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Unlike normal liver with the sinusoids, hepatocellular carcinomas (HCCs) possess capillaries. Whether these capillaries derive from the sinusoids remains unclear in human HCCs. This study aimed to examine sinusoidal capillarization in human HCCs and its relationship to the tumor size, arterialization and dedifferentiation. Thirty-eight HCCs with a diameter of 10 - 140 mm were pathologically and angiographically examined. By electron microscopy, the microvasculature of tumors was classified into sinusoidal, intermediate and capillary types, which were all negative, partially positive and all positive, respectively, for four parameters, i.e., endothelial defenestration, continuous basement membrane, lack of Kupffer cells, and lack of lipid-containing hepatic stellate cells. Well-, moderately and poorly differentiated HCCs displayed sinusoidal / intermediate / capillary types, intermediate / capillary types and only capillary type, respectively, suggesting the transition from the sinusoids to capillaries in well-differentiated (and probably moderately differentiated) HCCs. Furthermore, well-differentiated HCCs with a diameter of less than 30 mm often received preferential portal venous blood, while moderately and poorly differentiated ones were all supplied with arterial blood, indicating a relationship between dedifferentiation and arterialization. In contrast, the microvascular type displayed no significant relationship with tumor size or arterialization in well-differentiated HCCs. The present study has demonstrated that sinusoidal capillarization occurs in human well-differentiated HCCs and seems to be related to dedifferentiation of parenchymal tumor cells, but not to tumor size or arterialization.

To investigate the monoclonality of hepatocellular carcinoma (HCC) and dysplastic nodule (DN) and the origin of multiple lesions, patterns of inactivation of X-linked human androgen receptor gene were studied. Fourteen of 15 patients (93%) were heterozygous in the size of the target, and were informative for clonal analysis. Monoclonal composition was demonstrated in all 17 HCCs and two DNs, whereas all non-cancerous hepatic tissues were polyclonal. Of four patients with more than two lesions of HCC or DN, two patients had two lesions with different patterns of X-chromosome inactivation, indicating that the two lesions were multicentric in origin.

To clarify the variables related to survival after recurrence of resected hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV), we studied 17 clinicopathological factors in 99 patients with recurrence of HCC associated with HCV infection after hepatic resection. The 1-, 3-, and 5-year survival rates after first resection in these patients were 91%, 81%, and 49%, while after recurrence they were 81%, 51%, and 29%, respectively. Multivariate analysis showed that the following six variables were independent prognostic factors after recurrence: platelet count, albumin level, bilirubin level, number of hepatic lesions, distant metastasis, and any treatment at recurrence. A correlation between second hepatic resection (SHR) and liver function tests was seen in regard to albumin and total bilirubin values at recurrence. Indeed, hepatic function and progression of intrahepatic tumors at recurrence were significant prognostic factors after recurrence of HCC associated with HCV infection, while any treatment at recurrence was also a significant prognostic factor. Therefore, in order to improve prognosis after recurrence, we should actively treat the recurrent hepatic lesions whenever possible.

We investigated the role of hepatitis B virus infection in development of hepatocellular carcinoma in hepatitis C virus-infected patients without hepatic fibrosis. Of 253 patients, 8 lacked hepatic fibrosis (group 1); group 2 included the remaining 245 patients. Clinicopathologic findings were compared between the groups. Hepatitis B x gene was sought in cancers and adjoining noncancerous liver. Group 1 showed better liver function parameters and milder active hepatitis than group 2. The proportion of patients with anti-hepatitis B virus antibody tended to be higher in group 1 than in group 2. The proportion of patients with hepatitis B x RNA in cancers was significantly higher in group 1 than in group 2. All group 1 patients had previous or occult hepatitis B virus infection. Previous or occult hepatitis B virus infection may be critical in development of hepatocellular carcinomas in hepatitis C virus-infected patients without hepatic fibrosis.

Worldwide, patients with hepatitis B virus (HBV) number as many as 280 million. HBV infection is a risk factor for hepatocellular carcinoma (HCC), 1 most effectively treated by resection. Recent progress in the preoperative evaluation of liver function, surgical procedures, and perioperative management has improved the results of liver resection. 2,3 However, resection in patients with chronic liver disease still can lead to postoperative hepatic failure, resulting in decompensation and death. The Child-Pugh classification 4 has been used frequently to evaluate preoperative liver function. Risk factors for postoperative hepatic failure have been studied by many investigators, and various new methods have been proposed for evaluating preoperative liver function. 3,5–12 After undergoing liver resection for HBV-related HCC, some patients again develop hepatitis. Four years ago, we treated an HBV carrier and who underwent right lobectomy for HCC and 6 weeks later developed fatal acute hepatic failure with remarkably increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (≥3,000 IU/L). The patient had well-preserved liver function before surgery and was discharged from the hospital 4 weeks after surgery. Although acute hepatic failure has been reported to occur from reactivation of HBV replication after liver transplantation, 13 whether reactivation of HBV replication occurs after liver resection is not known, nor is the relation of such an event to postoperative hepatitis. In the present study, we retrospectively studied the incidence of postoperative hepatitis. Beginning in 1994, we also prospectively investigated reactivation of HBV replication after liver resection and factors that might be associated with reactivation.

Background: The adrenal gland is a common site of extrahepatic metastases from a hepatocellular carcinoma (HCC). However, treatment of adrenal metastases has not been well characterized. Methods: Of 562 patients who underwent hepatic resection for a HCC, 91 developed extrahepatic metastases. We reviewed the medical records of 10 patients with adrenal metastases (9 males and 1 female; mean age 63 years at the time of hepatic resection). Results: The mean diameter of the primary tumors was 5 cm, and all were located in the right lobe of the liver. The mean interval from hepatic resection to recurrence was 18 months. Seven patients underwent treatment of intrahepatic recurrence. To treat the adrenal metastases, surgical resection was performed in 4 patients, and transcatheter arterial embolization was performed in 1 patient. The patients treated had no other extrahepatic metastases. The mean diameter of the resected adrenal tumors was 6 cm. There was no hospital mortality. With surgical resection, 1 patient has been alive 63 months after recurrence. Conclusions: Adrenal metastases from a HCC were often large at the time of diagnosis. Since surgical resection was a safe procedure, and some patients could be alive for a long time, it should be performed whenever possible.

We present a 72-yr-old woman who underwent surgical resection of a large pancreatic tumor. On preoperative imaging, an intratumoral cavity containing necrotic tissue was noted, mimicking the appearance of a cystic tumor. There was no invasion of adjacent organs nor distant metastasis, and histopathologic examination revealed the tumor to be a giant cell carcinoma. Postoperatively, the patient has been followed for 1.5 yr without evidence of recurrence. Giant cell carcinoma generally is associated with a poor prognosis, and patients usually die within months despite intensive multimodality therapy. Some patients with giant cell carcinomas, however, achieve long-term survival when invasion of adjacent organs and distant metastases are absent. Surgical resection is the appropriate treatment for tumors with these favorable characteristics.

22歳,男性.平成11年9月20日に交通事故のため,大阪府下の救命センターに搬送された. IIIB型肝外傷による腹腔内出血と診断され,肝動脈塞栓術が施行された.術後発熱が続くため胆嚢炎と診断,同月24日に胆摘術が施行された.しかし発熱は遷延し, 29日に発熱の原因と考えられたS5, S6の挫滅肝の非定型的部分切除が行われた.術後ドレーンより胆汁痩がみられ,保存治療で軽快せず,平成12年3月7日に当院転院となった. 瘻孔造影でS7肝内胆管が描出され,後枝の損傷による胆汁瘻と診断し, 4月5日に再々開腹した.肝門部で後枝胆管の肝側断端を確認しえたため胆道造影を施行し,肝管走行を確認した後に肝右葉切除を施行した.切除肝重量は425g. 術後経過は良好で,術3週後に軽快退院した. 肝外傷では胆管損傷を伴うことも多いため,胆道造影を行った後に,可能な限り定型的な肝切除を行うことが望ましいと思われた.

Although there have been many studies of the risk factors for recurrence after resection of hepatocellular carcinoma (HCC), the subjects were patients with various viral status in the previous studies, and hepatitis C viremia has not been evaluated. We investigated risk factors, including hepatic C viremia and histologic findings of noncancerous hepatic tissue, for recurrence after resection of hepatitis C virus (HCV)-related HCC. A total of 223 patients who underwent liver resection for HCV-related HCC were studied. HCV viremia, laboratory data, degree of HCC malignancy, histologic findings in noncancerous hepatic tissue, preoperative interferon therapy, and operative methods were evaluated for recurrence risk by univariate and multivariate analyses. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin, and the proportion of patients with a high histologic activity score (mild to severe active hepatitis) were significantly higher in patients with HCV viremia than in those without viremia. Serum albumin was significantly lower in patients with HCV viremia. By univariate analysis, older age (> 65 years old), HCV viremia, elevated AST (> 40 IU/L) and ALT (> 45 IU/L), large tumors (> 40 mm), multiple HCCs, moderately or poorly differentiated HCC, portal invasion, mild to severe active hepatitis, and lack of preoperative interferon therapy were risk factors for recurrence. Multivariate analysis showed that older age, HCV viremia, high AST, multiple HCCs, and portal invasion were independent risk factors. For HCV-related HCCs, not only the degree of malignancy of the HCC but also HCV viremia and active hepatitis are risk factors for recurrence.

The presence of small additional hepatocellular carcinomas (HCCs) undetectable before hepatic resection is a crucial topic for hepatic surgeons. We assessed the incidence of pathologically diagnosed multiple HCCs in 267 patients who underwent hepatic resection for HCC. Ninety-five additional HCC nodules were detected in 72 of the patients (27%). The survival rate of these 72 patients was significant worse than for the 195 with single nodular HCC (p = 0.0013). Twenty-one (22%) were detected before surgery, 29 (31%) during surgery, and 45 (47%) on pathologic examination after surgery. The mean nodule diameters for each group were 2.1, 1.0, and 0.9 cm, respectively (p0.0001). None of the 21 nodules detected before surgery was well differentiated, whereas 30 of the 74 nodules in the other two groups were well-differentiated. Although the mean nodule diameter of the well-differentiated HCC group was the smallest, there was no significant difference among the three groups assigned according to tumor differentiation (p = 0.2355). Altogether, 9 of 16 patients with additional nodules detected before surgery (56%) and 49 of 59 with additional nodules detected during or after surgery (88%) had cirrhosis of the liver. The odds ratio for detecting a new HCC nodule during or after surgery in the presence of cirrhosis was 5.444 (p = 0.0087). Improvement in the detection of small additional HCC nodules before and during surgery and meticulous follow-up after surgery are necessary for patients with cirrhosis. For patients without cirrhosis, surgical treatment may be performed according to the results of preoperative imaging studies.

The frequency of lymph node (LN) metastasis in patients undergoing surgery for hepatocellular carcinoma (HCC) has rarely been studied. We evaluated the clinicopathologic characteristics and outcomes of six patients with nodal metastases from HCC among a total of 504 patients who underwent hepatic resection for HCC in our department over a 16-year period. The nodal metastases were diagnosed preoperatively in two patients. The average diameter of the resected tumors was 7.8 cm and all were confirmed as poorly differentiated HCC. All of the six patients had intrahepatic metastatic nodules and five also had portal vein invasion. One patient underwent limited resection, and the other five underwent bisegmentectomy. All of the regional LNs were removed in one patient, while only enlarged LNs were removed in the other five. One patient died of postoperative liver failure and the others all died later of intrahepatic or nodal recurrence. Our findings suggest that the prognosis of patients with nodal metastasis from HCC is generally poor, even if hepatic resection with regional LN dissection is performed.

We studied the relationship between the findings of computed tomography during arteriography (CTA) and computed tomography during arterial portography (CTAP), and pathologic findings of 81 small nodular lesions (3 cm or less in diameter) in resected liver specimens. The 81 lesions consisted of 8 dysplastic nodule (DN) lesions, 23 well‐differentiated hepatocellular carcinomas (early HCCs) and 50 moderately or poorly differentiated HCCs (advanced HCCs). We also performed standard computed tomography (CT), digital subtraction angiography (DSA), magnetic resonance imaging (MRI), and ultrasonography, and compared sensitivities with CTA, CTAP, or combination of CTA and CTAP with other imaging methods. Forty‐four of the 50 advanced HCCs, 12 of the 23 early HCCs, and none of 8 DNs hyperattenuated with CTA and hypoattenuated with CTAP. The sensitivity for the early HCCs was significantly higher for CTA and CTAP in combination as compared with DSA or standard CT. The sensitivity for the advanced HCCs was significantly higher for CTA and CTAP in combination than with DSA. The sequential changes of the blood supply from the portal vein to the hepatic artery during the development of the HCCs were observed. Although CTA and CTAP in combination were useful for the distinction of advanced HCC from early HCC or DN, CTA and CTAP used in combination were not superior to CTA alone in the detection of such lesions.

われわれが切除した肝細胞癌562例のうち1998年7月までに臨床的に肺転移を来たした23例を肺転移巣切除8例 (肺切群) と非切除15例 (非肺切群) に分け各群の臨床像を比較した.肺転移時に残肝再発を併存した症例は肺切群, 非肺切群でそれぞれ5例, 10例であった. このうち非肺切群3例には追加治療を行いえなかった. 肺転移までの期間, 肺転移巣の局在に差はなかったが, その個数は肺切群では全例countableで, 非肺切群では3例がuncountableであった.肝切除後累積生存率および肺転移後累積生存率とも肺切群が良好であった (p=0.0447, p=0.0020).また, 非肺切群死亡11例中3例が肺転移に起因する癌死であったが, 肺切群死亡4例の死因は肺転移によるものでなかった.肺転移巣数がcountableで, 残肝再発の制御されている肝癌切除後肺転移例に対して肺切除を行うべきであると考える.

BACKGROUND The effect of prior hepatitis B virus (HBV) infection on the clinicopathologic findings for patients with hepatitis C virus (HCV) RNA and hepatocellular carcinoma (HCC) is still unclear. METHODS Of 59 patients who underwent liver resection for HCV-related HCC (≤2.0 cm in greatest dimension) without metastases between 1990 and 1997, 38 patients had anti-HB core antibody (anti-HBc) and did not have HB surface antigen in their sera (Group 1). Their clinicopathologic findings and outcomes after surgery were compared with those of the remaining 22 patients without anti-HBc (Group 2). RESULTS The proportion of well-differentiated HCC was significantly lower in Group 1 than in Group 2 (P = 0.0214). The percentage of patients with cirrhosis was significantly lower in Group 1 than in Group 2 (P = 0.0228). The cumulative survival rate was significantly lower in Group 1 than in Group 2 (P = 0.0224). The risk ratio of anti-HBc for shorter survival time was 3.817. CONCLUSIONS HCC more often developed before cirrhosis in patients with HCV RNA and anti-HBc than in patients positive for HCV RNA alone. Prior HBV infection was a risk factor for poor outcome after liver resection for patients infected with HCV. [See editorial on pages 741–3, this issue.] Cancer 1999;86:793–8. © 1999 American Cancer Society.

Background/Aims: Although the activity of the liver in metabolizing and eliminating various drugs decreases in endotoxemia, the mechanism remains to be elucidated. The generation of nitric oxide by the inducible type of nitric oxide synthase increases in endotoxemia. Nitric oxide readily reacts with heme proteins such as cytochrome P450 that metabolize various compounds, including steroids and eicosanoids. The purpose of this study was to determine the effect of nitric oxide on the function of hepatic cytochrome P450 in endotoxemic rats. Methods: To determine the dynamic aspects of nitric oxide metabolism, hepatic levels of the inducible type of nitric oxide synthase and heme-iron nitrosyl complexes, and plasma levels of nitrite and nitrate were determined in rats before and after intravenous administration of lipopolysaccharide. Changes in the levels of P450 isoforms and testosterone hydroxylation activity in hepatic microsomes were also determined. To evaluate in vivo CYP3A2 activity, midazolam sleep time was measured. Results: When lipopolysaccharide increased the hepatic inducible type of nitric oxide synthase and plasma levels of nitric oxide metabolites, the intensity of low-spin signal of electron spin resonance responsible for the ferric form of P450 decreased with a concomitant increase in heme-iron nitrosyl complexes in the liver. Lipopolysaccharide-related nitric oxide generation is followed by an early decrease in the levels of cytochrome P450 and of testosterone hydroxylation activity in liver microsomes. Midazolam sleep time was prolonged by lipopolysaccharide. All these early changes were prevented by the inhibitor of nitric oxide synthase, N G -iminoethyl-L-ornithine. Moreover, lipopolysaccharide suppressed the gene expression of CYP2C11 and CYP3A2. Decreases in levels of cytochrome P450 and their mRNAs were more pronounced at 24 h after LPS administration, but apparently they are NO-independent. Conclusions: These results suggest that lipopolysaccharide-induced modulation of cytochrome P450 may occur via the interplay of two different mechanisms and that, especially in the early phase, nitric oxidedependent inhibition is more important.

The effect of persistent hepatitis C viremia on the outcome after resection of hepatocellular carcinoma (HCC) was investigated in 59 consecutive patients with a single small HCC (< or = 3.0 cm in diameter). The presence of serum hepatitis C virus (HCV) RNA was evaluated using a reverse transcription polymerase chain reaction method as well as a branched DNA probe method. Clinicopathologic findings were compared between patients with and without viremia and the risk factors for poor outcome were evaluated. Hepatitis C virus (HCV) RNA was not detected in the sera from 7 patients (group 1), but was detected in the sera from the other 52 patients (group 2). Alanine aminotransferase (ALT) activity was significantly higher in group 2 than in group 1. The proportion of patients with active hepatitis was significantly higher in group 2. In group 2, new HCC often developed after the operation and four patients died of liver dysfunction. HCV viremia, high ALT activity, high concentration of total bilirubin, and liver cirrhosis were related to recurrence after the operation. Multivariate analysis indicated that HCV viremia and high ALT activity were independent risk factors for recurrence of HCC. Continuous hepatitis with persistent HCV viremia worsened the outcome after the resection of HCC by causing new development of HCC and deterioration of liver function. In patients with HCV-related HCC, but without HCV viremia, satisfactory results can be expected after liver resection.

We treated 30 patients with hepatocellular carcinoma (HCC) by laparoscopic microwave coagulation therapy (LMCT) and 5 patients with hepatic tumors by laparoscopic hepatectomy (LH). LMCT : The HCC was between 10 and 35 mm in longest diameter. After observation of the surface of the liver during laparoscopy as usual, the lesions were punctured with a electrode needle, coagulated with 60 to 80 W for 45 seconds. The efficacy of LMCT was evaluated by dynamic CT or dynamic MRI. After LMCT, 3 lesions of 3 patients were thought to be coagulated insufficiently and additional therapy was needed. The lesions of the other patients seemed to be coagulated sufficiently. LH : We treated 5 patients by LH under general anesthesia. The longest diameters of tumors were between 13 mm and 45 mm. All tumors were located at the edge of the liver. We coagulated the surrounding tissues around the tumors with the above mentioned method and resected the coagulated lesions with Laparoscopic Coagulating Shears System. The bleeding were few and no serious complications were not found. Conclusions : Laparoscopic treatment for HCC was useful but the indication was restricted by location of HCC.

The hepatic sinusoids are preferentially supplied with portal venous blood and equipped with fenestrated endothelial cells that are distinct from capillary endothelial cells. We previously observed in rats that sinusoidal capillarization proceeded concurrently with arterial blood supply during hepatocarcinogenesis. This study aimed to clarify the inducing role of arterialization in sinusoidal capillarization by investigating phenotypical, morphological and functional alterations to sinusoidal endothelial cells (SECs) in arterialized rat livers induced by portal branch ligation. At one week, after massive hepatic necrosis following ligation, the livers were restored to their normal architecture without causing post-necrotic fibrosis. At 12-21 weeks, they exhibited a normal histology except for mild pericellular fibrosis which developed along sinusoids or between adjacent hepatocytes. SECs expressed factor VIII-related antigen and showed a decrease in the number of fenestrae and porosity, still lacking any basement membrane but further retaining the functional capacity for carmine dye uptake. Stellate cells, while occasionally associated with large amounts of collagen bundles, contained many lipid droplets and expressed no alpha-smooth muscle actin, indicating a quiescent property. Kupffer cells were commonly found within the sinusoids. The present results indicate that arterialization of the liver induces a partial (but not complete) transition of SECs into capillary-type endothelial cells, suggesting that arterialization might be one of the factors which induce sinusoidal capillarization in the development of hepatocellular carcinoma.

Erythrocyte deformability is an important factor in the microcirculation. The deformability in patients with chronic liver disease is less than normal. We studied changes in erythrocyte deformability in 32 patients undergoing liver resection for hepatocellular carcinoma with underlying chronic liver disease to investigate whether the measurement of deformability gives information useful for postoperative management. We measured erythrocyte deformability as erythrocyte transit time (ETT) before and after resection, as well as the erythrocyte adenosine triphosphate level, mean corpuscular volume, mean corpuscular hemoglobin concentration, and indices of liver function. The 15-minute indocyanine green retention rate (ICGR15) was measured before resection. Correlations between the change in deformability and these values were evaluated, as was correlation with the scale of the operation and with the occurrence of postoperative complications. Mean ETT was higher in the patients before resection than in healthy volunteers. ETT was correlated with serum high density lipoprotein-cholesterol (p0.05). The incidence of postoperative complications was higher (p = 0.001) in the patients (group A) with ETT increased during the first 3 postoperative days by/=1 SD of the mean of the preoperative value than in patients (group B) with less change. Of the 12 patients whose ICGR15 value was/=20%, all 9 patients in group A had postoperative complications. The increase in ETT (decrease in erythrocyte deformability) is associated with the development of postoperative complications. The measurement of erythrocyte deformability gives information useful for postoperative management, and special monitoring for postoperative complications is necessary in patients with the increase soon after liver resection.

Although extracellular ATP and ADP which are released from activated platelets and injured cells are important for various biological functions, their roles in the regulation of porto-sinusoidal circulation are not known. When infused in isolated perfused liver of the rat, ADP, ATP and UTP but not adenosine transiently increased the perfusion pressure (UTP>>ATP>ADP). Infusion of adenosine, ADP, and ATP, but not UTP transiently increased the generation of nitric oxide (NO) as measured by an NO-selective electrode. N G -Nitro- l -arginine, an NO synthase inhibitor, strongly inhibited the generation of NO and enhanced the nucleotide-induced increase in the perfusion pressure. These observations suggested that ATP and related nucleotides simultaneously induce purinoreceptor-mediated contractile response and NO-mediated relaxation, consequently.

In an attempt to define better surgical strategies for patients with hepatocellular carcinoma (HCC), we conducted a retrospective analysis of 452 patients who underwent hepatic resection at our institute during a period of 15 years. The patients were divided into two groups: group A, comprising 188 patients who underwent hepatic resection before 1988, and group B, comprising 264 patients after 1989. These groups were compared clinicopathologically. The percentage of patients with Child's A disease but without cirrhosis, in group A was lower. The diameter of the resected tumor was larger in group A, and major hepatic resections and curative operations were more frequently performed in group A. In group B, there was less blood loss, the specimen weighed less, and the hospital mortality was lower. Although the tumor-free survival rates were similar between the two groups, the survival rate in group B was significantly better. While even minor hepatic resection accompanied by a lower rate of surgical margin-free surgery has contributed to making hepatic resection safer, it has not improved the tumor-free survival rate. Conversely, recent advances in imaging modalities used during follow-up for the early detection of recurrence and for planning multimodality treatment have contributed to increasing the survival rate.

1997年3月末までにCT during arterioportographyとCT during arteriography (CTA) を併用した血管造影下CT (angio-CT) を施行後に開腹した肝細胞癌 (肝癌) 103例中, angio-CT単独陽性結節は9例 (10結節, 9%) にみられた. 男女比は8: 1, 平均年齢は63歳. 8例にHCV抗体, 1例にHBs抗原を認めた. 臨床病期I期6例, II期3例で, 5例には肝硬変を認めた. 単独陽性結節径は平均1cm. 全例主病巣は別に存在し, CTAでhigh density areaを呈しangio-CT以外の画像診断法で描出されなかった. 術後平均観察期間は608日で, 5例に残肝再発がみられたが, angio-CT単独陽性結節からの残肝再発は肝深部に存在していた2結節 (20%) にみられた.angio-CT単独陽性結節のうち少なくとも20%は真の肝癌結節であるが, 肝辺縁部の結節は偽陽性結節の可能性が高い.

Tumor metastasis can be prevented by inhibiting angiogenesis. In the present study, we have demonstrated that the angiogenesis inhibitor TNP-470 also suppresses the development of primary hepatic nodules. Hepatocarcinogenesis was performed by the feeding of 2-acetylaminofluorene to hepatectomized rats during 8-14 weeks of age. Predominantly arterial-to-portal circulation and sinusoidal capillarization were determined by the staining of nodules with arterially infused ink and immunostaining for factor VIII-related antigen, respectively. Intraperitoneal administration of 30 mg/kg b.w. of TNP-470 twice a week significantly reduced the number of hepatic nodules. Among the nodules, hyperplastic nodules stained with ink, atypical hyperplastic nodules and hepatocellular carcinoma, all of which possess structurally altered sinusoidal endothelial cells or capillary-type endothelial cells, were dramatically decreased in number. Suppression was observed equally in nodules of all sizes. TNP-470 was more effective when administered during 8-20 weeks than during 14-26 weeks. In contrast, ink-non-stained hyperplastic nodules, which have normal sinusoidal endothelial cells, were not affected at all. The present results indicate that TNP-470 suppresses the development of primary hepatic nodules whose microvessels are capillaries or transitional forms from sinusoids to capillaries.

Conclusion. Serous cystadenomas of the pancreas may have the biologic ability to undergo malignant transformation. Background. It is generally recognized that: serous cystadenomas of the pancreas are benign and that their malignant potential is low. Methods. A serous cystadenoma of the pancreas was resected from a 53-yr-old woman. In the central portion of the tumor, papillary structures were found on the cyst wall. Immunohistologic studies using antibodies to carbohydrate antigen 19-9, carcinoembryonic antigen, and proliferating cell nuclear antigen were performed to determine the malignant potential of this tumor. Results. On histology, most tumor cells were positive for periodic acid-Schiff but were negative for periodic acid-Schiff after diastase digestion and Alcian blue, a staining pattern typical of serous cystadenomas. The cells found in the papillary structure of the cyst wall were mildly atypical. These cells were stained with antibodies to carbohydrate antigen 19-9, carcinoembryonic antigen, and proliferating cell nuclear antigen, indicating that the cells comprising the papillary structure were proliferating more rapidly than cells in other parts of the tumor and strongly suggesting that the cells are premalignant.

We treated 2 patients with hepatocellular carcinoma by laparoscopic partial hepatectomy. The longest diameters of the tumors were 25 mm and 30 mm. The both tumors were located at the edge of segment 3 in the liver. After observation of the surface of the liver during laparoscopy as usual, we punctured the surrounding tissues around the tumors with electrode needle and coagulated 80 W for 45 seconds with microwave tissue coagulator. And resected the coagulated lesions with Laparoscopic Coagulating Shears System. The bleeding were few and no serious complications were not found. The resected specimens showed that the tumors were completely resected. Laparoscopic partial hepatectomy was useful for hepatocellular carcinoma located at the edge of the liver.

症例は52歳の男性. 1990年10月左腎癌の診断のもと左腎摘出術をうけ, 術後インターフェロンを投与された. 1996年10月検診の上部消化管造影検査にて異常陰影を指摘され, 精査の結果胃癌と診断された. 11月18日開腹すると胃角部に3×2cmのIII+IIc類似進行癌を認め, さらに空腸起始部に6×9cmの腫瘤を認めた. 胃癌に対し胃幽門側切除術, D2リンパ節郭清を, 小腸腫瘍に対し口側断端を十二指腸第4部とした小腸部分切除術を行った. 再建は空腸断端を十二指腸第2部に側側吻合したのち, BillothII法による胃空腸吻合を行った. 病理組織診断は胃癌は高分化型管状腺癌, 小腸腫瘍はmalignantlymphoma of mucosa-associated lymphoid tissueであった. 術後VEPA療法を施行し術1年7か月後の現在, 再発の徴候なく健在である.

Multicentric occurrence is an important characteristic of hepatocellular carcinoma. We evaluated clinicopathological criteria for multicentric hepatocellular carcinoma and identified risk factors for such carcinogenesis. Subjects were 251 consecutive patients undergoing liver resection for hepatocellular carcinoma. One kind of multicentric hepatocellular carcinoma had at least one tumor consisting of well-differentiated hepatocellular carcinoma, together with moderately or poorly differentiated hepatocellular carcinoma located in a separate region. The other kind had an area of well-differentiated component around hepatocellular carcinoma with less differentiation in all occurrences. The outcome of patients with tumors classified in this way was studied. Univariate and multivariate analyses were done to identify risk factors for multicentric hepatocellular carcinoma. The cumulative survival rate was significantly higher in patients with multicentric hepatocellular carcinoma than in patients with hepatocellular carcinoma associated with intrahepatic metastasis. Analysis by Cox's proportional hazard model showed that multicentricity was not a factor in the outcome. The risk of multicentric occurrence increases with progression of chronic liver disease. Univariate analysis showed hepatitis C virus marker and hepatitis B core antibody to be risk factors. By multivariate analysis, the odds ratio for multicentric occurrence in patients infected with hepatitis C virus and with serum hepatitis B virus core antibody compared with patients without either hepatitis C virus or hepatitis B virus was 10.86. This ratio in patients with hepatitis C virus alone was 4.30. These criteria for multicentric hepatocellular carcinoma seem to be clinically useful. Hepatitis C virus infection with or without former infection by hepatitis B virus is a strong risk factor for multicentric hepatocarcinogenesis.

We investigated morphological and functional changes after portal vein occlusion in rats. Portal branches for the median and left lateral lobes were ligated, after which the lobes were examined micromorphologically. After embolization of the same branches, regenerative capacity was evaluated in normal livers and in livers with CCl4-induced cirrhosis. Indocyanine green elimination, antithrombin III activity, and Kupffer cell density were also investigated. In another set of rats, the embolized lobes were resected 0, 2, 4, or 7 days after portal vein embolization (PVE), and endotoxin was injected intravenously 48h after each hepatectomy. In the ligated lobes, apoptotic hepatocytes were detected mainly around a widespread necrotic area on day 2, and among normal hepatocytes on day 7. In the nonembolized livers of control rats, increases were noted in liver weight, ornithine decarboxylase (ODC) activity, DNA synthesis, and mitosis of hepatocytes. In the cirrhotic livers, ODC activity was stimulated in a fashion similar to that seen in control liver, but DNA synthesis and weight change was delayed, although not significantly. On days 2, 4, 7, and 14 PVE, Kupffer cell density was about twice that seen in rats before PVE. Endotoxin-induced liver injury was slight if the rats had received PVE 4-7 days before the hepatectomy.

Hepatocellular carcinoma (HCC) is often associated with chronic liver disease, such as hepatitis or cirrhosis, and this association may limit the use of surgery as a therapy, and if surgery is pursued, may give rise to postoperative hepatic failure. We evaluated the outcome in patients with HCC given preoperative portal vein embolization (PVE) before they underwent major hepatectomy. After PVE, portal pressure increased significantly. Two weeks after PVE, both the volume of the non-embolized lobe and the 15-min indocyamine green retention rate (ICG R15) were significantly increased. The prognostic score, calculated on the basis of age, ICG R15, and the resection rate, was significantly decreased. The operative mortality rate was significantly lower in patients who underwent PVE before surgery than in patients who did not receive PVE. The cumulative survival rate of the PVE patients, even those with cirrhosis of the liver, was significantly higher. Prior PVE appears to allow more extensive major hepatectomy and to lessen the risk of this invasive surgery. However, patients in whom the portal pressure immediately after PVE was more than 30cm H2O and/or whose prognostic score exceeded 50 points developed postoperative hepatic failure. These features should be kept in mind when it is decided whether surgery is indicated. Nevertheless, preoperative PVE appears to be a beneficial procedure for patients undergoing major hepatectomy, particularly those with chronic liver disease.

Background/Aims: The role of the hepatitis GB virus C in chronic liver disease is unclear. The clinical findings, results of laboratory tests, pathological findings, and outcome after liver resection for hepatocellular carcinoma in patients infected or not infected with GB virus C were compared. Methods: Serum samples from 213 patients were tested for hepatitis B virus, hepatitis C virus, and GB virus C. Of the 213 patients, 159 had hepatitis C viral RNA or antibodies (group 1), seven had both hepatitis C viral RNA or antibodies and hepatitis B surface antigen (group 2), 25 had hepatitis B surface antigen (group 3), and 22 did not have hepatitis C viral RNA, hepatitis C antibodies, or hepatitis B surface antigen (group 4). Results: GB virus C RNA was detected in 12 of the 213 patients. Of the 12 patients, 11 were in group 1 and one was in group 4. There were no patients with hepatocellular carcinoma associated with GB virus C RNA alone. In groups 1 and 4, there were no differences in clinical findings, results of laboratory tests, pathological findings, or outcome after surgery in patients with and without GB virus C RNA. Conclusions: These results indicate a poor association of GB virus C viremia with hepatocellular carcinoma. We did not find any clinically significant interaction between hepatitis C virus and GB virus C.

We investigated the relationships between alcohol consumption, the degree of malignancy evaluated histologically, and tumor-free survival rates.In 80 male patients with the hepatitis C virus and small hepatocellular carcinomas (diameter of main tumor, 3.0 cm or less), 38 patients had drunk 86 gm or more of ethanol per day for at least 10 years until the detection of hepatocellular carcinoma (group 1), whereas the remaining 42 patients were nondrinkers or occasional drinkers (group 2).Differences in the results of liver function tests between the groups were not statistically significant. The operative methods used in the groups were comparable. The proportion of well-differentiated hepatocellular carcinoma was lower in group 1 than in group 2 (p0.0001). The prevalences of extracapsular invasion, portal tumor thrombi, and intrahepatic metastasis were higher in group 1 than in group 2 (p = 0.0085, p = 0.0319, and p = 0.0428, respectively). The tumor-free survival rate after operation was lower in group 1 than in group 2(p = 0.041 by the log-rank test; p = 0.032 by the generalized Wilcoxon test).These findings indicate that in group 1, even though tumors were small, the carcinomas were advanced and the outcomes after surgery were poor, suggesting that alcohol affects the grade of malignancy of this disease.

A 55-year-old woman underwent a laparotomy with a preoperative diagnosis of cholelithiasis. During operation, a mass occupying the cystic duct was found and intraoperative frozen section diagnosis was made with primary carcinoma of the cystic duct. Primary cystic duct carcinoma is rare. We found 15 cases of the disease in the Japanese literature, of which only four cases were diagnosed preoperatively. Of the methods currently used for diagnosis of this disease, endoscopic ultrasonography may be the most useful when the cystic duct is obstructed.

To understand the recurrence rate and transplantability after liver resection (LR), which are essential factors to predict the prognosis of initial resection and salvage transplantation for hepatocellular carcinoma (HCC), we reviewed the clinical records of 279 consecutive HCC patients who met the Milan criteria and underwent LR between 1990 and 2000. Recurrence-free survival rates after 1, 2, 3, 5, and 10 years following LR were 84%, 62%, 49%, 29%, and 17%, respectively. Multivariate analysis using clinical factors such as age, sex, histological differentiation, serum levels of alpha-fetoprotein and 7S domain of type IV collagen (7S collagen), platelet counts, indocyanin green retention test after 15 minutes, and type of LR (resection of one or more segments, or less than one segment) revealed 7S collagen to be a independent factor that significantly affects recurrence-free survival. Yearly recurrence rates up to 5 years after resection ranged from 14% to 27%, averaging 20%. Concerning 169 patients who underwent tests for 7S collagen, the average yearly recurrence rate (27%) in patients with 7S collagen levels 8.0 ng/mL or higher was remarkably greater than that in the patients with levels less than 8.0 ng/mL (16%). The transplantability rate at the time of recurrence meeting the Milan criteria was roughly 60%. There were no pre-LR factors that significantly predicted transplantability. This result indicates that patients with lower 7S collagen levels are more eligible for initial LR and then salvage LT rather than primary LT.

A 69-year-old Japanese woman underwent a curative operation for rectal cancer (T2, N0, M0, Dukes B, R0, and stage IIA of American Joint Committee on Cancer) 3 years ago. On subsequent routine follow-up, a right-side thyroid nodule and a regional lymph node of up to 1.5 cm in diameter was palpated. FDG-PET demonstrated high FDG accumulation in the right lobe of the thyroid gland, neck lymph nodes, and sacral periosteum. We diagnosed a local recurrence of rectal cancer and a primary thyroid cancer. We chose radiotherapy for the periosteal recurrence, and then right hemithyroidectomy with regional lymph node dissection for the thyroid tumor was performed. Pathological examination demonstrated mucinous carcinoma, the same as the previous surgical specimen from the rectum. She had been treated with postoperative chemotherapy and had been alive and well for 26 months with lung metastases. Although thyroid gland metastasis from colorectal cancer is rarely reported, physicians should consider the possibility of thyroid gland metastasis when performing routine follow-up examinations for recurrence of colorectal cancer.

The sinusoidal structure and blood supply of 38 liver nodules less than 2 cm in diameter were investigated. There were 18 cases of adenomatous hyperplasia (AH) and 20 cases of hepatocellular carcinoma (HCC). Growth pattern, encapsulation and vascularity were examined, and immunohistochemistry performed for factor VIII related antigen (factor VIII), type IV collagen (collagen IV), laminin and CD68. There were significant differences between AH and small HCC, except for the expression of CD68. There were differences in tumor size, vascularity and the components of the basement membrane between AH and small, well differentiated HCC. The cases of AH were supplied by the portal system and maintained the sinusoidal structure, but small well-differentiated' HCC were supplied by a mixture of portal and arterial vessels. In spite of their small size, moderately and poorly differentiated HCC had capillary and were supplied by branches of the hepatic artery.

To characterize hepatocellular carcinoma (HCC) cells with mutant (m) p53 protein histologically, we examined 68 main nodules and 20 accessory lesions of 72 patients with HCC who underwent hepatic resection between October 1990 and September 1993. Some sections were fixed in periodate-lysine-paraformaldehyde, embedded in OCT compound, and stained with the mouse monoclonal antibody PAb1801 to m-p53 protein by the immunoperoxidase technique with avidin-biotin complexes. Other sections were fixed in 20% buffered formalin, embedded in paraffin, and stained with the mouse monoclonal antibody DO-1 to m-p53 protein in the same way. Lesions in which cells had nuclei stained for m-p53 protein were defined as being positive for the protein; 25 of the 68 main nodules and 14 of the 20 accessory lesions were positive. Large main nodules were more likely to be positive than small ones. Microscopic examination showed that a larger proportion of poorly differentiated main nodules than well differentiated nodules were positive. Larger proportions of main nodules with extracapsular invasion, septa, portal thrombi, or intrahepatic metastases were positive than main nodules without these features. Accessory lesions that seemed to be metastatic were almost all positive, but few accessory lesions that seemed to be of multicentric occurrence were positive. Our results suggest that lesions with m-p53 protein had a high grade of malignancy and metastasized readily.

Cytokines and acute phase-proteins are important in infectious diseases and under surgical stress, especially in postoperative infections. To study the effects of antibiotics on changes in cytokines and acute-phase proteins after surgery, we measured serum levels of interleukin 6 (IL-6), elastase from granulocytes, pancreatic secretory trypsin inhibitor (PSTI), C-reactive protein (CRP), and fibrinogen after liver resection in 12 patients with hepatocellular carcinoma. In the six of the 12 patients (group A), flomoxef (FMOX, 4 g/day) was administered intravenously for 3 days after surgery. In six other patients (group B), imipenem-cilastatin (IPM/CS, 1g/day) was administered for the same period. Group A was comparable to group B in age distribution of patients, preoperative hepatic function, operating time, and intraoperative bleeding volume. No patients had postoperative complications. The mean changes in serum levels of IL-6 in group B were smaller than those in group A. The changes in serum levels of elastase, PSTI, CRP, and fibrinogen were also smaller than those in group A. These results suggest that IPM/CS suppressed the usual increases after major surgery in the levels of IL-6 and acute-phase proteins. This preparation may suppress the progress of hypercytokinemia in the systemic inflammatory response. The effects of antibiotics on cytokines and acute-phase proteins should be considered in the choice of antibiotics for severe infectious diseases.

All 69 patients with amebic liver abscess that we treated in 1981-1992 were studied retrospectively. Men predominated by a 10:1 ratio. Of our 227 patients with amebiasis, some 30% yearly had liver involvement. The incidence peaked in 1988, decreasing later but increasing again in 1992. Most patients were 30-50 years old, the overall mean age being 45 years (range, 22-79), and decreasing with time. Patients with the related factors of travel abroad, positive results of a test for Treponema pallidum hemagglutination, and homosexuality have increased in number in recent years. Fever, abdominal pain, and hepatomegaly were the most frequent findings, and 39 patients had neither bloody stools nor diarrhea. Only 8 patients had had amebiasis previously. A solitary abscess in the right lobe of the liver was found in 40 patients. Entamoeba histolytica was found in the stool of 31 patients and in the pus of 39 patients. Sixty-one patients had positive results for an amebic serological test(s). The abscesses ruptured into the peritoneal cavity in 4 patients. All patients received metronidazole. Percutaneous or surgical drainage (or both) was done in 62 patients. The outcome was good, with 1 exception, and only 2 patients had recurrences.

1993年末までの主腫瘍径2cm以下の小肝細胞癌 (肝癌) 切除82例を対象に, 術式と肝機能評価法, 予後との関係を検討した. 施行術式はHr2: 8例, Hr1: 11例, HrS: 20例, Hr0: 43例であり, 広範囲切除例の肝機能は良好であったが, 術式決定には術中の肝肉眼所見が最も重視されていた. 82例中39例が残肝再発したが, Hr2の予後は他の肝切除術式より良好であった. そこでHr2可能条件をICGR1515%以下, CS1, Z1以下と仮定すると, Hr2未満切除74例中12例がHr2可能例であったが, 再発は2例にすぎなかった. 逆にHr2未満施行で再発をきたした37例のうちHr2を行えば切除領域に再発病巣が含まれた症例は7例であったが, Hr2可能例は1例に過ぎなかった. 小肝癌に対する切除術式は再発からみると, 術前の肝機能成績および術中所見を考慮した現行の基準が適切であると考えられた.

高齢者肝細胞癌に対する拡大肝切除の限界と対策を検討するため, 肝切除施行肝癌391例のうち70歳以上を高齢者 (34例), 75歳以上を超高齢者 (7例) と定義, これらを他の非高齢者 (357例) と対比した. 非高齢者群の術死, 在院死は13例4%であったが, 高齢者群では6例15%であった (p

A 44-year-old woman with known progressive systemic sclerosis was seen at the hospital because of anal discomfort and bloody stool. Digital examination revealed a grayish polypoid lesion in the posterior wall of the anal canal. With a preoperative diagnosis of internal hemorrhoid or anal polyp, the lesion was extirpated. Histopathologically the extripated tumor was malignant melanoma. So rectal amputation with lymph node dissection through abdomino-sacral approach was carried out. About one month later a metastasis to the inguinal lymph node developed. Malignant melanoma has a poor prognosis, because of delayed diagnosis, the high vascularity of the anal region, and high biological malignancy such as vascular and lymphatic spread. Though there was no statistical difference in the prognosis between local resection and rectal amputation, a few patients undergoing rectal amputation could live for more than 5 years. Rectal amputation of the abdomino-sacral method with lymph node dissection is recommended. The disease presents difficulty in diagnosis from macroscopic findings and absolutely demands intraoperative or emergent microscopic frozen section diagnosis.

Hilar bile duct carcinoma has a poor prognosis, but this has been improved in recent years by an aggressive surgical approach. We treated a 73-year-old woman who had obstructive jaundice due to bile duct carcinoma at the hepatic hilum. The jaundice decreased after percutaneous transhepatic biliary drainage. The tumor was resected with the left and caudate lobe of the liver and a part of portal vein. The right hepatic artery was located behind the common hepatic duct, and was suspected to be invaded by the tumor. We dissected the tumor from the arterial wall without carrying out combined resection of the hepatic artery. On the 6th postoperative day, the hepatic artery ruptured and the patient suffered hypovolemic shock. Resection of the hepatic artery and reconstruction were done, but the patient died 2 days later. Histological examination of the resected artery showed that the tumor had been curatively removed by dissection and that no tumor remained at the arterial wall. The rupture of the right hepatic artery was thought to have been caused by damage to the wall during the dissection procedure.