Transarterial chemoembolization in hepatocellular carcinoma: Can easy to use criteria determined after the first session predict survival? A multivariate analysis

GASTROENTEROLOGY Vol. 118, No.4

A526 AGA ABSTRACTS

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TRANSARTERIAL CHEMOEMBOLIZATION IN HEPATOCELLULAR CARCINOMA: CAN EASY TO USE CRITERIA DETERMINED AFTER THE FIRST SESSION PREDICT SURVIVAL? A MULTIV ARIATE ANALYSIS. Said EI Khaddari, Jean-Louis Gaudin, Georges Picaud, Henri Abidi, JeanChristophe Souquet, Hosp de la Croix-Rousse, Lyon, France; Ctr Hospitalier Lyon Sud, Lyon, France. The efficacy of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is still a matter of debate because of conflicting results, explained in part by variations in treatment indications and modalities. The aim of the present study was to determine whether simple routine parameters evaluating the Ist session ofTACE can predict survival. Patients and methods: From January 90 to January 99, 251 patients with HCC were treated in our department. Patients were included only when they were treated at least with one session of TACE and completed evaluation one month after TACE with CT scan. TACE session included hepatic arteriography, lipiodol and doxorubicin (50 mg/sm) emulsion injection, followed by gelatin sponge embolization. The following variables were studied in univariate and multivariate analysis: i) patient parameters (age, cirrhosis etiology, Child-Pugh class; ii) tumor parameters (tumor number, largest lesion size, alpha-fetoprotein concentration, existence of associated treatment) iii) TACE evaluation (variation in alfa-fetoprotein concentration, presence of post-embolization syndrome, i.e. hyperthermia, andlor cytolysis occurring within 2 days following TACE, and tumor lipiodol uptake. This last parameter was determined by the same radiologist by reading all CT scan without being informed of the study aim or patients survival. Results: 72 patients (mean age 66 yrs) fulfilled the inclusion criteria. HCC diagnosis was cytological in 94% and clinical in the remaining cases (imaging, alfa-fetoprotein level). 96% of patients had liver cirrhosis with Child-Pugh class A, Band C in respectively 66.7%, 27.5% and 5.8% of cases. Mean tumor number was 1.9 and the largest lesion had a mean diameter of 4.6 cm. Patient received a mean of 3 TACE session. 31 patients had associated treatment during folllow-up, Mean follow-up was 22.7 months. Mean survival was 30.4 months (median 22 months). Actuarial survival at 1,2,3 and 5 years was respectively 67.5%, 47.5%, 32.5%, and 20%. The only independant prognostic factor in multivariate analysis was the Child-Pugh class (p
HISTONE DEACETYLASE INIDBITOR (SODIUM BUTYRATE) INDUSES ACETYLATION OF P53 AND APOTOSIS IN HUMAN GASTRIC CANCER CELLS IN VITRO AND IN VIVO. Takeshi Terui, Ken Murakami, Tsuzuku Murakami, Koichi Takada, Rishu Takimoto, Junji Kato, Yoshiro Niitsu, Sapporo Med Univ, Sapporo Hokkaido, Japan. Sodium butyrate (SB) is a four-carbon straight chain fatty acid inhibits deacetylation of histones leading to alteration of chromosomal structure and gene expression. 5B facilitates differentiation and apoptosis in several neoplastic cells in vitro and in vitro with no toxicity for normal cells. Recent studies demonstrated that p21/WAFI is involved in the growth inhibitory regulation by SB. However, the mechanisms of apoptosis by SB has not been clarified, bacause p21 binds to cyclintCDK2 and CDK4 inducing G I arrest of cell cycle and inhibiting apotosis. In the present study, we investigated whether SB induces apoptosis via a p53-dependent pathway and whether the mechanism of p53 activation are to induce acetylation of p53. Human gastric cancer cell line KATO-II1 cells, which have a homozygous deletion of p53 gene and are not susceptible to SB, were transduced in vitro with the human wt-p53 eDNA by exposure to Adenovirus-p53 (KATO-IIllp53). Immunocytochemical staining and western blot analyses showed high effeciency and high level ofwt-p53 and p21 protein expression, but no p53 and p2l was detected in parental (uninfected) cells or in control cells infected with Adenovirus-nLacZ(KATOIIlInLacZ). Overexpression of p53 alone induced growth arrest but did not promote DNA fragmentation. SB raidly reduced viability of KATO-III/p53 cells with DNA fragmentation. However SB did not damage parental KATO-III cells, nor KATO-IIllnLacZ cells. Recently, it was reported that acetylation of Lysine residue is an important post-tranlational modification that activates p53. Considering SB as a histone deacetylase inhibitor, we investigated whether SB induces acetylation of p53. Western blot analysis revealed that in KATO-IIllp53 cells p53 was acetylated at Lys373 and Lys382 residues after treatment with SB. Based on these data, we injected adenovirus-p53 into KATO-Illtumrs s.c. implanted into nu/nu mice and administered SB i.p. This novel chemo-gene therapy induced massive apoptotic destruction of the tumors. In conclusion, it is suggested that SB could activate p53 by acetylation of lysine residues and induce apotosis in cancer cells transduced wt-p53 gene in vitro and in vivo.

2792 THERAPEUTIC ULTRASOUND IRRADIATION IN COMBINATION WITH PHOTODYNAMIC THERAPY DRUGS TO COLON CANCER: IN VITRO AND EARLY CLINICAL STUDY. Katsuro Tachibana, Akira Tomita, Nobuya Yamashita, Toshiki Uchida, Hisashi Oka, Teruo Nakayoshi, Norimichi Yamada, Fukuoka Univ Sch of Medicine, Fukuoka, Japan; Showa Univ Sch of Medicine, Yokohama, Japan: Yokohama-Shin-Midori Hosp, Yokohama, Japan. Background: We previously reported enhancement of gastric cancer cell killing in vitro by non-thermal, low intensity ultrasound in the presence of photosensitive drug, porfirner sodium (Photofrin, QLT). The aim of the present study was to apply this method to colon cancer and determine its efficacy in human subjects. Method I: Cancer cell line, Colon26 (5X1051 ml) were exposed to 1.3 MHz frequency ultrasound (US) for 0, 10,20,30 seconds in the presence of porfimer sodium (Pf; 50, 100, 200J.(.g/ml). A miniature US transducer (size:IXIXlmm) was inserted directly into the cell suspension for each ultrasound irradiation (n=5) at an intensity of 0.3 W/cm 2 • Cell survival rate were measured immediately after treatment. Method 2: Five patients with multiple colon cancer metastasis to the liver were administered with Pf (2.0 mglkg), 24 hrs prior US irradiation. Ultrasound was irradiated diffusively to the whole liver from the skin surface by means of a physical therapy apparatus (lMHz, 2 W/cm 2 ) for a total of 3 hrs. Tumor marker (CEA) were measured and lesion volume was examined with CT and MRI. Results: Comparison of in vitro cancer cell survival after ultrasound irradiation with or without drug showed significant differences (p<0.05: ANOVA). Whereas, no decrease in cell survival were observed with drug alone at all concentrations tested. Four of the human subjects (80%) treated with US and drug showed significant decrease in CEA levels and tumor size. Local necrosis of the mass were observed. One patient revealed marked decrease of CEA level from 1300 to 455 nglml within 2 weeks after US treatment. Conclusion: Synergetic colon cell killing was observed by combining porfimer sodium and low intensity ultrasound energy in vitro. Furthermore, early clinical study of this novel ultrasound treatment proved to be effective for metastatic colon cancer in the liver.

2795 TREATMENT OF GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS WITH OCTREOTIDE LAR. Paola Tomassetti, Marina Migliori, Sergio Lalli, Roberto Corinaldesi, Lucio Gullo, Dept of Internal Medicine and Gastroenterology, Bologna, Italy. Background: Octreotide LAR is a new somatostatin analog whose activity lasts for as long as 28 days. The aim of this study was to assess its therapeutic efficacy, tolerability, and safety in patients with gastroenteropancreatic neuroendocrine tumors. Methods: Ten patients with carcinoid tumors, 3 with nonfunctioning pancreatic tumors, 2 with Zollinger Ellison syndrome (ZES) associated with multiple endocrine neoplasia type I (MEN I), and I with glucagonoma were studied. Octreotide LAR was administered intramuscularly at a dose of 20 mg every 28 days for a mean of 10.7 months (range 6-15 months). Eleven patients were treated previously with octreotide or lanreotide. Results: Regarding carcinoid tumor patients, octreotide LAR normalized bowel movements in 9/10 cases, and flushing episodes disappeared in 7/8 cases. Even in the remaining 6 patients the symptoms disappeared. In carcinoid tumor patients, urinary 5-hydroxyindoleacetic acid decreased from 64.4 ± 17.9 mg/24 h to 16.2 ± 8.4 mg/24 h; in the 2 with ZESIMEN I, serum gastrin decreased from 9000 and 475 pg/ml to 3480 and 220 pglml, and in the patient with glucagonoma plasma glucagon decreased from 860 pg/ml to 160 pg/ml. Tumor size remained unchanged in 14116 patients, and increased in the remaining 2. No side effects were observed. In the II patients previously treated with octreotide or lanreotide, no differences in response to therapy were observed with octreotide LAR. Conclusions: Octreotide LAR appears to have a good therapeutic efficacy, tolerability and safety in the treatment of neuroendocrine tumors. Its effects are similar to those of octreotide and lanreotide. However, since it only needs to be administered once every 28 days, it is preferable in clinical practice.

2796 ENDOSCOPIC TENTING: A NEW TECHNIQUE IN COLONOSCOPIC REMOVAL OF LARGE, FLAT AND SESSILE POLYPS. Tat-Kin Tsang, Michael C. Jean, McGaw Med Ctr, Evanston Northwestern Hosp, Evanston, IL. Purpose: Large, flat and sessile polyps are often technically difficult to remove cleanly, even for the experienced endoscopist. Different methods have been described in the past(e.g. submucosal pre-injection with saline solution). We have attempted a new technique to safely remove large, flat and sessile polyps. Method: The first step in endoscopic tenting involves pinching the polyp with hot biopsy forceps. The next step involves applying tension to the polyp, pulling it toward the center of the colonic lumen. Electrocautery is then applied to the polyp while in this "tenting" position. A minimal amount of current is used to create a retraction of the mucosa, forming a polypoid structure. This is followed by routine snare resection. For larger polyps, this tenting technique can be repeated several times on