th isc international conference & 1 gocci international ... · from 2011 to 2013 included)...

SICSocietà Italiana

di Chemioterapia

SICOSocietà Italiana di

Chirurgia Oncologica

AIROAssociazione Italiana diRadioterapia Oncologica

COMUCollegio degli Oncologi

Medici Universitari

SIGESocietà Italiana diGastroenterologia

SIFSocietà Italianadi Farmacologia

AIOMAssociazione Italiana

Oncologia Medica

Focus onGastrointestinalTract Oncology

Florence, Italy, 4-5 March 2011 FINAL PROGRAMME AND ABSTRACT BOOK

Gruppo oncoloGico chirurGico

cooperativo italiano

Under the auspices of

Azienda OspedalieraUniversitaria Careggi

Ordine dei Medicidi Firenze

Università degliStudi di Firenze

5th ISC International Conference & 1st GOCCI International Conference onCancer Therapeutics - Molecular Targets, Pharmacology and Clinical Applications

1II

Chairs Co-ChairsTeresita Mazzei Andrea GalliCalogero Surrenti Enrico Mini

Department of Preclinical and Clinical Pharmacology, Chemotherapy Section andDepartment of Clinical Pathophysiology, Gastroenterology Section - University of Florence

Viale Pieraccini, 6 - 50139 Florence, Italy

Organising Committee Scientific Committee

Scientific Secretariat Organising Secretariat

Gianni Amunni, Florence

Francesco Boccardo, Genoa

Nicola Caporaso, Naples

Gian Franco Delle Fave, Rome

Andrea Galli, Florence

Roberto Labianca, Bergamo

Lucio Luzzatto, Florence

Teresita Mazzei, Florence

Enrico Mini, Florence

Calogero Surrenti, Florence

Paolo Bechi, Florence

Giampaolo Biti, Florence

Luigi Cataliotti, Florence

Francesco Di Costanzo, Florence

Roberto Mazzanti, Florence

Renato Moretti, Florence

Bruno Neri, Florence

Gian Luigi Taddei, Florence

Francesco Tonelli, Florence

Andrea Valeri, Florence

Stefania Nobili, Ida LandiniDepartment of Preclinical and ClinicalPharmacology, Chemotherapy SectionUniversity of Florenceviale Pieraccini, 6 - 50139 Florence, Italyphone +39-055-4271306e-mail [email protected] [email protected]

Mirko TarocchiDepartment of Clinical Pathophysiology,Gastroenterology Section University of Florenceviale Pieraccini, 650139 Florence, Italye-mail [email protected]

O.I.C. SrlAnnalisa BatistiniViale G. Matteotti, 7 - 50121 FirenzePh. +39 055-5035320Email [email protected]

Provider

Scientific PressViale Matteotti, 750121 Florence

Conference Venue

Chiostro del Maglio

Via Venezia, 5 - 50121 Florence (Italy)Tel./Fax 0039 055/582615

A brief description of the conference venue:

This historic site is an ancient convent and the word “Maglio” indicatesthe ancient game practiced in late Renaissance, which consisted in strikingan iron ball with a long hammer towards a target. The church, which nowadays is used as “Aula Magna” (main room), wasbuilt at the end of the XIII century and is decorated with frescoes byGiotto’s School. Its structure is strangely modern: thin columns supportthe whole building, and were appreciated by Vasari.The cloister was built more recently than the convent, and it was classifiedas “not concluded”. Actually, the south east side of the cloister is not present and since 1924it is replaced by an artistic wrought iron gate, which symbolizes both theglory and the pain of medical duties in war.In 1865 this building was used as a barracks for Italian Bersaglieri, then in1882 it became the Italian Army Medical School. Since 1998, Medical head-quarters are located in this building. In the garden you can find the im-portant bronze memorial by Arrigo Minerbi dedicated to Medical Doctorsvictim of wars.

Organising Secretariat

O.I.C. SrlOrganizzazione Internazionale CongressiViale G. Matteotti, 7 – 50121 Florence (Italy)Tel. 0039/055/50351 – Fax 0039/055/[email protected]

The organising secretariat desk is located at Chiostro del Maglio near tothe conference room (Aula Magna) and is open according to the followingschedule:

Friday, 4 March 7.30-18.30Saturday, 5 March 7.30-13.30 3

GENERAL INFORMATION

Dear Colleagues,

It is our pleasure to welcome you to attend the 5th ISC International Con-ference and 1st GOCCI International Conference on Cancer Therapeutics,Molecular Targets, Pharmacology and Clinical Applications “Focus on Gas-trointestinal Tract Oncology”.

This is one of a series of important scientific meetings where the latestknowledge in the field of anticancer drug research and development,pharmacology and clinical applications is presented and discussed.

This year the focus will be on gastrointestinal oncology.

This meeting will be a great opportunity for medical, surgical and radiationoncologists, gastroenterologists, cancer research scientists and otherhealthcare professionals involved in the care of patients with gastrointesti-nal tract cancer to meet and discuss.

Expert faculty from various cancer disciplines will participate in the sci-entific program, and their presentations will provide attendees with infor-mation on the latest developments in translational and clinical research.The general focus of the meeting is to highlight how new informationmay apply to the treatment of cancer patients in your own institution orpractice setting.On behalf of the Organising Committee and the Scientific Advisory Board,we wish you a fruitful meeting and a pleasant stay in beautiful Florence,

Teresita Mazzei, ChairCalogero Surrenti, ChairEnrico Mini, Co-ChairAndrea Galli, Co-Chair

2

projector is at disposal in the conference room and it is not possible touse personal laptops at the podium. The management of the scientificprojections is guaranteed by this single computerised system that auto-matically forwards each presentation to the podium and on the mainscreen. Speakers are kindly requested to use PowerPoint for windows (XPversion). Those speakers with PowerPoint presentations on CD Rom orUSB pens must go to the slide centre at least one hour before presentation,meanwhile those with presentations on their own laptop and/or usingMacintosh/Apple at least two hours before presentation in order to convertthe files into windows format and/or download them on the slide system.

Italian CME AccreditationThe programme of this conference, submitted for the Italian CME accred-itation by the official CME Provider Scientific Press S.r.l. (nr. 245), has ob-tained 5,5 credits according to the new guidelines issued by the NationalCommission for Continuing Medical Education last 13 January 2010. The CME credits are provided by Scientific Press S.r.l. to gastroenterolo-gists, oncologists, radiotherapists and surgeons and they will be notifiedafter the conference according to the 75% correct answers criterion. Del-egates also receive the usual certificates of attendance with the conferencekit. Participants are entitled to receive the CME credits by registering forCME at the secretariat desk every day upon arrival and before leaving thevenue, attending all the conference sessions and returning the due CMEquestionnaires to the secretariat desk the last day of the conference beforeleaving the premises. According to the decision taken by the NationalCommission on Continuing Medical Education last 18 January each par-ticipant can obtain one-third of the three-year credits (150 credits in totalfrom 2011 to 2013 included) through a direct sponsorship for registrationthat must be declared to the Provider officially. For this purpose a dedi-cated form is included in the CME questionnaire that the involved partic-ipants must fill out properly, considering that Age.na.s may not assigncredits in case of missing obligatory information.

Coffee Breaks and Working LunchDuring the conference coffee breaks and a working lunch are scheduledaccording to the official programme. The catering area is located near tothe Aula Magna (main room) and to the secretariat desk. The workinglunch is scheduled for Friday 4 March.

5

GENERAL INFORMATION

Registration Fees Registration fees in EUR (VAT 20% included) By 31/01/2011 After 31/01/2011

and on site

Participant € 300,00 € 350,00

Postgraduate* € 200,00 € 250,00

*Registration fee reserved for postgraduates. It is necessary to send copy of the identity card and the specialty course certificate.

The registration fees include:

• access to the scientific sessions;• conference kit;• certificate of participation;• personalised name badge;• final programme and abstract book;• Italian CME kit;• coffee breaks;• working lunch on 4 March.

Conference Name BadgeA personalised name badge is included in the conference kit for all regis-tered participants to be collected at the secretariat desk upon arrival ac-cording to the official opening times before the conference start.Participants are required to wear the badge during the scientific sessionsand at all times since this is an official document and proof of registra-tion.

Slide CentreA computerised slide centre for the management of all scientific presen-tations is located in the conference room (Aula Magna) and available forspeakers to rehearse and upload their presentations according to the fol-lowing schedule:

Friday, 4 March 7.30-18.30Saturday, 5 March 7.30-13.30

Speakers are invited to strictly follow the allotted times for a smooth flowof the scientific sessions. Computer projection only is available, no slide4

GENERAL INFORMATION

7

GENERAL INFORMATION

Cloakroom During the conference coats and luggage can be left in an unattendedroom near to the secretariat desk. The organising secretariat can not beheld liable for this area.

Transportation to the Conference VenueThe conference venue is located near to Florence historical city centre,walking distance from the main railway station of Santa Maria Novella andmost hotels reserved by the organising secretariat.

By planeFrom Florence airport the conference venue is about 15-20 minutes by taxi or by bus(Ataf-Sita bus service “Vola-in-bus”, main stop at the railway station of Santa Maria Novellawith departures every 30 minutes).

For bus information www.ataf.netFor taxi reservation dial 055/4242 or 055/4798.For taxi information www.radiotaxifirenze.it

By trainThe most confortable railway station is Santa Maria Novella, located downtown at about15 minutes walking distance from the conference venue.For train information www.trenitalia.com

By carFrom North: exit Firenze Nord, follow directions for the city centre “Centro”.From South: exit Firenze Sud, follow directions for the city centre “Centro”.For maps and routes www.viamichelin.itNear to the conference venue different fee parking lots are available for delegates topark their cars.

6

GENERAL INFORMATION

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S.M.N. Railway Station

CongressVenue

The organisers can not be held liable for accidents or mishaps that may occur to partici-pants or to their accompanying persons during the conference or as a result of it.

According to the strict Italian law smoking is not permitted in any area of the conferencevenue, except for the external cloister under the arches.Participants are kindly requested to switch off the mobile phones in the main room duringthe scientific sessions.

Friday, March 4, 2011

8.30-9.00 Opening Ceremony

9.00-9.45 Keynote Lecture 1

DIGESTIVE TRACT CANCERS: EPIDEMIOLOGYCARLO LA VECCHIA (Milan, Italy) Introducer: CALOGERO SURRENTI (Florence, Italy)

9.45-11.30 Topic 1 / Session I

CANCERS OF THE OESOPHAGUS AND THE STOMACHPresident FRANCO BAZZOLI (Bologna, Italy) Moderators PAOLO BECHI (Florence, Italy) - DAVID CUNNINGHAM (Surrey, UK)

- Dysplasia and early malignancy in Barrett's oesophagus, from detection to treatmentMASSIMO CONIO (Sanremo, Italy)

- Oesophageal cancer treatment: the multidisciplinary approachDAVID CUNNINGHAM (Surrey, UK)

- Adjuvant or neoadjuvant treatment of resectable gastric cancer?FRANCESCO DI COSTANZO (Florence, Italy)

- Progress in the medical treatment of advanced gastric cancerALFREDO CARRATO (Madrid, Spain)

Discussion

11.30-12.00 Coffee break and poster viewing

12.00-13.15 Topic 2/Session II

CANCER OF THE LIVER AND OF THE HEPATOBILIARY TRACTPresident CALOGERO SURRENTI (Florence, Italy)Moderators ROBERTO MAZZANTI (Florence, Italy) - STEFANO MILANI (Florence, Italy)

- Toward new response evaluation criteria in hepatocellular carcinoma RICCARDO LENCIONI (Pisa, Italy)

- Progress in the medical treatment of hepatocellular carcinoma FRANCO TREVISANI (Bologna, Italy)

- Cholangiocarcinoma: still an orphan diseaseDOMENICO ALVARO (Rome, Italy)

Discussion

13.15-14.30 Lunch and poster discussion

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SCIENTIFIC PROGRAMME

Poster AreaThe poster area is located near to the secretariat desk, where tape is avail-able for fixing the posters to the boards.Posters must be 70cm wide and 100cm high, the title and names of theauthors must be included in the top side of the posters.On Friday 4 March from 8.30 to 12.00 presenters must fix the posters onthe boards, that can be recognised by the assigned numbers on the samebaords and in the final programme.On Saturday 5 March posters must be removed from 11.00 to 13.00; theposters left on the baords after 13.00 will be disposed of.On Friday 4 March during the poster discussion (13.15-14.30) presentersare required to wear the name badge and to stay close to the assignedposter boards to reply to the questions by the moderators and the partic-ipants. No poster discussion is scheduled in the conference room.The registration is absolutely necessary to have access to the conferencevenue and to present the poster.

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GENERAL INFORMATION

Saturday, March 5, 2011


ANTI-ANGIOGENESIS IN GASTROINTESTINAL TUMORS:VEGFR TARGETING WITH MONOCLONAL ANTIBODIESDAVID CUNNINGHAM (Surrey, UK)Introducer: ENRICO MINI (Florence, Italy)

9.15-10.30 Topic 4/Session V

PANCREATIC CANCERPresident NICOLA CAPORASO (Naples, Italy)Moderators PAOLO PEDERZOLI (Verona, Italy) - PHILIPPE ROUGIER (Paris, France)

- Surveillance of individuals at high risk for pancreatic cancerANDREA GALLI (Florence, Italy)

- Progress in the management of locally advanced and resectablepancreatic cancerPAOLO PEDERZOLI (Verona, Italy)

- Medical treatment of metastatic pancreatic cancer: what's new? PHILIPPE ROUGIER (Paris, France)

Discussion


11.00-12.30 Topic 5/Session VI

GASTROINTESTINAL STROMAL TUMORS President FRANCESCO BOCCARDO (Genoa, Italy)Moderators VITO ANNESE (Florence, Italy) - GUIDO BIASCO (Bologna, Italy)

- Updates in GIST molecular pathology and implications for clinical practiceLUCA MESSERINI (Florence, Italy)

- Adjuvant treatment of GISTs PAOLO G. CASALI (Milan, Italy)

- Updates and perspectives in the medical treatment of metastatic GISTs MARIA DEBIEC - RYCHTER (Leuven, Belgium)

Discussion

12.30-13.00 CME evaluation and Farewell

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COLON CANCER STEM CELLS: MOLECULAR AND CLINICAL ASPECTSGIORGIO STASSI (Palermo, Italy)Introducer: ANDREA GALLI (Florence, Italy)

15.15-16.30 Topic 3/Session III

CANCERS OF THE COLON AND RECTUMPresident FRANCESCO TONELLI (Florence, Italy) Moderators GIAMPAOLO BITI (Florence, Italy) - TERESITA MAZZEI (Florence, Italy)

- Risk factors and hereditary syndromesMAURIZIO GENUARDI (Florence, Italy)- Adjuvant treatment of stage II and III colon cancer ENRICO MINI (Florence, Italy)- Neoadjuvant treatment for locally advanced rectal cancer VINCENZO VALENTINI (Rome, Italy)

Discussion


17.00-18.15 Topic 3/Session IV

CANCERS OF THE COLON AND RECTUMPresident FRANCESCO PALLONE (Rome, Italy) Moderators DAVID KERR (Oxford, UK) - ANDREA VALERI (Florence, Italy)

- Liver metastases of colorectal cancer: the multidisciplinary approach HASSAN MALIK (Liverpool, UK)- Medical treatment of metastatic colorectal cancer: state of the art ALFREDO FALCONE (Pisa, Italy)- New targets and drugs in the treatment of metastatic colorectal cancerDAVID KERR (Oxford, UK)

Discussion

18.15-19.00 Merck Serono Satellite Meet the ExpertsMultidisciplinary approach in the management of patients withmetastatic colorectal cancer: cure as the goal LUCA ALDRIGHETTI (Milan, Italy) - GIANLUCA MASI (Pisa, Italy)

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Keynote Lectures

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SCIENTIFIC CONTRIBUTIONS

Keynote Lecture 1

DIGESTIVE TRACT CANCERS: EPIDEMIOLOGYCarlo La VecchiaIstituto di Ricerche Farmacologiche “Mario Negri” Milano e Istituto di Statistica Medica eBiometria “G.A. Maccacaro”, Università degli Studi di Milano, Milano, Italy

Recent trends for most digestive tract cancers have been favourable inmost European countries. This is not only due to the long term decline ingastric cancer, but also to the falls in mortality from colorectal cancer –due to improved diagnosis and management – and to declines in upperdigestive tract neoplasms, due to reduced alcohol and tobacco consump-tion in males. We considered several aspects of the Mediterranean diet oncancer risk using data from a series of case-control studies conducted inNorthern Italy on over 15,000 cases of 20 cancer sites and comparablenumbers of controls. For most digestive tract cancers, the risk decreasedwith increasing vegetable and fruit consumption. A number of antioxidantsand other micronutrients and food components (including carotenoids,lycopene, flavonoids and resveratrol) showed an inverse relation with can-cer risk, but the main component(s) responsible for the favourable effectof a diet rich in vegetables and fruit remain undefined. Fish, and conse-quently a diet rich in n-3 fatty acids, tended to be another favourable dietindicator. In contrast, subjects reporting frequent red meat intake showedRRs above unity, mainly for colorectal cancer. Whole grain food (andhence possibly fiber) intake was related to reduced risk of several cancers,particularly of the upper digestive tract. In contrast, refined grain intakeand, consequently, glycaemic load and glycaemic index were associatedto increased risk of different types of cancers. Olive oil and other mono-and un-saturated fats, which are also typical aspects of the Mediterraneandiet, were also inversely related to the risk of several cancer sites, partic-ularly of the upper digestive tract, but the role of various fats remains tobe quantified. A Mediterranean diet score appears to be favourable notonly on cardiovascular, but also on cancer, and specifically digestive tractcancers. This points to the importance of dietary patterns more than spe-cific foods, food components and nutrients.

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subpopulation showing both in vitro and in vivo metastagenic potential.These results establish an accurate roadmap of the signaling pathways thatcontrol CSCs tumorigenicity and metastatic potential, whose investigationwill allow the identification of specific molecular targets for innovative se-lective cancer therapy to minimize colon cancer relapse.

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Keynote Lecture 2

COLON CANCER STEM CELLS: MOLECULAR ANDCLINICAL ASPECTSGiorgio Stassi Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy

In the last few years, accumulating evidence has suggested that the ca-pacity of initiating a tumour, including colon cancer, is a unique featureof a small subset of stem-like cells, called “Cancer Stem Cells” (CSCs) or“tumour-initiating cells”. CSCs have the exclusive ability to self-renew ex-panding the CSCs pool and to sustain the tumour growth through differ-entiation into the heterogeneous non-tumorigenic cancer cell types thatconstitute the bulk of the tumor mass.Although solid evidence is lacking to date, CSCs are thought to derivefrom self-renewing normal cells that acquire epigenetic and geneticchanges required for tumorigenesis or from proliferative progenitors thatreprogram themselves acquiring self-renewal capacity.We provide evidence that Sam68 (Src-asociated in mitosis 68 kDa), a pro-totypical member of the STAR (signal transducer and activator of RNA)family of RNA-binding proteins, plays a crucial role in the tumorigenic po-tential of CSCs. Sam68 inhibition interferes simultaneously with CSCsgrowth and migration. Importantly, Sam68 blockage reduces the metasta-genic capacity regulating the expression levels of Snail and Twist and thesplicing of CD44v6 and Met. These latter molecules interact and regulatethe tumour progression and relapse.CD44 has been identified as new promising stemness marker; the majorphysiological role of CD44 is to maintain tissue structure via cell-cell andcell-matrix adhesion. CD44 gene undergoes multiple alternative splicing,resulting in high number of variants. The CD44 splicing variant containingvariable exon 6 (CD44v6) can form a complex with the extracellular he-patocyte growth factor (HGF) and its tyrosine kinase receptor Met. For-mation of this complex induces Met activation promoting cell proliferation,migration and invasion. We observed that CD44 is widely expressed in allcancer tissue analysed, while Met expression resulted enhanced along theadenoma to carcinoma sequence. Interestingly, only a small fraction ofepithelial cells expressed CD44v6 containing isoform. Interestingly, CSCsbut not differentiated cells express CD44v6 and the CD44v6/Met over-lapped population is limited to a small number of cells that are the unique16

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Scientific Sessions

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Keynote Lecture 3

ANTI-ANGIOGENESIS IN GASTROINTESTINALTUMORS: VEGFR TARGETING WITH MONOCLONALANTIBODIESDavid Cunningham Royal Marsden Hospitals, Medical Oncology, GastroIntestinal and Lymphoma Units, Surrey, UK

Angiogenesis is required for the growth of solid tumours, but has only alimited physiological role in adults; therefore disruption of this processhas been widely investigated as a therapeutic target in solid tumour on-cology. Antibodies directed against vascular endothelial growth factors(VEGF) and their receptors, circulating antagonists which prevent receptorbinding and small molecule tyrosine kinase inhibitors have been devel-oped. The addition of bevacizumab, an anti-VEGF-A monoclonal antibody, tocytotoxic chemotherapy improves outcome in metastatic colorectal cancer.However, in the early disease setting, there is no benefit from combiningbevacizumab with adjuvant FOLFOX chemotherapy. In gastric cancer, im-proved response rate and progression-free survival was reported from theaddition of bevacizumab to a cisplatin/fluoropyrimidine doublet in the ad-vanced disease setting, but no significant difference in overall survival wasdemonstrated. Evaluation of bevacizumab in combination with peri-oper-ative ECX chemotherapy for localised gastroesophageal cancer is currentlyunderway in the UK, with early data confirming safety in this setting. Ramucirumab, an anti-VEGFR2 antibody is currently undergoing phase IIIevaluation in advanced gastric cancer in the 2nd line setting, as monother-apy and in combination with paclitaxel. The results of a randomised studyof chemotherapy with or without Aflibercept, a recombinant fusion proteinwhich acts as a VEGF-trap, in metastatic colorectal cancer are awaited.Despite extensive pre-clinical and correlative translational research in largeclinical trials, no predictive biomarkers for benefit from anti-angiogenictherapy have been identified. Due to rare, but potentially serious toxicitiesassociated with anti-angiogenic agents, the selection of patients who willbenefit from these agents would be particularly valuable.

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Topic 1 / Session I CANCERS OF THE OESOPHAGUS AND THE STOMACH

OESOPHAGEAL CANCER TREATMENT: THEMULTIDISCIPLINARY APPROACHDavid CunninghamRoyal Marsden Hospitals, Medical Oncology, GastroIntestinal and Lymphoma Units, Sur-rey, UK

Oesophageal cancer is the eighth most common cancer diagnosed world-wide, with almost half a million new cases diagnosed each year. Multi-modality therapy has improved the outcome from localized disease, butsurvival rates remain relatively poor. Current treatment options are largelydetermined by anatomical location and histology, however following suc-cess in other solid tumours, the evaluation of new targeted agents in com-bination with chemotherapy and radiotherapy is underway in largerandomised trials.

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(CDDP) were evaluated in several randomized clinical trials. Asiatic studiesshowed a statistically significant advantage in terms of survival with theuse of adjuvant CT, and these data were not confirmed in Western trials(5,6). The differences could be attribuited to the differences highlightedin the two different populations, regarding the seat of the primary tumor,the high incidence of early diagnosis, accurate assessment of pre-operativestaging and extensive lymphadenectomy (<D2) performed in Westerncountries , or to the different tumor biology. The standard optimal treatment in early gastric cancer cannot be definedyet. Bibliography1. Ajani JA. Evolving chemotherapy for advanced gastric cancer. Oncologist 2005;10(suppl 3):49-58

2. Cunningham D, Allum WH, Stenning SP, Thompson JN, van de Velde CJ, Nicolson M,Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S,Chua YJ, MAGIC Trial Participants. Perioperative chemotherapy versus surgery alonefor resectable gastroesophageal cancer. N Engl J Med 2006; 355(1):11-20

3. Boige V, Pignon J, Saint-Aubert Bet al. Final result of a randomized trial comparingpreoperative 5-fluorouracil(F)/cisplatin(P) to surgery alone in adenocarcinoma ofstomach and lower esophagus (ASLE). FNLCC ACCORD07-FFCD 9703 trial. Proc ASCO2007; abst 4510

4. Roth AD. Curative treatment of gastric cancer: towards a multidisciplinary approach?Crit Rev Oncol Hematol 2003; 46:59-100

5. Sun P, Xiang JB, Chen ZY. Meta-analysis of adjuvant chemotherapy after radical sur-gery for advanced gastric cancer. Brit J Surg 2009; 96:26-33

6. Buyse ME, Pignon J. Meta-analysis of randomized trials assessing the interest of post-operative adjuvant chemotherapy and prognostic factors in gastric cancer. J Clin Oncol2009; 27:15s (abstr 4539)

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ADJUVANT OR NEOADJUVANT TREATMENT OFRESECTABLE GASTRIC CANCER?Francesco Di Costanzo & Elisa Giommoni S.C. Oncologia Medica, AOU Careggi, Firenze, Italy

Gastric cancer, with 760,000 new cases annually worldwide, is one of themost common malignancies. In recent years there has been a general ten-dency to a progressive reduction of incidence and mortality, but this de-crease appears to be restricted to tumors arising below thegastroesophageal junction. In Europe the gastric cancer incidence is about162,000 cases per year, with a ratio M:F equal to 1.6:1. The poor prognosis,as demonstrated by the overall rate of survival of only 20% is due to thehigh percentage of advanced-stage diagnosis (50%) and strong tendencyto relapse in patients with resected cancers. In sixty per cent of patientswith tumors diagnosed in early stage and treated with surgery R0 (no mi-croscopic residual), there is an early locoregional distant recurrence, withan average survival rates of 30-50% at 5 years. Surgery remains the onlycurative treatment in gastric cancer. Patients with locally advanced disease(stages pT3-4N2), are often not candidate for radical surgery (1). Several clinical studies were published to define the role of neoadjuvantor adjuvant chemotherapy (CT). The preoperative CT was first introducedto achieve a downstaging of locally advanced gastric cancer and to im-prove the rate of resectability. The controlled clinical trial MAGIC demon-strated a survival advantage at 5 years in absolute terms by 13% with theuse of peri-operative CT when compared to surgery performed in the firstinstance (36.3% vs 23%), with a reduced risk of death by 25% (2). Anotherphase III clinical trial (ACCORD FNLCC 07/FFCD 9703), designed by Boigeet al. (3), confirmed that the pre-operative treatment in gastric cancer canbe considered safe and effective. All these studies show that the percent-age of patients who can receive a pre-operative CT is about twice thosewho can receive it postoperatively. Therefore, in these patients the possi-bility of a primary CT should be considered. The role of pre-operativechemo-radiotherapy remains to be determined. The role of adjuvant CT has been evaluated in clinical trials in recentdecades with the purpose of improving the prognosis of patients with gas-tric cancer who undergo surgery (4). New regimens containing cisplatin22

ABSTRACT BOOK

Antiangiogenic treatment with bevacizumab has not yielded positive OSresults in the AVAGAST phase III trial. PFS and RR were significantly better(6.7 vs 5.3 months and 46% vs 37%, respectively). Other anti-angiogenicagents such as ramucirumab (anti-VEGFR2), and tyrosine-kinase inhibitorsare being tested. Other drugs with different mechanisms of action likecatumaxumab, which binds to anti-CD3 (T cell) and anti-EpCAM (tumorcell) and the mTOR inhibitor everolimus, are also being studied.

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PROGRESS IN THE MEDICAL TREATMENT OFADVANCED GASTRIC CANCERAlfredo CarratoRamon y Cajal University Hospital, Madrid, Spain.

Overall, more than 80% of patients with gastric cancer will have advanceddisease at some time-point (60% at diagnosis and the rest at relapse).Chemotherapy increases survival and improves the quality of life of thesepatients. Cisplatin-based regimens have resulted in being superior to for-mer non- cisplatin containing schemes. Both cisplatin plus 5Fluorouracil(CF) and Epirubicin-CF (ECF) may be considered as reference regimens.Median progression-free survival (PFS) of 4-5 months and median overallsurvival (OS) of 7-10 months are usually reached. Adding docetaxel to CFincreases efficacy (PFS of 5.6 months versus 3.7 months) at a cost of highertoxicity (grade 3-4 neutropenia, febrile neutropenia and diarrhoea). Withinthe ECF regimen, the REAL study compared 4 different treatments, substi-tuting oxaliplatin for cisplatin and capecitabine for 5FU (EOF, EOX, ECXand ECF). No significant differences in response rate (RR) and PFS wereobserved. EOX showed a superior OS than ECF (11.2 versus 9.9 months,p=0.02). Cisplatin/capecitabine (XP) has been compared to CF. MedianXP improved OS (10.5 vs 9.3 months) and RR (41% vs 29%), with a similarsafety profile, except for hand-foot syndrome (22% versus 4%). The FLAGSphase III study compared the combination of S-1 plus cisplatin versus CF.No difference between the two arms in OS was found and the S1-cisplatinregimen was less toxic.New drugs: The addition of trastuzumab to chemotherapy in patients withnon-previously treated HER2+ advanced gastric cancer was evaluated ina phase III study (TOGA). A significant improvement in OS, (13.8 vs 11.1months, HR 0.74, p=0.0048), PFS (6.7 vs 5.5 months, HR 0.71) and RR(47.3% vs 34.5%, p=0.0017) was achieved. Future studies will include acombination of trastuzumab with other chemotherapy regimens or target-oriented drugs, assessment of efficacy in 2nd or 3rd line, and maintenanceof trastuzumab after tumor progression. New promising drugs in this set-ting include the HER2-antibody drug conjugate T-DM1, pertuzumab, lap-atinib, neratinib, PF299804, a pan-HER inhibitor, etc. Cetuximab andpanitumumab are being tested.24

ABSTRACT BOOK

Topic 2/Session II CANCER OF THE LIVER AND OF THE HEPATOBILIARYTRACT

PROGRESS IN THE MEDICAL TREATMENT OFHEPATOCELLULAR CARCINOMAFranco Trevisani Dipartimento di Medicina Clinica, Semeiotica Medica, Alma Mater Studiorum, Universitàdi Bologna, Bologna, Italy

Among the currently available therapeutic options for HCC, liver transplan-tation, hepatic resection and percutaneous ablation techniques (based onalcohol injection, radiofrequency, microwave and laser) are considered cur-ative and reserved for very early/early HCCs (fulfilling the Milan criteria),whereas transarterial chemoembolization (TACE) is a palliative approach forintermediate-stage HCC deemed to be able to improve the survival of wellselected patients.The technique of conventional TACE (cTACE) has been continuously refinedin order to increase the tumoricidal effect and safety of this procedure. Thereis evidence that a novel drug delivery embolization technique, based on thesuperselective (subsegmental or segmental) infusion of drug (doxorubicin)eluting bead (DEB-TACE) is better tolerated due to a significant reduction inserious liver toxicity and chemotherapic-related side effects. For this reason,in fragile patients, i.e. those with a more advanced liver dysfunction (Child-Pugh class B) or symptomatic (Performance Status 1) or bilobar tumoral in-volvement, DEB-TACE would achieve better cancer response than cTACE.One retrospective study indicated that DEB-TACE also provides a prognosticadvantage over the conventional technique.Moreover, the advent of transarterial radioembolization (TARE) with Yt-trium90 radiolabeled microspheres has enriched the panel of transarterialoptions. Preliminary evidence coming from cohort studies indicates thatTARE and TACE provide equivalent results in intermediate-stage HCC, andTARE is safe and effective even in patients with portal vein invasion (ad-vanced-stage HCC). Even the pharmacological armamentarium for HCC, a cancer resistant toconventional chemotherapy, has reached a keystone. Two randomizedphase 3 clinical trials have in fact demonstrated that sorafenib, a multikinaseinhibitor and anti-angiogenic agent, is able to prolong the survival of patientswith advanced HCC, opening the road to systemic molecular targeted ther-apy, utilized alone or in combination with other treatments, for this cancer. 27



TOWARD NEW RESPONSE EVALUATION CRITERIA INHEPATOCELLULAR CARCINOMARiccardo LencioniUniversità degli Studi di Pisa, Facolta’ di Medicina e Chirurgia, SOD Diagnostica Inter-ventistica Epatologica Universitaria, Pisa, Italy

The main end-point in cancer research is overall survival. Nonetheless,other potential surrogate end-points, such as response rate and time toprogression, are currently used. Measurement of response rate in hepato-cellular carcinoma (HCC) has become a controversial issue. The classicalWHO criteria underestimate the actual response rate, and, thus, wereamended in 2000 by a panel of experts convened by the European Asso-ciation for the Study of the Liver to take into account treatment-inducedtumor necrosis. Applying these guidelines there was an association be-tween response rate and outcome prediction. More recently, ResponseEvaluation Criteria In Solid Tumors (RECIST) guideline was proposed asa method for measuring treatment response based on tumor shrinkage,which is a valuable measure of antitumor activity of cytotoxic drugs. Thismethod was initially adopted by regulatory agencies –such as the FDA-for drug approval. Again, though, anatomical tumor response metrics canbe misleading when applied to molecular targeted therapies or loco-re-gional therapies in HCC. In 2008, a group of experts convened by theAmerican Association for the Study of Liver Diseases developed a set ofguidelines aimed at providing a common framework for the design of clin-ical trials in HCC and adapted the concept of viable tumor – tumoral tissueshowing uptake in arterial phase of contrast-enhanced radiological imag-ing techniques - to formally amend RECIST. These amendments are re-ferred as the modified RECIST (mRECIST) assessment for HCC. Furtherstudies are needed to confirm the accuracy of this measurement comparedwith conventional gold-standards such as pathological studies of explantedlivers.

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majority of patients present with advanced stage disease, which is notamenable to surgical therapies. Recently, proposed serum and bile bio-markers could help in the screening and surveillance of categories at riskand in diagnosing CCA at an early stage. The molecular mechanisms trig-gering neoplastic transformation and growth of biliary epithelium are stillundefined, but significant progress has been achieved in the last few years.

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CHOLANGIOCARCINOMA: STILL AN ORPHAN DISEASEDomenico AlvaroDipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Università “La Sapienza”di Roma, Roma, Italy

Cholangiocarcinoma (CCA) is a devastating cancer arising from the neo-plastic transformation of the biliary epithelium. It is characterized by aprogressive increase in incidence and prevalence. In Italy, a recent epi-demiologic study (Alvaro D. et al. Dig. Liv. Dis. 2010) demonstrated a pro-gressive increase of incidence with crude incidence rates higher forEH-CCA (extra-hepatic CCA) than for IH-CCA (intra-hepatic CCA) and inmen with respect to women. For IH-CCA, the mortality rates progressivelyincreased from 0.15 per million in 1980 to 5.9 per million in 2003 whenthis cancer overcame EH-CCA. Mortality rates for EH-CCA showed an in-creasing trend from 1980 to 1994 but, in contrast with IH-CCA, a stable orslightly decreasing trend from 1995 to 2003. A national survey on clinicalcharacteristics, diagnostic modalities and treatment (Alvaro D. et al. Dig.Liv. Dis. 2011) demonstrated in 218 incident CCA (47% EH-CCA, 53% IH-CCA) that age at the diagnosis was higher for EH-CCA. Coexistence of cir-rhosis or viral cirrhosis was more frequent in IH-CCA than EH-CCA. Anincidental asymptomatic presentation occurred in 28% of IH-CCA vs 4%EH-CCA whilst, 74% EH-CCA vs 28% IH-CCA presented with jaundice.91% of IH-CCA presented as a single intra-hepatic mass, whilst 50% ofEH-CCA was peri-hilar. In the diagnostic work-up, 70% of all cholangio-carcinoma cases received at least 3 different imaging procedures. Tissue-proven diagnosis was obtained in 80% cholangiocarcinoma. Open surgerywith curative intent was performed in 45% of IH-CCA and 29% EH-CCA.18% IH-CCA vs 4% EH-CCA did not received treatment. These findings in-dicate that in Italy IH-CCA is managed as frequently as EH-CCA. In com-parison to EH-CCA, IH-CCA occurs at younger age and is more frequentlyassociated with cirrhosis and with an incidental asymptomatic presenta-tion. In contrast, most EH-CCAs are jaundiced at the diagnosis. Finally,CCA diagnostic management is cost- and time-consuming with curativesurgical treatment applicable more frequently in IH-CCA. The only curativetherapy is radical surgery or liver transplantation but, unfortunately, the28

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Topic 3/Session III CANCERS OF THE COLON AND RECTUM

ADJUVANT TREATMENT OF STAGE II AND III COLONCANCEREnrico Mini Department of Pharmacology, University of Florence, Florence, Italy

Colorectal cancer represents a major public health problem, being the sec-ond cause of death for cancer in the Western world. Although potentiallycurable at early stages, a substantial number of patients will eventually re-lapse, developing metastatic disease which is mainly incurable. Adjuvantchemotherapy has been shown to lead to definite improvements in stageIII colon cancer patients. However, a relevant percentage of these patients(30-35%) still develop disease recurrence within 5 years from surgery. Thebenefit of adjuvant chemotherapy in stage II patients remains uncertain.70-75% of stage II patients are cured by surgery alone and at present ad-juvant chemotherapy can cure an additional 5% of them whereas up to40% of treated patients will experience serious side effects.Thus, a great deal of effort and resources must to be put into improvingearly diagnosis and prevention tools as well as the efficacy of adjuvanttreatment. Post-operative adjuvant chemotherapy with 5-fluorouracil,folinic acid and oxaliplatin is now considered the standard of care in com-pletely resected stage III colon cancer patients, but there remains contro-versy with regard to the indication and type of adjuvant treatment in stageII patients. Oral fluoropyrimidines play a growing role in the managementof colon cancer and can be currently considered a more favorable alter-native to 5-fluorouracil in terms of cost-benefit also in the adjuvant setting.As the association of targeted agents (e.g. bevacizumab or cetuximab) withanticancer cytotoxic agents has improved the efficacy of cytotoxicchemotherapy alone for metastatic disease, various clinical trials have fo-cused on the role of biological agents in the adjuvant setting. Despite ex-pectations based on apparently robust biological rationales, so far studyresults with the additional use of bevacizumab or cetuximab to chemother-apy have been disappointing. The identification of molecular prognosticand predictive markers of the tumor as well as the pharmacogenetic pro-file of the patient may help in the future in selecting patients who canbenefit from personalized adjuvant treatment.

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Topic 3/Session III

CANCERS OF THE COLON AND RECTUM

RISK FACTORS AND HEREDITARY SYNDROMESMaurizio GenuardiDepartment of Clinical Pathophysiology, University of Florence, Florence, Italy

Family history and DNA sequence variants are the best characterized riskfactors for colorectal cancer (CRC) so far known. It has been estimatedthat the heritability of CRC is about 0.35, and that about 15-20% of CRCsare familial. Single gene mutations that confer high risk (up to 100%) ofdeveloping CRC throughout lifetime can be identified in a relatively smallproportion (1/3rd to 1/4th) of familial cases. In these cases, mendelian pre-disposition to CRC is transmitted either as an autosomal dominant (Lynchsyndrome, familial adenomatous polyposis, and hamartomatous polyposissyndromes) or as an autosomal recessive trait (MUTYH-associated poly-posis). More recently, genome-wide association studies have identified anumber of low penetrance susceptibility alleles, whose clinical utility iscurrently limited by their low predictive power. The use of high through-put genetic technologies provides promising scenarios for the discoveryof further DNA susceptibility variants and for unravelling the complexbundle of genetic susceptibility to CRC.

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Topic 3/Session IV CANCERS OF THE COLON AND RECTUM

LIVER METASTASES OF COLORECTAL CANCER: THEMULTIDISCIPLINARY APPROACHHassan Malik Liver Cancer Surgery, University Hospital Aintree, Liverpool, UK

Introduction: colorectal cancer is a major cause of morbidity and mor-tality. Metastatic colorectal cancer is associated with a poor prognosis.

Discussion: surgical resection for metastatic colorectal cancer can offerlong term chance of cure. A pragmatic onco-surgical approach can in-crease the numbers of patients being brought to resection.

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Topic 3/Session III CANCERS OF THE COLON AND RECTUM

NEOADJUVANT TREATMENT FOR LOCALLY ADVANCEDRECTAL CANCERVincenzo ValentiniCattedra di Radioterapia, Università Cattolica S. Cuore, Roma, Italy

Although surgery remains the most important treatment of rectal cancer,the management of this disease has become multidisciplinary. During the past decades different treatment schedules have been exam-ined, now the recommended approach is preoperative radio(chemo)ther-apy followed by surgery if the tumor is cT3-4 and/or N+, and thenpostoperative chemotherapy can be considered.Short course radiotherapy definitively reduces local recurrence risk for pa-tients with most rectal cancers. The relative risk reduction may actuallybe higher, the lower the absolute risk of a local failure is. The largest ab-solute gains in trials have been seen in patients with extramural spreadand node-positive disease. Two recent randomized trials have showed improvement in the results ofpreoperative radiation in patients with intermediate stage rectal cancerwhen 5FU-based chemotherapy is added to radiotherapy. A statisticallysignificant decrease in local recurrence was observed in those receivingchemotherapy as well as an increased rate of pCR. Five year overall sur-vival was not changed by chemotherapy, but the trials were underpow-ered to detect a 5% difference in overall survival.

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Currently, there is no standard screening protocol for pancreatic cancer,although this will change in the future as technology improves. Addition-ally, there is little information regarding the perceptions and intent toscreen for pancreatic cancer among those with an increased risk due to ahereditary cancer predisposition syndrome.Thus pancreatic imaging remains the cornerstone for the early detectionof PC. Multiple imaging modalities are available for PC detection in generaland high-risk populations. These include computed tomography (CT),magnetic resonance imaging (MRI), positron emission tomography, andendoscopy-based techniques such as endoscopic retrograde cholan-giopancreatography (ERCP) and endoscopic ultrasonography (EUS) withor without fine needle aspiration or biopsy (EUS-FNA). Of all the screeningmodalities available EUS-FNA is the most sensitive and specific screeningtoll to evaluate the pancreas and has been proven to detect early precan-cerous changes in clinical studies. Early detection and screening for pancreatic cancer in a current stateshould be limited to high risk patients that account for only 10% of patientswith pancreatic cancer. Continued efforts are needed to discover an ef-fective test to identify patients with nonhereditary risk factors who willbenefit from screening and also to develop less invasive and more cost-effective screening aimed at controlling pancreatic cancer.

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Topic 4/Session V PANCREATIC CANCER

SURVEILLANCE OF INDIVIDUALS AT HIGH RISK FORPANCREATIC CANCERAndrea Galli Gastrointestinal Unit, Department of Clinical Pathophysiology, University of Florence,Florence, Italy

Pancreatic cancer has the poorest survival rate of any common malig-nancy. Survival rates are stage-dependent, with a 5-year survival rate inthe USA of 17% for local disease. However, only a minority of patientspresent with local disease. This is a consequence of our inability to diag-nose pancreatic cancer early based on symptoms alone, and the currentlack of a blood test or other screening techniques that can accurately de-tect pancreatic cancer in the general population before the onset of symp-toms. Although presently available techniques for detecting earlypancreatic cancer in the general population are unfeasible, impractical ornot cost-effective, they may have a use for surveillance in certain well-de-fined, high-risk groups of patients.The existence of hereditary pancreatic cancer (PC) was initially suggestedby several case reports of a familial aggregation of ductal pancreatic ade-nocarcinomas. Until the late 1980s, only case reports have suggested thatPC aggregates in some families. The first systematic study of a larger cohortof families with PC was published in 1989. Afterward, several registriesfor PC families were established in the United States and Europe to collectand analyze data on these rare families. There is much confusion in the literature regarding the use of the termsfamilial pancreatic carcinoma and hereditary pancreatic carcinoma, be-cause there is a large phenotypic heterogeneity. An inherited predisposi-tion to PC is believed to occur in three distinct clinical settings. First, itoccurs in hereditary tumor predisposition syndromes that are defined pri-marily by a clinical phenotype other than PC but are known to be associ-ated with an increased risk of PC. The second setting is hereditarypancreatitis (HP) and cystic fibrosis (CF), in which genetically determinedearly age onset changes of the pancreas can predispose to the develop-ment of PC. In contrast, the term familial pancreatic cancer (FPC) is ap-plied by most experts to families with two first-degree relatives with PCwithout fulfilling the criteria of another inherited tumor syndrome.34

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MEDICAL TREATMENT OF METASTATIC PANCREATICCANCER: WHAT’S NEW?Philippe RougierDepartment of Digestive Oncology, HEGP, Paris, France

Metastatic pancreatic cancer (MPC) has a very poor prognosis with overallsurvival (OS) around 3-4 months (m) without treatment and 5-6 with a 5-FU (FU) or gemcitabine (G) based protocol.

Concerning chemotherapy until recently, no combination has performedbetter than G alone in terms of OS and quality of life (QOL). However, 4advances in chemotherapy have been reported:1- one meta-analysis using the individual data reported a superiority of acombination of G + platinum salts (CDDP or LOHP) over G (Heinemannet al. BMC cancer 2008);2- the combination of G and capecitabine results in a small increase inPFS and OS (Cunningham et al, J Clin Oncol 2009);3- the FOLFOX regimen has demonstrated its efficacy in second line treat-ment after failure of G with a significant increase in OS;4- more recently the triplet: FU + irinotecan + L-OHP (FOLFIRINOX) hasbeen shown superior to G in a large phase III trial conducted on 342 pa-tients with MPC in PS 0-1 with respectively a PFS of 6.4m vs 3.3m(p=0.0001) and an OS of 11.1m vs 6.8m (p=0.0001 and HR=0.57) (Prodige04 trial: TH Conroy, ASCO 2010, abstract # 4010).

Concerning targeted therapy since the report by Moore of the significantbenefit (marginally significant from a clinical point of view) of a combi-nation of G and erlotinib (Moore et al) there are no significant advancesin the treatment of MPC; MMP inhibitors are not efficient as well as an-tiangiogenic (anti-VEGF and aflibercept) and anti-EGFR. Recently testedConatumumab (AMG 655; proapoptotic agent) and an anti-IGFR (AMG479) resulted in a marginal improvement of PFS (Kindler, ASCO 2010#4035), and, a combination of capecitabine + erlotinib was superior to G+ erlotinib only on on TTF (3.4 vs 2.4m; p=0.003) but not on PFS and OS(6.9m vs 6.6m) (Boeck et al, ASCO 2010 # 4011).Last but not least it has been demonstrated that an anti-coagulation(enoxaoarin) combined with chemotherapy significantly decreases the risk 37



PROGRESS IN THE MANAGEMENT OF LOCALLYADVANCED AND RESECTABLE PANCREATIC CANCERPaolo PederzoliSurgical Department, University of Verona, Verona, Italy

Pancreatic ductal adenocarcinoma (PDA) represents one of the mostdeadly malignancies; surgical resection is necessary to ensure long-termsurvival. However, the majority of patients present with advanced-stagedisease which precludes surgery and most patients die within one yearfrom diagnosis. In this context, neoadjuvant chemotherapy/chemoradio-therapy are frequently performed in patients with locally advanced or bor-derline resectable PDA. After re-staging and appropriate patient selection,up to 50% of patients with borderline resectable PDA can undergo surgicalresection, compared to less than 20% of those with locally advanced tu-mors. In this setting, limited data on perioperative outcomes are availableand the real impact in terms of surgical complications in neoadjuvant treat-ment in patients who undergo surgical resection is not known. In factthese patients may have had a previous laparotomy (with or without gas-tric and/or biliary by-passes) and neoadjuvant radiotherapy can be asso-ciated with fibrosis in the operative field. Finally, the effects of neoadjuvanttreatments on tumor histology and lymph node status in patients with lo-cally advanced PDA have been poorly investigated. The identification ofclinical and histological characteristics associated with tumor responseafter neoadjuvant treatments may be of great clinical interest. Moreoversurgical resection after downstaging of locally advanced and borderlineresectable pancreatic cancer should be offered to all surgically-fit patientswithout increasing postoperative mortality/morbidity. Patients resectedafter neoadjuvant treatment have at least the same survival as those withresectable disease who undergo primary resection.

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Topic 5/Session VI GASTROINTESTINAL STROMAL TUMORS

UPDATES IN GIST MOLECULAR PATHOLOGY ANDIMPLICATIONS FOR CLINICAL PRACTICELuca MesseriniUniversity of Florence, Florence, Italy

Gastrointestinal stromal tumors (GIST) are rare, but they represent themost common mesenchymal tumors of the gastrointestinal tract. The di-agnosis of GIST relies on histological features and positive immunoreac-tion for sensitive antibodies such as CD117 and DOG1. The potential riskof unfavorable evolution is estimated on the basis of tumor site, tumorsize and mitotic rate. Most GIST show mutations of the KIT gene (80% ofcases) or of the PDGFRA gene (5-10% of cases), the remaining cases arewild-type. KIT and PDGFRA mutations are mutually exclusive. Most of themutations affecting KIT or PDGFRA lie in the iuxtamembrane (JM) domain(KIT exon 9 and 11 and PDGFRA exon 12) or in the kinase domains (KITexon 13-14 and 17 and PDGFRA exon 14 and 18) of the receptor. Thetype of mutation is the strongest predictor of sensitivity to therapy. KITexon 11 mutations are considered the most sensitive to therapy (responserate 70%) with imatinib; GIST with exon 9 mutations are less sensitive (re-sponse rate 30%), and this subgroup of cases has been shown to benefitfrom a dose increase from 400 to 800 mg of imatinib. PDGFRA exons 12and 14 mutations are sensitive to imatinib in vitro, while exon 18 mutans(D842V mutants) are generally resistant. Several mechanisms have beenshown to account for imatinib resistance: a) primary resistance (wild-typeGIST, KIT exon 9 or PDGFRA mutation) b) secondary resistance (sec-ondary mutation in another exon, KIT exon 13 or 17 in most cases).

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of thromboembolic events from 10 to 3% compared to chemotherapyalone (CONKO 004 trial: Riess et al, ASCO 2010 # 4033). The future of medical treatment in MPC lies in better knowledge of its bi-ology and in the exploration of new targets and new combinations.

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UPDATES AND PERSPECTIVES IN THE MEDICALTREATMENT OF METASTATIC GISTSMaria Debiec-Rychter Department of Human Genetics, University of Leuven, Leuven, Belgium

GISTs should be managed within a multidisciplinary setting. Imatinib at adosage of 400 mg per day remains the standard treatment for metastaticand inoperable GISTs. Sunitinib has been approved for use as second-linetherapy in imatinib-resistant GISTs. Better understanding of the signallingpathways in GIST has led to the development of new, targeted therapies.We are looking beyond imatinib and sunitinib and examining a wide va-riety of new, small molecules for the treatment of imatinib/sunitinib-résis-tant GISTs. These include PI3K and mTOR, BRAF, HSP90 and HDACinhibitors. Some of these have unique mechanisms of action and are beinginvestigated as single agent therapies or in combination.

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ADJUVANT TREATMENT OF GISTSPaolo G. Casali Istituto Tumori, Milan, Italy

After revolutionizing the treatment of metastatic GIST, imatinib was testedin the adjuvant setting. As of today, there is evidence from a randomizedplacebo-controlled clinical trial (Lancet 2009;373:1097) that, given for oneyear, imatinib improves the relapse-free survival of patients with com-pletely resected localized GIST. At the moment, it is unknown if this trans-lates into an overall survival benefit and whether a longer treatment periodmay further improve results. Data from a trial comparing one versus threeyears of adjuvant therapy are awaited in 2011. It is logical to propose theadjuvant treatment to those patients with a significant risk, estimated byconsidering the mitotic rate, tumor size and disease site. It is also logicalto treat those patients with sensitive mutations of KIT or PDGFRA. Imatinibmay well be used also in a pre-operative setting, when cyto-reductionmay result into more conservative and/or safer surgery. On the other hand,when surgery disclosed already metastatic (e.g., hepatic and/or peri-toneal), the intent of treatment is therapeutic, and imatinib should be pro-longed indefinitely.

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Abstracts of Proffered Papers

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TWO IN VIVO MODELS TO DEMONSTRATE THEEFFICACY OF TELOMERASE-ACTIVATED THYMIDINEANALOGUE PRODRUG IN HEPATOCELLULARCARCINOMA THERAPYTarocchi M1, Polvani S1, Calamante M2, Mello T1, Buccoliero F1,Cioni L1, Ceni E1, Luchinat C3,4, Bertini I3,4, Milani S1, Galli A1

1Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence,Florence; 2ProtEra s.r.l., University Scientific Campus, Sesto Fiorentino, Florence; 3Ma-gnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Florence; 4De-partment of Chemistry, University of Florence, Florence, Italy

Background. Hepatocellular carcinoma (HCC) is one of the most com-mon malignancies worldwide.However, there is no effective treatment for HCC. It has been shown thatsustained activation of telomerase is essential for the growth and progres-sion of HCC, suggesting that telomerase is a rational target for HCC ther-apy. We developed a thymidine analogue pro-drug, acycloguanosyl5’-thymidyltriphosphate (ACV-TP-T), that is specifically metabolized bytelomerase and releases the active form of acyclovir. We investigated theanti-tumor efficacy of ACV-TP-T in in vitro and in vivo models.Methods. We evaluated the proliferation and apoptosis of different he-patic cancer cell lines (HepG2, Hep3B, HuH7 and Hepa1-6) incubatedwith ACV-TP-T. We tested the in vivo efficacy of the treatment in HBVtransgenic mice (TgAlb43Bri), that spontaneously develop hepatic tumors,and in a syngeneic orthotopic murine HCC model, where HCC cells wereimplanted directly in the liver.Results. The pro-drug was metabolized inside the hepatic cancer cellsinto the active form of acyclovir; proliferation assessed by thymidine in-corporation, was reduced, and apoptosis, assessed by caspase activity,was increased. Alteration in the cell cycle profile was induced by pre-in-cubating the hepatic cancer cells with ACT-TP-T. Treatment with ACT-TP-T reduced growth, increased apoptosis, and reduced proliferation of thetumors in the transgenic and in the orthotopic murine model.Conclusion. ACT-TP-T, a thymidine analogue pro-drug, is activated bytelomerase in HCC cells and releases active acyclovir that reduces prolif-eration and induce apoptosis in human and murine cancer cell lines aswell as in animal models.

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by RGZ, most likely through PPARγ-independent non-genomic mecha-nisms. Knockdown of Pontin effectively reduces the number of cancer le-sions in a new orthotopic mouse model as well as hepatoma cell lineproliferation in vitro. We suggest that targeting Pontin expression couldbe of potential interest for developing novel anti-cancer strategies.

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PONTIN52 IS A PPARγ TARGET GENE AND ITSKNOCKDOWN REDUCES HEPATIC CANCER IN ANORTHOTOPIC-SYNGENIC MOUSE MODEL Mello T, Tarocchi M, Buccoliero F, Ceni E, Polvani S, Cioni L, Milani S, Galli ADept. of Clinical Pathophysiology, University of Florence, Florence, Italy

Background and aim. Pontin52 is an AAA+helicase involved in manycellular processes including cell growth and cancer. Pontin has been re-cently shown to be overexpressed in HCC and to be a negative prognosticfactor. By using a proteomics approach, we identified Pontin as a genedownregulated by Rosiglitazone (RGZ) in transgenic mice prone to HBV-related HCC (Galli et al. Hepatology 2010). The aim of this study was toassess the usefulness of Pontin inhibition in reducing HCC growth in vivoand to investigate the mechanisms of its inhibition by RGZ.Material and methods. Mouse (Hepa1-6) and human (HepG2) liver can-cer cells were used for in vitro assays.We developed a new orthotopic mice model that allows the growth of he-patic cancer cells directly injected in the liver. Pontin expression was eval-uated by western-blot and qPCR. Pontin promoter activity was evaluatedby luciferase reporter assay. Gene expression knockdown was performedusing RNA interference. Results. RGZ down-regulation of Ruvbl-1 expression was confirmed bothby qPCR, Western Blotting and Immunofluorescence analysis on Hepa1-6 (mouse) and HepG2 (human) liver cancer cells. After 48h of RGZ treat-ment (20uM) Pontin expression was effectively reduced by 50% at mRNAand protein levels.Surprisingly, PPARγ silencing significantly reduced both Pontin mRNA lev-els and promoter activity. Over-expression of PPARγ induced both Pontinpromoter activity and mRNA levels. Moreover, the non-TZD PPARγ agonistGW1929 induced Pontin expression, while the PPARγ inhibitor GW9662reduced it. On the other hand, RGZ treatment had negligible effects on Pontin pro-moter activity.Pontin down-regulation by either RNA interference or RGZ treatment sig-nificantly inhibited hepatoma cells proliferation in vitro. Pontin-silencedhepatoma cells formed significantly fewer tumor foci than control cells inthe orthotopic mice model. Conclusions. Pontin expression is induced by PPARγ, but downregulated46

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HIPEC IN PERITONEAL DISSEMINATIONGraziosi L1*, Renga B2, Santorelli C1, Mencarelli A2, Cavazzoni E,Donini A1, Fiorucci S21Dipartimento di Scienze Chirurgiche, Radiologiche e Odontostomatologiche. Nuova Fa-coltà di Medicina e Chirurgia, Sant’Andrea delle Fratte, Perugia; 2Dipartimento Diparti-mento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia,Università di Perugia, S. Andrea delle Fratte, Perugia, Italy

Introduction. Peritoneal dissemination is the most frequent pattern ofmetastasis in patients with locally advanced gastric cancer. There is cur-rently a consensus about the use of cytoreductive surgery and hyperther-mic intraperitoneal chemotherapy (HIPEC) for the treatment of PC fromgastric cancer. Our study demonstrates the effects of HIPEC on gastric can-cer peritoneal dissemination in an experimental murine model. Materials and methods. MKN45 cells lines were injected into the peri-toneal cavity of NOD-SCID mice. After peritoneal carcinogenesis induc-tion, animals were randomized into four treatment groups: hyperthermicintraperitoneal chemotherapy (HIPEC) with mitomycin and cisplatin, nor-mothermic intraperitoneal chemotherapy (NIPEC), normothermic intraperi-toneal saline; hyperthermic intraperitoneal saline. 10 days after theintraperitoneal treatment animals were sacrificed and the extent of peri-toneal carcinogenesis was evaluated. Results. HIPEC was also compared with the other groups intraperitoneallytreated. It reduced the extent and severity of peritoneal dissemination asmeasured by assessing the total number of peritoneal and mesenteric nod-ules. We have investigated the effects of HIPEC and NIPEC on the expres-sion of genes by the gene array analysis. We observed that in vivo, theprotective effect of the treatment with HIPEC compared to NIPEC is cor-related with a downregulation of various genes involved in tumor meta-stasis. Conclusion. In the present study we have provided evidence that theprotective effect of HIPEC against peritoneal dissemination of gastric can-cer is correlated with up- and down-regulation of various genes.

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THE NUCLEAR RECEPTOR COUP-TFII IS EXPRESSEDIN HUMAN PANCREATIC ADENOCARCINOMA ANDREGULATES TUMOR GROWTH IN VITRO AND IN VIVOPolvani S1, Buccoliero F1, Ceni E1, Cioni L1, Mello T1, Tarocchi M1,Moretti R2, Nesi G3, Milani S1, Galli A1

1Dept. of Clinical Pathophysiology, University of Florence, Firenze, 23rd Unit of GeneralSurgery, Azienda Ospedaliero-Universitaria di Careggi, Firenze; 3Dept. of PathologicalAnatomy, University of Florence, Firenze, Italy

Background and Aims: Pancreatic cancer is a devastating disease with a5-year survival less than 5%. Despite the accumulating knowledge of mo-lecular alterations characterizing this cancer, no substantial improvementsin the clinical prognosis have been made.Nuclear receptors (NRs) are ligand-dependent, nuclear acting, transcriptionfactors that bind DNA and regulate gene expression. Given their roles, it’snot surprising that several NRs are inappropriately activated in tumors.COUP-TFII is an orphan nuclear receptor highly expressed during devel-opment and in a multiplicity of adult tissues, and influences key biologicalprocesses. COUP-TFII is also expressed in various tumor and tumor celllines. Interestingly, recent papers demonstrated that COUP-TFII may exerta pro-oncogenic role predominantly regulating tumor vascularization.The aim of this study is to evaluate the expression of COUP-TFII in pri-mary human pancreatic tumors and to examine its role in the regulationof tumor behavior in adenocarcinoma cell lines.Methods: Expression of COUP-TFII in paraffin embedded pancreatictumor samples were evaluated by immunohistochemistry. MiaPaca-1 andPANC-1 cell lines expressing shRNA against COUP-TFII in an induciblemanner were produced. Nude mice carrying xenograft tumours were pro-duced by injection of tumor cells.Results: Immunohistochemistry on primary samples demonstrate thatCOUP-TFII expression correlates with tumor staging. To investigate thefunctional relevance of the NR in pancreatic cancer we generated cell linesproducing shRNA against the receptor. COUP-TFII silencing reduces theproliferation, cell motility and anchorage independent growth in vitro andaffects VEGF secretion. In a nude mice xenograft model, silencing ofCOUP-TFII reduces tumor growth.Conclusions: All together, our results suggest that COUP-TFII is a criticalregulator of pancreatic adenocarcinoma development, thus representinga possible new target for pancreatic cancer therapy.

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INFLUENCE OF TS EXPRESSION AND GENOTYPE INNORMAL AND TUMOR CELLS ON THE CLINICALOUTCOME OF COLORECTAL CANCER PATIENTSTREATED WITH 5-FLUOROURACILVignoli M1-2, Nobili S3, Napoli C3, Putignano AL1-2, Morganti M3,Papi L2, Valanzano R4, Cianchi F5, Tonelli F4, Mazzei T3, Mini E3,Genuardi G1-2

1Fondazione Farmacogenomica Fiorgen, Sesto Fiorentino, Italy; 2Dipartimento di Fisio-patologia Clinica, Sezione di Genetica Medica, 3Dipartimento di Farmacologia, Unità diChemioterapia, 4Dipartimento di Fisiopatologia Clinica, Sezione di Chirurgia, 5Diparti-mento di Area Critica Medico Chirurgica, Università degli Studi di Firenze, Firenze, Italy

Background and Objectives. Thymidylate synthase (TS) expression lev-els appear to be related to response to 5-fluorouracil-(5-FU)-basedchemotherapy in colorectal cancer (CRC) patients. Three polymorphismshave been proposed as modulators of TS expression: a tandemly repeatedsequence (2R/3R) in the 5’ UTR, a SNP (G>C) within the 3R allele and a6bp deletion in the 3’ UTR. To evaluate the influence of TS expression and polymorphisms on clinicaloutcome of 5-FU-treated patients we performed a comprehensive geneticanalysis on 63 CRC patients.Methods. TS expression levels were analyzed in normal and tumor tis-sues. TS coding sequence and UTR polymorphisms were investigated onDNA from normal tissue. LOH analysis was performed to determine tumorgenotype.Results. A difference in disease-free survival (DFS), although not statisti-cally significant, was observed between high and low mRNA expressionlevels: patients with low levels showed longer DFS. The 2R2R genotypeshowed significantly lower expression than the 3R3R and 2R3R genotypesin normal tissue. No other TS polymorphism was associated with mRNAexpression or clinical outcome.Conclusions. The results obtained in this pilot study indicate that thenumber of 5’ UTR repeats is the major genetic determinant of TS expres-sion. The lack of association with other polymorphisms might be partiallyexplained by the existence of linkage disequilibrium in the TS gene. Ourdata support the growing evidence that TS control may require multiplemechanisms acting in close coordination with one another and suggestthat TS genotyping alone in tumor samples is not sufficient to accuratelypredict response to 5-FU.

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EXPRESSION OF hERG1 POTASSIUM CHANNELS ANDLACK OF Glut-1 EXPRESSION AS INDEPENDENTPROGNOSTIC INDICATORS OF WORSE OUTCOME INNON METASTATIC COLORECTAL CANCER Lastraioli E, Bencini L, Bianchini E, Romoli MR, Crociani O, Giommoni E, Messerini L, Gasperoni S, Moretti R, Di Costanzo F,Boni L, Arcangeli ADipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze,Italy, Firenze, Italy

Background. There is a need to identify new markers to assess recur-rence risk in early stage colorectal cancer patients. In this study we deter-mined the prognostic impact of hERG1 channels and hypoxia-relatedparameters, in patients with stage I, II and III colorectal cancer.Patients and Methods. The expression of hERG1, VEGF-A, Glut-1, CA-IX, EGF-R and p53 were tested by immunohistochemistry in 135 patients.The median follow-up was 35 months. Clinicopathological parameters andoverall survival were evaluated.Results. hERG1 displayed a statistically significant association with Glut-1, VEGF-A, CA-IX and EGF-R; p53 with VEGF-A and CA-IX; Glut-1 withthe age of the patients; EGF-R with TNM and mucin content. TNM andCA-IX were prognostic factors at the univariate analysis, TNM, hERG1 andGlut-1 at the multivariate analysis. Risk scores calculated from the finalmultivariate model allowed us to stratify patients into four different riskgroups: A) stage I-II, Glut-1 positive, any hERG1; B) stage I-II, Glut-1 andhERG1 negative; C) stage I-II, Glut-1 negative, hERG1 positive; D) stageIII, any Glut-1 and any hERG1.Conclusions. hERG1 positivity with Glut-1 negativity identifies a poorprognosis patient group, within stage I-II colorectal cancer, who mightbenefit from adjuvant therapy, independently from the tumor stage.

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PHASE I AND PHARMACOLOGIC STUDY OFDOCETAXEL (D), OXALIPLATIN (O), CAPECITABINE(C) FOR UNTREATED PATIENTS (PTS) AFFECTED BYADVANCED GASTRIC CANCER (AGC)Buonadonna A*, Torrisi E*, Miolo G*, Corona G◆, Elia C◆, ToffoliG◆, Turchet E°, Tumolo S▲, Frustaci S**Medical Oncology B, °Clinical Trials Office, ◆Experimental and Clinical PharmacologyCentro Riferimento Oncologico, Aviano, ▲Medical Oncology, Pordenone Hospital, Italy

The activity of the DCF and EOX regimens indicates that new drugs (DOC)should be further studied to represent a new standard in the treatment ofAGC.Objectives. 1)Maximum tolerated dosed (MTD) and dose limiting toxici-ties (DLT) of DOC; 2)Advice a dose for DOC for Phase II trials.Methods. CT consisted of D 25-35 mg/m2 iv days 1,8; O 60-70 mg/m2 ivdays 1,8; C 700-1000 mg/m2 po, days 2-15, q3 weeks. Pts were treated atthe same dose level until progression, pt refusal or unacceptable toxicity,in cohorts of 3 until DLT, evaluated in the first 2 cycles. If a DLT was ob-served in the first 3 pts, a further 3 were treated at that same dose level.Dose escalation continued until 3 or more DLTs occurred in 6 pts; the pre-ceding dose level was defined as the MTD. The pharmacokinetics of D was investigated during cycle 1 for correlationwith toxicity.

Drugs Dose levels in mg/m2

I II III IV

D 25 30 30 35O 60 70 70 70C 700 800 1000 1000

Results. From Apr 2008 to Apr 2010, 18 pts were enrolled , 3, 6, 6 and 3in I, II, III and IV level respectively, median age was 62 years (range 32-79), PS 0/1 = 14/4.

Level G3-4 Non-haemat. G3-4 Haemat.toxicity toxicity

I 0 0II 0 1III 2 0IV 3 0 53


CAN WE USE DYNAMIC CONTRAST-ENHANCEDULTRASONOGRAPHY (DCE-US) TO EVALUATEBEVACIZUMAB RESPONSE?Giuliani I1, Marzola M1, Tombesi P2, Sartori S21Clinical Oncology Unit, 2Internal Medicine – Section of Interventional Ultrasound, St. Anna Hospital, Ferrara, Italy

Background. The Response Evaluation Criteria in Solid Tumors (RECIST)were designed primarily for cytotoxic agents and are not applicable to allnew agents. For example, these criteria do not consider durable modestregressions or prolonged disease stability as activity, which we now knowis an effect of several agents such as bevacizumab. Dynamic contrast-en-hanced ultrasonography (DCE-US) using the contrast agent Sonovue andvascular recognition imaging software, is a novel technique that allowsdetection of microvessels and quantitative assessment of solid tumor per-fusion, drawing perfusion curves derived from the video display screenafter logarithmic compression of the raw data. There is no evidence aboutthe use of DCE-US for the evaluation of colorectal metastases treated withbevacizumab in the literature.Materials and methods. We present a case of a 58-year-old woman, thatunderwent radical surgery for sigmoid adenocarcinoma with bilateral ovar-ian metastases (pT4pN2pM1). After post-operative chemotherapy with 12courses of FOLFOX, she developed a liver metastasis. The patient wastreated with 12 cycles of chemotherapy with FOLFIRI and bevacizumab.A DCE-US evaluation was performed at basal time, after 6 and 12 courses.Results. After 6 cycles of chemotherapy with FOLFIRI and bevacizumaba sizeable reduction in tumor vascularization was evident. After comple-tion of the treatment, DCE-US showed only a small residual metastaticfocus with angiogenetic activity, that was radically treated with percuta-neous laser thermal ablation. The patient is now receiving maintenancetherapy with bevacizumab every 3 weeks, and at present there is no evi-dence of metastatic disease (no vascular signal).Conclusions. This case report suggests a possible role of DCE-US in theevaluation of the treatment response of liver metastases treated with an-tiangiogenic drugs. DCE-US, allowing documentation of the reduction oftumor vascularisation, could assess the efficacy of antiangiogenic therapieswhen conventional criteria, based on the variation of lesion size depictedby imaging techniques, are not suitable for the actual evaluation of tumorresponse. 52

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SURVIVAL AFTER RADIOFREQUENCY OF STAGE IIIPANCREATIC CARCINOMA: A WIND OF CHANGE?

Regi P1, Girelli R1, Frigerio I1, Giardino A1, Salvia R2, Bassi C2

1Hepato-Pancreato-Biliary Unit, Casa di Cura Dott. Pederzoli Peschiera del Garda (VR),2Surgical and Gastroenterological Department, Policlinico G.B. Rossi, B.go Roma, Verona,Italy

Background and aim. Radiofrequency ablation (RFA) is a surgical procedurelargely accepted for the treatment of several malignancies. The feasibility andsafety of RFA in locally advanced pancreatic cancer according to UICC clas-sification (LAPC), has recently been described. This study aims to evaluatethe survival rate after a multidisciplinary approach based on RFA plus chemo-radiotherapy (Cht-Rdt). Patients and methods. We performed a retrospective analysis of our data-base between the date February 2007 and December 2008, searching for pa-tients with a histological diagnosis of LAPC and who underwent open RFA.Demographics, clinical and follow-up data of the study cohort were reported. Results. We enrolled 50 patients, of which 25 were males and 25 females(M/F ratio: 1/1), with a median age of 61 years. Tumour location was thehead-uncinate process (N=30; 60%) or the body-tail (N=20; 40%). For 38 pa-tients (76%) RFA was carried out as up-front treatment, while 12 patients(24%) underwent different neoadjuvant therapy associations such as Chtalone (N=3; 6%), Cht-Rdt (N=7; 14%) or Cht-Rdt plus locoregional Cht (N=2;4%). Surgical by-pass was associated with RFA in 30 patients (60%). Postop-erative Cht-Rdt was adopted for 37 patients (74%). Follow-up length wasequal or more than 12 months, with a mean of 15 months. Thirty-four patients(68%) showed progression of disease, 20 of whom eventually died of theirdisease. The 1- and 2-year overall survival rate was 67% and 45%, respectively(median of 20 months), while the disease specific survival rate was 74% at 1year and 51% at 2 years (median of 28 months). The 6- and 12-month pro-gression free survival rate was 62% and 24%, respectively, with a median of10 months. Timing of RFA (up-front treatment or after neoadjuvant therapy)and the tumor site did not correlate with a statistically significant differencein survival rate. Conclusions. Pancreatic cancer is a very aggressive entity and the results ofchemo and/or radiotherapy in locally advanced stage are still dismal. Al-though RFA seems to offer a valid alternative as part of a new multidiscipli-nary approach, further randomised trials are needed for clinical conclusions.

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DLTs were 0/6 , 2/6, 2/6 and 3/3 in I, II, III and IV level respectively.The plasma pharmacokinetics profile of D was investigated by LC-MS/MSin each patient enrolled in the study for all dose levels investigated. The D exposure represented by the mean±SD AUC at each dose levelwas: 1546.5± 698.5 mg L-1 h (n=4), 1733.1±582 mg L-1 h (n=9) and 1892.9mg L-1 h (n=1) for 25 mg/m2 , 30 mg/m2 and 35 mg/m2. For high inter-pa-tient variation (33-45% CI) the trend observed between AUC and dose didnot reach statistical significance.Conclusions. DLTs were observed in Level IV, therefore the MTD is de-fined by the Level III expanded to 9 pts to better define toxicity for thenext phase II study. Further PK analysis will be investigated to confirmpreliminary results.

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IMPACT OF PALLIATIVE RADIOFREQUENCY ABLATIONOF LIVER AND LUNG METASTASES FROMCOLORECTAL CARCINOMA: A RETROSPECTIVEANALYSIS OF A MONO-INSTITUTIONALINTERDISCIPLINARY TEAM

Oliva C1, Perron Cabus G2, De Paolis P3, Bianco L1, Pochettino P1,Bossotti M2, Giubellino E1, Pittana LS1, Inguì M1, Bona A2, Bergnolo P1, Comandone A1

1Department of Medical Oncology, 2Radiology and 3Surgery, Ospedale Gradenigo, Torino, Italy

Introduction: Radiofrequency Ablation (RFA) is the most widely usednon-surgical technique for the local therapy of liver and lung colorectalcancer (CRC) metastases. A recent metanalysis concluded that RFA is auseful adjunct to surgery and chemotherapy in well-selected patients butcannot substitute surgery or chemotherapy. In our interdisciplinary teamRFA is used to complete difficult liver resections, and is used as uniquetherapy in selected patients not suitable for surgery. We also utilize liverand/or lung RFA with explicit palliative intent. The aim of this retrospectiveanalysis is to evaluate the impact of palliative RFA on the survival of col-orectal cancer stage IV pts.

Methods: From December 2005 until now we treated 21 patients (pts),12 M and 9 F, median age 68 yrs (48-86), median ECOG PS 1 (0-2). Fifteenpts had a primary colon cancer and 6 a rectal carcinoma. Twelve pts hadonly hepatic disease; three lung metastases only and six both liver andlung. Four pts had also lympho-nodal involvement, two peritoneal andone had CNS metastases. Treatment was considered with palliative aimbecause of the disease extension or other important contraindications forsurgery. RFA was performed in 7 pts after the completion of the plannedchemotherapy; in 6 cases was done after 3 months chemotherapy and fol-lowed by further CT and in 8 events it was given independently from anyother treatment.

Results: We performed 45 RFA sessions in total. 12 patients needed twosessions of RFA because of disease position or extension; 11 patients re-ceived more than one RFA, median RFA was 2; range 1-5. Toxicities weremoderate; we recorded only one case of sub-pleural empyema with sub-sequent hospitalization. Median progression free survival was 8.6 months

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THE CLINICAL PICTURE OF GISTS ONSET, TYPICALAND ATYPICAL: DESCRIPTION OF 12 CASES

Rinnovati A*, Cammillini C*, Del Buono S^, Rosito MP^, Floridi D°*U.O General Surgery Casentino Hospital, USL8, Arezzo; ^Oncologic Department USL8,Arezzo; °Surgical Pathology Unit, USL8, Arezzo, Italy

Worldwide, GISTS represent 10-20 cancers per million of inhabitants, but it isimportant to establish the standard clinical onset for the goal of unusual clin-ical symptomatology. We studied 12 consecutive cases and we defined the di-agnostic lines on clinical suspect. Moreover we tried to understand the growthpattern, modality of diffusion and the important role of the Surgical Pathologistto determine the therapeutic path after surgery . The growth pattern reflectsthe way the clinical onset could be: 1)Endoenteric growth, 2)Intramuscular orsubmucosal growth. In the first type we can observe early ulceration andbleeding, hidden blood in the positive stools, anemia with hyposideremicblood level, weakness, hematic vomiting, hematemesis. In this situation werecommend such a diagnostic pathway, EGDS, CT or MRI, biopsy wheneverpossible to set a C-Kit that could be positive for CD 117 and Tyrosine Kinasegrowth factor receptor usually >80%. For the lower intestinal tract we suggestendoscopy of the lower bowel tract, jejunal transit X-ray, CT or MRI. Whenbiopsy is performed it can result more than 80% positive at the C-Kit. Whenthe GIST is intramural and the growth pattern is muscular, in the early stagesit can present no symptoms. Afterwards the patient may show early abdominalfullness, palpable mass, dysphagia. But interestingly the symptoms becomequite similar for both ways of growth when the tumour reaches the criticalmass. In such case symptoms become quite similar because of the mucosalulceration. In any case the histologic pattern showing the typical cytoplasmaticvacuolization targeting the nuclear poles is fundamental. The clinical onsetusually brings to a late diagnosis when the disease is often metastatic andthen has a severe prognosis. GISTS with a metastatic clinical situation at sur-gery present low probability of achieving 5-year survival. Nodal involvementis rare and standard lymphectomy is not contemplated in standard surgicalprocedure. When nodal involvement is present, then wider surgical resectionis performed and the prognostic outcome is worse. Metastatic diffusion ismainly in neightbouring organs, the most common being peritoneum, thenomentum. Patients submitted to surgery must receive biologic chemotherapyas soon as the pathologic assessment is performed.

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DESMOPLASIA INFLUENCED MORTALITY IN STAGEIII COLORECTAL CANCER WITHIN FIVE YEARS AFTERSURGERY AND ADJUVANT THERAPY Crispino P§*, Colarusso D§, De Toma G°, Ciardi A#, Di Nardo E^,Minervini G§, Schiava A§, Tripodi B§, Corazziari ES*, Paoluzi P**Gastroenterology Unit, Department of Clinical Sciences, °Department of Surgery and#Pathology Unit, ‘’Pietro Valdoni’’, University ‘’Sapienza’’ of Rome. § Medicine and UrgencyUnit, San Giovanni Hospital, Lagonegro (PZ). ^Epidemiology Unit, ARPAB Basilicata,Italy

Background: About 40-60% colorectal cancer (CRC) patients who un-dergo resection for potential cure have advanced locoregional disease(stage III) and were suitable of adjuvant treatment with a definite disease-free-survival benefit. Desmoplasia is characterised by excessive productionof connective tissue around group of tumour cells, but its role in tumourprogression is still a matter of debate. Aim of the present study was todemonstrate if desmoplasia influenced the mortality rate of III stage CRCwithin five years from surgery and adjuvant therapy.

Methods: 65 patients with III stage CRC underwent resection and adjuvanttherapy with Oxaliplatin/5-Fluorouracil/Leucovorin for 6 months. Quali-tative categorisation of desmoplasia was obtained using Ueno’s stromalCRC classifications. Desmoplasia was related to mortality using Spearmancorrelation and stratified with the other histological variables (inflamma-tion, grading) that concurred to the major determinant of malignancy (ve-nous invasion and lymph nodes) using the chi-square test.

Results: At five years survival rate arose 65% and relapse incidence wasof 37%. Mortality rate in patients with immature desmoplasia was 86%,27% in intermediate desmoplasia and 0% in mature desmoplasia (Spear-man correlation coefficient: -0.572, p=0.05) (Table 1).

Conclusions: These observations suggests that immature desmoplasiahave a role in disease recurrence and mortality in stage III CRC due to anincrease of nodal involvement.

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(95%C.I. 6.3-11.3) and overall survival was 32.2 months (95%C.I. 23.4-38.0).Discussion: RFA plays an important role in the treatment of metastaticcolorectal carcinoma even in a palliative setting. At present a prospectivestudy is ongoing.

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ROLE OF NBI IN THE DIAGNOSIS OF DEGENERATIONOF BIG VILLOUS ADENOMASBandettini L, Manetti A, Basiricò F, Bartolini N, Foppa CDept. Medical and Surgical Critical Area, Division of Surgical Endoscopy, University ofFlorence, Florence, Italy

Introduction. Large tubulo-villous colorectal adenomas are a big problemfor the endoscopist, pathologist, and surgeon as well as for the chemother-apist too: they are neoplasias with neoplastic transformation or neoplasiaswith high risk of transformation (1-2-3).If sizes make us think that transformation has already taken place, we can-not be sure, therefore every therapeutic decision can be criticizable. En-doscopic therapy with tight follow up, possible following drainages andadjuvant chemotherapy if invasion reaches serosa, or immediate surgicalresection regardless of the presence of malignant degeneration?For the pre-operative diagnosis of malignant villous adenoma we cannotignore the number of biopsies that cannot be less than 6, they must berandom and in the areas where we suspect neoplastic transformation.Echoendoscopy is another very helpful procedure to visualize a probableinfiltration of the wall that is an expression of neoplastic degeneration ofbig polyps (4-5).CEA is unreliable since it is positive in only 37 % of cases (6-7).In recent years the utility of NBI associated with zoom, is becoming moreand more apparent in the endoscopic diagnosis of neoplastic transforma-tion of big colorectal polyps (8-9). NBI endoscopy allows us to judge withgreat precision which parts of the polyp are malignant and therefore doselective biopsies, reducing their number. The purpose of presentation of this clinical case is to bring another con-tribution to what other authors have previously demonstrated.Clinical case. Man, 59 years old, came under our observation for mucor-rea and occasional rectal bleeding, lasting for 6 months. CEA = 1.1. Digitalrectal examination showed a lesion that was confirmed at rectalsigmoi-doscopy. It was an extended polypoid lesion. it was vegetating and easilybleeding that extended at all the circumference from 6-7 cm to 15 cm fromanal orifice. Using a colonscope with NBI technology with zoom and ap-plying the endoscopic classifications of Kudo and Hirata-Takata, we iden-tified areas of the same polyp with different features. We performed 5random biopsies in the areas with the characteristic feature of villous ade-noma (tube A), and 5 random biopsies in areas with malignant feature

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Table 1

Variables Immature vs Intermediate Intermediate vs Mature Mature vs Immature

OR (95%CI) and p

Grading

• 1 3 (0.05-151.39); p=1 9 (0.22-362.81); p=0.33 27 (0.32-2060); p=0.2

• 2 6.5 (1.05-40.96); p=0.07 4.3 (0.21-87.58); p=0.3 81 (1.29-5051); p=0.03

• 3 27 (1.04-699.35); p=0.02 1.4 (0.05-4186); p=1 63 (0.98-4046); p=0.02

Inflammatory infiltrate

• Low 20.7 (0.92-427.3); p=0.03 10 (0.46-215.72); p=0.1 209 (3.6-12106); p=0.0005

• High 9.18 (1.5-39.95); p=0.01 1.9 (0.8-45.63); p=1 21 (0.78-564.6); p=0.04

Nodal involvement

• ≤5 lymph nodes 25 (2.6-239); p=0.001 5 (0.25-95.5); p=0.3 85 (2.98-2419); p=0.0014

• >5 lymph nodes 5 (0.38-64.4); p=0.3 7 (0.27-178.61); p=0.23 72 (1.22-4854); p=0.017

Venous invasion

• Present 0.85 (0.04-16.86) p=1 7.5 (1.15-48.73); p=0.02 65 (0.99-4264); p=0.03

• Absent 21.7 (3.2-147); p=0.001 0.62 (0.09-3.96); p=0.6 49 (2.02-1208); p=0.002

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(tube B). Histological samples were analyzed by the same pathologist.Samples in tube A were all villous adenoma, those in tube B were degen-erated villous adenoma.Conclusions. In our experience and in that one of other authors , NBIsystem with zoom is a reliable method to diagnose neoplastic degenera-tion of big villous colorectal adenomas.Bibliography. 1. Rectocolic villous tumors. Study of 69 cases. Orcel L, Hervé de Sigalony JP, LegendreC. Ann Gastroenterol Hepatol (Paris). 1984; 20(6):315-23

2. Clinical,enteroscopic,and pathological characteristics of 796 cases of colorectal polyps.Li Fe, Ye HJ, Wang JP, Liu YG, Yu GY, Yin WH. Zhong Nan Da Xue Xue Bao Yi XueBan. 2005; 30(4):463-6.

3. Efficacy,risk factors and complications of endoscopic polypectomy: ten year experi-ence at a single center. Consolo P.,Luigiano C.,Strangio G.,Scaffidi MG.,GiacobbeG.,Zirilli A.,Familiari L. World J Gastroenterol 2008; 21; 14(15):2354-9.

4. Role of rectal endoscopic ultrasonography in the pre-therapeutical study of villoustumors. Roseau G, Palazzo L, Rahme T,Paolaggi JA. Gastroenterol Clin Biol. 1992;16(10): 787-90.

5. The use of endoscopic ultrasonography and other imaging modalities in the preop-erative staging of rectal villous tumors : a case of overstaging by magnetic resonanceimaging. Buresi MC,Zandieh I, Nagy AG, Spielmann A, Yee WC, Weiss AA, YoshidaEM. Can J Gastroenterol 2009; 23 (9): 639-41.

6. A combination of serum markers for the early detection of colorectal cancer. Wild N,Andres H, Rollinger W, Krause F, Dilba P, Tacke M, Karl J. Clin Cancer Res 2010 15;16(24): 6111-21.

7. Diagnostic value of serum tumor markers in asymptomatic individuals. EleftheriadisN, Papaloukas C, Pistevou-Gompaki K. J Buon 2009; 14 (4): 707-10.

8. NBI in the evaluation of villous morphology : a feasibility study assessing a simplifiedclassification and observer agreement. Singh R, Nind G, Tucker G, Nguyen N, Hol-loway R, Bate J, Shetti M, George B, Tam W. Endoscopy 2010; 42(11): 889-94.

9. Novel approaches in colorectal endoscopy: what do we need biopses for? East JE,Guenther T, Saunders BP. Pathol Res Pract 2008; 204 (7): 459-67

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Acknowledgements The Organisers wish to thank the following companies that have

contributed to the 5th ISC International Conference and 1st GOCCI InternationalConference on Cancer Therapeutics, Molecular Targets, Pharmacology and

Clinical Applications “Focus on Gastrointestinal Tract Oncology”:

Roche

Bayer HealthCare

Eli Lilly Italia

Merck Serono

Organising Secretariat

O.I.C. srlAnnalisa Batistini

Viale G. Matteotti, 7 - 50121 FirenzePh. +39 (0)55-5035320

Email [email protected]

th isc international conference & 1 gocci international ... · from 2011 to 2013 included)...

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