Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin.

E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonami de), an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of 26 human tumor cell lines (IC50 = 0.06-0.8 microg/ml), in contrast to vincristine (VCR; IC50 = 0.0002-0.04 microg/ml), 5-fluorouracil (IC50 = 0.2-30 microg/ml), Adriamycin (IC50 = 0.002-0.7 microg/ml), mitomycin C (IC50 = 0.007-3 microg/ml), 1-beta-D-arabinofuranoxylcytosine (IC50 = 0.005 to >30 microg/ml), camptothecin (IC50 = 0.002-0.4 microg/ml), and cisplatin (IC50 = 0.5-20 microg/ml). It caused a dose-dependent increase in the percentage of mitotic cells in parallel with a decrease in cell proliferation, like VCR. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth-inhibitory activity. 14C-labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR-resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, four E7010-resistant P388 cell lines showed no cross-resistance to VCR, a different pattern of resistance to podophyllotoxin, and collateral sensitivity to Taxol. Therefore, E7010 is a novel tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol.

In vivo tumor growth inhibition produced by a novel sulfonamide, E7010, against rodent and human tumors.

The search for compounds active against solid tumors has led us to the discovery of a novel sulfonamide, E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide), which inhibits tubulin polymerization. When administered orally, E7010 showed good antitumor activity against various rodent tumors and human tumor xenografts. In tests on mouse tumor, E7010, administered in doses of 25-100 mg/kg daily for 8 days, inhibited the growth of colon 38 carcinoma inoculated s.c. in mice by 60-99%. E7010 was active against s.c. inoculated M5076 fibrosarcoma (75% tumor growth inhibition), s.c. inoculated Lewis lung carcinoma (84% increase in life span), and i.p. inoculated P388 leukemia (118% increase in life span). In a test on rat tumor, E7010 inhibited the growth of SST-2 mammary carcinoma inoculated s.c. in rats by 84%. In tests on s.c. inoculated human tumor xenografts, E7010, when administered orally, showed a broad spectrum of activity. E7010 inhibited the growth of: four kinds of gastric cancer, H-81, H-111, SC-2, and SC-6 by 60-78%; three kinds of colon cancer, H-143, COLO320DM, and WiDr by 58-83%; three kinds of lung cancer, LC-376, LC-6, and LX-1 by 63-82%; and two kinds of breast cancer, H-31 and MX-1 by 79-87%. In studies on drug-resistant P388 leukemia, E7010 was effective against vincristine-resistant P388, cisplatin-resistant P388, and 5-fluorouracil-resistant P388 sublines in mice. Because of its good activity against rodent tumors and human tumor xenografts, E7010 is currently undergoing Phase I clinical trials.

Induction of antitumor immunity by tumor cells treated with abrin.

Abrin is known as a cytotoxic lectin. Immunization with Meth-A tumor cells which were treated in vitro with abrin induced a strong antitumor immunity in syngeneic BALB/c mice. The immunizing effect was stronger than that produced by an irradiated Meth-A tumor cell vaccine. Studies on the mechanisms of the immunizing effect with the abrin-treated tumor cells demonstrated that abrin acts as an immunoadjuvant. Furthermore, the regression of a growing Meth-A tumor was observed after abrin was injected into the tumor, while the induction of a strong antitumor immunity also occurred. It appears, therefore, that the antitumor effects of abrin are attributable to two kinds of activity: cytotoxicity and adjuvant activity.

E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo.

E7070 (N-(3-Chloro-7-indolyl)-1,4-benzenedisulphonamide) was selected from our sulphonamide compound collections via antitumour screening and flow cytometric analysis. Following treatment with E7070, the cell cycle progression of P388 murine leukaemia cells was disturbed in the G1 phase. The cell-killing effect on human colon cancer HCT116 cells was found to be time-dependent. In the panel of 42 human tumour cell lines, E7070 showed an antitumour spectrum that was distinct from those of other anticancer drugs used in clinic. Animal tests using human tumour xenograft models demonstrated that E7070 could cause not only tumour growth suppression, but also tumour regression in three of five colorectal and two of two lung cancers. In the HCT116 xenograft model, E7070 was shown to be superior to 5-FU, MMC and CPT-11 (irinotecan). Furthermore, complete regression of advanced LX-1 tumours was observed in 80% of E7070-treated mice. All of these observations have promoted this drug to clinical evaluation.

Synthesis and antitumor activities of novel 6-5 fused ring heterocycle antifolates: N-[4-[omega-(2-amino-4-substituted-6,7-dihydrocyclopenta [d]pyrimidin-5-yl)alkyl]benzoyl]-L-glutamic acids.

Novel antifolates with a 6-5 fused ring system, 6,7-dihydrocyclopenta [d]pyrimidine, (3a,b and 4a,b) were synthesized on the basis of combined modification of the heterocycle and bridge regions of the folate molecule. The synthetic method involves (1) synthesis of key intermediates of tert-butyl 4-[omega-(2-substituted-3-oxocyclopentanyl) alkyl]benzoates (8a,b and 9a,b) by a carbon-carbon radical coupling of tert-butyl 4-(omega-iodoalkyl)benzoates (7a,b) with 2-substituted-2-cyclopenten-1-ones (5 and 6) utilizing tributyltin hydride, (2) cyclization of either the methyl enol-ethers derived from the 2-cyanocyclopentanones (8a,b) or the 2-(methoxycarbonyl)cyclopentanones (9a,b) themselves by treatment with guanidine which leads to 6,7-dihydrocyclopenta [d]pyrimidines with a 4-(tert-butoxycarbonyl)phenylalkyl group (11a,b and 14a,b), (3) deprotection to the corresponding carboxylic acids (12a,b and 15a,b), and (4) amidation with diethyl glutamate and deesterification. Potent dihydrofolate reductase inhibition and highly potent cell growth inhibition were found with 2,4-diaminopyrimidine-fused cyclopentene compounds containing the trimethylene (3a) or ethylene bridge (3b) but not with the corresponding 2-amino-4-hydroxy analogs (4a,b). Compounds 3a and 3b were more growth inhibitory to several tumor cell lines (P388, colon 26, colon 38, and KB) than was methotrexate, with 3a being the most potent. Both 3a and 3b gave increases in the lifespan of P388 leukemic mice comparable to that observed with MTX. Both compounds were therapeutic against colon 26 colorectal carcinoma in mice. Compound 3a was highly effective against LC-6 non-small cell lung carcinoma in nude mice.

Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle.

Described herein is the discovery of a novel series of antitumor sulfonamides targeting G1 phase of the cell cycle. Cell cycle control in G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). We previously reported our first antitumor sulfonamide E7010 as a novel tubulin polymerization inhibitor. Interestingly enough, continuous research on structurally related compounds led us to the finding of another class of antitumor sulfonamides that block cell cycle progression of P388 murine leukemia cells in G1 phase, but not in M phase. Of the compounds examined, N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) showed significant antitumor activity against HCT116 human colon carcinoma both in vitro (IC(50) 0.11 microg/mL in cell proliferation assay) and in vivo (not only growth suppression but also a marked reduction of tumor size in nude mice). Because of its promising efficacy against human tumor xenografts and its unique mode of action, E7070 is currently undergoing phase I clinical trials in European countries.

Lack of preventive effect of branched-chain amino acid solution on postoperative hepatic encephalopathy in patients with cirrhosis: a randomized, prospective trial.

The purpose of this randomized, prospective study was to determine whether the infusion of branched-chain amino acid (BCAA)-enriched solution had a preventive effect for treating postoperative hepatic encephalopathy in patients with cirrhosis. Among the 56 patients with cirrhosis, 29 were given BCAA-enriched solution, and 27 were given the conventional amino acid solution for 14 days postoperatively. These groups were indistinguishable with regard to clinical and laboratory criteria at entry, except by sex. The molar ratio of BCAA to aromatic amino acids in the BCAA group was increased postoperatively, whereas the ratio in the control group was decreased, the difference being statistically significant. Among the 29 who received BCAA, three (10.3%) had hepatic encephalopathy; two died and one recovered. Of the 27 control patients, hepatic encephalopathy occurred in three (11.1%); one died and two recovered. There was no significant difference in rate of occurrence of hepatic encephalopathy between the groups. Thus the infusion of BCAA-enriched solution apparently had no preventive effect with regard to hepatic encephalopathy for patients with cirrhosis who underwent surgical treatment.

Effect of E7010 on liver metastasis and life span of syngeneic C57BL/6 mice bearing orthotopically transplanted murine Colon 38 tumor.

PURPOSE: E7010 is an orally active sulfonamide antitumor agent showing good activity against various subcutaneously inoculated rodent tumors and human tumor xenografts. The purpose of this study was to evaluate the effect of E7010 on liver metastasis and life span of mice bearing orthotopically transplanted murine Colon 38 tumor. METHODS: Orthotopic transplantation of murine Colon 38 tumor as intact tissue yielded hepatic metastasis with a high incidence in about 1 month in C57BL/6 mice, and the mice died in about 2 months with cachexia. In this model, the maximum tolerated dose of E7010 (100 mg/kg per day) was administered orally on various schedules, including for 14 days or daily until death, starting at 14 days after transplantation, or for 8 days from 21 days after transplantation. RESULTS: E7010 showed tumor growth inhibition (T/C=40%) at the orthotopic site similar to that at the subcutaneous site (T/C = 32%) when administered from 14 days after transplantation. When E7010 was started from 21 days after transplantation, it significantly decreased the number of hepatic metastases (control 17.1+/-20.8, E7010 2.6+/-5.3), although inhibition of tumor growth at the orthotopic site was only moderate (T/ C=60%). The administration of E7010 until death produced a significant increase in life span (control 49.8+/-8.9 days, E7010 62.5+/-6.1 days). Although the tumor weight of the E7010-treated group on the day of death was similar to that of the untreated group (control 1.166+/-0.507 g, E7010 1.211+/-0.632 g), there were significantly fewer liver metastases in the E7010-treated group (control 41.3+/-31.1, E7010 2.0+/-2.0). CONCLUSION: E7010 suppressed tumor growth at both primary and metastatic sites and increased life span in an orthotopic transplantation model of murine Colon 38 tumor in syngeneic C57BL/6 mice. Hepatic metastasis was inhibited more effectively than the growth of the primary tumor.

Increased platelet count as a screening test for distal splenorenal shunt patency.

Hypersplenism was not relieved by distal splenorenal shunting in 46 of 47 Japanese patients with nonalcoholic cirrhosis of the liver. However, the platelet count significantly increased by 40 percent of the preoperative value, whereas the increment in the white blood cell count was nil. Though the platelet count in 47 patients with a patent shunt did not significantly differ from that in another 7 patients with an occluded shunt, the rate of increase was significantly higher in those with patency than in those with early occlusion throughout the postoperative period and in those with late occlusion 6 months after operation. The increased rate of the platelet count can thus serve to screen patients for shunt patency.

Transit endoscopic ultrasound of colorectal cancer using a 12 MHz catheter probe.

The objective of this study was to examine the accuracy of a 12 MHz ultrasound catheter probe in the pre-operative staging of colorectal cancer by assessing the depth of tumour infiltration and involvement of pericolonic lymph nodes. 159 patients with colorectal cancer who underwent ultrasound examination with a 12 MHz catheter probe were studied prospectively. The results of this imaging procedure were compared with the histological findings of the resected specimens. The accuracy of the 12 MHz ultrasound catheter probe for depth of invasion (T category) was 85% (131/154) for all tumours, 87% (46/53) for pT1 tumours, 60% (9/15) for pT2 tumours, 89% (74/83) for pT3 tumours and 67% (2/3) for pT4 tumours. The accuracy for tumours of the rectum and colon was 81% and 89%, respectively. The accuracy of the probe for nodal staging (N category) was 67% (76/114) overall. The sensitivity was 70% (33/47), the specificity 64% (43/67), the positive predictive value 58% (33/57) and the negative predictive value 75% (43/57). Endoscopic ultrasound using a 12 MHz catheter probe accurately assessed tumour stage, although nodal staging remained suboptimal. This method may aid in the selection of treatment for patients with colorectal cancer.

Leiomyosarcoma of the thyroid gland with rapid growth and tracheal obstruction: A partial thyroidectomy and tracheostomy using an ultrasonically activated scalpel can be safely performed with less bleeding.

Primary leiomyosarcoma of the thyroid gland is rare, and to the best of our knowledge only nine well-documented cases have been previously reported in the world literature. We herein report a 90-year-old female patient with primary leiomyosarcoma of the thyroid gland who showed a rapid tumor growth and tracheal obstruction. The patient was successfully treated by a partial resection of the thyroid gland using an ultrasonically activated scalpel and emergency tracheostomy. Immunohistochemically, the tumor cells showed positive reactivity to smooth muscle actin and negative reactivity to thyroglobin. Palliative surgery successfully allowed the patient to recover from the symptoms of dyspnea related to this rare disease. The use of an ultrasonically activated scalpel and tracheostomy thus allowed us to safely perform a thyroidectomy with substantially less bleeding than normal.

Natural history of hepatectomy regarding liver function: a study of both normal livers and livers with chronic hepatitis and cirrhosis.

BACKGROUND/AIMS: The cirrhotic liver has been shown to regenerate after hepatectomy based on the findings of various imaging techniques. However, little has been reported so far regarding the restorative process using the liver function test in a long series after hepatectomy of both normal and injured livers. METHODOLOGY: A retrospective review was performed of 48 patients who underwent hepatic resection due to either primary or secondary liver cancers. They were histologically divided into three groups of 6 normal, 23 chronic hepatitis and 19 cirrhotic liver patients. In addition, the hepatitis group was divided into two groups according to the resected volume, which were 16 of a small resected volume and 7 of a large volume. For these patients, both a complete blood count and normal liver function test were performed before operation, and 7 and 14 days, 1, 3, and 6 months, and 1, 2, and 3 years, postoperatively. RESULTS: In the normal patient group, almost all test results recovered to their preoperative levels by 14 days to 1 month postoperatively. In the cirrhotic group, however, the red blood cell count and hematocrit levels did not recover to preoperative levels until 3 months postoperatively, while the GPT levels, the total bilirubin and albumin all recovered by one month postoperatively. However, the total cholesterol level needed 6 months to recover. In the large resection hepatitis group, the GPT level needed 7 days to recover, while the albumin and total cholesterol level needed three months to do so. In addition, the platelet level decreased significantly at 3 months postoperatively and thereafter it seemed to remain at a lower level. CONCLUSIONS: We demonstrated that a hepatic resection in patients with chronic liver disease requires a longer period of time to recover to preoperative levels based on the type of underlying liver parenchymal disease and the extent of resection.

Does a long pre-operative hospital stay before hepatectomy improve liver dysfunction in HCC patients with chronic liver disease?

BACKGROUND/AIMS: We retrospectively evaluated whether or not hepatic dysfunction improved in patients with chronic liver disease who had been waiting to undergo a hepatectomy after admission. MATERIALS AND METHODS: Fifty-two hepatocellular carcinoma patients had been admitted for more than 2 weeks prior to undergoing a hepatectomy. They had a liver function test twice, at admission and just before surgery, during the hospitalization period. Twenty-six of them were histologically diagnosed as having chronic hepatitis while the remainder had liver cirrhosis. In the liver function test, the serum levels of albumin, total bilirubin, glutamic pyrubic transaminase (alanine transaminase), total cholesterol and the Child grade were examined. RESULTS: First, including the pre-operative treatment cases for small tumors under angiography, the total bilirubin and transaminase levels improved in the chronic hepatitis patients with a statistically significant difference, but no difference was observed in the Child grade. In the examined cirrhotic patients, no significant difference was shown in the tests. Second, after excluding the pre-operative treatment cases, we performed the same investigation as that for chronic liver disease cases and only the transaminase level significantly improved. CONCLUSIONS: A long pre-operative hospital stay might only by justified in patients with a high level of transaminase corresponding to chronic active hepatitis.

Clinical and angiographic assessments and treatment of patients with recurrent varices after transabdominal transection of the esophagus.

BACKGROUND/AIMS: Risk factors regarding the recurrence of esophageal varices and were researched preoperative clinical and angiographic findings in patients with variceal recurrence and/or rebleeding after transabdominal esophageal transection were analyzed. MATERIALS AND METHODS: Clinical and angiographic assessments of recurrence of varices after transabdominal esophageal transection were made on 55 patients with portal hypertension. In all these patients, postoperative endoscopy was performed at 3-6 monthly intervals. RESULTS: Varices recurred in 13 patients and 4 patients re-bled during the 5-106 month follow up. There was a significant increase in the rate of recurrence in patients with a history of hematemesis, and in those with a higher grade of development of cephalad collateral vessels in the lesser splanchnic area, as seen on the preoperative portography. Eight of the 13 patients were then effectively treated by endoscopic injection sclerotherapy. CONCLUSIONS: Despite transabdominal transection of the esophagus, varices may well recur if the patient has had a history of hematemesis and a higher grade of development of cephalad collateral vessels. In such cases endoscopic injection sclerotherapy should be done.

Ethanolamine oleate is superior to polidocanol (aethoxysklerol) for endoscopic injection sclerotherapy of esophageal varices: a prospective randomized trial.

Thirty-four consecutive patients with liver cirrhosis and esophageal varices were included in a prospective randomized trial done to investigate the efficacy and safety of two sclerosants 5% ethanolamine oleate (EO) and polidocanol (1% Aethoxysklerol [AS]) for use in endoscopic injection sclerotherapy (EIS). Eighteen patients were randomly allocated to the group given EO and 16 to the AS group. These two groups were comparable with regard to age, sex, etiology and severity of the liver disease. The bleeding rate from esophageal ulcers which developed during the course of repeated EIS was significantly (P less than 0.05) higher in the AS group (31.3%, 5/16) than in the EO group (0%, 0/18). In 4 occasions bleeding from the esophageal ulcer could not be controlled with AS. In 3 of these 4 bleeding episodes, EO successfully halted bleeding from esophageal ulcer. In the other patient, a Sengstaken-Blakemore tube was inserted to stop the hemorrhage. The period and number of sessions of EIS for eradication of esophageal varices were significantly (P less than 0.05) shorter in the EO group than the AS group (EO: 4.0 +/- 0.8 [means +/- SD] sessions during 4.7 +/- 1.5 weeks versus AS: 4.8 +/- 1.2 sessions during 5.4 +/- 1.6 weeks). The rate of early mortality did not differ between the two groups. We conclude that 5% ethanolamine oleate seems to be superior to 1% Aethoxysklerol when used for sclerosing esophageal varices.

Comparative effects of 5% ethanolamine oleate versus 5% ethanolamine oleate plus 1% polidocanol for sclerosing esophageal varices.

Sixty-six patients with portal hypertension and esophageal varices due to liver cirrhosis were randomized to receive either 5% ethanolamine oleate (EO) or 5% EO plus 1% polidocanol (EOP) as a sclerosant for endoscopic injection sclerotherapy (EIS). The two groups were well matched with regard to age, sex and the severity of liver disease. In no patient in the two groups was there any major complication, such as esophageal perforation or esophageal bleeding. Eradication of esophageal varices was attained with an average of 4.7 and 4.3 sessions of endoscopic injection sclerotherapy in the ethanolamine oleate and polidocanol groups, respectively. Data on one patient in the ethanolamine oleate group had to be excluded because he left the hospital after 2 sessions of endoscopic injection sclerotherapy. Esophageal ulcers occurred earlier in the polidocanol group (after an average of 2.8 weeks) than in the ethanolamine oleate group (3.8 weeks), the difference being statistically significant (P < 0.01). The rate of occurrence of esophageal stricture requiring more than 2 sessions of bougienage was significantly (P < 0.01) higher in the polidocanol group (16/33, 48%) than in the ethanolamine oleate group (4/32, 12%). This study suggests that the two sclerosants have equal efficacy for treating patients with esophageal varices. With polidocanol there was ulceration and stricture in the distal esophagus.

Small hepatic nodules surrounding hepatocellular carcinoma.

BACKGROUND/AIMS: We investigated whether or not small hepatic nodules surrounding the main hepatocellular carcinoma were malignant, while also analyzing the role of intraoperative ultrasonography in detecting these small nodules. MATERIALS AND METHODS: Thirty-three small hepatic nodules near the main tumor in 17 patients were retrospectively studied. They were first detected either during or after the operation using intraoperative ultrasonography and/or after examining a cross-section of the resected specimen. RESULTS: Twenty-six of the 33 small nodules were shown to be malignant when studied histologically (79%). The reliability of intraoperative ultrasonography was higher than 80 per cent for detecting nodules measuring more than 5 mm in diameter. However, it was only 25 per cent reliable with smaller nodules measuring less than or equal to 5 mm. CONCLUSIONS: These results suggest that most small hepatic nodules with hepatocellular carcinoma should be considered to be malignant. In addition, smaller nodules measuring less than 5 mm in size can hardly be detected by intraoperative ultrasonography.

Surgical results of spontaneously ruptured hepatocellular carcinoma.

Seventeen patients with ruptured hepatocellular carcinoma (HCC) underwent a hepatic resection from 1985 to 1992 at either Kyushu University Hospital or Iizuka Hospital in Japan. They all underwent elective surgical procedures except for one patient who experienced a repeated rupture during hospitalization. A comparative study between the patients with ruptured HCC and non-ruptured large HCC measuring more than 6 cm in size (n = 29) revealed that the 3-year disease-free survival rate of the ruptured HCC group was 14.5% which was worse than that of the non-ruptured group at 39.9%. There was no difference in the rates of peritoneal dissemination, distant metastasis or intrahepatic recurrence between the two groups. Regarding the intrahepatic recurrence pattern, widespread multinodular recurrence frequently occured in the ruptured patients, which was thought to be caused by the high incidence of venous invasion in the primary tumor. The intratumor pressure of the ruptured HCC appeared to be elevated and is considered to be one of the main reasons for the high incidence of venous invasion.

Tumor stage in the proximal colon under conditions of a proximal shift of colorectal cancer with age.

BACKGROUND/AIMS: Although the incidence of proximal colon cancer is known to increase with age, the prognosis of proximal colon cancer remains unclear. METHODOLOGY: One thousand two hundred and five patients with colorectal cancer were analyzed with regard to tumor location, age and Duke's stage. RESULTS: When Duke's stage was compared with tumor location, an advanced Duke's stage was found more frequently in the proximal colon than in the distal colorectum (p<0.01). In Duke's A colorectal cancer, the incidence of tumors limited to within the submucosal layer decreased from 73.1% in patients under 65 years of age to 60.9% in patients over 65 years of age. CONCLUSIONS: Since advanced stage cancer was more frequently found in the proximal colon than in the distal colorectum, careful examination for the early detection of proximal colon cancer, particularly in the elderly, is called for.

Appraisal of a manual blunt dissection for an intraoperative diagnosis of extrahepatic cancer invasion.

BACKGROUND/AIMS: Liver cancer extension to the adjacent organs does not necessarily indicate tumor invasion. It is very hard to diagnose extrahepatic cancer invasion to the adjacent organs using preoperative imaging. This study was undertaken, therefore, to determine the real cancer invasion using a manual dissection. METHODOLOGY: Of the 51 consecutive patients with liver cancer, 6 cases with extrahepatically growing tumors were suspected to have cancer invasion both preoperatively and intraoperatively. Thus, we diagnosed whether or not any real extrahepatic cancer invasion was present by either removing the tumour by hand or by performing a blunt gauze dissection. RESULTS: Three hepatocellular carcinomas and one metastatic cancer were stripped off from the adjacent organ using a manual blunt dissection. However, the other two tumors could not be removed in the same manner and therefore a combined resection of the invaded portion had to be performed along with the hepatectomy. A postoperative detailed pathological examination revealed no cancer cells on the surface of the adjacent organ in the former 4 tumors. Cancer invasion was recognized, however, on the outside of the liver in the latter 2 combined resected tumors. CONCLUSIONS: An accurate intraoperative diagnosis of extrahepatic cancer invasion can be made using manual blunt dissection.