Conclusions: Multivariate analysis is a useful instrument, which enables to ...... (Covidien, USA) twice. Methods: ..... Abdominal esophagus is cut with purse string.
8th International Gastric Cancer Congress
8 th IGCC Krakow, Poland
June 10-13, 2009
Honorary Patronage L ech K ac z y ńsk i President of the Republic of Poland
Organizing Committee Tadeusz P o piel a , MD, PhD, FACS, h.c.m. 8 th IGCC President J an K uli g , MD, PhD 8 th IGCC Vice-President P i ot r K o ło dzie j c z y k , MD, PhD 8 th IGCC Secretary General
Honorary Committee
IGCA Council Members
Chief Local Organizing Committee
Assistance Organizing Committee
e Wa K o Pac z Ministry of Health
J. a . a Ja n i (USA) P. c o r r e a (USA) F. c a r n e i r o (Portugal) J. g a M a -r o d r i g u e s (Brazil) T. h a K u L i n e n (Finland) P. K a s s a B (Brazil) M. K i Ta J i M a (Japan) K . M a r u ya M a (Japan) y. J. M o K (Korea) s.h. n o h (Korea) r . r o s i (Chile) M. s a s a Ko (Japan) h.K . ya n g (Korea) M.F. B r e n n a n (USA) F. c a LV o (Italy) J.W.L. F i e L d i n g (UK) a . g a r o Fa L o (Italy) h. h a r Tg r i n K (The Netherlands) y. K aT o (Japan) M. s. K a r P e h (Japan) B. M a n n (Australia) T. n a K a J i M a (Japan) T. P o P i e L a (Poland) e. s a n T o r o (Italy) c. W i T T e K i n d (Germany) W.c. yo u (China)
M. Barczyński J. Bucki A. Czupryna A. Hartwich D. Hodorowicz-Zaniewska K. Kosowski T. Kruszyna J. Krzeszowiak J. Legutko C. Osuch P. Richter M. Sierżęga J. Skuciński R. Solecki A. Szczepanik M. Szura
A. Aseńko Ł. Bobrzyński K. Bucki R. Choruz W. Dancewicz K. Figuła T. Gach K. Gara J. Jędrys G. Kamtoh W. Kawiorski W. Kibil T. Kowalczyk M. Kowalewski M. Kratochwil P. Kulig A. Matyja G. Mocny B. Niekowal R. Pach Ł. Turczynowski D. Wąchol A. Zając
Jerzy MiLLer Governor of Małopolska Province M a r e K n aWa r a Marshall of Małopolska Province J ac e K M a J c h r o W s K i Mayor of the City of Krakow c a r d i n a L s Ta n i s ł aW d z i W i s z Metropolitan of Krakow K aroL Musio ł Rector of the Jagiellonian University, Krakow W o J c i e c h n o Wa K Vice-Rector of the Jagiellonian University, Krakow To M a s z g r o dz i c K i Dean of the Faculty of Medicine, Jagiellonian University, Krakow Janusz M eder Chairman of the Polish Union of Oncology
IGCA Honorary Members h. s u g a n o (Japan) T. Ta K a h a s h i (Japan)
IGCA Honorary Presidents J.P. K i M (Korea) J.r . s i e W e r T (Germany) M.F. B r e n n a n (USA)
IGCA Officers President: J. g a M a -r o d r i g u e s (Brazil) President-elect: T. P o P i e L a (Poland) Past President: M. K i Ta J i M a (Japan) Secretary General: T. ya M ag u c h i (Japan) Treasurer: h.y. ya n g (Korea) Editors: T. s a n o (Japan), J.r . s i e W e r T (Germany)
IGCA Office Secretary M. K a M i n i s h i (Japan) M a e h a r a (Japan) y. J M o K (Korea) T. s a n o (Japan) T. ya M ag u c h i (Japan) y. K i Tag aWa (Japan) M. M a r u ya M a (Japan) y. o Ta n i (Japan) y. s e T o (Japan) W. ya s u i (Japan)
The Public Relations Officer Jerzy Skuciński
International Scientific Committee
National Scientific Committee
T. Aikou (Japan) J.A. Ajani (USA) W.H. Allum (UK) Y-J. Bang (Korea) M.F. Brennan (USA) F.A. Calvo (Spain) F. Carneiro (Portugal) K.M. Chu (Hong Kong) P. Correa (USA) M. De Giuli (Italy) G. De Manzoni (Italy) D. D’Ugo (Italy) P.D. Fomin (Ukraine) J. Gama-Rodrigues (Brazil) A. Garofalo (Italy) S. Gonzalez-Moreno (Spain) M. Hakama (Finland) T. Hakulinen (Finland) H. Hartgrink (The Netherlands) N. Hiki (Japan) Y. Hiki (Japan) M. Kaminishi (Japan) M. Karpeh (USA) P. Kassab (Brazil) Y. Kato (Japan) G. Keller (Germany) M. Kitajima (Japan) O. Kobori (Japan) P. Konturek (Germany) V. Kryshen (Ukraine) T. Kubota (Japan) B. Mann (Australia) K. Maruyama (Japan) P. McCulloch (UK) H.J. Meyer (Germany) Y. Minasi (USA) Y.J. Mok (Korea) P. Morgagni (Italy) T. Nakajima (Japan) S.H. Noh (Korea) Y. Otani (Japan) F. Pacelli (Italy) D. Roukos (Greece) F. Roviello (Italy) T. Sano (Japan) E. Santoro (Italy) M. Sasako (Japan) J.M. Schiappa (Portugal) C.P. Schuhmacher (Germany) A. Sendler (Germany) R. Seruca (Portugal) Y. Seto (Japan) J.R. Siewert (Germany) M.S. Simões (Portugal) T. Takahashi (Japan)
J. Dadan M. Drews A. Dziki M. Frączek Z. Grzebieniak A. Jeziorski B. Kędra W. Kielan J. Kładny I. Krasnodębski M. Krawczyk M. Krzakowski P. Lampe J. Lubiński P. Misiuna J. Mituś M. Murawa W. Noszczyk M. Nowacki W. Olszewski W. Polkowski Z. Puchalski T. Starzyńska A. Szawłowski Z. Śledziński G. Wallner W. Witkiewicz W. Zegarski
TABLE OF CONTENTS
WELCOME MESSAGES OPENING LECTURE
6 7
PLENARY SESSIONS
9
INVITED LECTURES 12 Nishi-Takahashi Lecture 12 Presidential Lecture 12 Jin Pok Kim Memorial Lecture Distinguished Lecture 13
13
ORAL PRESENTATIONS – SYMPOSIUMS FREE PAPERS SESSIONS VIDEO SESSIONS
15
35
90
CONSENSUS CONFERENCE
96
EUNE (EUROPEAN UNION NETWORK OF EXCELLENCE FOR GASTRIC CANCER) SESSION POSTER SESSIONS Index
178
101
97
WELCOME MESSAGES
OPENING LECTURE
Ladies and Gentlemen, Dear Colleagues
as far as the surgical treatment of malignant cancer is concerned we have reached the limit.
TRUST: THE SOCIAL CONTEXT OF THERAPY
It is my privilege to welcome you to Krakow for the th International Gastric Cancer Congress, under the motto “Basic translational and clinical research in gastric cancer. Can we do this puzzle?”.
New solutions must be sought. The present development of medicine spreads in many directions. Immunology and physiopathology have reached the level of molecular biology. Molecular biology and genetics, in turn, allow for the insertion of genetic material into an organism with the purpose of achieving a therapeutic effect – genetic therapy. It is now possible to isolate and transfect cancerous cells, then to select stable transfected cells and prepare an autovaccine. It is also possible to cultivate isolated cancerous cells from blood and bone marrow, facilitating research into the mechanisms of metastasis and the development of effective antimetastatic drugs. The basic sciences have powerful tools at their disposal, genomics and proteomics with micro-arrays amongst them. Further progress in these fields will certainly enable us to identify clinically significant biomarkers of gastric cancer and the indivisualisation of therapy for optimum efficacy.
Theoretical Sociology, Jagiellonian University at Krakow
I am delighted we shall discuss a broad spectrum of topics that will address on a high level the most relevant and recent conceptual, surgical and technological advances in the areas of stomach cancer treatment. The Congress will coincide with the th anniversary of the first partial gastric resection performed on a patient with cancer. The operation was performed by Jules-Emile Pean on th April, . The following years saw two more cancer related gastric resections; performed by Ludwik Rydygier on th November, , and by Theodor Billroth on th January, . In , Jan Mikulicz-Radecki successfully diagnosed and described gastric cancer by employing, for the first time in history, a gastroscope of his own construction. He maintained that it would be the best method of diagnosing gastric cancer. These four pioneers of gastric cancer surgery shall accompany us throughout the congress, having been portrayed on the official congress poster, designed by one of Krakow’s leading graphic artists. Some of these events happened in Krakow, a city of great scientific and cultural traditions and an important scientific centre of the time. The turn of the th and th century saw the dawn of the golden age of surgery. This was due to general and local anaesthesia and the understanding of the principles of asepsis and antisepsis, making it possible to carry out safer operations. And it was then that the basic assumptions and clinical guidelines for dealing with the majority of surgically treated diseases, including gastric cancer, were formulated. Further improvements in the operative therapy of gastric cancer were determined by progress in diagnostic methods, which allowed for more precise and effective surgical treatment. In fact, it became the only method of treating gastric cancer. Of course, the modernisation of equipment and materials is very dynamic, and lasers, ultrasonic knives, staplers, robotics etc. and the development of endoscopy and laparoscopy in turn led to the introduction of minimally invasive methods of surgical treatment. The surgery of gastric cancer achieved an intellectual and technological peak, however, this was not reflected in the results of treatment of gastric cancer patients. They are still unsatisfactory, far below expectations. From the perspective of my years as a physician, during which I have applied all presently used surgical methods of treatment of cancer, I am obliged to say that the patient’s body simply cannot be wounded any further. We must admit it humbly –
Dear Colleagues, On behalf of the International Gastric Cancer Association I welcome all the members and guests of the International Gastric Cancer Congress (th IGCC), which will take place on June -, , in Krakow, Poland. The scientific agenda was organized with broad input from the Scientific Committee members, and will include thorough discussions about the progresses in the scientific knowledge of gastric cancer and other gastric diseases in general. The Polish International Gastric Cancer Association organizing committee has prepared numerous cultural, social and tourist activities you can enjoy during your stay in Poland. Your registration in the International Gastric Cancer Association, as well as in its national affiliate organizations will assure lower cost benefits for your participation in this and future meetings. The IGCA started a rich scientific tradition, expressed by the intellectual fraternity established in the remarkable first Congress in Kyoto, Japan, held in . This tradition was consolidated in the memorable bi-annual Congresses that followed, of which the meeting in Munchen, Soul, New York, Rome, Yokohama and Sao Paulo are extraordinary examples.
Bearing in mind all of the above, it is evident that the battle against cancer is currently waged both in the operating theatre and the laboratory. The resolve to face these ambitious and truly formidable challenges dictates the following invitation: we warmly encourage active participation in this Congress, not only by surgeons, pathologists, epidemiologists and radiologists but also clinical oncologists, molecular biologists, and immunologists. We hope that such a deep, interdisciplinary discussion will result in new ideas, which will enable us to make real progress in treating gastric cancer. I hope you all have a very happy and rewarding meeting.
Tadeusz Popiela, MD, PhD, FACS, h.c.m. President of th International Gastric Cancer Congress
We are confident that, due to the cooperation of all IGCA members and of the National Associations, and overall to do the enthusiasm and determination of the colleagues who are organizing the event, the th IGCC to be held in Krakow, Poland will be an outstanding success. We are very grateful to Prof. Tadeusz Popiela, President of the th IGCC, Prof. Jan Kulig Vice-President of the th IGCC and Dr. Piotr Kolodziejczyk for their efforts in putting together such an expressive number of members and remarkable scientific program.
Joaquim Gama-Rodrigues, M.D., PhD, FACS (Hon) President of International Gastric Cancer Association
8th IGCC, June –, , Kraków, Poland
Sztompka P. Relations with others are fundamental for human existence. All our lives are spent with other people, among other people, for other people, against other people. We relate to others with love and hate, cooperation and competition, exchange and exploitation, reciprocity and egoism, tolerance and xenophobia, solidarity and exclusion, sympathy and envy, help for and abuse of others. We live in the interpersonal space. This is the meaning of the ancient wisdom that humans are social animals. Relations with others are always pervaded with uncertainty and risk. We can never be absolutely certain how they will react to our actions, or how they will act toward ourselves. But to satisfy our needs we have to interact, at least with some of them. Hence, to alleviate the uncertainty and risk we need trust. Trust is the bet we make about the future uncertain actions of others. Or in other words, it is the tentative belief that others will be acting in ways beneficial for us: competently and responsibly, fairly and honestly, extending help and sympathy, disinterestedly and altruistically. It is tentative, until further notice, because once breached trust collapses immediately. It is a very brittle resource. In the relationship between the patient and the physician trust acquires a specific form. The therapy fits within the wider category of “helping relations” (Merton ), i.e. those where the rationale of the interaction for one party is seeking help, and for another party extending help. Other examples besides the patient-physisian relationship include also the bond of an attorney and a client, a priest and a parishioner, a teacher and a pupil etc. All these relations manifest: • hierarchy: unequal status of help-seekers and help-givers, e.g. in a case of medical profession visible clearly not only in the environment of the hospital, but also in the prestige rankings in the wider society, • monopoly of highly specialized knowledge, competences and skills on the part of help-givers, • command by help-givers of resources necessary to extend help, e.g. in the case of medical doctors – writing prescriptions, hospitalizing patients, applying expensive technologies or procedures, legitimizing sick leave or sick pay etc. • power over help-seekers expressed in the possibility of refusing or limiting help, especially strong in medical area, where patients entrust to the physician the ultimate and highest values – their own health and life, and they cannot resign of seeking help without endangering their fate. This is of course particularly true of terminal diseases: cancer or HIV patients. • abdication of any personal control over events, e.g. in medicine giving a surgeon by means of an informed consent a full licence to do what he deems proper, once a patient lies under sedation on the operating table. The patient has no choice; seeking a medical help is a life-and-death imperative. And yet one acts in the condition of triple uncertainty: • about a concrete medical doctor (this is a micro-context of therapeutic relation). Here the patient has to extend some measure of personal trust. • about the institution where he/she seeks medical help: a hospital, outpatient clinic, private medical practice (this is the mezzo-context of therapeutic relation). Here the patient extends some measure of institutional trust. • about the whole medical system; its organization, functioning, efficiency, transparency (this is the macro-context of therapeutic relation). Here the patient employs generalized, impersonal trust. Entrusting so much as his own body to the physician, the patient has a whole scale of expectations: • that the doctor will be competent, knowledgeable, skillful and will have access to the technical equipment and other resources necessary in modern medicine. This is the least demanding, but crucial expectation. • that the doctor will be honest, truthful, fair in dividing time and efforts among many patients. This is obviously a more demanding expectation of a moral integrity. • that the doctor will extend “fiduciary care” (Barber , p.) i.e. will express personal sympathy and attention for the patient treating him/ her as a person and not only as a “case”. This is even more demanding expectation of a personal bond. • that the doctor will be at the “service” of a patient, i.e. will be ready to forfeit some of his interests if they conflict with the interests of the patient, e.g.to work overtime, be accessible on weekends or at night etc. This is the most demanding expectation of some form of altruism.
8th IGCC, June –, , Kraków, Poland
These expectations are sometimes contradictory and put the physicians in the condition of ambivalence. For example the imperatives of treatment may demand cold detachment rather than sentimental sympathy for a patient (see Merton , p. on “detached concern”). Or too much personal concern for one patient may limit the time and energy needed for another. Such ambivalences underlie two opposite models of therapy (or even of medicine as such): • technical, instrumental with emphasis on efficiency and impersonal treatment of a patient, with an extreme division of labor among medical personnel, • humanistic, compassionate with emphasis on holistic treatment and personal consideration for the patient’s autonomy, uniqueness and dignity. Of course these are the analytic poles, with usual combinations of both systems, or some middle-of –the-road medical strategies (e.g. “family doctors”, or “general practitioners”). The extensive empirical research carried out at Stanford University (Cook and others ) indicates – a bit surprisingly – that putting their trust in physicians, patients expect primarily the “soft”, humanistic qualities, and the “hard” competence and efficiency come only later in their hierarchy of preferences. Having a choice, they prefer to be treated by a compassionate personal friend, than detached expert. The list of traits of a trustworthy physician, in the preference order includes: • caring and empathy, • eye contact and positive body language (smile, keeping the hand of a patient etc.), • attentive or active listening, • providing and explaining information about treatment, • truthful but tactful presentation of a diagnosis, • patient participation in the decision-making process, • perceived competence of physician (note: listed as the seventh among important demands!!!), • physician availability, • physician time management (equal division of attention among many patients). In the study of cancer patients Penman and others () found out that trust based on “soft factors” was crucial for the decision to accept therapy. Such pervasive intuitions of patients seem to coincide with the ample clinical evidence on psycho-somatic effects in treatment. All relations of trust are lasting and intense only if they are mutual. As the patients trust physicians, the physicians also have to trust the patients. The content of their “bet of trust” expressed by accepting a patient for treatment, or coninuing therapy, is of course different. The doctor expects the patient to be: • a “competent patient” i.e. one who is able to report about the symptoms, has some insight into the functioning of his/her organism, and some awareness of the possible diseases (but of course not to the extent of pretending to specialized, second-hand knowledge. Such “wise patients” are a nuisance, usually detested by doctors). • a “responsible patient” i.e. one who accepts and meticulously follows prescribed procedures, • open and truthful: providing all necessary information, • fair: not demanding any special treatment at the expense of other patients, • respecting the privacy of the doctor, the right to leisure, family life etc. Apart of all these factors determining trust on the side of the patient and on the side of the physician, an important role is played by a generalized climate of trust (or “culture of trust”) toward the medical profession. Being in some sense the masters of human fate – life and death – physicians have always found their profession very high in the rankings of social prestige or esteem. They have usually belonged to the professions endowed with high trust. But the conditions of modern, industrialized, consumer society create some dangers of the erosion of trust in medicine and medical profession: • the exaggerated media reports of experimental successes in medicine – alas still far from practical application – may raise unfounded hopes and condemnation of each case of medical failure as “malpractice” or “negligence”, paradoxically lowering generalized trust, • the exaggerated media reports of singular, spectacular cases of corruption in the medical profession (e.g. in the patient-doctor contacts, or in the links between doctors and pharmaceutical corporations), lead to the “moral panics”, when such cases are generalized and treated as typical, • the hindrances in the access to medical help, due partly to the “democratization” of medical services, partly to the enefficiency of the orga-
OPENING LECTURE nization, and partly to the lack of sufficient funding, lead also to the erosion of generalized trust, • the “fiscalization” of social awareness, i.e. treating income as the single criterion of personal worth, endangers the prestige of medical doctors, especially in the countries like Poland, where at least in the dominating public sector of medicine medical doctors are poorly paid, but also in other more affluent societies where the income of physicians rarely reaches the level of “celebrities” successful in business, professional sports or the media. As trust – in all forms and at all levels – is such a crucial ingredient in medical systems, the imperative of public policy is to cultivate and build trust. This may be equally important as raising material resources and organizational efficiency of medicine.
PLENARY SESSIONS
L i T e r aT u r e : Barber, Bernard, The Logic and Limits of Trust, New Brunswick : Rutgers University Press Cook, Karen (and others), “Trust and distrust in patient-physician relationships: perceived determinants of high and low trust relationships in managed-care settings”, in: Roderick Kramer and Karen Cook (eds.) , Trust and Distrust in Organizations, New York : Russell Sage Foundation, pp. - Merton, Robert, (with Vanessa Merton and Elinor Barber), “Client ambivalence in professional relationships: the problem of seeking help from strangers”, in: B.M..DePaulo (ed.), New Directions in Helping, New York : Academic Press, pp. - Merton, Robert, Sociological Ambivalence, New York : Free Press Penman, Doris (and others), “Informed consent for investigational chemotherapy”, in: Journal of Clinical Oncology, Vol. /, pp. - Sztompka, Piotr, Trust: A Sociological Theory, Cambridge : Cambridge University Press
P S1 EPIDEMIOLOGICAL TRENDS IN GC AND THE POSSIBILITY OF PREVENTION Hakulinen T.
Konturek P.
Finnish Cancer Registry
Institute of Physiology, Jagiellonian School of Medicine, Cracow, Poland
More than ten million new cancer cases occur each year in the world. GC is the fourth most common cancer with almost one million new cases in , the most recent year from which estimates are available. GC is in general a larger problem in the less developed countries.
Gastric cancer (GC) is a major public health issue as the second leading cause of cancer death worldwide with Helicobacter pylori (Hp) as a paradygm for infection-induced chronic mucosal inflammation-mediated predominantly distal or non-cardia cancer. Numerous epidemiological studies revealed that Hp infection is associated with approximately a twofold increase of developed distal GC. Meta-analyse studies in Japanese patients followed up to . years after enrollment showed that GC developed in about .% but none in the uninfected patients. Corpus-predominant atrophic gastritis with intestinal metaplasia was identified phenotype giving a relative risk of GC of .. Virulent Hp strains (cagA and VacA positive) were reported to to increase the risk of non-cardia GC. Our studies on Hp-infected patients or gerbils revealed a marked hypergastrinemia in chronic corpus-predominant gastritis and it was proposed that increased risk of distal GC may result, at least in part, from altered susceptibility of gastric epithelial cells to undergo apoptosis suggesting that this altered susceptibility is one factor predisposing to gastric cancerogenesis both in humans and animals infected with Hp. The atrophic gastritis in Hp-infected humans and animals was also accompanied by an overexpression of cyclooxygenase- (COX-) and COX- polymorphism leading to excessive production of prostaaglandins (PG) that are important factor in then development of GC through promotion of cancer cell proliferation, inhibition of apoptosis and enhancement of cell invasion and angiogenesis. Furthermore, the disturbance of apoptosis-related proteins such as an upregulation of anti-apoptotic gene, Bcl-, counteracting the pro-apoptotic gene Bax and survivin expression have been described in Hp induced atrophic gastritis. Other studies indicated that a significant interaction exists between pepsinogen C (PGC) polymorophism and Hp infection. At the acute stage of infection, the bacteria were shown to increase PGC secretion from human peptic cells but at the later stage of infection, the virulence and inflammation factors released by Hp damaged the PGC gene and decreased PGC expression and production that were associated with the tumor aggressiveness and overall survival periods of patients with GC. In addition, the upregulation and generic polymorphisms of major inflammation related cytokines such as IL-, IL-, IL- as well as TNF-alpha were found to be associated with Hp-related gastric diseases including atrophic gastritris and GC. Hp is known to colonize the stomach of over half the world population and is generally considered to be a non-invasive pathogen present only in the gastric lumen and/or attached to gastric epithelial cells, but a number of more recent in vivo and in vitro studies have demonstrated that Hp is in fact invasive. As originally proposed by A. Dubois, GC may originate in adult gastric stem cells that may be invaded by viable Hp, which can survive within epithelial cells and lead to DNA mutation especially because their virulence genes are known to be expressed within the rapidly growing adult stem cells. Thus, as many cancers are believed to have evolved from one single cell, a few intracellular Hp may trigger immune, carcinogenic or other developmental response pathways leading to adenocarcinoma or MALT lymphoma.
But even within these groups of countries, large variations exist: GC is frequent in Eastern Europe but rather rare in Southern Asia. Huge differences in incidence exist also within countries, e.g., in China and Italy. The incidence trends are invariably in a decrease. However, for example in Japan where incidence is high, the decrease has been so far rather modest. The Japanese rates are affected to an extent by a screening program and different diagnostic criteria. Migrant studies show that the migrants’ and their descendants’ incidence rates gradually approach the rates in the new host country. Although the overall GC incidence has been in a decrease, the incidence of cancer in gastric cardia has been reported to increase in the USA and some Western countries. Possibilities that have been discussed as a background for this increase include increased specificity of location and misclassification with distal oesophageal adenocarcinoma. For example, the Swedish Cancer Registry’s data from the late s show a marked classification problem but in general it may be concluded that cancer in gastric cardia is epidemiologically a different entity from the rest of GC. GC tends to be more common in males than females. The international variations and trends suggest that GC is particularly dependent on external factors and may thus be to a large extent preventable by affecting those factors, once they have been identified. This has been a good challenge to analytic epidemiology and basic research on cancer. The research has given important results. Most of the GC cases excluding cardia are associated with a Helicobacter Pylori infection. The decreasing incidence trends may well reflect a natural, non-targeted success against this infection. Smoking nearly doubles the GC risk and a successful control of it may well lead to further reductions in GC risk in different parts of the world. Dietary modifications, e.g., an increase of fruit and vegetable consumption, may further make a beneficial contribution to a decrease in the global burden. Prevention of cardiac cancer based on its known risk factors, obesity in males and reflux disease may be challenging. GC is still a major cancer globally offering good possibilities of prevention, also with an improvement of general living conditions and affecting smoking and diet.
8th IGCC, June –, , Kraków, Poland
PS2 GASTRIC CANCER CARCINOGENESIS STATE OF ART LECTURE
8th IGCC, June –, , Kraków, Poland
PLENARY SESSIONS P S3 THE LATEST ADVANCES IN CLINICAL GENETICS OF TUMOURS INCLUDING GASTRIC CANCER Lubinski J. International Hereditary Cancer Center Pomeranian Medical University, Szczecin, Poland In order to solve problem – be successful, it is critical to work hard and wise, but also to be lucky. Polish society is a lucky one for effective performance of studies on clinical–genetic correlations, because Poland is relatively big country – with almost mln population additionally showing high level of genetic homogeneity. This is the main reason why in the field of genetic–clinical correlations, at least in oncology, studies conducted in Poland are frequently of unique international value. Historical milestone in our understanding of genetic characteristic of Polish population were studies performed years ago, in which we sequenced BRCA/BRCA genes in almost families with strong aggregations of breast/ovarian cancers. Górski et al. shoved that Poland is dominated by BRCA mutations and, additionally, only of them constitute around % of all BRCA mutations in Poland. DNA test designed especially for Polish population allowed to detect BRCA mutations a few dozen times quicker and cheaper than in rich but genetically heterogenous Western countries. This is why in our centre only we performed almost of BRCA tests detecting almost carriers. This is the largest worldwide registry of females with mutations and under surveillance of cancer genetic outpatient clinics from almost all regions of Poland. Genetic homogeneity of Polish population has been confirmed in studies of other genes associated with predisposition to cancers. As a consequence, we noted very rapid progress in identification of genetic markers for almost all sub-groups of tumours. In , we published the first panel of genetic markers covering more than % of breast cancers. This work suggests directly for the first time that carcinogenesis of all tumours is caused by both groups of features–environmental and genetic, however their relative contribution in tumorigenesis of particular case can be variable ranging from a few to a few dozen of per cent. In last years almost all genes associated with monogenic high risk of cancers characterized by strong aggregation of tumours such as i.e. BRCA/BRCA (~% risk of breast/ovarian cancers), MSH/MLH/APC (~% risk of colorectal cancers) or E-cadherin (~% risk of diffuse stomach and lobular breast cancers) have been identified (Tab. ). At present, investigations aimed to identify markers on moderate/low cancers risk are the most frequently performed. Their identification seems to be very important also from clinical practice perspective because these markers:
PLENARY SESSIONS
Spectacular progress was noted recently in chemotherapy of breast cancers dependent on BRCA. In Byrski T. et al. published retrospective observation on the lack of effectiveness of taxans – in out of females – mutation carriers with breast cancers treated using AT scheme remissions were not seen in neo-adjuvant therapy. Such results were in accordance with observation of British researchers who found that cell lines from breast cancers in BRCA carriers are resistant to taxans. These scientists in the same publication reported high sensitivity of cancer cells lines to cis-platinum. This is why, we launched clinical trial on cis-platinum efficiency in treatment of breast cancers among BRCA carriers. Results of this first completed clinical trial have been published in July . In all recruited patients, we observed clinical and pathologic remissions which was complete in of them. Recently, another paper by Byrski T. et al. has been accepted for J Clin Oncol in which efficiency of different schemes of neo-adjuvant therapies in BRCA carriers with breast cancers was compared retrospectively. Frequency of complete remissions in monotherapy with cis-platinum was above %, in AC scheme – % and using CMF or AT (taxans) – %. At present, we perform clinical trial on the use of cis-platinum for affected BRCA carriers independently on cancer site thus including gastric cancer patients with germline mutations. Ta b l e . Syndromes with familial susceptibility to gastric cancers (GC) Syndrome Hereditary gastric/ breast cancer BRCA2 breast/ovarian cancer BRCA1 breast/ovarian cancer Peutz-Jeghers Cowden
Gene(s)
Evidence of association of GC Sites of other primary cancers E-cadherin high risk of diffuse GC among lobular breast cancer (CDH1) mutation carriers BRCA2 RR of GC increased 2.5–5 times breast, ovary, prostate BRCA1
RR of GC increased ~4 times
breast, ovary
STK11 PTEN
RR of GC increased ~200 times GC reported in a patient with Cowden syndrome Germline TP53 mutations in GC families CHEK2 truncating mutations confer ~2.5 fold risk of GC 30 reported GC cases among published FAP families GC risk increased in carriers with atrophlcans gastritis
breast, intestine, pancreas breast, thyroid, endometrium
Li-Fraumeni
TP53 CHEK2
Familial adenomatous polyposis HNPCC/Lynch
APC
MSH2, MLH1, MSH6 Ataxia telangiectasia ATM Werner
WRN
Excess risk – RR 3.5 of GC in heterozygotes GC has been reported in association with the syndrome
breast, adrenal cortex, connective tissue, kidney, nervous system, pancreas, white blood cells colon, rectum duodenum, thyroid, pancreas colon, rectum, endometrium, small bowel, urothelium, kidney, ovary skin, breast, eyes connective tissue, skin, thyroid
Zembala M. Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Krakow, Poland In many types of cancer isolated (circulating or disseminated) tumour cells (ITC) are found in blood and bone marrow. The rate of their detection varies considerably not only in different, but also in the same, types of cancer and also depends on the method of detection. Their association with stage of disease and prognosis is controversial. As ITC are very rare we have developed the sensitive method which allows “concentration” of ITC by sorting out CD+ cells (all WBC) and detecting them among CD- cells by staining for cytokeratins (CK). CK+ cells were isolated from some samples by laser capture microdissection system and found to express MAGE- or MAGE- mRNA implicating that they are indeed tumour cells. Overall, ITC were detected in ,% of blood and ,% bone marrow samples from patients. No correlation was found with TNM stage, but ITC ware more frequent in patients with >% metastatic lymph nodes and diffuse type of cancer. No association with survival was observed but stage IV patients with ITC showed tendency for shortened survival. Studies of membrane microfragments or microvesicles (MV) in plasma of patients and control showed that were of similar size (- nm) but had different distribution. Higher frequency of MV was seen in plasma of cancer patients and some of them carried tumour associated antigens (both proteins and mRNA), implicating their tumour origin. However, the role of MV in cancer is unclear. They may be involved in inducing immunosuppression or used as antitumour vaccines.
P S5 PERSONAL GENOMICS AND SYSTEMS BIOLOGY: NOVEL MODEL FOR A PATIENTTAILORED MANAGEMENT STATE OF ART LECTURE
PS8 STAGING CLASSIFICATION TODAY AND TOMORROW STATE OF ART LECTURE Yamaguchi T. (Japan) PS9 ADJUVANT AND NEOADJUVANT APPROACH IN WEST STATE OF ART LECTURE Allum W. (UK) P S10 ADJUVANT AND NEODJUVANT APPROACH IN EAST STATE OF ART LECTURE Sano T. (Japan) P S11 D1 OR D2 OR D2+ OR D3 LYMPHADENECTOMY FOR GC STATE OF ART LECTURE Sasako M. (Japan) P S12 LAPAROSCOPY IN EARLY AND ADVANCED GC STATE OF ART LECTURE Uyama I. (Japan) P S13 ADENOCARCINOMA OF THE EG JUNCTION STATE OF ART LECTURE Stein H. (Germany)
Roukos D. (Greece) PS6 MOLECULAR MARKERS AND RESPONSE TO NEOADJUVANT CHEMOTHERAPY OF GASTRIC CARCINOMAS STATE OF ART LECTURE
P S14 UPDATING IN TREATMENT FOR NONADENOCARCINOMA GASTRIC TUMORS STATE OF ART LECTURE Santoro E. (Italy)
Keller G. (Germany) P S7 IDENTIFICATION OF POTENTIAL DIAGNOSTIC AND THERAPEUTIC TARGETS IN GASTRIC CANCER BY BASIC AND TRANSLATIONAL RESEARCH STATE OF ART LECTURE
• can interact – i.e. women carrying CHEK mutation and some BRCA variants can be at -fold increased risk of breast cancer. • can identify high risk persons if combined with family history – i.e. ~ fold increased risk of prostate cancer occurs in men–carriers of NBS, CHEK or some BRCA mutations if even one prostate cancer was diagnosed among relatives. • are identifying multiple site predisposition – i.e. CHEK mutations are associated with increased risk of cancer of the: breast, ovaries, colon, kidney, stomach, prostate and thyroid and decreased risk of cancers of the lung and larynx and are associated with distinct clinical characteristics of cancers – i.e. breast cancers in families with NOD or CDKNA changes are characterized by occurrence of microcalcifications and significantly increased risk already at age yrs, and cancers dependant on CHEK are ER(+) what suggests potential value of tamoxifen in their chemoprevention.
PS4 CIRCULATING TUMOUR CELLS AND THEIR MEMBRANE MICROFRAGMENTS IN PATIENTS WITH GASTRIC CANCER
Yasui W. Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima -, Japan Serial analysis of gene expression (SAGE) is a powerful technique to allow genome-wide analysis of gene expression in a quantitative manner. We have created one of the largest SAGE libraries of gastric cancer in the world, containing a total of , expressed tags including unique , tags (GEO accession number GSE ). By SAGE data analysis in combination with other technologies, many candidate genes were identified as novel diagnostic and therapeutic targets. Of those, both regenerating islet-derived family, member (Reg IV) and Olfactomedin (OLFM, also called GW) were frequently overexpressed in gastric cancer. Reg IV activated EGFR and participated in -fluorouracil resistance and peritoneal metastasis. OLFM protein interacts with GRIM-, cadherin and lectins and participates in inhibition of apoptosis and cell adhesion and invasion. Combinatory measurement of Reg IV and OLFM in sera revealed a sensitivity of % for detection of gastric cancer, indicating highly sensitive serum tumor marker. Expression of signal peptidase complex KDa (SPC) was associated with advanced gastric cancer. SPC participated in tumor growth and invasion partly through TGF-alpha and EGF up-regulation, and may serve as a marker of high-grade malignancy as well as therapeutic target. A signal sequence trap method called Escherichia coli ampicillin trap (CAST) method is also useful to extract novel secreted and membrane proteins in cancer. Random-primed cDNA libraries were generated from gastric cancer cell lines and normal gastric mucosal tissue, ligated into pCAST, and more than of the randomly selected ampicillin-resistant clones were sequenced. Many genes overexpressed in gastric cancer were identified. Information obtained from transcriptome analysis greatly contributes to new developments for diagnosis and treatment of gastric cancer.
8th IGCC, June –, , Kraków, Poland
8th IGCC, June –, , Kraków, Poland
INVITED LECTURES
I L1 NISHITAK AHASHI LEC TURE
IL2 PRESIDENTIAL LECTURE
ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION
STEM CELLS IN GASTRIC CANCER IN SEARCH OF A CURE
Siewert J.R., Stein H.J., Feith M.
Gama-Rodrigues J.
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Ismaningerstr. , D- München, Germany
President of the IGCA (Brasil)
B a c k g r o u n d : The border between the esophagus and stomach gives rise to many discrepancies in the current literature regarding the etiology, classification and surgical treatment of adenocarcinoma arising at the esophago-gastric junction. We have consequently used the AEG-criteria (adenocarcinoma of the esophago-gastric junction) for classification and have based the selection of the surgical approach on the anatomic topographic subclassification.
INVITED LECTURES IL3 JIN POK KIM MEMORIAL LECTURE
IL4 DISTINGUISHED LECTURE
DIAGNOSIS AND TREATMENT OF GASTRIC CANCER IN JAPAN, DRAMATIC CHANGES IN THE LAST 20 YEARS
MINIMALLY INVASIVE INDIVIDUALIZED TREATMENT FOR EARLY GASTRIC CANCER
Maruyama K.
Kitajima M.
Department of Surgical Oncology, University of Health and Welfare Sanno Hospital, Tokyo
International University of Health and Welfare Hospital
Incidence of gastric cancer has been decreasing in Japan, but total number of the patients are stable because of increase of old people. Gastric cancer is the second causes of death among malignant diseases. Progress of early detection and treatment for the cancer are one of the most important social demand.
The minimalization of surgical invasiveness for the preservation of patients’ gastro-intestinal functions has been widely discussed in the management of gastric cancer. Since the first case of laparoscopic gastrectomy successfully performed in by Japanese surgeons was reported, an enthusiasm to develop laparoscopic procedures has grown steadily for gastric surgery. In the initial phase, early gastric cancer limited to the mucosal layer without risk of lymph node (LN) metastasis was treated by laparoscopic wedge resection or intragastric mucosal resection. With the emergence of intraluminal endoscopic approaches these cases can be well managed without surgery since technical and instrumental advances in endoscopic treatment were improved by gastroenterologists. The surgeons then started to pay attention to more radical procedures such as laparoscopic gastrectomy with standard LN dissection, which is comparable to open surgery in the context of curability. However, we have to recognize the potential risk of peritoneal dissemination in this type of surgery if we are to extend the indication of laparoscopic surgery to more advanced cases. While earlyphase recovery after surgery has been improved by laparoscopic surgery, preservation of late-phase gastro-intestinal functions should be considered from the viewpoint of modified gastrectomy. The sentinel node (SN) concept, in which individualized minimalization of LN dissection would be realized, has been a major interest to find a way in this aspect. A number of single institutional studies have already demonstrated the validity of the SN concept. Data of prospective multicenter trials will be shown. Theoretically, various types of surgery with smaller loss of stomach volume and functions are applicable for those early gastric cancer patients who have negative SNs, and less invasive management with improved longterm gastro-intestinal functions are expected. We could focus on a confluence of these two major streams, laparoscopic surgery and SN navigation surgery, which would enable us to apply a novel minimally invasive and individualized approach, both in terms of degree of incisional access and extent of function preservation in the gastric cancer treatment.
To reduce gastric cancer, social education is important; less salty food, no smoking, more Vitamin C and A. Field studies were proceeding whether HP eradication could reduce gastric cancer or not. Mass screening covered now approximately % of population over years old. Screening method was shifted from double contrast barium study to endoscopy, and proportion of endoscopy screening increased from .% () to .% (). All instruments innovated digital imaging and small-size nasal endoscopy was newly developed. Serum pepsinogens to detect intestinal metaplasia and genetic screening are now in trial to find high-risk group.
M e t h o d s : In the following we report an analysis of a large and homogeneously classified population of consecutive patients with adenocarcinoma of the esophago-gastric junction, with an emphasis on the surgical approach, the pattern of lymphatic spread, the outcome after surgical treatment and the prognostic factors. Demographic data, morphologic and histopathologic tumor characteristics, and long-term survival rates were compared among the three tumor subclassifiations.
“Japanese style D gastric resection” reduced dramatically the local recurrence and improved the survival rates. Japanese nationwide registry reported that year survival rate was .% for Stage-I, .% for Stage-II, .% for Stage-III, .% for Stage-IV. However, we had a new trend in the last years; from “Extended surgery for radicality” toward “Reasonable or individual surgery considering safety and QOL”. The backgrounds were increase of early stage cancer, demand of curability and better QOL, progress of surgical technique and instruments, and storage of knowledge and experience. We have now large variation in surgical treatments. Japanese Gastric Cancer Association published the “Gastric cancer treatment guidelines” in . The guidelines were separated into two parts; “Standard or recommendable treatments” and “Treatments in clinical research”. The intention was to provide a common basis of understanding of the extent of disease and selection of proper treatment among doctors, patients, and their families. The guidelines should be revised every years to innovate new progress and to evaluate the results. The latest guideline was published in (shown on the table below). Laparoscopic and robotic surgery will be included in the next version.
R e s u l t s : The study confirms the marked differences in sex distribution, associated specialized intestinal metaplasia in the esophagus, tumor grading, tumor growth pattern, lymphatic spread, and stage between the three tumor entities. The degree of resection and lymph node status were the dominating independent prognostic factors by multivariate analysis. The data show no significant differences of long-term survival after abdomino-thoracic esophagectomy and extended total gastrectomy in these patients. C o n c l u s i o n: The classification of adenocarcinomas of the esophago-gastric junction in three types, AEG type I, type II and type III shows marked differences between the tumor entities and is recommended for selection of a proper surgical approach. Complete tumor resection and adequate lymphadenectomy are associated with good long-term prognosis. Better surgical management and standardized procedures will improve the outcome also of patients who need to undergo more radical surgery, i.e. abdomino-thoracic esophagectomy.
Endoscopic mucosal resection (EMR) is indicated for a small well differentiated mucosal cancer less than . cm in diameter. Modified resection A (D+A) removes the perigastric lymph nodes (N) and nodes along the left gastric and common hepatic arteries. The D+A is indicated for the N mucosal cancer and the N submucosal cancer less than . cm in diameter. Modified resection B (D+B) additionally removes nodes around the celiac artery. Extended resection includes combined resection of neighboring organs and lymphadenectomy in the hepatoduodenal ligament and paraaortic nodes. Standard surgical procedures by Stage, Japanese Guideline T1 (mucosa) T1 (submucosa) T2 T3 T4 N3,M1
8th IGCC, June –, , Kraków, Poland
N0 N1 EMR, D1+A D1+B, D2 D1+A, D1+B D1+B, D2 D2 D2 D2 D2 extend extend extend, palliative, chemotherapy, radiation
N2 D2 D2 D2 D2 same bellow
8th IGCC, June –, , Kraków, Poland
ORAL PRESENTATIONS SYMPOSIUMS
ABSTRACTS
S1 D2 LYMPHADENECTOMY: 30YEARS EXPERIENCE AT THE UNIVERSITY OF SAO PAULO Jacob C., Zilberstein B., Bresciani C., Lopasso F., Deutsch C., Leonardi P., Mester M., Yagi O., Mucerino D., Kondo A., Gerbasi L., Oda A., Gama-Rodrigues J., Pinotti H., Cecconello I. University of Sao Paulo School of Medicine O b j e c t i v e s : The aim of this study is to analyse the results of D lymphadenectomy in treatment of gastric adenocarcinoma in a western population over the last thirty years. M e t h o d s : We retrospectively reviewed the records of patients with diagnosed gastric malignancy. Clinico-pathologic features, treatment and outcomes were evaluated. R e s u l t s : Between January and December , patients were treated with gastric adenocarcinoma at the Department of Gastroenterology – University of Sao Paulo School of Medicine. One thousand, six hundred and ninety three patients were submitted to any type of lymphadenectomy. One thousand, one hundred and eleven patients were submitted to D lymphadenectomy. There is an increase of this procedure in the last third years. Nowadays it represents more than % of resected cases. The male-female rate was . and the mean age was . years. Median time of operation was minutes. Blood transfusion was necessary in % and the risk factors were extended surgery and larger tumors. Resection of other organs was emploued in %. Post operative complications were observed in . %. The median hospital stay was days and overall mortality was .% Mean number of dissected lymph nodes was . and an increase tendency was observed in the last twenty years. Age and resection of other organs were correlated to higher complication rate. Multivariate analysis showed increase age were correlated with higher mortality.
S2 SITE AND PERIGASTRIC NODAL STATUS ARE THE MOST IMPORTANT PREDICTORS OF PARAAORTIC NODAL INVOLVEMENT. AN ITALIAN RESEARCH GROUP FOR GASTRIC CANCER STUDY de Manzoni G., Verlato G., Roviello F., Di Leo A., Marrelli D., Giacopuzzi S., Minicozzi A. – st Division of General Surgery, University of Verona – Dept. of Epidemiology and Medical Statistics, University of Verona – Division of Surgical Oncology, University of Siena O b j e c t i v e s : The present study aimed at identifying pathological predictors of para-aortic nodal invasion in gastric cancer. M e t h o d s : We considered patients undergoing gastrectomy with D lymphadenectomy para-aortic node dissection in Siena and Verona between -. After excluding early and Bormann IV cancer, patients were enrolled. Of these, (%) presented metastates to para-aortic nodes. Sensitivity of each lower station excised (-), in identifying para-aortic nodal involvement, was computed as the percentage of patients with positive para-aortic nodes, who also presented metastases to that station. R e s u l t s : Nodal stations , , displayed the highest sensitivity, amounting to %, %, %, respectively. Metastases to para-aortic nodes were never observed when both stations and were negative. According to cancer site, histology and T status, patients were divided into: i) High-risk group, which presented a risk of para-aortic node invasion close to % and comprised patients with T/T cancer with mixed/nonintestinal histology, arising from the fundus (n=, .%). ii) Low-risk group, whose risk remained
