Can CA IX be used as an endogenous marker of hypoxia in HNSCC? An evaluation of the dahanca 5 study

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Posters better radiotherapy delivery.. In addition the utility of chemotherapy both as part of the initial mangement and its subsequent use in the setting of metastatic disease is now better understood than hitherto. Because of the ethnic make-up of the population whom we serve we are in relatively unique position in a North American setting to study this cancer and its management.The purpose of this study was to review our experince in the treatment of nasopharyngeal cancer with a particular emphasis on the patient with locally recurrent disease. Materials/Methods: The records of 443 patiets with nasopharyngeal cancer registered with the BC Cancer Agency over a 10 year period were reviewed. The overwhelming majority(97%) had not received any treatment prior to referral. The majority of these patients were male (68%) and oriental (82%). The median age at diagnosis was 46 yrs. The initial management which depended on the stage and the general condition of the patient involved radiotherapy and in more recent years concomitant chemotherapy. Results: 108 patients developed recurrent disease. The median time to local relapse was 18 months and to distant relapse 12 months. Salvage stratagies employed depended on the site and volume of recurrence along with the general condidtion and wishes of the patient. These included surgery, radioactive gold seed implantaion, further external beam radiotherapy with or without concomitant chemotherapy or palliative chemotherapy. The details of these treatment stratagies will be presented. Conclusions: In appropiately selected patients woirthwhile results can be obtained with an appropiate and individualised salvage strategy. Because a significant number of recurrences were asymptomatic we reccomend close follow-up of these patients. In spite of optimal local therapy a significant number of patients will continue to fail distally and there remains a need for more effective adjuvant/ systemic therapies. 69 poster THE WHOLE SPECTRUM OF SALVAGE SURGERY FOR LARYNGEAL CANCER RECURRING AFTER RT: FROM ENDOSCOPIC RESECTIONS TO OPEN-NECK PARTIAL AND TOTAL LARYNGECTOMIES G. Peretti~ C. Piazza, A. Cattaneo, R Garrubba, L Redaelli De Zinis, R Nicolai UNIVERSITYOFBRESCIA~Otolaryngology-Head and Neck, Brescia,Italy

Purpose/Objective: Salvage surgery after RT has been traditionally considered the realm of total laryngectomy (TL) with few papers focusing on organ preservation strategies. Aim of this study was to retrospectively evaluate our experience in management of such a condition by the whole spectrum of surgical procedures, ranging from endoscopic resections (ER) by C02 laser to partial laryngectomies (PL) and TL. Materials/Methods: Between January 1995 and March 2004, 71 patients affected by laryngeal cancer previously managed by RT in 69 cases and chemo-RT in 2 were treated by salvage surgery for recurrences. All patients were preoperatively evaluated by fiberoptic laryngoscopy, CT and/or MR, and intraoperative rigid endoscopy. Our treatment policy encompassed ER for glottic rTla, rTlb with limited anterior commissure involvement, and rT2 with normal cord mobility (Group A). Supracricoid PLs were performed for rT1 and rT2 with suboptimal endoscopic exposure, rT2 with impaired cord mobility and/or transcommissural extension, and rT3 for limited paraglottic space invasion or involvement of the inner portion of the thyroid cartilage (Group B). TL was planned in patients not suitable to PL for general conditions, for rT3 with massive involvement of the paraglottic space, and rT4 (Group C). A retrospective charts review was performed in order to obtain clinical, radiological, surgical, and pathological data. Survival curves were calculated by the KaplanMeier method. Results:The pre-RT staging was: cT1 in 33 patients, cT2 in 16, cT3 in 12, and cT4 in 10. The mean interval between the end of RT and sur-

gery was 19 months (range, 3-I 13). Salvage surgery consisted of ER in 22 patients (Group A) distributed as follows: 12 Type III, I Type IV, and 9 Type V cordectomies according to the European Laryngological Society Classification; open-neck PL in 15 (Group B) including: I horizontal supraglottic laryngectomy, I tracheo-crico-hyoido-epiglottopexy, 9 crico-hyoido-epiglottopexy, and 4 crico-hyoidopexy; TL in 34 (Group C) with pedicled or free flap in 6. The pT status after salvage surgery was: pT1 in 12, pT2 in 20, pT3 in 20, pT4 in 19. Complication rate was 32% (9%, 47%, and 41% for Group A, B, and C, respectively). Five-year determinate, disease-free survival, and laryngeal preservation rates for the whole series were 72%, 61%, and 41% respectively (Group A: 95%, 63%, and 77%, respectively; Group B: 100%, 83%, and 80%, respectively; Group C: 48%, 51%, and 0%, respectively). Conclusions: Survivals for the whole series are not different from those reported in the literature by using a more aggressive approach without any surgical organ preservation attempt. Moreover, the laryngeal preservation rate observed justifies a conservative treatment in case of limited recurrent lesions, even though the not negligible complication rate makes the management of these patients much more demanding.

MolecularBi01ogy/Pathol0gy 70 poster CAN CA IX BE USED AS AN ENDOGENOUS MARKER OF HYPOXIA IN HNSCC? AN EVALUATION OF THE DAHANCA 5 STUDY J.G. Eriksen.J. Overgaard AARHUSUNIVERSITYHOSPITAL,Dept. ExperimentalOncology, Aarhus, Den-

mark Purpose/Objective: Carbonic anhydrase 9 (CA IX) has been shown to be an active player in glucose transportation and pH-regulation in normal non-malignant tissue and it might serve as an indirect marker of hypoxia in tumours like squamous cell carcinomas of the head and neck (HNSCC). CA IX has been found near areas of necrosis and in a certain distance from vessels but in spite of that, data comparing CA IX expression and partial oxygen pressure has been with discrepancies. The aim of the present study was to investigate whether CA IX served as a prognostic factor for outcome in a large population of HNSCC and if CA IX was able to discriminate the tumours that did benefit from hypoxic modification with Nimorazole. Materials/Methods: We had access to sufficient paraffin-embedded formalin-fixed pre-treatment tumour tissue from 320 (77%) of the 414 patients treated in the randomized DAHANCA 5 protocol with primary radiotherapy, 66-68Gy in 33-34fx, 5fx/wk + the hypoxic radiosensitizer Nimorazole. CA iX was measured using immunohistochemistry (clone M75) and the area of positive tumour staining was dichotomized by the cut-point of 10%. Correlation of CA IX and tumour/patient characteristics were done using descriptive statistics whereas outcome data were analysed by the Kaplan Meier method and the Cox-regression model. Results: There were no correlations between high expression of CA IX and turnout/patient characteristics and high expression of CA IX were not related to local T-site control or disease-specific survival. However, tumours with low expression of CA IX had increased local T-site control when concomitantly treated with Nimorazole compared to placebo (p=O.01) whereas no difference were observed in tumours with high expression of CA iX (p=0.77). The same observation was reflected using disease-specific survival as endpoint (p=O.O09 and p=0.89 respectively). In a Cox multivariate regression analysis these data remained significant:The concomitant treatment with Nimorazole decreases the risk of local T-site failure (p=O.O03, HR=0.5, range 0.3-0.8) and disease-specific death (p=O.02, HR=0.6, range 0.4-0.9) in tumours with low expression of CA IX whereas no difference were found among tumours with high CA IX expression. Conclusions: These results are up-side down of what is expected

Posters

theoretically. Furthermore, using other cut-points reported in the literature also reflects the data presented above. The reported data suggests that turnouts with a low grade of hypoxia (i.e. low CA IX) do better when treated with Nimorazole than tumours with high expression of CA IX. Importantly, CA IX is under influence of other factors than just hypoxia like pH-regulation, glucose transportation and metabolisation as well as the interstitial pressure and that might influence the usefulness of CA IX as an endogenous marker of hypoxia. At the meeting a possible explanation for the obtained data will be presented. 71 poster CAN ENHANCED EXRESSION OF COX2 PREDICT LATERAL LYMPH NODE METASTASIS FROM PAPILLARY MICROCARCiNOMA OF THYROID? Y-J. Suh 1, C. Chun 1, S. Jung 2,B. Song ~ ~THECATHOLICUNIVERSITYOF KOREA,Surgery,Seoul,South Korea, 2THECATHOLICUNIVERSTYOFKOREA,Surgery,Seoul,South Korea

Purpose/Objective: Recently, the incidence of papillary microcarcinoma of thyroid (PMT) has been increasing very rapidly. This is mainly because of the early detection by the ultrasonography on the neck. However, the involvement of the lateral neck lymph nodes from the PMT is known to have poorer prognosis than the others having none of them involved. The enhanced expression of COX2 (cyclooxygenase 2) has been well known to be related to various cancers. We tried to elucidate some probable relations between the expression of COX2 by immunohistochemical staining (IHC) and the involvement of lateral cervical lymph nodes in PMT. Materials/Methods: We retrospectively evaluated the degree of COX2 expression in 40 patients having PMT from JAN. 2004 to AUG. 2006 in my institution. Patients were classified into two groups according to the lymph node involvement status. Group A (20 patients) were proved to have nodal metastasis, while group B (20 patients) having none. All cervical lymph nodes in the central compartment and enlarged lateral lymph nodes greater than 0.8 cm in diameter detected preopoeratively by uSG (ultrasonography) were harvested for the pathologic confirmation for the metastasis.The degree of the intensity of COX2 expression was determined by two independent pathologists and cross checked, and the intensity was stratified from 0 to I(Q5%), II (25-50%), III (50-75%) IV(75-100%). Results: The mean age of patient in group A was 43.5 years, and group B was 45.7 years. The number of male patients was 3 in group A, 1 in group B. The number of patients having positive expression of COX2 more than score 2 was 8 (I-3, 11-3,II1-1, IV-1)(40%), and none in group B. In group A, IHC score I was found in one patients. The average number of lymph nodes detected to have metastasis was 2.3 in group A. The number of lymph nodes in the lateral cervical region was 1.1 in group A. Conclusions: Even though far greater number of patients should be recruited for th evaluation like this, we think thre is possible relation between the expression of COX2 and the lateral cervical lymph node metastasis in PMT. And there is some of reports concerning on the probable causal relationshiop between lateral cervical lymph node involvement and the prognosis of PMT. We think this study can back up the previous reports on this matter. So, the patient who have enlarged lateral cervical lymph node preoperatively should have the lateral lymph node dissection or sampling thoroughly in order to prevent Iocoregional recurrence that mandates high-risk reoperation and poorer survival.

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72 poster DISTRIBUTION OF NUCLEAR AND CYTOPLASMIC SURVIVIN IS A PREDICTIVE MARKER OF SURVIVAL AND SENSITIVITY TO CHEMOAND RADIATION-INDUCED APOPTOSIS IN ORAL SQUAMOUS CELL CARCINOMA R. Stauber ~, K. Engels 2, S.K. Knauer3, D. MetzleP, W. Mann s, A.F. Kovacs~ 1UNIVERSITYHOSPITALOF MAINZ~Department of Otorhinolaryngology, Molecular and Cellular Oncology,Mainz, Germany, 2UNIVERSITYHOSPITALOF FRANKFURT,Department of Pathology, Frankfurt, Germany, 3INSTITUTE FOR BIOMEDICALRESEARCH,Georg-Speyer-Haus, Frankfurt, Germany, 4UNIVERSITYOFFRANKFURT,Institute for Informatics, Frankfurt, Germany, SUNIVERSITYHOSPITALOF FRANKFURT,Department of Oral and Maxillofacial Plastic Surgery,Frankfurt, Germany

Purpose/Objective: Survivin functions as an apoptosis inhibitor and a regulator of cell division in many tumors. The intracellular localization of survivin in tumors is discussed as a potential prognostic marker. However, current reports are inconsistent and the underlying molecular mechanisms are not understood. The present study was therefore designed to analyze the prognostic value of nuclear and cytoplasmic survivin in the pathogenesis of oral and oropharyngeal squamous carcinoma (OSCC) patients, and to dissect the underlying molecular regulation and functional consequences of survivin's dynamic localization. Experimental Design and Results: We systematically examined the localization and prognostic value of nuclear and cytoplasmic survivin in the pre-therapeutic biopsies from 71 OSCC patients, who received intra-arterial induction chemotherapy. Immunohistochemical and statistical analysis indicated that preferential nuclear versus cytoplasmic survivin is correlated with favorable versus unfavorable disease outcome. Uni- and multivariate analysis showed that in contrast to total survivin expression the difference of cytoplasmic and nuclear survivin is a strong predictor for relapse free survival (P= .0003). As a potential underlying molecular mechanism, we show in OSCC cell lines that predominantly cytoplasmic survivin mediates protection against chemo- and radiotherapy induced apoptosis. Importantly, we here show that the cytoplasmic localization of survivin is regulated by its nuclear export signal (NES). Export deficient nuclear survivin is not cytoprotective but dominant negative and inhibited tumor growth in xenotransplantation studies. Conclusions:Our study suggests the difference of cytoplasmic and nuclear survivin as an indicator for survivin activity in tumor cells. Thus, this difference may serve as a predictive marker of outcome in OSCC patients undergoing multimodality therapy. We also propose to pursue the pharmacogenetic interference with survivin's cytoplasmic localization as a potential therapeutic strategy. 73 poster ENHANCEMENT OF RADIOSENSITIVlTY OF NASOPHARYNGEAL CANCER CELLS BY KNOCKDOWN THE EXPRESSION OF GP96 OR GDF-15 LY. Lee~, J.T.C. Chang 2,AJ. Cheng 3 7CHANGGUNG MEMORIALHOSPITAL,Department of Pathology, Taoyuan,

Taiwan, 2CHANG GUNG MEMORIALHOSPITAL,Department of Radiation Oncology,

Taoyuan, Taiwan, 3CHANGGUNGMEMORIALHOSPITAL,Department of Medical Biotechnology,

Taoyuan, Taiwan Purpose/Objective: Nasopharyngeal carcinoma (NPC), one of the ten leading cancers in Taiwan, usually occurs in middle age male. Since radiotherapy is the major treatment modality, to define specif-