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259 The association of MMP-1, MMP-3 and MMP-9 genotypes with prognosis of hepatocellular carcinoma
Category 3: Liver Tumors (Epidemiology, Diagnosis, Management) 257 LOW-DOSE, LONG-TERM INTERFERON ALFA 2B DELAYS CLINICAL RECURRENCE AFTER CURATIVE RADIOFREQUENCY ABLATION IN PATIENTS WITH HEPATITIS C RELATED HEPATOCELLULAR CARCINOMA
M. Kudo 1 , Y. Sakaguchi 2 . 1 Department of Gastroenterology and Hepatology, Osaka, Japan; 2 Department of Gastroenterology and Hepatology, Osaka, Japan Background/Aim: In our institution, more than 810 hepatocellular carcinoma (HCC) cases have been treated by radiofrequency ablation (RFA) over 5 years. Although local recurrence rate remains as low as 3.5% for the small HCCs less than 3 cm, recurrence at the different sites of the liver is as high as 15-20%/year in cases of hepatitis C related HCCs. This study was prospectively performed whether low-dose, long-term interferon (IFN) therapy after curative RFA inhibits the recurrence of HCC in the different sites of the liver. Patients and Methods: A total of 34 patients with small HCCs less than 3 cm in diameter and less than 3 nodules received 3 M units of IFN alpha-2b twice a week for a median period of 3.3years (1.6-5.1 years). A total of HCC 33 patients, who received curative RFA therapy and did not receive IFN was defined as control group. Age, platelet counts, and size of nodules were matched to the IFN group. The period to the time of first recurrence, cumulative recurrence rate, cumulative disease free rate, recurrence pattern and serial changes of ALT levels were compared between IFN group and control group. Results: Patient background in terms of liver function, tumor morphology or tumor markers showed statistically no difference between the 2 groups. Period to the first recurrence after RFA was 3.4 years (IFN group) and 1.4 years (control) (p=0.022). Cumulative recurrence rate at 4 years was 14% in IFN group and 73% in control group (p<0.01). Cumulative survival rate at 4 years was 100% in IFN group and 90% in control group (NS), whereas cumulative disease free rate was 100% in IFN group and 56% in control group (p<0.05). Conclusion: Low-dose, long-term IFN therapy does inhibits or delays clinical recurrence after curative RFA therapy for HCC by suppressing the growth of HCC.
258 EVALUATION OF HEPATOCELLULAR CARCINOMA USING SONOVUE, A NEW ULTRASOUND CONTRAST AGENT: CORRELATION WITH CELLULAR DIFFERENTIATION
C. Nicolau, R. Vilana, L. Bianchi, V. Catala, R. Gilabert, C. Bru. Diagnosis Imaging Center/Hospital Clinic, Barcelona, Spain Objective: To describe the appearance of hepatocellular carcinoma (HCC) with Contrast-Enhanced Ultrasound (CEUS) in the vascular phase, and to evaluate whether the enhancement pattern correlates with the degree of cellular differentiation. Methods: One hundred four HCCs were prospectively evaluated with CEUS using Coherent-Contrast Imaging (CCI), and SonoVue, with a low mechanical index (< 0.2). The enhancement of HCCs in the vascular phase was analysed according to the degree of pathological differentiation obtained by fine needle biopsy. Results: In the arterial phase, all HCCs except 4 well differentiated (96.2%) showed enhancement (p<0.05). Histological differentiation of hypoechoic lesions in the early portal phase (7 HCCs; 16%), significantly differed from hyperechoic (1 HCC, 1%) or isoechoic lesions (87 HCCs; 83.6%) (p<0.05), with a significant probability of a worse differentiation in hypoechoic lesions. Histological differentiation of isoechoic lesions in late phase (30 HCCs; 28.8%), significantly differed from hypoechoic lesions (74 HCCs, 71.2%) (p<0.05) with a significant probability of a better differentiation in isoechoic lesions. Conclusion: CEUS using CCI and SonoVue revealed enhancement in arterial phase in >95% of HCCs, with a few well-differentiated cases being non diagnosed due to the absence of enhancement. Echogenicity in portal and late phases correlated with cellular differentiation.
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259 THE ASSOCIATION OF MMP-1, MMP-3 AND MMP-9 GENOTYPES WITH PROGNOSIS OF HEPATOCELLULAR CARCINOMA
K. Okamoto 1 , K. Mimura 1 , Y. Murawaki 1 , I. Yuasa 2 . 1 2nd. Dept. of Internal Medicine, Tottori University, Yonago, Japan; 2 Dept. of Legal Medicine, Tottori University, Yonago, Japan The matrix metalloproteinases (MMPs) play important roles in the cancer invasion and metastasis. Recently, functional gene polymorphisms in the promoter regions of MMP-1 1G/2G, MMP-3 5A/6A and MMP-9 C/T have been found. The transcriptional activity is higher in 2G, 5A and T alleles. These MMP genotypes have been reported to be associated with the prognosis of various cancers except of hepatocellular carcinoma (HCC). In this study, we examined the association of the MMP-1, -3, -9 genotypes with the prognosis of HCC in a Japanese population. Methods: One hundred twenty nine patients with HCC were enrolled to the study. Clinicopathological features of patients were referred to the first diagnosis of hepatocellular carcinoma. Genomic DNA samples were extracted from peripheral white blood cells and gene polymorphisms were detected by PCR - RFLP methods. Survival rate divided by each genotype has examined by Kaplan-Meier analysis. Result: There were no significant differences in the clinicopathological features between MMP-1 1G carriers and 2G homozygotes, MMP-3 5A carriers and 6A homozygotes, and MMP-9 T carriers and C homozygotes among HCC patients. Kaplan-Meier analysis showed no significant difference of survival rate of HCC patients between MMP-1 1G carriers and 2G homozygotes, and between MMP-9 T carriers and C homozygotes. In MMP-3 genotypes, HCC patients with 5A allele have a marginally significant poor-prognosis than those with 6A homozygotes. Conclusion: Unlike MMP-1 and MMP-9 genotypes, MMP-3 5A allele with higher transcriptional activity may be a risk factor for the poorprognosis of HCC patients.
260 HEPATOCELLULAR TELOMERE SHORTENING IS A GENERAL DIAGNOSTIC MARKER AND CORRELATES WITH CHROMOSOMAL INSTABILITY OF HUMAN HEPATOCELLULAR CARCINOMA
R.R. Plentz 1 , M. Caselitz 2 , J.S. Bleck 1 , M. Gebel 1 , P. Flemming 3 , S. Kubicka 1 , M.P. Manns 1 , K.L. Rudolph 1 . 1 Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany; 2 Department of Internal Medicine, Klinikum Deggendorf, Deggendorf, Germany; 3 Department of Pathology, Medical School of Hannover, Hannover, Germany Introduction: The diagnosis of hepatocellular carcinoma (HCC) remains a mayor clinical problem in the surveillance of cirrhosis patients. A current hypothesis indicates that telomere shortening plays a role in tumor initiation by induction of chromosomal instability. To test whether the telomere hypothesis applies to human HCC and whether telomere length measurement could help to diagnose early stage HCC, we analyzed the telomere length of hepatocytes in fine needle biopsies of tumors from cirrhosis patients. Patient and Methods: We chose 10 biopsies of diploid HCC, 10 biopsies of aneuploid HCC and 10 cases of regenerative nodules. The patients age was between 33-82. For histology and cytology the samples were paraffin embedded and stained with hemotoxylin and eosin (H&E). The cytological smear preparations were stained according to H&E and Papanicolaou. Hepatocyte specific analysis of telomere length was performed by quantitative fluorescence in situ hybridization (qFISH). Results: Our study shows significantly shortened telomeres in hepatocytes of HCC compared to regenerative nodules. The study shows that there is no overlap in mean telomere length between non-cancerous and HCC samples. The mean hepatocyte telomere length over all samples showes a significant shorter telomeres in the group of aneuploid HCC compared to the group of diploid HCC.
M. Kudo 1 , Y. Sakaguchi 2 . 1 Department of Gastroenterology and Hepatology, Osaka, Japan; 2 Department of Gastroenterology and Hepatology, Osaka, Japan Background/Aim: In our institution, more than 810 hepatocellular carcinoma (HCC) cases have been treated by radiofrequency ablation (RFA) over 5 years. Although local recurrence rate remains as low as 3.5% for the small HCCs less than 3 cm, recurrence at the different sites of the liver is as high as 15-20%/year in cases of hepatitis C related HCCs. This study was prospectively performed whether low-dose, long-term interferon (IFN) therapy after curative RFA inhibits the recurrence of HCC in the different sites of the liver. Patients and Methods: A total of 34 patients with small HCCs less than 3 cm in diameter and less than 3 nodules received 3 M units of IFN alpha-2b twice a week for a median period of 3.3years (1.6-5.1 years). A total of HCC 33 patients, who received curative RFA therapy and did not receive IFN was defined as control group. Age, platelet counts, and size of nodules were matched to the IFN group. The period to the time of first recurrence, cumulative recurrence rate, cumulative disease free rate, recurrence pattern and serial changes of ALT levels were compared between IFN group and control group. Results: Patient background in terms of liver function, tumor morphology or tumor markers showed statistically no difference between the 2 groups. Period to the first recurrence after RFA was 3.4 years (IFN group) and 1.4 years (control) (p=0.022). Cumulative recurrence rate at 4 years was 14% in IFN group and 73% in control group (p<0.01). Cumulative survival rate at 4 years was 100% in IFN group and 90% in control group (NS), whereas cumulative disease free rate was 100% in IFN group and 56% in control group (p<0.05). Conclusion: Low-dose, long-term IFN therapy does inhibits or delays clinical recurrence after curative RFA therapy for HCC by suppressing the growth of HCC.
258 EVALUATION OF HEPATOCELLULAR CARCINOMA USING SONOVUE, A NEW ULTRASOUND CONTRAST AGENT: CORRELATION WITH CELLULAR DIFFERENTIATION
C. Nicolau, R. Vilana, L. Bianchi, V. Catala, R. Gilabert, C. Bru. Diagnosis Imaging Center/Hospital Clinic, Barcelona, Spain Objective: To describe the appearance of hepatocellular carcinoma (HCC) with Contrast-Enhanced Ultrasound (CEUS) in the vascular phase, and to evaluate whether the enhancement pattern correlates with the degree of cellular differentiation. Methods: One hundred four HCCs were prospectively evaluated with CEUS using Coherent-Contrast Imaging (CCI), and SonoVue, with a low mechanical index (< 0.2). The enhancement of HCCs in the vascular phase was analysed according to the degree of pathological differentiation obtained by fine needle biopsy. Results: In the arterial phase, all HCCs except 4 well differentiated (96.2%) showed enhancement (p<0.05). Histological differentiation of hypoechoic lesions in the early portal phase (7 HCCs; 16%), significantly differed from hyperechoic (1 HCC, 1%) or isoechoic lesions (87 HCCs; 83.6%) (p<0.05), with a significant probability of a worse differentiation in hypoechoic lesions. Histological differentiation of isoechoic lesions in late phase (30 HCCs; 28.8%), significantly differed from hypoechoic lesions (74 HCCs, 71.2%) (p<0.05) with a significant probability of a better differentiation in isoechoic lesions. Conclusion: CEUS using CCI and SonoVue revealed enhancement in arterial phase in >95% of HCCs, with a few well-differentiated cases being non diagnosed due to the absence of enhancement. Echogenicity in portal and late phases correlated with cellular differentiation.
81
259 THE ASSOCIATION OF MMP-1, MMP-3 AND MMP-9 GENOTYPES WITH PROGNOSIS OF HEPATOCELLULAR CARCINOMA
K. Okamoto 1 , K. Mimura 1 , Y. Murawaki 1 , I. Yuasa 2 . 1 2nd. Dept. of Internal Medicine, Tottori University, Yonago, Japan; 2 Dept. of Legal Medicine, Tottori University, Yonago, Japan The matrix metalloproteinases (MMPs) play important roles in the cancer invasion and metastasis. Recently, functional gene polymorphisms in the promoter regions of MMP-1 1G/2G, MMP-3 5A/6A and MMP-9 C/T have been found. The transcriptional activity is higher in 2G, 5A and T alleles. These MMP genotypes have been reported to be associated with the prognosis of various cancers except of hepatocellular carcinoma (HCC). In this study, we examined the association of the MMP-1, -3, -9 genotypes with the prognosis of HCC in a Japanese population. Methods: One hundred twenty nine patients with HCC were enrolled to the study. Clinicopathological features of patients were referred to the first diagnosis of hepatocellular carcinoma. Genomic DNA samples were extracted from peripheral white blood cells and gene polymorphisms were detected by PCR - RFLP methods. Survival rate divided by each genotype has examined by Kaplan-Meier analysis. Result: There were no significant differences in the clinicopathological features between MMP-1 1G carriers and 2G homozygotes, MMP-3 5A carriers and 6A homozygotes, and MMP-9 T carriers and C homozygotes among HCC patients. Kaplan-Meier analysis showed no significant difference of survival rate of HCC patients between MMP-1 1G carriers and 2G homozygotes, and between MMP-9 T carriers and C homozygotes. In MMP-3 genotypes, HCC patients with 5A allele have a marginally significant poor-prognosis than those with 6A homozygotes. Conclusion: Unlike MMP-1 and MMP-9 genotypes, MMP-3 5A allele with higher transcriptional activity may be a risk factor for the poorprognosis of HCC patients.
260 HEPATOCELLULAR TELOMERE SHORTENING IS A GENERAL DIAGNOSTIC MARKER AND CORRELATES WITH CHROMOSOMAL INSTABILITY OF HUMAN HEPATOCELLULAR CARCINOMA
R.R. Plentz 1 , M. Caselitz 2 , J.S. Bleck 1 , M. Gebel 1 , P. Flemming 3 , S. Kubicka 1 , M.P. Manns 1 , K.L. Rudolph 1 . 1 Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany; 2 Department of Internal Medicine, Klinikum Deggendorf, Deggendorf, Germany; 3 Department of Pathology, Medical School of Hannover, Hannover, Germany Introduction: The diagnosis of hepatocellular carcinoma (HCC) remains a mayor clinical problem in the surveillance of cirrhosis patients. A current hypothesis indicates that telomere shortening plays a role in tumor initiation by induction of chromosomal instability. To test whether the telomere hypothesis applies to human HCC and whether telomere length measurement could help to diagnose early stage HCC, we analyzed the telomere length of hepatocytes in fine needle biopsies of tumors from cirrhosis patients. Patient and Methods: We chose 10 biopsies of diploid HCC, 10 biopsies of aneuploid HCC and 10 cases of regenerative nodules. The patients age was between 33-82. For histology and cytology the samples were paraffin embedded and stained with hemotoxylin and eosin (H&E). The cytological smear preparations were stained according to H&E and Papanicolaou. Hepatocyte specific analysis of telomere length was performed by quantitative fluorescence in situ hybridization (qFISH). Results: Our study shows significantly shortened telomeres in hepatocytes of HCC compared to regenerative nodules. The study shows that there is no overlap in mean telomere length between non-cancerous and HCC samples. The mean hepatocyte telomere length over all samples showes a significant shorter telomeres in the group of aneuploid HCC compared to the group of diploid HCC.