Incidence Of Liver Metastasis Research Articles

Impact of Octreotide and SOM-230 on liver metastasis and hepatic lipidperoxidation in ductal pancreatic adenocarcinoma in Syrian Hamster

Octreotide is a somatostatin analogue binding on two receptor subtypes. In previous trials Octreotide showed inhibitory effects on tumour growth and liver metastasis in experimental pancreatic cancer. Thus we evaluated whether the new somatostatin analogue SOM-230 binding on 4 receptor subtypes has superior effects on carcinogenesis in pancreatic carcinoma. About 120 Syrian hamsters were randomised into six groups (n = 20): Gr.1: Aqua/Aqua, Gr.2: BOP/Aqua, Gr.3: Aqua/Octreotide, Gr.4: BOP/Octreotide, Gr.5: Aqua/SOM-230, Gr.6: BOP/SOM-230. Tumour groups 2,4,6 subcutaneously received 10 mg/kg body weight N-nitrosobis-2-oxopropylamin (BOP) weekly for 10 weeks, healthy control Gr.1,3,5 were given aqua. In the 17th week therapy started with Octreotide and SOM-230 for 16 weeks, after 32 weeks animals were sacrificed. Pancreas and liver were histopathologically analysed. Hepatic lipidperoxidation was determined by activities of antioxidative enzymes gluthation-peroxidase (GSH-Px) and superoxiddismutase (SOD) as well as concentration of thiobarbituric-acid reactive substances (TBARS). Incidence of liver metastases was 88.2% in Gr.2 (BOP/Aqua), it was decreased in Gr.4 (BOP/Octreo: 40%) and Gr.6 (BOP/SOM-230: 50%) (P < 0.05). Mean number/animal and mean-2-dimensional size of liver metastases did not differ between tumour groups. Comparing GSH-Px-activity in intrametastatic and extrametastatic hepatic tissue revealed a significant increase extrametastatically in Gr.2 (BOP/Aqua) and Gr.6 (BOP/SOM-230). SOD-activity in liver metastases was decreased in Gr.2 (1,801) (P < 0.05) versus Gr.4 (8,304) and Gr.6 (7,038). Intrametastatic TBARS concentration was increased in Gr.2 compared to Gr.4 (BOP/Octreotid) and Gr.6 (BOP/SOM-230) (P < 0.05). Octreotide and SOM-230 equally reduced liver metastasis in ductal pancreatic adenocarcinoma probably by a reduction of lipidperoxidation.

Preoperative hepatic and regional arterial chemotherapy in the prevention of liver metastasis after colorectal cancer surgery

4090 Background: To investigate whether preoperative hepatic and regional arterial chemotherapy are able to prevent liver metastasis and improve overall survival in patients receiving curative colorectal cancer resection. Methods: Patients with Stage II or Stage III colorectal cancer (CRC) were randomly assigned to receive preoperative hepatic and regional arterial chemotherapy (PHRAC group, n=256) or surgery alone (control group, n=253). The primary endpoint was disease-free survival, whereas the secondary endpoints included liver metastasis-free survival and overall survival. Results: There were no significant differences in overall morbidity between PHRAC and Control groups. During the follow-up period (median, 42 months), the median liver metastasis time for patients with stage III CRC was significantly longer in the PHRAC group (16±3 months v.s. 8±1 months, P=0.01). In stage III patients, there was also significant difference between the two groups with regard to the incidence of liver metastasis (18.9% vs 27.3%, P=0.01), 5-year disease-free survival (70.2% vs 52.0%, P=0.0076), 5-year overall survival (80.3% vs 69.5%, P=0.020) and the median survival time (40.1± 4.6 months vs 36.3 ± 3.2 months, P=0.03). In the PHRAC arm, the risk ratio of recurrence was 0.63 (95% CI, 0.51–0.79, P=0.0001), of death was 0.50(95% CI, 0.32–0.67; P=0.005), and of liver metastasis was 0.70 (95% CI, 0.52–0.86; p=0.01). In contrast, PHRAC seemed to be no benefit for stage II patients. Toxicities, such as hepatic toxicity and leucocyte decreasing, were mild and could be cured with medicine. Conclusions: Preoperative hepatic and regional arterial chemotherapy, in combination with surgical resection, could be able to reduce and delay the occurrence of liver metastasis and therefore improve survival rate in patients with stage III colorectal cancer. No significant financial relationships to disclose.

Effect of multiple-phase regional intra-arterial infusion chemotherapy on patients with resectable pancreatic head adenocarcinoma.

Regional intra-arterial infusion chemotherapy (RIAC) has been more valuable to improve prognosis and quality of life of patients with inoperable pancreatic adenocarcinomas, and adjuvant RIAC plays an important role in prolonging survival and reducing risk of liver metastasis after radical resection of pancreatic cancer, but the effect of preoperative or multiple-phase RIAC (preoperative combined with postoperative RIAC) for resectable pancreatic cancers has not been investigated. In this prospective study, the effect of multiple-phase RIAC for patients with resectable pancreatic head adenocarcinoma was evaluated, and its safety and validity comparing with postoperative RIAC were also assessed. Patients with resectable pancreatic head cancer were randomly assigned to two groups. Patients in group A (n=50) were treated with new therapeutic mode of extended pancreaticoduodenectomy combined with multiple-phase RIAC, and those in group B (n=50) were treated with extended pancreaticoduodenectomy combined with postoperative RIAC in the same period. The feasibility, compliance and efficiency of the new therapeutic mode were evaluated by tumor size, serum tumor markers, clinical benefit response (CBR), surgical complications, mortality and toxicity of RIAC. The disease-free survival time, median survival time, incidence of liver metastasis, survival rate at 1, 2, 3 and 5 years were also observed. Life curves were generated by the Kaplan-Meier method. The pain relief rate and CBR in group A was 80% and 84% respectively. Serum tumor markers decreased obviously and tumors size decreased in 26% of patients after preoperative RIAC in group A. No more surgical complications, mortality or severe systemic side effects were observed in group A compared with group B. The incidence of liver metastasis in group A was 34% which was lower than 50% in group B. The disease-free survival time and median survival time in group A were 15.5 months and 18 months respectively. The 1-, 2-, 3- and 5-year survival rates were 54.87%, 34.94%, 24.51% and 12.25% respectively. There was no significant difference of survival time or survival rates between two groups. Multiple-phase RIAC is effective in combined therapy of resectable pancreatic head carcinomas by enhancing inhibition of tumor growth and reduction of liver metastasis, without negative effect on patients' safety or surgical procedure.

Risk factors of Ever metastasis from colorectul cancer

Objective To explore the risk factors of liver metastasis from colorectal cancer. Methods The clinic data of 1341 patients with colorectal cancer who had been admitted to our department from January 1989 to December 2004 were analyzed retrospectively. Results The incidence of the liver metastasis from colorectal cancer was 11.56% (155/1341). Univariate analysis showed that sex, location and size of the primary tumor site, regional lymph node metastasis, infiltration depth of the bowel wall, involvement of the adjacent viscera, complications and peritoneal implantation were relevant to liver metastasis (X2=6.517, 10.208, 11.173, 42.160, 80.731,6.593, 3.887, 14.352, P < 0.05). Logistic regression analysis showed that sex, regional lymph node metastasis, infiltration depth of the bowel wall, complications and primary tumor site were correlated with liver metastasis ( b = 0.655, -0.488, 1.355, -0.752, 0.273, P <0.05). Conclusions Male patients, patients with regional lymph node metastasis or with involvement of tissues out of the serosa have higher chance of liver metastasis from coloreetal cancer. Patients with colon cancer are apt to develop liver metastasis than those with rectal cancer. The incidence of liver metastasis in colorectal cancer patients complicated with other diseases is low. Key words: Colon cancer; Rectal cancer; Liver metastasis; Risk factor

CO2 pneumoperitoneum increases systemic but not local tumor spread after intraperitoneal murine neuroblastoma spillage in mice

Minimally invasive techniques are increasingly used for biopsy and resection of neuroblastoma, but the impact on the behavior of spilled tumor cells is unknown. We aimed to investigate whether CO(2) pneumoperitoneum can affect local or systemic tumor manifestation after spillage of neuroblastoma cells into the peritoneal cavity. Murine neuroblastoma cells (Neuro2a, 1x10(6)) were inoculated into the peritoneal cavity of 25 male A/J mice, which subsequently underwent CO(2) pneumoperitoneum (n = 12) or laparotomy (n = 13) for 1 h. At the 28th postoperative day, local (peritoneal and surface of the gut) and systemic (liver, lung, spine) tumor spread was graded in a blinded manner (1-4 point scale) and specimens were histologically examined for tumor manifestation (hematoxylin and eosin stain) and tumor cell proliferation rate (Ki-67-stain). In the case of no visible lesion, five random sections were histologically examined. Peritoneal carcinosis was graded macroscopically. Tumor manifestations were detected in 10 out of 12 (83%) animals after CO(2) pneumoperitoneum, and in 9 out of 13 (69%) after laparotomy (n.s.). Incidence of liver metastasis was higher after CO(2) pneumoperitoneum versus laparotomy (83% versus 31%; p < 0.05). Incidence and grading of peritoneal carcinosis was not significantly different between the groups (n.s.). Intrapulmonary metastasis was found in one mouse of each group, but no metastasis of the spine. However, the grading of liver metastasis was higher after CO(2) pneumoperitoneum compared to laparotomy (p < 0.05). Tumor cell proliferation (Ki-67 stain) in the liver did not differ between both groups. Moreover, proliferation always exceeded 50% of tumor cells, irrespective local or systemic tumor manifestation. CO(2) pneumoperitoneum increased intrahepatic metastasis, but not local peritoneal carcinosis in a murine neuroblastoma model. This suggests that laparoscopy could promote systemic dissemination of intraperitoneally spilled tumor cells when no chemotherapy is applied. It remains to be determined whether this is due to local immune suppression or direct modulation of tumor cell behavior.

Differences in Organ System of Distant Metastasis by Renal Cell Carcinoma Subtype

The majority of the published data regarding the rates of renal cell carcinoma metastasis to specific locations has examined renal cell carcinoma as a whole. We evaluated site of distant metastasis by renal cell carcinoma histological subtype. We studied 910 patients treated with radical nephrectomy for clear cell, papillary or chromophobe renal cell carcinoma at the Mayo Clinic between 1970 and 2000 who had distant metastasis at nephrectomy or who had metastasis during followup. The sites of metastases were compared by histological subtype using the chi-square and Fisher exact tests. There were 853 (94%) patients with clear cell, 39 (4%) with papillary and 18 (2%) with chromophobe renal cell carcinoma. Median followup for the 65 patients who were still alive at last followup was 11.6 years. Patients with clear cell renal cell carcinoma were more likely to have metastasis to the lungs (53.6%) compared to those with papillary (33.3%) and chromophobe (33.3%) renal cell carcinoma (p = 0.012). Patients with chromophobe renal cell carcinoma were more likely to have metastasis to the liver compared to those with clear cell renal cell carcinoma (33.3% vs 9.7%, p = 0.007), but there was not a statistically significantly difference in the incidence of liver metastases between patients with chromophobe and papillary renal cell carcinoma (33.3% vs 18.0%, p = 0.308). Site of distant metastasis varies significantly by renal cell carcinoma histological subtype. Patients with clear cell renal cell carcinoma are more likely to have metastasis to the lungs while patients with chromophobe renal cell carcinoma are more likely to experience liver metastasis.

Inhibition of colon tumor metastasis in an orthotopic nude mouse model with the dual selective Src/Abl kinase inhibitor, AZD0530

14032 Background: Colorectal cancer is the leading cause of cancer deaths in the USA, largely due to metastatic disease in the liver. The specific activity of the non-receptor protein tyrosine kinase, Src, is increased during colon tumor progression and contributes to metastasis; thus, Src inhibitors may have efficacy in the treatment of advanced-stage colon cancer. AZD0530 is a potent, orally available Src/Abl kinase inhibitor currently in clinical trials. Methods: We examined the effects of AZD0530 alone and in combination with oxaliplatin on two colon tumor cell lines, KM12L4 and LS174T in vitro and in orthotopic nude mouse models. AZD0530 inhibits in vitro proliferation and cellular migration of KM12L4 and LS174T, and decreases phosphorylation of the Src substrates FAK and paxillin in a dose- dependent manner. To examine the ability of AZD0530 to affect colon cancer growth and metastasis in a nude mouse model, we inoculated 1x106 cells into the cecum of nude mice. After 2 weeks, mice were treated with vehicle (n=12), AZD0530 alone (n=13; 25mg/kg/day by oral gavage), oxaliplatin alone (n=13; 5mg/kg/day twice weekly), or AZD0530 and oxaliplatin (n=13). Mice were sacrificed after 4 weeks of treatment. Results: Tumor incidence in all groups of mice was greater than 80%. Mice treated with AZD0530 had an average cecal tumor weight of 0.26 g compared with 0.32 g for control (P=0.24). In contrast, the incidence of liver metastases was reduced by 50% in mice treated with AZD0530 alone or oxaliplatin alone, and no mice developed pathologically evident liver metastases when the combination of inhibitors was used. Furthermore, in mice that developed liver metastases, AZD0530 decreased the size of these metastases 9-fold compared with control. Immunohistochemical analysis of primary cecal tumors demonstrated a decrease in phosphorylated Src (Y418) and FAK (Y861) in AZD0530-treated mice compared with control. Conclusions: These results support further investigation of AZD0530, both alone and in combination, as a new therapeutic strategy for the treatment of advanced colon cancer. No significant financial relationships to disclose.

Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: Inhibition of matrix metalloproteinases in pancreatic cancer

Background Matrix metalloproteinases (MMP) are proteolytic enzymes which degrade the extracellular matrix and therefore play an important role in metastasis. However, the impact of MMP inhibitors (MMPI) on pancreatic cancer is still unclear. Thus we evaluated the influence of selective MMPI Ro 28-2653 on the incidence of liver metastases and the concentration of MMP-2 and MMP-9 in ductal pancreatic adenocarcinoma in Syrian hamster. Material and methods One hundred and thirty male Syrian hamsters were randomised into 8 groups (Gr.1–3: n = 15 , Gr.4–8: n = 17 ). Pancreatic cancer was induced by weekly subcutaneous injection of 10 mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight (Gr.4–8) while healthy control Gr. 1–3 received 0.5 ml sodium chloride 0.9%. Gr.1 and 4 had free access to a standard diet, Gr. 2, 3 and 5–8 received a diet rich in polyunsaturated fatty acids, which increases liver metastasis in this model. In week 17 oral therapy started: Gr.3 and 6: 60 mg Eudragit/kg body weight/d (vehicle of MMPI), Gr.7 and 8: 40 mg, respectively, 120 mg RO 28-2653/kg body weight/d; Gr.1, 2, 4, 5: no therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP-2 and MMP-9 were measured in non-metastatic liver and liver metastases. Results Concentrations of MMP-2 and MMP-9 in liver metastases were decreased by high- and low-dose therapy with MMPI. Furthermore, the incidence of liver metastases was significantly reduced by low-dose therapy with Ro 28-2653. Conclusion Low-dose therapy with Ro 28-2653 decreased liver metastasis due to an inhibition of MMP-2 and MMP-9 concentration in ductal pancreatic cancer.

Impact of polyunsaturated fatty acids on hepato-pancreatic prostaglandin and leukotriene concentration in ductal pancreatic cancer—Is there a correlation to tumour growth and liver metastasis?

Type and composition of polyunsaturated fatty acids (PUFAs) are suspected to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 PUFAs on tumour growth, liver metastasis and concentration of prostaglandins (PG) and leukotrienes (LT) in experimental ductal pancreatic adenocarcinoma. Ninety male hamsters were randomised into six groups (Gr.) ( n = 15 ). While Gr. 1–3 were healthy control groups, Gr. 4–6 weekly received subcutaneous injections of 10 mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight for 12 weeks in order to induce ductal pancreatic adenocarcinoma. Between week 1 and 16 all animals were fed with a standard diet with a raw fat content of 2.9%. In week 17 Gr. 1–6 were allocated to three types of diets: Gr. 1: standard high fat (=SHF diet, rich in n-6 PUFAs)/Gr. 2: FISH-OIL (rich in n-3 PUFAs)/Gr. 3: SMOF (=mixture of n-3, n-6 and n-9 PUFAs)/Gr. 4: BOP+SHF/Gr. 5: BOP+SMOF/Gr. 6: BOP+FISH-OIL. After 32 weeks all animals were sacrificed and pancreas as well as liver were analysed histologically. Furthermore pancreatic and hepatic concentrations of prostaglandins (PGF1 α, PGE 2) and LT were measured. FISH-OIL decreased number of macroscopically visible pancreatic tumours (Gr. 4–6: 54.5% vs. 45.5% vs. 9.1%, P < 0.05 ) as well as incidence of liver metastasis (Gr. 4–6: 90.9% vs. 72.7% vs. 36.4%, P < 0.05 ). Furthermore concentration of PGF 1 α , PGE 2 and LT were significantly increased in pancreatic carcinoma compared to tumour-free tissue. Moreover levels of PGF 1 α and PGE 2 were higher in liver metastasis than in extrametastatic hepatic tissue. However, in Gr. 6 (FISH-OIL) intrametastatic concentration of LT was significantly lower than in non-metastatic hepatic tissue as well as in Gr. 4 and Gr. 5. FISH-OIL decreased number of visible pancreatic tumours and incidence of histological proven liver metastasis. This effect might be caused by a decrease of intrametastatic concentration of LT compared to extrametastatic hepatic tissue.

Mouse Colon Carcinoma Cells Established for High Incidence of Experimental Hepatic Metastasis Exhibit Accelerated and Anchorage-Independent Growth

Highly metastatic variants of mouse colon 38 colon carcinoma cells were established by repeated selection in vivo for liver metastasis and designated as SL4 cells. The SL4 cells formed colonies in the liver of 100% of syngenic mice when injected intrasplenically, while the incidence of liver metastasis was 27% of mice injected with parental cells. The weight of livers, which is an indicator of experimental hepatic metastasis formation, was significantly higher after intrasplenic injection and subsequent splenoctomy with SL4 cells than colon 38 cells. The incidence of hepatic metastasis after intracecal injection of SL4 cells was significantly higher than that of colon 38 cells. The SL4 cells were tested in vitro for their properties. Differences were not detected in the motility and invasive behavior between colon 38 cells and SL4 cells. SL4 cells showed a higher proliferation rate than colon 38 cells under adherent conditions. SL4 cells maintained a capacity to proliferate under non-adherent conditions whereas parental cells did not. SL4 cells should be a useful tool to study the mechanism of hepatic metastasis of colon carcinoma cells and to develop methods to prevent hepatic metastasis.

Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter, and GABA receptors have been recently detected on epithelial colon cancer cells. Nembutal (pentobarbital) is a barbiturate with GABA-agonistic effects. We demonstrate that GABA receptors are present on colon cancer cell lines (KM12SM, HT29, RKO). Nembutal (0.1-500 ?g/ml) continuous exposure resulted in an IC50 level of 58 ?g/ml for the KM12SM cells and 120 ?g/ml for the HT29 cells. Nembutal reduced cellular cAMP concentration in colon cancer cells and resulted in a dose and time dependent decrease in MMP-2 and MMP-9 levels. In the KM12SM intracecal injected mice, 9 of 10 mice in the metaphane group developed a primary tumor (mean weight =2.16g + 0.76) compared to 7 of 10 mice in the nembutal group (mean weight = .41g + 0.21, p=0.03). In the KM12SM intrasplenic injected mice, the tumor weight in the spleen was 85% smaller in the nembutal group compared to the metaphane group (p=0.008). In the HT29 injected mice, the metaphane group and nembutal group had similar tumor incidence, but combined tumor weight (primary tumor and liver metastases) was significantly higher in the metaphane group (1.61+ 0.45g) versus 0.07+ 0.05g; p=0.008. The incidence of liver metastases in the nembutal group was zero compared to eight out of nine in the metaphane group. To the best of our knowledge, this is the first evidence that nembutal is a potent inhibitor of primary colon cancer and metastasis. These findings may have therapeutic implications for the treatment of colon and other cancers.

Endometrial carcinosarcomas have a different prognosis and pattern of spread compared to high-risk epithelial endometrial cancer

Objective The endometrial origin of uterine carcinosarcoma has recently been well established. The current study investigates whether uterine carcinosarcomas can be included in protocols on high-risk endometrial cancer, given the similarities in biologic behavior of both entities. Methods Pathological and surgical notes of patients diagnosed with grade 3 endometrioid, carcinosarcoma, serous and clear cell endometrial cancer subtypes were retrospectively analyzed with special attention to the spread pattern of the different subtypes. Information on site of relapse and time to recurrence was obtained. Results We traced 146 patients of which 9 patients were ineligible. Histological subtypes of the remaining 137 patients were as follows: 50 (37%) grade 3 endometrioid carcinoma, 54 (39%) serous or clear cell carcinoma (non-endometrioid carcinoma), and 33 (24%) carcinosarcomas. Distribution of early stage disease (I and II) was 67, 46, and 78% for grade 3 endometrioid, non-endometrioid, and carcinosarcoma, respectively. Although we could not trace differences in hematogenic and transperitoneal spread among the three subtypes, non-endometrioid and carcinosarcomas were more likely to spread to pelvic and paraaortic lymph nodes ( P < 0.01). Using univariate analysis, both stage ( P < 0.006, Wald statistic) and histological type appear to determine the outcome, whereas lymphovascular space infiltration ( P < 0.25) and age ( P < 0.07) were not significantly different between the three histological subtypes. Cox Regression multivariate analysis on 127 women suffering from the three histological subtypes suggested that both stage III–IV disease ( P < 0.00001) and histological type (carcinosarcoma) ( P < 0.003) were of prognostic significance [hazard ratio (CI 95%) were, respectively, 3.8 (2.1–7.0) and 3.2 (1.7–5.9)]. Analyzing cases limited to stage I–II endometrial cancer, 24/28 (86%) grade 3 endometrioid, 18/24 (75%) non-endometrioid, and 11/25 (44%) carcinosarcomas survived, suggesting a worse outcome for endometrial carcinosarcoma when compared to the other subtypes ( P < 0.008, Log Rank). A higher incidence of pulmonary metastases explained the worse outcome for early stage carcinosarcoma ( P < 0.006), whereas the incidence of liver metastasis, transperitoneal spread, or recurrences in lymph nodes or vagina were comparable between the three pathologic subtypes. Conclusions Although endometrial carcinosarcoma originates from epithelial cancer, the intrinsic more aggressive tumor biology suggests that this subtype should not be incorporated in studies on high-risk epithelial endometrial cancer.

Therapy for Colorectal Cancer

Recent advances in systemic therapy involve the biochemical modulation of fluorouracil. New trials combining either leucovorin or N-(phosphonoacetyl)-L-aspartate (PALA) with fluorouracil have demonstrated increased response rates. Recent trials of interferon-alpha with fluorouracil have not confirmed the high response rates reported in previous trials. Advances in regional therapy include the addition of either leucovorin or systemic therapy to fluorodeoxyuridine. Some adjuvant trials of portal vein infusion have shown increased survival, though the incidence of liver metastases was not decreased. A large adjuvant trial in rectal cancer demonstrated improved survival and decreased local recurrences when fluorouracil and methyl-CCNU were added to radiation therapy.

Effect of SU5416 on the inhibition of growth and metastasis of human gastric cancer implanted in nude mice

OBJECTIVE: To study the effects of the angio­genesis inhibitor SU5416 on the growth and liver metastasis of gastric cancer and to investigate its effects on the apoptosis of gastric cancer cells.METHODS: A model simulating the metastasis of human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into the gastric wall of nude mice, which were randomly divided into four groups: control group (saline solution), 5‐FU group (fluorouracil 30 mg/kg per day i.p), SU5416 group (SU5416 15 mg/kg per day i.p.), and combined treatment with 5‐Fu and SU5416. Eight weeks after implantation, the tumor weight, inhibition rate, intratumoral microvessel density (MVD), apoptotic index (AI), and the status of metastasis were evaluated after the mice were killed.RESULTS: Compared with the control group, the growth of the orthotopically‐implanted tumors was significantly inhibited, with reduced weight, and the tumor inhibition rate was 44.5%, 79.3%, and 84.4%, respectively, in the mice treated with 5‐FU, SU5416 and both. The incidence of liver metastasis was also significantly decreased in the 5‐Fu, SU5416, and combination groups compared with the control group (36.4%, 25.0%, and 0% vs 90.0%). The MVD of the 5‐FU group, the SU5416 group and the combined group was 13.1 ± 4.7, 3.9 ± 1.8 and 2.1 ± 1.5, respectively, which was decreased significantly compared with the control group (14.6 ± 5.8). The AI was increased significantly in the treated mice (6.81 ± 4.92%, 9.82 ± 3.76% and 17.65 ± 9.85% vs 3.76 ± 2.25%). The growth of and liver metastasis of the human gastric cancer implanted in the nude mice were both more significantly inhibited in the SU5416 group and the combined group than in the control and 5‐FU groups (P &lt; 0.05).CONCLUSIONS: SU5416 can induce apoptosis in gastric cancer by inhibiting tumor angiogenesis and has a strong inhibitory effect on both the growth and liver metastasis of gastric cancer implanted in nude mice. The combination of SU5416 with other cytotoxic agents is more effective.

25: Incidence of Liver Metastases in Patients Receiving Adjuvant Chemotherapy After Lymph Node Positive Primary Colon Cancer

25: Incidence of Liver Metastases in Patients Receiving Adjuvant Chemotherapy After Lymph Node Positive Primary Colon Cancer

Liver metastasis at the time of initial diagnosis of lung cancer.

In order to evaluate clinicopathological features associated with liver metastases from lung cancer, we reviewed our experience of lung cancer patients seen in our division. Of the 1073 lung cancer patients diagnosed between October 1976 and May 2002, 62 (5.8%) patients had liver metastasis. The incidence of liver metastasis was 17.5% in small-cell lung cancer (SCLC) patients, whereas the incidence in non-small-cell lung cancer patients was 3.8%. Of the 62 patients, 17 had sole liver metastasis, and the remaining 45 had synchronous spread to the liver and one or more other organs. Six of 12 squamous cell carcinoma patients and 10 of 28 SCLC patients had sole liver metastasis. However, 19 of 20 adenocarcinoma patients showed liver metastasis with one or more other organs. In morphological liver metastasis, 26 of the 28 SCLC patients had multiple nodules, whereas 16 of the 34 non-small-cell lung cancer patients had a solitary liver nodule (p = 0.0006). Liver is a possible site of extrathoracic spread of disease for some patients with lung cancer, especially with SCLC. When the histological types are squamous cell carcinoma or SCLC, it would also be considered likely that an isolated liver mass represents a metastasis even though there is no metastatic disease elsewhere.

Inhibition of liver metastasis from orthotopically implanted colon cancer in nude mice by transfection of the TIMP-1 gene into KM12SM cells.

To determine whether the tissue inhibitor of metalloproteinases 1 (TIMP-1) can modulate in vivo tumor growth and metastasis, we transfected TIMP-1 cDNA into KM12SM human colon carcinoma cells and determined the implanted tumor volume and incidence of liver metastasis in orthotopically implanted colon cancer in nude mice. We also treated the implanted tumors with repeated intraperitoneal injections of recombinant human TIMP-1 (rTIMP-1), and compared the inhibitory efficacy on liver metastasis with that achieved by the TIMP-1 transfectants. The TIMP-1 transfectants had a significantly greater inhibitory effect, in association with TIMP-1 expression, on the growth of the primary tumor and on liver metastasis as compared with the controls. However, the intraperitoneal administration of rTIMP-1 did not decrease the rate of liver metastasis. In situ hybridization demonstrated that TIMP-1 mRNA in the cecal tumors implanted with the highly produced KM12SMT-2 cells with TIMP-1 was mainly expressed by the tumor cells. These results suggest that the increased expression of TIMP-1 in KM12SM cells was responsible for their decreased metastatic potential, and that the endogenous increase in TIMP-1 production by the tumor cells might be more effective for counteracting the matrix metalloproteinases (MMPs) in tumor tissue and for inhibiting liver metastasis from colon cancer than the exogenous administration of TIMPs.

The impact of laparoscopic biopsy of pancreatic lymph nodes on lipid peroxidation using helium and carbon dioxide in BOP-induced pancreatic cancer in hamsters.

Increased lipid peroxidation is believed to stimulate liver metastasis in pancreatic cancer. However, the effect of the laparoscopic biopsy of pancreatic lymph nodes on liver metastasis is still unknown. We hypothesized that the effects of a pneumoperitoneum with carbon dioxide (CO2) increase lipid peroxidation and stimulate liver metastasis. Ductal pancreatic adenocarcinoma was induced in Syrian hamsters (n = 30) by weekly subcutaneous injections of N-nitrosobis-2-oxopropylamine (BOP) for 12 weeks. In group 1, a laparotomy and biopsy of pancreatic lymph nodes was performed. Groups 2 and 3 underwent laparoscopic biopsy with either CO2 or helium. In the 5th postoperative week, the hamsters were killed and the incidence of liver metastasis was analyzed histopathologically. We then made determinations of the level of lipid peroxidation (thiobarbituric acid-reactive substances [TBARS])as well as the activity of glutathionperoxidase (GSH-PX) and superoxidismutase (SOD) in pancreatic carcinoma and liver metastases of the animals. The incidence of liver metastasis was higher in the CO2 group (60%) than in the helium (30%) and laparotomy groups (20%) (p < 0.05). The concentration of TBARS was greater in pancreatic carcinoma and intrametastatic hepatic tissue than in extratumorous pancreatic and extrametastastic hepatic tissue in all groups. Extrametastatic hepatic concentration of TBARS was higher in the CO2 group (19.4 +/- 0.88 nmol/mg protein) than the laparotomy (10.66 +/- 0.95 nmol/mg protein) and helium groups (10.79 +/- 0.58 nmol/mg protein). GSH-PX and SOD activity was significantly lower in pancreatic carcinoma tissue and intrametastatic hepatic tissue than in extratumorous pancreatic and extrametastatic hepatic tissue. However, in the CO2 group (1.24 +/- 0.48 107 U/mg protein), extrametastatic GSH-PX activity was lower than in the laparotomy (1.73 +/- 0.4 107 U/mg protein) and helium groups (1.63 +/- 0.28 107 U/mg protein). After laparoscopic biopsy of pancreatic lymph nodes in the CO2 group, lipid peroxidation was increased and GSH-PX activity was decreased in extrametastatic hepatic tissue compared to the intrametastatic sections. This mechanism may be responsible for the increased liver metastasis in the CO2 group.

Rare occurrence of metastatic colorectal cancers in livers with replicative hepatitis B infection

Background: It has been demonstrated that colorectal carcinomas rarely metastasize to diseased livers. However, this phenomenon has not been thoroughly evaluated in patients with various forms of chronic hepatitis B virus (HBV) infection. Therefore, the present study examined the relationship between the incidence of hepatic metastasis of colorectal carcinomas and chronic HBV infection, with emphasis on the influence of HBV viral replication and chronic liver damage. Methods: We analyzed the clinicopathological data of 512 patients undergoing surgical treatment of colorectal carcinomas at our department from 1992 to 1998. Among these cases, 74 had chronic HBV infection, including 28 cases with HBV replication and 21 with chronic liver damage. Results: The incidence of liver metastasis in the HBV infection group (13.5%) was significantly lower than that of the noninfection group (27.1%, P <0.05). In addition, patients with HBV infection survived longer than those without infection ( P = 0.018). Furthermore, liver metastatic rate in patients with HBV replication (3.6%) was lower than those without virus replication (19.6%, P <0.05). In contrast, there was no significant difference in liver metastasis between HBV infected patients with or without chronic liver damage ( P >0.05). Conclusions: Chronic HBV infection with viral replication reduces hepatic metastasis of colorectal cancer, and thus prolongs the survival of patients.

Imbalance between Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinases 1 Expression by Tumor Cells Implicated in Liver Metastasis from Colorectal Carcinoma.

We have evaluated the degree of MMP-9 and TIMP-1 messenger RNA (mRNA) expressions according to cell types in tumor tissues, and evaluated the implication of balance between the MMP-9 mRNA and the TIMP-1 mRNA expression in liver metastasis using orthotopic-implanted colon cancer in nude mouse, and also in 47 patients with colorectal cancer. The grade of MMP-9 or TIMP-1 mRNA expression was classified into 4 categories according to positive cell ratio. A higher grade of MMP-9 mRNA expression in tumor cells was correlated with liver metastasis in the experimental colon cancer, but was not statistically correlated in the clinical colorectal cancer. In contrast, the expression of TIMP-1 mRNA in the stromal cells of human colorectal cancer was correlated with liver metastasis. In both experimental and clinical colorectal cancer, a balance between the expression of MMP-9 mRNA and that of TIMP-1 mRNA was correlated with the occurrence of liver metastasis. The imbalance of MMP-9 dominance in tumor cells was implicated in liver metastasis. However, there was no significant relationship between the incidence of liver metastasis and the expression patterns of MMP-9 and TIMP-1 mRNA in the stromal cells. These results suggest that the balance between the expressions of MMP-9 and TIMP-1 in the tumor cells is more closely related to tumor biological behavior rather than the balance in the stromal cells.