Innovation in Franceand 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

Once upon a time.... 1958

Ordonnances Debré Triple threatLa 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

Recherche clinique/Clinical researchLaws Huriet 1988-2004-2009 Laws HPST

• Claude Bernard• Clinical Research

– Physiopathology– Classification– DIAGNOSTICS– THERAPEUTICS (Clinical trials)

– ETHICS

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 « des 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)

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)

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

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)

Multiparametric flow cytometryMC Béné, on behalf of GEIL, GTLLF, GOELAMSNormal Bone marrowMinimal Residual DiseaseRare events: detection and quantification in « bermudes »

CD34 CD45

CD13 SSC

With patients'help

From immune deficiencies (congenital, acquired) to every medical specialty?

Rheumatology, Oncology, Neurology..HaematologyFrom phenotypes to rare events detection

and quantification and cytokine signatures

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

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.

Methods

• 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

CellTracks AutoPrep System

CellTracks Analyzer II

Cancer type

Breast Lung Melanoma

Tu

mor

cel

ls /

5m

L L

CR

0,1

1

10

100

1000

10000

100000

LM and « CSFTCs » in Breast Cancer (BMC Clinical Pathology 2012)

• Detection• Quantification: 1 to 103-4

• Characterization– Her2-Neu

Specificity: no contaminating ependymal cellsSensitivity: detection and quantification in all

established LM patients studied compared to cytology

High homogeneity (and reproducibility) of images

High purity compared to blood samples

Sequential analysis of CSFTCs confirms repetability of numerations with two subgroups (high > 700/mL vs low)BMC Clin Pathol 2012

Sample number

1st 2nd 3rd 4th 5th

Tu

mora

l ce

lls

/ 5 m

L L

CR

0,1

1

10

100

1000

10000

100000

DM CTCWA CTCCJ CTCDMB CTCVT CTCPV CTCBE CTCCS CTCHE CMCST CMCDC CTC

Melanoma CSFMCsMedical 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

LUNG CancerCSFTCs + 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

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

… 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

...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!

… impossible For costs of research

• Exchange of « free » innovative reagents

• Lack of funding for human-based IVDs research

• to Crowdfunding?

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

Consequences for Laboratory Hospitals

• Implementation of Quality procedures in University Hospitals

CE labelling, ProceduresTotal Laboratory AutomationIndustry based only• Policy of reducing costs of

healthcare– Biology is a commodity , first to be

strangled? – Outsourcing

Consequences For individuals

For medical lab peopleAdministrative burden

Stress and burnout, Demotivation

For techniciansProcedures + commercial kits usage

Loss of competences of technicians for research

For future medical pathologistsLess attractivity

Teaching and Learning

No hands on experience of trainees

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

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

Extracts of Clin Chemistry 2015A 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)

Extracts of Clin ChemistryA 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)

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 meetingsActions of Medical and Biology societies

CDCNumber of biological assays

• CLIHCsImpact 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.

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.

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.

A global world is a challenge for infectious diseases

and might be an opportunity • Africa/Asia...

– Scientific meetings– CME/CPD

Knowledge networkopportunity of Big Data

Team Science medicine.. For Rare Diseases and Personalized medicine

• US Nat Acad SciMetcalfe'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