Pan Arab Journal of Oncology - CiteSeerX

Pan Arab Journal of Oncology

Effect of radiotherapy on malignant

pleural mesothelioma in adjuvant,

radical or palliative basis.

Original ArticlesProteomic approach for the detection of

breast cancer biomarkers.

ISSN: 2070-254X

new publication

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | December 09

Special Report: COMO 8 | Nov 2009 | Beirut, Lebanon

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www.amaac.info Pan Arab Journal of Oncology | vol 2; issue 3 | December 09 < 1

¼ Editor-in-ChiefMarwan Ghosn, MD, MBA / MHM> [email protected]> [email protected]

¼ Deputy EditorSami Khatib, MD> [email protected]

¼ Associate EditorsKhaled Al-Saleh, MD> [email protected]

Jamal Khader, MD> [email protected]

Hussein Khaled, MD> [email protected]

Nazar Makki, MD> [email protected]

¼ Design & LayoutZŽ na Khairallah> [email protected]

¼ PAJO Editorial Board> [email protected]

ISSN: 2070-254X

Pan Arab Publishing Company P. O. Box: 2509 Amman 11953 - Jordan Beer Al SabeÕ St Shocair Medical Complex 2nd Fl, office No. 201 Phone + 962 6 566 78 53 Fax + 962 6 562 38 53 www.e-pamj.com

AMAAC Introduction > 2International Advisory Board > 3Editorial > 4 Special Thanks > 5

Original Articles ¼ Analysis of the effect of radiotherapy on malignant pleural mesothelioma when given on adjuvant or palliative basis Hesham A. El Hossieny et al. > 6 - 10 ¼ Proteomic apprroach for the detection of breast cancer biomarkers using two dimensional gel electrophoresis and mass spectrometry Bechr Hamrita et al. > 12 - 15 ¼ Risk of ovarian cancer in breast cancer patients- prognostic factors and time interval Noha Ibrahim et al. > 16 - 19 ¼ Cisplatin and Vinorelbine in unresectable malignant pleural mesothelioma Nivine Gado > 20 - 23

COMO 8 > 24 - 39

Meeting Highlights ¼ The First GCC & Middle East Highlights > 40 - 41 ¼ Workshop Colorectal Cancer & GIST > 42 - 44 ¼ The 2nd KHIBC MENA Cancer Research Conference > 45 - 46 ¼ The First Sudanese Oncology Conference > 47

News from the Arab World > 48 - 58 ¼ The 4th Middle East Best of CTRC-AACR ¼ The 2nd Annual Kuwait Breast Diseases and Oncoplastic Reconstructive Surgery Conference ¼ Francophones d'Oncologie MŽ dicale ¼ The 5th SEMCO-ASCO Conference ¼ Initiative to improve Cancer Care in the Arab World ¼ First EURO-ARAB Congress ¼ The 3rd Regional Congress of Cancer and Blood Disorders of Childhood ¼ International Symposium on New Frontiers in Breast Cancer ¼ Conference on Topics in Therapeutic and Diagnostic Medical Physics ¼ The 10th Pan Arab Cancer Congress ¼ The 7th International Jordan Oncology (JOS) Conference

Call for abstracts > 59

Cancer Awareness Calendar > 60

Instructions for Authors > 61 - 64

editorial board < contents <

Pan Arab Journal of Oncology | vol 2; issue 3 | December 09 www.amaac.info2 >

AMAAC Introduction

The Arab Medical Association Against Cancer (AMAAC) is a medical body that was established in 2001 as part of the Arab Medical Association where its main office is located in Cairo - Egypt, and it is also a continuation of the Arab Council Against Cancer that was founded in 1995. The Executive Committee of (AMAAC) is represented by two members who are named officially by the Oncology Society of each Arab Country.

The Arab Medical Association Against Cancer aims at strengthening relationships between members in different Arab Countries to raise the level of cooperation in the field of oncology on both scientific and practical aspects. Exchanging information and researches between members through Regional and Arab Conferences and Publications. Holding Public Awareness Campaigns in the field of oncology that are organized by Arab Countries. Participating in scientific activities with International Oncology Societies. Finally, encouraging researchers and doctors to meet and exchange experiences together with finding training opportunities in the field of oncology inside and outside the Arab World.

> The Executive Board of AMAAC

Sami Khatib, MD (Jordan) Secretary General Hussein Khaled, MD (Egypt) Associate Secretary General Maha Manachi, MD (Syria) Associate Secretary GeneralKhaled Al-Saleh, MD (Kuwait) Associate Secretary GeneralBrahim El Gueddary, MD (Morocco) Associate Secretary GeneralSaid Al-Natour, MD (Jordan) Associate Secretary General (for financial affairs)

> The officially nominated members of AMAAC by the Oncology Societies of Each Country

Algeria Adda Bounedjar, MD Kamel Bouzid, MD

Bahrain Abdulla Ajami, MD

Egypt Hussein Khaled, MD Sherif Omar, MD

Iraq Abdul MonÕ em Ahmed, MD Nezar Taha Maki, MD

Jordan Sami Khatib, MD Said Al-Natour, MD

Kuwait Khaled Al Khalidi, MD Khaled Al Saleh, MD

Lebanon Marwan Ghosn, MD Nagi El-Saghir, MD

Libya Hussein A Hashemi, MD Rammah Rumaihi, MD

Morocco Ashraki Abdel Kader, MD Brahim Khalil El Gueddari, MD Oman Bassim Bahrani, MD

Palestine Fuad Sabatin, MD Abdel Razaq Salhab, MD

Saudi Arabia Om Al Kheir Abu Al Kheir, MD Shawki Bazarbashi, MD

Sudan Hussein Mohammad Hamad, MD Kamal Eldein l Hamad, MD

Syria Wassma Achawi, MD Maha Manachi, MD

Tunisia Hamouda Boussen, MD Khalid Rahhal, MD

Yemen Arwa Awn, MD Afif Nabhi, MD

amaac <


international advisory board <

Matti AAPRO, MDDirector, Multidisciplinary Oncology Institute, Genolier, SwitzerlandConsultant to the Scientific Director, European Institute of Oncology, Milano, ItalyConsultant, Division of Oncology, Geneva University HospitalGeneva - Switzerland

Hoda ANTON-CULVER, PhD Professor & ChairDepartment of EpidemiologyProfessor, Department of Microbiology and molecular Genetics, School of MedicineDirector, Genetic Epidemiology Research InstituteUniversity of CaliforniaIrvine – USA

Jean-Pierre ARMAND, MDProfessor & General DirectorCentre de Lutte contre le Cancer Institut Claudius RegaudToulouse – France

Ahmad AWADA, MDHead of Medical Oncology ClinicJules Bordet Cancer InstituteBrussels - Belgium

Patrice CARDE, MDChairman Lymphoma CommitteeGustave Roussy InstituteParis - France

Franco CAVALLI, MDProfessor & President UICC Director Oncology Institute of Southern SwitzerlandBellinzona - Switzerland

Joe CHANG, MDAssistant Professor of Radiation OncologyClinical Service Chief, Thoracic Radiation OncologyMD Anderson Cancer CenterHouston - USA

William DALTON, MDPresident and Chief Executive OfficerH.Lee Moffitt Cancer Center and Research InstituteUniversity of South FloridaFlorida - USA

Jean-Pierre DROZ, MDProfessor & Former Head of Oncology DepartmentCentre de Lutte contre le Cancer Leon BerardLyon - France

Alexander EGGERMONT, MD, PhDProfessor of Surgical Oncology Head of Department of Surgical Oncology Erasmus University Medical Center Daniel den Hoed Cancer Center Rotterdam - The Netherlands

Jean-Pierre GERARD, MDProfessor of Radiation OncologyGeneral Director of Antoine-Lacassagne Cancer CenterLyon - France

Joe HARFORD, MDDirector of the Office of International Affairs National Institute of Health United States Department of Health and Human ServicesBethesda - USA

Alan HORWICH, MDProfessor of RadiotherapySection of Academic Radiotherapy andDepartment of Radiotherapy The Institute of Cancer ResearchLondon – United Kingdom Fritz JANICKE, MDDirector Clinic & Polyclinic of GynecologyUniversity Medical Center Hamburg-EppendorfHamburg – Germany

Sima JEHA, MD Director of the Leukemia / Lymphoma Developmental TherapeuticsSaint-Jude Children’s Research Hospital Memphis - USA

Hagop KANTARJIAN, MDProfessor of Medicine Chair of the Department of LeukemiaThe University of Texas - MD Anderson Cancer CenterHouston - USA

Fadlo R. Khuri, MD Professor and Chair, Department of Hematology and Medical Oncology Roberto C. Goizueta Distinguished Chair in Cancer Research Deputy Director, Clinical and Translational Research - Winship Cancer Institute Emory University School of Medicine Atlanta - USA

Jean-Francois MORERE, MDProfessor at University Paris XIIIHead of the Department of OncologyAssistance Publique – Hôpitaux de Paris Paris - France

Mack ROACH, MDProfessor & ChairmanRadiation Oncology & Professor of UrologyUniversity of California, IrvineCalifornia - USA

Philippe ROUGIER, MDProfessor of Medical OncologyGastrointestinal CancerLiver and Pancreas TumorsAmbroise-Pare HospitalBoulogne - France

Youcef RUSTUM, PhD Chairman of the Department of Cancer BiologyRoswell Park Cancer InstituteAcademic Research ProfessorAssociate Vice ProvostUniversity at BuffaloNew York - USA

Sandra M. SWAIN, MDMedical Director, Washington Cancer InstituteWashington Hospital CenterWashington – USA


editorial <

Dear Colleagues,

As we are celebrating the 2nd Anniversary of the PAJO, we would like to thank you for your contributions

and efforts and to promise you that bigger efforts will be dedicated to PAJO this year in order to be

referenced.

After adjusting the number of scientific papers for a nation's size or income,

per capita comparisons can offer "surprises" to us. The number of papers

posted on pubmed from our region is shy. There is no small country and no

small journal, any good quality work in any part of the world can contribute

to improve our knowledge and learning.

Why should we publish? Because it is the reflection of what we do and

a learning to us. What to publish? simple, clear and structured research

work… Observational studies, real life practices, case reports, literature

reviews are highly encouraged.

We want PAJO to be a meeting space and a reference for our countries by publishing your works, reports

of activities, advertisements for events and by sharing comments and feedbacks. We know that you

possess abilities. PAJO has an author-friendly approach from manuscript submission through publication.

We welcome your input and suggestions in hope that in the near future, we will be closer to our ideal

of well-known peer-reviewed and cited journal.

Marwan Ghosn, MD, MBA / MHM


special thanks <

Gerard Abadjian, MDHamdi Abdel Azim, MDWafaa Abdel-Hadi, MDA. Abdelkefi, MDAbdel Rahman M., MDFatma Aboulkasem, MDOmalkhair Abulkhair, MDMohsen Abdel Mohsen, MDArabi Abdessamad, MDNoha Abdou, MDMiguel Aboud, MD Philippe Aftimos, MDSalim Adib, MDB. Allani, MDBekadja Mohamed Amine, MDElie Attieh, MDFadwa Attiga, MDAhmad Awada, MDAmal Baccar, MDJean-Marc Bachaud, MDThouraya Baroudi, MDAli Bazerbachi, MD Amel Ben Ammar Elgaaied, MDKhaled Ben Rhomdhane, MDAlain Bernard, MDGhislaine Bernard, MDNizar Bitar, MDH. Boussen, MDKarim Chahed, MDGeorges Chahine, MDAnouar Chaieb, MDNicolas Chemali, MDLotfi Cherni, MDLotfi Chouchane, MDElizabeth Cohen, MDMichel Daher, MDGŽ raldine Dalmasso, MDKamal El-Dein Hamed Mohamed, MD

Thank you for all contributors, authors and reviewers of PAJO

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 1 | January 09


new publication

Special ReportHighlights on the Speech and Language

Pathologist’s role in Head and Neck Cancer

MENA 2008

BLOM Beirut Marathon 08

Original ArticleBreast Cancer in Tunisia

ReviewSoft Tissue Sarcoma in Young Individuals

www.amaac.info

ournal of O

Special ReportHighlights on the Speech and Language

Pathologist’s role in Head and Neck Cancer

MENA 2008

BLOM Beirut Marathon 08

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 1; issue 2 | June 08


new publication

Health Economics A cost-minimization analysis of 1st line polyCT regimens in advanced NSCLC

Review ArticlesPresent & Future of Radiation OncologyReview of the Current Management of advanced prostate cancer

www.amaac.info

ournal of O

Review ArticlesPresent & Future of Radiation OncologyReview of the Current Management of advanced prostate cancer

Pan Arab Journal of Oncology Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 2 | April 09

Special Issue Including the Proceedings of PACC 20099TH PAN ARAB CANCER CONGRESS7 - 9 May 2009 - Cairo, Egypt

new publication

ournal of O www.amaac.info

Special Issue Including the Proceedings of PACC

PAN ARAB CANCER CONGRESS

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 1; issue 3 | September 08


new publication

Meeting HighlightsASCO 2008UICC 2008

ReviewTreatment of Acute Lymphoblastic Leukemia

Targeted Therapy DevelopmentAngiogenesis review

www.amaac.info

ournal of O

Meeting Highlights

Pan Arab Journal of Oncology Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | September 09

new publication

While there’s

life

,

there’s

hope.

(Cicero, 106 - 43 BC)

Original ArticlesLow dose Gemcitabine and Cisplatin

in Advanced NSCLC

PRAME and WT1 Genes expression

in CML Patients

ISSN: 2070-254X

Meeting Highlights9th Pan Arab Oncology Congress

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ournal of O www.amaac.info

Whi

Meeting Highlights9th Pan Arab Oncology Congress

Best of ASCO 2009


Effect of radiotherapy on malignant

pleural mesothelioma in adjuvant,

radical or palliative basis.

Original ArticlesProteomic approach for the detection of

breast cancer biomarkers.

ISSN: 2070-254X

new publication

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | December 09

Special Report: COMO 8 | Nov 2009 | Beirut, Lebanon

Dalia Darwish, MDJean-Pierre Droz, MDTayssir Eyada, MDAhmad El-Ezzawy, MDFadi Farhat, MDNivine Gado, MDMarwan Ghosn, MDHeba Gouda, MDE. Gouider, MDAmin Haddad, MDMohammad El-Hajj, MDKhaled Halahlah, MDBechr Hamrita, MDGregory Hangard, MDColette Hanna, MDMohamed A Hassan, MDHassan A. Hatoum, MDJohan Hoebeke, MDHesham El Hossieny, MDAhmad Husari, MDNoha Ibrahim, MDElias Jabbour, MDSima Jeha, MDMaria Kabbage, MDFadi El Karak, MDJoseph Kattan, MDM. Kefi, MDJamal Khader, MDHussein Khaled, MDSami Khatib, MDAnne Laprie, MDRobert Launois, MDKatell Le Lay, MDChristelle Lemaitre-Guillier, MDRami Mahfouz, MDNazar Makki, MDCarole Massabeau, MDAndre Megarbane, MD

Brahimi Mohamed, MDMohsen Mokhtar, MDWalid Moukaddem, MDJonathan Moyal, MDElie Nasr, MDFadi Nasr, MDGhazi Nsouli, MDBen Othman, MDZaher Otrock, MDMartine Piccart, MDShadi Qasem, MDSilvia Al Rabadi, MDKarim Rashid, MDSami Remadi, MDKamel Rouissi, MDRaya Saab, MDEbtessam Saad El Deen, MDLaurence Ehret-Sabatier, MDGamal Saied, MDNagi El-Saghir, MDIbrahim Saikali, MDKhaled El-Saleh, MDZiad Salem, MDLobna Sedky, MDAli Shamseddine, MDAhmad Shehadeh, MDSana Al-Sukhun, MDIyad Sultan, MDAli Taher, MDPaul-Henri Torbey, MD Wafa Troudi, MDVirginie Vandenberghe, MDAlain Vergnenegre, MDLaure Vieillevigne, MDBesma Yacoubi-Loueslati, MDMahmoud Yassein, MDRiad Younes, MD


Abstract

Purpose of study: This retrospective study was designed to evaluate the response and survival of malignant pleural mesothelioma to radiotherapy when delivered with surgery and chemotherapy and when delivered alone or with chemotherapy.Patients & Methods: A study for 110 patients with malignant pleural mesothelioma who presented to radiotherapy department , National Cancer Institute , Cairo and received radiation therapy in the period from January 1999 to July 2007.Results: 46 patients (41.8%) received trimodality therapy (surgery & adjuvant or neoadjuvant chemotherapy & adjuvant radiotherapy) , bimodality therapy (chemotherapy & radiotherapy) in 38 patients (34.5%), 26 patients (23.6%) received single modality therapy( palliative radiotherapy), 22 patients (20%) developed local recurrence, 22 patients (20% ) developed distant metastases 7 months after end of treatment, 14 patients (12.7%) developed local disease progression, 25 patients (22.7%) are still alive and free of disease at time of reporting. The median survival for all patients was 16 months, 12 & 18 months overall survival were 63.6% & 31.8% respectively and median survival for stage II , III , IV patients was 16.5, 12.5 & 8 months respectively. Conclusion: Multimodality approach involving surgery, chemotherapy & radiotherapy seems to be a promising treatment modality especially in stages II, but still with low survival rates which results in the needs to explore for newer treatment strategies and well designed randomisied trials.

Introduction

Malignant pleural mesothlioma( MPM ) is considered as an aggressive disease with dismal prognosis especially in its diffuse form. Lot of difficulties in accurate diagnosis and staging and even in its treatment contributed actively to this dismal prognosis (1) , its etiology is related to asbestos fibers exposure especially the blue crocidolite and is characterized by a long latency period(2), its incidence is increasing in western countries and in countries with poor regulations of asbestos mining ,industrial production and house hold use (3).Reports of National Cancer Institute Cairo University showing increased relative frequency of MPM in the last few years(4).Single modality therapy has failed in significantly changing the natural history of the disease and its median survival, except in early localized disease which could be completely resected by surgery without the need of adjuvant therapy(5).

Multimodality aggressive therapy which include extensive surgical resection of the disease up to extrapleuralpneumonectomy (EPP) to be followed by radiotherapy and chemotherapy( pre or postoperative chemotherapy) had proved to increase median survival especially in stages 2 and 3 (6,7).The use of radiotherapy for MPM faces many difficulties including a very large target volume to be covered and also the need of high tumercidal dose which when given it could damage the surrounding normal tissues including lung ,spinal cord ,heart etc., thus the use of radiation as a single radical modality therapy is not possible as the tolerance of the lung is 20 Gy with the V20 of the contralateral lung not exceeding 20 Gy , mean liver dose not exceeding 30 Gy, spinal cord 45 Gy (more than 10 cm segment), 70% of the heart should receive less than 45Gy while oesophagus 45-50 Gy (8). There are several approaches to integrating postoperative radiotherapy into the trimodality program. The lowest locoregional recurrence rates post-EPP are in those series using high-dose postoperative hemithorax irradiation (9).Surgery in an attempt for aggressive debulking and cytoreduction can be either pleurectomy – decortication ( P\ D ) or EPP. Each of there procedures has no major effect on survival in diffuse type and more treatment is needed , so adjuvant chemoradiotherapy was attempted in selected patients who can tolerate such aggressive therapy regarding their organ functions especially lung, heart, renal and hepatic functions. Single agent and combination chemotherapy have been evaluated in single and combined modality studies. The most studied agent is doxorubicin, which has produced partial responses in approximate 15% -20% (30).Some combination chemotherapy regimens have been reported to have higher response rates in small phase II trials. However the toxicity reported is also higher and there is no evidence that combination regimens result in longer survival or longer control of symptoms. Recurrent pleural effusions may be treated with pleural sclerosing procedures; however, failure rates are usually secondary to the bulk of the tumor, which precludes pleural adhesion due to the inability of the lung to fully expand(31,32).Byrne et al. (10) first described a 47% response rate with a combination of cisplatin and gemcitabine, and a follow-up multicenter trial from Australia with 53 patients reported a 26% rate of activity but a median survival of only 7.5 months.The activity of the combination in other multicenter phase II studies,(11)in patients previously treated with other chemotherapy, and of the gemcitabine/carboplatin regim(12) has led to its widespread use. Gemcitabine,166,167-13,14 cisplatin, and carboplatin all have independent but modest single agent activity.A novel antifolate, pemetrexed, demonstrated broad antitumor activity in phase I

original article <

Analysis of the effect of radiotherapy on malignant pleural mesothelioma when given on adjuvant or palliative basis

Hesham A. El Hossieny, MD1, Fatma Aboulkasem , MD2, Abdel Rahman M.,MD3.

(1) Department of Radiation Oncology, National Cancer Institute, Cairo, Egypt(2) Department of Medical Oncology , National Cancer Institute, Cairo, Egypt(3) Department of Surgery, National Cancer Institute, Cairo, Egypt

Corresponding Author: Hesham A. El Hossieny - E-mail: [email protected]

Key words: Malignant, Pleural, Mesothelioma, Radiotherapy.

Submitted: 17 September 2009 - Accepted: 20 November 2009

ISSN: 2070-254X


and II trials.(15) When combined with cisplatin, pemetrexed induced regressions in 38% of pleural mesothelioma patients. (16) Another antimetabolite, raltitrexed (Tomudex; an agent not available in many countries), a 240 patient phase III trial comparing cisplatin to raltitrexed plus cisplatin has been reported showing that the median survival of patients treated with the doublet was 11.4 months compared to the survival after cisplatin alone of 8.8 months (P=.048). (17)

The aim of this study

is to evaluate the effect of radiotherapy when given on adjuvant basis and combined with chemotherapy or when given on palliative basis either alone or combined with chemotherapy.

Patients and Methods

A study for 110 patients with malignant pleural mesothelioma who presented to radiotherapy department in National Cancer Institute Cairo and received radiation therapy in the period from January 1999 to July 2007.Data from patients files were revised regarding stage of disease, pathologic subtype, full details of radiotherapy received, other therapy received ( surgery or chemotherapy), response to treatment and survival. Overall survival was calculated using the Kaplen- Meier estimates, while the Log-rank test was used for comparing survival curves.

Results

Table 1: The characteristics of patients

Percent

63.6%36.4%

Number

7040

Sex

malesfemales

63.6%20 %16.4 %

702218

Pathology Epithelioid. Sarcomatoid. Biphasic.

54.5 % 27.3 % 18.2 %

603020

Stage II III IV

100%73 %82 %56 %

110 809062

Clinical presentation Dyspenia Chest pain Cough Haemoptesis

86%29%68%

953275

Habitat , Work & Smoking living in endemic areas Industrial workers Smokers

The age of patients ranged from 29 to 73 years with median age of 49 years, they were 70 (63.6%) males & 40 (36.4%) females, 95 patients (86%) living in endemic areas( around asbestos factories), 75 patients (68%) were smokers, 32 patients (29%) were industrial workers.

Clinical picture at presentation were:all patients had dyspnea, 80 patients (73%) had chest pain, 90 patients (82%) had cough while 62 patients (56% ) had haemoptesis.

Histopathologic subtypes were:Epithelioid subtype were encountered in 70 patients (63.6%), sarcomatoid subtype in 22 patients (20%) , biphasic subtype were in 18 patients (16.4%).

Stage The patients were staged according to (Inernational Mesothelioma Interest Group[IMIG] ): 60 patients (54.5%) had stage II and 30 patients (27.3%) had stage III while stage IV was encountered in 20 patients (18.2%).Patients who underwent EPP were staged radiologicaly and pathologically (i:e 40 patients), the rest of the studied patients were staged radiological only .

Treatment receivedPatients were treated with each treatment modality according to their stage of disease and their performance status, so that patients with operable and early stage disease and with good performance were offered the trimodality treatment while those with more advanced stage and poor performance was offered either the bimodality or the single modality treatment. Forty six patients (41.8%) received trimodality (adjuvant) therapy ( surgery & adjuvant or neoadjuvant chemotherapy & adjuvant radiotherapy which started at 6 weeks median duration following surgery) , all of them received 50Gy\25f \ 5w ( all patients were stage II , i:e 77% of stage II patients received trimodality therapy), bimodality (palliative) therapy ( chemotherapy & radiotherapy) in 38 patients (34.5%),( 25 patients of them received 50 Gy \25 f \ 5w , 13 patients received 40 Gy \ 20 f \ 4w) ( 24 patients of them were stage III & 14 were stage II , all of them were treated on palliative basis , 22 patients of them were treated to prevent skin metastases ) , 26 patients ( 23.6% ) received single modality (palliative) therapy( palliative radiotherapy) 15 patients of them received 30 Gy \ 10 f \ 2w and 11 patients received 500cGy \4 f\1w ,( 6 patients of them were stage III & 20 patients were stage IV , all of them were treated on palliative basis , 15 patients of them were treated to prevent skin metastases ) , patients with antroposterior more than 20 cm received photon energy 6MV ( 43(39%) patients ) while those who were less than 20 cm received on Cobalt machine ( 67 (61%) patients ) , patients who received electron beam irradiation we used energies ranging from 12 Mev to 15 Mev sing the 90% isodose line as the reference depth . Forty patients ( 36.4 % ) underwent EPP and all of them achieved negative surgical margin , 6 patients underwent pleural decortication .Eighty four patients (76.4%) received chemotherapy either neoadjuvant (30 patients) or adjuvant (16 patients) , 38 patients received chemotherapy with radiotherapy ( 28 patients of them received chemotherapy before radiotherapy , 10 patients received chemotherapy after radiotherapy) , different drug regimens were used 67 patients received gemcitabine and cisplatin or carboplatin while the remaining patients received different protocols including vepsid or navelbine or adriamycin or alemta , patients typically received 4-6 cycles . Thirty patients ( 27.3 % ) received photon beam only , 70 patients ( 63.6 % ) received combined photon and electrone beams, 10 patients ( 8 % ) received electron beam only ( for palliation ) . Regarding field extent 90 patients ( 81.8%) received hemithoracic fields , 20 patients ( 23%) received localized fields, 92


patients (83.6%) received 2 parallel opposing fields , 13 patients (11.8%) received direct field using either photon or electron beam fields , 4 patients (3.6%) received 2 wedged oblique fields while 1 patient (0.9%) received 3D conformal hemithoracic radiotherapy.Regarding the most commonly induced radiation therapy complications were grade 2 – 3 oesophagitis in all patients and skin complications including dry desquamation in 78% of patients and 22% of patients developed wet desquamation.

Response to treatmentResponse to treatment were evaluated 2-3 weeks after end of radiotherapy using C.T chest and abdomen and clinical examination also by recording the patients complaints of pain , dyspnea , cough , etc….Twenty five patients developed complete response through EPP & chemoradiotherapy, 20 patients developed temporary partial response which lasted for 3-5 months.Twenty seven patients (24.5%) have no response regarding tumor size , dyspnea, chest pain & cough , of them ( 17 patients were stage II , 6 patients stage III & 6 patients were stage IV , 4 patient was biphasic subtype & 25 patients were epetheliod subtype , 21 patients received 50 Gy \ 25 f \5w & 4 patient received 40 Gy \ 20 f \ 4w & 4 patient received 30 Gy \ 10 f \ 2w , 17 patients did not receive chemotherapy ).Twenty two patients (20%) developed local recurrence after an average duration of 8 months after end of treatment, of them (6 patients underwent P\D & 16 patients underwent EPP while 18 patients of them received chemotherapy , 17 of them were stage II & 5 patient was stage III , all patients received adjuvant radiotherapy to hemithorax to a dose of 50Gy \ 25f \ 5w ), 15 patients developed local recurrence intrathoracically ( at operation side ) , 7 patient developed in addition chest wall skin nodules).Twenty two patients (20%) developed distant metastases after an average duration of 7 months after end of treatment of them ( 7 patients with liver mets. and malignant ascites , 10 patients developed bone metatases & 5 patient with liver and bone mets., 15 patients of them received chemotherapy , 14 patients of them were in the single modality group while 8 patients were in the bimodality group these data was at the time of reporting ).Fourteen patients (12.7%) developed local disease progression with increasing in tumor size , pleural effusion and dyspnea , chest pain & cough after an average duration of 5 months after end of treatment of them ( 10 patients were stage IV & 4 patient was stage III , all of them underwent pleural biopsy only , 8 patient did not receive chemotherapy , while all of them received hemithoracic irradiation to a dose of 30 – 50 Gy .).Twenty five patients (22.7%) are still alive till time of reporting and free of disease, ( 23 of them underwent EPP & 2 of them underwent pleural decortication , 15 patients of them received neoadjuvant chemotherapy , all of them received adjuvant radiotherapy to a dose of 50 Gy\25 fractions\5 weeks , 23 patients of them were stage II and 2 of them were stage III ).Patients who received radiotherapy only (26 patients) had improved chest pain in 15 patients of them (57.7%).

Survival

Fig 1: Overall survival of all studied patientsMedian survival for all patients was 16 months , 12 months & 18 months overall survival rates were 63.6 % & 31.8% respectively (fig. 1)

Table 2: Median survival by stage of disease : P value=0.00012

Stage of disease Median Survival16.5 months 12.5 months 8 months

IIIIIIV

original article <

Fig 2: Overall survival by stage of diseaseComparing overall survival by different stages of disease , it showed that 18 months overall survival for stages II , III & IV were 41.6% , 33.3% & 0% respectively, which was statistically significant ( P value= 0.00012) (fig. 2).

Table 3: Median survival by pathologic subtype : P value=0.365

Median survival Pathologic subtype17 months (range 4-37)13 months) range 2-29)

Epitheloid subtypeBiphasic & sarcomatoid subtypes


Table 4: Median survival by treatment modality

Median survival Treatment modality16 months11 months8 months

Trimodality(surgery+Rth+Cth)Bimodality ( Cth + Rth )Singlemodality ( Rth palliative )

Discussion

Results of radiotherapy for malignant pleural mesothelioma have been generally disappointing, doses below 30Gy have produced only temporary relief of symptoms in some cases, and doses in excess of 40Gy are needed to achieve adequate palliation, with photon alone or combined with electron beam then followed by a boost ( localized to residual tumor ) to a dose of 60 – 70Gy(18,19).Higher doses to a larger volume can produce significant complications such as radiation pneumonitis , myelitis and hepatitis which could be fatal(20). Recent guidelines for three-dimensional conformal radiotherapy suggest a dose of 54 Gy in 30 fractions five days per week to the ipsilateral thoracic cavity, chest wall incisions, and drains, with attention to normal tissue tolerance for the contralateral lung, spinal cord, heart, esophagus, and other vital structures. (21) Intensity-modulated radiotherapy (IMRT) is a promising newer technology that may deliver better local control results; (22 ) however it is not widely available , and there have been reports of subsequent fatal pneumonitis which suggest caution in implementing this technology.(23,24,25) Nevertheless, only patient series using an aggressive multimodality approach achieve clinically meaningful five-year survival rates. (26,27)Radiation therapy is used effectively to prevent seedling in the biopsy track and open biopsy scar by using a dose of 21 Gy over 3 fractions , as it decreases the incidence of wound implants by malignant cells from 60% to less than 5 %(28,29).Malignant pleural mesothelioma is a challenging disease in all of its aspects either at presentation , diagnosis , staging or treatment.In comparison with Calavrezos et al,(33) and Sugarbaker et al,(27) who reported that the median survival in patients who received trimodality treatment was 13 and 17 months respectively , which is comparable to this study that the median survival for patients who received trimodality treatment in this study was 16 months.Malignant seeding in approximately 20% to 50% of mesothelioma patients along thoracentesis tracts, biopsy tracts, chest tube sites, and surgical incisions is a common complication of procedures in these patients, 40 patients were randomised after an invasive diagnostic procedure to either RT or no treatment. No patient in the radiation treatment group developed subcutaneous nodules. Alternatively, eight of 20 patients in the untreated group developed metastases (34)These results also compared favorably with the series from MD Anderson with a median survival after neoadjuvant chemotherapy which was followed with extrapleural pneumonectomy followed by adjuvant intensity modulated radiotherapy which showed a median survival of 15 months.(35)Also in comparison to El-Shafiey MM ,(4) it showed a median survival of 9 months for patients who received bimodality treatment ( RTH + CTH) while in this study it showed 11 months median survival, also our study showed comparable median survival regarding patients who received radiotherapy only , this is attributed to that patients in both studies were with advanced or recurrent disease and with poor performance status which results in poor radiation response. Also it was found that palliative radiotherapy as a single modality can improve pain in around 60% of patients (36) , but the effect is generally short-lived , this was

in concordance with this study were (57.7%) of patients who received palliative radiotherapy had improved chest pain.

Conclusions

Single modality therapy was the initial approach to this disease, its generally has not been effective in changing natural history of the disease. Multimodality approach involving surgery, chemotherapy & radiotherapy seems to be a promising treatment modality especially in stages II , but still with low survival rates which results in the needs to explore for newer treatment strategies and well designed randomisied trials.

Acknowledgement

Fatma Aboulkasem , Abdel Rahman M., both of them helped the main author in collecting patients data.

Conflict of interest statement:

There is no conflict of interest (Non declared).

References

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31. Ong ST, Vogelzang NJ. Chemotherapy in malignant pleural mesothelioma. A review. J Clin Oncol. ,1996 14 (3): 1007-17.32. Zellos LS and Sugarbaker DJ . Multimodality treatment of diffuse MPM ; Semin. Oncol., Feb. 2002, 29 (1) : 41-50 .33. Calavrezos A ,Koschel G , Husselman H . MPM , Klin Wochenschr. , 1998, 66 , 607 – 613 .34. Agarwal PP, Seely JM, Matzinger FR, et al. Pleural mesothelioma: sensitivity and incidence of needle track seeding after image-guided biopsy versus surgical biopsy. Radiology 2006;241:589.35. Rice DC , Stevens CW , Correa AM et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007 ; 84 : 1685 – 92 , discussion 1692 – 3.36. Bissett, D.,Macbeth, F. R. and Cram, I. The role of palliative radiotherapy in malignant mesothelioma. Clin. Oncol. (R. Coll. Radiol.) 1991 , 3, 315–7.


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Abstract

Aims: The major tool of the proteomic approch in breast cancer is to identify the differentially secreted proteins, which may work as a potentiel biological markers. We examined the protein expression patterns of infiltrating ductal carcinoma of the breast (IDCA) tissues and serum from Tunisian women using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and matrix-assisted laser desorption/ionization-time of fight (MALDI-TOF) mass spectrometer.Methods: Serum protein and tumor protein tissues were solubilized and analysed with 2D-PAGE and visualised by a sensitive Colloidal Coomassie G250 stain. Protein expression was identified using MALDI-TOF MS/MS and evaluated using PDQuest 2-D softwarer. The proteins spectrums were identified by searching NCBI and Swiss Prot databases.Results: Comparaisons of the protein spots identified on the 2D-PAGE maps from human serum and breast tumor tissues showed that Apolipoprotein AI were up-expressed in both tumor tissue and pre-treatmant serum compared with their counterparts. Conclusion: 2-DE and MALDI-TOF/MS offers total protein expression profiles of breast cancer tissues and serum and will give a chance to identify tumor-specific diagnostic markers for breast cancer. The differentially up expressed of Apolipoprotein A I may play a key role during tumorigenesis of breast cancer.Abbreviations: Apolipoprotein AI,(Apo AI),Isoelectrofocalisation ,(IEF), Matrix Assested Laser Desorption Ionisation Time of Flight, (MALDI-TOF),Mass spectrometry,(MS), Two Dimensional Gel Electrophoresis, (2D-PAGE).

Introduction

Breast cancer is a leading cause of death among women and a major problem of public health, considering the number of women who are diagnosed and who die annually of this pathology. This high mortality rate is usually ascribed to late diagnosis of this tumor, which lacks early symptoms 1. As with other cancers, metastasis in breast cancer is the leading cause for mortality. Therefore, Early detection can greatly reduce breast cancer mortality and there is an urgent need for reliable biomarkers pathologies. Biomarkers have the potential to aid in the

Proteomic approach for the detection of breast cancer biomarkers using two dimensional gel electrophoresis and mass spectrometry

Bechr Hamrita1, Karim Chahed1.2, Maria Kabbage1, Laurence Ehret-Sabatier3, Christelle Lemaitre-Guillier3, Sami Remadi4, Anouar Chaieb5, Johan Hoebeke3 and Lotfi Chouchane1.

(1) Laboratoire d'Immuno-Oncologie Moléculaire, Faculté de Médecine de Monastir; (2) Institut Supérieur de Biotechnologie de Monastir, Tunisia;(3) Plate-forme protéomique, Institut de Biologie Moléculaire et Cellulaire, CNRS, Strasbourg, France;(4) Laboratoire Cytopath, Sousse, Tunisia; (5) Service d’Obstétrique et des maladies féminines, Hôpital Universitaire Farhat Hached, Sousse Tunisia.

Corresponding Author: Bechr Hamrita, Laboratoire d'Immuno-Oncologie Moléculaire, Faculté de Médecine de Monastir, 5019 Monastir, Tunisia - E-mail: [email protected]

Key words: Apolipoprotein A I, 2D-PAGE, Breast cancer, serum, Tumor.

Submitted: 5 May 2009 - Accepted: 3 September 2009

ISSN: 2070-254Xdiagnosis, prognosis, detection and treatment of breast cancer. Some current proteomic technologies are particularly suitable for protein profiling in the search for new biomarkers 1. Recent improvement in mass spectrometry technologies has increased the accuracy and sensitivity of this tool. It can use for the analysis of complexes mixtures such as tumor tissues or serum 2. Mass Spectrometry has been applied to breast cancer tissue, serum, serum and nipple aspirate fluid (NAF). Two dimensional electrophoresis (2D-PAGE) is a valuable tool for the separation and characterization of proteins from complex biological samples prior to MS analysis 1, 2. Its widely used for separing proteins since 20 years ago. The combination of high-resolution protein separation by two-dimensional gel electrophoresis and mass spectrometry has proven to be an essential tool for proteomics to identify proteins 3. In such investigation, a biomarker is defined as a protein having more or less intensity on one gel compared with the other as well as between different diseases stages, is, thererfore of crucial importance. Searching for human protein serum and tumor tissue alterations using 2D-PAGE with regard to neoplastic disease has been extensively investigated in many authors report. For more than three decade, 2D-PAGE was carried to look analysis the protein profils in cancerous versus normal tissues with the goal of identifying the protein markers that are differentially expressed between benign and malignant tissues or plama. Increased levels of molecular markers such as prostate specific antigen (PSA) and CA 125 are now routinely used for the detection of cancer in the prostate and ovary respectively. In a more focused study, Cho WC et al (2004), reported an increased level of serum amyloid A and it could be useful a biomarker for the nasopharyngeal cancer 4. Other markers like carcinoembryonic antigen (CEA) are used for detecting colorectal cancer, Her2/neu, CA 15-3 and RS/DJ-1 for advanced breast cancer 5. In the same way, Ostergaard et al (1997) analysed the bladder tumor, using 2D-PAGE, and observed a decreased level of galactine and stratifin 6. In other studies, using 2D-PAGE and MALDI-TOF/MS, Franzen et al (1993) identified a decreased level of tropomyosin3 in malignant breast tumor as compared to benign lesions 7. Furthermore, 2D-PAGE analyses of breast tumor (invasive carcinomas) exhibited the presence of proliferating cell nuclear antigen. Kallikreins, a family of secreted serine proteases were highly associated with ovarian carcinoma as well as with breast and prostate cancers. By the same proteomic approach, Vercoutter- Edouart et al (2001) found that the 14-3-3γ chaperone protein, down-regulated in primary breast carcinoma and


to be involved in the transition of breast epithelial cells to neoplasia 8. In the present study we tried to identify new proteins in breast tumor (serum or tissue) by 2D-PAGE with mass spectrometry (MS) and to make a standard 2D-PAGE of human breast cancer tissue and serum. Here, by comparing 2 D -PAGE profiles of human serum and tumor proteins and using MALDI-TOF mass spectrometry of their trypsinized fragments, we have found an increased level of Apolipoprotein AI among Tunisian breast carcinoma women.

Material and methods

Serum and tissues samples Serum and tumor tissues were obtained between September 2008 and October 2009 from the department of Gynecological oncology (Sousse Hospital, Tunisia) at the time of diagnosis. Sera were obtained from 40 women with untreated breast cancer (IDCA) and we collected 42 womens control subjects (having no evidence of any personal or family history of cancer or other serious illness). Peripheral venous blood samples were obtained and after centrifugation the serum was alicoted in 100 µl frozen and stored at -80 °C until analysed.Breast tumor tissue were obtained during surgical resection from the same serum samples patients (10 biopsies) during the same moment of serum levying.After excision, sample tissue were conserved in RNA later, and frozen immediately at -80°C and stored until use.

Protein sample preparation Samples Handling (serum, tumor tissues) To the serum, four volumes of cold acetone (-20°C) were added and the solution was incubated for 1 Hour at -20°C. The pellet was washed with cold acetone (80%), dried under partial vacuum and solubilised in 150 µl of 2D-PAGE buffer containing 7.0 M urea, 2.0 M Thiourea, 4% (w/v) CHAPS, 0,5% w/v DTT and 2% ampholytes (1 part pH 3/10, 1 part pH 5/7, 2 parts pH 6/8). Tissue samples were snap-frozen in liquid nitrogen and stored at -80˚C until used. Prior to analysis by 2D-PAGE, sections (100 mg) of tumor and adjacent normal breast tissue, erified by histological analysis, were suspended and mechanically homogenized in 200 μl of the same serum 2D-PAGE lysis buffer. The extracts were incubated at room temperature for 10 min with vortexing. The homogenate was centrifuged at 12500 g for 15 min and the yellow lipids were discarded from the supernatant and the clear supernatant transferred to a sterile microcentrifuge tube.

Protein assayProtein contents were determined according to the procedure described by Bradford and modified by Ramagli and Rodriguez 9,10. Bovine serum albumin (Fraction V, Sigma) was used as a standard. Analytical 2D-PAGE was carried out in a Bio-Rad system (Miniprotean II). Equal amounts of proteins issued from control breast cancer samples proteins were subjected simultaneously to isoelectrofocalisation (IEF) and SDS-PAGE analysis. Extraction of proteins, solubilisation, IEF, SDS-PAGE and staining were carried under very similar conditions for the different samples. Each experiment was repeated for at least three times. Focused strips were equilibrated in SDS equilibration buffer and were then loaded onto SDS gel slabs for separation in the second dimension 11.

2D-PAGE and protein quantificationTwo dimensional gel electrophoresis: gel staining, maldi-tof/ms and protein identification Protein contents were determined according to the procedure described by Bradford and the Bovine serum albumin (Fraction V, Sigma; www.sigmaaldrich.com) was used as a standard. Analytical 2D-PAGE was carried out in a Bio-Rad system

(Miniprotean II, (www.biorad.com)) according to O'Farrell 12. Equal amounts of proteins (150 μg) issued from patients serum and controls, tumoral and adjacent normal breast tissues were subjected simultaneously to isoelectrofocalisation (IEF) and SDS-PAGE analysis. Proteins were fractionated on 7-cm IEF rod gels (pHi 4.0-8.0) with a low voltage at 200 V for 15 min, followed by 300 V for 15 min and 400 V for 20 h. After IEF was terminated , Focused strips were equilibrated in SDS equilibration buffer [125 mM Tris-Hcl pH 6.8, 2.5% (w/v) SDS, 10% (w/v) glycerol, 0.025% (w/v) bromophenol blue].The second dimension of SDS-PAGE (11%)was performed on vertical system. The upper and lower electrophoresis buffers contained (Tris 25 mmol/L ; 192 mmol/l glycine; 0,25% SDS adjusted to pH : 8,8). Electrophoresis run at 80V for the 15 min and then a maximum of voltage at 140V for 1 Hour.The temperature of the cooling plate was set at 22°C. Isoelectric points and molecular weights of individual proteins were evaluated with polypeptide SDS-PAGE standard. After SDS-PAGE the gels were stained with a protocol compatible with mass spectrometry. After separation in SDS-PAGE, gels were stained overnight by using a sensitive colloidal coomassie G-250 stain and destained in 1% acetic acid 13. The dye solution contained 14% (w/v) ammonium sulfate, 3% (v/v) phosphoric acid, 0,1% (w/v) coomassie G250 and 34% (v/v) methanol. The colloidal coomassie G-250 stain were scanned into adobe photoshop 6.0. Differential protein levels among the normal breast, breast tumor tissue and serum were confirmed and piked out by comparaison of 2D-PAGE images using melanie 3.0 software tools and analyzed by mass spectrometry. The protein spots of interest were excised manually and washed three times with milli-Q water. The excised spots were destained with the destaining solution (15 mM potassium ferricyanide, 50 mM sodium thiosulfate) and washed with 25 mM ammonium bicarbonate/ 50% acetonitrile till the gels were changed opaque and colorless. After having been dried with a vacuum concentrator (SpeedVac Plus), the gel was rehydrated with 3-10 Al of trypsin solution (10 ng/Al) at 4-C for 30 min and then incubated overnight at 37-C. The tryptic peptides were extracted with 60% acetonitrile, 0.1% trifluoroacetic acid, and dried with a vacuum concentraton.Tryptic peptide mixtures were dissolved in 0.5% trifluoroacetic acid (TFA). After digestion the peptides were treated by elution from Zip Tip-C18 reversed phase pipette tips (Millipore). Recovered peptides were prepared for MALDI-TOF mass spectrometry by mixing with a saturated solution of alpha-cyano-4-hydroxy cinnamic acid in 50% acetonitile as a matrix, and droplets were allowed to dry on the MALDI sample plate. Internal calibration of the MALDI mass data was applied using the masses of two trypsin autolysis products : [M + H] + 842.51 and [M + H] + 2211.10 Da. Data generated were screened in databases using a mass tolerance <50 ppm. Peptide mass maps were obtained using a Voyager DE (Applied Biosystems, Foster City, CA) MALDI-TOF mass spectrometer operated in positive ion reflectron mode. Proteins were identified from the peptide masse maps using MASCOT program (http ://www.matrixscience.com) to search the nonredundant protein data base Swiss-prot or NCBInr.

Results

The breast cancer marker:SubjectsTo optimize protein identification, the 2D-PAGE, was performed on serum and tissue from subjects without breast cancer. The total proteins were separated by 2D-PAGE using a pH range of 4-to 8 in the first and 12% SDS-PAGE in the second dimension. Gels were stained overnight by using colloidal Coomassie Brillant Blue (G 250) Fig 1. Each experiment was repeated for at least three times. After optimization, we tested with 2D-PAGE, 82 serum samples and 10 tumor tissues (with their control tissues) from the same women patient. The major goal of this


study is to identify a protein marker that is differentially expressed from serum or tissues versus controls.2D-PAGE analysis (serum and tumor proteins)To identify a breast markers from the serum and tissues, a comparaison of proteome by two dimensional gel electrophoresis on control serum sample and tissue with the proteome patient. The proteins extracted from serum and tumor tissues were separated and localized in the pH range of 4-8. The molecular masse ranging from 10 to 140 kDa. Fig 1 is annotated to show the localization of the Coomassie blue stained 2D-PAGE image. In 98% of the detected protein spot there were no difference in abundance between the gels.Only one spot were up expressed in all of the breast cancer samples compared to that of healthy controls. The proteins spots were excited from the gels, digested with trypsin and analysed using MALDI-TOF/MS .Peptide mass fingerprints from the protein were obtained and the resulting spectra were used to identify the protein with the Mascot Search program. These two proteins identified was the same one, Apolipoprotein AI Fig 2. The mass spectrum of the identified proteins (Apolipoprotein AI) and the sequences of the assigned peptides were presented Fig 3.

Fig 1: Two dimensional gel electrophoresis analyses of serum and tumor proteins derived from (A), a serum and (B) tumor healthy donor.

A. ph8 ph4

A.

B.RHFWQQDEPP QSPWDRVKDL ATVYVDVLKD SGRDYVSQFE GSALGKQLNL KLLDNWDSVT STFSKLREQL GPVTQEFWDN LEKETEGLRQ EMSKDLEEVK AKVQPYLDDF QKKWQEEMEL YRQKVEPLRA ELQEGARQKL HELQEKLSPL GEEMRDRARA HVDALRTHLA PYSDELRORL AARLEALKEN GGARLAEYHA KATEHLSTLS EKAKPALEDL RQGLLPVLES FKVSFLSALE EYTKKLNTQ

B. ph4 ph8

Fig 2: Two dimensional gel electrophoresis patterns of proteins focusing on areas containing ApolipoproteinA1.(A): serum proteins (A1: normal sample, A2: tumor sample), SAP: serum amyloid P. (B): proteins issued from normal and tumor tissues (respectively B1,B2).

Fig 3: Representative example of MALDI-TOF spectrum for Apolipoprotein AI (A) and the matched peptide sequences were underlined (B) showing differential expression in the serum and tissues of the breast (IDCA).

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Discussion

There is a very need action to identify and discover tumor markers that may detect the breast cancer at an early stage. The objective of this study was to identify, using quantitative assessment with 2D-PAGE and mass spectrometry, proteins with altered serum and tissue expression in infiltrating ductal carcinoma of the breast. Serum and tumor proteomic analysis of malignant breast cancer and samples from human healthy donors were compared by high resolution two dimensional gel electrophoresis. One protein is up-regulated in all of the breast cancer samples compared to that of healthy controls. This protein identification appeared to represent differences in overall abundance. Serum 2D-PAGE investigations showed elevated level of Apolipoprotein AI in serum from patients diagnosed with breast cancer. An increased expression of the apolipoprotein A1, is identified as being significantly overexpressed in the tumor (Figure 2).To our knowledge, this study, is the first one that report an elevated of the same protein in the serum and tumor tissue.Several other 2D-PAGE studies have identified an expression of apolipoprotein AI in metastasis colonic adenocarcinoma. These findings are consistent with the notion that expression of ApoAI is associated with colonic adenocarcinoma progression, and thus ApoAI is a potential marker of aggression. Kozak KR et al (2005) identified ApoAI, as a serum biomarker that could be useful in the diagnosis of ovarian cancer 14. We conclude that ApoAI combined with CA125 should significantly improve the detection of early stage ovarien cancer 14. However other study found decreased levels of apolipoprotein AI, Zhang et al (2004) reprted a dowen-regulated level of ApoAI with transthyretin in the serum of ovarian cancer patients 15.Additionally, Steel LF et al (2003), reported the same result in the serum study. A decreased levels of apolipoprotein AI in the hepatocellular carcinoma, detected with 2D-PAGE 16. Apolipoprotein AI, present a single polypeptide chain with 243 aminoacid residues.It’s an excellent cofactor for leucethin cholesterol acyltransferas (LCAT), protein official for the formation of the cholestery esters in serum. Apolipoprotein AI is the major protein constituent of high density lipoproteins (HDL) and plays a crucial role in lipid transport and metabolism. Many atherosclerosis study, reported a relation ship between the incidence of coronary atherosclerosis disease (CAD) and lower expression of ApoA I. Overexpression, in the serum and tumor sample, of apolipoprotein A1 presursor (ApoA1), could be linked to its anti-inflammatory functions .The high density lipolipoprotein (HDL) associated apolipoprotein A I allow the specific inhibition of essential inflammatory cytokine production. The tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1 β) 17.This cytokines are the regulator of the immune response, induction of inflammatory acute phase and transition to chronic inflammation. A cellular contact between stimulated T cells and activated monocytes is bloked by Apolipoprotein A I 17. Bloking the production of these cytokines by Apolipoprotein A I, may constitue a new therapeutic approch. As well as to its potential inhibition of TNFα and interleukin-1β by bloking contact mediated activation of monocytes by T lymphocytes 17. This finding suggest that change of apolipoprotein A-I levels inversely correlate with disease activity.In conclusion, we have used a proteomic approach to analyze serum and tumor tissues of the breast. We have identified interesting tumor-associated proteins that may help in under-standing the carcinogenesis of this disease and eventually serve as potential diagnostic markers.

Acknowledgments

This work was supported by le Secrétariat d’Etat de la Recherche Scientifique et de Technologie, le Ministère de l’Enseignement Supérieur and le Ministère de la Santé

Publique de la République Tunisienne and by the centre National de Recherche scientifique (Strasbourg, France) and the DGRST-CNRS funding program.

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original article <

Abstract

Breast cancer is the most common malignancy diagnosed in women accounting for 23% of all malignancies worldwide. Epithelial ovarian cancer is the most lethal gynecologic cancer leading to 47% of all deaths from cancers of female genital tract. Women with a history of breast cancer have a two fold higher risk of developing a subsequent ovarian cancer.Patients and methods: Among 770 patients with cancer breast diagnosed between 1998 to 2005, ten patients developed ovarian cancer. Analysis of various predisposing factors was done retrospectively. These factors included age at first diagnosis, histopathologic subtype, family history and time to diagnosis of secondary ovarian cancer. Results: Mean age at diagnosis of breast cancer was 43 years (range 34-50). During a mean follow up of 54 months, 10 cases of secondary ovarian cancer were recorded in the study cohort of 770 women with breast cancer. Mean time to ovarian cancer diagnosis was 6 years. Positive family history was recorded in 25% of the patients whose relatives had either breast or ovarian cancer.Conclusion: In our interim analysis, it was founded that the development of secondary cancer in the study group was higher among younger patients (<40 years) as well as patients with positive family history. Close medical surveillance, and perhaps even prophylactic oophorectomy, might be justified in high-risk group.

Introduction

Breast cancer is the most common malignancy diagnosed in women accounting for 23% of all malignancies worldwide 1. Epithelial ovarian cancer is the most lethal gynecologic cancer leading to 47% of all deaths from cancers of female genital tract 2.

Women with a history of breast cancer have a two fold higher risk of developing a subsequent ovarian cancer 3. This risk seems to be highest among or even confined to women who are younger than 50 years at diagnosis of breast cancer4. Particularly the high rate of primary ovarian cancer is found in breast cancer patients with mutations in the high penetrance genes BRCA1 or BRCA2, which are associated with hereditary breast cancer and ovarian cancer5,6. Such women experience almost 50% cumulative risk of developing ovarian cancer by the age of 70 years 7.

Risk of ovarian cancer in breast cancer patients- prognostic factors and time interval

Ebtessam Saad El Deen, Dalia Darwish, Noha Ibrahim, Mahmoud Yassein, Mohsen Mokhtar.

Oncology Department, Faculty of medicine, Cairo University.

Corresponding Author: Noha Yehia Abdou Ibrahim, Misr El gedida, Cairo, Egypt - E-mail: [email protected]

Key words: Ovarian cancer in breast patients, Prognostic factors, Time interval.

Submitted: 10 September 2009 - Accepted: 26 December 2009

ISSN: 2070-254X

To estimate the risk of subsequent ovarian cancer in clinical setting, use of information such as age at onset of breast cancer, and presence of family history would be more practical than mutation screening8, especially if not present in many centers. Moreover, mutation in BRCA1 or BRCA2 are present in small numbers in all patients with breast cancer and ovarian cancer, and they seem to account for only a limited fraction of all breast cancers with a genetic component9,10 The average interval between the diagnosis of the two primaries is unknown.11

Patients and Methods

In this study, we explored a large population of breast cancer patients diagnosed between 1998 and 2005 in the department of clinical oncology private section, Cairo University, Aswan oncology institute and health insurance patients. We analyzed cases that developed secondary ovarian cancer as regards age at first diagnosis, stage and histology of each cancer type at diagnosis. Special emphasis was directed to the age at diagnosis of breast cancer, pathology and time interval to develop secondary ovarian cancer as well as the presence of family history (first-degree relative such as mother, sister, daughter or father or brother or close relative as grandparent, aunt or uncle, nephew or niece). Patients with a time interval less than 12 months between the two diagnoses were excluded to reduce the likelihood of including patients with a metastatic primary tumor 4.

Study outcome included overall survival and time to progression, each measured from the time of definitive surgery. The duration of overall survival was the interval between diagnosis and death. Data were censored at the last follow-up of patients.

Statistical method

Kaplan Meier method was used for estimating overall survival, and relapse free survival. P-value is considered significant at 0.05 level. Numerical data were described in terms of means and medians for central tendency and standard deviation and range, minimum and maximum for dispersion.


Results

Among the study group, 770 women with breast cancer presented to department of clinical oncology private section, Cairo University Aswan oncology institute and health insurance between 1998 and 2005, 10 patients developed secondary ovarian cancer. The demographics of the studied population are presented in table 1. The mean age at breast cancer diagnosis was 43 years (range 34-50) during a mean follow up of 54 months.

Table 1: Correlation between various clinical and pathological variables in patients with cancer breast and secondary ovarian cancer

Variables Breast cancer

Number %

Ovarian cancer

Number %Age34-44>44-50

73

70%30%

46

40%60%

Mean age 43 48

StageI, IIIII, IV

82

80%20%

37

30%70%

HistologyDuctalLobular

SerousMucinousEndometroidClear cell

91

90%10%

6121

60%10%20%10%

GradeGrade I,IIGrade III

37

30% 70%

46

40%60%

Family history 3 30% 1 10%

Eighty percent of primary breast cancer patients were stage I-II, 90% were invasive duct carcinoma with 70% being high grade. The histology of ovarian cancer was mostly serous 60%, 20% endometroid and 10% mucinous as well as clear cell. Estrogen Receptor (ER) and Progesterone Receptor (PR) were available in 80% of cases of breast cancer. We found that ER+/PR+ tumors were documented in 5 cases of breast cancer who developed ovarian cancer (62.5%). Among 3280 relatives, 7 cases of breast or ovarian cancer were documented. The pathological characteristics of the study population are presented in table 2.

Table 2: Time interval between diagnosis and survival times in months

Variables Months P valueTime interval between diagnosis MeanMedianRange

603624- 128

Variables Months P valueSurvival timesBreast cancer DFSOvarian cancer DFS

Breast cancer OSOvarian cancer OS

Combined breast and ovarian cancer OS

6139

11542

115

0.013

0.019

Disease free survival (DFS), Overall survival (OS)

Mean time interval to ovarian cancer diagnosis was 60 months with a median of 36 months ranging from 24 to 128 months. The overall survival of breast cancer was 115 months compared to 42 months in those developing secondary ovarian cancer. The overall survival of both groups was 115 months. The progression free survival of primary breast cancer was 61 months versus 39 months for the secondary ovarian.

Table 3: Relation between different variables and secondary ovarian cancer

Variable Number % P valueAge34-44>44-50

73

70%30% 0.06

StageI, IIIII, IV

82

80%20% 0.01

HistologyDuctalLobular

91

90%10% 0.001

GradeGrade I,IIGrade III

37

30%70% 0.06

Discussion

In our study two-fold increased risk of primary ovarian cancer in women with primary breast cancer was reported. Women without a family history of breast or ovarian cancer, this high risk seemed confined to patients diagnosed at young age.

Our most interesting finding, however, was the increased risk in women with early-onset breast cancer, and those with family history of breast cancer or ovarian cancer. Also noteworthy is the finding that patients with family history, especially if an ovarian cancer is present, have a higher risk of ovarian cancer. This risk is present for postmenopausal women, and seems to be constant over time.

In a study done by Bergfeldt, et al, the Mean age at breast-cancer diagnosis was 48 years (range 11–66 years). During a mean follow-up of 6 years, 122 cases of ovarian cancer were recorded in the study cohort of 30 552 women with breast cancer. Mean time to ovarian cancer diagnosis was 7 years (SD=5·9). Among 146 162 relatives, 3689 cases of breast or ovarian cancer were documented. Patients without any family history of breast or ovarian cancer had a 60% increased risk overall, but the excess risk seemed confined to premenopausal ages, and was three-fold in women younger than 40 years (3·3, 2·2–4·9). A family history of breast or ovarian cancer in a close relative was associated with a four-fold (4·3,


2·9–6·0) increased risk of ovarian cancer, and in women diagnosed before the age of 40 years, the risk was seven-fold (7·3, 3·1–14·3). In patients older than 40 years at diagnosis, the SIRs were smaller but remained raised11.

In our study the mean age of patients at the diagnosis of breast cancer was 43 years, with a range of (34-50) years. The mean time to ovarian cancer diagnosis was 5 years with a range of (2- 10.6) years. Increased risk was found in women with primary breast cancer at the age range of 34-44 years (70%). Our results expand the knowledge of an association between breast cancer and the risk of subsequent ovarian cancer. . Euhus et al, reported that diagnosis at a young age has been noted as a minor risk factor, and patients with breast cancer who have mutations in BRCA1 or BRCA2 have increased risk 12. Although such mutations are rare (present in <5% of all breast cancer cases), hereditary factors might account for close to 25% of breast-cancer13-15. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% for breast cancer and 39% for ovarian cancer16. Therefore, our study lends support to theories of a connection between as yet unknown genes and cancer susceptibility. A reasonable proxy for unknown genetic risk factors might be a family history of breast or ovarian cancer.

In our study the pathology of the majority of breast cancer patients was found to be infiltrating ductal carcinoma (90%). While in ovarian cancer patients papillary serous adenocarcinoma (60%) was found to be more than the other types. This goes with various studies done that revealed the pathology of the breast cancers was found to be infiltrating ductal carcinoma (63%). And showing that invasive ductal carcinoma is the most common pathology in both familial and sporadic breast carcinoma16. On the other hand, the ovarian cancer pathology was more varied. They found papillary serous adenocarcinoma (53%) to be the most frequent type of ovarian cancer histology. This finding is also not unexpected as previous studies have shown that familial ovarian cancer has a higher proportion of serous adenocarcinoma compared to non-familial tumors17, 18.

There is limited data on the reciprocal time interval between metachronous primary breast and ovarian carcinomas. Time interval of women with breast cancer ranged from 48 to 84 months, with a mean of 58 months in many studies9,19. However, many of these studies are limited by small sample sizes obtained from single academic institutions, and it is non significant. In our study the time interval ranged from 24-128 months with a mean of 60 months.

Moreover, we found that the most independent prognostic variables were age at diagnosis and presence of familial history of breast or ovarian cancers.

Therefore we recommend close follow up using radiological (CT chest, abdomino-pelvic) and laboratory investigations (CA125, CA15-3) for detection of early signs of ovarian cancer especially in young patients and those with a positive family history.

Conclusion

In our study, there was an increased risk of secondary ovarian cancer in young patients with breast cancer and those with family history of the disease. Future directions should include searching for gene mutations in this subgroup of patients to determine patients at risk in an earlier stage of disease. Close medical surveillance, and perhaps even prophylactic oophorectomy, might be justified in high risk group.

References

1. D.M. Parkin, F. Bray, J. Ferlay and P. Pisani, Global cancer statistics, 2002, CA Cancer J. Clin. 55, pp. 74–108, 2005.2. P.J. DiSaia and W.T. Creasman, Epithelial ovarian cancer. In: P.J. DiSaia and W.T. Creasman, Editors, Clinical gynecologic oncology, Mosby, St. Louis 2002. 3. Alexander Olawaiye, Lori Caesar, Debra Walsh et al., Analysis of the time interval between diagnoses in women with double primary breast and ovarian or primary peritoneal cancers, Vol 94, p 796-802 sept, 2004.4. Wen-Shiung Liou, Chad A. Hamilton, Michael K. Cheung, et al., Outcomes of women with metachronous breast and ovarian carcinomas, vol 103, 190-194 Oct, 2006.5. A. Antoniou, P.D. Pharoah and S. Narod et al., Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies, Am. J. Hum. Genet. 72, pp. 1117–1130 [Erratum appears in Am J Hum Genet. Sep; 73(3):709, 2003.6. Fishman, E. Dekel and A. Chetrit et al., Patients with double primary tumors in the breast and ovary—clinical characteristics and BRCA1-2 mutations status, Gynecol. Oncol. 79, pp. 74–78, 2000.7. N Loman, O Johannsson, U Kristoffersson, H Olsson and A Borg, Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer, J Natl Cancer Inst 93, pp. 1215–1223, 2001.8. Lichtenstein, NV Holm and PK Verkasalo et al., Environmental and heritable

Percents surviving

Fig 1: Kaplan–Meier analysis of overall survival (OS) for breast cancer

Fig 2: Kaplan–Meier analysis of overall survival (OS) for ovarian cancer

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factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland, N Engl J Med 343, pp. 78–85, 2000. 9. Anglian Breast Cancer Study Group, Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases, Br J Cancer 83, pp. 1301–1308, 2000.10. Trentham-Dietz A, Newcomb PA, Nichols HB, Hampton JM. Breast cancer risk factors and second primary malignancies among women with breast cancer. Breast Cancer Res Treat. Oct;105(2):195-207, 2007.11. DrKjell Bergfeldt MD, Bosse Rydh BSc, Fredrik Granath PhD et al., Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study, vol 360, p 891-894, Sept, 2002. 12. D.M. Euhus, K.C. Smith and L. Robinson et al., Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO, J. Natl. Cancer Inst. 94, pp. 844–851, 2002.13. M.H. Skolnick, T. Frank, D. Shattuch-Eidens and S. Tavtigian , Genetic susceptibility to breast and ovarian cancer. Pathol. Biol. (Paris) 45, pp. 245–249, 1997. 14. D. Ford and D.F. Easton , The genetics of breast and ovarian cancer. Br. J. Cancer 72, pp. 805–812, 1995.15. M. Cvelbar, M. Ursic-Vrscaj and S. Rakar, Risk factors and prognostic factors in patients with double primary cancer: epithelial ovarian cancer and breast cancer, Eur. J. Gynaecol. Oncol. 26, pp. 59–63, 2005.16. H.T. Lynch, M.J. Casey, T.G. Shaw and J.F. Lynch, Hereditary factors in gynecologic cancer, Oncologist 3, pp. 319–338, 1998.17. Breast Cancer Linkage Consortium, Pathology of familiar breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases, Lancet 349, pp. 1505–1510, 1997.18. O.T. Johannsson, I. Idvall and C. Anderson et al., Tumour biological features of BRCA1-induced breast and ovarian cancer, Eur. J. Cancer 33, pp. 362–371, 1997.19. A. Olawaiye, L. Caesar and D. Walsh et al., Analysis of the time interval between diagnoses in women with double primary breast and ovarian or primary peritoneal cancers, Gynecol. Oncol. 94, pp. 796–802, 2004.


original article <

Abstract

Objective: To evaluate the activity of cisplatine and vinorelbine as a first line, in unresectable patients with malignant pleural mesothelioma. Patients & Methods: The study included 48 patients [77%- males] epithelial subtype (73%), stage III (43%), and stage IV (52%), performance status 0, 1 and 2, 23, 73 and 4%, respectively. The median age was 57 years [22 – 65 years]. Vinorelbine 25 mg/m2 I.V. weekly and cisplatin 100 mg/m2 I.V. every 4 weeks were given with hydration and anatiemetic treatment.Results: Median number of administered cycles was four. Objective response were observed in 29.2 % with no complete response Median time to progression was 7.8 months (1.8 – 40.2 months) and median survival 17.2 months (0.6 – 43 months). There were 14 PR (response rates 29.2%). The fraction of patients alive at 1 and 2 years were 62.5 and 31% respectively. Grade 3 or 4 leucopenia occurred in 33% and 11% of patients respectively, nausea in 10%, neurotoxicity in 12%, nephrotoxicity in 4%. There were no toxic deaths. Conclusion: Cisplatin and vinorelbine is an active regimen in malignant pleural mesothelioma with a response rate and survival comparable to the most active regimens so far reported.

Introduction

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy with an increasing incidence world-wide, due to the widespread of asbestos containing materials on a global scale over the last five decades(1). Most patients with MPM, treated or untreated, will die from complications of local disease due to increasing tumor bulk. The diffuse spreading growth of this neoplasm makes surgery difficult and hence an option for only a minority of the patients (2).Chemotherapy is the treatment of choice in the majority of cases. Among recently introduced chemotherapeutic agents only vinorelbine, edatrexate, gemcitabine and raltitrexed have demonstrated 20% of response rates (RR) (3). Platinum compounds and doxorubicin are active and are usually included in the chemotherapy regimens for MPM (4). Cisplatin alone showed a response rate of 14% as a single agent and about 30% response rate when used in a combination regimen. Doxorubicin has been studied extensively in the treatment of MPM. It demonstrated a response rate of 18% as a single agent and 25 – 28% when used in a combination regimen. High – dose

Cisplatin and Vinorelbine in unresectable malignant pleural mesothelioma

Nivine M.A. Gado, MD

Corresponding Author: Nivine M.A. Gado, Radiation Oncology, Nuclear Medicine Department, Ain Shams University - Email: [email protected]

Key words: Malignant pleural mesothelioma, cisplatin, vinorelbine.

Submitted: 25 October 2009 - Accepted: 26 December 2009

ISSN: 2070-254X

methotrexate was the most active antimetabolite, with a response rate of about 38%(1). The third generation vinca alkaloid vinorelbine has attracted interest in a phase II trial using vinorelbine 30 mg/m2 i.v. weekly. Each cycle consisted of 6 weekly injections and the median number of injections was 12. The intention to treat response rate among chemotherapy – naive MPM patients was 24% (95% confidence level 10 – 44%) and the fraction of patients alive at 1 year from time of first treatment was 41%, which ranks vinorelbine among the most active agents in MPM. Toxicity of this regimen was modest (5).On the basis of these results, we decided to evaluate the activity of vinorelbine in combination with cisplatin as first line treatment in MPM.

Materials and Methods

Patients were eligible if they had histological proven MPM, no previous radiotherapy or chemotherapy, measurable disease, ECOG performance status (PS) score ≤ 2 or less, life expectancy ≥ 3 months, age ≥ 18 years and written informed consent. Adequate organ functions were required, defined as WBC ≥ 3000 UL-1, platelets ≥ 100000 UL-1, hemoglobin > 10 gm/dl, total bilirubin < 1.5 times the upper limit of normal (ULN), AST and ALT < 2 times the ULN, serum creatinine < 2.0 mg per 100 ml, or a calculated serum creatinine clearance > 60 ml/min.Exclusion criteria included: significant medical or psychiatric co-morbidity, brain metastases, pregnant or lactating women, and previous or concurrent malignancies. All patients of fertile capacity were to use safe contraception.

Treatment planVinorelbine 25 mg/m2 was administrated i.v. weekly as a 10 – min infusion, cisplatin 100 mg/m2 was administrated as a 1h. i.v. infusion together with intravenous hydration and antiemetic treatment, every 4 weeks. Weekly complete blood cell counts and chemistry panel were performed. Treatment was delayed by 1 week in case of bone marrow suppression (WBC < 3000 UL-1, neutrophil count < 1500 UL-1 or platelets < 100000 UL-1 ). Cisplatin was not administrated if creatinine clearance below < 50 ml min-1.Dose was adjusted in case of grade 4 hematological toxicity, or grade 3-4 non-hematological toxocities. Dose-delay up to 3 weeks were permitted for recovery from drug toxicity. Granulocyte colony stimulating factors were not routinely used.


Treatment assessmentBaseline complete history, physical examination, complete blood cell count, liver and renal function tests, blood electrolytes were done.Baseline creatinine clearance was performed and then before every second treatment (every 8 weeks). Spiral CT-scan was performed at baseline, before start of every other treatment cycle (every 8 weeks), and every 2 months after end of therapy. Chest x – ray was performed at baseline and before each treatment cycle. Response was assessed by new modified RECIST criteria, (8).Change in disease was assessed by measuring the tumor thickness perpendicular to the chest wall or mediastinum in up to three involved areas of pleural rind at least 2 cm apart on computed tomography scan, at baseline and at every other cycle (at least one measurement was > 1.5 cm). A reduction of at least 30% on two occasions 4 weeks apart defined a partial response, an increase of 20% over the nadir measurement, progressive disease.A complete response (CR) was defined as complete absence of all signs of disease without any new lesions or disease – related symptoms.

Statistical AnalysisSurvival was defined as the time from onset of treatment to the time of death from any cause. Time to progressive disease was defined as the time from onset of treatment until progression or death from any cause. Statistical analysis was done using Kaplan – Meier method to estimate overall survival and time to progression.

Results

Patients characteristics Forty eight patients were enrolled from March 2006 till November 2008. Most patients were males (77%), had epithelial subtype (73%), performance status 0 – 1 (96%), previous asbestos exposure (83%), and IHIG stage III – IV (94%) (Table 1). Median age was 57 years (range 22 – 65 years).

Table 1: Patients Characteristics

VariablesTotal

No. of patients (%)48 (100)

Gender Male Female

37 (77)11 (23)

Asbestos exposure No Yes

8 (17) 40 (83)

Pathology Epithelial Sarcomatous Biphasic

35 (73)4 (8)9 (19)

IMIG stage I II III IV

-3 (6)

20 (42)25 (52)

Performance status 0 1 2

11 (23)35 (73)

2 (4)

Age Median Range

57 years (22 – 65)

ToxicityA total of 248 treatment courses were given, with a median of 4 (range 1 – 6). Grade 3 or 4 leucopenia occurred in 21 patients (44%), with 5 patients having grade 4 (11%) (Table 2). Four patients (8%) had febrile neutropenia with no septic deaths. None had grade 3 or 4 thrombocytopenia. Non-hematological grade 3 or 4 toxicity occurred with respect to nausea (10%), neurotoxicity (12%), nephrotoxicity (4%) and other toxicities as constipation and tiredness in 8%. Seven patients (15%) were hospitalized due to toxic effects of chemotherapy. One patient died due to pulmonary embolism.

Table 2: Toxicity Profile

Grades No. of patients (%)0 1 2 3 4

HematologicToxicityLeucopenia NeutropeniaThrombocytopeni

10 (21)7 (15)44 (92)

3 (6)7 (15)3 (6)

14 (29)17 (35)1 (2)

16 (33)13 (27)

-

5 (11)4 (8)

-

Non-hematologicToxicityNausea Vomiting Nephrotoxicity Neurotoxicity Other toxicity

17 (36)29 (60)23 (48)19 (40)5 (10)

21 (44)10 (21)11 (23)15 (31)21 (44)

5 (10)9 (19)12 (25)8 (19)18 (38)

5 (10)-

2 (4)4 (8)3 (6)

---

2 (4)1 (2)

Treatment intensity is shown in table 3 where a median of 4 treatment courses were given

Table 3:Treatment Intensity

Variables

No. of treatment courses No. of patients (%)123456

2 (4)2 (4)3 (6)3 (6)7 (15)31 (65)

Dose reduction was necessary in 17 patients (35%) most frequently due to hematological toxicity (9 patients) nephrotoxicity (2 patients) or neurotoxicity (6 patients), other less frequent causes were nausea, hearing loss and tinnitus. These reasons were non-exclusive. Retreatment postponement due to delayed hematological recovery occurred in 18 patients (37.5%). These delay were due to non – exclusive reasons as delayed hematologic recovery, hematuria, pneunomonia and poor performance

Response and Survival Fourteen cases responded to this protocol with an overall response rate of 29.2% (CR 0%, PR 29.2%), Thirty four patients (71%) had stable and progressive disease(S.D. in 16 patients (33.3%) -P.D in 18 patients (37.5%). Eleven responses occurred among the 35 cases having epithelial subtype (31.4%) and in one and two patients respectively among the 4 sarcomatous and nine biphasic cases. Six responses were noted among 11 female patients (54.5%) compared to eight responses among 37 males (29%). The fractions of patients alive after 1 and 2 years were 30 patients (62.5%) and 15 patients (31%), respectively. Median time


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to progression was 7.8 months (1.8 – 40.2 months), whereas median survival was 17.2 months (0.6 – 43 months). Curves of overall survival and time to progression are shown in figure 1 and 2, respectively.

Fig 1: Overall survival.

Discussion

Patients with MPM are reported to have poor survival rate because of the advanced stage of disease at presentation and its chemoresistance (9). In 1996, Ong and Vogelzang(10) identified only six regimens showing a response rate superior than 20%.They recommended further Phase II trials to search for agents that are effective against local and systemic disease .. In this study, the response rate of 29% is noteworthy, if compared to the most used regimens in MPM (table 4). However, it is difficult to compare differences in activity between the regimens due to several reasons. First, most of the studies are phase II trials or retrospective analyses except for the randomized trials by Vogelzang et al, 2003(11) and van Meerbeeck et. al, 2005 (12), which usually showed tendency towards higher response rates in the very selective non-randomized trials. Second, is the different prognostic variables between the trials. (table 4)

Table 4: Selected combination chemothegrapy regimes in MPM

Author, year Regimen N Response rate (%)

Median survival(months)

Time to PD

(months)

1- yearsurvival (%)

Current study Van Meerbeeck, 2005a

Vogelzang, 2003a

Obasaju, 2007Santoro, 2007Ceresoli, 2006Andreopoulou, 2004 Byrne, 1999Van Haarst, 2002Favaretto, 2003Berghmans, 2005

CDDP+vinorelbineCDDP+raltitrexedCDDP+pemetrexedCDDP+pemetrexedCBDCA+pemetrexedCBDCA+pemetrexedCDDP+MMC+VBLCDDP+gemcitabineCDDP+gemcitabineCBDCA+gemcitabineCDDP+epirubicin

4812622672886110215021325069

29.224.041.320.521.718.615.348.016.026.019.0

17.211.412.110.8NA12.77.010.09.614.713.3

7.85.35.7NANA6.5NANA6.08.9NA

62.5465145645231NA365350

In CALGB (13), EORTC (14), and in the randomized trial by van Meerbeeck(12), they pointed to better outcome for MPM patients having epithelial histological subtype. The frequency of epithelial subtype in the current study was 73%, which is higher than that in Vogelzang et al (15), thus explaining the tendency towards a higher response rate. The frequency of epithelial subtype was however, similar to that in newer studies, such as those by Vogelzang et al 2003 (11) (68% epithelial), van Meerbeeck et al 2005 (12) (75%), Berghmans et al, 2005 (15) (74%), and van Haarst et al 2002 (16) (81%), pointing toward a uniform rate of epithelial subtype of 70 – 80% in more recent trials and with the current study being in accordance

0 10 20 30 40 50 60 70 80 90

100

6 9 12 18 24 30 36 42

Fig1: Overall Survival

Time (months)

Ov

era

ll S

urv

iva

l %

Fig.2: Time to Progression

Time (months)

Tim

e to

pro

gre

ssio

n %

0

10

20

30

40

50

60

70

80

90

100

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

CDDP – cisplatin; CBDCA = carboplatin; MMC = mitomycin C; VBL = vinblastine, NA = not available, a = Data from randomized trial.

Fig 2: Time to progression.


with these trials. In the current study,the response rate is comparable to that of single agent vinorelbine, which revealed a 24% partial response rate (5).Hematological toxicity was relatively high in the current study where 44% of the patients experienced Grade 3 or 4 leucopenia (Table 2). This was in accordance with Berghmans et al, 2005 (15) and lower than the 81% of NSCLC patients who had Grade 3 or 4 granulocytopenia in the randomized SWOG trial (6). It’s however, considerably higher than was observed in randomized trial in MPM patients with cisplatin and pemetrexed (18%) (11), or cisplatin and ralitrexed (7%) (12). Also, febrile neutropenea was somewhat higher, being 8% compared to 2 and 1% respectively, in the two randomized trials cited above. There were no septic deaths. The febrile neutropenia rate of 8% in this study is not only a potential risk but also an inconvenience for those patients who have to be admitted for intravenous antibiotics, as well as a cost for the healthcare system. Other toxicities weren’t pronounced (Table 2). In the current study, a median survival of 17.2 months and 2 year survival rate of 31% were impressive, even though patients with adverse prognostic variables such as performance status 2 was included (Table 1). The survival results compares favorably with those reported on for either active regimens, ranking this regimen among the most active cytotoxic treatments for MPM reported to date (Table 4). On the other hand, this regimen is inconvenient for patients and for health care system because of the weekly administration but still it could be more convenient to be used in an oral form. Both cisplatin and pemetrexed as well as cisplatin and raltitrexed have proved superior to single agent treatment with cisplatin in randomized trials (11, 12). The high antitumor activity of cisplatin and vinorelbine deserves attention for use as induction treatment before surgery in resectable cases. Development of platinum compounds, together with vinorelbine in the palliative setting, also seems justified both in the light of the documented activity of the two–drug combination used in the current study and also because the single agent activity of vinorelbine with a response rate of 24% (5) which ranks this agent among the most active single agent in MPM. However, it must be kept in mind that these results are obtained from relatively small and non – randomized trials. Improvement of the current regimen is necessary if it is to be used in palliative situation to make it more feasible & vinorelbine may be applied in the oral formulation. Also, evaluation of new targeted agents is necessary to improve prognosis for this dismal disease. Vinorelbine may also be explored as second – line treatment for patients not previously exposed to this drug.

References

1. Favaretto A.G., Aversa S.M., Paccagnella A., Manzini, VDP, Palmisano V., Oniga F., Stefani M., Rea F., Bortolotti L., Loreggian L., Monfardini S. (2003), Gemcitabine combined with Carboplatin in patients with malignant pleural mesothelioma. Cancer, 97: 2791 – 97. 2. Treasure T., Sedrakyan A (2004): Pleural mesothelioma: little evidence, still time to do trials, Lancet 364 : 1183 – 85.3. Favaretto A (2005): Overview on ongoing or planed clinical trials in Europe. Lung cancer; 49 (suppl 1): S117 – S21-4. Sorensen JB (2008): Current concepts in chemotherapy for malignant pleural mesothelioma Clin Respir J 2 : 74 – 79.5. Steale JPC, Shamash J, Evans MT, Gower NH, Tischkowitz MD, Rudd RM (2000). Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 18 : 3912 – 17. 6. Wozmak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridomidis CH, Baker LH, Albain KS, Kelly K, Taylor SA, Gandara DR, LivIngston RB (1998) : Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of

advanced non – small cell lung cancer : A southwest Oncology Group Study, J Clin Oncol 16 : 2459 – 65.7. Le Chevalier T, Brisgand D, Douillard JY, Pajol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S (1994) : Randomized study of navelbine and cisplatin versus vindesine and cisplatin versus navelbine alone in advanced non – small cell lung cancer. Results of a European multicenter trial including 612 patients. J Clin Oncol 12 : 360 – 67.8. Byrne MJ, Nowak Ak (2004): Modified RECIST criteria for assessment of response in malignant plural mesothelioma. Ann Oncol 15 : 257 – 60.9. Pollack RE, Karnell LH, Menck HR, Winchester DP, (1996): The national cancer data base report on soft tissue sarcoma. Cancer; 78 : 2247 – 57. 10. Ong ST, Vogelzang NJ (1996): Chemotherapy in malignant pleural mesothelioma: a review J Clin Oncol; 14 : 1007 – 17.11. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denhan C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S., Mangegold C, Niyikiza C, Paoletti P (2003): Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21 : 2636 – 144.12. Van Meerbeeck JP, Gaafar R, Manegold C, van Klaveren RJ, van Merck EA, Vincent M, Legand C, Bottomley A, Debruyne C, Giaceone G (2005). Randomized phase III study of cisplatin with or without ralitrexed in patients with malignant pleural mesothelioma. An intergroup study of the EORTC Lung Cancer Group and the NCIC. J Clin Oncol 23 : 6881 – 89. 13. Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ (1998): Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the cancer and Leukemia Group B. Chest 113 : 723 – 31.14. Curran D, Sahmoud T, Theressa P, van Meerbeeck J, Postmus PE, Giaccone G (1998) : Prognostic factors in patients with pleural mesothelioma : The European Organization for Research and Treatment of Cancer Experience. J Clin Oncol 16 : 145 – 52. 15. Berghmans T, Lafitte JJ, Paesmans M, Stach B, Berchier MC, Wackamier P, Lecomte J, Collon T, Mommen P, Sculier JP (2005): A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma Cancer 50 : 75 – 82.16. Van Haarst JMW, Baas P, Manegold C, Schouwink JH, Burgers JA, de Bruin HG, Mooi WJ, van klaveren RJ, de jonge MJ, van Meerbeeck JP (2002 ): Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer 86:342- 45.17. Obasaju CK, Ye Z, Woyniak AJ, Belani CP, Keohan ML, Ross HJ, Polikoff JA, Mintzer DM, Monberg MJ, Janne PA (2007): Single – arm, open label study of pemetrexed plus cisplatin in chemotherapy naive patients with malignant pleural mesothelioma: outcomes of an expanded access program. Lung Cancer 55 : 187 – 94. 18. Santoro A, O’Bruin S, Stahel R, Nackaerts K, Baas P, Paz – Ares L, Sundstrom S, Visserem – Grut C, Blatter J, Manegold C (2007): Pemetrexed plus cisplatin (P + Cis) or pemetrexed plus carboplatin (P + Cb) for chemonaive patients with MPM. Results of the International Expanded Access program (EAP). J Clin Oncol 25 (18S) : 24 S, abstract, 7662.19. Ceresoli GL, Betta GP, Gastagneto B, Facciolo F, Arcangeli G, Zucali PA., Libener R, De Giovamni D, Melis E, Mirri Oncol 17:13 – 16 20. Andreopoulou E, Ross PJ, O’Brien MER, Ford HER, Priest K, Eisen T, Norton A, Aschley S, Smith IE (2004): The palliative benefits of MVP (mitomycin C, vinblastine and Cisplatin) chemotherapy in patients with malignant mesothelioma. Ann of Oncol 15 : 1406 – 12.21. Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, Buck M, de Klerk NH, Robinson BWS (1999): Cisplatin and gemcitabine treatment for malignant pleural mesothelioma: a phase II study. J Clin Oncol 17 : 25 – 30.


como 8 | nov 2009 | beirut, lebanon <

Cancer is one of the major health problems that the human being is facing today and its importance is highlighted with increase in age. Overall, 12 percent of all deaths worldwide are due to cancer. (WHO 2007)

Throughout the world, there are 10 million new cases of cancer and 6 million deaths annually from this non communicable disease. These numbers will continue to grow; by 2020, that figure will double with approximately 70% occurring in developing countries reflecting better prevention strategies in the developed world.

One way to tackle this problem is scientific data exchange among researchers, doctors, nurses, and also benefiting from European-American experiences in this area.With respect to the above issue, the Middle East Oncology Congress / Congrès d’Oncologie du Moyen-Orient (COMO) is held biannually, hosted by the Lebanese Cancer Society with the aim of providing the grounds for the researchers in this area to exchange their experiences and to come with a close contact with each other.

Since 1993, the Lebanese Cancer Society has organized periodically the Middle East Oncology Congress (COMO) (see attached fig) which has usually been conducted under the auspices of the UICC (Union Internationale Contre le Cancer / International Union Against Cancer), and has attracted participants from Lebanon and throughout the Arab region.

The last 8th Middle East Oncology Congress (COMO8), held from 5-7 November 2009 in Beit Al Tabib- LOP- Beirut was a real success. It was a multidisciplinary scientific event which covered all aspects of cancer – prevention – detection – diagnosis - treatment and supportive care. (Attached the flyer of the event).

The scientific program surpassed the expectations, setting a new level of value and impact. Twenty five prominent and renowned international speakers alongside with Lebanese and Regional speakers took part in our meeting. Two hundreds and eighty attendees registered for the event from Lebanon and the neighboring Arab countries. Twenty two pharmaceutical companies participated in the Scientific Exhibit.

It was an occasion for the participants from abroad to get familiar with the history and culture of our country. Lebanon is a country with a very rich historical, cultural

MIDDLE EAST ONCOLOGY CONGRESS A TRADITION AND A NECESSITY

and human sciences background. We show the world that we are a peace-loving, science-driven people who strive for continuing medical education, for better research, and better medical care of our patients under all circumstances.

I take this opportunity to remind you that the Lebanese Cancer Society is one of the largest voluntary, non-profit, and non-governmental health organization in Lebanon. It was founded in 1954 and recognized of Public Utility (Decree No. 4825). It is composed of medical and non-medical members, which gives it a social outreach to match the fact that cancer is a society problem and not just a medical problem.

The Society’s national mission is to work for the control of cancer as a major health problem by:• Promoting prevention and early detection of cancer,• Improving treatment methods and saving lives from cancer,• and Diminishing suffering from cancer with a better quality of life through

education, advocacy, and service.

I would like to thank Dr. Sami Khatib, President of the Arab Medical Association Against Cancer (AMAAC) for his support, and Dr Marwan Ghosn, editor-in-Chief of the Pan Arab Journal of Oncology (PAJO) for the integration of the abstracts in this special issue of the Journal.

Finally, I take the opportunity to send to all the readers of the PAJO and their families my best wishes for a Happy New Year 2010 full of Health, Prosperity and Happiness.

Michel Daher, MD, FACSPresident, Lebanese Cancer SocietyProfessor of Surgery- Univ of BalamandSaint George Hospital- UMCPOBox: 166378- Achrafieh, Beirut, LebanonE-mail: [email protected]


• COMO I : 7 - 10 Juillet 1993• COMO II : 19 - 22 Avril 1995• COMO III : 1er - 3 Mai 1997• COMO IV : 29 Avril - 2 Mai 1999

• COMO V : 25 – 28 Avril 2001• COMO VI : 1 – 4 May 2003• COMO VII: 28 – 30 April 2005• COMO VIII: 5-7 November 2009

Middle East Oncology Congress


como 8 abstracts <

ALL IN ADOLESCENTS AND YOUNG ADULTSJulio C. Barredo, MD. Toppel Family Professor of Pediatric Hematology-Oncology. Director, Division of Pediatric Hematology-Oncology. Associate Chair for Basic Research, Holtz Children's Hospital. Director, Children's Cancer Programs at UM Sylvester Comprehensive Cancer Center. University of Miami Miller School of Medicine.

Refined chemotherapy regimens have led to significant improvements in outcome for children with Acute Lymphoblastic Leukemia (ALL). Nevertheless, the cure rates for adolescents and young adults (AYA) with ALL lag behind, and significant gap exists when comparing event-free survival (EFS) with younger patients and even older adults with cancer. This gap continues to result in the highest mortality for ALL for patients between 15-34 years of age, when compared with all other age groups. The causes behind this sobering reality are multifactorial, and include biological differences in ALL, differences in treatment approaches and socio-economic factors. Among the latter, this age group has the lowest percentage of participation in clinical trials, and is the one more likely to be uninsured in North America. Significant biological differences also exist between ALL in younger children and in AYA patients, with the more chemotherapy sensitive phenotypes (hyperdiploid and TEL/AML1) more prevalent in the younger age groups while AYA patients exhibit higher incidence of BCR/ABL positive ALL. More important, significant differences exist in the treatment approach when pediatric type ALL therapies are compared with adult type ALL therapy. Among these differences, the more important are differences in the approach to induction therapy, intensity and duration of post-remission therapy, type and intensity of CNS prophylaxis, and the duration of maintenance chemotherapy. While pediatric type ALL therapies rely more on the use of higher doses of corticosteroids, L-asparaginase, methotrexate and vincristine, adult type regimes have higher doses of anthracyclines and alkylating agents. Nonetheless, several retrospective comparisons have indicated that when treated with pediatric type ALL regimens, AYA patients achieve significantly higher cure rates. Therefore, improving participation of AYA patients on clinical trials, better understanding of biological differences and the use of pediatric type regimens should lead to improve cure rates for adolescents and young adults diagnosed with ALL.

TREATMENT OF RELAPSED ALLJulio C. Barredo, MD. Toppel Family Professor of Pediatric Hematology-Oncology. Director, Division of Pediatric Hematology-Oncology. Associate Chair for Basic Research, Holtz Children's Hospital. Director, Children's Cancer Programs at UM Sylvester Comprehensive Cancer Center. University of Miami Miller School of Medicine.

Acute Lymphoblastic Leukemia (ALL) is a heterogeneous disease in which the presence of non-random translocations and chromosomal aberrations correlates with prognosis, biological behavior and molecular subtypes characterized by specific gene expression profiles. Although significant increases in cure rates have been attained in childhood ALL (EFS ~80%), the outcome for patients after relapse continues to be dismal. Major challenges and questions remain in relapsed ALL including: a) many relapses occur in favorable risk patients; b) difficulty in predicting response to retrieval therapies; and c) failure of therapy intensifications strategies to yield improved outcomes. Among the clinical determinants of outcome after relapse in ALL, time to relapse and site of relapse remain the most relevant. Consequently patients who suffer an early relapse (< 18-36 months form diagnosis) and those who relapse in the bone marrow, have significantly lower cure rates compared to late relapses and those with isolated extramedullary relapses. In

this context, published studies worldwide demonstrate EFS ranging from 5-19% and 33-50% for patients with early systemic relapse compares to late relapse, respectively. Current strategies being pursued to improve outcome after relapsed ALL include: prioritization and incorporation of new agents of promise into established backbone regimens, development of efficient ways to measure the activity of new agents, identification of predictors of outcome after relapse that may guide treatment decisions, and developing better understanding of the mechanisms of drug resistance and relapse. The two major treatment strategies being pursued include the incorporation of novel molecular targeted agents into a backbone of established cytotoxic chemotherapy, and the development of novel combinations of targeted agents. Combinations of highly effective anti-leukemia cytotoxic drugs like corticosteroids and methotrexate with HDAC inhibitors and mTOR inhibitors are under investigation. The use of the proteasome inhibitor, bortezomib, in combination with VPLD chemotherapy has also yielded encouraging results in early phase trials for relapsed ALL. Finally, simultaneous targeting of signaling pathways in ALL cells that determine cell survival and tumor metabolism are also being tested.

CANCER PATTERNS IN NORTHERN SYRIA: A RECENT ESTIMATESFouad M. Fa,b, Rastam Sa.(a) Syrian Center for Tobacco Studies (SCTS)(a,b) Syrian Cancer Society

ObjectiveThere are no recent estimates of the incidence of cancer in Syria. The only and the first one were conducted in 1999. This study was set in Aleppo province (population of 3.9 millions) to estimate the cancer pattern in 2004.

MethodsInformation about cancer was obtained from Aleppo Cancer Registry which collects data on all new diagnosed cases of cancer from all public hospitals (n=6) and pathology labs (n= 12) in the city. Since cancer is not a notifiable disease in Syria, registration is carried out by active data collection by the registry staff.

ResultsIn 2004, in Aleppo Governorate, Syria, there were an estimates of 1835 incident cases of cancer newly diagnosed (974 male and 861 female). The most common incident form of cancer in male was urinary bladder (13.7%) followed by lung cancer (11.1%) and prostate cancer (7.8%). In female the most common cancer was breast cancer (28.8%) followed by colo-rectal (7.4%) and overian cancer (6.2%). The main distinguished figure is the raise of stomach cancer in male (6%). In conclusion, the presented data shows that the number of new cases of cancer is still underestimate, this is due to lack of specialized cancer center or well-established cancer control program, so many cases either prefer to go to the capital (400 km far) to get diagnosis and treatment, or remain hidden cases and under-diagnosed. It calls for the importance of establishing good national cancer registry and high quality cancer control program.


VENOUS THROMBOEMBOLISM PROPHYLAXIS AND TREATMENT IN PATIENTS WITH CANCERIsmail Khalil

Arterial and, more frequently, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer.

The presence of cancer increases the risk of VTE four to six fold. Cancer related interventions such as chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of VTE. Similarly, patients undergoing surgery for cancer have a higher risk of VTE than those undergoing surgery for benign diseases. Furthermore, patients with cancer and VTE have a higher risk of death than patients with cancer alone or with VTE alone.

Cancer patients also have different benefits and risks from anticoagulant treatment than those without cancer. For instance, during oral anticoagulation therapy for VTE, patients with cancer, compared to those without cancer, have a higher incidence for recurrent VTE (27.1 versus 9.0 events per 100 patient years, p=0.003) and of major bleeding (13.3 versus 2.2 events per 100 patients years, p=0.002)

Recommendations for VTE prophylaxis and treatment will be presented.

GASTROINTESTINAL CANCER IN THE ELDERLYPelagia G. Tsoutsou, MD, PhDSenior Lecturer, Radiation Oncology Department,Univerity General Hospital of Alexandroupolis,Dragana 68 100, Greece

IntroductionGastrointestinal cancer in the elderly consists of a disease entity that primarily presents in the elderly, with more than two thirds of the patients being over 65 years old. Its presentation and symptoms, as well as stage and histologies in the elderly do not differ from those of the younger patients.

PurposeTreating gastrointestinal cancer in the elderly, has a great clinical interest, since the elderly consists of a group of patients with particularities regarding the treatment strategy to be adopted, such as treatment intent and tolerance. Therefore, given the fact that data regarding their treatment come from trials dealing with younger people, there arises the need to know more about whom, when and how to treat when dealing with an old person with gastrointestinal cancer.

MethodsA literature search through PubMed was performed, giving emphasis to the guidelines published by prestigious groups, such as the National Comprehensive Cancer Network (NCCN) and the International Society of Geriatric Oncology (SIOG), with a special interest on the study of colorectal cancer.

ResultsFrom the literature review comes the following information: a. When treating an elderly patient it is extremely important to perform a thorough geriatric assessement first, so that the performance status (physical and mental) of the patient is evaluated, thus highlighting the need of a multidisciplinary approach. b. Within the concept of the multidisciplinary approach, it is important to keep in mind that the biologic age of the patient does not always correspond to the chronological one, while

comorbidities must also be carefully assessed. c. After the multifactorial patient evaluation, it is important to clarify the treatment goal: radical treatment when the life expectancy without cancer is superior to life expectancy with cancer and palliative when the contrary holds true. d. The elderly do not participate in screening programs as much as the younger population, while they should (this is particularly important for colorectal cancer). e. The elderly usually present with more advanced stages of the disease and are more often submitted to emergency surgery, which bears a worse outcome. f. The elderly are usually undertreated and are not offered optimal surgery, radiotherapy or chemotherapy, as much as the younger people. g. When older people are optimally treated, their survival is not different from that of the younger patients. h. The elderly are anticipated to have diminished treatment tolerance and express higher toxicity rates. i. Out of all gastrointestinal cancers, a substantial amount of literature has been published only on colorectal cancer, while all the rest is characterized by a paucity of data in the elderly.

ConclusionsTreating gastrointestinal cancer in the elderly must be done within the context of a multidisciplinary approach and following the published guidelines. More data are needed to better define optimal treatment strategies for this group of patients.

BREAST HEALTH CARE IN LOW AND MIDDLE INCOME COUNTRIES: ALLOCATION OF RESOURCES FOR DIAGNOSIS AND TREATMENT Nuran Bese MD.Professor in Radiation Oncology, Istanbul UniversityCerrahpasa Medical School, Department of Radiation OncologyIstanbul/Turkey

Cancer is the second most common cause of death in low and middle income countries. Among women breast cancer is the most common cause of cancer -related death worldwide and fatality rates are higher in low and middle income settings. The breast cancer burden in these countries is expected to increase because of increased life expectancy and shifting reproductive and behavioral patterns associated with heightened breast cancer risk. On the other hand in low and middle income countries there is a lack of major components of healthcare infrastructure. In order to deal with this major problem Breast Health Global Initiative (BHGI) strives to develop evidence based economically feasible guidelines that can be used in nations with limited resources to improve breast cancer outcomes. Before the introduction of these guidelines due to the disparities in healthcare infrastructure in different regions, levels of resources were stratified. Guidelines including early detection, diagnosis and pathology, treatment and breast cancer programs were developed adaptable to each specific level of resources.

CHEMOTHERAPY IN THE MANAGEMENT OF BRAIN METASTASESLauren AbreyMemorial Sloan Kettering Cancer Center

Brain metastases are a devastating complication of any solid tumor; prognosis is poor with an average survival ranging from 3 months to 1 year. Lung cancer is the most common primary malignancy associated with brain metastases followed by breast cancer and melanoma. The standard of care for brain metastases include whole brain radiotherapy and surgical resection or stereotactic radiosurgery in selected patients. In general chemotherapy has been deemed ineffective in the management of brain metastases with a common perception that the blood brain


barrier prohibits effective delivery of chemotherapy. However, in many instances the blood brain barrier is sufficiently disrupted to allow delivery of chemotherapy and some chemotherapeutic agents and newer biologic and molecular agents are able to penetrate the blood brain barrier. Therefore, it may be possible to rationally incorporate chemotherapy into the management of selected patients with brain metastases. In particular it may be reasonable to consider giving chemotherapy to patients with recurrent brain metastases after standard therapy who have a good performance status with a chemosensitive malignancy and limited prior exposure to systemic chemotherapy. Strategies for incorporating chemotherapy into the management of brain metastases and results of recent clinical trials will be discussed.

RADIOFREQUENCY ABLATION IN THE TREATMENT OF LIVER AND LUNG TUMORSAntoine HAKIME, MD, MSAssistant in Interventional Radiology Department, Gustave Roussy Institute, Villejuif, FranceFellowship Harvard Medical School

Radiofrequency (RF) ablation is a technique of thermotherapy which emerged over the last fifteen years in the field of oncology. RF directed toward a specific tumor mass is known to be very effective (over 90%) for treating tumors less than 3 cm. RF is used for patients with early-stage lung or liver cancers who are not surgical candidates, With improvements in systemic therapy, increasing interest in the use of local therapy for metastases has arisen. Eradication of residual metastases via local therapies is justified in patients with stabilized disease. A non surgical alternative like RF has become popular being less invasive than surgery and having demonstrated great efficiency.In this presentation, we review the technique, indications, and clinical results of percutaneous RF ablation in the treatment of HCC, primary lung tumor, hepatic and lung metastases.

PORTAL EMBOLISATIONAntoine HAKIME, MD, MSAssistant in Interventional Radiology Department, Gustave Roussy Institute, Villejuif, FranceFellowship Harvard Medical School

Preoperative portal vein embolization (PVE) has become an important tool in the management of selected patients before major hepatic resection. PVE redirects portal flow to the intended future remnant liver (FRL) to induce hypertrophy of the non-diseased portion of the liver and thereby may reduce complications and shorten hospital stays after surgery. This presentation reviews the technical considerations for performing PVE including the use of the ipsilateral or contralateral approaches, how to choose a particular embolic agent for PVE, the importance of liver volumetric measurements to estimate functional hepatic reserve, the pathophysiology of PVE, and some of the results showing the benefit of the procedure. In addition, the indications and contra-indications for performing PVE in patients with and without chronic liver disease, the use of combination therapies, and the concern for tumor growth after PVE will be discussed.

RATIONALE FOR PHARMACOVIGILANCEThierry Trenque Regional Pharmacovigilance Centre, Reims, France

Patient safety is an important issue in healthcare.When a product is marketed, safety and efficacy experience is limited to its use in clinical trials. The drug has not been studied in clinical practice.Four per cent of licensed drugs are withdrawn after launch because of safety problem.

Pharmacovigilance is the science and activities relating to the detection, assessment,understanding and prevention of adverse effects or any possible drug-related problem.An adverse reaction is a response to a drug which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the modifications of physiological function.

Pharmacovigilance depends on the submission of case reports of suspected adverse effects of medicines in individual patients by their doctors, pharmacists and other health care practitioners. The reports are sent to pharmacovigilance centres.The most widely used method in pharmacovigilance is called spontaneous reporting system. Analysis of spontaneous reports of suspected averse drug reactions is a valuable tool in the detection of previous unknown drug adverse reactions.

In France, more than twenty thousands spontaneous reports are collected per year. French pharmacovigilance data base contains 400 000 reports.The adverse drug reactions kill more than the road crashes.

We describe the french pharmacovigilance system and the european organisation (EMEA). Regulatory actions vary from the product labeling changes to market withdrawal. The reporting of individual cases remains an essential part of pharmacovigilance today.

FDG-PET IN HEAD AND NECK CANCERDima Hammoud, MDNational Institutes of Health/Clinical Center

Unlike anatomic imaging modalities (MRI, CT), nuclear imaging techniques target the pathophysiologic changes underlying disease entities rather than the associated anatomic changes. PET is the only quantitative, noninvasive in vivo technique to probe metabolism. The disadvantages of PET however are the poor resolution, long acquisition times, limited spatial resolution, poorly identifiable anatomic structures and possible asymmetric uptake in normal structures.

[18F]FDG (2-[18F]fluoro-2-deoxyglucose) is the most widely used radiotracer in PET. Physiologic FDG uptake in the head and neck area should not be confused for malignancy. It can be intense (soft palate, palatine tonsils, lingual tonsils), variable (salivary glands) or low (vocal cords, spinal cord). PET/CT fusion imaging has the advantage of providing anatomic detail with functional information in a single image set which results in better staging of tumors and better distinction of pathological from physiologic uptake. In fact, PET/CT was proven superior to PET alone in a multitude of tumors including head and neck cancer.

Indications for using FDG PET in head and neck cancer:1. Diagnosis: in patients with suspected head and neck cancer by exam or

como 8 abstracts <


patients with biopsy-proven cancer in a lymph node without a known primary tumor.

2. Staging: initial staging of patients with known head and neck cancer3. Restaging: check for tumor recurrence and evaluate response to therapy

By providing a whole body survey, FDG PET can also detect distant sites of metastatic disease and other primary neoplasms. The timing of post-therapy PET imaging is important for an accurate assessment of response to treatment.

Use of FDG-PET in thyroid cancer:The normal thyroid gland can have high physiologic uptake in 3% of the patients. If a hot nodule is seen, this could represent primary malignant tumors, adenoma or metastasis. Diffuse increased metabolic activity is more specific for inflammation such as seen with thyroiditis.

In thyroid cancer, well-differentiated tumors can show low uptake of FDG, but are usually detected by 131I scan. However, poorly differentiated tumors usually demonstrate marked increased FDG uptake, but lose their Iodine avidity (flip-flop phenomenon). The only currently approved (reimbursable) indication for thyroid cancer imaging with FDG-PET is in patients with elevated thyroglobulin levels AND negative 131I scan.

In conclusion, FDG-PET scan has many advantages over anatomic imaging for Staging, restaging and follow-up of head and neck cancer. The limitations however include limited resolution, lack of anatomical details and increased baseline uptake in normal structures.

MOLECULAR IMAGING: BASICS AND CURRENT APPLICATIONS IN ONCOLOGYDima Hammoud, MDNational Institutes of Health/Clinical Center

Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems, in vivo. Unlike other radiologic subspecialties, molecular imaging is not limited to one organ system or one imaging modality. It also is not limited to humans with the majority of applications at this point being in small animals.

Molecular imaging system: there are three components to the molecular imaging system:• Target: can be DNA, mRNA but most commonly proteins• Modality: can be ultrasound, optical imaging techniques (fluorescence,

bioluminescence), MRI and nuclear medicine techniques (PET/SPECT). The choice of the imaging modality is implied by the biologic question to be answered. It usually comes down to the different advantages of different modalities, such as high sensitivity versus high resolution, as well as the practicality of use. Also, different techniques have different human or animal applications.

• Agent: usually has a component which interacts with target molecules within tissues thus conferring the spatial localization. A good molecular imaging agent should be able to reach and be sufficiently specific to its target. Most importantly, it has to be detected externally.

Agent-target interaction: There are three major methods of agent-target interaction:

1. Targeted binding: agent binds to its target in a specific manner and for enough time to allow external detection.

2. Imaging agent accumulation in the cell: usually due to enzymatic action that modifies the structure of the agent.

3. Activation of imaging agent by cellular component: the cellular components are usually enzymes, resulting in signal amplification.

Small animal molecular imaging: constitutes the bulk of molecular imaging applications at this point. This is made possible by the availability of high resolution, multi-modality scanners in small sizes, and the availability of animal models of human diseases such as genetically engineered mice (knockout mice).

Translational molecular imaging: is the work that goes into bringing the promising experimental therapies and diagnostic tests to the clinic, after extensive evaluation in experimental models.

Translational Molecular imaging examples in Oncology:MRI applications: one example is the use of coated iron oxide particles to detect metastatic disease in lymph nodesNuclear medicine: examples include the use of FDG-PET (targeting increased glucose metabolism), 11C-methionine (MET) (targeting increased amino acid transport), 18F-fluorothymidine (FLT) (targeting cellular proliferation) and 18F-Galacto-RGD (targeting integrin αvß3, highly expressed on activated endothelial cells during angiogenesis), in different tumors.

NEW TECHNIQUES OF RADIATION THERAPY FOR METASTASIS.WITH A FOCUS ON LIVER METASTASESXavier Mirabel

Aggressive treatment of oligometastatic diseases showed curative effect on liver or lung metastases from colorectal cancer, with overall survival of more than 30% at 10 years. In this situation, conventional oncology treatments remain palliative. Surgery, radiofrequency and also other focal treatments were developed following the awareness of the results of local therapy for metastases. Commonly accepted indications are metastases from colorectal cancer, melanoma, renal carcinoma, sarcomas but also, for selected patients, metastases from breast or lung cancer.

For years, intracranial stereotactic radiation therapy has been proven but is limited to cerebral metastases and necessitates an invasive and heavy technology.

Technological developments in radiation therapy make stereotactic or ultra-conformational irradiations, possibly with tracking, possible allowing new extracranial radiation therapy with “ablative” intent.

In the last months publications increased, specifically on lung or liver metastases.

We will report our experience on metastases irradiation with new radiotherapy technologies with a focus on liver metastases. They allow us to control 90% of the treated lesions with a low morbidity.


PREOPERATIVE RADIOCHEMOTHERAPY (RCT) FOR GASTRO-INTESTINAL CANCERSXavier Mirabel

Theoretical benefits of neoadjuvant treatments are numerous. In the digestive oncology clinical practice, this type of treatments increases rapidly.

In oesophagus cancer, it is after the publication of Herslovic study in 1992 that exclusive radiochemotherapy (RCT) expanded rapidly.vHowever, surgery remains the standard treatment of lower oesophagus cancer, especially cancers without lymph node involvement. However, overall survival and local control are still not satisfactory. Logically, RCT studies were initiated. In a recent meta-analysis, the relevance of such treatment, not recognized as standard, seemed to be confirmed and justified to continue investigations.

In gastric cancer, relevance of adjuvant RCT was shown but the results are criticized and the feasibility of such a heavy treatment remains limited. Therefore, neoadjuvant RCT is currently under investigation. It is, with no doubt, a very promising approach.

On the contrary, for pancreas, liver and biliary tract cancer, even if few neoadjuvant RTC experiences have been published, results are hardly convincing. Prescription of neoadjuvant RCT can only be done in a clinical trial setting.

The situation is completely different in rectal cancer where neoadjuvant RCT has become a standard of care that can’t be ignored.

Around those neoadjuvant RCT strategies in digestive oncology, major stakes emerged:• the importance of lateral margins has been discovered, it seems that

neoadjuvant RCT could significantly modify the prognosis of patients at risk of positive or border-line lateral margins

• neoadjuvant RCT can modify surgical indication. Up to where can we go? Challenge surgery in case of complete response?

• What should be the delay between the end of neoadjuvant RCT and surgery, keeping in mind that neoadjuvant treatment response rate increases while the delay increases?

• Shall we assess the response during the neoadjuvant treatment? What is the clinical relevance of this information?

• How to improve the quality and the efficacy of radiation therapy? What is the role of new technologies?

• How to improve chemotherapy and what is the role of targeted therapies.

Finally, in these heavy oncology practices where chemotherapy, radiation therapy and surgery are combined, a comprehensive work-up is critical. Furthermore, clinicians experience and more specifically surgeon and radiation oncologist experience is a fundamental prognosis factor.

IRM DES CANCERS DU RECTUMProfesseur Frank Boudghene-StambouliService de Radiologie - Hopital Tenon - 75020 Paris

La chirurgie du cancer du rectum expose à la récidive en cas de résection incomplète. Pour améliorer les résultats de cette intervention il est donc indispensable d’obtenir un staging tumoral préalable correct, d’utiliser une technique de résection appropriée et d’effectuer si besoin une radio chimiothérapie pré opératoire.

L’imagerie aura pour objectif principal d’identifier les patients ayant une extension extra rectale et relevant d’une radio chimiothérapie préopératoire (+/- néo adjuvante), ainsi que les patients dont le sphincter n’est pas ou peu atteint et qui pourront bénéficier d’une chirurgie de conservation sphinctérienne (colo-rectale ou colo-anale voire d’une résection inter sphinctérienne partielle ou complète).

L’IRM de haute résolution est donc essentielle pour faire cette évaluation pré thérapeutique et notamment une cartographie précise des lésions ainsi que pour évaluer l’extension péri et extra rectale.L’utilisation de la haute résolution permet d’éviter l’utilisation d’une antenne endorectale qui non seulement provoque une déformation des rapports anatomiques, mais dont l’insertion peut aussi être douloureuse du fait de la présence de la tumeur et alors être préjudiciable au patient. C’est pour les mêmes raisons qu’on évite tout remplissage du rectum : l’examen sera réalisé ampoule rectale vide et évacuée à l’aide de Dulcolax® inséré 2h avant, et après immobilisation du tube digestif par du Spasfon Lyoc®.D’autre part si l’antenne endorectale est plus précise pour l’étude la paroi elle n’est performante ni pour l’extension vers le fascia recti ni pour l’étude des ganglions pelviens, et ne permet pas non plus de réaliser une imagerie de perfusion. Les séquences T2 FSE haute résolution seront effectuées dans les 3 plans de l’espace et complétées par des séquences T1 fatsat Gado. Elles permettront d’identifier les repères anatomiques (releveurs, complexe sphinctérien, pubo rectal). La paroi rectale en hyposignal est bien délimitée dans la graisse du mésorectum, et elle-même limitée à l’extérieur par le fascia recti.Les cancers du rectum sont de signal intermédiaire et l’IRM ne permet pas de distinguer les stades T1 et T2, et parfois T2 et T3.

La cartographie tumorale permet de préciser la localisation des tumeurs en sachant qu’il faut préciser la distance séparant le pole inférieur de la tumeur du sphincter interne et qu’une marge de 2 cm est classiquement nécessaire pour conserver le sphincter en évitant l’amputation abdomino-périnéale et qu’on peut ainsi distinguer les atteintes :• du bas rectum < 2 cm (+/- résection inter sphinctérienne, +/- amputation

abdomino-perinéale)• du moyen rectum < 7 cm (résection en bloc du mésorectum avec anastomose

colo-anale)• du haut rectum < 11 cm (résection antérieure avec anastomose colo-rectale)L’élément anatomique essentiel est la marge circonférentielle du mésorectum qui précise l’extension en profondeur dans la cavité pelvienne puisqu’elle sépare la limite la plus externe de la tumeur du fascia recti : c’est cette distance qui conditionne la radiothérapie pré opératoire puisqu’elle est indiquée en cas de T3 et T4 mais complétée par une chimiothérapie néo adjuvante pour les T4.Lorsque la CRM est inférieure à 5 mm en IRM c’est qu’elle est inférieure à 1 mm en histologie et qu’il s’agit alors d’un T4 puisque le fascia recti est envahi.Cependant il est possible d’observer une réaction desmoplastique péri rectale sous la forme d’un aspect spiculé de la graisse du mésorectum, au sein duquel il n’est pas possible de distinguer ce qui relève d’une réaction de fibrose de la présence

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d’éventuelles cellules tumorales malignes ou d’emboles vasculaires.Mais pour la prise en charge thérapeutique ce qui importe c’est plus la valeur de la CRM que le stade tumoral exact. Les critères diagnostiques de l’envahissement ganglionnaire ne sont pas faciles à utiliser (8mm, limites, homogénéité……) et le risque de micro métastases reste constant même sur de petit ganglions : c’est d’ailleurs lui qui peut en partie expliquer certains des bons résultats qu’on obtient en terme de récidives après radiothérapie pré opératoire.L’IRM est cependant mise en difficulté au niveau de 2 régions anatomiques, que sont la partie antérieure (avec le fascia de Denonvilliers chez l’homme) et la partie basse (avec l’atteinte du sphincter). L’analyse précise de ces 2 régions est essentielle puisque leur atteinte conditionne les résultats mais aussi le traitement à mettre en œuvre. C’est aussi pour cela qu’il ne faut pas hésiter à multiplier les incidences dans les différents plans de l’espace y compris après injection de Gadolinium.

Les conditions du succès de l’examen IRM des cancers du rectum sont donc :• l’antenne ad hoc• la préparation du patient• les séquences haute résolution• l’emploi de critères diagnostics précis

MANAGEMENT OF LOCALIZED RENAL CELL CARCINOMABarret E, Sanchez-Salas R, Rozet F, Cathelineau X, Vallancien G.Institut Montsouris. Paris, France

Renal cell carcinoma (RCC) accounts for approximately 3.5% of all malignancies and is the third most common cancer of the urinary tract. Although historically patients presented with symptoms, most cases today are identified by chance, due to diagnostic imaging. An evolution in treatment options has accompanied this differing presentation of RCC. Surgery remains the mainstay of treatment for localized RCC but several alternatives have become available to reduce or avoid morbidity. Laparoscopic radical nephrectomy shows equal outcomes to open radical nephrectomy for RCC, but offers patients the advantages of lower blood loss, shorter hospital stay, reduced pain medicine requirements, improved cosmesis, and faster return to work and normal activities. Open partial nephrectomy or laparoscopic partial nephrectomy can be considered for patients with indication for renal preservation. Open partial nephrectomy and laparoscopic partial nephrectomy for localized RCC provide benefits and may be superior to radical nephrectomy. Although NSS may have a higher rate of complications, open partial nephrectomy or laparoscopic partial nephrectomy should be initially considered in the treatment of incidental RCC when technically feasible. Ablative are nephron-sparing procedures have been applied to RCC. These approaches rely on needle/probe placed into the target tumor. Depending on tumor location, ablation can be attempted through laparoscopy, or percutaneously using image guidance. Ablative procedures avoid potential complications associated with tumor resection. They have several limitations and disadvantages. Active surveillance may be beneficial in allowing avoidance of intervention except for patients whose tumors show low risk growth in follow-up. Robotic-assisted laparoscopic partial nephrectomy facilitates operations that are technically difficult using traditional laparoscopic instruments. Preliminary reports describe favorable outcomes for robotic-assisted laparoscopic partial nephrectomy, showing operative parameters such as renal ischemia time, blood loss, and complications to be similar to those of open partial nephrectomy. Current evidence supports surgical resection of RCC and recognizes an advantage for NSS and minimally invasive approaches over open radical nephrectomy. For patients who are poor surgical risks or in whom surgery is contraindicated, active surveillance may be preferable.

ROBOTICS IN PROSTATE CANCERBarret E, Sanchez-Salas R, Rozet F, Cathelineau X, Vallancien G.Institut Montsouris. Paris, France

Radical prostatectomy (RP) remains the gold standard for the surgical treatment of localized prostate cancer. Evolution of the technique was started by the timely work by Walsh and Donker. Schuessler et al described the initial experience in laparoscopic radical prostatectomy (LRP), which they initially considered with no benefits when compared to its open counterpart, however, they rationalized that technical progress and experience could improve results. In 1998, the Montsouris team started the experience in LRP with their self-developed technique and even then robotic technology was tested in the performance in the operation. The deploy of the robot have the potential to reduce the learning curve due to the endo-wrist technology, the three-dimensional vision and the magnification but still there is need for solid evidence to back up the analysis on learning curve, as completing the procedure or been able to perform it does not necessarily means it is done well. The robot represents a useful instrument for the surgeon and it should be regarded as an element to follow in the future as its results will surely improve in upcoming years. The symbiosis of robotic technology with novel surgical approaches such as single port is very promising for surgery. However, the incorporation of new devices into surgical practice – such as the robot- requires that surgeons acquire and master new skills. Like any new technology, robotics surgery demands dedication to achieve expertise. For a skilled laparoscopic surgeon the learning curve to achieve proficiency with robotic radical prostatectomy is estimated at 40 to 60 cases. For the laparoscopically naive surgeon the curve is estimated at 80 to 100 cases. The Da Vinci assisted approach incorporates the advantages of minimally invasive approach while presenting comparable results to the open approach. Robotic interface appears to offer a significant benefit to the laparoscopically naive surgeon with respect to learning curve, at an increased cost. We have previously demonstrated that the laparoscopic extraperitoneal radical prostatectomy is equivalent to the robotic assisted laparoscopic prostatectomy in the hands of skilled laparoscopic urological surgeons with respect to operative time, operative blood loss, hospital stay, length of bladder catheterization and positive margin rate. Our aim is to present the role of robotic surgery in radical prostatectomy now-a-days.

RETROPERITONEAL LYMPH NODE LAPAROSCOPIC DISSECTIONBarret E, Sanchez-Salas R, Rozet F, Cathelineau X, Vallancien G.Institut Montsouris. Paris, France

The improved cure rates observed in patients with testis cancer have been based on the joint efforts of medical and surgical therapies. Although surveillance or chemotherapy regimens are some of the possible therapeutic options for stage I nonseminomatous germ cell testicular tumors (NSGCT), open retroperitoneal lymph node dissection (O-RPLND) remains the most reliable method for detecting lymph node metastasis in this setting. However, perioperative morbidity and invasiveness are concerning issues that have been addressed by several authors. The retroperitoneum represents the first, and sometimes the only echelon in testis carcinoma spreading. Primary RPLND has the advantage of a minutely precise and effective pathological staging in germ cell tumors, but even more, it could be a curative procedure in 70% of patients with stage B1 disease. Clinical understaging, significant relapse rate in surveillance protocols, and the presence of teratoma or viable carcinoma in resected tissue from patients exposed to chemoteraphy protocols constitute the reasons why surgery could be preferred over other therapeutical options in testis cancer.


Since its original description RPLND has been modified in order to diminish morbidity while keeping the oncological standards. Lessons learned after years of laparoscopic surgery and the advances in laparoscopic reconstructive techniques allowed us today to attempt even more demanding procedures. Laparoscopic RPNLD (L-RPLND) has been proved feasible with low complication rates in highly experienced hands. Nonetheless, there is controversy regarding its therapeutic efficacy as an alternative to the open approach for the management of NSGCT. Intermediate and long term oncologic results are lacking in the literature. Our objective is to present the state of the art in RPLND.

NEOADJUVANT CHEMOTHERAPY FOR INVASIVE BLADDER CANCERBarret E, Sanchez-Salas R, Rozet F, Cathelineau X, Vallancien G.Institut Montsouris. Paris, France

The standard treatment for invasive transitional cell carcinoma (TCC) is radical cystectomy (RC) with lymphadenectomy, however, defining adequate therapy in every patient with invasive TCC remains difficult, because multiple biologic behavior patterns can be found in this disease. Quality indicators in RC are well established nowadays: Mortality should not be higher than 2% to 4%. Positive surgical margin rates should be lower than 10% overall and 15% in pT3 or pT4 and the median number of pelvic nodes retrieved in the lymphadenectomy should be 10-14. Simultaneously, orthotopic neobladder has become a surgical standard that improved the quality of life of these patients. Nowadays, the best outcomes in bladder cancer therapeutics are probably obtained when there is radical cystectomy in a systemic treatment setting. Neoadyuvant treatment has shown interesting advantages in patients with bladder cancer because it offers 5% of survival and 14% decreased risk of associated disease mortality. One might argue that two third of the patients would be treated without any response and survival advantage may be outweighed by potential treatment morbidity, with an important number of patients receiving chemotherapy to reach the 5% benefit, however, selection of the population incorporated in the protocols should address this issue.Combining neoadyuvant therapy and RC, would add the benefits of each one, and perhaps offer a more effective treatment for patients with invasive bladder cancer. Another option for chemotherapy is adjuvant treatment, that provides also a systemic approach in a probable different clinical situation. Clinical protocols addressing results of perioperative chemotherapy in invasive bladder cancer would be responsible for final answers in the ideal timing of chemotherapy. At the beginning of our experience with LRC the main consideration for surgery in bladder carcinoma was the precarious health of this patient’s population. Things have not changed much and laparoscopic RC might represents the low morbidity surgical option for the patient who had neoadyuvant therapy or are planned for adjuvancy. Minimizing operative trauma becomes even more important for these patients. The combination of two effective treatments -medical and surgical- would probably offer a great advantage to patients with invasive bladder cancer.

PITFALLS IN THE DIAGNOSIS OF INFLAMMATORY BOWEL DISEASEHala El-Zimaity, MD FRCPath

There are numerous traps for the unwary, but also areas that are just plain difficult irrespective of ones level of experience, which exist in interpreting biopsies, and sometimes resections, from patients with inflammatory bowel disease (IBD). These can exist at the initial level of even whether IBD is present or not, or if present what the underlying subtype really is, but also at the gross/endoscopic level or histologically when biopsies (and sometimes resections) do not have the typical

histological pattern or distribution associated with UC, or sometimes masquerade as other conditions. Sometimes extracolonic disease, especially that occurring in the upper GI tract, may lead to immediate consideration of upper GI involvement of Crohn’s disease (CD) rather than UC, which may not always be correct.

GI MALIGNANCIES, INCIDENCE AND EVOLUTIONHala El-Zimaity, MD, FRCPC pathology

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Appropriate risk stratification of individuals and compliance with recommended screening strategies are important. Clinical, pathological and molecular evidence supports classifying colorectal cancer into different subtypes. The standardized reporting of colorectal cancer, and indeed all forms of cancer, has assumed great importance in recent years and is used increasingly in audit and therapeutic decision making. A straight forward checklist for synoptic reporting increases the likelihood that important features will be recorded. Colonoscopy continues to play an important role in screening; however, several different screening options are available for average-risk individuals.

GI NEURO-ENDOCRINE TUMORSHala El-Zimaity, MD FRCP pathology

For many decades, NETs were considered rare malignancies that were only discovered incidentally. The most recent analysis of NETs in the United States lends credence to the concept that the incidence of NETs is increasing. The primary objective for most oncologists or cancer care providers is to assess the extent of tumor involvement and to establish prognostic parameters. This requires radiologic evaluation to localize the site of primary disease, determine the extent of disease spread, and assess functionality of the disease by evaluation for overproduction of hormones or bioactive amines. Radiologic, endoscopic, and ultrasonographic workup is necessary to (1) determine the extent of tumor involvement, (2) localize the site of primary tumor, and (3) obtain a tissue diagnosis. Stage, site of primary tumor, histologic differentiation, and plasma chromogranin A (CgA) are important prognostic factors associated with survival in NETs.

CANCER IN THE ELDERLY: TREATMENT ACCORDING TO AGE OR MORBIDITY?Matti AaproMultidisciplinary Oncology Institute, Genolier, Switzerland

Elderly patients constitute a large group, and after assessment only a minor part of them are found in perfect health (=fit), while the remaining display one or more physical or functional limitations or familial/social problems and are therefore categorized as vulnerable or frail (=unfit). There is a general consensus that age alone should not prevent surgical local treatment but this needs careful evaluation as some surgical procedures are actually potentially harmful. Radiation therapy guidelines also need to take into account the impact of local relapse on patient’s quality of life. Activity and safety of many drugs including targeted agents appear comparable in elderly study patients compared to younger counterparts, although concomitant renal and cardiovascular comorbidity and osteoporosis should be closely monitored.. Of note, compliance to oral therapy and possible interferences with concomitant medications are still poorly documented issues. Single agent sequential chemotherapy regimens are often to be preferred to

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of iron along with ESAs. Whilst 5 randomized studies in cancer patients show a positive impact with the use of iv iron (i.e. resulted in a faster time to response with a lower dose of epoetin), the long term safety data of iron use on cardiac function, tumor response and possible iron overload are lacking. In cancer patients it is probably prudent to use iron only if the patient has absolute or functional iron deficiency even if studies show efficacy of iv iron in other situations. Functional iron deficiency is defined in oncology with a cut off ferritin level of 100 ng/ml and in nephrology of 200ng/ml and the transferrin saturation for both groups is below 20%. Guidelines help us in making decisions in our daily practice. These guidelines are currently under pressure to change, but have not yet been modified, as until recently the experts have felt that there was no strong evidence to indicate that use of ESAs within the limits of the guidelines could harm patients. Although the more recent meta-analyses show an increased risk of mortality and decreased survival with the use of ESAs, they fail to do so when the drugs are used within the indication. Particular care has to be taken with regards to risk factors for developing thromboembolism, which is also related to transfusions. We continue to conclude that recombinant erythropoietins are safe and effective in alleviating anemia, diminishing transfusion use and improving QoL in symptomatic anemic patients, when used according to current guidelines.

THERANOSTIC AND GENOMIC APPLICATIONS IN UROLOGIC CANCERSGeorge J. Netto MD Departments of Pathology, Urology and OncologyJohns Hopkins Medical InstitutionsBaltimore, Md

Prostate Carcinoma: Theranostic and Genomic ApplicationsCurrently, prostate needle biopsy remains the gold standard for establishing the diagnosis of prostate carcinoma in patients with elevated serum PSA and or positive digital rectal exam. At this time, firmly established parameters such as clinical stage, pathologic stage, histologic Gleason grade and serum PSA levels are routinely used for prognostication and guidance of disease management (1-3) .Given the existing need to improve upon the prognostic and predictive power of the above established parameters, an extensive list of molecular biomarkers have been evaluated in the last decade for their potential role in enhancing our ability to predict disease progression, response to therapy and survival (4-8) . These research efforts have been greatly facilitated by the wealth of information garnered from gene expression array studies and by sophisticated bioinformatics tools evaluating the overwhelming datasets generated from genomic, transcriptomic and proteomic studies. These genomic technologies continue to yield new markers that can in turn be evaluated for clinical utility in a high throughput manner using immunohistochemistry and FISH labeled tissue microarrays and state of the art image analysis systems (9-11) Among the many recent research achievements in the field of prostate cancer biology, the identification by Tomlins et al. of a recurrent chromosomal rearrangement in the majority of their analyzed prostate carcinoma cases is ranked as one of the most notable discoveries (12, 13) . The recurrent chromosomal rearrangements lead to a fusion of the androgen-responsive promoter elements of the TMPRSS2 gene (21q22) to one of three members of the ETS transcription factors family members ERG, ETV1 and ETV4 located at chromosomes 21q22, 7p21 and 17q21 respectively. Although the prognostic role of the TMPRSS2-ETS rearrangements remain controversial at this time, the discovery no doubt will have great implications in term of furthering our understanding of the steps involved in the development and pathogenesis of prostate carcinoma and provide a new marker

combination regimens, which are usually more toxic with a limited survival gain even in younger patients. When and how dose reductions should be applied to unfit patients is highly controversial and use of G-CSFs is often recommended.

ReferenceAapro MS, Köhne CH, Cohen HJ, Extermann M. Never too old? Age should not be a barrier to enrollment in cancer clinical trials. Oncologist. 2005 Mar;10(3):198-204

AROMATASE INHIBITORS AND SURVIVALMatti AaproClinique De Genolier1272 Genolier, Switzerland

In the metastatic disease setting there is ample evidence of the superiority of aromatase inhibitors over tamoxifen, with even survival advantage in one study. In the adjuvant setting there is evidence which is debated, but highly suggestive of a survival advantage. This has been true in the specific setting of patients treated initially with tamoxifen and the with an aromatase inhibitor. But one may object that these data fail to take into account patients with a high risk of an early relapse. The ATAX upfront study data continue not to show any survival advantage. The updated results of BIG 1-98 are stated to only “suggest” superior overall survival with letrozole compared with tamoxifen. It is because the 2005 results of letrozole superiority in terms of relapse-free survival ( including distant disease-free survival ) led to unblinding of the tamoxifen-alone arm. This resulted in 619 (25.2%) patients selectively crossing over to letrozole mostly in years 3-5 of treatment, leading to a median duration of letrozole use by these patients after crossover of 18 months at the time of the report. This complicated comparisons with tamoxifen alone and thus the comparison of tamoxifen to letrozole was done by intent-to-treat and censoring at crossover. The TEAM study results have confirmed that upfront aromatase inhibitors ( in this case exemestane ) bring an advantage over tamoxifen in terms of relapse-free survival to the treated patients. Again, censoring patients shows that also in this large study where 4817 patients received tamoxifen and 4853 patients received exemestane the hazard ratio for disease-free survival at 2.75 years of observation is 0.83 with confidence intervals 0.71-0.97, p= 0.022.

For many years, tamoxifen was the cornerstone of adjuvant endocrine therapy forpostmenopausal women with endocrine-responsive early breast cancer. The aromatase inhibitors are more effective as adjuvant therapy than tamoxifen alone in most cases and are now the therapy of choice in many postmenopausal women with endocrine-responsive disease. But tamoxifen may still be a viable option for some patients with very low-risk disease, where the prognosis is excellent. These are patients who would have a modest benefit from an upfront aromatase inhibitor, or from an aromatase inhibitor in general. There seems to be a consensus about this fact, yet one struggles to define who these women are.

MANAGING CANCER RELATED ANEMIAMatti AaproMultidisciplinary Oncology Institute, Genolier, Switzerland

In the last twenty years there have been many changes in the management of anemia. In the 1980s, recombinant human erythropoietin (rHuEPO) was introduced to eliminate or decrease the need for transfusions and found to improve patient’s quality of life (QoL). Recently oncologists started to learn about the importance


for molecular diagnosis and potential target(s) of therapy in prostate cancer (14-20) .The perceived need to identify “objective” markers to supplement, or conceivably supplant, the more “subjective” established histologic parameters has been a major driving force behind biomarker discovery efforts. It is crucial to recognize and account for the potential variability that can exist even with the new molecular parameters. Sources of variability include differences in molecular technique methodologies, tissue fixation and processing, inter and intra-observer variability (in immunohistochemistry based biomarkers) and differences in cut off points (21) . Furthermore, illustration of statistical significance for a particular biomarker does not alone assure its utility in a given patient. Therefore, a promising prognostic or therapeutic target biomarker should endure a rigorous “evidence based” analysis and be validated in large size, prospective, clinical trials before transition into standard practice (22) . Such approach is currently underway in an NCI sponsored multi-institutional effort involving 11 prostate cancer SPORE recipient cancer centers in the United States.

Emerging Prognostic FactorsAccording to the 1999 College of American Pathologists Consensus Statement, prognostic and predictive factors in prostate carcinoma are stratified into three categories. Category I factors are considered proven to be useful in clinical practice and include: preoperative PSA, TNM stage, Gleason grade and surgical margins (23) . Category II factors that have been extensively studied but await statistically robust trials include: tumor volume, histologic type and DNA ploidy analysis. Category III factors are those still needing additional studies to assure their prognostic utility before undergoing clinical trials. The majority of prognostic molecular biologic markers are currently considered among category III factors. Markers such as proliferation index (ki67), microvessel density, nuclear morphometry, tumor suppression genes (eg p53, p21, p27, NKX3.1, PTEN, retinoblastoma gene “Rb”), oncogenes (eg Bcl2, c-myc, EZH2 and HER2/neu), adhesion molecules (CD44, E-Cadherin), PI3K/akt/mTOR pathway (24) , apoptosis regulators (eg survivin and transforming growth factor β 1), androgen receptor status, neuroendocrine differentiation markers, and prostate tissue lineage specific markers expression (PSA, PSAP and prostate specific membrane antigen “PSMA”) (25-27) .a. Proliferation Index: A single study has demonstrated that proliferation of

cancer on biopsy as measured by ki67 and percentage of cells in S-phase and G2M better correlated, than biopsy grade, with PSA failure after radical prostatectomy (28) . Two additional studies have shown a similar role for ki67 index measurement as an independent prognosticator in prostatectomy specimen (29, 30) . Conflicting reports have been furthered by others (31-34) . Ki67 is one of multiple promising markers under study by an NCI sponsored multi-institutional Inter-Prostate SPORE prospective validation study (that also includes p27 and caveolin-1) that will assess the utility of this marker.

b. Angiogenesis: The mean number of microscopic blood vessels in tissue is higher in prostate cancer and prostatic intraepithelial neoplasia (PIN) than normal prostate tissue. In a study evaluating microvessel density (MVD) on needle biopsy the authors found MVD, when combined with Gleason score and preoperative PSA, provided improved ability to predict extraprostatic extension at radical prostatectomy (35) . Although microvessel density was significant in the multivariate analysis, Gleason score and serum PSA were much more powerful predictors of extraprostatic disease. Three additional studies revealed a prognostic role for MVD in prostatectomy specimens (36-38) . Others however failed to confirm such a role (39-41) . Differences in vascular antibodies used, and topography of vessel measurements could account for the variable results. It appears that microvessel density will have a marginal adjunctive role if any to established current parameters.

c. Tumor Suppressor Genes (TSG) and Oncogenes: Among tumor suppressor genes, there is mounting evidence to support a role for p53 expression in predicting prognosis in prostate carcinoma. Brewster et al. found p53 expression and Gleason score in needle biopsy to be independent predictors of biochemical relapse after radical prostatectomy (42) . Another study found p53 status on prostatectomy but not needle biopsies to be predictive raising the issue of sampling (43) . Many studies evaluating prostatectomy specimens found p53 to be of prognostic significance independent of grade, stage, margin status (33, 41, 44-49) . The results of these studies suggest that p53 evaluation could become a clinically utilized parameter, at least in prostatectomy specimens, once standardization of cut-offs and immunostaining methodologies are achieved in large prospective studies. The majority of studies of another tumor suppressor gene p27, a cell cycle inhibitor, have also supported a correlation with progression after prostatectomy (34, 50) . Less robust evidence exists for the prognostic role of p21 (51) , a downstream mediator of p53 , PTEN (52, 53) , and transcription factors such as NKX3.1 (9, 54). A preponderance of evidence supports a prognostic role for Bcl2 (29, 42, 44, 46, 48) and myc oncogenes (55, 56) as potential adjuncts to histologic prognostic parameters. Despite great interest in HER2/neu and its potential use as a target of therapy, the data on its relation to prognosis in prostate carcinoma are conflicting with one study by Veltri et al. showing HER2/neu to be an independent prognosticator and a more recent study using both immunohistochemistry and FISH assessment showing lack of its utility in predicting progression (57, 58) .

d. Neuroendocrine Differentiation: Two studies have shown neuroendocrine differentiation to be predictive of prognosis in organ confined prostate carcinoma (59, 60) . However, several more recent studies have shown no prognostic role for neuroendocrine differentiation on needle biopsy or prostatectomy (61-64) .

e. Morphometry/Karyometry: Nuclear morphometric measurements on needle biopsy have also been demonstrated in limited studies to correlate with prostate cancer prognosis. The same group however found lack of correlation in nuclear measurements between needle and corresponding prostatectomy tissue (65, 66) . Several studies from our institution have looked at the prognostic role of the integration of multiple nuclear morphometry parameters variables (67, 68) and at the potentials of integration of nuclear morphometry parameters with other established factors such as grade and stage. The latter appear to enhance the prediction accuracy of established parameters (69, 70) .

f. Prostatic Lineage Specific Markers: The expression of prostatic markers such as prostate specific alkaline phosphatase (PSAP) and PSMA (71, 72) have been linked to prognosis in an occasional study. The degree of PSA expression does not appear to correlate with progression (72) .

g. Genomic Based Approaches: Gene expression profiling studies using cDNA microarrays containing 26,000 genes identified three subclasses of prostate tumors based on distinct patterns of gene expression (73) . High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. Furthermore, two surrogate genes were differentially expressed among tumor subgroups by immunohistochemistry. These included MUC1, a gene highly expressed in the subgroups with ‘‘aggressive’’ clinicopathological features and AZGP1, a gene highly expressed in the favorable subgroup were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Such study suggests that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

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In another study, Tomlins et al (74) used laser-capture microdissection to isolate 101 cell populations to illustrate gene expression profiles of prostate cancer progression from benign epithelium to metastatic disease. By analyzing expression signatures in the context of over 14,000 'molecular concepts', or sets of biologically connected genes, the authors generated an integrative model of progression. Molecular critical transitions in progression included protein biosynthesis, E26 transformation-specific (ETS) family transcriptional targets, androgen signaling and cell proliferation. Known prognostic markers such as grade could be ascribed to noted attenuated androgen signaling signature seen in high-grade cancer (Gleason pattern 4), similar to metastatic prostate cancer, which may reflect dedifferentiation and explain the clinical association of grade and prognosis. Taken together, these data show that analyzing gene expression signatures in the context of a compendium of molecular concepts is useful in understanding cancer biology.At the DNA level, array-based comparative genomic hybridization (array CGH) identified recurrent aberrations (243) including: i) deletions at 5q21 and 6q15 deletion group associated with favorable outcome group; ii) a 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion) deletion group and 8q24 (MYC) and 16p13 gains, and loss at 10q23 (PTEN) and 16q23 groups correlating with metastatic disease and worse outcome. Genomic studies suggest that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease.

Emerging Early Detection Markers and Targets of TherapyEarly detection markers include two major groups. The first group is molecular markers that can be applied to tissue biopsies in order to better stratify at risk groups. The second group is cancer-associated markers that can be detected in blood, urine, ejaculates or prostatic massage fluid as a non-invasive diagnostic alternative to needle biopsy. There have only been a few studies utilizing molecular techniques to predict which men with high grade PIN on needle biopsy are more likely to have cancer on subsequent biopsy. Using fluorescent in situ hybridization to assess c-myc, HER-2/neu, and the chromosome region of 7q31, Bastacky et al. analyzed 11 cases of high grade PIN with benign repeat biopsies and compared them to 14 cases of high grade PIN with a subsequent cancer diagnosis (75) . Amplification of HER-2/neu was common both in patients with and without cancer on repeat biopsy. Abnormalities in chromosome 7q31 and c-myc were greater in patients with cancer on follow-up. The only other study to address this issue by Al-Maghrabi et al. (76) analyzed 24 cases of high grade PIN on needle biopsy with no subsequent diagnosis of cancer and compared them to 20 cases of high grade PIN with cancer on follow-up. Using fluorescent in situ hybridization techniques to analyze chromosomes 4, 7, 8, and 10, there were no statistically significant differences between the two groups. Recently, in two studies (77, 78) , the expression of a nuclear matrix protein, early prostate carcinoma antigen “EPCA”, in benign biopsies from patients with suspected prostate carcinoma have been suggested to strongly predict the presence of an associated carcinoma. A subsequent study however, revealed a high false negative rate of EPCA expression in benign needle biopsies from patients with associated prostate carcinoma on different cores calling into question the utility of this marker (79) . Markers of prostate carcinoma detection that can be applied to blood, urine or prostatic secretion fluid (ejaculate or prostate massage fluids) are of great interest and have been the focus of active research. A serum assay for a second generation antibody (EPCA-2) has been recently proposed as a non-invasive early detection marker for prostate carcinoma (80) . Markers that have been investigated in the urine or prostatic secretions include gene promoter hypermethylation profile

assays (81-84) , and DD3 (differential display code 3), also know as PCA3. DD3 is a noncoding RNA that was initially identified by Bussemakers et al. (85) as one of the most specific markers of prostate carcinoma. Quantitative real time reverse transcriptase polymerase chain reaction (RT-PCR) assay detecting DD3 can be applied to blood, urine or prostatic fluid (86) . These non-invasive detection assays are considered by most authorities to be in the research stage and should undergo statistically robust clinical trials before making their transition into the clinical realm. Likewise, it remains to be seen if an RT-PCR based assays that identify the above mentioned newly discovered genetic TMPRSS2-ETS rearrangements that is found in the majority of prostate carcinoma will offer any additional non invasive detection method.

Finally, several markers are being investigated as potential targets of therapy for prostate cancer (78-80). The list includes: tyrosine kinase receptors (eg.EGFR), angiogenesis targets (eg VEGF) (87) , fatty acid synthase (FAS) (88) , PI3K/akt/mTOR mammalian target of rapamycin (89) , endothelin receptors (90, 91) , and PSMA (92-95) to name a few. In summary, a wide array of molecular markers discussed in this chapter may be utilized in the near future as adjuncts to currently established prognostic parameters. Among those, DNA ploidy analysis, proliferation index (ki67) and p53 appear to be poised for the earliest transition into the clinical arena. Current research efforts in prostate are also focused on biologic markers that can serve as target of therapy.

Figure [Lapointe et al Cancer Res 2007;67(18):8504-10]

Urothelial Carcinoma Genomic and Theranostic ApplicationsIn line with the distinct contrasting clinical behavior and prognosis of the two phenotypes of URCa, current molecular evidence is increasingly in support of two distinct pathways of pathogenesis for superficial and invasive urothelial carcinoma. A “linking” progression pathway that would account for the known progression of a subset of superficial URCa into muscle invasive disease has also emerged. Superficial URCa is thought to originate from benign urothelium through hyperplasia with only a small contribution (10-15%) to the pool of high grade non-invasive and subsequently invasive URCa. However, the majority of invasive tumours appear to originate through progression from dysplasia to flat CIS and high grade non invasive URCa where genetic instability lead to accumulation of genetic alterations promoting progression to invasive lesions (96, 97) .Clinically, a significant portion of superficial tumours (pTa and pT1) is deemed to recur after TURB with only a small minority showing ultimate progression into higher grade aggressive deeply invasive tumors. The superficial URCa pathogenesis pathway is primarily based on alterations in tyrosine kinase receptor FGFR-3 and H-RAS oncogene (98) while the pathogenic


pathway for muscle invasive URCa primarily involves tumor suppressor genes p53, p16 and Rb (96, 97, 99) . As illustrated in Figure, p53/Rb alterations are also needed for the progression of the small portion of superficial lesions to higher grade muscle invasive URCa.

Figure: Divergent Molecular Pathways in superficial and muscle invasive urothelial carcinoma.

Evidently, prognostic parameters that can accurately predict the subset of superficial tumors that will progress are invaluable for tailoring a more aggressive surveillance and management approach in such subset. Current established clinicopathologic prognostic parameters in superficial lesions include: pTNM stage, WHO/ISUP grade, size of tumor, multifocality and presence of CIS and frequency and rate of prior recurrences, (100) . Sylvester et al. (101) recently suggested a scoring system, based on the above clinicopathologic parameters, to improve our ability in predicting recurrences and progression in superficial tumours. Additionally, improved prognostication in muscle invasive disease is equally crucial to allocation of aggressive therapy protocols, given the current poor outcome (60% 10 year overall survival) in this group of bladder cancer patients (102) . The need is most pressing in this cohort given the paucity and imperfections of current clinicopathologic prognostic parameters in invasive URCa. Our recent understanding of complexed molecular alterations involved in the development and progression of URCa is yielding novel diagnostic and prognostic molecular tools and opening the doors for experimental targeted therapies in bladder cancer.

Beyond Immunohistochemistry: Anatomic Molecular Diagnostic ApplicationsChromosome 9 alterations are established to be the earliest events in both pathways of URCa development setting up the stage for genetic instability that in turn leads to accumulation of subsequent genetic events. Among other common chromosomal gains and deletions, gains of chromosomes 3q, 7p, and 17q and 9p21 deletions (p16 locus) are of special interest given their potential daignstic value. A multitarget interphase FISH based urine cytogenetic assay was developed (103) based on the above numerical chromosomal alterations. Such test is now commercially available and was initially FDA approved for surveillance of URCa recurrence in previously diagnosed URCa patients and subsequently approved for screening of URCa in high risk patients with hematuria. The multicolor FISH assay appears to enhance the sensitivity of routine urine cytology analysis and can be used in combination with routine cytology as a reflex testing in cases with atypical cytology. A sensitivity range of 69-87% and a specificity range of 89-96% have been reported with the multitarget interphase FISH assay. With the exception of one study by (104) , the multitarget FISH urine assay has been shown to be more sensitive than routine cytology. An additional advantage of urine based FISH testing could be the anticipatory positive category of patients identified by such assay. The latter category refer to patients where FISH assay detects molecular alteration of URCa in urine cells several months prior to cancer detection by cystoscopy and routine cytology (343). In the study by Yoder et al. (105) , two thirds of the 27% of patients categorized as “anticipatory positive” developed URCa that was

detected by cystoscopy up to 29 months later. Such encouraging results point to the great potential of molecular testing in early detection and allocation of vigorous/frequent follow up cystoscopy to at risk patients (344) (Figure adapted from Moonen et al.(104) ).

Figure : Molecular pathways in invasive urothelial carcinoma. Adapted from Mitra et al. (96)

As mentined above, the current detailed understanding of the molecular pathways involved in URCa development and progression (Figure) has fueled the field of molecular prognostication, theranostics and targeted therapy in bladder cancer (106-121) .A series of recent studies have pointed to the potential prognostic value of receptor tyrosine kinase (RTK) markers such as FGFR-3, EGFR and other ERB family members (ERBB2/HER2 and ERBB3) (97) in superficial and invasive bladder cancer disease (Table). Early studies by Sarkis et al. revealed p53 alterations to be a strong independent predictor of disease progression in URCa (superficial, muscle invasive as well as CIS) (122-124) . P53 has also been shown to be predictive of increased sensitivity to chemotherapeutic agents that damage DNA (125, 126) . More recent studies have demonstrated a synergistic role for combining p53 evaluation with cell cycle control elements such as pRb, p21 and p27(116, 118) demonstrating the superiority of multimarker approach compared to prior single marker approach for prognostication (122-124, 127) . In a recent study by Shariat et al. (118) , superficial URCa patients with tumors on TURB demonstrating synchronous immunohistochemical alterations in all four tested p53, p21, pRb and p27 markers were at significantly lower likelihood of sustained disease free survival (DFS) compared to patients with only three markers altered. In turn, those with three altered markers did worse than patients with only two altered markers altered which in turn had a lower DFS than those with only one marker alteration, as shown in Figure adapted from Shariat et al. (118).

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Table: Potential Molecular Prognostic Markers in Urothelial Carcinoma

Figure : Synergistic prognostic role of immunohistochemical analysis of four markers (p53,p21,pRb and p27) in superficial URCa. (118)

A similar synergistic prognostic role of multiple molecular markers (p53, pRb and p21) was also demonstrated by Chatterjee et al. (116) in patients undergoing cystectomy for invasive URCa using IHC technique. It is expected, in the near future, that such approach of prognostication will constitute a new standard of care in URCa patients management once additional multi-institutional, preferably prospective, trials confirm the above findings. An encouraging example is the recent bladder consortium based multi-institutional trial confirmed the role of proliferation index (as measured by Ki67 on IHC) as a prognosticator in URCa (128).In the near future, the current clinicopathologic based prognostic categorization approach will be supplemented by a molecular based approach as shown in Tables.

Table: Risk categories of URCa according to current clincopathologic parameters.(100).

Table : Risk categories of URCa according to new molecular markers (100).

From a targeted therapy perspective, RTK-HRAS-MAPK (superficial disease) and p53-pRb (muscle-invasive disease) pathogenic pathways as well as angiogenesis pathway of the tumor microenvironment offer tremendous new opportunities for future management of URCa. Phase II trials evaluating the role of tyrosine receptor kinase inhibitors (TKI) targeting EGFR with small molecules such as

Gefitinib and Sorafinib or monoclonal antibodies( MoAb) such as Cetuximab are underway. Other Phase II trials are addressing the role of Herceptin (anti HER2 MoAb) and Bevacizumab (anti VEGF MoAb) in URCa. Phase I trials testing the safety of p53 or Rb gene intravesical therapy are being evaluated. One strategy example is the intravesical introduction of a wild type p53 loaded replication deficient Adenovirus (Ad5CMV-TP53) in an ambitious attempt to compensate for the loss of p53 function in invasive URCa (129-133).

Renal Cell Carcinoma Beyond Immunohistochemistry: Anatomic Molecular Diagnostic Applications

Table . Current and future prognostic parameters in RCCCurrent Prognostic Parameters:

•Patient Factors: Age and Gender•Anatomic Factors: pTNM•Histologic Factors: Histologic Type; Fuhrman Grade•Clinical Factors: ECOG Performance Status, Hgb level, LDH etc

Future Molecular Parameters: Prediction of Behavior & Prediction/Guidance of Rx

Hypoxia inducible:•HIF-1•CA IX•CA XII•CXCR4•VEGF/VEGFR-R•ILGF1

Cell Adhesion Markers:•EpCAM•E-Cadherin•A-Catenin•Catenin-6

Proliferation Markers:•Ki67•MCM2

Cell Cycle Regulators:•Cyclin•p27Apoptosis Regulators•p53•Bcl2•Smac/DIABLOmTOR Pathway•PTEN•akt•pS6k

Current established prognostic parameters in RCC include: pTNM stage, Fuhrman grade, histologic subtype and clinical parameters such as ECOG Performance Status, hemoglobin level and LDH levels among others (134-136) . Continuous refinements of staging criteria and development of nomograms to integrate the


sporadic CCRCC (155, 156) greatly widened the implication of our understanding the molecular mechanisms of VHL inactivation.

VHL can be thought of as a cellular oxygen sensor. Under normoxic conditions, HIF 1alpha is inhibited by normal VHL protein that facilitates elemination of HIF1-alpha (157) . Under hypoxic condition, HIF1-a escapes destruction by VHL and is allowed to exert its crucial role in inducing angiogenesis factors (VEGF), cell growth factors (TGF alpha and beta) and factors involved in glucose uptake and acid–base balance (GLUT-1 and CAIX respectively). A defective VHL function in CCRCC lead to abnormal accumulation of HIF1a even under normal condition, in turn resulting in the overexpression of the above proteins that are normally inducible only during hypoxia. The overexpressed VEGF, PDGF-B, and TGF-B act on neighboring vascular cells to promote tumor angiogenesis. The augmented tumor vasculature provides additional nutrients and oxygen to promote the growth of tumor cells. Furthermore, TGF-alpha acts in an autocrine manner on the tumor cells by signaling through the epidermal growth factor receptor, which promotes tumor-cell proliferation and survival.

Several of the above proteins are currently being investigated as targets of therapy for advanced CCRCC (158-163) . A randomized phase 2 trial involving patients with metastatic CCRCC investigated the efficacy of bevacizumab, a humanized anti VEGF-antibody (164) . Although the treatment resulted in only a few month extension in time to tumor progression, it provided a key "proof of principle" of the efficacy of anti-angiogenic therapy. Inhibitors of VEGF receptor tyrosine kinase activity alone and in combination with other tyrosine kinases are also under study. Multitargeted kinase inhibitors sunitinib and sorafenib have shown great promise in phase 2 and phase 3 trials, with at least stabilization of disease in as many as 70 percent of patients with cytokine-refractory disease. Another growth factor target is TGF-alpha which promotes RCC growth through its interaction with EGFR. A human monoclonal antibody against human EGFR (panitumumab (ABX-EGF)) as well as small-molecule inhibitors of the EGFR tyrosine kinase activity (Gefitinib and Erlotinib) are two strategies being tested to target the TGF alpha/EGFR axis (159, 161-163).Other options being pursued include the use of Temsirolimus (CCI-779), a selective inhibitor of the mammalian target of rapamycin. Partial responses were noted in 7 percent of patients, and minor responses in 26 percent. The median survival rate was 15 months. The notable activity of the drug in patients with poor prognostic features prompted a phase 3 trial (148, 160). Finally, agents targeting HIF1 alpha and CAIX including anti CAIX radiolabeled monoclonal antibody are also under development (156, 165).

above factors promise to yield a better prognostic and management discriminators (137).A large number of biomarkers are under current intense investigation for their potential utility as prognosticators and or therapy predictors in RCC (137-144) . Table lists some of these markers. Kim et al (139) evaluated a set of immunohistochemical markers including Ki67,CAIX,CAXII, p53,PTEN, Gelsolin, EpCAM and Vimentin in combination with established parameters . Their study suggested a new combined molecular and clinicopathologic prognostic model (CAIX, vimentin, p53, pTNM, ECOG-Performance Status) to be superior to prior models of clinical and pathologic parameters alone including the commonly used UISS clinical model.

A promising prognostic role for mTOR pathway members was recently pointed to by Pantuck et al. (145, 146) . Their study revealed an independent negative prognostic role for PTEN loss and pS6k overexpression. The same study showed increases pAKT cytoplasmic expression and loss of pAKT nuclear expression to be negative predictors of survival.

A prognostic role for angiogenesis pathway is illustrated in RCC. Bui et al (147) demonstrated that both low expression of CAIX and high Ki 67 proliferation index were independent negative predictors of survival in CCRCC. Interestingly, CAIX overexpression predicted response to IL2 immune therapy in metastatic RCC, a finding also documented in the study by Atkins et al (148) . In another study by Jacobsen et al (149) VEGF expression appeared to correlate with tumor size and pTNM stage in RCC. The authors found high VEGF expression to be a negative survival prognosticator on univariate but not multivariate analysis. Separately, Kluger et al. (140) analyzed tissue microarrays containing 330 CCRCC and PRCC using a novel method of automated quantitative analysis of VEGF and VEGF-R expression by fluorescent immuno-histochemistry. Unsupervised hierarchical clustering classified tumors by coordinated expression of VEGF and VEGF-Rs. The authors found high expression of VEGF and VEGF-Rs in tumor cells to be associated with poor survival. Finally, a study by Lidgren et al. (150) revealed high expression of HIF1-alpha to be a an independent negative prognosticator in CCRCC.Among cell cycle control molecules, p27 (Kip1) and cyclin D1 appear to have a promising prognostic role in CCRCC. Migita et al (151) found loss of p27 expression to be an independent predictor of poor disease specific survival. Similar p27 findings were also documented by Hedberg et al (152, 153).

Genomic and Theranostic ApplicationsRenal tumors are unique among human neoplasms in term of the tight correlation between their different morphologic phenotypes and underlying genetic alterations. Lessons learned from the relatively rare familial renal cancer syndromes have helped unlock the complex molecular oncogenic mechanisms involved in their sporadic counterparts. As a result, many potential new targets of therapy are now under investigation in the hereto unsuccessful endeavor of treating advanced RCC. The following discussion of the molecular basis of Von Hippel–Lindau disease (VHL) best illustrates the great therapeutic and theranostic potentials of uncovering the molecular mechanisms of renal oncogenesis (154).

VHL syndrome is a rare autosomal dominant familial cancer syndrome (retinal angiomas, hemangioblastomas, pheochromocytomas, CCRCC). VHL syndrome patients are born with a germline VHL mutation affecting all their cellular elements. Inactivation or silencing of the remaining wild-type allele in renal location facilitates the formation of CCRCC in VHL patients. The fact that similar defects in VHL gene are found to be responsible for approximately 60 percent of

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The First GCC & Middle East Highlights2009 ST GALLENBreast Cancer Symposium

Kingdom of BahrainApril 9, 2009

Under the patronage of H E the Minister of Health, and in collaboration with the Bahrain Medical Society. The first GCC & Middle East Highlights of the St Gallen breast cancer conference was organized in the Kingdom of Bahrain, by the Medical Oncology Unit at the Salmaniya Medical Complex. The attendees were around 120 participants from the Arab world including the host country Bahrain, the rest of GCC region, in addition to the Middle-East & North-Africa countries. Bahrain was presented by the largest delegate from the ministry of health, Salmaniya Medical Complex, the military hospital (BDF), the private hospitals, as well as most of the Faculties of Medicine. In addition, some of the staff members from the Princess Margaret Hospital, Toronto, Canada. The majority of the guests were distinguished medical & radiation oncologists, a selection of specialists in breast cancer patient care, such as oncology surgeons, pathologists, breast imaging & cancer screening radiologists. As well as, oncology residents in training, clinical pharmacists, and a group of oncology nurses involved in the process of breast cancer management.

Among the distinguished guests, Dr S. Al Khatib, chairman Pan-Arab Association Against Cancer, Prof Dr H. Khalid, Vice President Cairo University, Prof Dr Fazal Dar, Dean of the Faculty of Medicine-AGU in Bahrain, Prof Dr Akbar Mohsin, the scientific editor of Journal of Bahrain medical Society (JBMS), Prof Dr Khaled Tabbara, Director Biotechnology Program at AGU, and, chairpersons of the oncology services in Bahrain, Kuwait, Qatar, UAE, Yemen, Jordan, Lebanon, NEMROCK and NCI in Egypt. As well as Prof Dr Keiran Murphy, Princess Margret Hospital, Toronto, Canada. The conference was divided into two sessions, followed by panel discussion with Q and A. The interaction lasted long as the floor have shown great interest in exploring more details and exchange of opinions concerning several presented subjects mainly the compatibility of the recently established standard treatment strategies with emphasis to the regional culture, and the current economic status.

Seven speakers representing several cancer institutions & oncology centers in the Arab region. They covered the major aspects of breast cancer management.

With referral to the most recent studies, and the updated results of clinical trials presented at the 2009 St Gallen meeting held March 11-14, 2009, in Switzerland. Starting with the rational & role of pre-operative systemic chemotherapy in breast cancer therapy, presented By Prof Dr A. Kandil from Alexandria University, Egypt.

Next, Assoc Prof S. Al Sukhun at the University of Amman, Jordan analyzed the updated results of the. role of adjuvant endocrine therapy using

aromatase inhibitors, and the latest results f BIG 1-98 study presented at ST Gallen.

Then, the recently evolved role and background of Bisphosphonates in the early stage breast cancer (ESBC) treatment was discussed in details by Dr Abou Al Khair, head of the oncology service at the National Guard Hospital, Riyadh, KSA, & head of the MENA-NCCN BC committee.

The first session was closed with the presentation by Prof Dr L. Sedky, senior consultant medical oncology in Bahrain, and Prof Internal Medicine, Faculty of Medicine, AGU. A thorough analysis of the role of the (Taxanes) in the adjuvant setting,

During the second part of the conference, three important subjects were addressed. Prof Dr H. A. Azim Prof Clinical Oncology, Cairo University, School of Medicine & Head of MENA-NCCN Group, discussed the optimization of the use of different types of anti-Her-2 drugs in the management of Her-2 positive breast cancer. Then the most recent techniques in radiation therapy of the breast cancer were covered by Prof Dr F. Geara Head of the Cancer Institute, AUB, Lebanon, with especial emphasis to the role of conformal radiotherapy, partial radiation technique, and intra-operative (IORT) Mammosite therapy.

Finally, highlights of the 2009 St Gallen recommendations as discussed by the panel of international experts at the end session of the conference in Switzerland was presented by Prof Dr H. Al Zawahry, from NCI, Cairo University, Egypt, in comparison and review of the 2007 consensus, exploring recent changes in the


decision making towards the use of genetic profile to segregate & personalize patients subgroups, then individualize the adjuvant therapy of early stage breast cancer.

The last part of the symposium was the panel discussion session chaired by Dr A. Saad Al Deen, from the Oncology service at the Military Hospital, Riyadh, KSA. He guided the Q&A with panel of the speakers, together with other experts, and some members of the MENA-NCCN breast cancer committee. The interesting discussion covered in one part the role of more conservative surgery for the primary disease as well as the sentinel node biopsy, in another part the neo-adjuvant modality, but mainly the Her-2 techniques, patient selection and the use of targeted therapy with regard to the economic situation of the Arab region, addressing the issue of how to maintain a balance between clinical survival benefit using expensive drugs, while avoiding extra national financial burden. The closure remarks by the co-ordinator Prof Dr Sedky, rapped up that the objectives of the symposium were achieved, namely to summit regional experts in BC, to exchange the experience between the different regional cancer centers. Furthermore, to transfer the updated information from international meetings, aiming at improvement of the breast cancer patient standard of care in the Arab

world, as part of this major global health problem. With promise to maintain the activity and hopes to arrange for the 2011 highlights. Conference CoordinatorProf Dr Lobna SedkyS. Consultant Medical OncologyDepartment of Oncology & HematologySMC, Ministry of health



Workshop Colorectal Cancer & GIST

Alger 21-22 November, 2009

La salle de conférence de l’hôtel Sheraton d’Alger a abrité les 21 et 22 novembre un workshop consacré aux cancers colorectaux et aux tumeurs stromales.Ce workshop organisé conjointement par l’Arab Medical Association Against Cancer (AMAAC) et la Société Algérienne d’Oncologie Médicale (SAOM) a réuni les oncologues algériens des différentes villes d’Algérie et des différentes spécialités concernées par ces deux thèmes avec leurs collègues venus de pays arabes (Jordanie, Liban, Mauritanie, Maroc, Soudan, Syrie, Tunisie) et européens (France, Italie).

Au cours de la première journée consacrée aux cancers colorectaux, les 3 premières interventions ont abordés l’épidémiologie et l’anatomopathologie de ces cancers.

Au cours de la 1ère conférence intitulée ‘’ An overview of epidemiology colorectal in Jordan 1998-2007’’cancer , le Dr. Sami Khatib, président de l’AMAAC a présenté la situation épidémiologique du cancer colorectal en Jordanie durant la période 1998-2007 qu’il a comparé aux pays voisins (Liban, Syrie, Palestine et Arabie Saoudite). Pour le Dr. Khatib l’incidence de ce cancer est en augmentation

dans le monde arabe en rapport avec l’augmentation de l’espérance de vie, le changement de mode de vie et en particulier l’occidentalisation des habitudes alimentaires. Il insistera également sur la moyenne d’âge au diagnostic qui est comprise entre 49 et 59 ans au Moyen-Orient alors qu’elle est de 69 ans aux USA. .Ce cancer représente 9 à 12 % de l’ensemble des cancers dans cette région. Sur le plan histologique, il existe une nette prédominance de l’adénocarcinome bien ou moyennement différencié mais où on note un taux relativement élevé de carcinome mucineux (7 % en Jordanie, 24 % en Egypte).Dans ses conclusions, l’orateur insistera sur l’âge jeune des patients (¼ de moins de 50 ans) et rappellera les facteurs de risques essentiellement alimentaires .Il recommandera par ailleurs la mise en place de plan cancer basé sur les registres du cancer, l’encouragement de la recherche sur les facteurs de risques et la détection précoce voire le screening du cancer colorectal dans le monde arabe. La 2ème présentation du Pr. Abid d’Algérie, intitulée ‘’ epidemiology of colorectal cancer in Algeria, Northern Africa and Arab World’’, après une présentation de quelques aspects socio-économiques du monde arabe, un profil de la morbidité


cancéreuse en rapport avec le cancer colorectal dans les pays arabes disposant d’un registre du cancer a été présenté. Outre le volet d’épidémiologie analytique où l’orateur a insisté sur l’occidentalisation du mode de vie dans la plupart des pays arabes expliquant l’accroissement de l’incidence de ce cancer, le screening par le test FOBT dans les pays arabes a été discuté.A signaler également que le texte en anglais de cette communication a été distribué au cours de ce workshop (il sera mis en ligne dans les prochaines semaines). La 3ème conférence de cette 1ère session, présentée par J. Selves de l’hôpital Purpan de Toulouse, avait pour objet l’anatomopathologie du CRC. Après une présentation des différents types histologiques, l’oratrice rappellera également l’oncogenèse du cancer colorectal avec la classique séquence adénome/carcinome avec l’apparition des différentes anomalies génétiques (APC, kras, DCC, p53 etc.).Sur le plan génétique, dans 85 % des cas il existe une instabilité chromosomale (CIN: aneuploïdie, perte ou gain chromosomal, délétion, perte de l’hétérozygotie, mutation) et dans 15 % des cas une instabilité microsatellitaire (MSI - MLH1, MSH2, MSH6, PMS2). Pour le Pr. J. Selves , sur le plan de la classification moléculaire du cancer colorectal, l’évaluation du statut MSI est importante et validée alors que celle du statut CIMP nécessite une standardisation . Selon cette classification moléculaire: • 65 à 80 % des CRC sont CIN+/CIMP- (carcinome classique et polypose

familiale diffuse)• 12 % sont MSI +/CIMP + (cancer sporadique) • 8% sont CIN+/CIMP + • 3% sont MSI +/CIMP – (HNPCC)

Les marqueurs histopronostiques du CRC sont le stade TNM, le grade histologique et la qualité de la résection chirurgicale (R0, R1, R2). Pour ce qui est des nouveaux marqueurs tumoraux (morphologiques et moléculaires), ils permettent d’affiner le diagnostic, d’évaluer le pronostic et de prédire la réponse au traitement. Ainsi en présence d’un CRC chez un sujet jeune ou entrant dans le cadre d’un CRC familial , le test MSI permet de retrouver dans 15 % une tumeur MSI+ qui avec la recherche du gène MMR permet d’aboutir au syndrome de Lynch dans environ 58 % des cas . Il faut cependant signaler que les marqueurs pronostiques (MSI et réaction immunitaire) ne sont pas utilisés en pratique courante. Quant à leur utilisation comme marqueurs de la réponse thérapeutique (mutation KRAS), elle trouve son indication en cas d’utilisation d’une thérapie ciblée (anti-EGFR: cetuximab, panitumumab) chez les patients présentant un CRC métastatique chimiorésistant.

Au cours de la 2ème session de ce Workshop, le Pr. J.P. Armand de l’Institut Claudius Regaud de Toulouse présentera une excellente conférence intitulées ‘’ Les thérapeutiques ciblées – le changement de siècle – les cancers digestifs ‘’. Il rappellera les principales drogues utilisées au cours du 20ème siècle (5FU, capécitabine, camptothécine et oxaliplatine) et les nouvelles drogues du 21ème siècle (Avastin, Cetuximab , Glivec , Sutent , Sorafenib, Tarceva) qu’il distinguera en mammouths et renards . A l’heure actuelle c’est l’origine de la tumeur qui détermine le type de protocole de chimiothérapie (ex: cancer du poumon = EGFR, KRAS > gemcitabine + cisplatine ; cancer du sein HER2, ER > AC +/- traitement hormonal ; CRC WNT, KRAS > FOLFOX). Il donnera les résultats en matière de survie de l’Avastin dans le cancer du poumon, du sein, du rein et du colorectal (phase III trial AVF2107g). Les modalités d’action de la thérapie ciblée sont passées en revue avec l’exemple des tumeurs stromales et de l’utilisation de l’imatinib et du sunitinib. Pour l’orateur, l’augmentation du nombre d’agents antimitotiques actifs va finir par aboutir à un traitement personnalisé du cancer colorectal métastatique fonction des anomalies génétiques et moléculaires de la tumeur.

Le Pr. M. Pocard de l’hôpital Lariboisière de Paris, présentera le traitement de la carcinose péritonéale d’origine colorectale. Après un rappel sur le mode d’implantation de cette carcinose péritonéale, il donnera la durée de survie des traitements standard (en moyenne 6,2 mois de survie) et qui pourrait augmenter jusqu’à 12 voire 20 mois avec les nouveaux traitements et en particulier la thérapie ciblée. La classification de Sugarbaker est présentée de même que la chimiothérapie post-opératoire immédiate et ses résultats.L’évolution de la CHIP à l’institut Gustave Roussy est passée en revue depuis les premiers appareils artisanaux conçus par D. Elias jusqu’à la technique du coliseum. Les modalités technique de réalisation de l’exérèse de tous les nodules de carcinose est passée en revue de même que l’installation de l’opéré vue qu’il s’agit d’une intervention qui dure plusieurs heures ainsi que le chauffage de la salle opératoire aux alentours de 33 °C.Un guideline devant une carcinose péritonéale d’origine colorectale (découverte en peropératoire ou dans le cadre du suivi d’un patient traité pour cancer colorectal), est proposé du fait de l’impact économique de la procédure de CHIP. Devant une carcinose péritonéale synchrone découverte en peropératoire, le chirurgien doit décider soit d’arrêter l’intervention soit procéder à la résection du primitif et de la carcinose. Par contre devant une carcinose diagnostiquée dans le cadre du suivi d’un patient traité pour cancer colorectal, c’est au staff de la réunion de concertation pluridisciplinaire de décider soit d’une chimiothérapie systémique soit d’une CHIP.

Un panel de 7 oncologues médicaux et chirurgicaux a mis au point un guidelines basé sur 2 types de critère. Ces critères ont été soumis à l’ensemble de la communauté médicale française puis à un panel international (J.M. Bereder – V. Boige – D.Elias – O. Glehen – J.M. Gornet – B. Moran – M. Pocard – A.G. Portilla – P. Sugarbacker). 40 patients ont été opérés selon ces critères à Lariboisière et à l’IGR. Les critères majeurs sont :1. âge physiologique sup. à 70 ans 2. métastases hépatiques bilobaires, multiples ; 3. score OMS 2 ou plus 4. antécédents médicaux graves (essentiellement neurologique ou rénal) 5. aggravation clinique après chimiothérapie systémique 6. Malnutrition 7. métastases pulmonaires

Les critères mineurs sont :1. No drop markers with adjuvant chemotherapy 2. obésité (BMI> 40) 3. antécédents d’irradiation pelvienne4. Carcinose très étendu au scanner ou cliniquement perceptible5. plus de 4 procédures chirurgicales6. Occlusion 7. Association métastatique non reséquée - ovaire exceptée

Critères absents: Indication d’une CHIP (envoyer le patient vers un centre de référence ; en cas de carcinose synchrone ne pas réaliser de colectomie).Un critère mineur: indication d’une CHIP possible : contacter un centre de référence pour avis dès que le diagnostic est posé.Un critère majeur ou 2 critères mineurs: l’indication d’une CHIP est possible mais pas toujours. En cas de carcinose synchrone une CHIP peut être planifiée. Il faudra revoir le patient à 3 mois pour évaluer la réponse à une chimiothérapie systémique et voir si les critères sont toujours présents. Plus d’un critère majeur ou 3 critères mineurs: pas d’indication de CHIP.


En conclusion, le Pr. Pocard conclura en disant que pour la carcinose péritonéale, le décès ne doit plus être la seule issue. Un nouveau concept existe et est actuellement un standard : la CHIP qui n’est néanmoins possible que si la carcinose n’est pas trop étendue. Une stratégie doit être mise en place pour la sélection des patients et chaque patient doit faire l’objet d’une discussion par une équipe pluridisciplinaire dans le cadre d’une RCP.

Le Pr. B. Larbaoui d’Oran a présenté le traitement adjuvant du cancer du colon suivi par le Pr. C. Louvet de l’hôpital Saint Antoine- Paris qui lui traitera du traitement médical du cancer colorectal métastatique. (Ces 2 communications exhaustives seront mises en ligne prochainement sur le site).

La 2ème journée de ce workshop a été consacrée aux tumeurs stromales ainsi qu’à une mise au point sur l’hépatocarcinome. Le Pr. Chaouchi de Jordanie dans une communication intitulée ‘’Gastrointestinal Stromal Tumor G I S T an oncologic overview ‘’ rappellera la définition des ces tumeurs, leur épidémiologie (10-20 cas/million d’habitants aux USA) et leur pathogénie (mutation Génique entraînant la transformation maligne : KIT: 80%-85% ; PDGFRA: 5%-7% ; Wild Type: 12%). Sur le plan diagnostic, ces GIST sont asymptomatiques dans 1/3 des cas. La sémiologie prédominante étant dominée par les douleurs abdominales et les hémorragies digestives. Le diagnostic histologique est basé sur l’immunohistochimie avec la positivité au CD 117 dans 95 % des cas. Un autre marqueur est le PKC83 qui est positif dans 85 à 100 % des GIST.Les facteurs de gravité des GIST sont l’index mitotique et la taille de la tumeur Sur le plan thérapeutique, l’arme principale du traitement des GIST primitif résecables est la chirurgie qui doit être complète de type RO sans rupture de la tumeur. La récidive après chirurgie justifie un traitement adjuvant qui fait appel à l’Imatinib qui est bien toléré par la majorité des patients. Les taux de survie après


mise sous traitement sont rapportés par l’orateur. L’Imatinib en néoadjuvant est également discuté au cours de cette présentation, chez les patients potentiellement resécables, les patients en récidive et les patients métastatiques. Enfin en cas de résistance primitive ou secondaire à l’Imatinib, d’autres drogues peuvent être proposées : Sunitinib, Nilotinib, RAD001, PKC412 et enfin les inhibiteurs HSP90.

Le Pr. Sylvie Bonvalot, chef de service de chirurgie viscérale à l’IGR, dans une présentation sur ‘’Treatment of Gastro-intestinal stromal tumors (GIST) ‘’ reviendra sur la définition des GIST, leur répartition sur le tractus digestif, en 1996 puis en 2006. La majorité des GIST de l’œsophage et du colon sont malin alors que 25 M seulement des GIST gastrique le est. Les mutations kinases varient selon le siège des GIST et le taux de récidive après résection est fonction du type de mutation..

La chirurgie est le premier traitement des GIST résécables mais même dans ce cas 70 à 90 % récidivent. L’indication et le choix du type d’exérèse sont fonction du siège de la tumeur et du risque de malignité. L’abord coelioscopique est en cours d’évaluation. Le Pr. Bonvalot rappellera que la perforation est un facteur pronostique indépendant de survie globale dans les GIST du grêle. De même, outre la rupture, la sarcomatose, les métastases et l’invasion sont 4 facteurs de malignité clinique indépendants pour la survie sans rechute.

Les classifications de Fletcher (2002) et AFIP (2006) sont présentées avec les taux de récurrence.

Dans les GIST localement avancés, le traitement néoadjuvant est discuté s’il peut permettre une chirurgie conservatrice.Dans les GIST métastatiques, les résultats du traitement par l’Imatinib seul ou en association avec la chirurgie sont discutés.Après la présentation de 2 cas clinique, cette séance est clôturée par la présentation du Pr. Massimo Di Maio (Unité des essais cliniques du National Cancer Institute – Napoli, Italy) sur le ‘’ Treatment of hepatocellular carcinoma ‘’. Sur le plan épidémiologique, le CHC est la 3ème cause de décès par cancer dans le monde (679.871 décès en 2007).En Asie et en Afrique, le facteur de risque principal est l’hépatite B (70%) suivi par l’hépatite C (20 %). Quant au pronostic, il est fonction de la pathologie hépatique sous-jacente, le plus souvent la cirrhose évaluée par le score de Child-Pugh , le score CLIP ou encore le Barcelona Clinic Liver Cancer (BCLC) Staging Classification for HCC.

Selon ces différentes classifications, les options thérapeutiques sont exposées : transplantation hépatique (critères de Milan), résection chirurgicale, ablation percutanée par radiofréquence ou injection d’éthanol, chimio-embolisation et enfin le sorafenib dans les formes avancées. Les résultats de l’étude SHARP (Llovet et al, N Engl J Med 2008) sont passées en revue avec les questions qui restent en suspend : est ce que les résultats de cette étude réalisée en Europe peuvent être extrapolés aux pays de forte incidence de CHC comme l’Afrique sub-saharienne ? Est-ce que les résultats bénéfiques seront retrouvés en cas de fonctions hépatiques très altérées ?

L’étude menée par Cheng AL et al (Lancet Oncol 2009; 10: 25-34) tente d’y répondre : la survie médiane est plus faible que celle de l’étude de Llovet (6.5 vs10.7 mois) mais meilleure que dans le groupe placebo (6.5 vs 4.2 mois).

Le Dr. Bounedjar remettant une distinction honorifique au Dr. S. Khatib président de l’AMAAC.


The 2nd KHIBC MENA Cancer Research Conference

Amman, JordanOctober 2009“Barriers, Logistics, and Solutions for Cancer Research in the MENA region”On behalf of the Organizing Committee of the Conference, Corresponding Author: Khalid Matalka, Assistant Director for Research Infrastructure Development, King Hussein Institute for Biotechnology and Cancer, Amman- Jordan, [email protected]

Biomedical research is moving towards a new paradigm and the latest advances in science and technology are rapidly translated and integrated into clinical practice. This approach provides the opportunity to better understand the biology of cancer, so we can improve patient care, survival and quality of life in an unprecedented timeframe. Thus, to have a better integration in biomedical research and to follow on from the success of our first KHIBC Middle East and North Africa (MENA) Cancer Research Conference in 2007, the 2nd KHIBC MENA Cancer Research Conference was held in Amman-Jordan during October 2 and 3, 2009. The Conference was organized by the King Hussein Institute for Biotechnology and Cancer – Jordan, the National Cancer Institute – USA, Duke University – USA, and the European School of Oncology – Italy.

More than three hundred fifty researchers and students from the MENA region, US and Europe attended the conference, discussed 140 abstracts either through oral or poster presentations and exchanged the latest information in the field of biomedical research, focusing mainly in oncology and biotechnology research. You can visit the following website http://www.cancerresearchcon-mena.com for more information regarding the organization and scientific committees, and the abstracts presented at the conference.

Welcoming and introductory remarks by Samir Khleif, MD

2nd KHIBC MENA Cancer Research Conference audience

“Cancer Research in Jordan: Barriers, Logoistcs, and Solutions”, Khalid Matalka, PhD

Barriers, Logistics, and Solutions for Cancer Research in the MENA region

The organizers of the 2nd KHIBC introduced a new theme by inviting well-known scientific researchers from each participating MENA country to present in addition to their success stories, the barriers, logistics and solutions for cancer research in their home country. The presenters emphasized that the performance indicators for biomedical research are: number of important discoveries (i.e. patents), size and scope of its research portfolio, and the volume of publications. In that respect and in Jordan for example, the numbers of peer-reviewed publications from 2000 to 2009 are significantly increasing and as well as the number of peer-reviewed publications/faculty member. This however, does not mean that Jordanians have dissolved their research infrastructure problems. Looking into other aspects of research performance indicators, Jordan as the rest of MENA region fall significantly behind the developed world in the number of patents filed in the US or Europe patent offices.



Regarding the barriers of biomedical research in the MENA region, it generally includes; governance, funding, and research infrastructure. The governance could be described as relatively non focused, lacking in long term vision and appreciation of biomedical and biotechnology research, poor utilization of natural resources, and directing more efforts towards connecting scientific researchers to service-based sectors rather than research-based centers. In terms of funding, not only is there mismanagement of funding allocation, but also less than 0.5% of GDP goes to Research and Development expenditures in the MENA region. This percentage is too low when compared to industrialized countries that spend > 2.5% of their GDP towards R&D expenditures. Furthermore, it is jointly agreed that the scientific and biomedical research culture is lacking among the people of the MENA region. This can be attributed to several factors, one of which is the feeble research infrastructure within the universities, were the emphasis falls more on teaching rather than practical research. This reduces the time needed by faculty members to perform research, in addition to the lack of incentives to perform scientific research. Possible solutions were addressed: First, developing a creative environment by instilling a research culture in elementary schools via: (1) introduction of new curricula, (2) training of teachers, (3) utilize the media to create a scientific society, (4) implementing research incentives especially in higher education, and (5) promoting laboratory-based research at the undergraduate level; Second, indorse and implement regulations for research institutions; Third, implement effective strategies for collaborations and prioritize funding, which are essential elements of biomedical research. It should be stressed that institutions within the MENA region should open the opportunities for collaborative research with no barriers, especially when there is a lack of funding opportunities coupled with a weak research infrastructure.

2009 KHIBC Scholar Awards

During the conference, a panel of faculties from Duke University and National Institute of Health, USA reviewed all the oral and poster presentations and selected the best five presentations (Table 1). The presenters of these were chosen as 2009 KHIBC Scholars and awarded $1000 in addition to receiving a certificate award. The scholar awardees, titles of their presentation, and affiliations are shown in Table 1.

One of the 2009 KHIBC scholar awardees, Khaldon Bodoor, PhD

*Shared the fifth award

Concluding Remarks

The 2nd KHIBC MENA Cancer Research conference presented an opportunity for regional and international researchers to know more about the cutting edge biomedical research projects and initiatives. More importantly, it created a platform to facilitate cooperation and collaboration among institutions and researchers in the MENA region and worldwide to dissolve the barriers and overcome the logistics that render biomedical research in the MENA region fragmented and lagging behind. The outcome of latter will be observed in the 3rd KHIBC MENA Cancer Research conference 2011.

Table: Potential Molecular Prognostic Markers in Urothelial Carcinoma

KHIBC Scholars 2009 Title Affiliation

Lubna Tahtamouni Role of PAK-PIX Signaling to Cofilin in Mitosis

Hashemite University, Zarqa, Jordan

Youmna Kfoury The HTLV-1 oncoprotein Tax post translational protein modification : A cell Compartment Balance Between Tax degradation and NF-B activation

American University of Beirut, Beirut, Lebanon

Yazan Alwarawrah MicroRNA Regulation of Human Signaling Pathways: A Bioinformatics Study

Yarmouk University, Irbid, Jordan

Khaldon Bodoor Molecular Profiling of p53 & FGFR3 in Jordanian Bladder Cancer Patients

University of Science and Technology, Irbid, Jordan.

Hasan Zalzali & Lina Malaeb*

The DNA damage response is associated with p53-dependent senescence of Cyclin D1-driven pineoblastoma

American University of Beirut, Beirut, Lebanon


The First Sudanese Oncology Conference

In Collaboration with AMAAC, the Radiation & Isotope Center Khartoum (RICK) organized the First Sudanese Oncology Conference that was held in Khartoum on December 4-6, 2009; the conference was held under the patronage of his Excellency the vice president of Sudan Sheikh Ali Osman Mohamed Taha and the Health her Excellency Dr. Tabita Butrus. The President of the meeting was Dr. Siddik Mohammed Mustafa the Managing Director of RICK, and Dr. Kamal Eldin Hamad as chairman of the scientific committee.

The inauguration Ceremony was attended by more than 700 people, with very good coverage from the media and special social Programs was prepared; the guests enjoyed the Nile Cruise, the Folklore dancing show as well the Sudanese Hospitality.

The conference was a success and it achieved its objectives by gathering a remarkable group of the physicians treating cancer from many Arab foreign countries. The attendance of the conference exceeded the organizers’ expectations; the lectures halls were full even late in the afternoon, and there were very good debates, discussions and questions from the audience.

The speakers presented in their lectures discussed the recent advances in many fields related to cancer diagnostic and treatment in many topics like: Breast Cancer Surgery, Role of Radiotherapy in Treatment of Breast Cancer, Breast Cancer Surveillance, Hormonal Treatment of Breast Cancer, Role of Chemotherapy in treatment of Breast Cancer, Epidemiology of Colorectal Cancer in El-Sham Area, Role of Chemotherapy in Treatment of Colorectal

Cancer, Hormonal Treatment of Ca Prostate, Role of Anthracyclines in Treatment of Breast Cancer, Surgery of Ovarian Cancer, Treatment of Lung Cancer, and Role of Biomarkers in Diagnosis; there was also an interactive symposium about Palliative care in Cancer. Professor Ahmed Mohamed Elhassan the father of Pathology in Sudan gave a Memorial Lecture on Retinoblastoma.

Around 20 local oral presentations were presented, 20 papers in addition to 30 excellent posters were presented; free papers covered a wide range of Cancers: Breast, CRC, CNS tumors, H and N Cancers, Ca Esophagus, CML and GIST.

The organizing committee of the meeting had started early preparations for the conference since August 2009 by arranging an intensive Health Education Campaign about “Cancer Early Detection and treatment” to increase public awareness about Cancer, the programs continued even after the Conference.

The campaign and the meeting were well covered in the media; during the conference two main Sudanese TV stations hold interviews with the Secretary General of AMAAC Dr. Sami Khatib and the head of the conference scientific committee Dr. Kamal Hamed. Many other participants were met on TV and Radio and also Sudanese Journals to talk about the conference and cancer problems.

The organizing & scientific committees of the conference would like to take this opportunity to thank AMAAC represented by its General Secretary Dr. Sami Khatib for the unlimited encouragement and support to precede this conference, and also we would like to express our gratitude to her Excellency Dr. Tabita Butrus the Minster of Health for her support and cooperation, Sudan Ministry of Finance, and for the other companies: ZEIN, Novartis, Sanofis Aventis, Astra Zenica, Roche, Elhikma, Elshimalia, Dako, Amipharma, and Atlantic for supporting our conference.

Save the date of the Second Sudanese Oncology Conference that will be held in Khartoum, on December 10-12, 2010.

Dr Kamal El-Dein Hamed Mohamed, FFRRCSI, DMRT, DSNAssoc Prof of OncologyFaculty of MedicineUniversity of Khartoum, SUDAN


news from the arab world <


SAVE THE DATE!

ASCOMultidiscipl inaryCancerManagementCourse

(MCMC)

Hostedby:Gulf International CancerCenter

AbuDhabi, UAE.

February 25 – 27, 2010

President of the Conference International ASCO Course Director

Prof. Aly Abdel Razek Prof. Hugo Villar

ASCO:AmericanSocietyofCl inical Oncology

SEMCO:South&EastMediterraneanCollegeof

Oncology

Formoreinformation,pleasecontactProf. Dr. AhmedElzawawy

E‐mail : [email protected]@hotmail.com


ST. MORITZ AND PONTRESINA – APRIL 8-11, 2010

HE

VE

NT

OG

RO

UP

SAVE THE DATE!www.winteracademy.net

2N

DE

DIT

ION

First EURO-ARAB Congress.

KEY TOPICSBreast cancer: adjuvant therapyColorectal cancerGastrointestinal – non colon: updateGynecological sessionNon small cell lung cancer (NLSC)Genitourinary cancerFocus on new drugsAnti-angiogenic agents: from biology to clinical trialsChemotherapy side effects

PRESIDENTS

Prof. Francesco Cognetti, ItalyProf. Francesco Di Costanzo, ItalyProf. Sami Khatib, Jordan

INTERNATIONAL BOARD

Co-Chairman Hamdy Abdel Azim, EgyptOmalkhair Abulkhair, KSASaid Al Natour, JordanAssem Al Radi, KSAAguilar Enrique Aranda, SpainSandro Barni, ItalyCorrado Boni, ItalyAdda Bounedjar, AlgeriaEric Van Cutsem, BelgiumMircea Dediu, RomaniaHussein Hadi Hashmi, LibyaAlan Horwich, UKJoseph Kattan, LebanonGurunath Kilara, IndiaClaus-Henning Köhne, GermanyParis A. Kosmidis, Greece Stefan Madajewicz, USAMervat Saud Al-Saleh, Kuwait Mohsen Mokhtar, EgyptGiovanni Rosti, ItalyArmando Santoro, ItalyMichael Untch, GermanyYasser Abd El Kader, EgyptShahinaz Bedri, SudanFawaz Deirawan, SyriaKhaled Ahmad Al Saleh, Kuwait


Confirmed Invited speakers: Raul Ribeiro (USA) Maarten Egeler (Nether lands)

S ima Jeha (USA) Stefan J . Friedr ichsdorf (USA)

Monica Metzger (USA) Don Aaronson (Nether lands)

Sher i Spunt (USA) Mohab Ayas (KSA)

Matt Krasin (USA) Miguel Abboud (Lebanon)

Eric Bouffet (Canada) Sara Day (USA)

Victor Blanchette (Canada) Huda Huijer (Lebanon)



Conference on Topics in Therapeutic and Diagnostic

Medical Physics

Amman, Jordan

Dead Sea Resort

April 28th – May 2nd, 2010

Sponsored By:

The American Association of Physicists in Medicine

(AAPM)

International Scientific Exchange Program (ISEP)

Third Arab Radiology Conference (ARC)

Arab Medical Association Against Cancer (AMAAC)

Jordan Medical Physics Society (JMPS)

Program Director Dr. Adel Mustafa, AAPM, USA

Co-Directors Dr. Sami Al-Khatib, Secretary General, AMAAC, Jordan

Dr. Hazem Haboub, Chair of ARC Committee, Jordan

Dr. Mustafa Al-Majali, President of JMPS, Jordan

Dr. Samir Khraisat, President of Jordan Radiology Society, Jordan

Associate Directors Dr. Maysoon Al-Taher, AMAAC, Jordan

Dr. Matthew Al-Ghazi, AAPM, USA

For more details please contact Dr. Maysoon Al-Taher at

[email protected]



Amman - Jordan

July 29-31, 2010 Conference

Topics:

• Breast Tumors • GI/GIST Tumors

• Lymphoma/Leukemia • Lung Tumors

• Pall iative Care & Oncology Nursing

Abstracts:

• Awards wil l be granted to best 3 abstracts

• Deadline for submitting abstracts is May 31, 2010 For more details, you can contact Dr. Jamal Khader at:

[email protected]



call for abstracts <


cancer awareness calendar <

january

february

march

april

may

june

july

august

september

october

november

december

Cervical Cancer Awareness Month

Screening and Early Detection Awareness Month

Colorectal Cancer Awareness Month

Cancer Fatigue Awareness Month

Melanoma and Skin Cancer Awareness Month

National Cancer Survivors Day

Sarcoma Awareness Month

Pain Medicine and Palliative Care

Gynecologic Cancer Awareness MonthProstate Cancer Awareness MonthLeukemia and Lymphoma Awareness Month

Breast Cancer Awareness Month

Lung Cancer Awareness MonthSmoking Cessation

5 A Day Awareness Month


instructions for authors <

1. Manuscript Categories

1.1. Clinical trialsThe Editor-in-Chief and an Associate Editor generally review Reports from clinical trials. Selected manuscripts are also reviewed by at least two external peer reviewers. Comments offered by reviewers are returned to the author(s) for consideration. Manuscript acceptance is based on many factors, including the importance of the research to the field of oncology & the quality of the study. Authors should focus on accuracy, clarity, and brevity in their presentation, and should avoid lengthy introductions, repetition of data from tables and figures in the text, and unfocused discussions. Extended patient demographic data should be included in a table, not listed within the text. Reports from Clinical trials are limited to 3,000 words of body text, excluding the abstract, references, figures, and tables. They are limited to six total figures and tables. All abstracts are strictly limited to 250 words. Titles are to be descriptive, but succinct. Results of clinical studies should be supported by a clear description of the study design, conduct, and analysis methods used to obtain the results. Reports of phase II & III studies should include from the protocol a clear definition of the primary end point, the hypothesized value of the primary end point that justified the planned sample size, and a discussion of possible weaknesses, such as comparison to historical controls. Phase I studies will be well received if they have interesting clinical responses, unusual toxicity that pointed to mechanism of action of the agents, and important or novel correlative laboratory studies associated with the trials.

1.2. Review Articles All reviews must be clinically oriented, ie, at least half the review must describe studies that detail human impact, marker effect on prognosis, or clinical trials. Review Articles should be prepared in accordance with the Journal’s Manuscript Preparation Guidelines, and will be reviewed in the same manner as Reports from Clinical Trials. Reviews are limited to 4,500 words of body text, excluding the abstract, references, figures, and tables. The editors also suggest a limit of 150 references.

1.3. Editorials / Comments / Controversies The Editor-in-Chief may solicit an Editorial to accompany an accepted manuscript. Authors who wish to submit unsolicited Comments and Controversies should contact the Editor-in-Chief, before submission to determine the appropriateness of the topic for publication in the Journal. Editorials should be no more than four to five pages in length.

1.4. Articles on Health EconomicsArticles about health economics (cost of disease, cost-effectiveness of drugs, etc) are highly encouraged.

1.5. Case Reports / Correspondence / Special ArticlesCorrespondence (letters to the Editor) may be in response to a published article, or a short, free-standing piece expressing an opinion, describing a unique case, or reporting an observation that would not qualify as an Original Report. If the Correspondence is in response to a published article, the Editor-in-Chief may choose to invite the article’s authors to write a Correspondence reply. Correspondence should be no longer than three pages in length. Special Articles present reports, news from international, regional societies as well as news from our compatriots.

objectives & scope of the PAJO <

The Pan Arab Journal of Oncology (PAJO) is the official Journal of the Arab Medical Association Against Cancer (AMAAC). It is a quarterly publication targeting health professionals interested in the oncology field. It is a multidisciplinary peer-reviewed journal that publishes articles addressing medical oncology, malignant hematology, surgery, radiotherapy, pediatric oncology, geriatric oncology, basic research and the comprehensive management of patients with malignant diseases in addition to international oncology activities, congresses & news.

The journal will be addressed, as a first step, mainly to the professionals in the hematology & oncology field in the Middle East region and North Africa. The goal is to share local & regional research activities news and to be updated with international activities. We hope, with your support, to achieve our following objectives: 1. Promote and encourage research activities in the Arab World. 2. Disseminate & analyze epidemiological local, regional and international data. 3. Update health professionals with the most recent advances, news & developments in the field of oncology. 4. Improve the level of scientific publications arising form the Arab World. 5. Keep health professionals connected and exposed to the activities of different Arab cancer societies. 6. Share with our immigrant compatriots their activities & feedback in this field. 7. Involve all health professionals interested in the field of Oncology within the multidisciplinary scope of the Journal. 8. Encourage post graduates students to submit their research work.


2. Manuscript submission procedure

All manuscripts should be submitted in word and PDF format directly to the Editor-in-Chief by email at the following email: [email protected]. The manuscript should adhere to the journal requirements. Upon manuscript submission, corresponding authors must provide unique e-mail addresses for all contributing authors. Receipt of manuscripts will be acknowledged via e-mail. Upon completion of editorial review, the corresponding author will receive notification of the Editor’s decision, along with the reviewers’ comments, as appropriate, via e-mail.

3. Disclosures of Potential Conflicts of interest

In compliance with standards established and implemented by ASCO’s Conflict of Interest Policy (J Clin Oncol 24:519–521, 2006), it is the PAJO’s intent, as previously referred, to ensure balance, independence, objectivity, and scientific rigor in all of its editorial policies related to the Journal through the disclosure of financial interests, among other measures. All contributors to the Journal are required to disclose financial and other relationships with entities that have investment, licensing, or other commercial interests in the subject matter under consideration in their article. These disclosures should include, but are not limited to, relationships with pharmaceutical and biotechnology companies, device manufacturers, or other corporations whose products or services are related to the subject matter of the submission. Disclosures of financial interests or relationships involving the authors must be addressed on the Author Disclosure Declaration form. The corresponding author may complete the form on behalf of other authors, or authors may complete their own forms and forward them to the corresponding author. This information will be sent to the Editorial Board. Statements regarding financial support of the research must be made on the manuscript title page, and disclosed on the form. This form is available upon request from the Editorial Office. All disclosures will appear in print at the end of all published articles. The Journal requires all Editors and reviewers to make similar disclosures. Reviewers are asked to make disclosures when accepting a review.

4. Manuscript Preparation Guidelines

Title Page The first page of the manuscript must contain the following information: (1) title of the report, as succinct as possible; (2) author list of no more than 20 names (first name, last name); (3) names of the authors’ institutions and an indication of each author’s affiliation; (4) acknowledgments of research support; (5) name, address, telephone and fax numbers, and e-mail address of the corresponding author; (6) running head of no more than 80 characters (including spaces); (7) list of where and when the study has been presented in part elsewhere, if applicable; and (8) disclaimers, if any.

Abstract Abstracts are limited to 250 words and must appear after the title page. Abstracts must be formatted according to the following headings: (1) Purpose, (2) Patients and methods (or materials and methods, similar heading), (3) Results, and (4) Conclusion. Authors may use design instead of Patients and methods in abstracts of Review Articles. Comments and Controversies, Editorials and Correspondence do not require abstracts.

Text The body of the manuscript should be written as concisely as possible and must not exceed the manuscript category word limits described herein. All pages of a submission should be numbered and double-spaced. Helvetica and Arial at 12pt size are the recommended fonts for all text (see Figures section for acceptable fonts for figures). The Journal adheres to the style guidelines set forth by the International Committee of Medical Journal Editors.

References References must be listed and numbered after the body text in the order in which they are cited in the text. They should be double-spaced and should appear under the heading “REFERENCES.” Abbreviations of medical periodicals should conform to those used in the latest edition of Index Medicus and on MEDLINE. The «List of Journals Indexed in Index Medicus» includes the latest abbreviations. Inclusive page numbers must be cited in the reference. When a reference is for an abstract or supplement, it must be identified as such in parentheses at the end of the reference. Abstract and supplement numbers should be provided, if applicable. When a reference is a personal communication, unpublished data, a manuscript in preparation, or a manuscript submitted but not in press, it should be included in parentheses in the body of the text, and not cited in the reference list. Published manuscripts and manuscripts that have been accepted and are pending publication should be cited in the reference list.

Reference Style

º Journal article with one, two, or three authors 1. Dolan ME, Pegg AE: O6-Benzylguanine and its role in chemotherapy. Clin Cancer Res 8:837-847, 1997

º Journal article with more than three authors 2. Knox S, Hoppe RT, Maloney D, et al: Treatment of cutaneous T-cell lymphoma with chimeric anti-CD4 monoclonal antibody. Blood 87:893-899, 1996

º Journal article in press (manuscript has been accepted for publication) 3. Scadden DT, Schenkein DP, Bernstein Z, et al: Combined immunotoxin and chemotherapy for AIDS-related non-Hodgkin’s lymphoma. Cancer (in press)

º Supplement 4. Brusamolino E, Orlandi E, Morra E, et al: Analysis of long-term

instructions for the authors <


results and prognostic factors among 138 patients with advanced Hodgkin’s disease treated with the alternating MOPP/ABVD chemotherapy. Ann Oncol 5:S53-S57, 1994 (suppl 2)

º Book with a single author 5. Woodruff R: Symptom Control in Advanced Cancer. Victoria, Australia, Asperula Pty Ltd, 1997, pp 65-69

º Book with multiple authors 6. Iverson C, Flanagin A, Fontanarosa PB, et al: American Medical Association Manual of Style (ed 9). Baltimore, MD, Williams & Wilkins, 1998

º Chapter in a multiauthored book with editors 7. Seykora JT, Elder DE: Common acquired nevi and dysplastic nevi as precursor lesions and risk markers of melanoma, in Kirkwood JM (ed): Molecular Diagnosis and Treatment of Melanoma. New York, NY, Marcel Dekker, 1998, pp 55-86

º Abstract 8. Bardia A, Wang AH, Hartmann LC, et al: Physical activity and risk of postmenopausal breast cancer defined by hormone receptor status and histology: A large prospective cohort study with 18 years of follow up. J Clin Oncol 24:49s, 2006 (suppl; abstr 1002) 9. Kaplan EH, Jones CM, Berger MS: A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab refractory metastatic breast cancer. Proc Am Soc Clin Oncol 22:245, 2003 (abstr 981)

º Conference/meeting presentation 10. Dupont E, Riviere M, Latreille J, et al: Neovastat: An inhibitor of angiogenesis with anti-cancer activity. Presented at the American Association of Cancer Research Special Conference on Angiogenesis and Cancer, Orlando, FL, January 24-28, 1998

º Internet resource 11. Health Care Financing Administration: Bureau of data management and strategy from the 100% MEDPAR inpatient hospital fiscal year 1994: All inpatients by diagnosis related groups, 6/95 update. http://www.hcfa.gov/a1194drg.txt

º Digital Object Identifier (DOI) 12. Small EJ, Smith MR, Seaman JJ, et al: Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 10.1200/JCO.2003.05.147

º Government Announcement/Publication13. Miller BA, Ries CAG, Hankey BF, et al (eds): Cancer Statistics Review: 1973-1989. Bethesda, MD, National Cancer Institute, NIH publication No. 92-2789, 1992

º ASCO Educational Book 14. Benson AB 3rd: Present and future role of prognostic and predictive markers for patients with colorectal cancer. Am Soc Clin Oncol Ed Book 187-190, 2006

Figures Figures must be cited in the order they appear in the text using Arabic numerals. Figures should be submitted in a seperate documen. Figure legends are required for all article types. Figure legends must not exceed 55 words per figure and should be written below the figure.Images may be embedded in word or Power Point files.

Tables Tables must be cited in the order in which they appear in the text using Arabic numerals. The table’s legend may include any pertinent notes and must include definitions of all abbreviations and acronyms that have been used in the table. Tables submitted with multiple parts will be renumbered. Tables should be submitted in a seperate document. Legends must not exceed 55 words per table and should be written above the figure.

Appendices/Acknowledgments Appendices and acknowledgments will appear in the print version of the article. Language: Appropriate use of the English language is encouraged for publication in the Journal.

5. Post-acceptance Information

Copyright Form Corresponding authors must provide unique e-mail address for each contributing author at manuscript submission. Upon acceptance of the manuscript, each author will receive an e-mail invitation to sign a statement confirming that the manuscript contains no material for which publication would violate any copyright or other personal or proprietary right of any person or entity. Manuscripts will not be published until each author has completed the form.

Page Proofs Corresponding author will receive proofs and must carefully review them for data and typesetting errors. Corrections to proofs must be returned by e-mail, fax, or mail within 1 week. The corresponding author is responsible for collecting and submitting all author corrections into a single submission. Publication may be delayed if proofs are not returned by the publisher’s deadline. The Editor-in-Chief must approve all major alterations, which may delay publication of the manuscript.


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