Liver regeneration stimulates tumor metastases

BACKGROUND: Partial hepatectomy for patients with colorectal liver metastases is associated with a tumor recurrence rate approaching 80% post-resection. Different factors and phases associated with regeneration of the liver are implicated in tumor recurrence. This study investigates the effects of the early and late phases of liver regeneration and the impact of the degree of liver resection on stimulating tumor growth and metastasis. MATERIALS AND METHODS: Groups of mice underwent partial hepatectomy (37% or 70%) and were then challenged with colorectal liver carcinoma (CRC) tumors immediately after liver resection (early and late phase effect) or 6 days post liver resection (late phase effect). Tumor growth, degree of proliferation, tumor morphology, and the presence of extrahepatic metastases were investigated 21 days post-tumor induction. RESULTS: The late phase of liver regeneration plays a significant role in tumor stimulation and metastasis. The degree of hepatectomy also appears to be an important factor. The degree of hepatic resection significantly influences tumor growth and the extent of extrahepatic metastases, particularly in the lungs. CONCLUSIONS: Elucidation of the processes involved in the late phase of liver regeneration may assist in the development and timing of adjuvant agents to minimize tumor recurrence during this phase.     

Interval Period Tumor Progression: Does Delayed Hepatectomy Detect Occult Metastases in Synchronous Colorectal Liver Metastases?

Background  Rapid remnant liver recurrence in patients with synchronous colorectal liver metastases (CRLM) is occasionally experienced after simultaneous colorectal and liver resection. We evaluated the tumor progression during interval periods to determine whether delayed hepatic resection detects occult metastases. Methods  One hundred thirty-seven patients underwent hepatectomy for synchronous CRLM. Up to 2003, 116 patients underwent simultaneous colorectal and hepatic resection. From 2004 onward, we identified 21 patients undergoing delayed hepatectomy for synchronous CRLM. The tumor progression during interval was determined by a dynamic computed tomography scan. Results  Median/mean interval between the two evaluations prior to the first and second surgery was 2/2.4 months. The median/mean number of metastases detected at each evaluation was 2/3.3 and 3/4.6, respectively. Nine of the 21 (43%) patients had new detectable metastatic lesions after reevaluation. For 11 of the 21 patients, it was necessary to reconsider planned surgical procedure which was determined prior to colorectal surgery. Hepatic disease-free survival was significantly different between patients undergoing delayed and simultaneous hepatectomy. Multivariate analysis showed that the delayed hepatectomy was a significant independent prognostic factor in hepatic disease-free survival. Conclusion  Tumor progression was recognized and occult metastases were detected after the interval reevaluation. Delayed hepatectomy may be a useful approach to reduce rapid remnant liver recurrence in synchronous CRLM.     

Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases--activation of cell invasion and migration pathways.

Elucidating the mechanism of liver tumor growth and metastasis after hepatic ischemia-reperfusion (I/R) injury of a small liver remnant will lay the foundation for the development of therapeutic strategies to target small liver remnant injury, and will reduce the likelihood of tumor recurrence after major hepatectomy or liver transplantation for liver cancer patients. In the current study, we aimed to investigate the effect of hepatic I/R injury of a small liver remnant on liver tumor development and metastases, and to explore the precise molecular mechanisms. A rat liver tumor model that underwent partial hepatic I/R injury with or without major hepatectomy was investigated. Liver tumor growth and metastases were compared among the groups with different surgical stress. An orthotopic liver tumor nude mice model was used to further confirm the invasiveness of the tumor cells from the above rat liver tumor model. Significant tumor growth and intrahepatic metastasis (5 of 6 vs. 0 of 6, P=0.015), and lung metastasis (5 of 6 vs. 0 of 6, P=0.015) were found in rats undergoing I/R and major hepatectomy compared with the control group, and was accompanied by upregulation of mRNA levels for Cdc42, ROCK (Rho kinase), and vascular endothelial growth factor, as well as activation of hepatic stellate cells. Most of the nude mice implanted with liver tumor from rats under I/R injury and major hepatectomy developed intrahepatic and lung metastases. In conclusion, hepatic I/R injury of a small liver remnant exacerbated liver tumor growth and metastasis by marked activation of cell adhesion, invasion, and angiogenesis pathways.     

Treatment strategy for hepatic metastases of colorectal cancer

Over the past 25 years, 125 patients with colorectal liver metastases underwent 167 hepatectomies in our department. The 1-, 3-, and 5-year survival rates after the initial hepatectomy were 90%, 58%, and 51%, respectively, and those after repeated hepatectomy were 88%, 60%, and 42%, respectively. The predictive factors significantly associated with poor prognosis after initial hepatectomy were maximal diameter of metastasis (> or = 5 cm), distribution pattern in the liver (multiple bilobar), number of nodules (> or = four), and presence of extrahepatic metastases. A disease-free interval of > 6 months after initial hepatectomy was a significant factor for prolongation of survival after repeat hepatectomy. Patients with hilar node metastases at the initial hepatectomy did not receive a survival benefit from hepatectomy, while 5 patients underwent repeat hepatectomy with lymphadenectomy for remnant liver and hilar node metastases with a disease-free interval of > 8 months and 4 of them survived for > 5 years. Our treatment strategies for colorectal hepatic metastases are as follows: 1) hepatectomy is the first choice for < 4 liver metastases without extrahepatic disease; 2) a careful evaluation for liver resection is performed for patients with > or = 4 liver metastases receiving hepatic arterial infusion chemotherapy because of the high frequency of hepatic and/or extrahepatic recurrence after initial hepatectomy; 3) the presence of hilar node metastases at the initial hepatectomy should be excluded from surgical indications; 4) simultaneous single metastasis limited to the lung is an indication for lung resection; and 5) a suitable indication for repeat hepatectomy for hepatic recurrence is patients with a longer disease-free interval. Aggressive surgery based on the optimum patient selection can contribute to clinical benefit, including long-term survival in patients with colorectal liver metastases.     

Inhibition of hepatic DNA synthesis after partial hepatectomy in the rats with obstructive jaundice with special reference to the enhancement of hepatic protein synthesis

We studied the liver regeneration after partial (68%) hepatectomy in rats with obstructive jaundice followed by the relief of obstruction. Rats received bile duct ligation, then 5 or 14 days later choledocho-duodenostomy was performed. Partial hepatectomy was done at various intervals after the relief of obstruction. DNA synthesis of the regenerating liver, hepatic protein synthesis and mitochondrial swelling induced by exogenous phospholipase A2 (PLA2) were determined. Hepatic DNA synthesis was significantly inhibited in obstructive jaundiced rats compared to controls. While the inhibition disappeared 5 days after the relief of obstruction in 5-day-obstructed group, it was still detectable as late as 21 days after the drainage in 14-day-obstructed group. Hepatic protein synthesis was markedly increased by obstructive jaundice, and this increase continued until 10 days after drainage in 14-day-obstructed group. Partial hepatectomy also increased the hepatic protein synthesis significantly in normal rats, but failed to show any significant changes in obstructive jaundiced rats. Any difference could not be found in PLA2-induced hepatic mitochondrial swelling between obstructive jaundiced rats and normal rats. We concluded the preceding energy-requiring responses in obstructive jaundiced liver resulted in the reduction of hepatic DNA synthesis and in the lack of additional increase of hepatic protein synthesis as the responses to a further insult of partial hepatectomy.     

Analysis of predictive factors for recurrence after hepatectomy for colorectal liver metastases

Hepatectomy for liver metastases from colorectal cancer has recently received general acceptance as a safe, potentially curative treatment. Most patients, however, die of recurrent disease after hepatectomy. The predictive factors for recurrence after first resection of liver metastases have not yet been clarified. The authors aimed to determine the factors that can predict recurrence, especially hepatic-only recurrence after hepatectomy for colorectal liver metastases. Seventy-six patients who underwent liver resection of colorectal metastases were studied retrospectively. Forty-seven (61.8%) of the patients had a recurrence. The patients' disease-free survival after first hepatectomy and the second recurrence sites were univariately and multivariately analyzed using 16 clinicopathologic variables. Wall invasion, lymph node metastases, lymphatic invasion, venous invasion of the primary tumor, 24 months or longer disease-free interval after resection of the primary colorectal cancer, and bilateral liver metastases significantly influenced the disease-free survival (log-rank test: p < 0.05). The multivariate analysis revealed that venous invasion of the primary tumor and bilateral hepatic metastases were independent risk factors for recurrence after hepatectomy. The liver was the only site of second recurrence in 23 patients. Patients with lymph node metastases and venous invasion of the primary tumor had a significant difference between hepatic-only and extrahepatic recurrence after first hepatectomy (chi-square test or Fishers' exact test: p < 0.05). Recurrence after hepatectomy was influenced more by factors associated with the primary colorectal cancer than factors surrounding the first liver metastases. Venous invasion of the primary colorectal cancer was the most important predictable factor for hepatic-only second recurrence.     

Prognostic significance of entrapped liver cells in hepatic metastases from colorectal cancer

OBJECTIVE: To correlate the microscopic finding of entrapped liver cells in hepatic metastases from colorectal cancer with outcome after hepatectomy. SUMMARY BACKGROUND DATA: Reliable histopathologic prognostic factors in resected liver metastases from colorectal cancer have not been identified. METHODS: Seventy-one patients undergoing radical hepatectomy for liver metastases were assigned to rare (n = 36) or frequent (n = 35) groups according to the microscopically observed frequency of hepatocyte entrapment in the tumor. RESULTS: Five-year survival rates after hepatectomy were 44. 4% for the rare group and 27.2% for the frequent group. Multivariate analysis using the Cox proportional hazards model by a stepwise method identified this morphologic variable as a significant independent prognostic factor. CONCLUSIONS: The finding of entrapped liver cells in metastases from colorectal cancer reflects the biologic activity of the tumor and may be a useful prognostic indicator.     

Surgical management of recurrence after resection of colorectal liver metastases

The optimal treatment for recurrent lesions after hepatectomy for colorectal liver metastases is controversial. We report the outcome of aggressive surgery for recurrent disease after the initial hepatectomy and the influence on quality of life of such treatment. Forty-five (70%) of the 64 surviving patients developed recurrence after the initial hepatectomy for liver metastases. The determinants of hepatic recurrence were the distribution and the number of liver metastases. Twenty-eight (62%) of patients with recurrence underwent resection. A second hepatectomy was performed in 20 patients, and a third hepatectomy was done in 5 patients. Ten patients with pulmonary metastasis underwent partial lung resection on 14 occasions, while resection of brain metastases was performed in 3 patients on 5 occasions. There were no operative deaths after resection of recurrent disease. The morbidity rate was 28% after repeat hepatectomy, 21% after pulmonary resection, and 0% after resection of brain metastasis. The Karnofsky performance status (PS) after the last surgery was not significantly different from that after the initial hepatectomy. The 3- and 5-year survival rates after the second hepatectomy were 54% and 14%, respectively. The 3-and 5-year survival rates of the patients undergoing resection of extrahepatic recurrence were both 17%. The survival rate after resection of recurrent disease (n=28) was significantly better than that of patients (n=17) with unresectable recurrence (P < 0.05). For the 66 patients with colorectal liver metastases, the 5-year survival rate after initial hepatectomy was 50%. The distribution and the number of liver metastases and the presence of extrahepatic disease, as single factors, significantly affected prognosis after the initial hepatectomy. Multivariate analysis revealed that only the presence of extrahepatic metastasis and a disease-free interval of less than 6 months were independent predictors of survival after the initial and second hepatectomy, respectively. It is concluded that aggressive surgery is an effective strategy for selected patients with recurrence after initial hepatectomy. Careful selection of candidates for repeat surgery will yield increased clinical benefit, including long-term survival.     

Hepatic Resection for Metastatic Renal Tumors: Is It Worthwhile?

Background: Liver metastases of malignant renal tumors are regarded as having an ominous prognosis because they are infrequently amenable to radical surgery and respond poorly to chemotherapy. Little is known of the outcome of isolated metastases to the liver for which resection is potentially curative.Methods: Data on 14 patients with liver metastases from renal tumors who underwent a liver resection in a single center between 1982 and 2001 were analyzed retrospectively.Results: There was no operative or postoperative mortality. The median survival was 26 months, with a survival rate of 69% at 1 year and 26% at 3 years. The curative pattern of hepatectomy (2-year survival, 69% vs. 0%; P = .001), an interval between the nephrectomy and the diagnosis of liver metastases in excess of 24 months (2-year survival, 71% vs. 25%; P = .05), tumor size <50 mm (2-year survival, 83% vs. 17%; P = .006), and the possibility of achieving a repeat hepatectomy in the case of recurrence (2-year survival, 100% vs. 21%; P = .02) were associated with a better outcome after the liver resection. Four patients were alive without evidence of disease at 6, 12, 26, and 96 months after the first hepatic resection, and one was alive with hepatic recurrence 18 months after resection.Conclusions: In patients with liver metastases of malignant renal tumors, an aggressive policy for achieving tumor eradication seems to offer a chance for long-term survival, especially after a long disease-free interval from the nephrectomy. However, despite an aggressive policy for achieving tumor eradication, recurrence frequently occurs after liver resection.     

Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases

Background

Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans.

Staging and indications for hepatectomy in hepatic metastases of colorectal cancer

Factors adversely affecting prognosis after hepatectomy for hepatic metastases include residual tumor, hepatic lymph node metastases, satellite metastases, extrahepatic metastases, four or more hepatic metastases, resection margins of less than 10 mm, and carcinoembryonic antigen and carbohydrate antigen 19-9 values higher than normal preoperatively and 1 month postoperatively. As no significant differences were observed in terms of the H-number stipulated by the Japanese Classification of Colorectal Carcinoma, a new staging system based on the number of lymph node metastases from the primary lesion, the number of liver metastases number, and the size of metastatic tumors was developed. The proposed staging system appears to be useful in predicting the prognosis of patients with metastatic liver tumors from colorectal cancer. Favorable patient selection criteria for liver resection are: 1) medical fitness for hepatectomy; 2) radical resection of the primary colorectal lesion; 3) metastatic tumors anatomically confined within the liver allowing adequate preservation of the liver parenchyma; 4) no signs of disseminated disease; 5) no signs of hepatic lymph node metastases; 6) four or fewer metastatic tumors; and 7) resection margins of 10 mm or greater. Unilobar or bilobar disease with multiple lesions is not a significant prognostic factor.     

Aggressive surgery for liver metastases from gastrointestinal stromal tumors

Background/Purpose. The utility of hepatectomy for patients with metastatic liver tumors from gastrointestinal stromal tumors (GISTs) was evaluated in the present study. Methods. Between 1989 and 2001, ten patients with liver metastases from GIST (four men and six women; age, 34–77 years) underwent hepatectomy at our hospital. All patients underwent complete resection of the primary tumor and hepatectomy with or without microwave coagulation therapy (MCT) for all detectable hepatic tumors. Results. The median survival time after hepatectomy was 39 months (range, 1 to 96 months). There was one postoperative death. One patient is still alive with relapse of hepatic tumors, and the remaining eight patients died of disease (liver in six, peritoneum in one, and bone in one). Relapse of hepatic tumors occurred in seven patients. The disease-free rate after hepatectomy was 22% at 2 years and 11% at 5 years. The survival times of the four patients who received hepatic arterial chemoembolization for recurrent hepatic metastases were 7 months (still alive), 17, 23, and 28 months (average, 19 months). Conclusions. Our data suggest that aggressive surgery (hepatectomy and MCT) for all detectable hepatic tumors and hepatic arterial chemoembolization for recurrent hepatic metastases improve survival. Received: March 31, 2002 / Accepted: September 24, 2002 RID="*" ID="*" Offprint requests to: Y. Shima     

Liver transplantation for metastatic neuroendocrine tumors.

OBJECTIVE: This article describes the experience with liver transplantation in patients with irresectable neuroendocrine hepatic metastases. SUMMARY BACKGROUND DATA: Liver transplantation has become an established therapy in primary liver cancer. On contrast, there is little experience with liver transplantation in secondary hepatic tumors. So far, in the majority of patients being transplanted for irresectable liver metastases, long-term results have been disappointing because of early tumor recurrence. Because of their biologically less aggressive nature, the metastases of neuroendocrine tumors could represent a justified indication for liver grafting. METHODS: In a retrospective study, the data of 12 patients who underwent liver transplantation for irresectable neuroendocrine hepatic metastases were analyzed regarding survival, tumor recurrence, and symptomatic relief. RESULTS: Nine of 12 patients currently are alive with a median survival of 55 months (range, 11.0 days to 103.5 months). The operative mortality was 1 of 12, 2 patients died because of septic complications or tumor recurrences or both 6.5 months and 68.0 months after transplantation. all patients had good symptomatic relief after hepatectomy and transplantation. Four of the nine patients who are alive have no evidence of tumor with a follow-up of 2.0, 57.0, 58.0, and 103.5 months after transplantation. CONCLUSIONS: In selected patients, liver transplantation for irresectable neuroendocrine hepatic metastases may provide not only long-term palliation but even cure. Regarding the shortage of donor organs, liver grafting for neuroendocrine metastases should be considered solely in patients without evidence of extrahepatic tumor manifestation and in whom all other treatment methods are no longer effective.     

Liver resection for colorectal metastases: the third hepatectomy

OBJECTIVE: To determine the risk, the benefit, and the main factors of prognosis of third liver resections for recurrent colorectal metastases. SUMMARY BACKGROUND DATA: Recurrence following liver resection is frequent after a first as after a second hepatectomy. Second liver resections yield a similar survival to that obtained with first liver resection, but little is known about third hepatectomy. METHODS: This study reports a retrospective analysis of 60 patients who underwent a third liver resection for colorectal metastases in a 16-year experience (1984-2000). Patients were identified from a prospective database that collected 615 consecutive patients who cumulated 883 hepatectomies (615 first, 199 second, 60 thirds, and 9 fourths). Third hepatic resections were compared with first and second procedures, in terms of risk and benefit for the patient. Prognostic factors of survival after third hepatic resection were determined by univariate and multivariate analysis. RESULTS: A third hepatic resection was attempted in 68 of 115 of liver recurrences following a second hepatectomy (59%) and achieved in 88% of the cases (60 of 68). There was no intraoperative mortality or postoperative deaths within the 2 months. Fifteen patients developed postoperative complications (25%), a rate similar to that of first and second hepatectomies. Overall 5-year survival was 32% and disease-free survival was 17% after the third resection. Survival compared favorably to that of patients with recurrence following a second hepatectomy who could not be operated (5% at 3 years) or who failed to be resected (15% at 2 years, P = 0.0001). It also compared favorably to that of patients who underwent only two hepatectomies (5-year survival, 27%). When estimated from the time of first hepatectomy, survival was 65% at 5 years for the 60 patients who underwent three hepatic resections. Concomitant extrahepatic tumor was treated in 16 patients (27%) by 11 abdominal procedures and 5 pulmonary resections. By multivariate analysis, tumor size > 30 mm for first liver metastases, presence of extrahepatic tumor at second hepatectomy, and noncurative pattern of third liver resection were independent prognostic factors of reduced survival. CONCLUSIONS: Third hepatectomy is safe and provides an additional benefit of survival similar to that of first and second liver resections. It is worthwhile when curative and integrated into an intended multimodal strategy of tumoral eradication.     

Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a 15-year single center prospective study

BACKGROUND: The timing and benefits of hepatectomy remain controversial for metastatic well-differentiated endocrine neoplasms, which are generally considered slow growth tumors. However, surveillance alone yields only a 22% 5-year survival when metastases occur. The aim of this study was to determine the results of hepatic and extra hepatic resections and to clarify the indications of surgery. METHODS: To define the role of hepatic resection, a database regrouping all patients (n = 47) who underwent hepatectomy with curative intent (R0 status) for well-differentiated endocrine neoplasms in the Gustave-Roussy Institute was constructed in 1984. New prognostic factors such as tumor growth and liver tumor mitotic index were studied. Median follow-up was 62 months. RESULTS: Hepatectomy was associated with extrahepatic tumor resection in 77% of the patients (primary tumor in 51%, lymph nodes in 21%, peritoneal carcinomatosis in 25%, and other in 6%). Resection was curative (R0) only in 53% of the patients, despite removing at least 97% of the tumor in each patient. Mortality was 5%, and morbidity was 45%. Median survival was 91 months, 5-year and 10-year overall survival rates were 71% and 35%, respectively. Liver recurrence rate was 75% at 10 years. No prognostic factor was correlated with overall survival in this population in which at least 97% of the tumor load was resected. The completeness of surgery, the presence of bilateral liver metastases, the number of liver metastases (>10) and a primary tumor from pancreatic origin were all significantly correlated with the disease-free survival. Preoperative tumor growth rate, mitotic index, and Ki67 expression were not predictive of prognosis. No significant prognostic factors could be found by the comparison of the patients who did and did not recur during the 3 years after hepatectomy. CONCLUSION: Hepatectomy for liver metastases from well-differentiated endocrine neoplasms is indicated when all visible intra- and extra hepatic lesions can be resected safely. The number, size, and localization of the tumor sites are less important than performing a complete (or near-complete) resection.     

持久美蓝染色法在精准肝切除中的应用价值

目的 探讨持久美蓝染色法在精准肝切除中的应用价值.方法 回顾性分析2009年2月至8月解放军总医院对21例肝癌患者采用美蓝染色后行精准肝切除的临床资料.首先在肝门部解剖出拟切除肝段的肝蒂,然而在Glisson鞘内门静脉远端注射美蓝后结扎该段肝蒂,使拟切除肝段染色,按染色的界限行肝段切除.结果 Glisson鞘内注射美蓝染色的成功率为100%,美蓝在拟切除肝段的肝实质内停留(80±23)min.21例患者均行精准肝切除,其中右半肝2例,左半肝1例;右后叶2例,右前叶3例,左外侧叶1例;肝Ⅷ段2例,肝Ⅶ段3例,肝Ⅵ段1例,肝Ⅳ段2例;联合肝段切除4例.平均术中出血量为(236±6)ml,术后并发症发生率为14%(3/21),平均术后住院时间为(12±3)d.结论 注射美蓝后结扎肝蒂的染色方法成功率高,染色时间持久,对肝实质离断过程中的切面选择具有引导作用,有助于提高解剖性肝切除的精准性.     

Establishment of an experimental model with a high frequency of liver metastasis and recurrence from gastric VX2 cancer: histological analysis of the developmental process of primary and metastatic cancer lesions]

An experimental model with a high frequency of liver metastases and recurrence was established by the non-resection and resection of gastric cancer lesions induced with implanting VX2 cancer cells into the stomach of 35 rabbits. The frequency of liver metastases was 0% on Days 7 and 14, 40% on Day 21 and 60% on Day 28 in the non-resection group. In the resection group, primary lesions were resected on Days 7, 10 and 14, and the metastases were found in all the animals 14 days after the resection on Day 14, though they did not occur in every animal 18 and 21 days after the resection on Days 10 and 7. The metastatic lesions were found in the peri-lobular area, accompanied by cancer emboli in the interlobular veins. Vascular invasion was found in almost all (90%) the primary lesions of animals with liver metastases or recurrence. These results suggest that hepatic micrometastases occur between 10 and 14 days after implantation, and that vascular invasion plays an important role in the formation and extension of liver metastases or recurrence. They also suggest that this model is utilized as a useful tool for studying many aspects of liver metastases or recurrence in gastric cancer.     

Effects of prostacyclin on hepatic metastases from human pancreatic cancer in the nude mouse

Human pancreatic cancer is an aggressive malignancy, with systemic metastases ultimately accounting for its grave prognosis. Arachidonic acid metabolites known to affect platelet function also interfere with tumor growth and metastases. We evaluated the effect of prostacyclin on the hepatic metastases of a human pancreatic cancer in a nude mouse model. The mean surface area of tumor on the liver was significantly reduced in all treatment groups. In the control group 485 mm2 of tumor was present on the liver surface. Animals treated with 200 micrograms of prostacyclin 0.5 hr prior to the injection of tumor cells had 21 mm2 of tumor present on the liver surface (P = 0.004). Similarly, 400 micrograms of prostacyclin caused a reduction of tumor surface area to 20 mm2 (P = 0.004). The maximal reduction of tumor surface area, 11 mm2, was observed when 200 micrograms of prostacyclin was given 0.5 hr prior to and 4.0 hr after the injection of tumor cells (P = 0.003). For the group given 200 micrograms of prostacyclin 4.0 hr after the injection of tumor, the surface area of tumor was 85 mm2 (P = 0.017). The number of tumor colonies on the liver surface was significantly reduced from 20 to 11 when 200 micrograms of prostacyclin was administered intraperitoneally 0.5 hr before and 4.0 hr after the injection of tumor cells (P = 0.047). These results indicate that prostacyclin has antimetastatic activity on hepatic metastases from a human pancreatic adenocarcinoma in the nude mouse.     

Thrombospondin-1 promotes proliferative healing through stabilization of PDGF

BACKGROUND: Predicting liver metastasis from colon cancer is essential for improving its prognosis. We studied to what extent genetic detection of cancer cells in the resected liver tissue can predict the incidence of macroscopic liver metastasis with a similar mouse model to clinical colorectal cancer that causes a several decade percentage of metachronous hepatic metastases after resection of the primary lesions. MATERIALS AND METHODS: A LS174T human colorectal cancer cell suspension was injected into the spleens of nude mice. One to 10 days after splenic injection, 3 x 3 mm of liver tissue was removed, and a splenectomy was performed. Liver tissue was used for genetic detection and histological examination. Five weeks after splenic injection, the number of macroscopic metastases on the surface of the liver was counted. RESULTS: Eight of the 45 cases were positive for tumor cells in liver tissue genetically, while only 1 was positive for tumor cells histologically. Macroscopic liver metastases were seen 5 weeks after splenic injection in 11 of 37 (29.7%) cases negative for tumor cells genetically and in 8 of 8 (100%) cases positive for tumor cells genetically. Five or more metastases were seen in 3 of 37 (8.1%) cases negative for tumor cells genetically and in 7 of 8 (87.5%) cases positive for tumor cells genetically. CONCLUSIONS: The cases which were positive for tumor cells in liver tissue genetically at the time of splenectomy had more significantly macroscopic liver metastases some weeks later than the cases negative for tumor cells. This study suggests that if micrometastasis was detected genetically, the development of metachronous macroscopic liver metastasis could be predicted.     

Effects of preoperative transcatheter arterial embolization (TAE) on the liver following partial hepatectomy in rats

The safety of pre-operative transcatheter arterial embolization (TAE), especially on the relation to hepatic regeneration following partial hepatectomy, was evaluated in rats. TAE was done through a catheter cannulated into hepatic artery under laparotomy. The remarkable elevation of S-GOT and S-GPT levels were demonstrated a day after TAE, which returned to normal on third post operative day. No influence of the difference of embolized materials was seen on the changes of transaminase levels. TAE severely decreased hepatic microsomal functional mass measured by [14C]-aminopyrine breath test (ABT) and the recovery of microsomal functional mass was shown on the 14th day after TAE. Histologically, recanalization could not be revealed in embolized arterioles even on the 21st day after TAE. But trabecular pattern of hepatic lobules was preserved after TAE. The serious inhibition of DNA synthesis of regenerating liver was demonstrated when TAE was performed within 14 days prior to partial hepatectomy (p less than 0.001-0.05). The period from TAE to partial hepatectomy had a influence on the survival rate after partial hepatectomy, and when appropriate interval was taken after TAE, the survival rate increased significantly (33%-50% in 24 hours interval and 88% in 14 days interval). In conclusion, preoperative TAE remarkably suppressed hepatic regeneration after partial hepatectomy, and appropriate time when suppressed hepatic functional mass, such as microsomal functional mass measured by ABT, returned to pre TAE value was required to perform hepatectomy in safety.