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A 42‐year‐old man with schizophrenia was referred to our hospital after 2 weeks of worsening fatigue. His hemoglobin level was 2.8 g/dL owing to folic acid deficiency stemming from alcohol abuse and consumption of unbalanced meals. We induced behavioral changes in the patient by motivational interviewing. We had direct methodical conversations with medical staff involved with the patient as well as his family, and established new social support for him as well as public assistance. These have resulted in the patient maintaining a favorable lifestyle ever since.

The accuracy of measurements of the intima-media thickness (IMT) and flow-mediated dilatation (FMD) of the brachial artery made using a new semiautomated ultrasound system and the relationships among those parameters and the Framingham Risk Score (FRS) as a predictor of coronary heart disease (CHD) are unknown. We enrolled 70 subjects, including 47 patients with cardiovascular risk factors and 23 normal healthy volunteers. IMT and FMD were simultaneously measured using a new semiautomated ultrasound system, and the measurements were compared with those obtained manually as a reference standard (study 1). In addition, we enrolled 200 consecutive patients with risk factors but no CHD to examine the relationships among IMT, FMD and the FRS. The optimal cutoff values of FMD and IMT were determined in 200 patients without CHD, and the subjects were classified into four groups. The 10-year Framingham risks for each group were compared (study 2). FMD and IMT measurements made using the new semiautomated ultrasound system showed a good correlation with the measurements determined manually (study 1). Furthermore, FMD and IMT showed a significant correlation with the FRS. The 10-year Framingham risk was markedly higher in group D (FMD5.5% and IMT0.3 mm; 19.0±11.3%; study 2). In conclusion, the measurements made using a new semiautomated ultrasound system provided reliable and simultaneous evaluations of IMT and FMD. The combination of IMT and FMD measurements of the brachial artery may be beneficial for risk stratification of patients with cardiovascular risk factors but no CHD.

A 62-year-old man had been followed up for chronic hepatitis B (HB) since 1973. Hepatocellular carcinoma (HCC) was detected in 1985, at the age of 42 years. Serum HB surface antigen and anti-HB envelope antibody were positive at that time. A right hepatic lobectomy was performed. In 1995, serum HB surface antigen had cleared spontaneously and liver function had normalized. In March 2005, at the age of 62 years, a 1.5-cm diameter hepatic mass was detected in the left lateral segment. At that time, he was seropositive only for anti-HB core antibody. A diagnosis of recurrent HCC was made, and partial hepatectomy was performed. Covalently closed circular HBV DNA was detected in both cancerous and noncancerous tissues by nested polymerase chain reaction (PCR). Cassette-ligation-mediated PCR showed that HBV DNA was integrated into the telomerase reverse transcriptase gene located on chromosome 5p15.

Interferon therapy suppresses the development of hepatocellular carcinoma (HCC) and tumor recurrence after a resection of HCC in patients with chronic hepatitis C. However, the value of a liver resection and which method is best for the treatment of HCC detected after successful interferon therapy remains to be clarified. The risk factors for tumor recurrence after a liver resection for HCC detected after successful interferon therapy were investigated to determine the appropriate operative method for such HCC.Risk factors including the clinicopathologic findings and the operative methods for tumor recurrence were evaluated by univariate and multivariate analyses in 24 patients who underwent liver resection for HCC detected after successful interferon therapy (sustained viral response or biochemical response).According to a univariate analysis, large tumor (2 cm, P = 0.0326), multiple tumors (P = 0.0372), nonanatomic resection (P = 0.0103), and positive surgical margin (5 mm of a free surgical margin, P = 0.0245) were possible risk factors for short tumor-free survival time after surgery. A multivariate analysis showed that large tumor (P = 0.0407), nonanatomic resection (P = 0.0215), and positive surgical margin (P = 0.0253) were independent risk factors for a short tumor-free survival time after surgery.An anatomic resection with an appropriate surgical margin (or = 5 mm of a free surgical margin) is recommended for patients with HCC detected after successful interferon therapy.

Varenicline has been reported to achieve high rates of smoking cessation. It remains undetermined whether varenicline therapy improves vascular function in smokers.Consecutive Seventy-two smokers (age 57 ± 12 years) who succeeded in complete smoking cessation and 46 normal healthy volunteers (age 24 ± 3 years) with no cardiovascular risk factors were enrolled into this study. Vascular function and structure were assessed by flow-mediated dilation (FMD), nitroglycerin-induced vasodilation, and brachial artery intima-media thickness (baIMT) at baseline and 20 weeks after the initiation of varenicline therapy in smokers. FMD and baIMT were measured simultaneously using a semi-automatic vessel wall-tracking software program. 75 μg dose of a nitroglycerin tablet were sublingually administered for the nitroglycerin-induced vasodilation measurement.Exhaled-carbon monoxide concentration decreased significantly (20.0 ± 11.1 ppm at baseline vs 1.9 ± 1.5 ppm after 20 weeks, p0.001). FMD was significantly improved after 20 weeks (4.09% ± 1.83% at baseline vs 4.77% ± 2.33% after 20 weeks, p = 0.010), whereas nitroglycerin-induced vasodilation and baIMT were not significantly changed.Smoking cessation with varenicline therapy significantly increased FMD without significant changes of nitroglycerin-induced vasodilation or baIMT from baseline to 20 weeks. It appears to improve vascular function in smokers, which depends on endothelial function rather than on vascular smooth muscle function or changes in vascular structure.

A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed.

Background Clinically, portal vein embolization has been proven to be useful as a preoperative treatment for major hepatic surgeries with impaired liver function. However, its effects on the metabolism and elimination of various drugs after portal vein embolization or ligation remain to be elucidated. Materials and methods A portal vein branch that perfuses the central and left lobes of the liver of male Wistar rat was ligated, and changes in the weights of ligated and nonligated lobules as well as hepatic levels and activities of cytochrome P450 (CYP) isoforms, such as CYP3A2 and CYP2C11, were determined. To evaluate in vivo the effect of PVL on hepatic drug metabolism, the narcotic activity (sleep time) of midazolam, a specific substrate for CYP3A2, was measured. Results Although plasma levels of alanine aminotransferase and hepatic weight returned to basal levels at day 7 after the portal vein ligation, hepatic activities of CYP3A2 and CYP2C11 still remained low (53% and 54% of control levels, respectively), and returned to their initial levels after about day 14. The metabolism of midazolam was prolonged by approximately three times at day 7 after ligation and returned to basal levels at day 14. Conclusions Because hepatic CYP-dependent drug metabolism by CYP isoforms recovered more slowly than the apparent recovery of hepatic volume and plasma alanine aminotransferase levels, the therapeutics of drugs metabolized by the CYP isoforms should be used carefully in patients who receive major hepatectomy with portal vein branch embolization.

We examined the expression of mucin core protein 1 (MUC1) immunohistochemically in 186 surgical specimens of histopathologically nonmucinous hepatocellular carcinoma (HCC) and compared the clinicopathological features in patients with MUC1-positive HCC (MUC1-positive group) with those in patients with MUC1-negative HCC (MUC1-negative group).MUC1 immunoreactively was present in 85 of the 186 HCCs. Of the clinicopathological variables examined, the serum concentration of alpha-fetoprotein, tumor differentiation, bile duct invasion, lymph node metastasis, and cytokeratin 19 expression exhibited significant associations with MUC1 expression. Although cumulative and tumor-free survival rates were not different between the two groups, the percentage of patients with first recurrence of HCC in distant organs (distant metastasis) within 2 years after surgery was significantly higher in the MUC1-positive group than in the MUC1-negative group (P = 0.0104). The risk ratio of MUC1 positivity for this type of distant metastasis was 3.156 (95% confidence interval, 1.064-9.358).In patients with MUC1-positive HCC, careful follow-up is necessary, not only for intrahepatic recurrence but also for distant metastasis, after the resection of primary HCC.

The Liver Cancer Study Group of Japan established a tumor-nodule-metastasis (TNM) staging system for mass-forming intrahepatic cholangiocarcinoma, with T determined by tumor number and size and vascular or serosal invasion. Serosal invasion is not considered in the designation established by the International Union Against Cancer.Sixty-three patients who underwent hepatic resection for mass-forming intrahepatic cholangiocarcinoma were investigated retrospectively, with the investigation including univariate and multivariate analyses of potential prognostic factors.By log-rank test, tumor size more than 3.0 cm, vascular invasion, lymph node metastasis, intrahepatic metastasis, and involved resection margin, but not serosal invasion, were associated significantly with poor prognosis. Even in patients with serosal invasion, the postoperative outcome was much better in those without than in those with vascular invasion. Multivariate analysis identified vascular invasion, lymph node metastasis, and an involved resection margin as independent prognostic factors. When serosal invasion was excluded from tumor staging, the 5-year survival rates became more clearly stratified: 100% in those with stage I disease, 62% in those with stage II, 25% in those with stage III, and 7% for patients with stage IV.Serosal invasion showed no survival impact after hepatic resection for mass-forming intrahepatic cholangiocarcinoma. When serosal invasion was omitted from the TNM staging proposed by the Liver Cancer Study Group of Japan, stratification of postoperative survival between stages was more effective.

Pancreatoduodenectomy can be difficult in patients with obstruction of the celiac axis because of the development of collateral arteries around the head of the pancreas. Bleeding from a pseudoaneurysm is a rare and serious complication of pancreatoduodenectomy. We report a case of a pseudoaneurysm of an enlarged dorsal pancreatic artery, which formed as a result of obstruction of the celiac axis after pancreatoduodenectomy. We assumed that a weakness in the wall of this dorsal pancreatic artery caused by the dissection led to the formation of the aneurysm. Although transcatheter arterial embolization (TAE) could not treat the aneurysm or stop bleeding from the aneurysm completely, it achieved transient hemostasis, whereby the patient's condition improved, making laparotomy safe. This case demonstrates that the dissection of arteries that have developed around the head of the pancreas must be considered in patients with obstruction of the celiac axis.

The etiologic role of alcoholic liver disease for hepatocellular carcinoma is uncertain. To assess the role of alcoholic liver disease on the development of carcinoma, we examined history of alcohol abuse and viral markers in the sera and/or resected specimens in 454 patients who underwent liver resection for hepatocellular carcinoma. Sera from 20 of the 454 patients were negative for hepatitis B, C, and D viruses. Of the 20 patients, one patient had autoimmune hepatitis, one had primary biliary cirrhosis, two had non-alcoholic steatohepatitis. Of the remaining 16 patients, 8 patients were alcohol abusers and 5 of the 8 patients were heavy alcohol abusers. Hepatitis G virus was not detected in sera form the 16 patients. Although hepatitis B x gene was detected in the cancerous and/or non-cancerous tissues in all three alcohol abusers but not heavy abusers and in 5 of 6 non-alcohol abusers whose surgical specimens were available, the gene was detected in only one of the five heavy alcohol abusers. The five heavy alcohol abusers had advanced hepatic fibrosis and active hepatitis. Alcoholic liver disease with advanced hepatic fibrosis and active hepatitis is a possible cause for the development of hepatocellular carcinoma.

Aim: To clarify whether hepatocellular carcinoma (HCC) originates from hepatic progenitor cells and whether there is any correlation with the clinicopathologic factors of HCC, we reviewed 217 resected HCC specimens. Methods: Immunohistochemical examination of cytokeratin (CK) 7, CK19, CD34, and CD117 (c-KIT) was performed. Overexpression of CK7 and CK19 indicates differentiation from cholangiocellular and hepatic progenitor cells, while overexpression of CD34 and CD117 indicates hepatic stem cells. Fresh specimens were obtained from 20 HCC patients for mutation of the c-KIT gene. Results: CK7, CK19, and CD117 were positive in 41, 9.7, and 0.9% of the HCC specimens, respectively, and CD34 was never positive. None of the fresh HCC specimens demonstrated a c-KIT mutation. CK19 positivity was significantly correlated with a positive hepatitis B core antibody, and with poor survival outcome, and tended to correlate with poor histologic differentiation. Conclusion: These results suggest that: (i) about 10% of HCCs with typical histologic features originate from an intermediate hepatic progenitor cell, such as the canal of Hering and oval cells in the rat, or acquire the characteristics of cholangiocellular epithelium by metaplasia; (ii) HCC with typical histologic features rarely originates from hepatic stem cells, and (iii) patients with CK19-positive HCC have a poor prognosis.

We investigated the correlation between serum concentrations of type IV collagen 7s domain (7s collagen) and changes in the volume of the nonembolized liver lobe after subsequent portal vein embolization (PVE).The relationship between the pre-embolization results of laboratory tests and the increase in the left lobe volume was evaluated in 32 patients who underwent preoperative PVE via the right portal vein.By 2 weeks after PVE, the mean volume of the left lobe had increased significantly (P0.001). The percent increase in the left lobe volume correlated negatively with the pre-embolization serum concentration of 7s collagen (r = -0.472, P = 0.0063). In three of four patients with high serum concentrations (8 ng/ml), the percent increase was less than 100% and right lobectomy was not performed. The serum 7s collagen concentration correlated with the histologic activity score (r = 0.469, P = 0.0061) and the histologic fibrosis score (r = 0.425, P = 0.0145).The serum concentration of 7s collagen may predict the efficacy of PVE. Performing PVE before right lobectomy may not be indicated in patients with high serum concentrations of 7s collagen because the increases in left lobe volume may be insufficient.

Ischemia-reperfusion injury is responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. Recently, it has been reported that mitochondrial K A T P channel openers have an effect on myocardial protection via a pharmacological preconditioning action. However, it remains unclear as to whether K A T P channel openers can reduce ischemia-reperfusion injury in the liver. The aim of this study was to determine the effects of the mitochondrial K A T P channel opener, nicorandil, on ischemia-reperfusion injury in the rat liver. Male Wistar rats were subjected to 73% ischemia for 45 minutes followed by 120 minutes of reperfusion. Nicorandil (3 mg/kg) was orally administered 60 minutes before hepatic ischemia. Nicorandil significantly decreased plasma levels of alanine aminotransferase and lactate dehydrogenase by about 50% and inhibited the remarkably increased TUNEL-positive hepatocytes after reperfusion. Some mediators associated with apoptosis were analyzed by Western blotting. Cytochrome-c and caspase-3 levels in the cytosol increased after reperfusion; nicorandil inhibited the release of cytochrome-c and activation of caspase-3. The expression of Bax and Bcl-2 was significantly increased after reperfusion, being slightly inhibited by the administration of nicorandil. These results suggest that the protective effects of nicorandil against hepatic ischemia-reperfusion injury correlate with the inhibition of mitochondrial cytochrome-c release and caspase-3 activation. These findings demonstrate that nicorandil may become a therapeutic drug for ischemia reperfusion-related liver injury.

Background. In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed. Methods. Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography. Results. The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. Conclusions. FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.

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Background The prognosis of hepatocellular carcinoma originating in or mainly involving the caudate lobe (caudate HCC) is generally poor. We reviewed the clinicopathologic findings of patients who underwent liver resection of caudate HCC and correlated the outcome with the surgical strategy. Methods Records of 402 patients who underwent liver resection for HCC were reviewed. The patients were divided into 2 groups. One group consisted of 15 patients who underwent liver resection for caudate HCC. The other group included 387 patients with HCC in a site other than the caudate lobe. Results Anatomic resection of Couinaud segment I or IX (a partial caudate lobectomy), conforming to portal anatomy, was performed in 13 patients with caudate HCC, and segmentectomies of segments I and IX (a total caudate lobectomy) were performed in 2 patients with caudate HCC. The incidence of postoperative complications was similar in the caudate HCC group and HCC in other sites group, with no operative deaths in the caudate HCC group. Tumor-free survival and cumulative survival were similar in the 2 groups. However, among patients with caudate HCC, tumor-free and cumulative survival were lower in patients with than without microscopic portal venous involvement ( P Conclusions Partial caudate lobectomy (anatomic resection of segment I or IX) along the portal system is an appropriate procedure for caudate HCC, especially in patients with impaired liver function or a small HCC. Patients with caudate HCC who have microscopic portal venous involvement may require adjuvant therapy as early recurrence is likely.

To determine the predictive value of the preoperative serum concentration of type IV collagen 7s domain (7s collagen) for postoperative hepatic failure in patients undergoing liver resection for hepatocellular carcinoma.Clear and reliable criteria for predicting hepatic failure after liver resection are needed. The serum 7s collagen concentration correlates with the histologic degree of active hepatitis and hepatic fibrosis and may predict the regenerative potential of the liver.Potential risk factors for postoperative hepatic failure, including the serum 7s collagen concentration, were evaluated in 251 patients who underwent liver resection for hepatocellular carcinoma. Prognostic significance was determined by univariate and multivariate analyses.Hepatic failure developed postoperatively in 25 patients, 4 of whom died. The serum 7s collagen concentration correlated with the histologic degree of hepatitis activity and hepatic fibrosis. The serum 7s collagen concentration was a risk factor for postoperative hepatic failure by univariate analysis and was the only risk factor on multivariate analysis. No patient with a serum 7s collagen concentration12 ng/mL died of postoperative hepatic failure, and all 4 patients who died had a serum 7s collagen concentrationor=12 ng/mL.The preoperative serum 7s collagen concentration correlated independently with hepatic failure following liver resection for hepatocellular carcinoma. Patients whose serum 7s collagen isor=12 ng/mL are poor candidates for hepatic resection.

To better understand how benign hepatocellular tumors acquire nutrient vessels, we investigated the angioarchitecture of the smallest vessels in hepatocellular adenoma (HA) and focal nodular hyperplasia (FNH). In biopsy or resection specimens, microscopic angioarchitecture was characterized in terms of intratumoral fibrous septa and portal tract. Immunohistochemistry for CD34, factor-VIII-related antigen (F-VIII), type IV collagen (collagen IV), α-smooth muscle actin (α-SMA), and CD68 was performed. HA had no portal tract in fibrous septa although FNH showed portal tract in fibrous septa. The smallest vessels in HA stained diffusely for CD34, and arterial segments of the smallest vessels were stained for F-VIII, and collagen IV. Pericyte surrounding the smallest vessels in HA were stained for α-SMA. The smallest vessels in all but one FNH specimen stained for CD34, F-VIII, collagen IV, and α-SMA along portal tract or the artery. Both HA and FNH stained for CD68, as did normal liver. The results indicate that the smallest vessels in HA and FNH are incomplete capillaries, that have both characters of sinusoid and capillaries morphologically and phenotypically, i.e., capillarized sinusoid as in chronic hepatitis or early well-differentiated hepatocellular carcinoma. Benign hepatocellular tumors such as HA and FNH would acquire new vessels gradually by sinusoidal capillarization, not by rapid arterial angiogenesis.

Background: Epigenetic alteration through methylation is one of the most important steps in carcinogenesis. However, the relation between hepatitis virus infection and epigenetic alterations is poorly understood. Methods: Sixteen patients without hepatitis B virus (HBV) and hepatitis C virus (HCV) and 35 patients with HBV or HCV who underwent liver resection for hepatocellular carcinoma (HCC) were studied. Mutation of p53 was detected by direct sequencing. Methylation status of p16 was evaluated in tumor and noncancerous liver tissues by methylation-specific polymerase chain reaction. Results: In HCC without HBV and HCV, p53 mutations were detected in 5 (31%) of 16 HCCs. Methylation of p16 promoter was detected in 2 (25%) of 8 moderately differentiated HCCs, 6 (75%) of 8 poorly differentiated HCCs, and none of 16 noncancerous tissue specimens. In HCC with HBV or HCV, p53 mutations were detected in 8 (23%) of 35 HCCs. Methylation of p16 promoter was detected in 2 (100%) of 2 well-differentiated HCCs, 13 (76%) of 17 moderately differentiated HCCs, 12 (75%) of 16 poorly differentiated HCCs, and 9 (26%) of 35 noncancerous liver tissue specimens. Conclusions: Our results suggest that hepatitis viruses might induce methylation of p16 promoter in liver with chronic inflammation, before appearance of HCC.

Few studies have examined the etiology of hepatocellular carcinoma (HCC) in patients without hepatitis virus infection. We evaluated the role of occult hepatitis B virus (HBV) infection in the development of HCC in Japanese patients without hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C antigen (anti-HCV). Twenty-one HBsAg negative and anti-HCV negative (non-B, non-C) patients with HCC were studied. HBV DNA in serum and HBV transcripts in liver were examined by polymerase chain reaction (PCR) or reverse transcription and PCR. HBV DNA integration was examined by Southern blot analysis or cassette-ligation-mediated PCR as described previously. p53 mutations were examined by direct sequencing. HBV DNA was not detected in serum from any patients. HBV-related transcripts were detected in 5 of 7 HCCs from patients with antibodies to hepatitis core antigen (anti-HBc) and in 3 of 14 HCCs from patients without anti-HBc (P = 0.0261). HBV DNA was integrated into human genome in two non-B, non-C HCCs. Of the 14 patients without anti-HBc, 5 had a history of excessive alcohol intake. In exons 5 through 8 of the p53 gene, mutations were detected in 2 of 8 HCCs with HBV-transcripts and in 5 of 13 HCCs without such transcripts. p53 mutation at codon 159 was found in 2 of 6 patients with excessive alcohol intake without HBV-transcripts. These results suggested that occult HBV infection might play an important role in hepatocarcinogenesis in non-B, non-C patients with anti-HBc and that excessive alcohol intake might be related to HCC in non-B, non-C patients in Japan.

Background. Gastrointestinal stromal tumors (GISTs) are usually refractory to standard chemotherapeutic agents. We successfully treated a patient with a tyrosine kinase inhibitor (STI571) for GIST with peritoneal dissemination and liver metastases. Methods. In a 32-year-old man presenting with abdominal pain from diffuse peritonitis, a GIST and associated perforated small intestine were resected. Multiple liver metastases were present. After therapies with microwave coagulation, ethanol injection, and local and systemic antineoplastic drugs (fluorouracil, cisplatin, tegafur-uracil, and tegafur) failed, investigational treatment with a tyrosine kinase inhibitor was initiated (STI571, 300 mg, p.o. daily). Results. Anorexia and abdominal fullness resolved within a few days. At 24 days after initiation, positron emission tomography showed a remarkable decrease in the abdominal uptake of [18F] fluorodeoxyglucose. Adverse effects of STI571, including mild alopecia and anemia, were minimal. Conclusions. The tyrosine kinase inhibitor STI571 may be effective against GISTs.

A 65-year-old Japanese man underwent radiofrequency ablation (RFA) therapy of a hepatocellular carcinoma. Hemobilia from the intrahepatic bile ducts adjacent to the tumor developed on the fifth day after the RFA therapy. Ultrasonograms and computed tomograms showed swelling of the gallbladder, which was filled with a clot, suggesting the diagnosis of hemocholecyst. The hemobilia resolved with conservative therapy, but a cholecystectomy was performed to manage postprandial abdominal pain. The resected gallbladder was filled with a clot, but injury or ulceration of the gallbladder was absent, suggesting that the hemocholecyst developed secondary to the hemobilia. Secondary hemocholecyst is a rare complication of RFA therapy. The number of cases of secondary hemocholecyst is likely to increase as hepatocentestic therapy becomes more common. Cholecystectomy is indicated for hemocholecyst because spontaneous liquefication and drainage of a clot in the gallbladder usually does not occur.

Background. Although living-donor liver transplantation (LDLT) has been accepted for adult populations, the occurrence and pathogenesis of small-for-size syndrome remain highly controversial. Methods. Portal venous pressure (PVP) was measured in 79 cases of LDLT from anhepatic phase to day 14. PVP was monitored through a catheter inserted via the inferior mesenteric vein. In a separate series of seven cases of adult LDLT, the splenic artery was ligated following arterial reperfusion. Results. For days 2 to 4 and 9 to 11, recipients of small-for-size graft (

We investigated the incidence of recurrence after resection of small hepatocellular carcinomas (HCC) in patients infected with hepatitis C virus (HCV) to determine the appropriate surgical management of these patients. Sixty-one patients with anti-HCV antibody who underwent curative liver resection for small HCC (≦ 2.0 cm in greatest diameter) were categorized into two groups. Group 1 consisted of 27 patients with serum concentrations of type IV collagen 7S domain (7S collagen), a marker for hepatic fibrosis, < 8 ng/ml. Group 2 consisted of 34 patients with serum concentrations of 7S collagen ≧ 8 ng/ml. Serum concentration of 7S collagen correlated with the severity of active hepatitis and the degree of fibrosis in the noncancerous hepatic tissue, both of which are related to risk potential of hepatocarcinogenesis. Serum concentration of total bilirubin, aspartate aminotransferase activity, indocyanine green retention rate at 15 minutes, the proportion of patients who were Child-Pugh class B, and the proportion of patients with severe active hepatitis or cirrhosis (determined by histologic examination) were significantly higher in group 2 than in group 1. Platelet count was significantly lower in group 2. Tumor-free survival rates were not different between the groups. In group 1, nonanatomic resection was a risk factor for recurrence by univariate and multivariate analyses (odds ratio = 3.45, p = 0.040). In group 2, nonanatomic resection was not a risk factor for recurrence. In patients with small HCV-related HCC, anatomic resection is recommended when the serum concentration of 7S collagen is low (< 8 ng/ml) because the potential of hepatocarcinogenesis may be low even after the operation.

We examined the usefulness of a transcription-mediated amplification and hybridization protection assay (TMA-HPA) for the evaluation of the degree of active hepatitis and estimation of recurrence after resection of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We compared results obtained with TMA-HPA with results obtained with a branched DNA assay. Fifty-two patients with HBV-related HCC were divided into two groups; group 1 consisted of 28 patients with a high serum concentration of HBV (>/=3.7 LGE/ml) and group 2 consisted of 14 patients with a low serum concentration of HBV (

Background/Aims: Serum concentration of type IV collagen 7S domain (7S collagen) is a marker of hepatic fibrosis. We investigated the usefulness of measuring the serum 7S collagen concentration as a risk factor for recurrence after liver resection for hepatocellular carcinoma (HCC). Methods: The serum 7S collagen concentration was measured before liver resection for HCC in 219 patients. Group 1 included 102 patients with a high serum concentration of 7S collagen (≧8.0 ng/ml), and group 2 consisted of 117 patients with a low serum concentration of 7S collagen (Results: The results of liver function tests were better in group 2 than in group 1. The percentage of patients with cirrhosis or who underwent minor resection was higher in group 1 than in group 2. The percentage of patients with moderately or poorly differentiated HCC or portal invasion was higher in group 2 than in group 1. Univariate and multivariate analyses identified that a high serum concentration of 7S collagen (≧8.0 ng/ml) was an independent risk factor for recurrence. Conclusion: Measuring the serum 7S collagen concentration is useful to estimate the risk of recurrence after resection of HCC.

Vancomycin hydrochloride (VCM), a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). As it is known to induce renal dysfunction, the dose and the duration of its administration are limited. Moreover, the mechanism of VCM-induced renal dysfunction remains to be unclear. To evaluate the involvement of free radical on VCM-induced renal dysfunction, we carried out analysis with a hexamethylenediamine-conjugated superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Male Wistar rats (weighing 200-210 g) were intraperitonealy administered with 200 mg/kg of VCM twice a day for 7 days. AH-SOD 5 mg/kg/day was subcutaneously injected 5 min before every VCM injection. VCM induced renal injury dose-dependently. Biochemical analyses revealed that plasma levels of blood urea nitrogen and creatinine significantly increased in the VCM-treated group by an AH-SOD-inhibitable mechanism. VCM simultaneously elicited an increase of 8-OHdG levels and chemiluminescence intensity of free radical generation in the kidney. Histological examination revealed that VCM also elicited a marked destruction of glomeruli and necrosis of proximal tubules. AH-SOD inhibited these phenomena in the kidney. These results suggested that oxidative stress might underlie the pathogenesis of VCM-induced nephrotoxicity and targeting SOD and/or related antioxidants to renal proximal tubules might permit the administration of higher doses of VCM sufficient for eradication of MRSA without causing renal injury.

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited disorder characterized by extensively vascularized tumors and cysts in specific organs. Angiogenesis is a striking future of VHL disease with its characteristic cysts and well-vascularized tumors. The hypervascular nature of VHL lesions has been linked to the overproduciton of vascular endothelial growth factor (VEGF) through increased expression of hypoxia inducible factor-1alpha (HIF-1alpha). Here we describe a rare case of VHL disease with esophageal and gastric varices due to arterioportal shunt in a serous cystadenoma of the pancreas, which, upon immunohistochemical examination, exhibited HIF-1alpha and VEGF expression. Rupture of esophageal varices was successfully treated with endoscopic injection sclerotherapy.

Background/Aims: The improvement of diagnostic modalities and operative techniques has resulted in prolonged survival for cancer patients, but has also led to the diagnosis of an increasing number of patients with synchronous hepatocellular carcinoma (HCC) and extrahepatic primary cancer. It is necessary to determine the optimal surgical strategies for synchronous HCC and gastric cancer. Methods: In this retrospective study, clinicopathologic findings, diagnostic methods, treatment and outcome were reviewed in 13 patients who underwent curative surgery for synchronous HCC and gastric cancer. Results: Twelve of the 13 patients were men older than 60 years. All patients had chronic hepatic disease, and hepatitis viral infection was detected in 9 patients. Examinations of the esophagus to search for esophageal varices before liver resection for HCC, and imaging studies to rule out liver metastasis before gastrectomy for gastric cancer can lead to the incidental finding of a synchronous carcinoma. The most frequent postoperative complication was massive ascites, which occurred in 4 patients who underwent lymph node dissection, 1 of whom died of perioperative hepatic failure. HCC recurred in 7 patients, 4 of whom died of their disease; only 1 patient died of recurrence of gastric cancer. Conclusion: Careful follow-up for recurrence of HCC is necessary because the most common cause of death in patients with synchronous carcinoma is recurrence of HCC.

A 63-year-old woman successfully underwent a graft replacement of the retrohepatic inferior vena cava with a ringed polytetrafluoroethylene graft for primary leiomyosarcoma of the inferior vena cava (IVC). Although anticoagulant had been administered, a thrombus was found in the IVC just cranial of the downstream anastomosis 67 months after the operation. The patient remained free of symptoms, and she had no evidence of any tumor recurrence. She underwent a complete resection with a prosthetic reconstruction for leiomyosarcoma of the IVC and has since been able to enjoy a reasonably long-term survival. The occurrence of thrombosis must be kept in mind in the long-term follow-up of such cases.

Background Bile leakage is one of the frequent and disturbing complications of hepatic resection. Study design Clinical records of the 363 patients who underwent hepatic resections without biliary reconstruction for hepatic cancers between January 1994 and June 2001 were reviewed. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration of 20 mg/dL or 1,500 mg/d lasting 2 days. Leakage that continued longer than 2 weeks or that required surgical intervention was defined as uncontrollable. Differences in incidence and frequency of uncontrollable leakage for the different types of hepatic resection, tumors, and underlying liver disease were investigated. Outcomes after treatment for uncontrollable bile leakage were also reviewed. Results Postoperative bile leakage occurred in 26 of 363 patients (7.2%). Although the incidence in patients with cholangiocellular carcinoma (3/9 [33%]) was higher (p = 0.03) than in patients with hepatocellular carcinoma, rates of occurrence were similar among the different types of hepatic resection and underlying liver disease. Eight of the 26 patients (31%) had uncontrollable leakage. Two patients required reoperation to control leakage; one of these developed hepatic failure and died 2 months after surgery. Four patients underwent endoscopic nasobiliary drainage 21 to 34 days after hepatectomy, and the leakage resolved within 3 to 21 days. Fibrin glue sealing was effective in two patients whose leaking bile ducts were not connected to the common bile duct. Conclusions Although meticulous surgical technique can minimize the risk of postoperative bile leakage, some instances of leakage are unavoidable. Nonsurgical treatments, such as nasobiliary drainage or fibrin glue sealing, are preferable to reoperation.

Background The prognosis of patients without nodal metastasis of oesophageal cancer is generally good, but recurrence develops in some cases. Methods Data on 88 consecutive patients with squamous oesophageal cancer who underwent three-field lymph node dissection from 1986 to September 1998 and who had no evidence of nodal disease were reviewed retrospectively. Disease status was based on histological examination of the section of each node with the largest surface area, stained with haematoxylin and eosin. Results The 3- and 5-year survival rates of patients without lymph node metastasis were 85 and 81 per cent respectively, better than in patients with metastasis. Twelve patients died from recurrence. Recurrence was haematogenous in nine patients and locoregional in three. Survival was worse in men, for patients with lesions located in the upper thoracic oesophagus, and in those with lymphatic or blood vessel invasion. Only the presence of lymphatic invasion correlated with survival on multivariate analysis (P = 0·04). Conclusion Although survival was generally good in patients without nodal metastasis from oesophageal cancer following three-field lymph node dissection, patients with lymphatic invasion remained at risk for haematogenous dissemination.

Although curative surgical resection provides the best chance of long-term survival for patients with intrahepatic cholangiocarcinoma, the presence of bile duct invasion decreases postoperative survival rates in patients with mass-forming intrahepatic cholangiocarcinoma. We carried out this study to determine a surgical strategy for patients with bile duct invasion of these tumors. Forty-one patients with mass-forming intrahepatic cholangiocarcinoma were classified as either having bile duct invasion (n= 26) or not having bile duct invasion (n= 15). Clinicopathologic findings, including postoperative outcomes, were compared between these two groups. Perineural invasion, lymphatic invasion, and a positive resection margin were more frequent in patients with ductal invasion. Patients with ductal invasion had lower survival rates than those without ductal invasion. Intraoperative frozen section examination of the bile duct stump to confirm a clear resection margin is required in patients with mass-forming tumors. Resection of the extrahepatic bile duct should be considered when tumor cells are identified at the surgical margin of the resected bile duct.

肝細胞癌(以下HCC)に対する前区域切除術13年後に根治切除した食道癌の稀な異時性重複癌を報告する.症例は71歳,男性.1987年, HCCに対し肝右葉前区域切除を施行した.術後13年間順調に経過したが, 2000年7月上旬より嚥下困難が出現し,胸部中部食道左側に4cm, 2型の中分化型扁平上皮癌を認めた.術前血液検査で肝機能の軽度低下を認め, CEAが7.5ng/ml, HCV(+)であった. 2000年8月30日,慢性C型肝炎を合併していたため,開腹先行にて開胸開腹食道亜全摘術,胸部,腹部の2領域D2リンパ節郭清と後縦隔経路全胃管再建を行った.病理診断は中分化型扁平上皮癌, pStage IVa,総合的根治度pBで,術後経過は良好である. HCCとの重複癌においてはHCCが予後規定因子となることが多いが, HCCが根治であれば第2癌に対しては,肝機能が許される範囲であれば重複癌に対して根治的な手術をすべきと考える.

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.