3 AVol. 8, No.7S2004

STATE-OF-THE-ART -LECTURES

SAL-1Progress in the Treatment of Hilar Bile Duct CancerYuji NimuraSurgery, Nagoya University Graduate School of Medicine, Japan

Hilar cholangiocarcinoma represents about half of all bile ductcancers and is the most difficult not only to treat but also to makepreoperative precise diagnosis. And most of the cases have beentreated by palliative surgical procedures or nonsurgical techniquesas they are still encountered at an advanced stage. On the otherhand, aggressive surgical approaches to this disease using hepato-biliary resection with or without vascular resection have beenapplied by many surgeons with varying degree of success. In thislecture, I will talk about recent progress not only in the carefulpreoperative management and staging of difficult patients but alsoin aggressive surgical approaches to advance diseases. Althoughsome surgeons have reported disadvantages of preoperativePTBD, biliary decompression is mandatory before cholestatic liverresection for patients with / without cholangitis. Preoperative por-tal vein embolization (PE) actually increased resectability and thesafety of major liver resection. Bile replacement during periopera-tive external biliary drainage can restore the intestinal barrier func-tion and prevent perioperative infectious complications. Aggressivesurgeries with extended lymphadenectomy provided unexpectedlylong-term survival for patients with positive nodes. Combinedliver and portal vein resection and reconstruction offered signifi-cantly longer survival for patients with locally advanced diseasethan that for unresected patients. Clinical value of combined liverand hepatic artery resection and reconstruction will be clarified inthe near future.

SAL-2Outcome of Antireflux Surgery: Factors that Predict SuccessCarlos A. PellegriniDepartment of Surgery, University of Washington, USA

The ever increasing number of antireflux operations has allowedsurgeons to perfect the techniques and to measure outcomes.Studies have shown that this operation is extremely effective tocontrol GERD symptoms and also that over time its effectivenessdecreases. Indeed, some patients redevelop symptoms and somerequire reoperations. Between 35 - 62% of patients go back to takeH2 blocker antagonists or PPIs five and ten years postoperatively.Many of these patients take PPIs postoperatively for reasons otherthan reflux. For example, Hinder showed that 50% of patientswho were on PPIs following an antireflux procedure, had normal24-hour pH monitoring. We have found the same to be true in arecent study. Two prospective randomized studies have shown thatantireflux operations are better than medical therapy in the controlof symptoms, and on the amount, of GERD measured in theesophagus. Three recent studies have shown that the operationsare also effective in patients with Barrett’s disease. They are effec-tive in the control of symptoms, and in about half of the patientswith short Barrett’s eliminate columnar epithelium by 5 years.Thus, the operations, while not perfect, are better than medicaltherapy in the control of symptoms, remain effective for long peri-ods of time, and are effective in the treatment of the complications

of reflux, including Barrett’s esophagus.

SAL-3The New Generation of Transcriptomics and its Applicationto Medical ScienceYoshihide HayashizakiGenome Exploration Research Group, Riken Genomic SciencesCenter, Riken Yokohama Institute, Japan

We have established the comprehensive mouse full-length cDNAcollection and sequence database to cover as many genes as we can,named Riken mouse genome encyclopedia, organizing FANTOMconsortium. This comprehensive analysis gave a lot of strikinginformation sketching out the mammalian transcriptome. One ofthe most significant results was the discovery of large amount ofnon-coding RNAs (RNA continent) which includes 16,000 non-coding sequences much more than expected. Also, unexpectednumber of alternative spliced transcripts was found in transcrip-tome. More than half of all genes have alternative forms, 80% ofwhich change their amino acid sequence. The much more numberof transcripts and proteins were encoded than in the genome.Withthese new knowledge and information in hand, we now step in anew era of transcriptomics. The next stage that life science shouldstep into is analysis of expression regulatory regions, expressionprofiles, interactomes, intracellular dynamic kinesis of protein andRNA, thus ultimately unraveling the ‘Genome Network’.As thefirst step, we are establishing a large-scale system to identify CAPsites and promoter region, named CAGE, Cap Analysis GeneExpression. CAGE provides the enormous information of high-throughout promoter activities and profiling of transcriptionalstarting site (TSP) including promoter usage analysis. This systemis designed to collect the 20bp CAP site sequences which are con-catenated to be sequenced. One pass sequences could produce 10-20 tags each of which identifies the transcriptional starting sites.More than 10,000,000 CAGE tags were analyzed to discover newpromoters and new genes, and also it can be used for the analysisof the transcriptional network. The data of various types of cancersusing CAGE will be reported.Human genome sequence projecthas been completed. The genome structural database such asgenome and transcriptome sequence database, protein 3D struc-ture database, SNP and Hapmap are the database of chemicalstructure of biomolecules. The comprehensive database of variousfunctions of biomolecules, such as protein-DNA interactions, pro-tein-protein interactions and interacellular localization of tran-scripts is going to be established as done in lower organisms. Thegenome network to connect causative genes to symptoms and toconnect the target molecule of drugs to drug effects will be clari-fied using these genome structure and functional database.Unveil-ing the Genome Network (ie. detailed knowledge about mecha-nism and cascade of events that connect suspected gene and disor-der) makes us possible to develop multiple new drugs. Further-more, it allows prescription of drug to fit for each patient - it leadto the tailor made medical care.

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SAL-5Surgical Anatomy for Modern SurgeryTatsuo SatoClinical Anatomy, Tokyo Medical and Dental University, Japan

In order to view “modern” surgical anatomy, it is first necessary toconsider the progress of clinical anatomy. In the last 50 years thereseem to be three different generations of surgical anatomy. What Iwill call the 1st generation or basic surgical anatomy was that lead-ing up to about 1980’s. In that first generation surgical anatomy,like clinical anatomy, was rather general. In the second generation,after 1980, surgical anatomy became much more detailed. As thesurgical procedures for cancer surgery progressed and became rad-ical and heavily considered QOL, likewise the understanding ofanatomy had to be very precise. It was necessary to comprehendthe very smallest of structures to achieve the optimal QOL post-surgery benefits. The third generation of surgical anatomy thisnew millennium has even gone further into detail. The types andmethods of dissection are more advanced, more detailed and moremodern than were imaginable a mere decade ago. There used tobe a huge gap between surgeons and anatomists. However, withthe progress of the 2nd & 3rd generations of surgical anatomy,that gap has narrowed considerably. Now is the time for surgeonsand anatomists to work closely together to proceed into the ultra-modern 4th generation.

SAL-6Advances in Minimally Invasive SurgeryNathaniel J. SoperNorthwestern University Feinberg School of Medicine, USA

The performance of the first “minimally invasive” operations inthe late 1980’s has caused the field of general surgery to re-exam-ine its status quo. There are many reasons to perform MIS. Theseinclude less postoperative pain, shorter periods of hospitalizationand recuperation, and cosmetic advantages. More importantly,there is growing evidence that the diminished stress associatedwith MIS may lead to less perioperative acute phase response andimmunosuppression than conventional surgery, which may ulti-mately result in improved outcomes in patients undergoing laparo-scopic surgery for malignant diseases. The current themes of mini-mally invasive surgery are an ongoing evolution from large inci-sions to smaller incisions and, possibly, to no incision whatsoever.As most procedures are image guided, technology is being devel-oped for information management and display, as well as integra-tion of digital information. Surgeons are also developing the tech-niques and technologies to allow for computer assistance andenhancement using surgery robotics systems. A large effort isbeing made to simulate the MIS O.R. environment, including theuse of inanimate trainers, virtual reality devices, and the develop-ment of tests to assess competency in laparoscopic surgery. Track-less surgery will have a major impact on surgical practice in thecoming decades. Interventional procedures can either be appliedthrough natural orifices or by transcutaneous application offocused energy sources. Thus, minimally invasive surgery maysimply be a bridge between the maximally invasive surgery of thepast and truly non-invasive surgery of the future.

SAL-7Biologic Therapy of Cancer - Inflammation and NecrosisPromote Tumor GrowthMichael T. Lotze1, Richard DeMarco2, David Montag2

1Translational Research, Molecular Medicine Institute, Univ.Pittsburgh School of Medicine, USA, 2Molecular Medicine Insti-tute, Univ. Pittsburgh School of Medicine, USA

Our initial premise, that cancer is fundamentally a process of dis-ordered cell growth, driven by the accumulation of genes confer-ring a growth advantage or diminished cell death beyond whatwould occur following a replete lifespan and cellular senescence,has been challenged by the recognition that most tumors arise inadults in the setting of inflammation1, 2. Progressively as apoptoticpathways are blocked, necrosis drives the disordered tumormicroenvironment associated with immunosuppression and disor-dered tissue homeostasis. HMGB1 is a highly conserved 30kDeukaryotic nuclear regulatory factor, released from necrotic cellsand activated macrophages. It stimulates TNF and IL-6 produc-tion and inflammation, promotes sickness behavior, is an endoge-nous pyrogen, enhances tumor growth, promotes endothelial acti-vation, leukocyte recruitment and adhesion, and mediates death insepsis. When PBMC or cocultures of NK and monocytes, but notiDC/mDC, were costimulated with IL-1, IL-2 or IL-12 and 1-1000ng/ml of HMGB1, up to 2,000 pg/ml of IFNγ were produced.High levels of HMGB1 in all melanoma sera [30-2719ng/ml] isnoted [normal undetectable]. Conclusion. The major goal of can-cer biologic therapies is thus to enhance apoptotic death of tumorcells and diminish necrotic cell death, one of the prime stimuli forangiogenesis, stromagenesis and continued epithelial cell growthand remodeling3, 4.1. Vakkila J, DeMarco RM, Lotze MT. Rapid assessment ofblood-derived dendritic cell activation by imaging cytometry. JImmunological Methods 2004; in press.2. Vakkila J, Lotze MT. Opinion: Inflammation and necrosis pro-mote tumour growth. Nat Rev Immunol 2004; 4:641-8.3. Lotze MT, DeMarco RA. Dealing with Death: HMGB1 As aNovel Target for Cancer Therapy. Current Opinion in Investiga-tional Drugs 2003; 4:1405-9.4. DeMarco RA, Fink MP, Lotze MT. Monocytes promote Natur-al Killer Cell Interferon Gamma Production in Response to theEndogenous Danger Signal HMGB1. Molecular Immunology2004; inpress.

SAL-9Progress and Future in Living Donor Liver TransplantationKoichi TanakaTransplant Surgery, Kyoto University Hospital, Japan

In Japan, brain death had long been a subject of debate, and theidea that brain death was the death of a person had never beenaccepted, Consequently, many Japanese patients suffering fromend-stage liver disease had to go abroad for surgery and place theirtrust in foreign transplant technology. The law of brain deathorgan transplantation was established in 1997 in Japan, howeverthe availability of organ has been limited. This is the fourteenthyear after the introduction of living donor liver transplantation(LDLT) in 1990 in our institute. The member of LDLT hasreached to more one thousand including children and adults. Thismodality now covers a wide range from new born to advanced age.

5 AVol. 8, No.7S2004 STATE-OF-THE-ART -LECTURES

The three and five year cumulative survival rates is 83.5% and81.9% respectively in children, on the other hand 69.8% and68.1% in adults. The evolution has revealed many unresolved pro-grams such as the timing of transplantation, donor selection,pathophysiology, recurrence of original disease, complications andimmunology. I’d like to take the progress and future in LDLT.

SAL-10Navigating the Sentinel Node Technique Across Cancers andContinentsAnton Bilchik, Donald MortonJohn Wayne Cancer Institute, USA

Navigation Surgery (NS) involves the use of a radioactive probe toguide the surgeon to indiscernible tumor deposits or tissues. Thistechnique has become increasingly popular because of the sentinelnode concept which improves staging accuracy (table below) andreduces the morbidity of unnecessary lymph node dissections.Upstaging by Focused Analysis of the Sentinel NodeTumorMelanoma 15%Breast 16%Stomach 14%Small Bowel 20%Large Bowel 13%Pancreas 17%The prognostic significance of lymphatic mapping and SLND isbeing evaluated in prospective melanoma, breast and colon cancertrials at the John Wayne Cancer Institute. This presentationreviews the techniques of NS in solid neoplasms and provides areview of ongoing multi-center clinical trials. Some of the newerapplications of NS in gastrointestinal neoplasms as well as parathy-roid tumors are also discussed.

SAL-11The Role of Surgical Trials in OncologyC J.H van de VeldeProfessor of Surgery, Leiden University, The Netherlands

Results from randomised trials provide the best scientific evidenceof efficacy or inefficacy of the therapy. The evaluation of surgicalprocedures involves problems in addition to those associated withmedical experimentation. Surgery, unlike a pill, is not a standard-ised, reproducible entity, but an unique product whose details aredefined by, for example, the skill of the surgeon. Quality assuranceis important for treatment and also for data handling. The differ-ent treatments (surgery, pathology, radiotherapy, etc.) should befamiliar to all participating physicians prior to the start of the trial.Instructions can be given by means of a well-written protocol,videotapes, workshops and instructors at the dissection table. Thedata collection and data check should be done by data managersand co-ordinators for the separate disciplines. Errors and missingdata should be completed and feedback to the physician is essen-tial. Close contact between and active co-ordinating data centre,including co-ordinators for the separate disciplines, and all partic-ipating physicians is essential to conduct a quality controlled mul-ticentre, multidisciplinary trial. Continuous enthusiasm can bemaintained by the organisation of regular workshops, distributionof newsletter and trial up-dates at scientific meetings.

SAL-12Dual Liver Grafts in Living-donor Adult Liver Transplanta-tionSung-Gyu Lee, Shin Hwang, Chul-Soo Ahn, Kwang-Min Park, Ki-Hun KimDepartment of Surgery, Division of Hepato-Biliary Surgery andLiver Transplantation, Asan Medical Center, Ulsan University,Seoul, Korea

In Asian countries, the majority of organs for liver transplantationcome from live donations. Because many live liver donors deathhas been reported from many centers, the risk is not eliminatedand remains a major consideration in the potential donor’s deci-sion. In adult recipients, if a left-lobe graft is selected, the livergraft volume(GV) is often less than 40% of the standard liver vol-ume(SLV) of the recipient or 0.8 % of the graft-recipient-weight-ratio(GRWR); therefore, right-lobe liver transplantation wasintroduced, and this trend has been spreaded widely. However, therisk to the donor of the right-lobe graft is higher than the risk ofthe left-lobe graft. Recently, dual left-lobe grafts from two livingdonors for 1 recipient were obtained to make up the insufficientgraft size and to ensure donor safety, although it is technicallycomplex and requires long operation time. Furthermore, if a largerrecipient needs a bigger GV than the sum of dual left-lobes, andthe right-lobe hepatectomy from one potential donor is safe, thecombination of a right and a left-lobe from two donors can beapplicable to avoid a small-for-size graft problem. From March 21,2000 to July 13, 2004, 130 dual adult living donor liver transplan-tations(ALDLT) were performed at the Asan Medical Center.There was neither mortality nor morbidity in donors. In-hospitalmortality occurred in 8 patients and one-year graft survival wasequivalent to 91%. Dual ALDLT can be a viable option to allevi-ate a small-for-size graft problem and secure donor safety.

SAL-13Pancreatic Cancer — Surgery and Adjuvant TreatmentOsamu Ishikawa, Hiroaki Ohigashi, Hidetoshi Eguchi, TerumasaYamada, Yo Sasaki, Shingi ImaokaSurgery, Osaka Medical Center for Cancer and CardiovascularDiseases, Japan

Although surgical resection has offered the only curative modalityfor adenocarcinoma of the pancreatic head, the long-term outcomeis still poor because of high incidences of locoregional relapse andliver metastasis after surgery. Since 1981, we have tried to removea wide range of peri-pancreatic connective tissues, and whichresulted in 24% of overall 5-yr survival rate. For the furtherimprovement, we have added the postoperative liver perfusionchemotherapy: 5-Fu was continuously infused via both the hepaticartery and portal vein for 4 weeks after surgery. As a result, theincidence of liver metastasis has been decreased and 5-yr survivalhas been elevated to 35%. However, for T3-/T4-cancers, the inci-dence of local recurrence was high and the 5-yr survival rate was27%. Thereafter, for T3-/T4-cancers, we added both preoperativechemoradiation and postoperative liver perfusion chemotherapy tosurgery. As a result, the 5-yr survival rate has been improved to46%, and the patient’s survival was associated well with histologi-cal response. We are allowed to conclude that pancreatic head can-cer should be resected in combined with a well-balanced (beingaimed at locoregional control and prevention of liver metastasis)

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adjuvant therapies.

SAL-14Current Methods of Bowel Sparing Surgery in Crohn’s Dis-easeFabrizio MichelassiDepartment of Surgery, Weill Medical College of Cornell Univer-sity, NY, USA

The recurrent nature of Crohn’s disease may require repeated sur-gical procedures and, potentially, intestinal resections over time.Up to 30% of patients necessitate at least two surgical proceduresin their lifetime. Patients subjected to multiple intestinal resectionsare at risk of diarrhea, chronic malnutrition, electrolyte derange-ments, vitamin B12 and folate deficiencies, chronic anemia andshort gut syndrome severe enough to require temporary or perma-nent parenteral nutrition. In an effort to minimize the occurrenceof short gut syndrome, several bowel-sparing surgical techniques(i.e., strictureplasty) have been described in the last twenty years.They all address Crohn’s related complication without, as thename implies, sacrificing bowel. Strictureplasties are indicated inpatients who have duodenal, enteric and anastomotic strictures.Strictureplasties are contraindicated in the presence of activeintraabdominal sepsis (abscess or phlegmon) associated with thediseased bowel segment;free perforation of the affected bowel orgeneralized abdominal sepsis; long, tight strictures with a thick,unyielding intestinal wall; malignant strictures; and in patientswith severe weight loss and marked hypoalbuminemia. Dataaccrued over the course of the past two decades suggest that, withappropriate selection of patients, bowel-sparing surgical tech-niques are safe and effective. Morbidity is low and reoperative ratesseem to be comparable to those obtained after resection and anas-tomosis. In addition, several recent studies have provided com-pelling evidence that active Crohn’s disease regresses to quiescentdisease at the site of a strictureplasty. These observations providefurther support for bowel-sparing procedures in Crohn’s diseaseand offer hope that regression from active to quiescent disease maytranslate in return of intestinal absorptive function.

SAL-15Advanced Heavy Ion Radiotherapy for Digestive Organ Can-cersHirohiko TsujiiResearch Center for Charged Particle Therapy, National Instituteof Radiological Sciences (NIRS), Japan

Carbon ions have the advantage of favorable dose localization withincreasing biological effect with depth, thereby they are effectiveagainst locally advanced or pathologically radioresistant tumors.Between June 1994 and February 2004, a total of 1,796 patientswith various types of tumors including digestive system cancerswere treated with carbon ions at NIRS. Carbon ions have beenapplied to the patients with post-operative pelvic recurrences ofrectal cancer. Despite the fact that they are generally radioresistantto conventional RT with poor prognosis, improved results havebeen obtained in 29 patients: the 2-year local control rate is 80 %and the 2-year survival rate is 73 %. For the patients with poten-tially resectable pancreatic tumors, in which 5-year survival rate isonly 12.3% even after curative resection, carbon ion therapy hasbeen applied to 22 patients preoperatively for the purpose to

improve local recurrence in the retroperitoneum. In 7 patientswho was found to have liver metastases at surgery, one year sur-vival rate was 33.3%, while in 15 patients who had no evidence ofliver metastases at surgery, one and two-year survival rates were73.3% and 50.0%, respectively. In treatment of >200 patients withhepatoma positive results have been obtained using hypofraction-ated carbon ion therapy. Local control rates are >90% at 3 yearsand 3-years survival rates are 68%. Most deaths are related to pro-gressive cirrhosis or disseminated disease. There have been nocases of fatal liver injury. Compared to other non-surgical thera-pies these results stand above as superior. Carbon ion RT hasshown improvement of outcome for head and neck tumor (adeno-carcinoma, adenoid cystic carcinoma, malignant melanoma), early-stage NSCLC, bone / soft tissue sarcoma, hepatoma, and locallyadvanced prostate carcinoma. There is a rationale to justify the useof short-course RT due to the superior dose localization and theunique biological property of high-LET radiations. This has beenproved in treatment for NSCLC and hepatoma, where the fractionnumber has been successfully shortened to 1-4 fractions given in1-4 days. Even in prostate cancer and bone / soft tissue tumor,treatment has bee performed using 16 fractions in 4 weeks withacceptable morbidity.