (CSF)
and gadolinium enhanced MRI lack both
specificity and sensitivity.

12. Methods
CellTracksâ
AutoPrepâ System
• CellSave® tubes allowing multicentric
studies
• CellSearch® Veridex
– Cell Tracks AutoPrep
– Analyzer II... Multispectral imaging
• CellTracks® CTCs and CMC kits
– EpCAM enrichment, KT label, CD45
• Validation on image galeries
CellTracksâ
Analyzer II
Breast Lung Melanoma
Cancer type
Tumor cells / 5mL LCR
100000
10000
1000
100
10
1
0,1

13. LM and « CSFTCs » in Breast
Cancer (BMC Clinical Pathology 2012)
• Detection
• Quantification: 1 to 103-4
• Characterization
– Her2-Neu
Specificity: no contaminating ependymal cells
Sensitivity: detection and quantification in all
established LM patients studied compared to
cytology
High homogeneity (and reproducibility) of
images
High purity compared to blood samples

14. Sequential analysis of CSFTCs
confirms repetability of numerations
with two subgroups (high > 700/mL vs low)
BMC Clin Pathol 2012
1st 2nd 3rd 4th 5th
Sample number
Tumoral cells / 5 mL LCR
100000
10000
1000
100
10
1
0,1
DM CTC
WA CTC
CJ CTC
DMB CTC
VT CTC
PV CTC
BE CTC
CS CTC
HE CMC
ST CMC
DC CTC

15. Melanoma CSFMCs
Medical Oncology 2013;
• CMC kit (J&J, VERIDEX)
– CD146 capture, MEL14 , CD45
• Four patients 9 points
• Good reproducibility during follow-up
• Cell morphology of melanoma cells in CSF far
better than in blood

16. LUNG Cancer
CSFTCs + CSFTMs
Cytomorphology: cell galleries
allow to differentiate SCLC, NSCLC
(adenocarcinoma, squamous carcinoma)
and detect apoptosis, autophagy...
• Numerous CTMs in some NSCLC patients
up to 80%, in sequential study

17. CSFTCs: a new frontier!
• Tumoral (epithelial) cells can be detected
and quantified in CSF with the CellSearch®
technology (CSFTCs)
• Their numbers can be sequentially followed-up
in breast, lung and other cancers
– allowing to evaluate the efficacy of
treatments (intrathecal and/or systemic)
• Tumoral cell population in CSF might be
different from blood CTCs, allowing further
studies of metastatic properties
• CSFMCs can also be detected and quantified in
CSF

18. … impossible to-day
for ethical reasons
in clinical research protocols
• Implementation of regulations by
administrations
Samples for research!
– Blood (Serum), Bone Marrow, CSF
• Ethical constraints: pain, potential
risks...
– Patients'information with excessive
precautionary principle
– Collections' regulations:potential
genetical studies, destruction of
samples

19. ...impossible
for strict implementation of
regulations of medical devices
Use of unvalidated research only
reagents
Absence of previous clinical publication
… to CE labelling requirements of
everything used in IVDs
(Pseudo) Quality control of research
protocols by non-medics
Exclusion of biologists from IVD clinical
trials initiative!

20. … impossible
For costs of research
• Exchange of « free » innovative
reagents
• Lack of funding for human-based
IVDs research
• to Crowdfunding?

21. Consequences for clinical
research in University Hospitals
• Clinical research
– Administration
– Regression of biologists initiative
– Strict clinical trials or Medical devices
procedures applied to IVDs assays
developments... although non
interventional
– Destruction of sera and cell
collections
– Decrease of LDTs developments

22. Consequences for Laboratory
Hospitals
• Implementation of Quality
procedures in University Hospitals
CE labelling, Procedures
Total Laboratory Automation
Industry based only
• Policy of reducing costs of
healthcare
– Biology is a commodity , first to be
strangled?
– Outsourcing

23. Consequences For individuals
For medical lab people
Administrative burden
Stress and burnout, Demotivation
For technicians
Procedures + commercial kits usage
Loss of competences of technicians for research
For future medical pathologists
Less attractivity
Teaching and Learning
No hands on experience of trainees

24. Some hopes in a troubled
setting
• Access to information
– Curation tools to surf information
overload (Scoop.it story)
– Networking
• Growing awareness of an evolving
situation previously hidden
• Article Clin Chemistry 2015
• USA: CDC CLICH
• USA: LDTs discussion (Congress, FDA...)
• USA: AJCP to attract young people
• Africa and Asia...
• From Big Data to knowledge network

25. Access to information
• Scoop.it
– Curation tool
– Among Immunological Topics
– Medical Biopathology and Laboratory
Medicine
• On behalf of UEMS and EFLM DL/eL
• http://www.scoop.it/t/medical-biopathology-
and-laboratory-medicine

26. Extracts of Clin Chemistry 2015
A more service and less academically
oriented profession?
We are on the same way of thinking...
• « I have always strongly believed that the
triad of clinical service, teaching and
research should be the basis of laboratory
medicine profession » (Mauro Panteghini)

27. Extracts of Clin Chemistry
A more service and less academically
oriented profession: Situation analysis
• In UK (France... Italy, Australia), it
is difficult not to be pessimistic...
(Ian Young)
– The triple threat laboratory medicine professor
has almost disappeared... (IY)
– There is a loss of training positions (MO)
– There is a reduction of technical and academic
personnel and research infrastructure (MO)
– There is a danger that the focus becomes the
economies of the service rather than underlying
value of a quality pathology service... managed
by an organizational culture encouraging
quality, innovation and a clinical focus (Ken
Sikaris)

28. What should be done?
« Important to increase the awareness
of the academic discipline by the
public , by hospital and university
administrators and health policy
makers » (Michael Oellerich)
This meeting, other meetings
Actions of Medical and Biology societies

29. CDC
Number of biological assays
• CLIHCs
Impact on Patient Care
CLIHCTM’s current focus explores the challenges clinicians
face for appropriate laboratory test selection and
result interpretation. Solutions for these challenges
will improve utilization of laboratory services and a
reduce diagnostic and treatment errors and delays.

30. LDTs from CLIA to FDA
Among other topics, the U.S. House Energy & Commerce
Subcommittee on Health
heard stakeholder opinions on whether lab-developed tests
(LDTs) are a service or a medical product and whether the
FDA’s proposed LDT regulation framework complements
the Clinical Laboratory Improvement Amendments (CLIA)
on September 9, 2014.

31. ASCP: Leading edge
Attracting people (sept 2014)
..... they highlight the need for medical laboratory
professionals, an important step in the effort to attract
the best and the brightest to the laboratory workforce.
“Essentially 100 percent of the patients entering hospitals
across the United States today are dependent upon the
work of the medical laboratory team,” Chakkaphak says in
the special.
ASCP collaborated with Leading Edge to create the segment,
which is part of ASCP’s outreach to elevate awareness of
the profession and build the future workforce.

32. A global world
is a challenge for infectious diseases
and might be an opportunity
• Africa/Asia...
– Scientific meetings
– CME/CPD

33. Knowledge network
opportunity of Big Data
Team Science medicine.. For Rare
Diseases and Personalized medicine
• US Nat Acad Sci
Metcalfe's law and the biology information
commons
Stephen H Friend &
Nature Biotechnology 31, 297–303 (2013) doi:10.1038/nbt.2555
Published online 05 April 2013