CANCEROLOGY AT UCL 2004 - Université catholique de Louvain · cancerology at ucl 2004 ......

C A N C E R O L O G Y AT U C L

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Edited by D. Opfergelt (UCL ADRE) Dec. 2004With the contribution of : O.Tirions, M. Plevoets, A. Distelmans, F. Kinard and N. Burteau

Cover : “Acute myeloblastic leukaemia” (Bone marrow aspirate stained by the May-Grünwald/Giemsa technique; original magification : 460X)Hematology unit, St Luc Hospital - Prof. Jean-Marie Scheiff

This booklet “Cancerology at UCL” has been implemented by the Research

Administration of the Université catholique de Louvain (UCL) under the

supervision of Professor Pierre Scalliet, President of the Cancer Center of the

academic hospital, Professor and Head of department of the Radiation

Oncology Unit of UCL.

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U N I V E R S I T É C A T H O L I Q U E D E L O U V A I N - C A N C E R O L O G Y A T U C L

Foreword

Besides the fact of being a public health problem of first order, cancer is a complex pathology which study requests

the collaboration of all the scientific disciplines. By essence, oncology is an “interdisciplinary” field because of the

interaction between specialists in the design and implementation of complex sequences of research and care : surgery,

drug, therapy, radiotherapy, rehabilitation, etc.

Many research projects performed at the Université catholique de Louvain and specially on its biomedical campus in

Brussels, are part of international networks.

This booklet presents the topics of interest, recent achievements and current developments of research teams

involved in cancerology. These topics are classified in nine categories, according to the main scientific or technological

approaches.

The last part gathers the different research centers and non profit associations established on the UCL campus and

devoted to cancer.

◗ PREVENTION AND EPIDEMIOLOGY

◗ MECHANISMS OF CANCER

◗ DIAGNOSTICS :immunology - genetics

imaging

◗ TREATMENT : clinical studies

anti-cancer treatment

surgery

radiotherapy

◗ PSYCHO-ONCOLOGY

◗ RESEARCH CENTERS AND NON PROFIT ASSOCIATIONS

The main objective of this document is to catalyze the development of scientific research, to promote synergies and to enrich the partnerships so as to develop the scientific assets an the industrial level and bythe way, improve the quality health care.

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Content

A - PREVENTION AND EPIDEMIOLOGY

A.1 - Risk assessment of carcinogenic

chemicals

ALFRED BERNARD

A.2 - Early detection and prevention of post

transplant lymphoproliferative diseases

ETIENNE SOKAL, DOMINIQUE LATINNE, PATRICK GOUBAU, MONIQUE

BODEUS, BENOÎT KABAMBA MUKADI, YANNICK NIZET, FRANÇOISE SMETS

A.3 - Chemoprevention in liver cancer

YVES HORSMANS

A.4 - Methodological support in epidemiology

and biostatistics applied to research in cancer

ANNIE ROBERT, RENÉ TONGLET

A.5 - Genetic profile of breast cancers : implication

in preventive and predictive medicine.

CATHERINE E.T.SIBILLE, MARTINE BERLIÈRE, CHRISTINE GALANT

B - MECHANISMS OF CANCER

B.1 - Regulation of membrane trafficking and

motility by oncogenes

PIERRE COURTOY

B.2 - Mechanisms that regulate the migration of brain cells in vitro and in vivo

ANDRÉ M. GOFFINET

B.3 - Cytogenetic and molecular characterization of T-cell proliferation in hypereosinophilic patients.

CATHERINE E.T. SIBILLE

B.4 - Identification of human tumor-specific

antigens

THIERRY BOON, PIERRE VAN DER BRUGGEN, BENOÎT VAN DEN

EYNDE, PIERRE COULIE, ETIENNE DE PLAEN, BERNARD LETHE,

ALINE VAN PEL, CHRISTOPHE LURQUIN, FRANCIS BRASSEUR,

DANIÈLE GODELAINE

B.5 - Analysis of the intracellular processing

of tumor antigens recognized by cytolytic

T lymphocytes

BENOÎT VAN DEN EYNDE

B.6 - Mechanisms of tumor resistance to the immune

system and development of a mouse model of

inducible melanoma

BENOÎT VAN DEN EYNDE

B.7 - Aristolochic acid and ochratoxin A : etiological

factors of Balkan endemic nephropathy and

associated urothelial tumors

JEAN-PIERRE COSYNS

B.8 - AMP-activated protein kinase, a new potential

regulator of cytoskeleton organization : role in cell

proliferation and/or differentiation.

LOUIS HUE, MARK RIDER

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B.9 - Mammalian antioxidant enzymes

BERNARD KNOOPS, JEAN-PAUL DECLERCQ, JEAN-FRANÇOIS REES

B.10 - Mechanisms involved in apoptosis induced

by anticancerous drugs

MARIE-PAULE MINGEOT-LECLERCQ

B.11 - Hox transcription factors and cancer

RENÉ REZSOHAZY

◗ DIAGNOSTICS

C. IMMUNOLOGY – GENETICS

C.1 - Genetic analysis of brain tumours

MIIKKA VIKKULA, CATHERINE GODFRAIND

C.2 - Characterization of malignant hemopathies

by molecular and flow cytometry

DOMINIQUE LATINNE, JEAN-LUC VAERMAN, VÉRONIQUE DENEYS

C.3 - Assays of tumor markers

MARIANNE PHILIPPE, PHILIPPE DE NAYER

C.4 - Characterization of acute leukemias by gene

expression analysis : comparison of molecular and

immunological approaches ; impact on diagnosis

and prognosis.

PASCALE SAUSSOY, DOMINIQUE LATINNE, AUGUSTIN FERRANT

C.5 - Immunodiagnosis of paraneoplastic

neurological disorders

CHRISTIAN SINDIC

C.6 - Development of new molecular based

diagnostic strategies in prostate cancer.

BERTRAND TOMBAL, JEAN LUC GALA

◗ DIAGNOSTICS

D. IMAGING

D.1 - Rigid registration of PET, CT and

MR modalities for radiotherapy planning and

dense deformation field estimation for brain

intra-operative images registration

BENOÎT MACQ

D.2 - Functional magnetic resonance (NMR, EPR)

spectroscopy and imaging in tumors

BERNARD GALLEZ

D.3 - Anatomic and functional imaging of liver

tumors

BERNARD VAN BEERS

◗ TREATMENT

E. CLINICAL STUDIES

E.1 - Academic clinical trials in medical

oncology

JEAN-PASCAL MACHIELS, JEAN-FRANÇOIS BAURAIN

E.2 - Clinical studies in hematology

AUGUSTIN FERRANT, LUCIENNE MICHAUX, ERIC VAN DEN NESTE

E.3 - Clinical studies in hematology :

Multiple myeloma, Hodgkin’s lymphoma

AUGUSTIN FERRANT, LUCIENNE MICHAUX, ERIC VAN DEN NESTE

F. ANTI-CANCER TREATMENT

F.1 - Therapeutic vaccination of cancer patients

with tumor specific antigens

THIERRY BOON, MARIE MARCHAND, NICOLAS VAN BAREN

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F.2 - Isolation and structure determination of

active compounds from plants used in traditional

medicine to treat different forms of cancers.

Analysis of the mode of action.

JOËLLE QUETIN-LECLERCQ

F.3 - The tumor vascularity : bases for adjuvant

strategies to conventional anti-tumor treatments

and anti-angiogenic approaches.

OLIVIER FERON

F.4 - Phase II study of utilisation of a recombinant

chimeric protein in patients with recurrent

progressive glioblastoma

CHRISTIAN RAFTOPOULOS

F.5 - Cancer immunotherapy-clinical trials

JEAN-FRANÇOIS BAURAIN, JEAN-PASCAL MACHIELS

F.6 - Lung cancer - mesothelioma -

clinical research in diagnosis - active treatment -

supportive care

DANIEL RODENSTEIN, PHILIPPE COLLARD, GIUSEPPE LIISTRO,

THIERRY PIETERS

F.7 - Development of new calcium-based strategies

to induce apoptotic cell death in prostate cancer

cell lines.

BERTRAND TOMBAL, PHILIPPE GAILLY

F.8 - Breast cancer

JACQUES DONNEZ, MARTINE BERLIERE, JEAN-LUC SQUIFFLET,

ISABELLE LECONTE, LATIFA FELLAH, CHRISTINE GALANT, CATHERINE

SIBILLE, BÉNÉDICTE BAYET

◗ TREATMENT

G. SURGERY

G.1 - Cryopreservation of ovarian cortex removed

before chemotherapy allows the restoration of

ovarian function after orthotopic

autotransplantation

JACQUES DONNEZ, JEAN-LUC SQUIFFLET, PASCALE JADOUL,

CÉLINE PIRARD, CHRISTINE WYNS, DOMINIQUE DEMYLLE, MARIE-

MADELEINE DOLMANS, BELEN MARTINEZ-MADRID,

ANNE VAN LANGENDONCKT

G.2 - Limb salvage in tumor surgery with massive

bone allografts

CHRISTIAN DELLOYE, OLIVIER CORNU, XAVIER BANSE

◗ TREATMENT

H. RADIOTHERAPY

H.1 - Biological dosimetry and radiobiological

calibration of clinical hadron beams

JOHN GUEULETTE

H.2 - Radiobiology of light ions

ANDRÉ WAMBERSIE

H.3 - Molecular imaging for radiotherapy

VINCENT GRÉGOIRE

H.4 - Treatment planning of intensity modulated

radiotherapy (IMRT) for head and neck cancer :

optimization of the treatment technique

and validation by measurements and

Monte Carlo simulations

MILÀN TOMSEJ, NATHALIE DE PATOUL, STEFAAN VYNCKIER,

VINCENT GRÉGOIRE

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I. PSYCHO-ONCOLOGY

I.1 - Psycho-oncology - Physician patient

relationships - Communication skills training -

Quality of life - Professionnal stress - Burnout

CHRISTINE REYNAERT, PIERRE SCALLIET, YVES LIBERT

I.2 - The question of meaning in front of cancer.

Biographical approach.

JEAN-LUC BRACKELAIRE, MICHEL LEGRAND, PATRICK DE NEUTER

I.3 - Coping styles, anxio-depression,

alexithymia and evolution of breast cancer

VINCENT JADOULLE

J. RESEARCH CENTERS & NON-PROFITASSOCIATIONS

J.1 - Cancer Centre at UCL and Saint Luc academic hospital

J.2 - The Brussels Branch of the Ludwig Institute

for Cancer Research (LICR)

J.3 - European Society for Therapeutic

Radiology and Oncology (ESTRO)

J.4 - Federation of European Cancer Societies

(FECS)

J.5 - European Organisation for Research and

Treatment of Cancer (EORTC)

J.6 - European society of surgical

oncology (ESSO)

J.7 - International Life Sciences Institute

(ILSI Europe)

J.8 - European Oncology Nursing

Society (EONS)

J.9 - The U.S. National Cancer Institute Liaison

Office (NCI L.O.)

KEY WORDS INDEX 119

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Risk assessment of carcinogenic chemicals

SENIOR SCIENTIST :

�Alfred BERNARD

A 1

Research Field and Subjects

The research team conducts a variety of studies in populationsexposed to toxic chemicals in the environment or the workplace. The objectives of these studies include the evaluation of expo-sure, the identification of groups at risk, the derivation of safeexposure levels or the validation of non invasive biomarkers ofexposure or early effects. These studies are currently focused on food contaminants andair pollutants.

Products and Services

Expertise in health risk assessment in incidents of food con-tamination or environmental pollution.

Biomonitoring of exposure.

Representative References

BERNARD A. Overview of epidemiological studies on the car-cinogenicity of metals. In : Carcinogenicity of Inorganic Substances.Risks from Occupational Exposure. Ed. J.H. Duffus. Royal Society ofChemistry, Cambridge, UK., pp. 146 - 160, 1997.

BERNARD A., HERMANS C., BROECKAERT F., DEPOORTER G.,DECOCK A., HOUINS G. Food contamination by PCBs and dioxins.Nature 40, 231-232, 1999.

BERNARD A., BROECKAERT F., DEPOORTER G., DE COCK A.,HERMANS C., SAEGERMAN C., HOUINS G. The BelgianPCB/dioxin incident: analysis of the food chain contamination andhealth risk evaluation. Environmental Research 88, 1-18, 2002.

Funding Sources

European UnionNational Institute of Health, USA Fonds national de la recherche scientifique (FNRS)Brussels-Capital Region and Walloon Region

STAFF

Total : 5

KEY WORDS FOR R&D

air pollutantsbiomarkersdioxinsfood contaminantsheavy metals PCBsrisk assessment

SENIOR SCIENTIST

Alfred BERNARD [email protected] Tel. 32(0)2-764 39 34

WEB SITE

www.md.ucl.ac.be/toxi

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Early detection and prevention of post transplant lymphoproliferative diseases

SENIOR SCIENTISTS :

� Etienne SOKAL� Dominique LATINNE� Patrick GOUBAU� Monique BODEUS� Benoît KABAMBA MUKADI� Yannick NIZET� Françoise SMETS

A 2


Post Transplant Lymphoproliferative Disease (PTLD) is a commoncomplication following solid organ transplantation. PTLD is rela-ted to Epstein Barr Virus (EBV) infection. The virus is usuallytransmitted during the transplant procedure, via the graft itselfor the blood products. The virus infects B lymphocytes and cau-ses their clonal proliferation-immortalization. This clonal expan-sion is normally controlled by reactive T lymphocytes, but thesecells are inhibited by the immune suppression. PTLD can affectall organs and causes massive lymphoproliferation with severecomplications which may cause patient’s death.

Treatment includes arrest of immunosuppression, and possiblyanti- CD20 monoclonal antibodies. Chemotherapy is used onlyin the true malignant forms, i.e. Burkitt or Hodgkin like syndro-mes. Arrest of immunosuppression may lead to graft rejection.It is therefore important to have tools allowing to detect theright moment to decrease and/or to restore the immunosup-pression load.

EBV infection occurs usually in the first three months followingtransplant. Detection by serology is impaired due to poor anti-body response in these immunocompromized patients. Wehave therefore set up detection of EBV primary infection by EBVPCR and real time PCR to quantify viral load.

Viral load is a risk factor for PTLD. Our team has demonstratedthat the risk of PTLD is not uniquely related to viral load, butalso to the lack of anti EBV CD8 specific cells. These cells arecurrently detected by ELISPOT technique.

Peripheral blood mononuclear cells of the patients are first cul-tured and infected by EBV in vitro, as soon as the transplantindication is established.

Following transplant, and after appearance of primary EBVinfection (= first positive PCR), viral load is monitored by realtime PCR. ELISPOTS are then performed by detecting interferongamma release in vitro by the own patient’s T lymphocytes inpresence of his/her previously cultured B lymphocytes infectedby EBV. Presence of anti EBV specific T lymphocytes is therefo-

re detected and quantified by counting the number of positivespots of interferon gamma detected by ELISA.

We have established that viral load > 20000 copies per ml andanti-EBV T lymphocytes < 1/mm3 is at high risk of EBV develop-ment, while patients who have more than 1 anti-EBV T lym-phocyte / mm3 do not develop PTLD, even in presence of highviral load. This allows to better anticipate risk of PTLD, accor-dingly adapt immunosuppression, and restore appropriateimmunosuppression as soon as patient’s anti EBV cellular immu-nity appears, before onset of rejection.


Real time PCR for EBVElispot techniqueCell cultureClinical management

Main Equipment

TaqMan real time PCRFACS


SOKAL E. M. and al. Epstein-Barr virus serology and Epstein-Barr virus-associated lymphoproliferative disorders in pediatricliver transplant recipients. Transplantation X 56,1993, 1394-98.

SOKAL E. M. and al. Early signs and risk factors for theincreased incidence of Epstein Barr virus related post transplantlymphoproliferative diseases in paediatric liver transplant recipientstreated with Tacrolimus. Transplantation X 64.10, 1997, 1438-42.

SMETS F. and al. Indications and results of chemotherapy inchildren with posttransplant lymphoproliferative disease afterliver transplantation. Transplantation X 69.5, 2000, 982-84.

SMETS F. and al. Characteristics of Epstein-Barr virus primaryinfection in pediatric liver transplant recipients. J. Hepatol. 32.1,2000, 100-04.

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SMETS F. and al. Characteristics of Epstein-Barr virus primaryinfection in pediatric liver transplant recipients. Journal ofHepatology 32, 2000, 100-04.

SMETS F. and al. Ratio between Epstein-Barr viral load andvirus specific T-cell response as a predictive marker of post-transplant lymphoproliferative disease. Hepatology Mosby 34.4pt 2 of 2, 2001, 291A Abstract 745-291A.

SMETS F. and al. Ratio between Epstein-Barr viral load andanti Epstein-Barr virus specific T-cell response as a predictivemarker of posttransplant lymphoproliferative disease.Transplantation X 73.10, 2002, 1603-10.

Awards

Award 2002 Glaxo SmithKline - infectious diseases

Funding Sources

Grant from Télévie, Fonds de la recherche scientifique médicale

Partnership

Henogen

STAFF

Total : 10

KEY WORDS FOR R&D

Epstein Barr Virus EBV immunosuppressionpediatric transplantationpost transplant lymphoproliferative diseases

SENIOR SCIENTISTS

Etienne [email protected]. 32(0)2 764 13 87

Dominique [email protected]. 32(0)2 764 34 30

Patrick [email protected]. 32(0)2 764 34 20

Monique [email protected]. 32(0)2 764 34 20

Benoît KABAMBA [email protected]. 32(0)2 764 34 21

Yannick [email protected]. 32(0)2 764 35 33

Françoise [email protected]. 32(0)2 764 13 87

WEB SITES

www.pedi.ucl.ac.bewww.imex.ucl.ac.be

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Chemoprevention in liver cancer

SENIOR SCIENTIST :

� Yves HORSMANS

A 3


The aim of the project is to assess the potential role of drugs inthe chemoprevention of primary liver cancer, namely hepato-cellular carcinoma (HCC).

The two drugs that are studied are pioglitazone, a PPARgammaagonist, which has shown interesting results in in vitro models;and lanreotide, a somatostatine analogue, studied in vitro andin vivo, as in human population. The effect of the drugs is ana-lyzed in a sequential carcinogenic animal model. Focus is madeon the inhibitory effect on the apparition of early pre-neoplas-tic and neoplastic nodules in the rat liver, analysed by immuno-histochemistry and western blot. Analysis of the proliferativeand apoptotic events is made by western blot and immunohis-tochemistry.

Preliminary results show that pioglitazone is efficient in thereduction of the size of pre-neoplastic nodules in this model, onthe contrary to lanreotide, which decreases the size of thenodules, though non significantly. The mechanisms of thisaction are not fully understood at the present time, but preli-minary data show differential alteration of proliferation andapoptosis. Further analyses will be performed to determine theeffect of pioglitazone and lanreotide on the balance of prolife-ration and apoptosis in preneoplastic foci and surrounding liverparenchyma.

The effect of the two drugs will also be assessed in rats havinginduced cirrhosis, to look at the preventive effect on neoplasticnodules in an already pre-neoplastic organ. This study isongoing.

Main Equipment

Western BlotReal-time PCRImmunohistochemistryFlow CytometryLaboratory animal handling and surgery


STÄRKEL P., HORSMANS Y., SEMPOUX Y., DE SAEGER C.,WARY J., LAUSE P., MAITER D., LAMBOTTE L. After portalbranch ligation in rat, nuclear factor kB, interleukin 6, signaltransducers and activators of transcription 3, c-fos, c-myc, andc-jun are similarly induced in the ligated and nonligated lobes.Hepatology 29, 1999, 1463-1470.

STARKEL P., LAMBOTTE L., SEMPOUX C., DE SAEGER C.,SALIEZ A., MAITER D., HORSMANS Y. After portal branch liga-tion in rat, cellular proliferation is associated with selectiveinduction of c-Ha-ras, p53, Cyclin E and Cdk2. Gut 49, 2001,119-130.

PICARD Ch., STARKEL P., SEMPOUX Ch., SALIEZ A., LEBRUNV. and HORSMANS Y. Molecular mechanisms of apoptosis inthe liver of rats after portal branch ligation with and withoutretrorsine. Laboratory investigation, 2004, in press.

Funding Sources

Proper funding

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STAFF

Total : 4

KEY WORDS FOR R&D

chemopreventiongastroenterology, liverliver tumors

SENIOR SCIENTIST

Yves HORSMANS [email protected]. 32(0)2 764 28 20

WEB SITE

http://www.md.ucl.ac.be/gaen

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Methodological support in epidemiology and biostatisticsapplied to research in cancer

SENIOR SCIENTISTS :

� Annie ROBERT� René TONGLET

A 4


Epidemiology and biostatistics can be applied to cancerresearch especially in the study of cancer incidence by productsor in the estimation of anticancer drugs efficiency.

Cancer incidence and mortality among cohortsof pesticides producing workers, etc.

Epidemiological studies are conducted in order to assess if thereis an excess of cancer cases in current and ex-workers from aplant and to identify workplace exposures which may explainsuch a demonstrated excess.Vital- and cancer status according to the ICD10 codes (internatio-nal classification of diseases) are established for all workers, andlife table analyses are conducted, using the Belgian mortality andthe regional (Flanders, French community) registry of cancers.

Age- and sex standardised mortality (SMR) and incidence (SIR) ratiosare stratified by duration of employment, job title, time since firstemployment, and time between the end of the job at the plant forworkers who left the plant. These occupational data are used aslatency- and intensity surrogates for testing the hypothesis of a rela-tionship between occupational exposure and cancer development.

Progression-free survival in solid tumors: qualities of estimators of clinical efficiency and inefficiency for designing Phase II trials.

Phase II trials play a key role in the development of new poten-tial anticancer drugs because they are crucial in deciding whe-ther or not proceeding to a phase III trial. Phase II trials are conducted in order to assess the clinical effi-ciency (P1) or the clinical inefficiency (P0) of new treatments.The number of patients enrolled in a phase II trial closelydepends on P0 and P1 values. An underestimation of P1 canlead to rejection of an active treatment and an overestimationof P0 can lead to keep a useless treatment. The classical defini-tion of P0 and P1 is based on death rates because mortality isan objective measure of response to therapy. Recent develop-ments in anticancer agents are however oriented to antitumo-ral drugs, and consequently call for a new definition of earlyresponse to therapy, taking into account a decrease in the sizeof cancer lesions or a stabilization of disease.

“Progression-free survival” and “Time to progression” arevaluable alternative definitions of response to treatment, sincea recent harmonization of guidelines has been proposed toassess the progression of cancer in solid tumors (RECISTTherasse P. and al. J. Nat. Cancer Inst. 2000, 92:205).Progression-free survival can be estimated using retrospectiveanalyses of phase III trials, in order to derive P0 and P1 values.Such analysis has been done for soft tissue sarcomas (VanGlabbeke and al. Eur. J. Cancer 2002, 38:543-549). We plan toextend those analyses to other solid tumors such as lung can-cers, bladder cancers, or breast cancers. Efficiency and inefficiency estimations derived from such analysesmay be sensitive to loss-to-follow data, to left rather than rightcensored data, or to variations in the cancer progression assess-ment. Sensitivity analyses will be conducted, together with theconsequences on size computations in designing phase II trials.


Methodological support on a contractual basis.

Main Equipment

Statistical and Epidemiological softwares: BMDP, The SAS System,SPSS, Splus, EPIinfo, EPICURE.

Funding Sources

IndustryOccupational health servicesCompetitive research funds

Partnership

European Organization for Research and Treatment of Cancer(EORTC).

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STAFF

Total : 6

KEY WORDS FOR R&D

applied statisticsclinical trials, drug evaluation epidemiology health- and medical statisticsoccupational medicine, preventive medicine pharmacotherapy

SENIOR SCIENTISTS

Annie [email protected] Tel. 32 (0)2 764 33 21

René [email protected]. 32 (0)2 764 33 23

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/EPID

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Genetic profile of breast cancers : implication in preventiveand predictive medicine

SENIOR SCIENTISTS :

� Catherine E.T. SIBILLE� Martine BERLIÈRE� Christine GALANT

A 5


In the western countries, breast cancer is the most frequentfemale cancer. Its incidence is increasing and about 10 %women will develop a breast carcinoma in their lifetime.However, mortality does not progress proportionally, due toadvances in screening and treatment.Since the cloning (discovery) of the BRCA1/BRCA2 genes (1994-1995) both predisposing to hereditary breast and /or ovarian can-cers, we have developped in collaboration with the PsychologicalService a model of Oncogenetics clinics specially dedicated to thepredictive or symptomatic genetic diagnosis. Initially inspired by the “good practices” in use for the predictive diagnosis ofHuntington disease, this clinic was soon afterwards individualized,based on tumour screening and preventive treatment. The firstbelgian BRCA1 and BRCA2 mutations were also obtained andwere found to be present in approximatively 7% of the breast can-cer familial cases.

The first epidemiological trial in which our oncogenetics clinic wasinvolved was part of the “International BRCA1/2 Carrier CohortStudy” (IBCCS). To illustrate the interest of evaluating environ-mental factors in this high risk population, this cohort has allowedus to report recently about the increased sensitivity to low-doseionizing radiation in BRCA1/2 carriers.In 2002, we initiated a second study funded by the CEE and became part of the “BreastMed consortium”. This interna-tional study entitled “Genetic profile of breast cancers in Mediterranean countries : implications in preventive and predictive medicine” is conducted in collaboration with threemediterranean countries and France. In the mediterraneancountries, breast cancer represents also an important publichealth problem, but its prognosis is worse and it seems to exp-ress specific biological features. The BreastMed project aims atcomparing the genetic caracteristics of breast tumours inBelgium and France, on one hand, in Morocco, Tunisia andLebanon, on the other hand. One of its important clinical objec-tives is to examine the contribution of environmental factorsdifferent on both sides of the Mediterranean Sea, to the appa-rition of the disease in women exhibiting the same BRCA1/2mutation. It should also allow a better tumour sub-classificationand the discovery of new prognosis markers, in particular for

the evaluation of early anticancer treatment response. In addi-tion, the specific technological objectives are the generationand the standardization of low-density DNA chips (expressionarrays).

Main Equipment

DNA Sequencer, PCR blok ElectrophoresisLow density expression arrays


Clinical and fundamental researchDiagnostic and therapeutic developmentExpertise in low density expression microarraysGenetic counseling Preventive MedicinePsychologyCancer Epidemiology


C. SIBILLE, A. JOOS DE TER BEERST, O. FROMENT, Y.GILLEROT. Prise en charge des familles à risque génétique decancer: attitude en Belgique. Eurocancer, John Libbey, Eurotext,Paris, 179-180, 1996.

C. SIBILLE, A. JOOS DE TER BEERST, O. FROMENT.BRCA1/BRCA2 mutations in Belgian families with history ofbreast/ovary cancer. Journal of European Cancer Prevention, 7suppl. 1, 53-55, 1998.

C. SIBILLE, A. JOOS. D’une pierre, deux coups! A propos d’unmodèle de consultation en oncogénétique. Le Journal deCancer et Psychologie, December, 33, 1999.

Y.J. BIGNON, P. DESSENNE, C. SIBILLE, A. JOOS, A.LEHMANN. L’impact psychique de la consultation d’oncogéné-tique sur l’entourage familial. Bulletin de la Société Française dePsycho-Oncologie, 27: 10-12, 2000.

D. GOLDGAR, C. BONNARDEL, H. RENARD, O. YAQOUBI andthe IBCCS collaborators Group (belgian center participant C.

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SIBILLE). The International BRCA1/2 Carrier Cohort Study : pur-pose, rationale, and study design. Breast Cancer Res., 2, 6 :E010, 2000.

N. ANDRIEU, D. F. EASTON, J. CHANG-CLAUDE, M.A.ROOKUS, R. BROHET, E. CARDIS, A. C. ANTONIOU, S. PEOCK,C. NOGUES, F.E. VAN LEEUWEN, D. GOLDGAR and the IBCCScollaborators group (belgian participant C. SIBILLE), EMBRACE,GEO-HEBON, GENEPSO. Low-dose ionizing radiation signifi-cantly increases the risk of breast cancer among BRCA mutationcarriers in the IBCCS study (in press).

M. LACROIX, G. LECLERCQ, on behalf of BreastMedConsortium (belgian center participant C. SIBILLE). The “por-trait” of hereditary breast cancer. Breast cancer research andtreatment (in press).

W. MAHFOUTH, N. BOUAOUINA, Y.J. BIGNON, N.UHRHAMMER, L. CHOUCHANE, and Breast Med. Consortium :N. ZAMMATTEO, V. BERTHOLET, F. DE LONGUEVILLE, Y.J.BIGNON, J. REMACLE, A. MEGARBANE, N. BEN JAAFAR, A.SEFIANI, L. CHOUCHANE, A. BEN AMMAR-EL GAIED, G.LECLERCQ, M. LACROIX, C. SIBILLE, V. VIDAL. BRCA1 germlinemutations in Tunisian families with hereditary breast cancer.INCTR Annual Meeting, Cairo, 2004.

Breast Med. Consortium : N. ZAMMATTEO, V. BERTHOLET, F.DE LONGUEVILLE, Y.J. BIGNON, J. REMACLE, A. MEGARBANE,N. BEN JAAFAR, A. SEFIANI, L. CHOUCHANE, A. BEN AMMAR-EL GAIED, G. LECLERCQ, M. LACROIX, C. SIBILLE, V. VIDAL.Gene expression profiling of breast tumors in european andmediterranean countries. INCTR Annual Meeting, Cairo, 2004.

Patents

The two spin-offs (Diagnogen, France and EAT-Eppendorff,Namur, Belgium) associated with the CEE project, are in processof patenting their “breast cancer” low density arrays.

Funding Sources

Main source of funding : EEC Fédération belge contre le cancer

Partnership

ULB, Institut Bordet, Bruxelles, Belgium.FUNDP, Namur, Belgium.Clermont-Ferrand university, France.Mediterranean countries : Morocco, Tunisia, Lebanon.IARC, Lyon, France.

STAFF

Total : 5

KEY WORDS FOR R&D

gynecologymedical geneticsmolecular biologypathology

SENIOR SCIENTISTS

Catherine E.T. [email protected]. 32 (0)2 764 53 82

Martine BERLIÈ[email protected]. 32 (0)2 764 95 01

Christine [email protected]. 32 (0)2 764 17 88

WEB SITES

http://www.cjp.fr/breastmedhttp://rch.adre.ucl.ac.be/browse/list_alpha/GMEDhttp://rch.adre.ucl.ac.be/browse/list_alpha/ANPS

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Regulation of membrane trafficking and motility by oncogenes

SENIOR SCIENTIST :

� Pierre COURTOY

B 1


This research group addresses how the paradigmatic oncoge-nes, v-Src and K-Ras, subvert normal signal transduction path-ways, resulting in altered plasma membrane dynamics. As end-point, we focus on accelerated endocytosis and motility, twoproperties directly linked to cellular invasion.

In these studies, thermosensitive v-Src mutants are amply used.Key signalling molecular relays are identified and their hierarchyis established using pharmacological inhibitors, dominant-posi-tive and -negative constructs. Their localization is defined byanalytical subcellular fractionation combined with confocalimaging of fixed and living cells.


Molecular tracking in living and fixed cellsCell motility

Main Equipments

Electron microscopeConfocal microscopeLife-cell imaging microscopeUltracentrifugeMicroinjection


A. VEITHEN, Ph. CUPERS, P. BAUDHUIN, AND P.J. COURTOY.v-Src induces constitutive macropinocytosis in rat fibroblasts. J.Cell. Sci. 109, 2005-2012, 1996.

M. AMYERE, B. PAYRASTRE, A. VEITHEN, P. VAN DERSMISSEN, AND P.J. COURTOY. Constitutive macropinocytosis inoncogene-transformed fibroblasts depends on permanentcombined activation of phosphoinositide 3-kinase and phos-pholipase C. Mol. Biol. Cell. 11, 3453-3467, 2000.

K. CROIZET-BERGER, C. DAUMERIE, M. COUVREUR, P.J.

COURTOY, AND M.F. VAN DEN HOVE. The endocytic catalysts,Rab5a and Rab7, are tandem regulators of thyroid hormoneproduction. Proc. Natl. Acad. Sci. USA 99, 8277-8282, 2002.

PLATEK A., METTLEN M., CAMBY I., KISS R., AMYERE M. andCOURTOY P.J. v-Src accelerates spontaneous motility via phos-phoinositide 3-kinase, phospholipase C and phospholipase D,but abrogates chemotaxis in Rat-1 and MDCK cells. J. Cell. Sci.2004.

Awards

Pierre Courtoy was awarded the “Francqui Chair” 2004 atthe Facultés Universitaires de Namur, Medical school, Belgium.

Funding Sources & Partnership

Fonds national de la recherche scientifique (FNRS) Fondation pour la recherche scientifique médicale (FRSM)Télévie

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STAFF

Total : 12

KEY WORDS FOR R&D

cell biologyconfocal microscopyelectron microscopyendocytosisfractionationlife-cell imagingmembranemolecular biologymotilityproto(oncogenes)

SENIOR SCIENTIST

Pierre [email protected]. 32(0)2 764 75 69

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/CELL

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Mechanisms that regulate the migration of brain cells invitro and in vivo

SENIOR SCIENTIST :

� André M. GOFFINET

B 2


This laboratory investigates the basic mechanisms that regulatethe migration of brain cells during normal and abnormal deve-lopment.

Like other cells, brain cells migrate by leading extension, a stepthat is mostly actin-dependent, followed by nucleokinesis,which appears to depend on microtubules.

A new technique to study brain cell migration has been set upand is widely used in order to define basic mechanisms.

Two projects are pursued in order to take advantage of thatnew technology.

First, we target candidate signal transduction pathways usingsmall molecular weight inhibitors, such as Iressa or Gleevec, inorder to define which pathways are implicated in brain cellsmigration. This allowed us to identify a key role of Src familykinases, atypical PKCs and a few others.

The second project is in collaboration with the National CancerInstitute (NIH), which developed a diversity set of more than2000 leading compounds that is currently under evaluationusing our in vitro system. Thus far, a first pass of this screeninghas resulted in the identification of about 20 compounds thatremain to be better defined.

A second approach we pursue is to use transgenic mouse tech-niques in order to assess the role of some genes in brain cellsmigration.

We are currently building a knock-in mouse in which the repor-ter gene EGFP and the recombinase Cre are targeted to the p73locus, an oncogene of the p53 family that is important fortranscriptional regulation during brain development as well asin some mechanisms of neoplastic growth. Using homologousrecombination in mouse ES cells, we have also inactivated anew gene named Celsr3 that codes a protocadherin of theFlamingo family implicated in epithelial planar cell polarity.


Molecular biologyImmunohistochemistryHistotypic culture of vibratome sectionsTransgenic mouse techniques

Main Equipment

Cell cultureStandard molecular biologyStandard histologyTransgenic mice


MEYER G., SCHAAPS J.P., MOREAU L., GOFFINET A.M. (2000)Embryonic and early fetal development of the human neocor-tex. J. Neurosci., 20: 1858-1868.

BAR I., LAMBERT DE ROUVROIT C., GOFFINET A.M. (2000)The evolution of cortical development: An hypothesis based onthe role of the reelin signaling pathway. Trends Neurosci., 23:633-638.

HEVNER R.F., SHI L., HSUEH Y-P., SHENG M., SMIGA S.,BULFONE A., GOFFINET A.M., RUBENSTEIN J.L.R. (2000) Tbr1regulates differentiation of the preplate and layer 6. Neuron,29: 353-366.

LAMBERT DE ROUVROIT C., GOFFINET A.M. (2001) Neuronalmigration. Mech. Dev. 105: 47-56.

JOSSIN Y., GOFFINET A.M. (2001) Reelin does not directlyinfluence axonal growth. J. Neurosci. 21, RC183: 1-4.

TISSIR F., DE BACKER O., GOFFINET A.M., LAMBERT DEROUVROIT C. (2002) Developmental expression profiles of Celsr(Flamingo) genes in the mouse. Mech. Dev., 112: 157-160.

TISSIR F., BAR I., GOFFINET A.M., LAMBERT DE ROUVROIT C.(2002) Expression of the ankyrin repeat domain protein 6 gene(Ankrd6) during mouse brain development. Dev. Dyn. 224:465-469.

BAR I., TISSIR F., LAMBERT DE ROUVROIT C., DE BACKER O.,GOFFINET A.M. (2003) The Gene Encoding Disabled-1 (Dab1),

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the Intracellular Adaptor of the Reelin Pathway, RevealsUnusual Complexity in Human and Mouse. J. Biol. Chem. 278:5802-5812.

MEYER G., LAMBERT DE ROUVROIT C., GOFFINET A.M.,WAHLE P. (2003) Dab1 mRNA and protein expression in devel-oping human cortex. Eur. J. Neurosc. 17: 517-523.

JOSSIN Y., BAR I., IGNATOVA N., TISSIR F., LAMBERT DEROUVROIT C., GOFFINET A.M. (2003) The reelin signaling path-way : Some recent developments. Cereb. Cortex 13: 627-633.

TISSIR F., GOFFINET A.M. (2003) Reelin and brain develop-ment. Nat. Rev. Neurosci. 4: 496-505.

BOCK H.H., JOSSIN Y., LIU P., FORSTER E., MAY P., GOFFINETA.M., HERZ J. (2003) PI3-Kinase interacts with the adaptor pro-tein Dab1 in response to Reelin signaling and is required fornormal cortical lamination. J. Biol. Chem. 278 : 38772-9.

JOSSIN Y., OGAWA M., METIN C., TISSIR F., GOFFINET A.M.(2003) Inhibition of SRC family kinases and non-classical proteinkinases C induces a reeler-like malformation of cortical platedevelopment. J. Neurosci. 23 : 9953-9.

JOSSIN Y., IGNATOVA N., HIESBERGER T., HERZ J., LAMBERTDE ROUVROIT C., GOFFINET A.M. (2003) The central fragmentof Reelin, generated by proteolytic processing in vivo, is criticalto its function during cortical plate development. J. Neurosci.24: 514-521.

IGNATOVA N., SINDIC C.J.M., GOFFINET A.M. (2004)Characterization of the various forms of the Reelin protein inthe cerebrospinal fluid of normal subjects and in neurologicaldiseases. Neurobiol Dis.

TISSIR F., CHUAN-EN WANG; GOFFINET A.M. (2004)Expression of the chemokine receptor Cxcr4 mRNA duringmouse brain development. Dev. Brain Res.


Fonds national de la recherche scientifique (FNRS), BelgiumActions de recherche concertée (ARC), BelgiumFondation Médicale Reine Elisabeth, BelgiumEuropean UnionNational Cancer Institute, USA

STAFF

Total : 8

KEY WORDS FOR R&D

cortical developmentneuronal migrationreelinslice culture

SENIOR SCIENTIST

André M. [email protected]. 32 (0)2 764 73 86

WEB SITE

www.md.ucl.ac.be/dene

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Cytogenetic and molecular characterization of T-cell proliferation in hypereosinophilic patients

SENIOR SCIENTIST :

� Catherine E.T. SIBILLE

B 3


A study of regulatory pathways in lymphogenesis. Diagnosticand prognostic implications

In order to gain a better understanding of the mechanismsinvolved in the transformation of the aberrant CD3–CD4+ T-cells in vivo, the HES (HyperEosinophilic Syndrome) patientswere tested for clonal chromosome aberrations and transcrip-tional gene expression profile.

For two patients, among different subclones, an early andrecurrent 6q interstitial deletion was found by using molecularcytogenetics (Fluorescent In Situ Hybridization). Furthermore,during the evolution in acute T-lymphoma of one patient, the6q- clone was found overexpressed.

After FISH delimitation of the commonly deleted 6q segment, ournext goal was to identify the genes involved in this deletion and tounderstand their interactions with the other genes located onother chromosomes. This approach was made in collaboration byusing expression arrays (human A Affymetrix slides) in replicate.

We have found several candidate genes with tumour suppres-sive activity and we are presently confirming our results byquantitative PCR (Taqman).

Our next experiments will focus on the other T-Lymphomas andacute T-cell leukemias.


Applied and fundamental researchExpertise in expression microarrays, molecular cytogenetics,

cytogenetics

Main Equipment

Fluorescent and light microscopes, CGH Metasystem analyser,PCR blok


ROUFOSSE F., SCHANDENE L., SIBILLE C., KENNES B., EFIRAA., COGAN E., GOLDMAN M. T-cell receptor-independent acti-vation of clonal Th2 cells associated with chronic hypereosinophilia. Blood, 1999, 94(3): 994-1002.

ROUFOSSE F., SCHANDENE L., SIBILLE C., WILLARD-GALLOK., KENNES B., EFIRA A., GOLDMAN M., COGAN E. Clonal Th2lymphocytes in patients with the idiopathic hypereosinophilicsyndrome. Br. J. Haematology, 2000, 109(3): 540-548.

LEROUX D., MUGNERET F., CALLANAN M., RADFORD-WEISSI., DASTUGUE N., FEUILLARD J., LE MEE F., PLESSIS G.,TALMANT P., GACHARD N., UETTWILLER F., PAGES M.P.,MOZZICONACCI M-J., EDACHE V., SIBILLE C., AVET-LOISEAUH., LAFAGE-POCHITALOFF M. CD4+, CD56+, DC2 acuteleukemia are characterized by recurrent clonal chromosomalchanges affecting major targets: a study of 21 cases by the “Groupe Français de Cytogénétique Hématologique”.Blood, 2002, 99 (11), 4154-415.

SIBILLE C., RAVOET M., ROUFOSSE F., SCHANDENE L.,GOLDMAN M., WILLARD-GALLO K. 6q- is an early and persis-tant chromosomal aberration in 2 patients with hypere-osinophilic syndrome leading to T-cell lymphoma. (submitted).

WILLARD-GALLO K., BADRAN B.M., RAVOET M., ROUFOSSE F.,GOLDMAN M., BURNY A., SIBILLE C. Defect in gene transcriptionpotentially associated with the progression to T-cell lymphoma inpatients with hypereosinophilic syndrome (submitted).

Funding Sources

Fonds national de la recherche scientifique (FNRS)Télévie

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STAFF

Total : 3

KEY WORDS FOR R&D

cytogeneticshematology molecular biology

SENIOR SCIENTIST

Catherine E.T. SIBILLE [email protected]. 32(0)2 764 53 82 or 52 20

WEB SITE


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Identification of human tumor-specific antigensSENIOR SCIENTISTS :

� Thierry BOON� Pierre VAN DER BRUGGEN� Benoît VAN DEN EYNDE � Pierre COULIE� Etienne DE PLAEN� Bernard LETHE� Aline VAN PEL� Christophe LURQUIN� Francis BRASSEUR� Danièle GODELAINE

B 4


Most human tumors bear antigens that are recognized by cyto-lytic T lymphocytes (CTL) and that are strictly tumor-specific.Stimulating the immune system against these antigens maylead to a selective elimination of the cancer cells. The usefulnessof these tumor-specific antigens is presently evaluated in clini-cal trials involving the vaccination of cancer patients.The genes coding for the tumor-specific antigens have beenidentified by transfection and detection of the transfectants bythe CTLs. Several tumor-specific antigens are encoded byhuman MAGE genes. Genes of this family are silent in mosthealthy tissues (except male germ line and placental tropho-blast cells), but are activated in tumors of different histologicaltypes. Activation of the MAGE genes results from a demethyla-tion of their promoter that correlates with genome-wide deme-thylation. Since a large number of epitopes encoded by MAGEgenes have now been identified, every cancer patient whosetumor expresses a MAGE gene should have at least one HLAmolecule to present an epitope derived from a MAGE protein. We have identified additional human gene families named,BAGE, GAGE and LAGE that present the same pattern ofexpression as MAGE genes. They also encode tumor-specificantigens recognized by T lymphocytes.To find new genes that present the same pattern of expression as theMAGE genes, we recently applied subtraction of cDNA from a tumorwith cDNA from a panel of normal tissues. This approach applied toa sarcoma cell line led to the identification of two new genes, SAGEand HAGE that have a pattern of expression similar to MAGE genes.They are potentially coding for antigens recognized by CTL. The panel of tumor antigens that is now available may be usedin consecutive immunization. This could ensure a more effecti-ve rejection of tumor cells by reducing the risk of emergence ofantigen-loss variants.


Approaches to identify antigenic peptides recognized by T lymphocytes.

Technique of cDNA subtraction.Microarray.

Main Equipment

Peptide synthesizer


CHAUX P., VANTOMME V., STROOBANT V., THIELEMANS K.,CORTHALS J., LUITEN R., EGGERMONT A.M., BOON T., VANDER BRUGGEN P. (1999) Identification of MAGE-3 epitopespresented by HLA-DR molecules to CD4(+) T lymphocytes. J.Exp. Med.;189:767-78.

HUANG L.Q., BRASSEUR F., SERRANO A., DE PLAEN E., VANDER BRUGGEN P., BOON T., VAN PEL A. (1999) Cytolytic T lym-phocytes recognize an antigen encoded by MAGE-A10 on ahuman melanoma. J. Immunol.; 162 : 6849-54.

DE SMET C., LURQUIN C., LETHE B., MARTELANGE V., BOONT. (1999) DNA methylation is the primary silencing mechanismfor a set of germ line- and tumor-specific genes with a CpG-richpromoter. Mol. Cell. Biol.;19:7327-35.

VAN DEN EYNDE B.J., GAUGLER B., PROBST-KEPPER M.,MICHAUX L., DEVUYST O., LORGE F., WEYNANTS P., BOON T.(1999) A new antigen recognized by cytolytic T lymphocytes ona human kidney tumor results from reverse strand transcription.J. Exp. Med.;190:1793-800.

LUCAS S., DE PLAEN E., AND BOON T. (2000) MAGE-B5,MAGE-B6, MAGE-C2 and MAGE-C3 : four new members ofthe MAGE family with tumor-specific expression. InternationalJournal of Cancer, 87 : 55-60.

MARTELANGE V., DE SMET C., DE PLAEN E., LURQUIN C.,BOON T. (2000) Identification on a human sarcoma of two newgenes with tumor-specific expression. Cancer Res.; 60:3848-55.

VAN DEN EYNDE B.J., MOREL S. (2001) Differential process-ing of class-I-restricted epitopes by the standard proteasomeand the immunoproteasome. Curr. Opin. Immunol.;13:147-53.

SCHULTZ E.S., CHAPIRO J., LURQUIN C., CLAVEROL S.,BURLET-SCHILTZ O., WARNIER G., RUSSO V., MOREL S., LEVY F.,BOON T., VAN DEN EYNDE B.J., VAN DER BRUGGEN P. (2002)The production of a new MAGE-3 peptide presented to cytolyt-ic T lymphocytes by HLA-B40 requires the immunoproteasome.J. Exp. Med.;195:391-9.

VAN DER BRUGGEN P., ZHANG Y., CHAUX P., STROOBANT V.,

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PANICHELLI C., SCHULTZ E.S., CHAPIRO J., VAN DEN EYNDEB.J., BRASSEUR F., BOON T. (2002) Tumor-specific shared anti-genic peptides recognized by human T cells. Immunol.Rev.;188:51-64.

COULIE P.G., VAN DER BRUGGEN P. (2003) T-cell responsesof vaccinated cancer patients. Curr. Opin. Immunol.; 15:131-7.

LORIOT A., BOON T., DE SMET C. (2003) Five new humancancer-germline genes identified among 12 genes expressed inspermatogonia. Int. J. Cancer; 105: 371-6.

UYTTENHOVE C., PILOTTE L., THÉATE I., STROOBANT V.,COLAU D., PARMENTIER N., BOON T. and VAN DEN EYNDE B.(2003) Evidence for a tumoral resistance mechanism based ontryptophan degradation by indoleamine 2,3-dioxygenase.Nature Medicine, 9 : 1269-1274.

VIGNERON N., STROOBANT V., CHAPIRO J., OOMS A.,DEGIOVANNI G., VAN DER BRUGGEN P., BOON T. and VAN DENEYNDE B. (2004) An antigenic peptide produced by peptidesplicing in the proteasome. Science, 304 : 587-590.

Patents

About 80 patents

Awards

T. Boon :Prix Rik et Nel Wouters for cancer research, 1986Prix De Vooght d’Immunologie, 1986Cancer Research Institute, Award for Research in

Immunology, 1987Dr Joseph Steiner Cancer prize, 1990Prix Francqui, 1990Prix Louis Jeantet, 1994Rabbi Shai Shacknai Memorial Prize in Immunology and

Cancer Research, 1994Prix Sandoz d’Immunologie, 1995Prix Léopold Griffuel, 1999

Funding sources

Ludwig Institute for Cancer Research; FNRS

Partnership

- Ludwig Institute for Cancer Research- ULB, Brussels, Belgium (Th. Velu, Fr. Uks)- VUB, Brussels, Belgium (B. Neyns)- KUL, Leuven, Belgium (M. Stas)- Institut Curie, Paris (T. Dorval, S. Piperno)- Institut Gustave-Roussy, Villejuif, France, (M.F. Avril, B. Escudier)- CHU de Nantes, France (B. Dreno)

- Mannheim, Germany (D. Schadendorf)- University Benjamin Franklin, Berlin, Germany (U. Keilholz)- Glaxosmithkline Biologicals, Rixensart, Belgium- Aventis Pasteur, Lyon, France - BruCells, Brussels, Belgium

STAFF

Total: 79

KEY WORDS FOR R&D

antigenic peptidecDNA subtractioncytolytic T lymphocyteepitopeimmunotherapymicroarraytumor

SENIOR SCIENTIST :

Thierry BOONThierry [email protected]. 32 (0)2 764 75 80

Pierre VAN DER [email protected] (0)2 764 74 31

Benoît VAN DEN [email protected]. 32 (0)2 764 75 72

Pierre [email protected]. 32 (0)2 764 75 99

Etienne DE [email protected]. 32 (0)2 764 74 79

Bernard [email protected]. 32 (0)2 764 74 76

Aline VAN [email protected]. 32 (0)2 764 74 83

Christophe [email protected]. 32 (0)2 764 74 76

Francis [email protected]. 32 (0)2 764 74 56

Danièle [email protected]. 32 (0)2 764 74 82

WEB SITES

www.licr.ucl.ac.bewww.gece.ucl.ac.be

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Analysis of the intracellular processing of tumor antigensrecognized by cytolytic T lymphocytes

SENIOR SCIENTIST :

� Benoît VAN DEN EYNDE

B 5


The central research theme of our group is the study of tumorantigens recognized by T lymphocytes.

Besides our continued efforts to identify additional antigens ofclinical interest for cancer immunotherapy, we mainly want toaddress a number of fundamental or mechanistic issues thathave a direct impact on the utilization of such antigens as can-cer vaccines in human patients.

These antigens consist of peptides that are presented by MHCclass I molecules at the cell surface and derive from intracellularproteins that are degraded by the proteasome. The intracellularpathway leading from the protein to the peptide/MHC complexis known as “antigen processing”.

We are currently studying the processing of several humantumor antigens by the proteasome, and we are particularlyinterested by the processing differences we have observed bet-ween the standard proteasome, which is present in most cells,and the immunoproteasome which is found in some dendriticcells and in cells exposed to interferon-gamma.

Such processing differences are important to consider in thedesign of effective vaccination strategies, not only because theycondition the induction of the immune response per se, but alsobecause they represent a mechanism of tumor resistance to theimmune response, since tumors may change the proteasome typethey express and thereby escape the immune response.

We are also studying a novel activity of the proteasome, whichwe recently uncovered, and which allows the splicing of twonon-contiguous peptide fragments to produce an antigenicpeptide. The reaction occurs by transpeptidation within theproteasome.


Mass spectrometryProteasome purification

Main Equipment

Mass spectrometry


S. MOREL, F. LÉVY, O. BURLET-SCHILTZ, F. BRASSEUR, M.PROBST-KEPPER, A.-L. PEITREQUIN, B. MONSARRAT, R. VanVELTHOVEN, J.-C. CEROTTINI, T. BOON, J.E. GAIRIN, AND B.J.VAN DEN EYNDE. 2000. Processing of some antigens by thestandard proteasome but not by the immunoproteasome resultsin poor presentation by dendritic cells. Immunity 12:107-117.

B.J. VAN DEN EYNDE AND S. MOREL. 2001. Differential pro-cessing of class-1-restricted epitopes by the standard protea-some and the immunoproteasome. Curr. Opin. Immunol.13:147-153.

E.S. SCHULTZ, J. CHAPIRO, C. LURQUIN, S. CLAVEROL, O.BURLET-SCHILTZ, G. WARNIER, V. RUSSO, S. MOREL, F. LEVY, T.BOON, B.J. VAN DEN EYNDE, AND P. VAN DER BRUGGEN.2002. The production of a new MAGE-3 peptide presented tocytolytic T lymphocytes by HLA-B40 requires the immunopro-teasome. J. Exp. Med. 195:391-399.

N. VIGNERON, V. STROOBANT, J. CHAPIRO, A. OOMS, G.DEGIOVANNI, S. MOREL, P. VAN DER BRUGGEN, T. BOON, ANDB.J. VAN DEN EYNDE. 2004. An antigenic peptide produced bypeptide splicing in the proteasome. Science 304:587-590.

Patents

A large portfolio of about 80 issued patents and patent appli-cations on tumor antigens.

Awards

1998 : Prize of the “Fondation Clément Perdieus et Cécile Petit”1998 : Annual prize of the “Fondation Maggy et Robert de Hovre”1998 : Prize of the “Fondation Alexandre et Gaston Tytgat”2001 : Prize of the 165th anniversary of the “Académie

Royale de Médecine de Belgique”

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Funding Sources

Ludwig Institute for Cancer ResearchInstitut de Pathologie cellulaire Christian de Duve (ICP)Fonds national de la recherche scientifique (FNRS)TélévieFédération Belge contre le Cancer

Partnership

Dr. E. WARREN, Fred Hutchinson Cancer Institute, Seattle,WA, USA.

Dr. K.-I. HANADA and Dr. P. ROBBINS, National CancerInstitute, National Institutes of Health, Bethesda, MD, USA.

Dr. J.-E. GAIRIN, Institut de Pharmacologie et BiologieStructurale, CNRS, Toulouse, France.

Dr. F. LEVY, Ludwig Institute for Cancer Research, LausanneBranch, Switzerland.

STAFF

Total : 8

KEY WORDS FOR R&D

antigen processingbiochemistrycancer vaccinesimmunologyimmunotherapyproteasometumor antigens

SENIOR SCIENTIST

Benoît VAN DEN [email protected]. 32(0)2 764 75 72

WEB SITE

www.licr.ucl.ac.be/tiap/tiap.html

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Mechanisms of tumor resistance to the immune system anddevelopment of a mouse model of inducible melanoma

SENIOR SCIENTIST :

� Benoît VAN DEN EYNDE

B 6


Crucial to the success of cancer immunotherapy is a preciseunderstanding of the interplay between growing tumors andthe anti-tumor immune response. For example, tumors may develop a variety of mechanisms toescape immune attack. In that context, we have observed that a majority of tumor cellsexpress an enzyme called indoleamine 2,3-dioxygenase (IDO),which rapidly degrades tryptophan, an essential amino acidwhose supply is mandatory for the activity of T lymphocytes.Thus, by locally degrading tryptophan, tumor cells completelyinactivate T lymphocytes and thereby blunt the anti-tumorimmune response. We have also shown that this resistancemechanism can be blocked by treating animals with 1-methyl-tryptophan, an inhibitor of IDO. These results suggest that theefficacy of cancer immunotherapy could be improved by com-bining immunization strategies with a treatment aimed at inhi-biting IDO. We are trying to develop novel inhibitors of IDO forthat purpose. We are also studying other mechanisms of tumo-ral immune resistance.

In order to obtain meaningful information from mouse studieswith melanoma, we are also developing a new model of micethat will develop melanomas upon local application of tamoxi-fen. The induction of melanomas is based on Cre-lox recombi-nation and involves conditional activation of oncogene Ras andinactivation tumor-suppressor gene INK4A. Tumors developingslowly within a normal tissue are likely to represent the statusof human cancers much more closely than the transplantedtumors currently used. Such a model will be particularly useful to optimize strategies ofcancer immunotherapy, but will undoubtedly be also of greatinterest in other contexts, such as the molecular definition ofthe successive steps involved in carcinogenesis, local invasive-ness and metastasis.


Screening assay for the development of new IDO inhibitorsNew mouse model of inducible melanomas

Main Equipment

Laser-assisted microdissection and laser pressure catapulting(P.A.L.M.®, Microlaser Technologies AG, Benried, Germany)


UYTTENHOVE C., PILOTTE L., THÉATE I., STROOBANT V.,COLAU D., PARMENTIER N., BOON T., VAN DEN EYNDE B.J.Evidence for a tumoral immune resistance mechanism based ontryptophan degradation by indoleamine 2,3-dioxygenase.Nature Medicine 9 : 1269-1274, 2003.

Patents

A large portfolio of about 80 issued patents and patent appli-cations on tumor antigens and their use for cancer therapy.

Funding Sources

Ludwig Institute for Cancer ResearchInstitut de Pathologie cellulaire Christian de Duve (ICP)Fonds national de la recherche scientifique (FNRS)TélévieFédération Belge contre le Cancer

Partnership

The Netherlands Cancer Institute (NKI), Amsterdam, TheNetherlands.

Centre d’Immunologie INSERM-CNRS, Marseille-Luminy, MarseilleFrance.

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STAFF

Total : 8

KEY WORDS FOR R&D

biochemistrycancer vaccinesIDO inhibitors immune escapeimmunologyimmunotherapyinducible melanoma modeltumor antigens

SENIOR SCIENTIST

Benoît VAN DEN [email protected]. 32(0)2 764 75 72

WEB SITE

www.licr.ucl.ac.be/tiap/tiap.html

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Aristolochic acid and ochratoxin A : etiological factors ofBalkan endemic nephropathy and associated urothelial tumors

SENIOR SCIENTIST :

� Jean-Pierre COSYNS

B 7


Balkan nephropathy (BN), a 50 years old chronic interstitial fibrosingnephropathy of still unknown etiology, has been reported similar toso-called Chinese herbs nephropathy (CHN). The responsibility of aristolochic acid (AA) and ochratoxin A (OTA),two nephrotoxic and carcinogenic substances respectively of herbaland mycotic origin, has respectively been demonstrated and deniedin CHN. Exposure of BN patients to both alkaloids by the identifica-tion of specific tissular DNA adducts awaits further elucidation. The hypothetical dAMP incorporation by polymerase at the site ofAA-adenine adducts may be assessed by the analysis of likely muta-tions in the tumour suppressor gene p53 of AA exposed patients.

Several international collaborations were invaluable to achievethese researches, in particular for :

the local selection of BN patients and pathologic samples(University of Nis, and Clinical Center of Serbia, Belgrade, Serbia)

the evaluation of morphological aspects of BN (University ofLjubljana, Slovenia)

the analysis of AA-DNA adducts by the 32P post-labellingtechnique (University of Heidelberg, Germany)

the international collaborative works including validation of DNAadduct detection by 32P post-labelling techniques and evaluations ofOTA exposure (Institut National Polytechnique de Toulouse, France)

the supervision of a thesis on the relationship between malig-nancy and the functional status of p53 and contribution to theidentification of mutations in the gene p53 (UCL, Bruxelles).


Detection of carcinogen-DNA adducts in human tissues usingthe 32P post-labelling technique for diagnostic and researchpurposes (Carcinogenesis 1994; 15:1187-92).

Main Equipment

Standard equipment of University Laboratory of Pathologyand Molecular Biology.

Standard facilities of University Medical and Surgical Clinic.


COSYNS J.P., JADOUL M., SQUIFFLET J.P., DE PLAEN J.F.,FERLUGA D., VAN YPERSELE DE STRIHOU C. Chinese herbsnephropathy: a clue to Balkan endemic nephropathy ? KidneyInt, F.I.: 5.0160, 1994, 45, 1680-1688.

COSYNS J.P., JADOUL M., SQUIFFLET J.P., VAN CANGH P.J.,VAN YPERSELE DE STRIHOU C. Urothelial malignancy innephropathy due to Chinese herbs. Lancet, F.I.: 15.3970, 1994,344, 188.

SCHMEISER H.H., BIELER C.A., WIESSLER M., VAN YPERSELEDE STRIHOU C., COSYNS J.P. Detection of DNA adducts formedby aristolochic acid in renal tissue from patients with Chineseherbs nephropathy. Cancer Res, F.I.: 8.3180, 1996, 56, 2025-2028.

BIELER C.A., STIBOROVA M., WIESSLER M., COSYNS J.P., VANYPERSELE DE STRIHOU C. 32P -post-labelling analysis of DNAadducts formed by aristolochic acid in tissues from patientswith Chinese herbs nephropathy. Carcinogenesis, F.I.: 5.4050,1997, 18, 1063-1067

COSYNS J.P., GOEBBELS R.M., LIBERTON V., SCHMEISER H.H.,BIELER C.A., BERNARD A.M. Chinese herbs nephropathy-asso-ciated slimming regimen induces tumours in the forestomachbut no interstitial nephropathy in rats. Arch. Toxicol., F.I.:1.8520, 1998, 72, 738-743.

COSYNS J.P., JADOUL M., SQUIFFLET J.P., WESE F.X., VANYPERSELE DE STRIHOU C. Urothelial lesions in Chinese-herbnephropathy. 1011-7. Am. J. Kidney Dis., F.I.: 3.6880, 1999, 33,1011-1017.

GILLEROT G., JADOUL M., ARLT V.M., VAN YPERSELE DESTRIHOU C., SCHMEISER H.H., BUT P.P., BIELER C.A., COSYNSJ.P. Aristolochic acid nephropathy in a Chinese patient: time toabandon the term “Chinese herbs nephropathy”? Am. J. KidneyDis., F.I.: 3.6880, 2001, 38.

COSYNS J.P., DEHOUX J.P., GUIOT Y., GOEBBELS R.M., ROBERTA., BERNARD A.M., VAN YPERSELE DE STRIHOU C. Chronic aris-tolochic acid toxicity in rabbits: a model of Chinese herbsnephropathy ? Kidney Int., F.I.: 5.0160, 2001, 59, 2164-2173.

SOLEZ K., DAUGIRDAS J., GREGORY M.C., FROHNERT P.P.,BHOWMIK D.M., JHA V., COSYNS J.P. Is “Chinese herbsnephropathy” a prejudicial term ? Am. J. Kidney Dis., F.I.:3.6880, 2001, 38, 1141-1142.

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COSYNS J.P. When is “aristolochic acid nephropathy” moreaccurate than “Chinese herbs nephropathy”? Kidney Int., F.I.:5.0160, 2002, 61, 1178.

ARLT V.M., FERLUGA D., STIBOROVA M., PFOHL-LESZKOWICZA., VUKELIC M., CEOVIC S., SCHMEISER H.H., COSYNS J.P. Isaristolochic acid a risk factor for Balkan endemic nephropathy-associated urothelial cancer ? Int. J. Cancer, F.I.: 4.0560, 2002,101, 500-502.

KANAAN N., COSYNS J.P., JADOUL M., GOFFIN E. The impor-tance of a histology-based diagnosis of interstitial nephropathyin two patients with renal insufficiency. Nephrol. Dial. Transplant.,2003, 18, 440-442.

GILLEROT G., GOFFIN E., MOULIN P., ARLT V.M., PHILLIPSD.H., COSYNS J.P., DEVUYST O. Aristolochic acid nephropathyand the peritoneum: Functional, structural, and molecular stu-dies. Kidney Int., F.I.: 5.0160, 2003, 64, 1883-92.

COSYNS J.P. Aristolochic acid and ‘Chinese herbs nephropa-thy’: a review of the evidence to date. Drug Safety, F.I.: 3.3160,2003, 26, 33-48.

COSYNS J.P., VAN YPERSELE DE STRIHOU C. Chinese herbs andother rare causes of interstitial nephropathy, Oxford Textbook ofClinical Nephrology, edited by AM Davison, in press.

STEFANOVIC V., COSYNS J.P. Balkan Nephropathy, OxfordTextbook of Clinical Nephrology, edited by AM Davison, in press.

Funding Sources

Télévie

Partnership

Prof. V. Stefanovic, V. Savic (University of Nis, Serbia) and J.Nikolic (Clinical Center of Serbia, Belgrade, Serbia)

Prof. D. Ferluga (University of Ljubljana, Slovenia)Prof. Schmeiser (University of Heidelberg, FRG)Prof. Leszkowicz (Institut National Polytechnique de Toulouse,

France)Prof. J.L. Gala (UCL, Bruxelles)

STAFF

Total : 2

KEY WORDS FOR R&D

biomedical and agricultural sciencesenvironmental medicinehistopathologymedicine human pathologymolecular biologymolecular geneticsnephrology-urologyorganic chemistrypathologypharmaceutical chemistryprevention medicine

SENIOR SCIENTIST

Jean-Pierre [email protected]. 32 (0)2 764 17 21

WEB SITE


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AMP-activated protein kinase, a new potential regulator ofcytoskeleton organization : role in cell proliferation and/or differentiation

SENIOR SCIENTISTS :

� Louis HUE � Mark RIDER

B 8


The AMP-activated protein kinase (AMPK) has recently receivedmuch attention because of its important medical implications intype II diabetes. We believe that other medical implications existbecause of our recent preliminary evidence for new substratesof AMPK, such myosin light chain kinase involved notably in theorganization of actin cytoskeleton, the latter affecting cellshape and from this, division. Indeed it is well-known that alte-rations in cell shape often accompany changes in cellular activi-ties related not only to cell motility but also to differentiationand/or division. The aim of our project is to evaluate the effectof AMPK activation on cell motility and proliferation. This pro-ject relies on the implementation of technical approaches thatare at the forefront of molecular biology, biochemistry and cel-lular biology.

Adenoviral vectors expressing dominant-negative or constituti-vely active AMPK are currently under construction in the labo-ratory. Techniques currently reffered to proteomics andphosphoproteomics, aiming at identifying protein sequencesand phosphorylated peptides by mass spectrometry, represent atechnical achievement in the laboratory, as the measurement ofenzymatic activities. Finally, immunoblotting and immunocyto-chemistry techniques will allow us to investigate the phospho-rylation states of proteins and their localization or organization(for actin) in the cell.

Main Equipment

The laboratory contains the necessary equipment to developthis project. A collaboration with cell biologists is foreseen inorder to achieve reliable measurements of cell motility.


HORMAN S., BROWNE G.J., KRAUSE U., BEAULOYE C.,McLEOD L.E., VERTOMMEN D., BERTRAND L., LAVOINNE A.,HUE L., PROUD C.G., RIDER M.H. Activation of AMP-activatedprotein kinase by anoxia is associated with the phosphorylation

of elongation factor 2 and an inhibition of protein synthesis.Current Biology, 2002, 12, 1419-1423.

HUE L., BEAULOYE C., MARSIN A.S., BERTRAND L., HORMANS., RIDER M. Insulin and ischemia stimulate glycolysis by actingon the same targets through different and opposing signalingpathways. J. Mol. Cell Cardiol., 2002, 34, 1091-1097.

HUE L., BEAULOYE C., BERTRAND L., HORMAN S., KRAUSEU., MARSIN A.S., MEISSE D., VERTOMMEN D., RIDER M. Newtargets of AMP-activated protein kinase. Biochem. Soc. Trans.,2003, 31, 213-215.

HORMAN S., BEAULOYE C., VERTOMMEN D., VANOVER-SCHELDE J.L., HUE L., RIDER M.H. Myocardial ischemia andincreased heart work modulate the phosphorylation state ofeukaryotic elongation factor-2. J. Biol. Chem., 2003, 278,41970-6.

Funding Sources

Our laboratory is funded by Belgian (FRSM-Foundation forMedical Scientific Research, IAP-Interuniversity Attraction Pole,Télévie) and European (5th framework program) financial supports.

Partnership

EU program FP6 “EXEGENESIS” Health benefits of exercise:identification of genes and signalling pathways involved ineffects of exercise on insulin resistance, obesity and the meta-bolic syndrome.

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STAFF

Total : 5

KEY WORDS FOR R&D

AMP-activated protein kinasebiochemistrycellular biologycytologycytoskeletondifferentiationmotilitymyosin light chain kinaseproliferationstress fibers

SENIOR SCIENTISTS

Louis HUE [email protected] Tel. 32 (0)2 764 74 85

Mark RIDER [email protected] Tel. 32 (0)2 764 74 86

WEB SITE

www.icp.ucl.ac.be/horm

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Mammalian antioxidant enzymes

SENIOR SCIENTISTS :

� Bernard KNOOPS� Jean-Paul DECLERCQ� Jean-François REES

B 9


Oxidative stress is a major biological process involved in the deve-lopment of a number of acute or chronic pathological situations(inflammation, cancer, neurodegenerative diseases, atherosclerosis,lung diseases, aging). Our research is focused on identification andcharacterization of proteins that may play protective roles againstcell death caused by oxidative stress (apoptosis and necrosis). Afterexpression of these proteins in bacteria, in yeasts or in mammaliancells, their protective antioxidant activity is tested in different in vitromodels such as animal and human cell lines exposed to oxidative orpro-apoptotic compounds. The yeast Saccharomyces cerevisiae isalso used as model organism. Peroxide and peroxynitrite reductaseactivities of recombinant proteins are measured. Tridimensionalstructure is determined by X-ray crystallography.

One of the proteins currently under investigation is a novelmammalian thioredoxin peroxidase (PRDX5) which is a memberof the recently identified peroxiredoxin family of antioxidantenzymes. We have solved crystal structure of PRDX5. Enzymaticactivities of PRDX5 as well as its physiological implication in cel-lular protection against oxidative stress are also explored usingE. coli recombinant proteins and cell transfection strategies. Thedeletion of the gene homologous to human PRDX5 inSaccharomyces cerevisiae has been performed and revealed theimportance of this protein in the defence against oxidativestress but also against heavy metal toxicity.


Gene cloningRecombinant proteinsTransfection of mammalian cell linesCrystallography

Main Equipment

Cell culture equipmentConfocal and electron microscopyMolecular biology equipment


B. KNOOPS, A. CLIPPE, K. ARSALANE, R. WATTIEZ, C. HER-MANS, E. DUCONSEILLE, P. FALMAGNE and A. BERNARD(1999) Cloning and characterization of AOEB166, a novel mam-malian antioxidant enzyme of the peroxiredoxin family. J. Biol.Chem. 274, 30451-30458.

J.-P. DECLERCQ, C. EVRARD, A. CLIPPE, D. VANDER STRICHT, A. BERNARD and B. KNOOPS (2001) Crystal structure of humanperoxiredoxin 5, a novel type of mammalian peroxiredoxin at1.5 A resolution. J. Mol. Biol. 311, 751-759.

M.X. WANG, A. WEI, J. YAN, A. CLIPPE, A. BERNARD, B.KNOOPS and G.A. MURRELL (2001) Antioxidant enzymeperoxiredoxin 5 is upregulated in degenerative human tendon.Biochem. Biophys. Res. Commun., 284, 667-673.

N.T. NGUYEN-NHU and B. KNOOPS (2002) Alkyl hydroperox-ide reductase 1 protects Saccharomyces cerevisiae againstmetal ion toxicity and glutathione depletion. Toxicol. Letters.135, 219-226.

M.X. WANG, A. WEI, J. YAN, A. TRICKETT, B. KNOOPS &G.A.C. MURRELL (2002) Expression and regulation of peroxire-doxin 5 in human osteoarthitis. FEBS Letters. 531, 359-362.

F. PLAISANT, A. CLIPPE, D. VANDER STRICHT, B. KNOOPS & P.GRESSENS (2003) Recombinant peroxiredoxin 5 protectsagainst excitotoxic brain lesions in newborn mice. Free Rad.Biol. Med. 34, 862-872.

N.T. NGUYEN-NHU & B. KNOOPS (2003) Mitochondrial andcytosolic expression of human peroxiredoxin 5 inSaccharomyces cerevisiae protect yeast cells from oxidativestress induced by paraquat. FEBS Letters. 534, 148-152.

G. LEYENS, I. DONNAY & B. KNOOPS (2003) Cloning ofbovine peroxiredoxins: gene expression in bovine tissues andamino acid sequence comparison with rat, mouse and primateperoxiredoxins. Comp. Biol. Phys., 136, 943-955.

I. BANMEYER, C. MARCHAND, C. VERHAEGHE, B. VUCIC, J-F. REES & B. KNOOPS (2003) Overexpression of human peroxi-redoxin 5 in subcellular compartments of Chinese hamsterovary cells: effects on cytotoxicity and DNA damage caused byperoxides. Free Rad. Biol. Med., 36, 65-77.

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Patents

B. KNOOPS, C. HERMANS, A. BERNARD, R. WATTIEZ & P. FAL-MAGNE (1999) Peroxisome-associated polypeptide, nucleotidesequence encoding said polypeptide and their uses in the diag-nosis and/or the treatment of lung injuries and diseases, and ofoxidative stress-related disorders. WO9909054.

J.-P. DECLERCQ, C. EVRARD, A. CLIPPE, D. VANDER STRICHT, A. BERNARD & B. KNOOPS (2001) Crystal structure of PRDX5.European Patent Application n° 01870016.1.

Funding Sources

Fonds national de la recherche scientifique (FNRS)Fonds de la recherche fondamentale collective - FRFCFonds pour la formation à la recherche dans l’industrie et

dans l’agriculture (FRIA)Actions de recherche concertée (ARC)

Partnership

Member of the Institut des Sciences de la Vie, Louvain-la-Neuve, Belgium.

Prof. R. OUVRIER, New Children’s Hospital, Univ. Sydney,Australia.

Prof. J.P. BRION, ULB, Belgium.Dr. P. GRESSENS, INSERM, Paris, France.Prof. G. MURRELL, St George Hospital Sydney, Australia.Prof. L. POOLE, Wake Forest University School of Medicine, USA.Prof. W.H. KOPPENOL, ETH, Zurich, Switzerland.Prof. R.J. WANDER, University of Amsterdam,

The Netherlands.Dr. R. WATTIEZ, UMH, Belgium.

STAFF

Total : 16

KEY WORDS FOR R&D

animal cell cultureantioxidant enzymecrystallizationperoxidase activityprotein purificationrecombinant proteintransfection vectorstridimensional structure

SENIOR SCIENTISTS

Bernard [email protected] Tel. 32(0)10 47 37 60

Jean-Paul [email protected]. 32(0)10 47 29 24

Jean-François [email protected]. 32(0)10 47 35 17

WEB SITES

www.bani.ucl.ac.bewww.cstr.ucl.ac.bewww.isv.ucl.ac.be

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37


Mechanisms involved in apoptosis induced by anticancerous drugs

SENIOR SCIENTIST :

� Marie-Paule MINGEOT-LECLERCQ

B 10


The explosion of interest in apoptosis amongst cancer biologistshas been underpinned by the hope that an understanding ofcell death will enhance our knowledge of the mechanismsinvolved in tumor drug resistance.

Two areas of fundamental importance are: - the mechanism of the process of drug-induced apoptosis- the modulation of cellular resistance to conventional agents,which would derive from an understanding of the mechanismsthat allow cancer cells to evade apoptosis after drug-induceddamage.

Most of the polychemotherapeutic strategies in haematologicaloncology are based on the use of anthracyclines. Despite theirwidespread use, the intracellular events leading to apoptoticcell death are only partially understood.

Several organelles might initiate apoptosis by specific stress sen-sors and relay apoptosis-modulating signals to the rest of thecell. Stress management intending to repair damaged structu-res probably involves an orchestrated response affecting severalorganelles. During the last few years, lysosomal destabilizationwith release of hydrolytic enzymes to the cytosol has been rai-sed as an upstream event preceding apoptosis triggered by avariety of different agonists.

We and others previously observed that lysosomotropic agents(aminoglycoside antibiotics e.g.), which are concentrated insidelysosomes by endocytosis and proton trapping, cause lysosomalrupture and ensue apoptosis.

The first aim of this study is to investigate the role of lysosomes inapoptosis induced by anthracyclines. Due to their character of weakbases, these drugs can partly accumulate in lysosomes by a mecha-nism of proton trapping. Therefore, if lysosomes are involved inapoptosis induced by anthracyclines, we might study the involve-ment of a direct activation of pro-caspases by released lysosomalproteases, especially cathepsins B, L, and D. Alternatively, cytoplas-mic lysosomal enzymes might activate other cytosolic pro-enzymes,or proteins of Bcl-2 family like Bid, or proteolytically attack mito-

chondrial membranes, releasing cytochrome c and ensuing apopto-sis.

The second aim of this study is to provide an understanding ofthe apoptosisinduced by anthracyclines in resistant cells.Especially, it is of great interest to study the mechanism invol-ved in the increased accumulation of anthracyclines in the aci-dic organelles of a variety of drug-resistant cancer cells. This ele-vated accumulation may result from the action of transportersthat efflux the drug at the plasma membrane (or drive seques-tration into organelles). Alternatively, the enhanced lysosome-to-cytosol pH difference observed in resistant cell lines maycause sequestration of anthracyclines in the organelles.

The capacity of resistant- cells lines to compartmentalize anthracy-clines away from intracellular target sites by accumulating them inlysosomes could be taken as an advantage, allowing cancer cellsto enhance apoptosis after drug-induced damage.

The general aim of this work is to understand the molecularmechanisms underlying apoptosis induced by anticancer drugsin sensitive and resistant cells to overcome drug resistance andto generate novel molecular targets.


Cellular models for the evaluation of the capacity of drugs toinduce apoptosis.

In vitro models (liposomes) for the evaluation of the capacityof drugs to alter the membrane permeability.

Main Equipment

Cell culture facilities.General equipment for biochemical and molecular biology assays.General equipment for preparing liposomes, binding experiments

and biophysical techniques (fluorimetry).Microplate reader.Fluorescence microscopy.Equipment for assay of drugs by scintillation counting, HPLC.

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EL MOUEDDEN M., LAURENT G., MINGEOT-LECLERCQ M.P.and TULKENS P.M. (2000) Apoptosis in renal proximal tubulesof rats treated with low doses of aminoglycosides. Antimicrob.Agents Chemother., 44: 665-675.

EL MOUEDDEN M., LAURENT G., MINGEOT-LECLERCQ M.P.and TULKENS P.M. (2000) Gentamicin-induced apoptosis inrenal cell lines and embryonic rat fibroblasts. Toxicol. Sciences,56:229-239.

MINGEOT-LECLERCQ M.P., GALLET X., FLORE C., VAN BAMBEKEF., PEUVOT J. and BRASSEUR R. (2001) Experimental and confor-mational analyses of interactions between butenafine and lipids.Antimicrob. Agents Chemother., 45: 3347-3354.

MINGEOT-LECLERCQ M.P., LINS L., BENSLIMAN M., VANBAMBEKE F., VAN DER SMISSEN P., PEUVOT J., SCHANCK A.and BRASSEUR R. (2002) Membrane destabilization induced bybeta-amyloid peptide 29-42: Importance of the amino-termi-nus. Chem. Phys. Lipids, 120: 57-74.

MINGEOT-LECLERCQ M.P., LINS L., BENSLIMAN M., THOMASA., VAN BAMBEKE F., PEUVOT J., SCHANCK A. and BRASSEURR. (2003) Piracetam inhibits the lipid-destabilising effect of theamyloid peptide Abeta C-terminal fragment. Biochim. Biophys.Acta, 1609: 28-38.

TYTECA D., SCHANCK A., DUFRENE Y. F., DELEU M., COURTOYP.J., TULKENS P.M. and MINGEOT-LECLERCQ M.P. (2003) Themacrolide antibiotic azithromycin interacts with lipids andaffects membrane organization and fluidity: studies onLangmuir-Blodgett monolayers, liposomes and J774macrophages. J. Membr. Biol. 192: 203-215.

DOM G., SHAW-JACKSON C., MATIS C., BOUFFIOUX O.,PICARD J.J., PROCHIANTZ A., MINGEOT-LECLERCQ M.P.,BRASSEUR R. and REZSOHAZY R. (2003) Cellular uptake ofAntennapedia Penetratin peptides is a two-step process inwhich phase transfer precedes a tryptophan-dependenttranslocation. Nucleic Acids Res., 31: 556-561.

CHANTEUX H., PATERNOTTE I., MINGEOT-LECLERCQ M.P.,BRASSEUR R., SONVEAUX E. and TULKENS P.M. (2003) Cell han-dling, membrane-binding properties, and membrane-penetra-tion modeling approaches of pivampicillin and phthalim-idomethylampicillin, two basic esters of ampicillin, in comparisonwith chloroquine and azithromycin. Pharm. Res., 20: 624-631.

SERVAIS H., VAN DER SMISSEN P., THIRION G., VAN DERESSEN G., VAN BAMBEKE F., TULKENS P.M. and MINGEOT-LECLERCQ M.P. (2003). The antibiotic gentamicin inducesapoptosis in LLC-PK1: involvment of lysosomes and mitochon-drial pathway. Kidney Intern. Submitted.

Funding Sources

UCL – FNRS – Télévie - Région wallonne

STAFF

Total: 23

KEY WORDS FOR R&D

anthracyclinesapoptosisbiophysics lysosomesmembranesmolecular and cellular biology molecular and cellular pharmacology pharmaceutical sciences resistancetumor cells

SENIOR SCIENTIST

Marie-Paule [email protected]. 32 (0)2 764 73 74

WEB SITE

http:// www.facm.ucl.ac.be

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Hox transcription factors and cancer

SENIOR SCIENTIST :

� René REZSOHAZY

B 11


The homeotic Hox genes code for important transcription fac-tors that contribute to pattern the main body axis and the limbsand to govern several steps of organogenesis during theembryonic development of vertebrates. While these proteinsplay critical roles during embryogenesis, accumulating data alsoprovides evidence that they fulfil important functions in modu-lating differentiation processes at adulthood. These genes arefor example involved in the commitment of cell fates in hema-topoïesis or in the maturation of the mammary gland to sup-port lactation.

Our current research interests concern the mode of action ofthis class of transcription factors. What are their functional domains ? How do they specificallyachieve their roles? What are the target genes under theircontrol ? These are the questions we currently investigate.

While most of our investigations to date were connected to thedevelopmental functions of these genes, we recently turnedtowards the relationship between the activity of these proteinsand their involvement in differentiation or tumorigenesis.

A first approach is related to the Hoxa1 protein. Hoxa1 hasrecently been associated with breast cancer development uponincreased expression of the human growth hormone. In vitro,forced expression of Hoxa1 results in the oncogenic transforma-tion of human mammary epithelial cells. We will use such in vitroassays as a readout to identify new functional domains ofHoxa1. This will allow to further unravel the Hoxa1 partners andthe pathways leading to the Hoxa1 associated tumorigenesis.

We generated recombinant mice in which the Hoxa1 gene hasbeen replaced by an allele coding for a Hoxa1 protein unable tocooperate with Pbx, one of its key cofactors. In vitro data sug-gest that the partnership between Hoxa1 and Pbx is critical forthe oncogenic potential of Hoxa1. Our recombinant mice willallow to validate this hypothesis. If the Hoxa1-Pbx interaction isconfirmed to be crucial for the Hoxa1 associated cancer deve-lopment, the known interfaces between these proteins wouldbe considered as potential targets for antagonists design.

In the context of a collaboration involving the clinic (Prof. G.Cornu, Cliniques Universitaires St Luc), the Center for HumanGenetics (Prof. Ch. Verellen-Dumoulin) and our group, Hoxmutations have been identified in patients with lymphoid mal-ignancy. Here again, our goal will be to determine the impactof these mutations on the activity of the Hox proteins and toevaluate to what extent they convert Hox genes into oncoge-nes.

Main Equipment

Regular cellular and molecular biology.


REMACLE S., SHAW-JACKSON C., MATIS C., LAMPE X., PICARDJ. and REZSOHAZY R. Changing homeodomain residues 2 and3 of Hoxa1 alters its activity in a cell-type and enhancer depend-ent manner. 2002, Nucleic Acids Res., 30, 2663-2668.

DOM G., SHAW-JACKSON C., MATIS C., BOUFFIOUX O.,PICARD J.J., PROCHIANTZ A., MINGEOT-LECLERCQ M.-P.,BRASSEUR R. and REZSOHAZY R. Cellular uptake ofAntennapedia penetratin peptides is a two-step process inwhich phase transfer precedes a tryptophan-dependenttranslocation. 2003, Nucleic Acids Res., 31, 556-561.

LAMPE X., PICARD J.J. and REZSOHAZY R. The Hoxa2 enhancer2 contains a critical Hoxa2 responsive regulatory element. 2004,Bioch. Bioph. Res. Comm., 316, 898-902.

DIMAN N.Y.S.-G., CHAUVIER E., PACICO N., PICARD J.J. andREZSOHAZY R. The proximal 2-kb of the Hoxa3 promoterdirects gene expression in distinct branchial compartments andcranial ganglia. 2004, Dev. Brain Res., 150, 211-213.

REMACLE S., ABBAS L., DE BACKER O., PACICO N., GAVALASA., GOFFLOT F., PICARD J.J. and REZSOHAZY R. Loss-of-func-tion but no gain-of-function caused by amino acid substitutionsin the hexapeptide of Hoxa1 in vivo. 2004, Mol. Cell Biol, inpress.

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Funding Sources

Fonds national de la recherche scientifique (FNRS)Télévie

Partnership

Prof. Ch. Verellen-Dumoulin, Center for Human genetics, UCL.Prof. G. Cornu, Dept. Pediatric Hematology and Oncology,

Cliniques Universitaires St Luc, Belgium.Prof. F. Rijli, IGBMC, Strasbourg, France.Prof. M. Featherstone, Mc Gill University, Montreal, Canada.

STAFF

Total 4

KEY WORDS FOR R&D

breast cancerhox lymphoid malignancytranscription factors

SENIOR SCIENTIST

René [email protected]. 32(0)10 47 37 06

WEB SITE

www.mige.ucl.ac.be

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Genetic analysis of brain tumours

SENIOR SCIENTISTS :

� Miikka VIKKULA� Catherine GODFRAIND

C 1


We are interested in the genetic study of cerebral tumors (oligo-dendrogliomas and ependymal tumours) and of ocular melanoma.

Ours aims are : to establish a correlation between molecular markers and

diagnosis, prognosis and therapeutic response; to establish a correlation between (epi)genetic alterations and

tumourigenetic events.


Development of genetic tests

Main Equipment

Two institutional 8 capillaries sequencing unitsOne institutional whole genome analysis system for SNPs and

expression analysis (Affymetrix)Two semi-automated analysis systems for human genome

linkage analysis (LICOR)Array-CGHDHPLC


GODFRAIND C., ROUSSEAU E., RUCHOUX M.M., SCARAVIL-LI F., VIKKULA M. Tumour necrosis and microvascular prolifera-tion are associated with 9p deletion and CDKN2A alterations in1p/19q-deleted oligodendrogliomas. Neuropathology andApplied Neurology, 2003, 29:462-471.

ROUSSEAU E., GODFRAIND C., RUCHOUX M.M., SCARAVIL-LI F., CHAPON F., VIKKULA M. Tumor necrosis and microvascu-lar proliferation are associated with 9p deletion and CDKN2A,CDKN2B and p14ARF are frequently and differentially methylatedin ependymal tumors. Neuropathology and Applied Neurology,in press.

Funding Sources

Fonds national de la recherche scientifique (FNRS) TélévieFonds MaisinFédération Belge contre le Cancer

Partnership

Collaborations with Prof. M.M. Rouchoux, CHU Lille, FranceF. Scaravilli, Institute of Neurology, London, EnglandProf. I. Salmon, Erasme, Brussels, Belgium

STAFF

Total : 4

KEY WORDS FOR R&D

brain tumorCGH (comparative genomic hybridization)DNA microarraysependymomaLOH (loss of heterozygosity)molecular geneticsocular melanomaoligodendroglioma

SENIOR SCIENTISTS

Miikka [email protected] : 32 (0)2 764 74 96

Catherine [email protected] : 32 (0)2 764 52 60

WEB SITES

www.icp.ucl.ac.be/vikkulawww.md.ucl.ac.be/vasc_anom

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Characterization of malignant hemopathies by molecularand flow cytometry

SENIOR SCIENTISTS :

� Dominique LATINNE � Jean-Luc VAERMAN � Véronique DENEYS

C 2


Acute leukemia are generally divided into myeloid (AML) andlymphoid (ALL) leukemia. All diagnosis methods (cytology,immunophenotyping and cytogenetics) are complementary;none, on its own, is sufficient to allow precise diagnosis.The aim of our project is triple :

We would like to know if the approach of quantitative Realtime PCR (RTQ-PCR) allows to obtain easily and simultaneouslyquantitative expression profiles for multiple genes.

Specific lineage markers can be analysed by phenotypic (anti-genic) or genotypic (RNA) expression. We would like to com-pare the expression, by flow cytometry and by RTQ-PCR, of apanel of lineage or malignity specific genes.

We would like also to analyse the input of the analysis ofgene expression by Real time quantitative PCR in prognosis anddiagnosis of leukemia.

Up to now, we have analysed expression profiles of CD19,CD79a, CD3e and myelo-peroxidase (MPO) in 72 leukemicbone marrow samples at diagnosis. The expression level ofthese genes has been expressed as delta CT. The analysis of theco-expression of these genes allows to identify 3 patterns. Thefirst one shows a higher expression of CD3e and a lower one ofCD19, CD79a and MPO. The second one shows a higherexpression of MPO. The third one, a higher expression of CD19and CD79a. These 3 patterns have a perfect correlation with TALL, AML and B ALL respectively.

Preliminary conclusion is that the analysis of lineage markers byRTQ-PCR at diagnosis allows to differentiate AML, T ALL and BALL without specific blast selection and even if the blastic popu-lation is limited. In the future, we will extend this study to manyother genes in order to identify those of interest in diagnosisand/or prognosis of acute leukemia.


Real time quantitative PCRGene sequencing

Main Equipment

Genetic Analyser 310 Applied BiosystemsSequence Detect System 7700


SAUSSOY P., VAERMAN J.P., CORNU G., FERRANT A., LATINNED.L. Characterization of acute leukemias gene expression analy-sis: impact on diagnosis and prognosis. 8è Journée de BiologieClinique, 10 mai 2003, UCL. Abstract Acta Clinica Belgica.

SAUSSOY P., VAERMAN J.P., STRAEMANS N., CORNU G., FER-RANT A., LATINNE D.L. Differential diagnosis between acutemyeloid leukemia, B-lineage acute lymphoid leukemia and T-line-age acute lymphoid leukemia using real time quantitative reversetranscription-PCR. Accepted in Clinical Chemistry Dec. 20, 2003.

Awards

Price of the best poster hematology section, 2003

Funding sources & Partnership

Fonds national de la recherche scientifique (FNRS) TélévieSt Luc Hospital

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STAFF

Total: 9

KEY WORDS FOR R&D

hematology leukemiamolecular biology realtime PCRtranslocations

SENIOR SCIENTISTS

Dominique LATINNE [email protected] Tel. 32 (0) 2 764 31 45

Jean-Luc VAERMAN [email protected] Tel. 32 (0)2 764 31 75

Véronique DENEYS [email protected] Tel. 32 (0)2 764 17 31

WEB SITES

http://rch.adre.ucl.ac.be/browse/list_alpha/IMEXhttp://rch.adre.ucl.ac.be/browse/list_alpha/SANG

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Assays of tumor markers

SENIOR SCIENTISTS :

� Marianne PHILIPPE� Philippe DE NAYER

C 3


Assay of tumor markers in clinical settings and research.


Immuno assay of tumor markers in gynecology, gastroenterologyneuroendocrinology and endocrinology.

Main Equipment

Immunochemistry automates


WEYNANTS P., BAUDHUIN M., MAJOIS F., MOENS D. and DENAYER Ph. Dosage sérique de la neurone spécifique énolase :intérêt comme marqueur tumoral du cancer microcellulairebronchique. Acta Clin. Belgica, 44 (3) : 161-168, 1989.

VAN CANGH P.J., DE NAYER Ph., SAUVAGE Ph., TOMBAL B.,ELSEN M., LORGE Fr., OPSOMER R. and WESE F.X. Free to totalprostate specific antigen (PSA) ratio is superior to total PSA indifferentiating benign prostate hypertrophy from prostate can-cer. The Prostate, S7 : 30-34, 1996.

VAN CANGH P.J., DE NAYER Ph., DE VISSCHER L., SAUVAGEPh., TOMBAL B., LORGE F., WESE F.X., OPSOMER R.Free to total PSA ratio improves the discrimination betweenprostate cancer and benign hyperplasia in the diagnostic grayzone of 1.8 to 10 ng/ml total PSA. Urology, 48S : 67-70, 1996.

ROELANTS V., DE NAYER Ph., BOUCKAERT A. and BECKERS C.The predictive value of serum thyroglobulin in the follow-up of dif-ferentiated thyroid cancer. Eur. J. Nucl. Med., 24 : 722-727, 1997.

TOMBAL B., QUERTON M., DE NAYER Ph., SAUVAGE Ph.,COSYNS J.P., FEYEARTS A., OPSOMER R., WESE F.X. and VANCANGH P.J. Free to total PSA ratio (ft PSA) does not improveprediction of pathological stage and biochemical recurrenceafter radical prostatectomy. J. Urology, 59 : 256-260, 2002.

STAFF

Total : 2

KEY WORDS FOR R&D

clinical biology clinical chemistry clinical medicine diagnosis

SENIOR SCIENTISTS

Marianne [email protected] Tel. 32 (0)2 764 17 35

Philippe DE [email protected] Tel. 32 (0)2 764 25 63

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/LBCM

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Characterization of acute leukemias by gene expressionanalysis : comparison of molecular and immunologicalapproaches; impact on diagnosis and prognosis.

SENIOR SCIENTISTS :

� Pascale SAUSSOY� Dominique LATINNE� Augustin FERRANT

C 4


The prognosis in acute myeloid leukemia depends on numerousfactors, including the white blood cell count, age, cytogenetics,cell membrane immunological markers, and more recentlymolecular markers. The aim is to improve the prognostic infor-mation using less but more specific genetic markers.

Main Equipment

Sequencer, flow cytometry

Funding Sources

Fondation pour la recherche scientifique médicale (FRSM)Télévie

STAFF

Total : 6

KEY WORDS FOR R&D

acute leukemia clinical medicine diagnosisgene expressionhematology immunophenotypemolecular biologyprognosis

SENIOR SCIENTISTS

Pascale [email protected]. 32 (0)2 764 31 57

Dominique [email protected]. 32 (0)2 764 31 45

Augustin [email protected]. 32 (0)2 764 18 80

WEB SITES

http://rch.adre.ucl.ac.be/browse/list_alpha/SANGhttp://rch.adre.ucl.ac.be/browse/list_alpha/IMEX

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Immunodiagnosis of paraneoplastic neurological disorders

SENIOR SCIENTIST :

� Christian SINDIC

C 5


Paraneoplastic neurological disorders are devastating diseasesdue to an autoimmune injury of the peripheral and/or the cen-tral nervous system triggered by the presence of an often occultcancer, most frequently a small cell lung carcinoma, a gyneaco-logical or a breast cancer, etc.

The neoplastic cells express an antigen also present on neuralcells, and the anti-tumoral immune reaction leads to an auto-immune attack of the nervous system. A rapid diagnosis per-mits the detection of the cancer, its treatment and an immuno-suppressive therapy of the neurological disorder.


Detection of anti-neuronal nucleoproteins antibodies in theserum and the CSF (ANNA-1 or anti-Hu, ANNA-2 or anti-Ri,anti-Purkinje cell antibody or anti-Yo, anti-Myelin associatedGlycoprotein, anti-amphiphysine, anti-Ma1…).

Main Equipment

ELISAWestern-Blot apparatusUltracentrifugation


SINDIC C.J.M., BOUCQUEY D., BISTEAU M., LALOUX P.,BRUCHER J.M., LATERRE E.C. Monoclonal IgM gammapathywith anti-myelin associated glycoprotein (MAG) activity andpolyneuropathy. A study of three cases. Acta Neurol. Belg.,1989, 89 : 331-345.

SINDIC C.J.M., ANDERSSON M., BOUCQUEY D., CHALONM.P., BISTEAU M., BRUCHER J.M., LATERRE E.C. Anti-Purkinjecells antibodies in two cases of paraneoplastic cerebellardegeneration. Acta Neurol. Belg., 1993, 93 : 65-77.

PIERET F., SINDIC C.J.M., CHALON M.P., WARNY M., BOLYN

S., DEHAENE I., GOBIET Y., GOKA S., LALOUX P., MONTEYNEPH., PEETERS A., PIERRE PH., GILLET S., VAN DEN BERGH P.Y.K.,WINDHAUSEN K., LATERRE E.C. The anti-Hu syndrome : a clin-ical and immunological study of 7 cases. Acta Neurol. Belg.,1996, 96 : 117-125.

DREESSEN J., JEANJEAN A.P., SINDIC C.J.M. Paraneoplasticlimbic encephalitis : diagnostic relevance of CSF analysis andtotal body PET scanning. Acta Neurol. Belg., in press.

Funding Sources

Own resources (patronage)

STAFF

Total : 4

KEY WORDS FOR R&D

autoimmunityneurological diseasesonconeural antigensparaneoplastic disorderssmal cell lung carcinoma

SENIOR SCIENTIST

Christian [email protected]. 32 (02) 764 10 82

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/NCHM

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Development of new molecular based diagnostic strategiesin prostate cancer

SENIOR SCIENTISTS :

� Bertrand TOMBAL� Jean LUC GALA

C 6


Prostate cancer is the most frequent cancer in men aged morethan 55 years old. Despite important progress in early diagnos-tic and therapeutic procedures, there are still a lot of patientswho develop metastatic spread and require some form of sys-temic therapy.

It has become clear that in order to prevent metastatic spread,it is required to combine hormonal therapy, chemotherapy andnew biological agents earlier in the course of the disease.Such aggressive strategy requires identifying precisely patientsat risk of progression. Current staging procedures rely indeedonly on clinical, biological and pathological markers whichclearly lack specificity at the individual level.

In the last few years, our group has developed and implemen-ted molecular approaches to identify subjects at expression.These were initially based on the ability to identify early metas-tatic spread by retrieving the RNA of prostatic cells circulatingfreely in the blood of the patients.

Today with the development of modern DNA array technolo-gies, circulating cells are not only identified but also retrievedfrom the bone marrow of the patients and their molecular pro-file clearly identified.

These techniques are particularly useful to :Identify certain molecular patterns suggesting a higher risk of

progression.Apply molecular evaluation to new drugs by embedding

pharmacodynamic endpoints into early clinical trials.


The lab offers wide range of molecular diagnostic tools inclu-ding standard and real-time PCR techniques, sequencing ofgene products.

In collaboration with EPPENDORF Array Technology, we areimplementing low cost low density DNA Array techniques spe-

cifically designed for prostate cancer prognostic and geneticresponse to new biological agents.

The lab offers a direct connection with early human use (phaseI/II) trials and in vitro assays.

Main Equipment

Cell cultureCloning and sequencing of gene productsDNA array technologiesIsolation of metastatic cells from human samples by positive

selectionReal-Time PCR


VAN CANGH P.J., DE NAYER P., SAUVAGE P., TOMBAL B.,ELSEN M., LORGE F., OPSOMER R., WESE F.X. Free to totalProstate-Specific Antigen (PSA) ratio is superior to Total-PSA indifferentiating Benign Prostate Hypertrophy from ProstateCancer. Prostate 7 (supl.), 30-34, 1996.

VAN CANGH P.J., DE NAYER P., DE VISSCHER L., SAUVAGE P.,TOMBAL B., LORGE F., WESE F.X., OPSOMER R. Free to Totalprostate-specific antigen (PSA) ratio improves the discrimina-tion between prostate cancer and benign prostatic hyperplasia(BPH) in the diagnostic gray zone of 1.8 to 10 ng/ml total PSA.Urology. 48 (6A Suppl.): 67-70, 1996.

GALA J-L., HEUTERSPREUTE M., HANON F., TOMBAL B., VANCANGH P., DE NAYER P., PHILIPPE M.: Illegitimate transcriptionof the prostate specific antigen (PSA) and prostate-specificmembrane antigen (PSM) in blood cells: a genuine limitation forthe detection of prostate micrometastases. Clin. Chem. 44(3):472-481, 1998.

GALA J.L., LORIC S., GUIOT Y., BRASSEUR F., HEUSTERSPREUTEM., ESCHWÈGE P., HANON F., PHILIPPE M., DE NAYER P., VANCANGH P., TOMBAL B. Diagnostic and prognostic value ofProstate Specific Membrane Antigen in Transitional CellCarcinoma of the Bladder. Clinical Cancer Research, 6: (10)4049-4054, 2000.

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LARIBI A., BERTEAU P., GALA J.L., ESCHWÈGE P., BENOIT G.,TOMBAL B., SCHMITT F., LORIC S. Blood-borne RT-PCR assay forprostasin-specific transcript to identify circulating prostate cellsin cancer patient. Eur. Urol. 39 (1):65-71, 2001.

TOMBAL B., VAN CANGH P., LORIC S., GALA J.L. Prognosticvalue of circulating prostate cells in patients with a rising PSA afterradical prostatectomy. The Prostate, 56(3), 163-170, 2003.

Funding Sources

Fonds national de la recherche scientifique (FNRS)Fondation pour la recherche scientifique médicale (FRSM)TélévieFirst Entreprise Région Wallonne

Partnership

Pr. Sylvain Loric, Biochemistry & Genetics Laboratory, HenriMondor AP-HP University Hospital, Creteil, France.

Dr Samuel Denmeade, Division of Experimental TherapeuticJohns Hopkins Oncology Center, Baltimore, USA.

STAFF

Total : 9

KEY WORDS FOR R&D

DNADNA Arraymolecular diagnosticprostate cancerRNAtumor marker

SENIOR SCIENTISTS

Bertrand [email protected]. 32 (0)2 764 55 40

Jean LUC [email protected]. 32 (0)2 764 31 65

WEB SITES

http://www.fymu.ucl.ac.behttp://www.lbcm.ucl.ac.be

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Rigid registration of PET, CT and MR modalities for radiotherapy planning and dense deformation field estimation for brain intra-operative images registration

SENIOR SCIENTIST :

� Benoît MACQ

D 1


The Communications and Remote Sensing Laboratory hasdeveloped for ten years an activity in the field of medical ima-ges processing. We have undertaken a close collaboration withthe Oncology department (Pr. V. Gregoire and Dr. X. Geets). Thefocus of our work has been the development of a visualizationplatform called Medical Studio. Medical Studio includes facilitesfor computer aided contouring of head and neck tumors; 3Dregistration techniques to bring into alignment medical imagesacquired with different modalities.

Two target applications have emerged : fast non-rigid registra-tion algorithms to fuse pre-operative information (segmenta-tions, planning) and intra-operative MRI images acquiredduring neurosurgery and multi-modal registration of head andneck images for radiotherapy planning.

The intra-operative algorithm designed for brain intra-operativeand pre-operative images uses a Finite Element model of thebrain and fast segmentations algorithms. Surfaces (cortex, ven-tricles, tumor) are extracted in both modalities and correspon-dances are found using an active surface algorithm subject to alinear elastic regularization. These surface displacements arethen propagated to the whole volume using a Finite ElementModel (FEM) of the brain. This model allows to employ differentmaterial characteristics for different tissues.

Furthermore, the solving of the FEM linear system has beenimplemented for parallel architectures to meet computationtime requirements in the operating room. The same algorithmhas also been applied for intra-operative fusion of pre-operati-ve 1.5T MRI images in 0.5T MRI images acquired during pro-state biopsy. More recently, we have proposed a MutualInformation based non-rigid registration technique to improvethe matching of internal structures inside the prostate.

Radiotherapic planning has been shown to be significantlyimproved when different modalities are fused for a better deli-neation of the target volume. Therefore, we developed a colla-boration with the UCL Department of Radiation Oncology totest and validate Mutual Information based rigid registration

algorithms. The registration algorithm we developed is integra-ted in the Registration and Segmentation Toolkit(http://www.itk.org) and is based on the optimization of theMutual Information metric.

This software has been integrated in the Medical Studio visua-lization environment developed in our laboratory within theRégion Wallonne Mercator project.

The integrated modules contain facilities for the registrationand segmentation of medical images. The plug-in for registra-tion in Medical Studio provides an automatic and a manual pro-cedure. The use of the former increases considerably the varia-bility of inter-operator exchanges. Through automatic registra-tion it is now possible to obtain separately the same resultswithout consulting an expert. The fusion of the images can stillbe improved by manual registration.

The on levelset, growing treshold or watershed algorithmsbased automatic segmentation is used for automatic contou-ring of tumors. The presence of manual segmentation utilitiespermits high precision outlining. Due to these segmentationtools 3D reconstruction and size estimation of the contamina-ted tissues has become possible. Any part of the tissues can behighlighted by the use of differently contrasted masks, whichcan be individually created and colored.

Future developments will concern a medical aid module, desti-ned to help to evaluate the effectiveness of a patient’s treat-ment by statistical analysis. These should be based on the sizeestimation of the tumor and on different medical informationsintroduced by the medical staff during the treatment. An otherpart of the research is dedicated to intra-operative studies. Forthese parts the software is still in experimental stage.


Rigid and Non-Rigid registration tools.Visualization environment for 3D medical images (Medical

Studio).

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Main Equipment

Within a short time, a public version of Medical Studio will be downloadable from the www.medicalstudio.org website.This software includes visualization, hand segmentations, rigidregistration plugins.


A. BHARATHA, M. HIROSE, N. HATA, S. WARFIELD, M. FERRANT,K. ZOU, E. SUAREZ-SANTANA, J. RUIZ-AZOLA, A. D’AMIO, R. COR-MACK, F. JOLESZ, and C. TEMPANY. Evaluation of three-dimension-al finite element-based deformable registration of pre- and intra-operative prostate imaging. Med. Phys., Dec. 2001, 28(12) : 255-60.

M. FERRANT, A. NABAVI, B. MACQ, R. KIKINIS & S. WARFIELD.Serial registration of intra-operative MR images of the brain.Medical Image Analysis, Vol. 6, December 2002, pp. 337-359.

A. DU BOIS D’AISCHE, M. DE CRAENE, B. MACQ, V. GRE-GOIRE. Fully Automatic rigid-body registration for multi-modalhead and neck images. Technical Report TELE, 2002.

M. DE CRAENE, A. DU BOIS D’AISCHE, B. MACQ, F. KIPF-MUELLER, N. WEISENFELD, S. HAKER, S.K. WARFIELD. Multi-Modal Non-Rigid Registration using a Stochastic GradientApproximation. Accepted in International Symposium onBiomedical Imaging, 2004.

M. FERRANT. Physics-based deformable modeling of volumesand surfaces for medical image registration, segmentation andvisualization. Ph.D. Thesis, Communications and RemoteSensing Laboratory, UCL.

Awards

Informatics award, IBM Belgium.

Funding Sources

Mercator Project (Région Wallonne)Fonds pour la formation à la recherche dans l’industrie et

dans l’agriculture (FRIA)

Partnership

Oncology and Radiology departments (St-Luc Hospital), Brussels,Belgium.

Multitel asbl, Mons, Belgium.Brigham and Women’s Hospital, Surgical Planning Laboratory

and Computational Radiology Laboratory, Boston, USA.

STAFF

Total : 10

KEY WORDS FOR R&D

diffusion tensor imaging processingmulti-modal registration

SENIOR SCIENTIST

Benoît [email protected]. 32 (0)10 47 22 71

WEB SITES

http://www.medicalstudio.orghttp://www.tele.ucl.ac.be

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Functional magnetic resonance (NMR, EPR), spectroscopyand imaging in tumors

SENIOR SCIENTIST :

� Bernard GALLEZ

D 2


The major theme of the research is to understand how thetumor microenvironment influences the response to treat-ments. Two main areas of research are involved :1. Development of sensors for monitoring the oxygen in tissuesby EPR.Selection of paramagnetic materials possessing favourable featuresfor oximetry. Microencapsulation of oxygen sensors in biocompatiblefilms to improve their performance in vivo and their biocompatibility.2. Applications of MR (EPR and NMR) to characterize the micro-environment in tumors and modulate the response to anti-can-cer treatments.Use of combination therapies against cancer (vasoactive agents+ radiotherapy/antiangiogenesis + radiotherapy…) to improvethe response of tumors to treatments: characterization of pO2,flow, oxygen consumption, permeability of vessels, nitricoxide,… and correlation with the tumor growth.


EPR in vitro (free radicals, including spin trapping)EPR in vivo in small animalsNMR imaging in small animalsOxygen measurementsFlow measurements

Main Equipment

NMR spectrometer and imaging 4.7 Tesla for small animalsEPR spectrometer (9 GHz, X-Band) for in vitro experimentsEPR spectrometer (1 GHz, L-Band) for in vivo experimentsOxyLite (pO2 measurements by fluorescence quenching)OxyFlo (laser-doppler)


R.J. DEMEURE, B.F. JORDAN, Q.X. YANG, N. BEGHEIN, M.B.SMITH, V. GRÉGOIRE and B. GALLEZ. Removal of local field gra-

dient artefacts in BOLD contrast imaging of head and necktumors. Phys. Med. Biol. 47, 1819-1825, 2002.

B.F. JORDAN, V. GRÉGOIRE, R.J. DEMEURE, P. SONVEAUX, O.FERON, J. O’HARA, V. VANHULLE, N. DELZENNE and B. GALLEZ.Insulin increases the sensitivity of tumors to irradiation:Involvement of an increase in tumor oxygenation mediated bya nitric oxide dependent decrease of the tumor cells oxygenconsumption. Cancer Res. 62, 3555-3561, 2002.

C. BAUDELET AND B. GALLEZ. How Blood Oxygen LevelDependent (BOLD) contrast is correlated to the oxygen partial pres-sure of oxygen in tumors? Magn. Reson. Med. 48, 980-986, 2002.

P. SONVEAUX, C. DESSY, A. BROUET, B. JORDAN, V. GRÉGOIRE,B. GALLEZ, J.L. BALLIGAND and O. FERON. Modulation of the tumorvasculature functionality by ionizing radiation accounts for tumorradio-sensitization and promotes gene delivery. FASEB J. 16, 1979-1981, 2002.

B.F. JORDAN, N. BEGHEIN, M. AUBRY, V. GRÉGOIRE and B.GALLEZ. Potentiation of radiation-induced regrowth delay byisosorbide dinitrate in FSa II murine tumors. Int. J. Cancer103,138-141, 2003.

B.F. JORDAN, P. SONVEAUX, O. FERON, V. GRÉGOIRE and B.GALLEZ. Nitric oxide mediated increase in tumor blood flow andoxygenation of tumors implanted in muscles stimulated by electricpulses. Int. J. Radiat. Oncol. Biol. Phys. 55, 1066-1073, 2003.

C. BAUDELET and B. GALLEZ. A cluster analysis of fMRI timesseries in tumors to study the heterogeneity of hemodynamicresponse to treatments. Magn. Reson. Med. 49, 985-990, 2003.

M. ZDRAVKOVA, N. CROKART, F. TROMPIER, B. ASSELINEAU, E.GAILLARD-LECANU, B. GALLEZ and R. DEBUYST. Retrospectivedosimetry after criticality accidents using low frequency EPR : astudy on whole human teeth irradiated in a mixed neutron andgamma field. Radiat. Res. 160, 168-173, 2003.

P. MAHY, M. DE BAST, B. GALLEZ, J. GUEULETTE, C.J. KOCH, P.SCALLIET, and V. GRÉGOIRE. In vivo co-localization of 2-nitroimida-zole EF5 fluorescence intensity and electron paramagnetic resonanceoximetry in mouse tumors. Radiother. Oncol. 67, 53-61, 2003.

B.F. JORDAN, P. SONVEAUX, O. FERON, V. GRÉGOIRE, N.BEGHEIN, C. DESSY and B. GALLEZ. Nitric oxide as radiosensitizer :evidence for an intrinsic role additive to its effect on oxygen deliveryand consumption. Int. J. Cancer, 109, 768-773, 2004.

P. SONVEAUX, C. DESSY, P. MARTINIVE, X. HAVAUX, B.F. JORDAN,B. GALLEZ, V. GRÉGOIRE, J.L. BALLIGAND and O. FERON. Endothelin-

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1 is a critical mediator of myogenic tone in tumor arterioles : impli-cations for cancer treatment. Cancer Res. 64, 3209-3214, 2004.

M. LAN, N. BEGHEIN, N. CHARLIER, and B. GALLEZ. Carbonblacks as EPR sensors for localized measurements of tissue oxy-genation. Magn. Reson. Med. 51, 1272-1278, 2004.

C. BAUDELET, R. ANSIAUX, B.F. JORDAN, X. HAVAUX, B.MACQ and B. GALLEZ. Physiological noise in murine tumorsusing T2* gradient echo imaging : a marker of tumor acutehypoxia ? Phys. Med. Biol. 49, 3389-3411, 2004.

C. BAUDELET and B. GALLEZ. Effect of anesthesia on the signalintensity in tumors using BOLD-MRI. Comparison with flow meas-urements by laser-doppler flowmetry and oxygen measurements byluminescence probes. Magn. Reson. Imaging 22, 905-912, 2004.

B. GALLEZ, C. BAUDELET, B.F. JORDAN. Assessment of tumoroxygenation by EPR oximetry: Principles and applications. NMRBiomed. 17, 240-262, 2004

Patents

Carbon blacks as EPR sensors for localized measurements of tis-sue oxygenation. US Patent, submitted 2003.

Awards

B. Gallez :1995, Société Belge des Sciences Pharmaceutiques1998, Fondation Universitaire- AlumniAward Paul Van de Velde 2000 (Nouveaux outils diagnostiques

ou thérapeutiques) Young Investigator Award, International EPR Society 2000Award Léopold et Marthe Delsaux-Champy 2004 (Prévention,

traitement ou physiopathologie de maladies cardiovasculaires oucancéreuses)B. Jordan :

Ishango francophone 2003.

Funding sources

NCI (National Cancer Institute, USA)

FNRS (FRSM, Télévie)Fonds Joseph MaisinFonds spécial de recherche (Communauté Française)

Partnership

Pharmacotherapy Unit and Radiobiology Unit, UCL, Brussels,Belgium.

EPR Research Center, Dartmouth Medical School, USA.Arizona Cancer Center, Tucson, USA.

STAFF

Total: 9

KEY WORDS FOR R&D

angiogenesisbiocompatibilitybiomaterialsbiomedical engineeringbiophysicsbiosensorschemotherapyEPRfree radicalsfunctional imaginghemodynamicsimagingMRInitric oxideNMRoxygenpharmacologyradiotherapyradiosensitivityspectroscopyspin trappingtumor

SENIOR SCIENTIST

Bernard [email protected]. 32(0)2 764 27 92

WEB SITE

http://www.md.ucl.ac.be/rema

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Anatomic and functional imaging of liver tumors

SENIOR SCIENTIST :

� Bernard VAN BEERS

D 3


Our research in cancerology has been centred on the assess-ment of the value of non-specific and liver-specific contrastagents to detect and characterize hepatic tumors by magneticresonance imaging.These studies have been performed in humans with various pri-mary and secondary liver tumors and in rats bearing chemical-ly-induced or transplantable hepatocellular carcinomas. We have shown that, depending on the specific contrast agentused, several parameters such as the tumorous blood flow,blood volume, interstitial volume, Kupffer cell activity, andtumorous cellular differentiation determine the enhancementpattern in magnetic resonance imaging. Recently we have been interested in quantitative perfusion anddiffusion imaging of the liver. We have developed and validated the use of a pharmacokine-tic model to calculate the liver perfusion parameters fromcontrast-enhanced magnetic resonance or computed tomogra-phic images. Permeability changes of the hepatic sinusoids havebeen demonstrated by using multiple contrast agents of diffe-rent molecular weights.These quantitative imaging methods are used to assess the per-fusion and permeability abnormalities in liver tumors beingused to monitor the effects of various drugs, including inhibi-tors of angiogenesis.


MR imaging of liver tumorsPerfusion and diffusion weighted imaging of liver tumorsAssessment of specific contrast agentsDrug monitoring

Main Equipment

Three 1.5 Tesla MR scanners3 Tesla MR scannerFour multislices CT scannersImage processing workstations

Software for the analysis of perfusion and diffusion imagesAnimal facilities


GRANDIN C., VAN BEERS B.E., ROBERT A., GIGOT J.F., GEUBELA., PRINGOT J. (1995) Benign hepatocellular tumors: MRI aftersuperparamagnetic iron oxide administration. J. Comput.Assist. Tomogr. 19: 412-418.

GRANDIN C., VAN BEERS B.E., DEMEURE R., GOUDEMANTJ.F., MOTTET I., PRINGOT J. (1995) Comparison of gadolinium-DTPA and polylysine-gadolinium-DTPA-enhanced magnetic res-onance imaging of hepatocarcinoma in the rat. Invest. Radiol.30: 572-581.

VAN BEERS B., DAURES J.P., PRINGOT J., MATHIEU D., BRUELJ.M. (1996) Detection of hepatic metastases: ferumoxides-enhanced MR imaging versus unenhanced MR imaging and CTduring arterial portography. Radiology 200: 785-792.

VAN BEERS B.E., GALLEZ B., PRINGOT J. (1997) Contrast-enhanced MR imaging of the liver. Radiology 203: 297-306.

VAN BEERS B.E., LACROSSE M., JAMART J., GRANDIN C., GIGOTJ.F., HORSMANS Y., DEMEURE R., PRINGOT J. (1997) Detection andsegmental location of malignant hepatic tumors: comparison of fer-umoxides-enhanced gradient-echo and T2-weighted spin-echo MRimaging. Am. J. Roentgenol. 168: 713-717.

GRANDIN C.B., VAN BEERS B.E., PAUWELS S., DEMEURE R.,JAMART J., PRINGOT J. (1997) Ferumoxides and Tc-99m sulfurcolloid: comparison of the tumor-to-liver uptake in focal nodu-lar hyperplasia. J. Magn. Reson. Imaging, 7: 125-129.

VILGRAIN V., VAN BEERS B.E., FLEJOU J.F., BELGHITI J., DELOSM., GAUTIER A.L., ZINS M., DENYS A., MENU Y. (1997)Intrahepatic cholangiocarcinoma: MRI and pathologic correla-tion in 14 patients. J. Comput. Assist. Tomogr., 21: 59-65.

GOUDEMANT J.F., VAN BEERS B.E., DEMEURE R., GRANDINC., DELOS M., PRINGOT J. (1998) Comparison of unenhancedand gadoxetate disodium-enhanced spin-echo magnetic reso-nance imaging for the detection of experimental hepatocellularcarcinoma in the rat. Invest. Radiol., 33: 80-84.

VAN BEERS B.E., MATERNE R., LACROSSE M., JAMART J.,SMITH A.M., HORSMANS Y., GIGOT J.F., GILON R., PRINGOT J.(1999) MR imaging of hypervascular liver tumors: timing opti-

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mization during the arterial phase. J. Magn. Reson. Imaging, 9:562-567.

MATERNE R., HORSMANS Y., JAMART J., SMITH A.M., GIGOTJ.F., VAN BEERS B.E. (2000) Gadolinium-enhanced arterial-phase MR imaging of hypervascular liver tumors: comparisonbetween tailored and fixed scanning delays in the samepatients. J. Magn. Reson. Imaging, 11: 244-249.

MATERNE R., VAN BEERS B.E., SMITH A.M., LECONTE I.,JAMART J., DEHOUX J.P., KEYEUX A., HORSMANS Y. (2000)Non-invasive quantification of liver perfusion with dynamiccomputed tomography and a dual-input one-compartmentalmodel. Clin. Sci. (Lond) 99: 517-525.

VAN BEERS B.E., SEMPOUX C., MATERNE R., DELOS M.,SMITH A.M. (2001) Biodistribution of ultrasmall iron oxide par-ticles in the rat liver. J. Magn. Reson. Imaging, 13: 594-599.

MATERNE R., SMITH A.M., PEETERS F., DEHOUX J.P., KEYEUXA., HORSMANS Y., VAN BEERS B.E. (2002) Assessment ofhepatic perfusion parameters with dynamic MRI. Magn. Reson.Med. 47: 135-142.

VAN BEERS B.E., MATERNE R., ANNET L., HERMOYE L.,SEMPOUX C., PEETERS F., SMITH A.M., JAMART J., HORSMANSY. (2003) Capillarization of the sinusoids in liver fibrosis:Noninvasive assessment with contrast-enhanced MRI in the rab-bit. Magn. Reson. Med., 49: 692-699.

ANNET L., MATERNE R., DANSE E., JAMART J., HORSMANS Y.,VAN BEERS B.E. (2003) Hepatic flow parameters measured withMR imaging and Doppler sonography: correlations with degree ofcirrhosis and portal hypertension. Radiology , 229: 409-414.

Funding Sources

Fonds national de la recherche scientifique (FNRS)

Partnership

Division of imaging science and biomedical engineering,University of Birmingham, Great Britain.

Laboratoire de recherche en imagerie, Inserm U 494, Facultéde médecine Necker, Paris, France.

STAFF

Total : 4

KEY WORDS FOR R&D

contrast agentsdiffusion imaginghepatocellular carcinoma image processingliver tumors magnetic resonance imagingmedical imaging, radiology, tomography perfusion imaging

SENIOR SCIENTISTS

Bernard VAN [email protected]. 32(0)2 764 29 45

WEB SITE

http://www.md.ucl.ac.be/rdgn

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Academic clinical trials in medical oncology

SENIOR SCIENTISTS :

� Jean-Pascal MACHIELS� Jean-François BAURAIN

E 1


We have created a section able to design and conduct clinicaltrials non-sponsored by pharmaceutical companies. These arepurely academic studies asking important questions for clini-cians. Our section is taking care of designing, writing and coor-dinating (randomisation and monitoring) the protocols.

Topics: Efficacy of neoadjuvant chemotherapy in ovarian cancer.Efficacy of Gemcitabine in cholangiocarcinoma Preoperative radio-

chemotherapy in patients with locally advanced rectal cancer.Chemotherapy in elderly patients with metastatic colorectal cancer. A Belgian study to compare two chemotherapy regimens in

patients with hormone refractory prostate cancers. Meta-analysis of efficacy of chemotherapy in metastatic

salivary gland tumors.

Main Equipment

Data managing unit Randomisation programmes


MAZZEO F., BERLIÈRE M., SQUIFFLET J., LONGUEVILLE J.,BRICHARD J., D’HONDT V., HUMBLET Y., DONNEZ J. andMACHIELS J.P. Neoadjuvant chemotherapy followed by surgeryand adjuvant chemotherapy in patients with advanced-stageovarian cancer. Proceedings of the American Association ofClinical Oncology, 2002, 171b : abstr. 2501.

DUCK L., HUMBLET Y., GIGOT J.F., LONNEUX M., BAURAIN J.F.and MACHIELS J.P. Gemcitabine in advanced cholangiocarcinoma:a single-center retrospective study. Proceedings of the AmericanAssociation of Clinical Oncology, 2002, 125b : abst.2314.

MAZZEO F., BERLIÈRE M., KERGER J., SQUIFFLET J., D’HONDTV., HUMBLET Y., DONNEZ J. and MACHIELS J.P. Neoadjuvantchemotherapy followed by surgery and adjuvant chemotherapyin patients with advanced-stage ovarian cancer. GynecologicOncology, 2003; 90: 163-169.

BERLIÈRE M., GALANT C., MARQUES G., PIETTE P., DUCK L.,FELLAH L., DONNEZ J. and MACHIELS J.P. LHRH agonists offervery good protection against adverse gynaecological inducedby tamoxifen. Eur. J. Cancer, 2004, 40 : 1855-61.

DUCK L.; BAURAIN J.F. and MACHIELS J.P. Treatment of pul-monary angiosarcoma. Chest. 2004; 126(1):317-8

HENRY S., MACHIELS J.P., BAURAIN J.F. and DUCK L. Liverinsufficiency due to breast cancer metastases: fast biologicalresponse with capecitabine. Acta Oncologica, 2004; 43(3):302.

DUCK L., SEMPOUX C., HONHON B., COSTER B., COCHEJ.C., CANON J.L., KERGER J., SCALLIET P., HUMBLET Y. andMACHIELS J.P. A phase II study of preoperative oxaliplatin,capecitabine, and external beam radiotherapy in patients withlocally advanced rectal adenocarcinoma. Proceedings of theAmerican Association of Clinical Oncology, 2004, Submitted.

MACHIELS J.P. and al. A phase II study of preoperative oxali-platin, capecitabine, and external beam radiotherapy in patientswith locally advanced rectal adenocarcinoma. Journal of clinicalOncology, 2004, Submitted.

MACHIELS J.P., MAZZEO F. and BERLIÈRE M. Neoadjuvantchemotherapy versus primary surgery for advanced-stage ovar-ian cancer: the question remains opened. GynecologicOncology, 2004, In Press. (I.F.2,1).

Awards

J.-P. Machiels : 2002, AMGEN award, Belgian Society of Medical Oncology.2000, Translational Research award; First prize, Johns Hopkins

Oncology Center, Baltimore, USA

Funding Sources

Various grants

Partnership

KUL, Profs Van Custem et Haustermans, Leuven, Belgium.

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STAFF

Total 4

KEY WORDS FOR R&D

academic studieschemotherapyclinical trialradiotherapystatistics

SENIOR SCIENTISTS

Jean-Pascal [email protected]. 32 (0)2 764 54 57

Jean-François BAURAIN [email protected]. 32 (0)2 764 54 72

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/ONCO

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Clinical studies in hematology

SENIOR SCIENTISTS :

� Augustin FERRANT� Lucienne MICHAUX� Eric VAN DEN NESTE

E 2


HOVON Protocols

HOVON 42 : Randomized induction and post induction ther-apy in adult patients (<= 60 yrs of age) with acute myelocyticleukemia (AML) or refractory anemia with excess of blasts(RAEB, RAEB-t) with IPSS score ≥ 1.5.The aim is 1. to evaluate, comparing 2 different doses of cytarabineduring induction I and II, the complete and partial remissionand the global survival.2. to evaluate, by randomization, the therapeutic effect of a mye-loablative chemotherapy with allograft in medium or high risk ofAML in comparison with an intensive post remission chemotherapy.3. to estimate the value of a family- and nonrelated allograftamong patients with an AML.

HOVON 43 : Randomized induction and post induction ther-apy in older patients (>= 61 yrs of age).The aim is to evaluate the effect of high dose daunomycin duringthe first induction cure on survival without event, and to evaluate,by randomization, the effect of the GO-treatment post-remission.

HOVON 51 : A dose-ranging phase I/II study of STI571(Imatinib) in combination with Cytarabin in patients with firstchronic phase Chronic Myeloid Leukemia.Objectives: 1. to evaluate the feasibility of a treatment combining STI571and cytarabine2. to determine the rate and duration of molecular, completehematological and complete cytogenetic remissions3. to determine the time before progression and the global survival

LNH Protocols

LNH 01-5B : Randomized study comparing ACVBP + Rituximab vsCHOP + rituximab in patients between 60-65 years with diffuselarge cell B lymphoma.

LNH 03B : Randomized study comparing ACVBP vs ACVBP +Rituximab in patients between 18-65 years with localized dif-fuse lymphoma with large B CD20+ cells.

LNH 03-3B : Randomized study comparing ACVBP + Rituximabin patients between 18-59 years with high risk diffuse lymphoma

with large B CD20+ cells (IPI age adjusted= 2-3).LNH 03-6B : Randomized study comparing R-CHOP adminis-

tered each 14 days and 21 days respectively. For the secondpart, Darbepoietin alpha (ARANESP) vs symptomatic treatmentfor anemia in patients with diffuse lymphoma with large BCD20+ cells B in patients between 66-80 years.

Protocol 20031231 : darbepoetin alphaA randomized, double blind, active-controlled study of darbe-poetin alpha for the treatment of anemia in subjects with non-myeloid malignancy receiving multicycle chemotherapy.

GRAALL2003 Multicentric protocol testing the feasibility of a therapeuticapproach in acute lymphoblastic leukemia in young adults.Aim : collection of major prognostic factors on consolidation ofinduction therapy and on the indication of an allograft in CR1.

AFR Protocols

AFR03 : Phase II study of Imatinib (GlivecTM) associated tointensive consolidation chemotherapy in adults with ALL-Phi+and/or BCR-ABL+ leukaemia in first complete remission.Objective : evaluation of the combination Imatinib and chemo-therapy, on day 45 : rate of molecular response.

AFR09 : Evaluation of Imatinib (GlivecTM) after induction treat-ment in ALL Phi+ patients over 55 years old.Objective: improving the survival.

AUTO-LLC Protocol

Phase III randomized protocol comparing stem cell transplan-tation to a conventional treatment in stages B and C in 18-65years-old-CLL patients.


LOWENBERG B., VAN PUTTEN W.L., FERRANT A., OSSENKOP-PELE G., VELLENGA E., VERDONCK L.F., GRATWOHL A.,BOOGAERTS M.A. Peripheral blood progenitor cell transplanta-tion as an alternative to autologous marrow transplantation inthe treatment of acute myeloid leukemia. Stem. Cells. 1997; 15Suppl 1: 177-80, discussion 181.

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WENDUM D., SEBBAN C., GAULARD P., COIFFIER B., TILLY H.,CAZALS D., BOEHN A., CASASNOVAS R.O., BOUABDALLAH R.,JAUBERT J., FERRANT A., DIEBOLD J., DE MASCAREL A., GIS-SELBRECHT C. Follicular large-cell lymphoma treated withintensive chemotherapy: an analysis of 89 cases included in theLNH87 trial and comparison with the outcome of diffuse largeB-cell lymphoma. Groupe d’Etude des Lymphomes de l’Adulte.J. Clin. Oncol., 1997 (4): 1654-63.

PENIKET A.J., RUIZ DE ELVIRA M.C., TAGHIPOUR G., COR-DONNIER C., GLUCKMAN E., DE WITTE T., SANTINI G., BLAISED., GREINIX H., FERRANT A., CORNELISSEN J., SCHMITZ N.,GOLDSTONE A.H. An EBMT registry matched study of allo-geneic stem cell transplants for lymphoma: allogeneic trans-plantation is associated with a lower relapse rate but a higherprocedure-related mortality rate than autologous transplanta-tion. Bone Marrow Transplant., 2003 (8): 667-78.

VAN DEN NESTE E., SMAL C., CARDOEN S., DELACAUW A.,FRANKARD J., FERRANT A., VAN DEN BERGHE G., BONTEMPSF. Activation of deoxycytidine kinase by UV-C-irradiation inchronic lymphocytic leukemia B-lymphocytes. Biochem-Pharmacol., 2003 Feb 15; 65(4): 573-80.

Partnership

Multicentric, international studies

STAFF

Total : 3

KEY WORDS FOR R&D

AMLclinical medicinediffuse lymphomahematology hovonImatinibphase I/IIrandomizationstem cell transplantationSTI571

SENIOR SCIENTISTS

Augustin [email protected]. 32(0)2 764 18 80

Lucienne [email protected]. 32(0)2 764 18 09

Eric VAN DEN [email protected]. 32(0)2 764 18 75

WEB SITES

http://rch.adre.ucl.ac.be/browse/list_alpha/SANGhttp://rch.adre.ucl.ac.be/browse/list_alpha/GMED

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Clinical studies in hematology : Multiple myeloma, Hodgkin’s lymphoma

SENIOR SCIENTISTS :

� Augustin FERRANT� Lucienne MICHAUX� Eric VAN DEN NESTE

E 3


Multiple myeloma

IFM 99-03 : Treatment of aggressive myeloma by familial allo-geneic graft without myelo-ablation in patients lesser than 65years old. Objectives : study of the survival without progression, CR remis-sion after six months, death rate related to allograft.

IFM 99-04 : Comparison of an intensive therapy with allograftby melphalan 220mg/m2 and dexamethasone to melphalan220mg/m2 + anti-IL6 antibodies and dexamethasone.Objective : compare the CR rate between two intensive therapies.

IFM 99-06 : Treatment of multiple myeloma in patients between65 and 75 years old.Objective: survival rate between the three series of patients inthe protocol.

IFM 01-01 : Treatment of multiple myeloma in patients agedmore than 75 years old.Objective : compare survival in patients with 12 cures ofMelphalan-Prednisone, Clodronate (dubble blind) arm A : pla-cebo, arm B : Thalidomide.

CC-5013-MM-010 REVIMID : A multicenter, randomized, paral-lel-group, double-blind, placebo-controlled study of CC-5013plus Dexamethasone versus Dexamethasone alone in previous-ly treated subjects with multiple myeloma.

Hodgkin’s lymphoma

H9 : group favorable : Randomized prospective treatment trialeffect in sus-diaphragmatic stages I-II of Hodgkin’s disease.Objective : to evalutate the effectiveness of standard 6 cyclesEBVP + IF 36 Gy versus the experimental 6 cycles EBVP + IF 20Gy, to decrease the toxicity.

H 3-4 : Randomized prospective treatment trial in stage III-IVHodgkin’s disease : comparative evaluation of the effectivenessand toxicity of two therapies : ABVD and BEACOPP.

Representatives References

ROBIN V., LEBACQ J., MICHAUX L., FERRANT A. Hodgkin’sdisease and hypothermia : case report and review of the litera-ture. Ann. Hematol., 2002 Feb; 81(2): 106-7.

VAN DEN NESTE E., LOUVIAUX I., MICHAUX J.L., DELANNOYA., MICHAUX L., SONET A., BOSLY A., DOYEN C., MINEUR P.,ANDRE M., STRAETMANS N., COCHE E., VENET C., DUPREZ T.,FERRANT A. Phase I/II study of 2-chloro-2’-deoxyadenosine withcyclophosphamide in patients with pretreated B cell chroniclymphocytic leukemia and indolent non-Hodgkin’s lymphoma.Leukemia. 2000 Jun; 14(6): 1136-42.

Partnership

Multicentric international studies

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STAFF

Total : 3

KEY WORDS FOR R&D

allogenic graftclinical medicine hematology HodgkinIFMmyeloma

SENIOR SCIENTISTS

Augustin [email protected]. 32 (0)2 764 18 80

Lucienne [email protected]. 32 (0)2 764 18 09

Eric VAN DEN [email protected]. 32 (0)2 764 18 75

WEB SITE


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Therapeutic vaccination of cancer patients with tumorspecific antigens

SENIOR SCIENTISTS :

� Thierry BOON� Marie MARCHAND� Nicolas VAN BAREN

F 1


Tumor cells carry antigens such as MAGE antigens that areabsent from normal tissues, and that can be targeted by cyto-lytic T lymphocytes (CTL). While it is possible to make such CTL recognize and kill autolo-gous tumor cells in vitro, the precise way to induce an effectiveCTL response against a MAGE antigen in cancer patients is notknown yet. In clinical vaccination trials, patients with a MAGEexpressing cancer, often melanoma, are treated repeatedly witha MAGE vaccine.

These trials have two main objectives. First, the effectiveness of various vaccination modalities can beassessed by following the clinical evolution of the tumor, byanalyzing whether a specific CTL response to the vaccine anti-gen occurred, and by determining whether immunological andclinical responses are correlated. Secondly, T lymphocytes andtumor samples collected at different timepoints during vaccina-tion can be analyzed in detail, which improves our understan-ding of what happens in patients who experience regression ofmetastatic lesions, and which may explain why this does nothappen in the majority of patients with overall disease progres-sion.

This knowledge can then be used to design new vaccinationmodalities.


MARCHAND M., VAN BAREN N., WEYNANTS P., BRICHARDV., DRÉNO B., TESSIER M-H., RANKIN E., PARMIANI G., ARIENTIF., HUMBLET Y., BOURLAND A., VANWIJCK R., LIÉNARD D.,BEAUDUIN M., DIETRICH P-Y., RUSSO V., KERGER J., MASUCCIG., JÄGER E., DE GREVE J., ATZPODIEN J., BRASSEUR F., COULIEP.G., VAN DER BRUGGEN P., and BOON T. Tumor regressionsobserved in patients with metastatic melanoma treated with anantigenic peptide encoded by gene MAGE-3 and presented byHLA-A1. Int. J. Cancer 1999; 80 : 219-230.

BOON T., COULIE P.G., VAN DER BRUGGEN P., VAN BAREN N.Immunology of the cancer cell : T lymphocyte responses. In : Clinical

Oncology, 2nd Edition. Eds: M. D. Abeloff, J.O. Armitage, A.S.Lichter, J.E. Niederhuber. Churchill Livingstone, New York, 2000.

MARCHAND M., BRICHARD V., VAN BAREN N., and COULIEP. Biological and clinical developments in melanoma vaccines.Exp. Op. Biol. Trials 2001; 1 : 497-510.

COULIE P.G., KARANIKAS V., LURQUIN C., COLAU D.,CONNEROTTE T., HANAGIRI T., VAN PEL A., LUCAS S., GODELAINED., LONCHAY C., MARCHAND M., VAN BAREN N., BOON T.Cytolytic T-cell responses of cancer patients vaccinated with aMAGE antigen. Immunological Reviews 2002; 188 : 33-42.

MARCHAND M., PUNT C.J., AAMDAL S., ESCUDIER B., KRUITW.H., KEILHOLZ U., HAKANSSON L., VAN BAREN N., HUMBLET Y.,MULDERS P., AVRIL M.F., EGGERMONT A.M., SCHEIBENBOGEN C.,UITERS J., WANDERS J., DELIRE M., BOON T., STOTER G.Immunisation of metastatic cancer patients with MAGE-3 proteincombined with adjuvant SBAS-2: a clinical report. Eur. J. Cancer2003; 39 : 70-7.

Patents

Patents covering clinical applications of the tumor-specificantigens contained in our vaccines.

Funding sources

Ludwig Institute for cancer researchFB AssurancesFédération belge contre le cancer

Partnership

Academic collaborationsUCL, Centre du cancer, Brussels, Belgium ULB, Brussels, Belgium (Th. Velu)VUB, Brussels, Belgium (B. Neyns)KUL, Leuven (M. Stas)Institut Curie, Paris (T. Dorval, S. Piperno)Institut Gustave-Roussy, Villejuif, France, (M.F. Avril, B. Escudier)CHU de Nantes, France (B. Dreno)

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Mannheim, Germany (D. Schadendorf)University Benjamin Franklin, Berlin, Germany (U. Keilholz)

Industrial collaborationsGlaxoSmithKline Biologicals, Rixensart, BelgiumAventis Pasteur, Lyon, France BruCELLS, Brussels, Belgium

International networksEORTC : Melanoma Cooperative Group

STAFF

Total: 8

KEY WORDS FOR R&D

cancer treatmentcytolytic T lymphocytesimmunologyimmunotherapytumor antigens

SENIOR SCIENTISTS

Thierry [email protected] : 32 (0)2 764 7580

Marie [email protected] : 32 (0)2 764 7533

Nicolas VAN [email protected] : 32 (0)2 764 7533

WEB SITES

http://www.licr.ucl.ac.be/http://www.icp.ucl.ac.be/ICP_en.html

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Isolation and structure determination of active compoundsfrom plants used in traditional medicine to treat differentforms of cancers. Analysis of the mode of action.

SENIOR SCIENTIST :

� Joëlle QUETIN-LECLERCQ

F 2


Plants are a large reservoir of original molecules which may acton new targets or possess new modes of action and can beused as prototypes by chemists.

The aim of our studies is to isolate, by different preparative orsemi-preparative techniques (High speed Counter CurrentChromatography, MPLC…), cytotoxic and bio-active moleculesfrom plants selected on an ethnopharmacological basis.

Structures are determined by comparison with known com-pounds and spectroscopic methods (UV, IR, SM 1 or 2D, RMN).The mode of action and cellular targets of the most interestingcompounds are analysed in collaboration with specializedteams. Methods for quantification of these bioactive moleculesin extracts are also developed.


Analysis and quantification in complex extracts of naturalbioactive compounds.

Preparative purification techniques.

Main Equipment

High speed Counter Current, Chromatography (HSCCC)Preparative MPLC, HPLC/UV, HPLC-DAD, HPLC-MS, GC-FID GC-FTIR, GC-MS.


J. QUETIN-LECLERCQ, B. BOUZAHZAH, A. PONS, R. GREIMERS,L. ANGENOT, R. BASSLEER and H. BARBASON. Strychnopentamine,a potential anticancer agent. Planta Med., 59, 1993, 59-62.

K. BONJEAN, M.-CL. DE PAUW-GILLET, J. QUETIN-LECLERCQ,L. ANGENOT, R. BASSLEER. In vitro cytotoxic activities of twopotential anticancer drugs isolated from Strychnos :strychnopentamine and usambarensine. Anticancer Research,16, 1996, 1129-1138.

K. BONJEAN, M.C. DE PAUW-GILLET, M.P. DEFRESNE, P. COLSON,C. HOUSSIER, L. DASSONNEVILLE, C. BAILLY, R. GREIMERS, C.WRIGHT, J. QUETIN-LECLERCQ, M. TITS and L. ANGENOT. TheDNA intercalating alkaloid cryptolepine interferes with topoiso-merase II and inhibits primarily DNA synthesis in B16 melanomacells. Biochemistry, 37, 1998, 5136-5146.

L. DASSONNEVILLE, K. BONJEAN, M.-CL. DE PAUW-GILLET, P.COLSON, C. HOUSSIER, J. QUETIN-LECLERCQ, L. ANGENOT, C.BAILLY. Stimulation of topoisomerase II-mediated DNA cleavageby three DNA-intercalating plant alkaloids: cryptolepine, mata-dine and serpentine. Biochemistry, 38, 1999, 7719-7726.

S. BLOCK, C. STÉVIGNY, M.-C. DE PAUW-GILLET, E. DEHOFFMANN, G. LLABRÈS, V. ADJAKIDJÉ, J. QUETIN-LECLERCQ.Ent-Trachyloban-3ß-ol, a new cytotoxic diterpene from Crotonzambesicus. Planta Medica, 68, 2002, 647-649.

C. STÉVIGNY, S. BLOCK, M.-C. DE PAUW-GILLET, E. DEHOFFMANN, G. LLABRÈS, V. ADJAKIDJE, J. QUETIN-LECLERCQ.Cytotoxic aporphine alkaloids from Cassytha filiformis. PlantaMedica, 68, 2002, 1042-1044.

S. BLOCK, C. BACCELLI, B. TINANT, L. VAN MEERVELT, R.ROZENBERG, J.-L. HABIB JIWAN, G. LLABRÈS, M.-C. DE PAUW-GILLET, J. QUETIN-LECLERCQ Diterpenes from the leaves ofCroton zambesicus. Phytochemistry, 65, 2004, 1165-1171.

S. HOET, C. STÉVIGNY, S. BLOCK, F. OPPERDOES, P. COLSON,B. BALDEYROU, A. LANSIAUX, C. BAILLY, J. QUETIN-LECLERCQ.Alkaloids from Cassytha filiformis and related aporphines: antit-rypanosomal activity, cytotoxicity, and interaction with DNA andtopoisomerases. Planta Medica, 70, 2004, 407-413.

Funding Sources

Funds of Research of UCLFonds national de la recherche scientifique (FNRS)Coopération universitaire au développement (CUD)

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STAFF

Total: 6

KEY WORDS FOR R&D

pharmaceutical sciences pharmacognosy separation techniques structural chemistry

SENIOR SCIENTIST

Joëlle [email protected] Tel. 32 (0)2 764 72 54

WEB SITE

http://www.md.ucl.ac.be/cham

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The tumor vascularity : bases for adjuvant strategies toconventional anti-tumor treatments and anti-angiogenicapproaches.

SENIOR SCIENTIST :

� Olivier FERON

F 3


Adjuvant therapy to anti-tumor treatments:Identification of the determinants of the differential intrinsicand induced reactivity/phenotype of tumor blood vasculature. This goal is achieved through the microdissection of blood ves-sels (diameter between 80 and 300 µm) from mouse or humantumors, followed

by the analysis of their vasoreactivity by videomicroscopy inpressure and wire myographs. The effects of drugs and ofchanges in pressure or shear stress are analysed. Similarly, thechanges in reactivity consecutive to treatments (anti-angio-genic, radiotherapy) are examined.

by DNA profiling and quantification of genes involved in vaso-modulatory and adhesion processes; proteomics is applied insecond line.

In vivo validation and exploitation of the differential reactivity ofblood vessels to increase the efficacy of anti-tumor treatments. More particularly, these studies aim at identifying tumor-speci-fic pathways leading to an increase in tumor pO2 (radiothera-py), drug/gene delivery (chemo- and gene therapy) and lym-phocyte recruitment (immunotherapy). Besides specific end-points related to these specific goals, the follo-wing parameters are measured: tumor blood flow (Laser Dopplerimager and needle probe), tumor oxygenation (EPR, histochemistry),tumor vessel permeability (wick-in needle, Evans blue diffusion, his-tochemistry), tumor growth (caliper) and dissemination (histology).

Anti-angiogenic strategies:Dissection of the biochemical VEGF/Akt/nitric oxide pathway toidentify new therapeutic targets to decrease tumor angiogenesisor to reduce prosurvival advantages of tumor endothelial cells.Identification of the determinants of endothelial progenitor cellrecruitment in tumors to develop strategies aiming to block stemcell-derived angiogenesis.


Testing of drugs aiming to modulatetumor blood flowtumor oxygenation

tumor permeabilitytumor homing (stem cells and lymphocytes)tumor angiogenesistumor endothelial cell resistance to treatments

Testing adjuvant strategies to chemo-, gene-, radio- and immu-notherapy in dedicated animal models

Main Equipment

Pressure/ wire myographs and videomicroscopy setupCell culture equipment including 3-gas incubator (for hypoxia)Molecular biology equipment including adenovirus technologyImmunoblotting equipmentLaser Doppler imagingTumor invasion chambersImmunofluorescence microscopyAuthorized access to on-site FACS, DNA sequencer, real-time

PCR, EPR and NMR facilities


FERON O. and KELLY R.A. The Caveolar Paradox : suppressing,inducing and terminating eNOS signaling. Circulation Research,2001, 88, 129-131.

BROUET A., SONVEAUX P., DESSY C., BALLIGAND J.L. and FERONO. Hsp90 ensures the transition from the early Ca2+-dependentto the late phosphorylation-dependent activation of theendothelial nitric oxide synthase (eNOS) in VEGF-exposedendothelial cells. J. Biol. Chem., 2001, 276, 32663-9.

BROUET A., SONVEAUX P., DESSY C., MONIOTTE S., BALLIGANDJ.L. and FERON O. Hsp90 and caveolin are key targets for theproangiogenic nitric oxide-mediated effects of statins. Circ.Res., 2001, 89, 866-873.

JORDAN B.F., GREGOIRE V., DEMEURE R.J., SONVEAUX P.,FERON O., O’HARA J., VANHULLE V.P., DELZENNE N., GALLEZ B.Insulin increases the sensitivity of tumors to irradiation: involve-ment of an increase in tumor oxygenation mediated by a nitricoxide dependant decrease of the tumor cells oxygen consump-tion. Cancer. Res., 2002, 62, 3555-3561.

SONVEAUX P., DESSY C., BROUET A., JORDAN B.F., GRÉGOIRE

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V., GALLEZ B., BALLIGAND J.L. and FERON O. Modulation ofthe tumor vasculature functionality by ionizing radiationaccounts for tumor radio-sensitization and promotes genedelivery. FASEB J., 2002, 16, 1979-81.

VINCENT K.A., FERON O., KELLY R. A. Harnessing the Responseto Tissue Hypoxia: HIF-1a and Therapeutic Angiogenesis. TrendsCardiovasc. Pharmacol., 2002, 12, 362-7.

JORDAN B.F., SONVEAUX P., FERON O., GRÉGOIRE V., BEGHEINN. and GALLEZ B. Nitric oxide-mediated increase in tumor bloodflow and oxygenation of tumors implanted in muscle stimulated byelectric pulses. Int. J. Rad. Oncol. Biol. Phys., 2003, 55, 1066-73.

SONVEAUX P., BROUET A., DESSY C., GRÉGOIRE V., BALLIGANDJ.L. and FERON O. Irradiation-induced angiogenesis through theup-regulation of the NO pathway: implications for tumor radio-therapy. Cancer Res., 2003, 63, 1012-9.

SONVEAUX P., DESSY C., MARTINIVE P., JORDAN B., GALLEZB., GRÉGOIRE V., BALLIGAND J.L. and FERON O. Endothelin-1 isa critical mediator of myogenic tone in tumor arterioles: impli-cations for cancer treatment. Cancer Res., 2004, in press.

Patents

FERON O. and BALLIGAND J.L. Use of compound or pharma-ceutical composition for the prevention and/or the treatment ofischemic heart and cerebral diseases, tumour development andfor wound healing. PCT/EP00/07731 (filed in 2000).

DESSY C., SONVEAUX P. and FERON O. Evidence for an endothe-lin-1 mediated myogenic tone in tumor arterioles: implications forcancer treatment. PCT/EP2004/004554 (filed in 2003).

Awards

Société belge des Sciences Pharmaceutiques (1997)Prix Galien (1999)Prix de la Fondation Bekales (2000)Prix Orbita (2001)Prix MSD (2001)

Funding Sources FNRS, FRSM, Télévie, FSR

Fédération belge de recherche contre le cancerFonds J. MaisinFondation Fortis-Cancerology

Partnership

UCL (Brussels) : Prof. B. Gallez, Laboratory of Biomedical MagneticResonance; Prof. V. Grégoire, Laboratory of Radiobiology andRadioprotection; Prof. JL. Gala, Unit of Medical Genetics; Prof. E.Hermans, Unit of Pharmacology; Dr. JP Machiels, Unit of MedicalOncology, Prof. O. Devuyst, Nephrology Division.

ULg (Liège) : Profs. A. Noël and J.M. Foidart, Laboratoire deBiologie des Tumeurs et du Développement.

FUNDP (Namur) : Profs. C. Michiels and M. Raes, URBC-Biochimie et Biologie Cellulaire.

Prof. P. Boekstegers and Dr. C. Kupatt, Ludwig-Maximilians-Universitat, Internal Medicine University Klinikum GrosshadernMunich, Germany.

Prof. R. Bianchi and Dr. R. Rezzani, Department of BiomedicalSciences and Biotechnology, University of Brescia, Italy.

Prof. R.A. Kelly, Genzyme Corporation, Framingham, USA.

STAFF

Total : 9

KEY WORDS FOR R&D

angiogenesisblood flowchemotherapygene therapyhypoxiaimmunotherapynitric oxideradiotherapytumor vasculature

SENIOR SCIENTIST

Olivier FERON [email protected]. 32 (0)2 764 93 26

WEB SITE

http://www.mint.ucl.ac.be

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Phase II study of utilisation of a recombinant chimeric proteinin patients with recurrent progressive glioblastoma

SENIOR SCIENTIST :

� Christian RAFTOPOULOS

F 4


The aim of our research protocol is to evaluate the efficiency ofa recombinant chimeric protein composed of TransformingGrowth Factor (TGF) and a mutated form of the Pseudomonasexotoxin termed PE-38 (TP-38) in those patients with recurrentor progressive glioblastoma multiforme after resection andradiation therapy. The MRI must show one single target lesion with an area ofcontrast enhancement of at least 1 cm in diameter. The KarnofskyPerformance Status must be > 60% and life expectancy of > 3months. The primary objective is to determine whether TP38 given at any oftwo selected doses has sufficient activity to warrant further study. The treatment will consist of a continous, intratumoral infusionvia a micro-infusion pump connection system with three cathe-ters stereotacticly placed at investigator-determined areas. A total of 38 evaluable patients will be recruited in at least 7 active open centers in several European countries. Patientswill be followed until death with evaluation of the percentageof patients alive and progression free at 6 months.


Find a new treatment for patients suffering from progressive orrecurrent glioblastoma via in situ administration of TP38 byminimal-invasive surgery.

Main Equipment

Pump connection system with 3 catheters surgically placed bystereotactic technics.

Representative references

PAI-SCHERF L.H., VILLA J., PEARSON D. and al. Hepatotoxicityin cancer patients receiving erb-38, a recombinant immunotox-in that targets the rebB2 receptor. Clin. Cancer Res., 1999,5 :2311-2315.

RAND R.W., KREITMAN R.J., PATRONAS N. and al. Intratumoraladministration of recombinant circulary permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma.Clin. Cancer Res., 2000, 6 :2157-2165.

BASELGA J., PFISTER D., COOPER M.R. and al. Phase I stud-ies of anti-epidermal growth factor receptor chimeric antibodyC225 alone and in combination with cisplatin. J. Clin. Oncol.,2000, 18 :904-914.

FRANKEL A., KREITMAN R.J., SAUSVILLE E.A. Targeted toxins.Clin. Cancer Res., 2000, 6/326-334.

KEPPLER-HAFKEMEYER A., KREITMAN R.J., PASTAN I. Apoptosisinduced by immunotoxins used in the treatment of hematolog-ic malignancies. Int. J. Cancer, 2000, 87 :86-94.

KREITMAN R.J., WILSON W.H., WHITE J.D. and al. Phase I trialof recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) inpatients with hematologic malignancies. J. Clin. Oncol., 2000,18 :1622-1636.

ONDA M., WILLINGHAM M., WANG Q.C. and al. Inhibitionof TNF-alpha produced by Kuppfer cells protects against thenonspecific liver toxicity of immunotoxin anti-Tac(Fv)-PE38(LMB-2). J. Immunol. 2000, 165 :7150-7156.


IVAX Research, Inc.

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STAFF

Total : 4

KEY WORDS FOR R&D

cerebral tumor histopathologyintratumoral infusionneurologyneuropathologyneuroradiologyneurosurgeryrecombinant chimeric protein, TP 38recurrent multiforme glioblastomastereotaxysurgerysurgical medicine

SENIOR SCIENTISTS

Christian [email protected]. 32 (0)2 764 10 87

WEB SITE

http://www.chir.ucl.ac.be

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Cancer immunotherapy - clinical trials

SENIOR SCIENTISTS :

� Jean-François BAURAIN � Jean-Pascal MACHIELS

F 5


Tumor cells carry antigenic peptides bound to surface HLAmolecules that can be recognized by T lymphocytes. An impor-tant category of tumor specific antigens includes those enco-ded by “cancer-germline genes” such as members of theMAGE gene family. These antigens are not present on normaltissues, but are frequently found on various types of tumorssuch as melanoma, transitional bladder cancer, head and necksquamous cell carcinoma, non-small cell lung cancer and eso-phageal cancer. Because of these characteristics, MAGE-typeantigens are particularly attractive targets for cancer immuno-therapy.

Another important category of tumor antigens comprises the“melanoma differentiation antigens”, encoded by genes suchas tyrosinase, Melan-A and gp100, which are expressed exclu-sively by normal melanocytes and by melanoma cells.

Therapeutic vaccination with these antigens is only feasible inmelanoma patients, and carries an acceptable risk of inducingautoimmune depigmentation diseases.

During the last years, we have acquired a great experience inclinical vaccination trials with MAGE and with melanoma diffe-rentiation immunogens in patients with advanced cancer, witha special focus on melanoma. Our group has studied immuni-zation of patients with peptides, a recombinant protein and arecombinant viral vector. We coordinate a large network of cli-nical centers participating in these clinical trials. Our commonresearch project combines this shared experience with therapidly evolving knowledge of cellular immunology to designnew vaccination modalities with improved clinical and immu-nological effectiveness.

Main Equipment

Culture laboratory and molecular biology


M. MARCHAND, N. VAN BAREN, P. WEYNANTS, V.G. BRICHARD,B. DRÉNO, M.-H. TESSIER, E. RANKIN, G. PARMIANI, F. ARIENTI, Y.HUMBLET, A. BOURLOND, R. VANWIJK, D. LIÉNARD, M. BEAUDUIN,P.-Y. DIETRICH, V. RUSSO, J. KERGER, G. MASUCCI, E. JÄGER, J. DEGREVE, J. ATZPODIEN, F. BRASSEUR, P.G. COULIE, P. VAN DERBRUGGEN, and T. BOON., 1999. Tumor regression observed inpatients with metastatic melanoma treated with an antigenic pep-tide encoded by gene MAGE-3 and presented by HLA-A1. Int. J.Cancer 80:219-230.

BRICHARD V., MACHIELS J.P., PIPERNO S. and DORVAL T. 2001.Peptide–based immunization against tumor-specific antigenNA17.A2 in HLA-A2 patients with metastatic cutaneousmelanoma. Proceedings of the American Association of ClinicalOncology 272a : 1084.

BRICHARD V.G., DORVAL T., SALMON R.J., and MACHIELSJ.P. Peptide-based immunization against tumor specific antigenNA17.A2 in HLA-A2 patients with metastatic cutaneous or ocu-lar melanoma. Proceedings of the American Association ofClinical Oncology 42: 699, 2001.

MACHIELS J.P., VAN BAREN N., and MARCHAND M., 2002.Peptide-based cancer vaccines. Seminar in Oncology. 29: 494-502.

Funding Sources

Fonds national de la recherche scientifique (FNRS)Fédération Belge contre le Cancer

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STAFF

Total : 4

KEY WORDS FOR R&D

clinical trialimmunologytumor antigensvaccination

SENIOR SCIENTISTS

Jean-François [email protected]. 32 (0)2 764 54 72

Jean-Pascal [email protected]. 32 (0)2 764 54 57

WEB SITE


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Lung cancer - mesothelioma - clinical research in diagnosis -active treatment - supportive care

SENIOR SCIENTISTS :

� Daniel RODENSTEIN� Philippe COLLARD� Giuseppe LIISTRO� Thierry PIETERS

F 6


The pulmonology unit has participated for many years to rando-mized phase I, II, III or IV clinical trials in the treatment of lung cancer or mesothelioma and in the diagnosis of lung cancer. Mostof studies are financially supported and/or conducted by pharma-ceutical companies.

Diagnostics Project of detection of mutations of the Epidermal Growth

Factor Receptor in lung cancer.Early detection of lung cancer by low-dose computed tomog-

raphy (and FDG-PET). Comparison of FDG-PET and transthoracic needle biopsy for

the diagnosis of lung cancer. Use of a radiolabelled antibody to Annexin V for imaging of

chemotherapy-induced apoptosis in lung cancer.The value of FDG-PET and endoscopic ultrasound-guided fine-

needle aspiration to detect mediastinal lymph node involve-ment in lung cancer.Treatment

Several clinical studies of chemotherapy combinations. Studies with different Tyrosine Kinase Inhibitors (of EGFR and

VEGFR).combination of an inhibitor of the CDK2/cyclin E complex with

chemotherapy.Detection of malignant cells by intra-operative pleural lavage.Detection of micro-metastasis in mediastinal lymph nodes

and bone marrow at the time of pulmonary resection.Combination of a texaphyrin derivative and whole brain radi-

ation therapy for cerebral metastasis of lung cancer.In the future, the unit will develop studies in the early diagno-sis (autofluorescence endoscopy) and local tumor therapy(radiofrequence coagulation).

Products and services

Opportunities for clinical research on about one hundred newpatients each year.

Facilities for data collection (oncology care coordinator full-time available).

Main Equipment

Modern endoscopic equipment for diagnostic and therapeu-tical approach of bronchial carcinoma and pleural diseases.

Modern computed radiological tomographic systems and nuclearimaging technics (SPEC-PET).

18 in-hospitalisation beds for cancer management plus day-center oncological beds.

Funding Sources

External funds from pharmaceutical companies, FNRS (FondsNational de la Recherche Scientifique).

Partnership

UCL multidisciplinary thoracic oncology group.Numerous studies in collaboration with the pharmaceutical indus-

try. Collaboration with the Belgian Society of Pneumology (oncol-

ogy and interventional endoscopy).International interuniversity program in pneumology, includ-

ing onco-pneumology.

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STAFF

Total : 4

KEY WORDS FOR R&D

chemotherapycytologydiagnosishistologyimmunotherapyinternal medicinelung cancermolecular biologypronostic factor of molecular markerspulmonologysurgical medicinetreatment

SENIOR SCIENTISTS

Daniel [email protected]. 32(0)2 764 28 86

Philippe [email protected]. 32(0)2 764 28 30

Giuseppe [email protected]. 32(0)2 764 28 43

Thierry [email protected]. 32(0)2 764 28 33

WEB SITES

http://rch.adre.ucl.ac.be/browse/list_alpha/PNEUhttp://pneu.ucl.ac.behttp://www.saintluc.be/english/index.html

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Development of new calcium-based strategies to induceapoptotic cell death in prostate cancer cell lines

SENIOR SCIENTISTS :

� Bertrand TOMBAL� Philippe GAILLY

F 7


Prostate cancer is the most frequent cancer in men aged more than55 years old. Despite important progress in early diagnostic and the-rapeutic procedures, there are still a lot of patients who developmetastatic spread and require some form of systemic therapy.

Prostate cancer is characterized by a very low proliferation rate and aselective tropism to bone, which made it almost insensitive to modernchemotherapeutical regimens. Progression and metastatic spread ofPCa result instead of a defect in the induction of apoptosis. Apoptosisis a widespread, universal, cell suicide mechanism which helps multi-cellular organisms to control global cellular homeostasis.

The apoptotic potential can be initially restored in PCa cells bylowering the circulating level of testosterone. Rapidly however,PCa cells engage in a series of epigenetic and genetic mecha-nisms to overcome the apoptotic process and become hormo-ne resistant (HRPCa).

In a previous work, we have demonstrated that this resistanceto apoptosis could be overcome by drugs that mobilize calciumfrom the surrounding tissues and by disrupting growth factorsignaling pathways.

Our group is currently studying these pathways to test anddevelop new agents targeted to inhibit growth of HRPCa. Ourmajor focuses are drugs modulating calcium entry and drugsthat block the spread of PCa to bone.


The lab has developed several original techniques to investiga-te apoptosis and ionic changes during apoptosis.

We have a particular competence in imaging technologiesusing GFP/modified proteins in living and apoptotic cells.

The lab offers a direct connection with early human use (phaseI/II) trials and up-to-date pharmacogenomics and pharmacody-namic implementations.

Main Equipment

3 setups for imaging of living cells (including calcium measure-ment and GFP expression and trafficking studies)

patch-clamp equipment for early wide range of urological cell lines for in vitro techniques


TOMBAL B., GAILLY P., VAN CANGH P.J., GILLIS J.M. Role ofintracellular calcium in the programmed cell death of prostaticcancer cells. Acta Belgica Urologica 63(1), 1-5. 1995.

AU W.C., MOORE P.A., LAFLEUR D.W., TOMBAL B., PITTA P.Characterization of the interferon regulatory factor-7 and itspotential role in the transcription activation of Interferon Agene. A.J. Biol. Chem. 273(44), 29210-29217, 1998.

GAO J., TOMBAL B., ISAACS J.T. A Rapid In Situ HybridizationTechnique for Detecting Malignant Mouse Cell Contamination inHuman Xenograft Tissue from Nude Mice and In Vitro Culturesfrom such Xenograft. The Prostate 39(1), 67-70, 1999.

DENMEADE S.R., LIN X.S., TOMBAL B., ISAACS J.T. Inhibition ofcaspase activity does not prevent the signaling phase of apoptosisin prostate cancer cells. The Prostate 39(4), 269-79, 1999.

CHRISTENSEN S.B., ANDERSEN A., KROMANN H., TREIMANM., TOMBAL B., DENMEADE S.R, and ISAACS J.T. ThapsigarginAnalogues for Targeting Programmed Death of Androgen-Independent Prostatic Cancer Cells. Bioorg. MedicinalChemistry 7,1273-1280, 1999.

TOMBAL B., DENMEADE S.R., ISAACS J.T. Assessment and vali-dation of a microinjection method for kinetic analysis of [Ca2+]iin individual cells undergoing apoptosis. Cell Calcium. 25(1):19-28, 1999.

TOMBAL B, WEERARATNA A.T., DENMEADE S.R. and al.Thapsigargin induces a calmodulin/calcineurin-dependentapoptotic cascade responsible for the death of prostatic cancercells. Prostate 43: (4) 303-317, 2000.

JACKISCH C., HAHM H.A., TOMBAL B., McCLOSKEY D.,BUTASH K., DAVIDSON N.E., DENMEADE S.R. DelayedMicromolar Elevation in Intracellular Calcium PrecedesInduction of Apoptosis in Thapsigargin-Treated Breast CancerCells. Clin. Canc. Res. 6, 2844-2850, 2000.

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TOMBAL B., DENMEADE S.R, GILLIS J.M., ISAACS J.T. A suprami-cromolar elevation of intracellular free calcium ([Ca2+]i) is consis-tently required to induce the execution phase of apoptosis. CellDeath and Differentiation, 9, 561-573 2002.

PIGOZZI D., TOMBAL B., DUCRET T., VACHER P., GAILLY PH.Role of store-dependent influx of Ca2+ and efflux of K+ in apop-tosis of CHO cells. Cell Calcium, In press.

Funding Sources

Fonds national de la recherche scientifique (FNRS)Fondation pour la recherche scientifique médicale (FRSM)Télévie.Pharmaceutical industry

Partnership

Dr Jean-Luc Gala, Laboratory of Applied Molecular Technologies,Cliniques universitaires Saint Luc, Bruxelles, Belgium.

Dr Samuel Denmeade, Division of Experimental Therapeutic JohnsHopkins Oncology Center, Baltimore, USA.

STAFF

Total : 9

KEY WORDS FOR R&D

apoptosiscalciumfluorescencegrowth factorsprostate cancer

SENIOR SCIENTISTS

Bertrand [email protected]. 32 (0)2 764 55 40

Philippe [email protected]. 32 (0)2 764 55 42

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/FYMU

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Breast cancer

SENIOR SCIENTISTS :

� Jacques DONNEZ � Martine BERLIERE� Jean-Luc SQUIFFLET� Isabelle LECONTE� Latifa FELLAH� Christine GALANT� Catherine SIBILLE� Bénédicte BAYET

F 8

Since 1998, a specialist breast clinic has been under develop-ment at St Luc’s Hospital.In those European countries where such breast centres alreadyexist, studies have shown that women have a much betterchance of being cured.This concept implies the creation of different multidisciplinary sub-units in all domains linked to breast cancer (diagnosis, molecularbiology, genetics, surgical treatment, techniques of radiotherapy,chemotherapy, endocrine therapy and immunotherapy).

Evidence from scientific literature suggests that all phases of thecontinuum of care have an important impact on breast canceroutcome.Quality of care is based on the results of well-designed rando-mized, controlled trials.

Here are some examples of trials in which our breast clinic iscurrently involved :

Pathology : European project initiated by the EORTC, study-ing the genetic profile of breast tumors and their role as prog-nostic and predictive factors.

Adjuvant therapy : implication in different international clini-cal studies : chemotherapy trials investigating the place of tax-anes in early breast cancer.

Endocrine therapy : partner in the TEAM trial which studiesthe place and benefits of aromatase inactivators (aromasin,exemestane) in the adjuvant treatment of breast cancer.Academic study (neoadjuvant chemotherapy with taxanes andTrastuzumab for locally advanced breast cancer). This study willinvestigate the biology of the tumor and the changes in angio-genesis.

Immunotherapy :Preventive trials such as IBIS II study.

We are also engaged in research in the adjuvant setting (phase Istudies of immunotherapy and other studies of metastatic breastcancer, studies coupling hormone therapy and antibodies).In the coming months, we aim at conducting our own studieson the treatment of advanced breast cancer.

We are developing a multidisciplinary approach to optimize thedifferent therapeutic aspects of breast cancer. This multidiscipli-nary consultation implies the presence, at the same time and in

the same place, of different doctors involved in the variousaspects of breast cancer therapy (breast surgeon, oncologist,radiotherapist, psychologist).

The purpose of this type of consultation is : To acknowledge good clinical practices and promote its

development.To ensure that a maximum number of women fully under-

stand any proposed treatment options, including participationin clinical trials.

To ensure quality supportive care during and after treatment.To promote breast cancer research and its application to clin-

ical practice.To create meaningful partnerships between health professionals

and patient associations in the complex field of breast cancer(diagnosis, treatment and research). To this end, we will invitewomen from the “Vivre comme avant” association whompatients will be able to meet after their multidisciplinary consultation.

Partnership

Bordet Institute, Brussels, Belgium (Professor M. Piccart).French Federation of Cancer.

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STAFF

Total : 13

KEYWORDS

gynecology medical psychology multidisciplinary approachparticular pathology

SENIOR SCIENTISTS

Jacques [email protected]. 32 (0)2 764 94 07 or 764 95 01

Martine [email protected]. 32 (0)2 764 10 75

Jean-Luc [email protected]. 32 (0)2 764 10 71

Isabelle [email protected]. 32 (0)2 764 29 34

Latifa [email protected]. 32 (0)2 764 29 13


Catherine [email protected]. 32 (0)2 764 53 82

Bénédicte [email protected]. 32 (0)2 764 14 07

WEB SITES

http://rch.adre.ucl.ac.be/browse/list_alpha/GYNEhttp://rch.adre.ucl.ac.be/browse/list_alpha/GMEDhttp://rch.adre.ucl.ac.be/browse/list_alpha/ANPShttp://www.md.ucl.ac.be/rdgn

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Cryopreservation of ovarian cortex removed before chemothe-rapy allows the restoration of ovarian function after orthotopicautotransplantation. SENIOR SCIENTISTS :

� Jacques DONNEZ� Jean-Luc SQUIFFLET � Pascale JADOUL� Céline PIRARD� Christine WYNS� Dominique DEMYLLE� Marie-Madeleine DOLMANS� Belen MARTINEZ-MADRID� Anne VAN LANGENDONCKT

G 1


Modern management of childhood malignancy is becoming increa-singly effective. Aggressive chemotherapy and radiotherapy, as wellas bone marrow transplantation, can cure more than 90% ofpatients. Unfortunately, the ovaries are very sensitive to cytotoxictreatment, especially to alkylating agents and ionizing radiation,resulting in the loss of both endocrine and reproductive functions.In fact, it has been estimated that, by 2010, one in 250 people inthe adult population will actually be childhood cancer survivors.The different options available to preserve fertility in young womenrequiring chemo- and/or radiotherapy include cryopreservation ofoocytes, embryos or ovarian cortical tissue. For those patients whorequire immediate chemotherapy, cryopreservation of ovarian tis-sue is a possible alternative. Laparoscopy allows simple retrieval ofovarian tissue by either oophorectomy or multiple ovarian biopsies.The aim is to reimplant tissue into the pelvic cavity (orthotopic site)or a heterotopic site (like the forearm) once treatment is comple-ted and the patient is disease-free.

We described, in June 2003, the first successful orthotopicreimplantation of ovarian cortical tissue removed by laparosco-py from a woman with stage IV Hodgkin’s lymphoma beforeshe received chemotherapy. For the first time, survival of primordial follicles was histologi-cally demonstrated four months after reimplantation, and long-term restoration of ovarian function was proved by hormonemeasurements, reappearance of regular menstrual bleedingand vaginal echography. This is the first pregnancy after reim-plantation of frozen ovarian cortical tissue in human. The babyis born in september 2004.

One major concern surrounding the use of ovarian tissue is thepotential risk that the frozen-thawed ovarian cortex might har-bour malignant cells which could induce a recurrence of the dis-ease after reimplantation. A recent study using a NOD/ SCIDxenograft model suggested that ovarian tissue transplantationin Hodgkin’s disease was safe. A significant follicular loss occurs with freezing, thawing andgrafting. Hypoxic damage to ovarian tissue could be reduced byautografting a whole ovary after cryopreservation, or simplyisolated primordial follicles.

Our results on whole ovary cryopreservation with a passivecooling device showed, after thawing, a follicle viability rate of75.9%. Intact and live vessels were also found in the medullar tis-sue. This is the first time that entire human ovaries have beencryopreserved in liquid nitrogen using an accessible cryopreser-vation protocol and that follicle survival has been demonstrated.We are also working on the optimization of follicle isolationprocedures. Different enzymatic digestion methods are tested,as well as a new follicle recovery method based on Ficoll densi-ty gradient instead of filtration. Viability of isolated follicles istested by metabolic analysis of the follicles in culture withmicrofluorometry, and their integrity is analysed by electronmicroscopy and immunofluorescence. The isolated follicles aregrafted under the kidney capsule of immunosuppressed mice.The vascularisation, viability and functionality of the grafted iso-lated follicles will be compared to those of grafted ovarian cor-tical strips. Grafting isolated follicles offers the advantage of cir-cumventing the massive loss of follicles by ischaemia at earlystage of the grafting and excludes the theoretical reimplanta-tion of malignant cells which cannot pass through the basalmembrane circumscribing the follicle.


Ovarian cryobankingExperimental transplantation in nude mice and ratsViability and apoptosis assaysEvaluation of neoangiogenesis

Main Equipment

Microscopy, morphometry and immunohistochemistry :Orthoplan-Leitz microscope, 2 Axioscope Zeiss microscopes, 2CCD 72E dag-MTI cameras, 2 Kontron image analysers, LeicaDMIL inverted microscope with fluorescence and camera,Olympus fluorescence microscope.

Cellular culture : laminar flow hood, 2 CO2 incubators (Forma),tissue chopper.

Cryopreservation : 2 Planer freezing apparatus, liquid nitro-gen tanks, -85°C ultra low freezer Kryo 10 series III.

Biochemistry : electrophoresis and electrotransfer material, ELISAplate analyser Model 550 (Biorad), UV/visible spectrophotome-ter (Biorad).

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Molecular biology : GeneAmp PCR System thermocycler 9600Perkin-Elmer, agarose electrophoresis, transilluminator.

Funding SourcesFNRS, FRSM, private grants.

Partnership

Inter-university project (Télévie) : Ulg, ULB, UCL.Organizer of the first World Congress on Ovarian Cryo-

preservation and Ovarian Transplantation, June 2003.UCL, Anatomo-Pathology Dept., Prof. Marbaix, Prof. Rahier,

Belgium.VUB, Follicle Development Unit, Prof. Smitz, Brussels, Belgium.University of Roma La Sapienza, Anatomo-Pathology Dept.,

Prof. Nottola, Italy.


QU J., GODIN P.A., DONNEZ J. Expression of transforming growthfactor-, epidermal growth factor and epidermal growth factorreceptor in follicles of human ovarian tissue before and after cry-opreservation. Fertil. Steril., 2000, 74 : 113-21.

DONNEZ J., QU J., DE HERTOGH O., NISOLLE M. Gonadal cryop-reservation in the young patient with gynaecological malignancy. Anatlas of operative laparoscopy and hysteroscopy. Donnez J. andNisolle M. Eds, Parthenon Publishing, Carnforth, 2001, pp. 311-9.

DE HERTOGH O., QU J., NISOLLE M., DONNEZ J. Ovarian tissuecryopreservation : technical aspects and existing alternatives. Anatlas of operative laparoscopy and hysteroscopy. Donnez J. andNisolle M. Eds, Parthenon Publishing, Carnforth, 2001, pp. 321-34.

JADOUL P., DONNEZ J. Conservative treatment may be beneficialfor young women with atypical endometrial hyperplasia or endome-trial adenocarcinoma. Fertil Steril., 2003 Dec, 80(6) : 1315-24.

DONNEZ J., MUNSCHKE A., BERLIERE M., PIRARD C., JADOULP., SMETS M., SQUIFFLET J. Safety of conservative managementand fertility outcome in women with borderline tumors of theovary. Fertil Steril., 2003 May, 79(5) : 1216-21.

DOLMANS M.M., DEMYLLE D. Overview of the results of embryocryopreservation (D3, blastocysts); quality of embryos obtainedafter an IVF attempt following one regimen of chemotherapy.In: Program and Abstracts of the 1st World Congress onOvarian Cryopreservation & Ovarian Transplantation, Brussels,June 27-28, 2003. Gunaïkeia, 2003, 8: 61, FA16.

MARTINEZ-MADRID B., DOLMANS M.M., VAN LANGENDONCKTA., DEFRERE S., PIRARD C., DONNEZ J. Freezing entire humanovaries with a passive cooling device. In: Program and Abstracts ofthe 1st World Congress on Ovarian Cryopreservation & OvarianTransplantation, Brussels, June 27-28, 2003. Gunaïkeia, 2003, 8 :159,O4.

DOLMANS M.M., MARTINEZ-MADRID B., VAN EYCK A.S.,VANLANGENDONCKT A., DEFRERE S., DONNEZ J. Apoptosis and via-bility in human ovarian tissue culture In: Program and Abstracts ofthe 1st World Congress on Ovarian Cryopreservation & OvarianTransplantation, Brussels, June 27-28, 2003. Gunaïkeia, 2003, 8 :162, O2.

MARTINEZ-MADRID B., DOLMANS M.M., VAN EYCK A.S.,VANLANGENDONCKT A., DEFRERE S., DONNEZ J. Ficoll density gra-dient method for recovery of isolated human ovarian follicles.Fertility Sterility, 2004, in press.

DONNEZ J., DOLMANS M.M., DEMYLLE D., JADOUL P., PIRARDC., SQUIFFLET J., MARTINEZ-MADRID B., VAN LANGENDONCKT A.Livebirth after orthotopic transplantation of cryopreserved ovariantissue. Lancet, 2004 Oct, 364.

STAFF

Total : 14

KEY WORDS FOR R&D

cancercryopreservationfolliclesovary

SENIOR SCIENTISTS

Jacques DONNEZ - Head of [email protected]. 32 (0)2 764 94 07 or 764 95 01


Pascale [email protected]. 32 (0)2 764 95 02

Céline [email protected]. 32 (0)2 764 10 28


Dominique [email protected] : 32 (0)2 764 10 28

Marie-Madeleine [email protected]. 32 (0)2 764 52 47

Belen [email protected]. 32 (0)2 764 54 27

Anne VAN [email protected]. 32 (0)2 764 52 47

WEB SITES

http://www.gype.ucl.ac.behttp://rch.adre.ucl.ac.be/browse/list_alpha/GYNE

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Limb salvage in tumor surgery with massive bone allografts

SENIOR SCIENTISTS :

� Christian DELLOYE� Olivier CORNU� Xavier BANSE

G 2


Study of massive allografts complications (fracture, infection,non-union);

Bone allografts incorporation;Treatment of non union or delayed union by autologous cell

therapy;Osteo-induction by demineralised bone matrix.

Bone allografts have a long history as a substitute for limbreconstruction after tumor resection. They are commonly usedbecause they provide immediate structural support that can beassociated with a prosthesis or with osteosynthesis. Amongseveral advantages, their use allows anatomical reconstructionof the skeletal defect, biological union to host bone throughcallus formation, soft tissue adherence around the grafted boneand the possibility of tendon reinsertion on its counterpart lefton the bone graft. Among possible disadvantages, there are therisk, albeit remote, of disease transmission through the implant,and a high rate of non union and fracture. These complicationsare related to the non vitality of the bone graft. Research projects are conducted to remote disadvantages ofbone allografts. Methods of bacterial screening and graftdecontamination are assessed by in vitro testing. Using thegraft as an antibiotic delivering system is also considered.As a bone allograft serves primarily as an osseous spacer thatallows osteoconduction of host cells into its mass, biologicalanswer results in a progressive incorporation of the graft intothe host bone. Incorporation includes a series of events leadingto gradual replacement of the grafted bone by host bonethrough a mechanism of osteoclastic resorption followed bynew bone deposition. This intricate process however is verylimited in time and space, leaving eventually a mass of deadbone that has been poorly substituted by new bone. Efforts are made to overcome this limited substitution throughimprovement of the revascularisation and revitalisation of thebone. The research is organised to explore the different avenuesavailable to achieve a better incorporation and avoiding amechanical failure.


The Tissue Bank is able to deliver massive bone allografts tosurgeons for skeletal reconstruction ([email protected]). TheTissue Bank is applying the European standards and theBelgian and French national regulations (see http://www.eamst.org). Research projects may cover all fields of interests from micro-biological studies (in vitro testing of bacterial screening anddecontamination) to in vivo model of allografts incorporation(Tibial critical defect in sheep). Mechanical and morphologicalassessments of allograft reconstruction may be performed.Among the different avenues to improve allograft incorpora-tion and bone healing, autogenous cell augmentation repre-sents an indirect approach. Stromal cells from the patient’sbone marrow can be cultured and serve as a source of addi-tional osteogenic cells. This attractive concept awaits furtherin vivo research (rat nude model of osteoinduction) and clini-cal confirmation.

Main Equipment

Bone morphological analysisCell culture facilitiesCleanroom facilitiesDigitalisation tableExact sawFluoroskan AscentHip walking simulatorLeitz saw 1600Microradiography (Bemtograph)MicroscopyMicrotome LeicaMultiscan RC200-240Cp-QCT, model XCT Research SA+® Stratec (RUMA)Radiographic digitizer (Widar)Tissue BankUTS model 100-1 (ERM)Zwick model Z50/TH3A (ERM)

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BRESLER F., SIMON P., SCHMITT D., VERHELPEN M., DE GASPERIM., DELLOYE C. Digital image analysis of bone allograft union insheep. Acta Orthop. Scand., 1998 Apr., 69(2):181-3.

DELLOYE C., DOCQUIER P.L., CORNU O., POILVACHE P., PETERSM., WOITRIN B., ROMBOUTS J.J., DE NAYER P. Simple bonecysts treated with aspiration and a single bone marrow injec-tion. A preliminary report. Int. Orthop., 1998, 22(2):134-8.

DELLOYE C. Bone grafts using tissue engineering. Bull. Mem.Acad. R. Med. Belg., 2001, 156(7-9):418-25.

DELLOYE C., SIMON P., NYSSEN-BEHETS C., BANSE X., BRESLERF., SCHMITT D. Perforations of cortical bone allografts improvetheir incorporation. Clin. Orthop., 2002 Mar., (396):240-7.

DOCQUIER P.L., DELLOYE C. Treatment of simple bone cystswith aspiration and a single bone marrow injection. J. Pediatr.Orthop., 2003, 23(6):766-73.

DELLOYE C., CORNU O. Incorporation of massive bone allo-grafts: can we achieve better performance? Acta Orthop. Belg.,2003 Apr., 69(2):104-11.

SCHECROUN N., DELLOYE C. Bone-like nodules formed byhuman bone marrow stromal cells: comparative study andcharacterization. Bone, 2003 Mar., 32(3):252-60.

DELLOYE C., CNOCKAERT N., CORNU O. Bone substitutes in2003 : an overview. Acta Orthop. Belg., 2003, 69(1):1-8.

Awards

Dr D. Dufrane BELACT - 2000Dr A. Bavadekar EFORT – Rhodos - 2001Dr D. Dufrane ESACT – Tylösand - 2001Dr P.L. Docquier – SORBCOT– 2004

Funding Sources

Télévie-FNRSSalus Sanguinis fundation.

Partnership

Royal Military School - Engineering (Prof Van Thomme), Bruxelles,Belgium

Université de Strasbourg - Orthopaedic Department (Prof Simon),Strasbourg, France.

Université de Nancy – Experimental Surgery (Prof Schmitt),Nancy, France.

University of Bristol - Collagen Biochemistry Laboratory (ProfBailey), Bristol, UK.

University of Toronto – Phospho-calcic metabolism Lab (ProfGrynpas), Toronto, Canada.

Institut Rizzoli (Prof Donati), Bologne, Italie.Azienda Ospedaliera Careggi (Prof Capanna), Florence, Italie.

STAFF

Total : 20

KEY WORDS FOR R&D

allograftsanatomopathology autologous cell therapybacteriology biomechanic bone inductionbone remodelingdelayed-unionfractureinfectionlimb salvageorthopaedic surgery transplantation

SENIOR SCIENTISTS:

Christian [email protected]. 32 (0)2 764 29 50

Olivier [email protected]. 32 (0)2 764 53 88

WEB SITE

http://rch.adre.ucl.ac.be/browse/list_alpha/ORTO

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Biological dosimetry and radiobiological calibration of clinical hadron beams

SENIOR SCIENTIST :

� John GUEULETTE

H 1


Hadron beams (e.g. neutrons, protons heavy ions) are used inadvanced radiation therapy techniques. Due to their physicalcharacteristics (e.g. density of ionization or Linear EnergyTransfer, LET), these beams might exhibit a biological effective-ness (ratio of the biological effect to the dose) very differentfrom that of classical photon beams. From there, the necessityof calibrating them, and determining the “gamma dose equi-valents” allowing the radiation oncologist to refer to his clinicalexperience with photons. However, the Relative Biological Effectiveness (RBE) of a giventype of radiation is not constant but varies with different physi-cal (e.g. energy of the beam) and biological (e.g. biological sys-tem, fractionation) factors. Therefore, it was necessary to determine the physical and bio-logical conditions relevant to the clinical applications and towork out a specific experimental procedure for determining theactual value of the dose weighting factors. This procedure was applied to the radiobiological calibration ofmost clinical hadron beams worldwide and is now called for asthe standard biological Quality Assurance (QA) procedure pre-vious to the clinical implementation of new beams.


Radiobiological calibration and QA of clinical hadron beams.Biological control of dynamic beam delivery systems (scannedbeams). Determination of irradiation protocols and design ofirradiation devices (e.g. animal holders) for the radiobiologicalexperimentation in extreme physical conditions (e.g. importantdose gradients, short distance from the source, continuous lowdose rate, etc.).

Main Equipment

Linear accelerator (St-Luc hospital)250 kV X-ray machine (faculty of Medicine) Clinical neutron beam (cyclotron of Louvain-la-Neuve)Biological laboratory and histology equipment


GUEULETTE J., BEAUDUIN M., GREGOIRE V., VYNCKIER S.,DE COSTER B.M., OCTAVE-PRIGNOT M., WAMBERSIE A.,STRIJKMANS K., DE SCHRIJVER A., EL-AKKAD S., BOHM L.,SLABBERT J.P., MAUGHAN R., ONODA J., YUDELEV M., PORTERA.T., POWERS W.E., SABATTIER R., BRETEAU N., COURDI A.,BRASSART N., CHAUVEL P. RBE variation between fast neutronbeams as a function of energy. Intercomparison involving 7neutrontherapy facilities. Bull. Cancer. Radiother., 1996, 83Suppl:55s-63s.

GUEULETTE J., SLABBERT J.P., BOHM L., DE COSTER B.M.,ROSIER J.F., OCTAVE-PRIGNOT M., RUIFROK A., SCHREUDERA.N., WAMBERSIE A., SCALLIET P., JONES D.T. Proton RBE forearly intestinal tolerance in mice after fractionated irradiation.Oncol., 2001 Nov., 61(2):177-84.

GUEULETTE J., BOHM L., SLABBERT J.P., DE COSTER B.M.,RUTHERFOORD G.S., RUIFROK A., OCTAVE-PRIGNOT M., BINNSP.J., SCHREUDER A.N., SYMONS J.E., SCALLIET P., JONES D.T.Proton relative biological effectiveness (RBE) for survival in miceafter thoracic irradiation with fractionated doses. Int. J. Radiat.Oncol. Biol. Phys., 2000 Jul 1, 47(4):1051-8.

YING H., SERHIR L., MAHY P., RENIERS B., GUEULETTE J.Design of a cylindrical brachytherapy implant applicator for theirradiation of an intestinal segment in mice. Radiat. Res., 2003Jan, 159(1):123-7.

Awards

Radié Kotze Commemorative Lecture Medal : NationalAccelerator Centre, Faure, Cape Town (South Africa), 1998.

Funding Sources

Fonds de la Recherche Scientifique Médicale (FRSM)International Atomic Energy Agency (IAEA)Various occasional foreign grants

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Partnership

FYNU, UCL, Louvain-la-Neuve, Belgium.Radiotherapy Oncology Department, St-Luc hospital, Brussels,

Belgium.Radiotherapy and Physics Departments of various foreign

Universities worldwide.

STAFF

Total : 4

KEY WORDS FOR R&D

biological dosimetryclinial hadron beamsradiation radiobiological calibrationRelative Biological Effectiveness (RBE)

SENIOR SCIENTIST

John [email protected]. 32 (0)2 764 54 84

WEB SITE

www.md.ucl.ac.be/rbnt

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87


Radiobiology of light ions

SENIOR SCIENTIST :

� André WAMBERSIE

H 2


Due to his large experience in non-conventional radiation the-rapy gained during clinical application of fast neutrons at thecyclotron CYCLONE of Louvain-la-Neuve (1972-2001),Professor A. Wambersie was selected as leader of the work pac-kage 4 of the the European Network for LIGht ion HadronTherapy (ENLIGHT).

Insofar, as ion beams can provide a chance of cure to a subsetof patients with radio-resistant tumours, ENLIGHT aims at acoordinated effort towards ion beam research in the EU. Its main objective is :1. to assess the respective strengths of each of the partners andthe advantages of the different approaches,2. to evaluate the already developed technology in the light ofemerging new developments 3. to agree on the common development of still missing toolsand for approaching the industry. Last but certainly not least, acommon strategy for clinical validation and implementation willbe developed.

Expected results

Technological objectivesThe aim is to have all the project groups responsible for thevarious facilities work together and in close connection with theEuropean radiation oncologists so as to make the projects clini-cally effective, reduce their cost and increase their reliability. Thetechnological objectives are thus :- to design and produce all technical systems (e.g. beam delive-ry system, patient positionning system, etc.) using all the avai-lable expertise so as to avoid work duplication and meet thestringent criteria imposed by the clinical applications;- to order jointly components to industry so as to reduce thecost and have a better quality control during construction,installation and running.

Scientific and Public Health objectiveThrough a European network coordinated by ESTRO, radiationoncologists throughout Europe will develop a co-ordinatedaction for the implementation of common treatment protocolsand clinical research.


A. BRAHME. Treatment optimization using physical and bio-logical objective functions. In: Radiation Therapy Physics, Ed.:Smith A, Berlin Springer (1995) pp 209-246.

U. AMALDI, B. LARSSON and Y. LEMOIGNE. Advances inHadrontherapy. Excerpta Medica, Elsevier Science, Amsterdam,1997.

J. GUEULETTE, L. BÖHM, B.M. DE COSTER, A. WAMBERSIEand al. RBE variation as a function of depth in the 200 MeVproton beam produced at the NAC. Faure, Radiotherapy andOncology, 42, 303-309, 1997.

U. AMALDI. Conformal radiation therapy with hadron beams andthe programs of the TERA Foundation. Rays 23/3 (1998) 486-507.

U. AMALDI. Cancer therapy with particle accelerators. Nucl.Phys. A654 (1999) 375c-399c.

H. ENGELS and A. WAMBERSIE. Cancer epidemiology and patientrecruitment for hadron therapy. Strahlentherapie und Onkologie,175(II), 95-98, 1999.

A. BRAHME, R. LEWENSOHN, U. RINGBORG, U. AMALDI, F.GERARDI, S. ROSSI. Design of a centre for biologically opti-mised light ion therapy in Stockholm. Nucl. Instr. Meth. Phys.Res. 2001.

A. WAMBERSIE and R.GAHBAUER: Hadrons (protons,neutrons,heavy ions) in radiation therapy: rationale, achievements andexpectations. Radiochimica Acta, 89, 245-253, 2001.

A. WAMBERSIE, H.G. MENZEL, R.A. GAHBAUER, D.T.L. JONES,B.D. MICHAEL and H. PARETZKE. Biological weighting of absorbeddose in radiation therapy. Radiation Protection Dosimetry, 99, 445-452, 2002.

A. WAMBERSIE, J. GUEULETTE, D.T.L. JONES and R. GAHBAUER.Ion-beam therapy: rationale, achievements and expectations,in Charged particles and photon interactions with matter. (Eds A. Mozumber and Y. Hatano), Marcel Dekker Inc., New York,2003, 743-784.

V. GRÉGOIRE, R. PÖTTER and A. WAMBERSIE. General principlesfor prescribing, recording and reporting a therapeutic irradiation.Radiotherapy and Oncology, special issue, 2004, in press.

A. WAMBERSIE, R. GAHBAUER and G. MENZEL. RBE and weight-ing of absorbed dose in ion-beam therapy. Radiotherapy andOncology, Special issue, 2004, in press.

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A. WAMBERSIE, J. HENDRY, J. GUEULETTE, R. GAHBAUER, R.PÖTTER and V. GREGOIRE. Radiobiological rationale and patientselection for high-LET radiation in cancer therapy. Radiotherapyand Oncology, Special issue, 2004, in press.

Patents

Results will be shared and published as open source information.

Funding Sources

European Commission, FP5, Quality of Life and Living ResourcesProgramme, Thematic Network.

Partnership

Facilities in different stages of development in several regionalcentres in Europe provided the national research efforts.Thework is distributed over 6 task groups working in parallel overa time frame of 3 years. 2 clinical groups will focus onEpidemiology-Patient Selection and on the Design and Conductof Clinical Trials. The Network will bring together 87 scientistsfrom 9 different disciplines: radiation oncology, epidemiology,nuclear medicine, basic physics, engineering, clinical physics,radiobiology, computing and health economics.

ESTRO: European Society for Therapeutic Radiology andOncology, Brussels, Belgium.

UCL, Radiobiology and radiation protection unit, Brussels,Belgium.

CERN, European Organisation for Nuclear Research, Geneva,Switzerland.

GSI, Gesellschaft für Scherionenforschung, Darmstadt, Germany.DKTZ, German Cancer Research Center, Heidelberg, Germany.TERA, Fondazione per Adroterapia Oncologica, c/o CERN,

Geneva, Switzerland.Karolinska Institute, Stockholm, Sweden.ETOILE, Université Claude Bernard, Lyon, France.Med-AUSTRON, AKH, University Hospital, Vienna, Austria.

STAFF

Total : 18

KEY WORDS FOR R&D

accelerator technologybeam cancer therapycarbon ion beamsDVHepidemiologyhigh LET radiationhigh LET radiobiologyion beamslate tissue reactionsmicrodosimetryradiation therapy radiobiologyRBEscanning beam simulationsocio-economicstreatment planning

SENIOR SCIENTIST

André [email protected]. 32 (0)2 764 54 68

WEB SITE

http://www.estro.be

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89


Molecular imaging for radiotherapy

SENIOR SCIENTIST :

� Vincent GRÉGOIRE

H 3


The aim of this project is to assess the value of functional ima-ging for tumor volume delineation and its impact on dose dis-tribution in 3D-conformal radiotherapy for head & neck tumors.

Positron Emission Tomography (PET) with various tracer ofmetabolism, (FDG), proliferation (FLT, BFU), hypoxia (EF3),magnetic resonance with perfusion and diffusion algorithms,and CT-scan are compared. All functional images are co-regis-tered on anatomic CT and MR images. Patients are imaged before radiotherapy and during treatmentto assess the volume change. Validation of the various functio-nal imaging modalities with anatomopathological examinationof tumor specimens is also foreseen in patients scheduled forsurgical treatment.

This project is conducted in collaboration with the former labora-tory of Positron Emission Tomography (TOPO), presently merged ina new entity Molecular Imaging and Experimental Radiotherapy(IMRE), and the departments of head and neck surgery, oral andmaxillofacial surgery, nuclear medicine and radiology.


Development and design study of 1 mm resolution PET.

Improved performance (speed-resolution) of PET-CT, MRSI andother imaging modalities for RT.

Methodologies, techniques, predictive assays and other tests, mar-kers, radiolabeled inhibitors etc., for the optimisation and verifica-tion of biologically optimised intensity modulated radiotherapy.

Main Equipment

Multi-modality imaging facilities.Molecular biology research laboratory.Radiotherapy simulation, planning treatment and verification

equipment and software.


J.F. DAISNE, M. SIBOMANA, A. BOL, T. DOUMONT, M.LONNEUX and V. GRÉGOIRE. Tri-dimensional automatic seg-mentation of PET volumes based on measured source to back-ground ratios: influence of reconstruction algorithms.Radiother. Oncol., 69: 247-250, 2003.

J.F. DAISNE, M. SIBOMANA, A. BOL, G. COSNARD, M.LONNEUX and V. GRÉGOIRE. Evaluation of a multimodalityimage (CT, MRI and PET) coregistration procedure on phantomand Head and Neck cancer patients: accuracy, reproducibilityand consistency. Radiother. Oncol. 69: 237-245, 2003.

X. GEETS, J.F. DAISNE, V. GREGOIRE, M. HAMOIR, M.LONNEUX. Role of 11-C-methionine positron emission tomog-raphy for the delineation of the tumor volume in pharyngo-laryngeal squamous cell carcinoma: comparison with FDG-PETand CT. Radiother. Oncol. 71: 267-73, 2004.

J.F. DAISNE, T. DUPREZ, B. WEYNAND, M. LONNEUX, M.HAMOIR, H. REYCHLER, V. GRÉGOIRE. Accuracy of CT scan,MRI and FDG-PET in delineating the tumor volume in pharyn-go-laryngeal squamous cell carcinomas treated by radiothera-py: validation with the macroscopic tumor specimen used asreference. Radiology, 2004 (in press).

Patents

Are subject to the TRIPPS clauses in the Consortium Agreement.

Funding Sources

TélévieEuropean Commission, FP6, Life Sciences, Major Diseases, CancerBelgian Federation against Cancer

Partnership

Telecommunication laboratory, UCL, Prof. B. Macq.Dept. of Radiation Oncology, KULeuven, Prof. K. Haustermans.Dept. of Radiation Oncology, RUGent, Prof. W. De Neve.BioCARE project, Karolinska Institute, Stockholm

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STAFF

Total : 20

KEY WORDS FOR R&D

head and neck tumorhypoxiametabolismMRIPETproliferationradiotherapytracers

SENIOR SCIENTIST

Vincent GRÉ[email protected]. 32 (0)2 764 94 43

WEB SITES

http://www.md.ucl.ac.be/rbnthttp://www.md.ucl.ac.be/ccmf

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Treatment planning of intensity modulated radiotherapy(IMRT) for head and neck cancer : optimization of thetreatment technique and validation by measurements andMonte Carlo simulations

SENIOR SCIENTISTS :

� Milàn TOMSEJ � Nathalie DE PATOUL� Stefaan VYNCKIER� Vincent GREGOIRE

H 4


Intensity Modulated Radiotherapy (IMRT) is a specific technique toirradiate with high homogeneity tumor volumes whilst sparing as much as possible the critical organs. This technique consists ofdelivering a radiation dose by the means of photon beams withnon-uniform irradiation fields obtained by the superposition insmall beamlets. The different beam intensities are then the resultof a powerful mathematical optimization algorithm based on theinput of dosimetric constraints on critical organs and tumor volu-mes into the treatment planning system software.In radiotherapy treatments of head and neck cancer, severalchallenges exist in terms of irradiation optimization, such as forinstance the complex geometry of the patient outline, the com-plicated shape of target volumes located in proximity of criticalorgans (parotid glands, spinal cord, etc) and obviously the presence of heterogeneities in the head and neck region (bonystructures and very small air cavities).Consequently, the implementation and the dosimetric valida-tion of such irradiation technique (IMRT) for this pathologyhave to be carried out.

Mathematic algorithms for the dose calculation used bymodern treatment planning softwares are becoming limited interms of accuracy for the calculation of the dose distributionsof such complex and sophisticated irradiation technique.Moreover, measurements made for the verification of thesetreatments show uncertainties inherent to the limitations of thecurrent detectors applied to these extreme conditions.

Therefore validation of IMRT requires the use of a very special cal-culation technique called “the Monte Carlo simulation”. Thisconsists in a numerical resolution of particle transport equationsin which it is possible to calculate energy losses into the body ofthe patient and thus the deposited dose received by the patient.Such technique is then able to consider the irradiation geometryby a modelisation of the mechanical and physical characteristicsof the linear accelerator as well as the physical properties of thepatient (external geometry and different internal density structu-res). This theoretical solution can be considered as a first step vali-dation of the treatment planning optimization.

Furthermore, the verification of IMRT treatments could be donewith in vivo dosimetry. Actually, a reconstruction of dose distri-butions inside the patient from portal images acquired during thetreatment can be envisaged by Monte Carlo simulation as well.


Verification of complex and sophisticated treatmentsMethodology to improve treatments for head and neck cancer

Main Equipment

Linear accelerator ELEKTA SLi25Treatment planning systems HELAX-TMS (NUCLETRON), KON-

RAD (SIEMENS), PLATO ITP (NUCLETRON), ECLIPSE (VARIAN)Monte Carlo code OTP (NUCLETRON)Monte Carlo code BEAMnrc (NRC-CNRC)


G. KUHN. Towards IMRT treatments in head and neck tumors:implementation of a new technique, preliminary dosimetric ver-ification and first results. Thesis submitted for the degree ofEuropean Master of Science, University of London, StBartholomey’s and the Royal London Hospital School ofMedicine and Dentistry London, (promotor: M. TOMSEJ), 2001.

M. TOMSEJ, V. GRÉGOIRE, S. VYNCKIER and P. SCALLIET. Sparingparotids and increasing conformity in H&N treatments: devel-opment of a new conformal technique, description of a QAprogram and first results. Radioth. and Oncol., 31, suppl.1,pp.S45, 2001.

A. MARGOUM. Radiothérapie par faisceaux modulés en intensitédans la région tête et cou : commissionnement et validationdosimétrique. Thèse Physique médicale (promotor : M.TOMSEJ), Janvier 2003.

M. TOMSEJ and al., Quality assurance program for intensitymodulated radiotherapy (IMRT) treatments of head and neckcarcinomas. Cancer/Radiothérapie 7, 2003, 172-178.

M. TOMSEJ and al., Recommandations pour un protocole

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d’assurance de qualité de la radiothérapie conformationnelleavec modulation d’intensité des cancers de la tête et du cou.Cancer/Radiothérapie, 2004, in press.

NCS group, Monte-Carlo Treatment Planning, an introduc-tion. Task group Monte Carlo treatment planning, in press.

Patents

PIGG IMRT phantom (GORTEC), M. Tomsej & V. Marchesi

Awards

Fondation Saint-Luc

Funding sources

Fondation Saint-Luc

Partnership

GORTEC, Groupe Oncologie Radiothérapie Oncologie, international scientific societyNCS (Nederlandse Commissie voor strahling dosimetrie),international scientific societyNRC-CNRC, Research centerNucletron, industrial companyVarian, industrial companySiemens-MRC, industrial company

STAFF

Total: 3

KEY WORDS FOR R&D

head and neck cancerIMRTMonte Carlo calculationstreatment planning

SENIOR SCIENTISTS

Milàn [email protected]. 32 (0)2 764 47 60 (61)

Nathalie DE [email protected]. 32 (0)2 764 47 60

Stefaan [email protected]. 32 (0)2 764 55 73

Vincent [email protected]. 32 (0)2 764 94 43

WEB SITE

www.md.ucl.ac.be/rbnt/pages/MTomsej.htm

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Psycho-oncology - Physician-Patient relationships -Communication skills training - Quality of life - Professionnalstress - Burnout

SENIOR SCIENTISTS :

� Christine REYNAERT � Pierre SCALLIET � Yves LIBERT

I 1


Cancer diagnosis, treatment and follow-up provoke highlyemotional reactions and lead to various coping strategiesexpressed by patients, their relatives and clinicians. The mainaim of psycho-oncology is to study these psychological andbehavioural reactions.

In the last decades, a lot of attention has been devoted to thestudy of patients’ and relatives’ ways of coping with cancer.Predictors of these ways of coping and of their consequences interms of quality of life and sometimes in terms of life expectancyhave been described. Moreover, psychosocial interventions devo-ted to improve their adjustment to cancer have been developed.

Numerous studies have also focused on oncologists’ professio-nal quality of life and on their ways of coping with professionalstress. These studies have highlighted numerous stress factorsassociated with practice in oncology that could lead to burnout. Among these factors, relationships with patients and thefeeling of being insufficiently trained in communication skillshave been widely underlined.

Consequently, specifically designed communication skills trainingworkshops have been developed and assessed. These research pro-grams have highlighted that only training techniques such as role-playing, case-discussion or feed-back could lead to significant chan-ges in physicians’ behaviours. Previous studies have moreover sug-gested that the benefit of these workshops could be transient andnot observed in physicians’ everyday practice. However, no studieshave yet assessed the efficacy of post-training consolidation works-hops following a basic training in communication skills.

The present project intended to explore the conditions of an opti-mal communication skills training program by assessing its effecti-veness directly on changes in physicians’ communication skills aswell as on changes in their patients satisfaction with care.

Funding Sources

Fonds national de la recherche scientifique (FNRS) – Télévie

Partnership

Université Libre de Bruxelles Université de Liège


REYNAERT CH., LIBERT Y., JANNE P., “Psychogenèse” du can-cer : entre mythes, abus et réalité. Bull Cancer., 2000; 87 :655-64.

REYNAERT CH., LIBERT Y., JANNE P., “Psychogenèse” du cancer :vers une piste psycho-neuro-endocrino-immunologique ? Ann.Med. Psychol., 2001, 159, 273.

REYNAERT CH., LIBERT Y., JANNE P., ZDANOWICZ N. Commentallez-vous, Docteur ? Le burn-out du médecin. Louvain Médical,2001; 120 : 296-310.

LIBERT Y., CONRADT S., REYNAERT CH., JANNE P., TORDEURSD., DELVAUX N., FONTAINE O., RAZAVI D. Améliorer les straté-gies de communication des médecins en oncologie : état deslieux et perspectives futures. Bull. Cancer. 2001; 88: 1167-1176.

JANNE P., TORDEURS D., MICHAUX G., GHISLAIN M.C., MAZYS., DE WISPELAERE J.F., LIBERT Y., REYNAERT C. Le cancer du seinet son approche psychologique : la famille, les autres, la chanceet… moi. Gynecol. Obstet. Fertil., 2001; 29 :28-33.

RAZAVI D., MERCKAERT I., MARCHAL S., LIBERT Y., CONRADT S.,BONIVER J., ETIENNE A.M., FONTAINE O., JANNE P., KLASTERSKY J.,REYNAERT CH., SCALLIET P., SLACHMUYLDER J.L., DELVAUX N.How to optimise physicians’ communication skills in cancer care:Results of a randomised study assessing the usefulness of post train-ing consolidation workshops. Journal of Clinical Oncology, 2003;16: 3141-3149.

LIBERT Y., JANNE P., RAZAVI D., MERCKAERT I., SCALLIET P.,DELVAUX N., ETIENNE A.M., CONRADT S., KLASTERSKY J.,BONIVER J., REYNAERT CH. Impact of medical specialist’s ocusof control on communication skills in oncological interviews.British Journal of Cancer, 2003, 88 : 2004-2005.

REYNAERT CH., LIBERT Y., JANNE P., ZDANOWICZ N. Le syndromed’épuisement du soignant ou burn-out syndrome. Approche cogni-tivo-comportementaliste. in Delbrouck M. (Ed.), Le burn-out dusoignant. Le syndrome d’épuisement professionnel, De Boeck &Larcier, 2003; Bruxelles: 37-42.

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REYNAERT CH., LIBERT Y., JANNE P., ZDANOWICZ N. Le stressprofessionnel et les stratégies d’adaptation du soignant. inDelbrouck M (Ed.), Le burn-out du soignant. Le syndromed’épuisement professionnel, De Boeck & Larcier, 2003;Bruxelles: 121-128.

JANNE P., DARRAS E., TORDEURS D., REYNAERT CH.,ZDANOVICZ N., LIBERT Y. Du “burn in” au “burn out” à proposde la réponse du berger malheureux à la bergère ingrate. inDelbrouck M (Ed.), Le burn-out du soignant. Le syndromed’épuisement professionnel, De Boeck & Larcier 2003;Bruxelles: 121-128.

LIBERT Y., REYNAERT CH., RAZAVI D., MERCKAERT I., SCALLIETP., DELVAUX N., ETIENNE A.M., CONRADT S., KLASTERSKY J.,BONIVER J., JANNE P. Impact of medical specialist’s Locus ofControl on communication skills in three-person oncological inter-views, 2004, submitted.

DELVAUX N., MERCKAERT I,. MARCHAL S., LIBERT Y., CONRADTS., BONIVER J., ETIENNE A.M., FONTAINE O., JANNE P, KLASTERSKYJ., REYNAERT CH., SCALLIET P., SLACHMUYLDER J.L., RAZAVI D.Impact of consolidation workshops on cancer specialists’ commu-nication skills in three-person interviews: a randomised study,2004, submitted.

CONRADT S., RAZAVI D., FONTAINE O., LIBERT Y., DUPUIS G.,BONIVER J., MERCKAERT I., REYNAERT CH., JANNE P.,SCALLIET P., KLASTERSKY J., DELVAUX N., ETIENNE A.M. Theimpact of the specialist physician’s communication skills on thecancer patient’s quality of life: A pilot study. Quality of life interms of goal attainment, 2004, submitted.

STAFF

Total : 3

KEY WORDS FOR R&D

applied psychology clinical psychology communication theory emotion and cognition emotion, stress and trauma health psychology human sciences information and communication interpersonal communication medical psychology palliative care professional stress psychology psychosomaticresearch methods in psychology social cognition

SENIOR SCIENTISTS :

Christine REYNAERT [email protected]. 32 (0)81 42 37 51

Pierre SCALLIET [email protected]. 32 (0)2 764 37 63 or 47 26

Yves [email protected]. 32(0)2 539 19 61

WEB SITES

http://www.md.ucl.ac.be/rbnthttp://rch.adre.ucl.ac.be/browse/list_alpha/PSME

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The question of meaning in front of cancerBiographical approach

SENIOR SCIENTISTS :

� Jean-Luc BRACKELAIRE� Michel LEGRAND� Patrick DE NEUTER

I 2


Questioning the place and the meaning of cancer within the“story of life” of the subjects. Device of Biographical Approach(+/- 10 interviews of 2 hours or 20 interviews of 1 hour).

We investigate the possibility of the participation of a psychicsuffering (a relational impasse) on the development and evolu-tion of cancer (in a multifactorial approach).

We question how the subjects, through the story of their life,deploy one discourse which reveals their existential drama –which is sometimes linked with cancer in the related story (evo-cation of one “psychological” origin of the disease).

The research is about how to think this link beetween psychicsuffering and somatic disease (the psychosomatic questioning).


Psychological consultations specialized in “stories of life”


PONCELET V. (2004). Un désespoir amoureux en attente dese dire : récit de vie d’une femme en rémission d’un cancergénital. Cliniques Méditérranéennes, 69, 159-174.

Funding Sources

Insitutional Funding

STAFF

Total : 4

KEY WORDS FOR R&D

biographical approachclinical psychology health psychology meaning medical psychology psychosomaticstory of life

SENIOR SCIENTISTS


Michel [email protected];Tel. 32 (0)10 47 44 70

Patrick DE [email protected]. 32 (0)10 47 90 55

WEB SITE

http://www.ucl.ac.be/cps/cpshistoiresdevie

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Coping styles, anxio-depression, alexithymia and evolutionof breast cancer

SENIOR SCIENTIST :

� Vincent JADOULLE

I 3


Study of the effect of psychological coping styles, depressionand alexithymia on the evolution of breast cancer.

Study of the longitudinal evolution of psychological adaptationto breast cancer.

Validation of the french version of a coping scale.


JADOULLE V., OGEZ D., ROKBANI L. Le cancer, défaite du psy-chisme ? Bull. Cancer., 2004, 91: 249-256.

STAFF

Total : 3

KEY WORDS FOR R&D

alexithymiabreast cancercoping stylesdepressionhealth psychology

SENIOR SCIENTIST

Vincent [email protected]. 32 (0)2 764 21 65

WEB SITE


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The Université catholique de Louvain (UCL) is located on two sites : Louvain-la-Neuve (pure and applied sciences and

human sciences) and Brussels (medical sciences).

The UCL-Brussels site extends on 52 ha and gathers university teaching, higher schools, an academic hospital and

research centers. The site is attended daily by more than 25.000 people.

At the education and research level, the site of UCL-Brussels, built around its Faculty of Medicine and the St Luc academic

hospital, associates multiple approaches around health : medicine, pharmacy, dentistry, public health, biomedical sciences...

Many research institutes of international reputation are also present on the site : the Institute of cellular pathology

(ICP) and the Ludwig Institute for cancer research (LICR), as well as an incubator where various research associations

are working in close relationship with the university and the hospital : EORTC, NCI, ESTRO, FECS, ESSO, ILSI, EONS.

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Cancer Center at UCL and Saint Luc academic hospital

J 1

Mission

Today, individual and isolated physicians no longer succeed inmastering the entire spectrum of knowledge required to deliverappropriate care in oncology.

Oncology has become an immense, multidisciplinary field.Actually, “interdisciplinarity” is a better word since it emphasi-ses the interaction between specialists in the design and imple-mentation of complex sequences of care (surgery, drug therapy,radiotherapy, rehabilitation, etc).

In the academic hospital of the UCL, a cancer centre was esta-blished in 1999, aiming at supporting the development of inter-disciplinary oncology across the entire institution.This transverse structure within the hospital is characterized byan organization focused on organs and systems rather than onindividual specialities.

Activities

Cancer patients often present associated pathologies and maytherefore be diagnosed in departments or units where oncolo-gy is not necessarily the main activity. A hospital of cancer mustbe able to treat the patient as a whole, resorting to consultantsin various oncologic and non-oncologic specialities. To formali-ze coordination between the departments and the specialists, acancer centre was created with three distinct divisions : orien-tation, treatment and research.

The “orientation“ division consists of a series of groups thatbring together the various specialists involved in a particular typeof cancer. Each includes an organ specialist (gynaecologist,ORL,...), a specialized surgeon, a medical oncologist, a radiationoncologist, an imaging specialist, a pathologist and, according tothe cases, a geneticist and any other specialist concerned. 13groups known as “groups of dialogue” are organized :

- group cervico-maxillo-facial cancerology - group tumours of the colon and rectum - group endocrine and thyroid cancerology

- group hematologic cancer - group paediatric hemato-oncology- group hepatobilio-pancreatic cancer- group skin and ocular melanoma- group oesophagus and stomach cancer - group neurological cancerology- group ophthalmologic cancerology- group breast cancer and gynaecology - group thoracic cancerology - group urologic cancerology

The “treatment“division gathers the units of radiation oncology,medical oncology (chemotherapy), palliative care and cancerscreening. These patients already have their treatment plan,determined during a multidisciplinary meeting.

The “teaching and research“ division coordinates the effortsin the field of teaching and research clinic, with the setting upof a coordination of clinical trials.

Methodology

Oncology boards are meant to bring together the various can-cer experts in the hospital, around individual patient cases, inorder to discuss the diagnosis, treatment and follow-up strate-gy that seems the most appropriate. The ultimate goal is tobring homogeneity in the quality of care in oncology at the levelof the hospital.

At regular intervals, depending on the type of cancer, the radiationoncologist, medical and surgical oncologist, pathologist, specialistin imaging, research nurse, psychologist meet to discuss the newcancer cases, diagnosed since the previous board meeting. For fre-quent tumours, like lung cancer, weekly meetings are required. Every individual case is discussed prior to any therapeutic inter-vention. The board makes proposals and a registry is maintai-ned for recording the board decisions. Doctors are seating aspeers and the decisions are collegial.

It is the mission of each board to produce documented proto-cols for diagnosis, treatment and follow-up, the so-called gui-

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delines or SOR (standards, options, and recommendations), andto enforce them in the routine practice.

The principles of operation are based on the collegial structurein the decisions, the correct stadification of all the patients andthe recording of all the data in a computerized way. The treat-ments are applied according to the “guidelines“, strictly andregularly confronted to the data of the literature; the doctors ofthe clinic take part in many clinical studies on the level ofvarious national and international authorities of cancerologicresearch (EORTC, GORTEC,…).

Structure of operation :- investigations necessary to allow a therapeutic decision - standardized staging (TNM). - protocols of treatment used in routine with their limits (age,index of performance, etc). They must be based on the evidence(french SOR, NCI, START...). - research protocols with their eligibility criteria.- recommendations in terms of monitoring (frequency, standardexaminations, patient contact or MT, etc.), including the decen-tralized monitoring. - a multidisciplinary decision-making for each patient, either befo-re or after surgical operation according to the anatomical site.- therapeutic discussion of the attitude at the time of newevents in the oncological history of a patient.- regular update of the protocols (staging and treatment). - discussion of research protocols and assessment.

Partnership

EORTCGELA (groupe d’études des lymphomes de l’adulte)GORTEC (Groupe d'oncologie et radiothérapie des cancerstête et cou)SIOP (Société internationale d'oncologie pédiatrique)

CONTACT PERSON

Prof. Pierre SCALLIETHead of cancer [email protected]. 32 (0)2 764 47 26

ADDRESS

Avenue Hippocrate, 101200 Brussels

WEB SITES

http://www.saintluc.be

http://www.saintluc.be/hospitalisation/dpts-serv/centre_cancer/index.html

http://www.saintluc.be/english/consultation/specialite_eng.php

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The Brussels Branch of the Ludwig Institute for CancerResearch – LICR

J 2

Mission

The purpose of the Ludwig Institute for Cancer Research is toconduct long-range research programmes directed to the ulti-mate goal of eradicating cancer.

The Brussels branch is active in the field of cancer immunologyand cancer genetics. Main orientations of the branch are thestudy of tumor rejection antigens and that of cytokines.

Activities

Cancer is a major concern in human health. The prospects forbringing cancer under control require linked innovative basicand clinical research. In this view, Daniel K. Ludwig created in1974 the Ludwig Institute for Cancer Research, an internationalorganization bringing together scientists and clinicians fromaround the world. Ludwig investigators are active in many areasof science, involving genetics, bioinformatics, immunology,virology, cell biology and signal transduction.

Faithful to the organizing principles laid down by Mr Ludwig, theInstitute conducts its research through ten Branches, located inseven countries. The Branch structure allows the Institute to inter-act with a number of different research and clinical environments.Each Branch is focused on a research program defined by theBranch Director in relation with the overall objectives of theInstitute. The Branches are established in association withUniversity Hospitals, to stimulate close collaborations betweenresearch laboratories and the clinic. By organizing and controllingits own clinical trials programs, the Institute has indeed created acontinuum that integrates laboratory and clinical research.

Branch staffs vary in size from 30 to over 70, and internationallythe Institute employs some 600 scientists, clinicians and supportpersonnel. The quality of the research is monitored on anongoing basis by the Institute’s Scientific Committee and by anexternal peer review process.

The biological properties of any given cancer cell constantlychange, allowing tumors to spread and become more aggressive.

To overcome these obstacles, the Ludwig Institute has develo-ped a broad-based discovery program that seeks to understandthe full complexity of cancer. Research is organized according tothe four major programmatic themes that define the Institute :genetics, cell biology, cell signalling and immunology.

Research fields

Tumor immunology and antigen processing group :www.licr.ucl.ac.be/tiap/tiap.html

Genes expressed in cancer and germline cells group :www.licr.ucl.ac.be/gecgc/gecgc.html

Identification of human tumor antigens group :www.licr.ucl.ac.be/ihta/ihta.html

Analysis of T cell responses of vaccinated cancer patients :www.licr.ucl.ac.be/tcr/tcr.html

Therapeutic vaccination group :www.licr.ucl.ac.be/tvac/tvac.html

Cytokines in immunity and inflammation group :www.licr.ucl.ac.be/jcr/index.html

Signal transduction group : www.licr.ucl.ac.be/stg/stg.html

Partnership with UCL

In 1978 the Ludwig Institute for Cancer Research decided tobase its Belgian branch within the walls of UCL, at the Christiande Duve Institute of Cellular Pathology (ICP). A happy collabo-ration between the two Institutions has been pursued sincethat time. Even though the two Institutes are completely inde-pendent, the collaborations between the scientists of ICP andthe Ludwig Institute is extremely close and the sharing ofresources is considerable.

The Brussels Branch, under the leadership of Thierry Boon, spe-cializes in cancer immunology and cancer genetics. The notionthat the immune system might be enlisted to rid the body of can-cer draws on past work at the Branch which revealed that mosthuman tumors bear antigens that can be recognized by cytotoxicT lymphocytes (CTLs). Some of these antigens are highly tumor-specific, others are expressed on certain normal cells. A number

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of antigens have been found on many different types of tumors,suggesting that a therapeutic strategy targeting such antigenscould be used to treat a wide range of cancers. The Branch conti-nues the search for tumor antigens, and evaluates their thera-peutic potential in vaccine trials of cancer patients.

The Brussels Branch is also involved in research on the immuno-logical functions of several cytokines, particularly IL-9 and IL-22,which have been discovered at the branch. Signal transductionby certain cytokine receptors is also under intense study.

STAFF

Total : 85

CONTACT PERSONS :

Prof. Thierry [email protected]. 32 (0)2 764 75 80

Dario [email protected]. 32 (0)2 764 73 34

ADDRESS

Avenue Hippocrate, 74 (building 7459)1200 Brussels

WEB SITES

http://www.licr.ucl.ac.be/http://www.licr.ucl.ac.be/tiap/tiap.htmlhttp://www.licr.ucl.ac.be/gecgc/gecgc.htmlhttp://www.licr.ucl.ac.be/ihta/ihta.htmlhttp://www.licr.ucl.ac.be/tcr/tcr.htmlhttp://www.licr.ucl.ac.be/tvac/tvac.htmlhttp://www.licr.ucl.ac.be/jcr/index.htmlhttp://www.licr.ucl.ac.be/stg/stg.html

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European Society for Therapeutic Radiology andOncology – ESTRO

J 3

Mission

The European Society for Therapeutic Radiology and Oncology,ESTRO, was founded in Milano in September 1980 as a Societyof individual members working in the field of radiotherapy andoncology.

Its principal objectives are to :

Foster radiation oncology in all its aspectsDevelop benchmarks, tools and methodologies for assuring

the quality of radiation oncology in Europe and stimulate theirimplementation in clinical practice

Improve the standards of cancer treatment by enscribing radiationoncology as a clinical specialty in the multidisciplinary approachto cancer treatment

Promote international exchange of scientific information onradiotherapy & oncology and related fields of science such asradiophysics and radiobiology and stimulate research

Develop guidelines for education and best practice in radia-tion oncology and associated professions

Establish relationships and co-operation with international,regional and national societies and bodies in the field of radiationoncology.

Activities

ESTRO imbedded in its early years in the UZ KULeuven hospi-tal environment, moved in 1997 to the UCL site to join othercancer societies such as EORTC and FECS already establishedthere.

ESTRO’s core activities are articulated in its mission statement.Besides activities for the exchange of scientific information and forthe education and training of radiotherapy professionals, as evi-denced below, ESTRO has generated with support from various EUprogrammes, a broad range of initiatives for the development ofguidelines and infrastructures for the surveillance of the quality inRT, for drafting best practice guidelines and encouraging researchfor the optimisation of radiation oncology.

ESTRO scientific meetingsEach year, ESTRO organises several scientific meetings, revie-wing advances in radiotherapy and oncology and encouraginga multidisciplinary approach to the treatment of cancer.

ESTRO education programThe society’s continuously evolving and expanding offer ofcourse modules is designed to assist national radiation oncolo-gy, medical physics and radiation technologists’ societies in theprovision of adequate teaching for the topics described asmandatory in the European curricula developed by it. Graduallyalso the offer in the field of continued professional develop-ment is being built up and broadened.

The ESTRO teaching courses play an important role in thegrowing cohesiveness of the European radiation oncology com-munity. By adding a European dimension to the education ofyoung professionals, mobility within Europe is both encouragedand supported. The ESTRO Board also recognised the impor-tance of exchange and transfer of expertise by committingresources to the extremely successful Technology Transfer GrantProgramme for short visits to other departments which, in pre-vious years, was funded by the European Commission


Besides its geographical proximity to the UCL Faculty ofMedicine campus as a tenant in an UCL-owned building, ESTRObecame closely associated with its ”landlord” through the acti-ve involvement of department heads and other professionals ofthe UCL radiation oncology department in ESTRO structuresand activities.UCL experts have served or still function as members of ESTROscientific, website and education committees, are active asmembers of the society’s international teaching faculty, coordi-nators or co-partners in ESTRO projects, co-editor of its journaland other publications. Finally they served in the ESTRO Boardas secretary and executive administrator.

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STAFF

International Board : 15Staff onsite : 12

CONTACT PERSON

Michel TAILLETExecutive Director [email protected]@estro.beTel. 32 (0)2 775 93 40

ADDRESS

ESTROAv. E. Mounierlaan 83B-1200 Brussels

WEB SITE

http://www.estro.be

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Federation of European Cancer Societies – FECS

J 4

Mission

Promote and co-ordinate collaboration between Europeansocieties active in the different fields of cancer research, pre-vention and treatment, with the ultimate goal of providing thebest possible treatment and care for all European cancerpatients.

Activities

Promotion of continuing medical education (CME) through thedevelopment of various CME activities (conferences, works-hops) and acceptance of the FECS accreditation system of CMEin oncology (ACOE) throughout Europe and the USA for amutual recognition of CME credits.

Promotion of the implementation throughout Europe of a mul-tidisciplinary approach in oncology through the establishmentof platforms for scientific exchanges such as ECCO, theEuropean Cancer Conference, the support of the developmentof guidelines on quality cancer care and the setting up of stan-dards for education and training in oncology.

Support of special projects of European dimension and multi-disciplinary nature, in collaboration with other organisations.

Communication with the authorities (European institutions),health care providers, the public and patients’ organisationsthrough the provision of reliable information based on researchresults and scientific data, the release of position statements onspecific cancer related issues in order to contribute to theEuropean legislation and policies, the development of proposalsto ensure the provision of sufficient support in Europe for onco-logy; the enhancement of the dialogue with national and inter-national organisations and authorities.

Contribution to the drafting process of EU research frameworkprogrammes and participation as co-ordinator or as partner inmultidisciplinary projects gathering organisations involved inoncology.

Activities in the field of the EU Public health programmes toraise awareness among public health authorities about dispari-ties and unequal access to quality care across European regionsand to suggest ways to build on existing European strengths inthe field of oncology for improving research synergies andpublic health strategies (implementation of medically significantprogress through an open but strictly co-ordinated network ofexperts and centres of excellence across Europe).


The partnership of FECS with UCL is mainly through the mem-bership of its member societies, some of which are also esta-blished onsite like ESTRO, ESSO, EONS or EORTC.

FECS workshops and Standing Committees welcome physiciansfrom the UCL and organisations established onsite to activelycontribute to the implementation of its mission and objectives.

In addition, their participation in conferences organised by theFederation, in particular ECCO, the European CancerConference, either as faculty members, speakers or participantscontribute to further develop interactions with UCL.

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STAFF

Total onsite : 13

CONTACT PERSONS

Harry [email protected]. 32 (0)2 775 29 31

Kathleen VANDENDAELExecutive [email protected]. 32 (0)2 775 29 31

Stuart BELLCommunication [email protected]. 32 (0)2 775 02 07

Kris VANTONGELENConference and Programme [email protected]. 32 (0)2 775 02 06

Françoise VAN HEMELRYCKProject [email protected]. 32 (0)2 775 02 03

ADDRESS

Avenue E. Mounier, 831200 Brussels

WEB SITE

http://www.fecs.be

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European Organisation for Research and Treatment ofCancer – EORTC

J 5

Mission

Establishing new standards of cancer care with high-qualityresearch

Activities

The European Organisation for Research and Treatment ofCancer (EORTC) is an international association under Belgianlaw, created in 1962 by prominent European cancer specialists.The aims of the EORTC are to promote, coordinate, analyze andpublish cancer research performed by multi-disciplinary groups ofclinicians and scientists in Europe. These research groups includesurgeons, radiotherapists, chemotherapists, pathologists, immu-nologists, basic researchers and numerous other specialists as wellas health care professionals. The ultimate goal of the EORTC is toestablish state-of-the-art cancer treatment to improve survival rate,quality of life and quality of care for all patients with cancer. The EORTC is primarily devoted to : -Translational research and clinical studies, to evaluate newanti-cancer agents including cytotoxic drugs but also innovativeagents as well as modalities such as vaccines, biological respon-se modifiers and other novel treatments resulting from break-through discoveries in genomics etc... - High-quality clinical research, to establish optimal therapeuticstrategies via large multi-center clinical studies in a multidisci-plinary approach leading to state-of-the-art treatment and qua-lity of cancer care.

The EORTC headquartersThe headquarters play a coordinating role in all activities anddeal with the scientific, legal and administrative issues relatedto the EORTC. The Central Office, the Data Center, theEducation Office and the Cancer Communications Office are alllocated in the EORTC headquarters, in Brussels.

Progress in the treatment of cancer requires high quality researchThe EORTC is collaborating with the pharmaceutical industry todecrease the time needed to develop new anti-cancer agentsand to minimize the delay between laboratory discoveries andtherapeutic benefit for patients.

After testing promising agents in the laboratory and on animals,the next step is testing on humans; these clinical studies will deter-mine whether or not a new anti-cancer agent will be registered,i.e. approved by health authorities and then marketed.

The EORTC also promotes and funds translational research onnew compounds/concepts discovered in universities and privateresearch institutions. In this way, it facilitates the passage ofexperimental discoveries into state-of-the-art treatment.

Evaluation of the best therapeutic approaches and developmentof new standards of cancer careEORTC clinical groups, are dealing with a specific type of cancer(breast cancer, lung cancer, gastrointestinal cancer, genito-urinarytract cancer, leukemia, soft tissue and bone sarcoma and others)or therapeutic modality (radiation therapy, chronotherapy).These groups conduct large clinical trials to quickly assess a sufficientnumber of patients for the results to be statistically meaningful,convincing and widely applicable and thereby to have maximumimpact on the quality of cancer care. These results are analyzed in ascientific, objective and independent manner at the Data Center.All studies are conducted according to national legal and ethi-cal requirements as well as to the international Guidelines ofGood Clinical Practice.All EORTC research projects and clinical studies are peer revie-wed and have to be approved by the relevant committee inclu-ding the protocol review committee.

The EORTC Data Center, a unique center of excellence in EuropeOverall, there are more than 6.500 new patients treated eachyear according to EORTC protocols.All research observations made by EORTC members are forwar-ded to the EORTC Data Center which comprises more than 100staff members (14 nationalities) including medical doctors, sta-tisticians, quality of life specialists, health economists, lawyers,other scientific and administrative staff, computer specialists, aswell as research fellows and health care professionals.The Data Center’s methodology (working procedures andStandard Operating Procedures) to evaluate new anti-canceragents and to conduct clinical studies was filed at the Food andDrug Administration in 1998. This greatly facilitates the sub-mission of EORTC clinical data for drug registration in the USA.The Data Center computerized clinical trials management system

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(VISTA) interfaces with the EORTC website. The central registrationand randomisation server (ORTA) allows clinicians to enroll theirpatients into EORTC clinical studies 24 hours a day. E-forms is aremote data entry system developed by the EORTC. A permanent Independent Data Monitoring Committee reviewsthe status of clinical trials and makes recommendations on safetyand efficacy leading to trial’s continuation, modification and/or dis-continuation.Quality control procedures are conducted by the QualityAssurance Unit in collaboration with the Quality AssuranceCommittee. The overall functioning of the groups is conductedby the Scientific Audit Committee. The activities of the EORTC Data Center are evaluated regular-ly by a committee of experts from the National Cancer Institute(NCI) of the USA. These assessments have always been verypositive and the financial support allocated to the EORTC DataCenter by the NCI has been continuous since 1974.Other sources of funding for the Data Center are the EORTCFoundation, the Fondation Cancer, corporate sponsorship, privatedonations and The National Lottery of Belgium. In addition, sup-port is provided by the pharmaceutical industry (for clinical studieson new anti-cancer agents performed in cooperation with theEORTC) and occasionally by the European Commission (for speci-fic research projects).The EORTC has initiated an European tumour bank project toimprove and harmonise the histological review and the use oftelepathology, which will also facilitate translational research inthe context of EORTC trials, by providing rapid access totumour tissues and to clinical databases.

“Strength through unity”The EORTC is a unique research network which coordinates theresearch of about 2000 European clinicians and scientists andworks in more than 300 university hospitals or affiliated institu-tions located in 32 countries.There is a true need to promote participation of all partners inclinical trials in Europe and worldwide. Therefore the EORTC isalso actively involved in intergroups studies. The Intergroup offi-ce deals with all logistic, legal and methodological issues toenable inter-group collaboration.

Publication of the results of EORTC researchEvery year, the EORTC has hundreds of scientific articles publis-hed in prestigious international journals and over 250 scientificcommunications are presented at international scientific mee-tings.This wide dissemination of EORTC studies plays a crucial role inassuring optimal treatment of all patients including for thosetreated outside research oriented institutions.


In 1972, the National Cancer Institute established its liaison officeadjacent to the EORTC headquarters on the UCL campus, inBrussels.

Scientific collaborations with St Luc Hospital and LudwigInstitute.

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CONTACT PERSON

Françoise MEUNIERDirector [email protected]. 32 (0)2 774 16 30

ADDRESS

Avenue Emmanuel Mounier 83, bte 111200 Brussels (Belgium)

WEBSITE

http://www.eortc.be

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European Society of Surgical Oncology – ESSO

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Mission

The mission of the European Society of Surgical Oncology,founded in 1981, is to advance the art, science and practice ofsurgery for the treatment of cancer.

Activities

By arranging scientific conferences, professional exchanges andseminars, ESSO endeavours to ensure that the highest possiblestandard of surgical treatment is available to cancer patientsthroughout Europe. It aims at fostering multi-disciplinary collabo-ration in the clinical management of cancer patients.

ESSO is increasingly involved in the training of surgeons con-cerned by cancer care throughout Europe and in promoting thedevelopment of guidelines of good practice in cancer surgery.

The Society also seeks to promote knowledge and educationabout cancer care and to facilitate basic and clinical research inoncology.

ESSO publishes the European Journal of Surgical Oncologyten times a year and grants fellowships to facilitate internation-al exchanges of surgeons specialising in oncology.

STAFF

Over 1000 membersBoard composition : see web site

CONTACT PERSON

PILKIEWICZ [email protected]. 32 (0)2 537 31 06

ADDRESS

Avenue Emmanuel Mounier, 83B 1200 Brussels

WEB SITE

http://www.esso-surgeonline.be

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International Life Sciences Institute – ILSI Europe

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Mission

To improve the well-being of the general public through thepursuit of balanced science.

ILSI Europe aisbl, European Branch of the International LifeSciences Institute, is a non–profit, worldwide foundation thatpromotes collaboration among industry, academia, governmen-tal institutions and consumer groups and provides a neutralforum for members of the scientific community to discuss andresolve issues of common interest.

Activities

Most of our activities are in nutrition and food science, somerelate to oncology. One of the Institute´s Task Forces addressesthe risk assessment of genotoxic carcinogens in foods.Background is that food may often be unavoidably contamina-ted with low levels of genotoxic carcinogens.

A theme group in the EC-sponsored PASSCLAIM project(Process for the Assessment of Scientific Support for Claims onFoods) also addresses diet-related cancer. Aims of this activityare: to collate potentials types of health claims in this area, todevelop a list of criteria to justify these claims, and to assess thesuitability of available markers.

Acrylamide is a chemical that can be produced in starch-richfoods that are prepared at high temperatures, such as crispsand French fries. In animal studies acrylamide was shown to becarcinogenic. ILSI Europe´s Acrylamide Task Force develops aframework for the assessment of the risk for men of acrylami-de in food.

Natural toxins addressed in one of the Task Forces includepotentially carcinogenic ones. Likewise, potentially carcinogenicchemicals are among those targeted in the Task Force on RiskAssessment of Chemicals and the FOSIE (Food Safety in Europe)EC project.


Scientific experts (including UCL staff) provide their expertiseto our working groups on an ad hoc basis.

Date of implantation on the UCL site : 1987.

STAFF

Total onsite : 20

CONTACT PERSON

Nico van BelzenExecutive [email protected]. 32 (0)2 771 00 14

ADDRESS

Avenue Mounier 83, 3rd Floor1200 Brussels

WEB SITE

http://europe.ilsi.org

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European Oncology Nursing Society – EONS

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Mission

The mission of the European Oncology Nursing Society (EONS)is to add value to the work of its individual members and socie-ties in delivering care to patients with cancer. It aims to assist inthe promotion of developing healthy communities throughinfluencing, research and education.

Activities

EONS has developed a strategic plan which aims to establish asolid foundation for the future serving to set direction and prio-rities for the organisation. The goals set out in this strategy are related to :

EducationEONS will develop and implement, in collaboration with members,post basic education and continuing education designed to impro-ve knowledge and competence in agreed areas of cancer nursing.In order to achieve this, EONS will act as a platform for multi-disciplinary exchanges at both scientific and educational level; itorganises and develops educational events and will pursue thework on accreditation.EONS will also be active in the support and implementation ofguidelines, recommendations and in the development of theframework of oncology nursing training programs.

CommunicationEONS, as the recognised representative of European oncologynurses at the Federation of European Cancer Societies (FECS),furthers and facilitates communication between EONS and itsmembership, as well as the communication between the diffe-rent member societies.EONS strives to provide a unified voice for Member Societies, toincrease the visibility of Member Societies and support theiractivities, to increase multidisciplinary exchanges at both clini-cal, scientific and educational level.This through the EONS Newsletter and the scientific journal,The European Journal of Oncology and our new website provi-ding more information about EONS and its activities as well asnew opportunities of communication.

ResearchEONS will collaborate with member societies and key stakehol-ders to raise the profile of oncology nursing research in Europe.It will have a facilitative role helping others to initiate researchthrough guidance with funding issues, mentoring, publicationand dissemination of results.

Influencing the political agendaEONS will assist and support members to lobby for recognisedstandards of oncology training / education, through recognitionof oncology nursing as a speciality within each membershipcountry.

EONS will provide current information to (inter)national profes-sional representatives to raise the knowledge and awareness ofthe contribution of cancer nurses in Europe.


Partnership through the membership with FECS (Federationof European Cancer Societies).

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STAFF

Onsite : 2

CONTACT PERSONS

Jan [email protected]. 32 (0)476 39 61 48

Rudi BRIKÉSecretariatTel. 32 (0)2 779 99 23

ADDRESS

Avenue Mounier 83/8B 1200 Brussels

WEB SITE

http://www.cancereurope.org/eons

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The U.S. National Cancer Institute Liaison Office – NCI L.O.

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Mission

The US National Cancer Institute is the US FederalGovernment’s principal agency for cancer research and training.It coordinates the National Cancer Program, which conductsand supports research, training, health information dissemina-tion and other programs with respect to the cause, diagnosis,prevention, and treatment of cancer.

The NCI Liaison Office was created in 1972 and was initially partof NCI’s Division of Cancer Treatment & Diagnosis. It is now anintegral part of the Office of International Affairs. It facilitatesthe interchange of information, ideas, experimental drugs, sci-entific expertise and scientists, and works in close collaborationwith the EORTC, the Cancer Research Campaign (CRUK), aswell as with other European cancer research institutes andpharmaceutical/chemical industries, in areas of mutual interestin preclinical and clinical cancer research. Recently, the collab-oration has been extended to closer interactions with theInternational Network for Cancer Research & Treatment, INCTR,a unique organization dedicated to helping patients in devel-oping countries, which is also located in Brussels and partiallysupported by the NCI’s Office of International Affairs.

The NCI Liaison Office is the European hub for NCI’s TELESYN-ERGY® Medical Consultation WorkStation, which wasinstalled in March 2004. The Telesynergy Workstation allowsnumerous research collaborators at greatly separated geo-graphic sites to interact as if they were in the same room, view-ing the same medical images. By integrating powerful telecom-muniations technology into health care research and delivery,telemedicine enables clinical researchers to simultaneouslycommunicate and view and manipulate data necessary for col-laborations, including patient diagnosis and care, such as x-rayfilms and pathology samples.

Activities

The Office provides a European contact point for NCI and theEuropean cancer research community, and assists NCI staff inmatters related to European collaborations and cancer researchprograms.

It acts as a link between NCI headquarters in Bethesda (USA)and EORTC, CRUK, SENDO and other European cancer researchorganizations and Institutes (i.e. the Mario Negri Institute inItaly, the Max-Delbrück Zentrum in Germany) as well as theEuropean pharmaceutical/chemical industries.

For more than 25 years the Office has assisted with the inter-national exchange of experimental drugs for preclinical andclinical evaluation. A web-based submission process for newpotential anti-cancer compounds to be tested in NCI’s in-vitroscreen has been made available via the NCI DevelopmentalTherapeutics Program (DTP) website (http://dtp.nci.nih.gov),and the NCI L.O. assists European suppliers with inquiries of allkinds related to the submission and selection of their com-pounds.

The Office collects, submits and updates European cancerresearch protocols for the International Cancer InformationCenter (ICIC), NCI, for inclusion in NCI's clinical databasePDQ/CancerNet. The office actively seeks new European groupswith an interest to submit their research protocols toPDQ/CancerNet, and assists them with the fullfilment ofrequirements for exemption from further protocol review by theNCI PDQ Editorial Board. It coordinates the additional review of EORTC PhIII protocol out-lines by selected NCI specialists.

Through the NCI Liaison Office, the NCI is represented on vari-ous European committees involved in new drug development,as well as on the EORTC Board and Council and the CRUK PhI/IIclinical trials committee. It participates in European workinggroups that disseminate cancer research and drug developmentinformation throughout Europe, and is also an observer on theEuropean Drug Development Network (EDDN).

The office assists with the organization of joint NCI-Europeanmeetings and symposia, and it coordinates the use of therecently installed TELESYNERGY® MEDICAL WORKSTATION

TELESYNERGY® MEDICAL WORKSTATION

Researchers of the National Cancer Institute and the Center forInformation Technology of the U.S. National Institutes of Health

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developed TELESYNERGY®, a telemedicine system with broad-cast-quality multi-site teleconferencing capabilities that is alsocapable of transmitting most types of diagnostic-quality med-ical images. By making the knowledge and experience ofoncology experts accessible regardless of where in the worldthose experts are, TELESYNERGY® has the potential to dramat-ically accelerate cancer research and improve cancer care byfacilitating unique collaborations and connections.

Note : The TELESYNERGY® Workstation is available to outsidecollaborators for a very low cost. For further information pleasefeel free to contact the NCI Liaison Office.


Through the collaboration with EORTC (EuropeanOrganization for Research and Treatment of Cancer)

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Onsite : 3

CONTACT PERSON

Susanne RADTKEPrograms [email protected]@eortc.beTel. 32 (0)2 772 22 17

ADDRESS

Av. E. Mounier 83B-1200 Brussels

WEB SITES

http://www.cancer.govhttp://www.cancer.gov/oia

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academic studies E1

accelerator technology H2

acute leukemia C4

air pollutants A1

alexithymia I3

allogenic graft E3

allografts G2

AML E2

AMP-activated protein kinase B8

anatomopathology G2

angiogenesis D2, F3

animal cell culture B9

anthracyclines B10

antigen processing B5

antigenic peptide B4

antioxidant enzyme B9

apoptosis B10, F7

applied psychology I1

applied statistics A4

autoimmunity C5

autologous cell therapy G2

bacteriology G2

beam H2

biochemistry B5, B6, B8

biocompatibility D2

biographical approach I2

biological dosimetry H1

biomarkers A1

biomaterials D2

biomechanic G2

biomedical and agricultural sciences B7

biomedical engineering D2

biophysics D2, B10

biosensors D2

blood flow F3

bone induction G2

bone remodeling G2

brain tumor C1

breast cancer B11, I3

calcium F7

cancer therapy H2

cancer treatment F1

cancer vaccines B5, B6

carbon ion beams H2

cDNA subtraction B4

cell biology B1

cellular biology B8

cerebral tumor F4

CGH (comparative genomic hybridization) C1

chemoprevention A3

chemotherapy D2, E1, F3, F6

clinial hadron beams H1

clinical biology C3

clinical chemistry C3

clinical medicine E2, C3, C4, E3

clinical psychology I1, I2

clinical trials, drug evaluation A4, E1, F5

communication theory I1

confocal microscopy B1

contrast agents D3

coping styles I3

cortical development B2

cryopreservation G1

crystallization B9

cytogenetics B3

cytology B8, F6

cytolytic T lymphocyte B4, F1

cytoskeleton B8

delayed-union G2

depression I3

diagnosis C3, C4, F6

differentiation B8

diffuse lymphoma E2

diffusion imaging D3

diffusion tensor imaging processing D1

dioxins A1

Key Words Index

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DNA C6

DNA (micro)arrays C1, C6

DVH H2

electron microscopy B1

emotion (cognition stress and trauma) I1

endocytosis B1

environmental medicine B7

ependymoma C1

epidemiology A4, H2

epitope B4

EPR D2

Epstein Barr Virus EBV A2

fluorescence F7

follicles G1

food contaminants A1

fractionation B1

fracture G2

free radicals D2

functional imaging D2

gastroenterology, liver A3

gene expression C4

gene therapy F3

growth factors F7

gynecology A5, F8

head and neck cancer H3, H4

health- and medical statistics A4

health psychology I1, I2, I3

heavy metals A1

hematology B3, C2, C4, E2, E3

hemodynamics D2

hepatocellular carcinoma D3

high LET radiation H2

high LET radiobiology H2

histology F6

histopathology B7, F4

Hodgkin E3

hovon E2

hox B11

human sciences I1

hypoxia F3, H3

IDO inhibitors B6

IFM E3

image processing D3

imaging, radiology, tomography D2, D3

Imatinib E2

immune escape B6

immunology B5, B6, F1, F5

immunophenotype C4

immunosuppression A2

immunotherapy B4, B5, B6, F1, F3, F6

IMRT H4

inducible melanoma model B6

infection G2

information and communication I1

internal medicine F6

interpersonal communication I1

intratumoral infusion F4

ion beams H2

late tissue reactions H2

leukemia C2

life-cell imaging B1

limb salvage G2

liver tumors A3, D3

LOH (loss of heterozygosity) C1

lung cancer F6

lymphoid malignancy B11

lysosomes B10

magnetic resonance imaging D3

meaning I2

medical genetics A5

medical psychology F8, I1, I2

medicine human pathology B7

membrane B1, B10

metabolism H3

microarray B4

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microdosimetry H2

molecular and cellular biology B10

molecular and cellular pharmacology B10

molecular biology A5, B1, B3, B7, C2, C4, F6

molecular diagnostic C6

molecular genetics B7, C1

Monte Carlo calculations H4

motility B1, B8

MRI D2, H3

multidisciplinary approach F8

multi-modal registration D1

myeloma E3

myosin light chain kinase B8

nephrology-urology B7

neurological diseases C5

neurology F4

neuronal migration B2

neuropathology F4

neuroradiology F4

neurosurgery F4

nitric oxide D2, F3

NMR D2

occupational medicine, preventive medicine A4

ocular melanoma C1

oligodendroglioma C1

onconeural antigens C5

organic chemistry B7

orthopaedic G2

ovary G1

oxygen D2

palliative care I1

paraneoplastic disorders C5

particular pathology F8

pathology A5, B7

PCBs A1

pediatric transplantation A2

perfusion imaging D3

peroxidase activity B9

PET H3

pharmaceutical chemistry B7

pharmaceutical sciences B10, F2

pharmacognosy F2

pharmacology D2

pharmacotherapy A4

phase I/II E2

post transplant lymphoproliferative diseases A2

prevention medicine B7

professional stress I1

prognosis C4

proliferation B8, H3

pronostic factor of molecular markers F6

prostate cancer C6, F7

proteasome B5

protein purification B9

proto(oncogenes) B1

psychology I1

psychosomatic I1, I2

pulmonology F6

radiation H1

radiation therapy H2

radiobiological calibration H1

radiobiology H2

radiosensitivity D2

radiotherapy D2, E1, F3, H3

randomization E2

RBE H2

realtime PCR C2

recombinant chimeric protein TP38 F4

recombinant protein B9

recurrent multiforme glioblastoma F4

reelin B2

Relative Biological Effectiveness (RBE) H1

research methods in psychology I1

resistance B10

risk assessment A1

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RNA C6

scanning beam H2

separation techniques F2

simulation H2

slice culture B2

smal cell lung carcinoma C5

social cognition I1

socio-economics H2

spectroscopy D2

spin trapping D2

statistics E1

stem cell transplantation E2

stereotaxy F4

STI571 E2

story of life I2

stress fibers B8

structural chemistry F2

surgery F4, G2

surgical medicine F4, F6

tracers H3

transcription factors B11

transfection vectors B9

translocations C2

transplantation G2

treatment F6

treatment planning H2, H4

tridimensional structure B9

tumor B4, D2

tumor antigens B5, B6, F1, F5

tumor cells B10

tumor marker C6

tumor vasculature F3

vaccination F5

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CANCEROLOGY AT UCL 2004 - Université catholique de Louvain · cancerology at ucl 2004 ......

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Transcript of CANCEROLOGY AT UCL 2004 - Université catholique de Louvain · cancerology at ucl 2004 ......