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PA28-gamma is the activator of 20S proteasome, the ATP-dependent proteolytic system that plays an important role in cell cycle progression in various cell types. In this paper, we show the abnormally high expression of PA28-gamma in various thyroid neoplasms. Thyroid samples were obtained from patients with normal thyroid (4 cases) and with the following diseases: papillary adenocarcinoma (13 cases), multinodular goiter (4 cases), and anaplastic carcinoma (1 case). PA28-gamma expression was estimated by immunohistochemical staining and Western blotting. In all of the papillary adenocarcinoma samples, PA28-gamma was abnormally overexpressed, especially in cancer cells existing at the peripheral region of the cancer mass or in cancer cells invading the capsular region surrounding the cancer mass. In cancer cells of these areas, PA28-gamma was predominantly distributed in nucleus rather than in the cytoplasm of cancer cells. On the other hand, no obvious PA28-gamma expression was observed in the adjacent normal thyroid follicular cells. In multinodular goiter, the expression of PA28-gamma was relatively low compared with papillary adenocarcinoma. In anaplastic carcinoma, PA28-gamma was expressed at the highest level, especially in poorly differentiated regions such as squamous metaplasia of anaplastic cancer tissue. Therefore, the PA28-gamma expression seems to be restricted to thyroid cancer cells, especially in the region where the growth rate of cancer cells is accelerated. This result is further confirmed by the fact that C2, alpha-subunit of 20S proteasome, and proliferating cell nuclear antigen are similarly overexpressed in this region. Thus, PA28-gamma might be involved in the regulatory system for the cell cycle. Moreover, the growth of thyroid cancer cell lines was affected by the proteasome inhibitor, clasto-lactacystin beta-lactone. These results demonstrate that PA28-gamma is overexpressed in thyroid cancer, especially in its growth-accelerated cells.

Background and Objectives: By comparing the survival rates of patients treated with or without surgery, the significance of, and the indication for, reduction surgery in the multidisciplinary treatment of patients with HCC with multiple intrahepatic lesions were examined., Methods: In patients with HCC with multiple intrahepatic lesions, cumulative survival rates were determined and compared for 28 patients (group S) who underwent reductive hepatic resection and 43 (group N) who were treated nonsurgically by transcatheter arterial infusion chemotherapy (TAI), transcatheter arterial chemoembolization (TACE), or percutaneous transhepatic ethanol injection therapy. In group S, 20 patients had adjuvant therapy, consisting of ethanol injection therapy or microwave coagulonecrotic therapy for the remaining satellite lesions during hepatectomy, and all patients in this group underwent TAI or TACE postoperatively. The influence of surgery on patient survival was examined by multiple regression analysis using the Cox's hazard model; then, for each prognostic factor, survival rates were obtained and compared between the groups., Results: In group S, the 1-, 3-, and 5-year cumulative survival rates were 58.2%, 27.1%, and 21.7%, whereas the corresponding values in group N were 34.3%, 4.7%, and 4.7%, the difference being statistically significant (P = 0.0239). In group S, the 1-, 3-, and 5-year cumulative survival rates for patients without intraoperative adjuvant therapy were 25%, 0%, and 0%, whereas those for patients with intraoperative adjuvant therapy were 72.7%, 41.3%, and 33.0% (P = 0.001). Multiple regression analysis showed that hepatic resection, the Child-Pugh score, and the size of the main tumor affected survival independently. Univariate analysis of differences in the cumulative survival rates between the groups as a function of prognostic factor showed that group S had statistically significant better survival rates than group N in those subgroups of patients who were <60 years old, with HBV infection, with a Child-Pugh score of 5 or 6, with a main tumor of <5-cm diameter, with <5 tumors, or without portal thrombi., Conclusions: When combined with intraoperative adjuvant therapy for remaining satellite tumors, reduction surgery provided survival benefit for patients with HCC with multiple intrahepatic lesions in those groups of patients selected by criteria determined in this study., (Copyright 2003 Wiley-Liss, Inc.)

Background/purpose: D-allose, a rare sugar, has been reported to inhibit segmented neutrophil production without causing any significant detrimental clinical effects. Our previous study demonstrated the immunosuppressive effect of D-allose in a rat model of liver transplantation. Neutrophils are closely involved in the process of hepatic ischemia/reperfusion (I/R) injury. One possible mechanism is the adherence of neutrophils to the hepatic sinusoidal endothelium following microcirculatory failure., Methods: The present study investigated the effects of D-allose on the involvement of neutrophils, with particular emphasis to the microcirculation in a model of hepatic I/R. Ischemia was induced by occluding the hepatoduodenal ligament for 90 min. D-allose was infused 2 h before ischemia. Normal saline was infused in the control group. Liver tissue blood flow (LTBF) and portal venous flow (PVF) were measured before and after ischemia. Myeloperoxidase (MPO) and ATP were measured at, before inducing ischemia, at the end of ischemia, and at the end of 2-h reperfusion. Liver enzyme analysis and histology were done at the end of reperfusion. Post-reperfusion animal survival was followed for 15 days., Results: D-allose significantly improved the liver hemodynamics and post-reperfusion animal survival, with a significant decrease in liver tissue MPO, liver enzymes, and the number of neutrophils. ATP level was improved significantly in the D-allose group. Histology revealed significant sinusoidal congestion and tissue necrosis after 2-h reperfusion in the control group., Conclusions: D-allose exerted its protective effects against liver damage incurred when the liver was injured by warm ischemia and reperfusion mainly by the suppression of activated neutrophils.

Background: Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5-fluorouracil (5-FU). The effect of DPD inhibitory fluoropyrimidines (DIF) is presumably related to DPD activity. We studied the efficacy of DIF (tegafur + uracil UFT], tegafur + gimeracil + osteracil [S-1 (TS-1)]) relative to DPD activity, with other fluoropyrimidines as controls., Methods: The efficacy of DIF relative to DPD activity was evaluated in 58 gastric cancer patients who received postoperative administration of fluoropyrimidines, consisting of DIF in 42 patients (UFT in 23; S-1 in 19) and non-DIF in 16 patients., Results: In patients with low DPD activity (under 40 U/mg protein), curative potential tended to be lower for DIF than for non-DIF, but the survival rate was the same for both. In patients with high DPD activity (40 U/mg protein or more), such a tendency was not detected. In a comparison between those treated with UFT and those treated with S-1, prognosis was better in the latter group, in spite of their predominance of lower curative potentials of B or C. In 27 patients with measurable lesions, a partial response (PR) or higher response occurred in 33% (5/15) of those with low DPD activity, and in 17% (2/12) of those with high DPD activity. In the patients with low DPD activity, non-DIF induced no change (NC) in 17% (16), and progressive disease (PD) in the rest. UFF induced PD in all 5 patients, while S-1 induced a response rate of 44% (7/16), with NC in 25% (4/16). In the patients with high DPD activity, on the other hand, non-DIF (n = 3) and UFT (n = 3) induced PD in all the patients, while S-1 induced PR in 33% (2/6) and NC or a higher response in 67% (4/6)., Conclusion: It is recommended to use S-1 rather than UFF in patients with high DPD activity. Measurement of DPD was useful in drug selection.

Background and Objectives: Tumor infiltrating lymphocytes (TILs) have been recognized as a tumor-host reaction in various primary neoplasms. Although several studies reported TILs surrounding metastatic liver tumors, to the authors' knowledge few evaluations of the clinical significance of such features in patients with colorectal liver metastases have been carried out., Methods: Forty-one patients who underwent initial hepatic resection for liver metastases from colorectal cancer were studied. Lymphocytic infiltration surrounding metastatic liver tumor was graded as weak or dense according to the mean number of TILs from 10 high-power microscopic fields (< or =50 or >50/HPF)., Results: Dense lymphocytic infiltration between the metastatic tumor and hepatic parenchyma was seen in 18 of 41 patients (44%). Histologically, tumor invasion of the portal vein was rare in patients with dense TILs (12%) compared with patients with weak TILs (36%). Patients with dense TILs survived longer than patients with weak TILs after hepatic resection (P = 0.013). Multivariate analysis using the Cox proportional hazard model identified this pathological variable as a significant independent prognostic factor after hepatic resection., Conclusions: The extent of lymphocytic infiltration between the metastatic nodule and hepatic parenchyma may reflect host defensive activity in the liver and is closely related to prognosis in patients who underwent hepatic resection for liver metastases from colorectal cancer., (Copyright 2002 Wiley-Liss, Inc.)

Background: This study aimed to evaluate the integrity of anastomotic wound healing after digestive surgery under septic conditions and define the participation of local expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) around the anastomotic segment., Materials and Methods: Experimental animals were divided into lipopolysaccharide (LPS) and control groups, which had either LPS or normal saline solution injected into the peritoneal cavity 24 h before transection and anastomosis of the colon. Anastomotic bursting pressure (ABP) and tissue hydroxyproline concentration (HP) were measured as indicators of wound healing. Immunohistochemical staining for TNF-alpha and IL-10 on tissue samples obtained from the anastomotic segment were examined 1, 6, and 24 h after the operation. The reactive cells were counted under light microscopy., Results: ABP and HP were significantly lower in the LPS group than in the control group 7 days after surgery. In the LPS group, TNF-alpha expression increased about threefold over that in the control group 1 h after the operation. TNF-alpha-reactive cells were observed until 24 h after the operation in the LPS group, but not in the control group. On the other hand, IL-10 was not expressed in the control group during the observed period, whereas IL-10 was observed 24 h after the operation in the LPS group., Conclusions: It is suggested that anastomotic wound healing was impaired after the digestive surgery in animals treated with intraperitoneal LPS, and that local expression of TNF-alpha and IL-10 at the anastomotic site acts as an inhibitory factor in the wound healing process.

Objective: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) as a trigger in lipopolysaccharide (LPS)-induced late preconditioning against myocardial infarction., Methods: Rats were pretreated intraperitoneally with two different doses of LPS (0.5 or 2.5 mg/kg) or normal saline (control) 24 h prior to lethal myocardial ischemia. Subsequently, all rats were subjected to a sustained 30-min coronary occlusion followed by 180-min reperfusion. In the second study, total RNA and protein were extracted from myocardium of the control and LPS-treated rats (after 4, 6 and 24 h of treatment) for reverse transcription-polymerase chain reaction and Western blot analysis., Results: In LPS (2.5 mg/kg, but not 0.5 mg/kg)-treated rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was significantly reduced to 42+/-4 and 24+/-2% (P<0.01) compared with the control group. The cardioprotection was abolished by injection of dexamethasone (4 mg/kg x 2, i.p.) or the selective iNOS inhibitor aminoguanidine (300 mg/kg x 2, s.c.) before LPS treatment. The expression of iNOS mRNA and the iNOS protein significantly increased 4 and 6 h after administration of LPS (2.5 mg/kg), respectively. The increases in iNOS mRNA and protein were eliminated by dexamethasone. But the iNOS mRNA and protein were not detectable 24 h after administration of LPS (2.5 mg/kg)., Conclusions: These data provide molecular and pharmacological evidence that LPS-induced late preconditioning against myocardial infarction is triggered by iNOS.

Objective: The present study was designed to test the hypothesis that intestinal ischemia results in an early preconditioning against myocardial infarction and that the mechanism of the early preconditioning involves the activation of protein kinase C-mitochondrial K(ATP) channel signaling pathway in anesthetized rats., Methods: Rats were either preconditioned with a 25-min occlusion of the superior mesenteric artery followed by 15 min of reperfusion or underwent a 40-min sham period. Subsequently, all rats were subjected to a sustained 30 min of coronary occlusion and 180 min of reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining., Results: In sham-operated rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was 73+/-4% and 31+/-2%, respectively, and these were significantly reduced to 44+/-4% and 23+/-1% (P<0.01) after intestinal ischemia preconditioning. Intravenous injection of protein kinase C inhibitors chelerythrine (5 mg/kg) and staurosporine (50 microg/kg) or a specific mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate (5 mg/kg) 5 min before sustained myocardial ischemia abolished the preconditioning afforded by intestinal ischemia. However, hexamethonium, a ganglion blocker, did not attenuate the preconditioning., Conclusions: These data provide pharmacological evidence that protein kinase C and mitochondrial K(ATP) channel are involved in the mechanism of the early preconditioning induced by intestinal ischemia.

Background: The effect of age on functioning hepatocyte mass and liver blood flow was examined using (99m)Tc-galactosyl-human serum albumin (GSA) liver scintigraphy in patients with liver tumors awaiting surgery., Materials and Methods: Seventy-two patients with liver tumors, but normal liver parenchyma, were included in this study; patients with compromised hepatic blood flow as a result of vascular invasion or thrombus were excluded. The liver volume, calculated liver volume, and liver blood flow index (K value) were preoperatively determined by liver scintigraphy using GSA. These three parameters and liver volume measured by computed tomography volumetry (CT-LV) and the standard liver volume (ST-LV), calculated from the patient's body surface area, were examined for correlations with the patient's age. The K value was compared with the indocyanine green dye retention rate, and both sets of results were examined for correlation with the patient's age., Results: Both the CT-LV and the ST-LV decreased with age, resulting in an unchanged CT-LV/ST-LV ratio with aging. The liver volume and calculated liver volume measured by scintigraphy both decreased with age, even when body size was taken into account. Therefore, in elderly patients, the liver was not morphologically smaller, but the hepatocyte mass in the liver decreased. Furthermore, liver blood flow per unit of functional liver volume determined from the blood flow index did not change with age., Conclusions: These results, suggesting a discrepancy between liver volume estimated by CT and actual functioning hepatocyte volume in the elderly, may have a critical impact on preoperative liver functional reserve evaluation prior to hepatic resection in elderly patients.

The study of systolic changes in both the inflow and outflow of the left ventricle after mitral repair elucidates the geometric characteristics after surgery. The study included eight normal subjects and six patients after mitral repair without a prosthesis. The left ventricular (LV) base, consisting of both mitral valve annulus (MVA) and left ventricular outflow tract (LVOT) orifice, was reconstructed from magnetic resonance images. The angle between the planes of the MVA and LV base (MB angle), and the proportionate share of the LVOT at the LV base were calculated. After mitral repair, both the MVA and LV base became almost normal in size, showing flexible change (i.e., contraction and dorsiflexion) in the MVA and contraction of the LV base in systole. Compared with the normal heart at 100 ms delay from the electrocardiogram R wave, the hearts of the patients at the same phase had a mean 1.05 cm2 larger LVOT orifice, resulting in a mean 8.0 degree larger MB angle. Furthermore, the LVOT orifice occupied a mean of 49.5% of the LV base (41.9% in normal subjects). We hypothesize that the higher MB angle at early systole may weaken the tension of the chordae of the anterior mitral leaflet.

Background/aims: Although preoperative portal vein embolization has been employed for hepatectomy to increase the safety of the surgery, patient selection criteria for hepatectomy following portal vein embolization have still not been established. In this study liver functional tests before and after portal vein embolization were evaluated in order to determine their influence on the outcome of subsequent hepatectomy and the prognostic potential of this approach., Methodology: Forty-five patients, who had undergone major hepatic resection after embolizing the right portal branch, were divided into the following 3 groups according to their postoperative course: complication(-), complication(+), and liver failure group. Clinical, analytical, and hemodynamic parameters obtained before and after portal vein embolization were compared between the three groups., Results: Significant differences were found between the complication(-) group and the liver failure group for 8 factors, and statistically significant cut-off points distinguishing the liver failure group could be determined. Based upon values measured before PVE these were: 1) portal pressure > 16 cmH2O; 2) pre-PVE serum cholinesterase < 160 U/L; 3) pre-PVE serum hyaluronate > 130 ng/mL. Based on values measured after PVE they were: 1) a hypertrophic ratio of the left lobe < 1.21; 2) post-PVE ICGR15 (%) > 16%; 3) a portal pressure measured immediately after PVE > 25 cmH2O; 4) post-PVE serum cholinesterase < 160 U/L; 5) post-PVE serum hyaluronate > 160 ng/mL. Discriminant function analysis in a stepwise manner showed that the portal pressure and serum levels of hyaluronate measured before and after portal vein embolization were the most useful in prediction of the outcome of the following hepatectomy., Conclusions: Patients whose data match the above criteria before portal vein embolization should be excluded as candidates for major hepatic resection with portal vein embolization. Even after portal vein embolization in patients whose data match post-portal vein embolization criteria major hepatic resection may have to be abandoned, or the extent of the hepatic resection reconsidered.

Background: Recently, the apoptotic volume decrease was suggested to be regulated by volume regulatory Cl- channels in cultured cell lines. We thus examined whether inhibition of volume-regulatory Cl- channels is cardioprotective, like caspase inhibition, by hindering the apoptosis of cardiomyocytes induced by global ischemia/reperfusion (I/R) in vivo., Methods: We performed global ischemia for 8 min at 37 degrees C or 4 degrees C in isolated rat hearts, followed by 24-hr reperfusion via heterotopic heart transplantation. The heart tissue was examined by means of the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method, genomic DNA electrophoresis, and caspase-3 activity. Two blockers of volume-regulatory Cl- channels, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), and a broad-spectrum caspase inhibitor, benzoyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-Asp-DCB), were administered intravenously. Triphenyltetrazolium chloride (TTC) staining and ultrasound cardiography were performed to examine myocardial viability. The TTC-unstained region was assessed by means of horseradish peroxidase (HRP) infiltration and the TUNEL method., Results: The transplanted hearts showed TUNEL-positivity and DNA laddering with a peak at 24 hr during reperfusion after ischemia at 37 degrees C, but not at 4 degrees C. NPPB and DIDS were as potent as Z-Asp-DCB for recovery of cardiac function and for blocking the appearance of TUNEL-positivity, DNA laddering, caspase 3 activity, and a TTC-unstained area. TTC-unstained areas were composed of either TUNEL- and slightly HRP-positive or TUNEL-negative and strongly HRP-positive cardiomyocytes., Conclusion: The present results demonstrated that myocardial DNA fragmentation, caspase activation, and loss of cardiac function after global I/R were blocked by NPPB and DIDS, similar to in the case of Z-Asp-DCB. These results suggest that inhibition of volume-regulatory Cl- channels is also effective for preventing cardiac I/R injury.

Objective: To assess the surgical results and clinicopathologic features of hepatic metastases from gastric adenocarcinoma to identify patients with a better probability of survival., Summary Background Data: Many studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, indications for a surgical approach for gastric adenocarcinoma involving the liver have not been clearly defined., Methods: Ninety (11%) of 807 patients with primary gastric cancer were diagnosed with synchronous (n = 78) or metachronous (n = 12) hepatic metastases. Of these, 19 underwent 20 resections intended to cure the metastatic lesion in the liver. The clinicopathologic features of the hepatic metastases in, and the surgical results for, the 19 patients were analyzed., Results: The actuarial 1-year, 3-year, and 5-year survival rates after hepatic resection were, respectively, 77%, 34%, and 34%, and three patients survived for more than 5 years after surgery. Solitary and metachronous metastases were significant determinants for a favorable prognosis after hepatic resection. Pathologically, a fibrous pseudocapsule between the tumor and surrounding hepatic parenchyma was found in 13 of the 19 patients (68%). The presence of a peritumoral fibrous pseudocapsule and a well-differentiated histologic type of metastatic nodule were significant prognostic factors. Factors associated with the primary lesion were not significant prognostic determinants in patients who underwent curative resection of the primary cancer., Conclusions: Solitary and metachronous metastases from gastric cancer should be treated by a surgical approach and confer a better prognosis. A new prognostic factor, the presence of a pseudocapsule, may be helpful in defining indications for postoperative adjuvant treatment.

Background: Clinical parameters influencing the effect of preoperative portal vein embolization (PVE) in hypertrophying the nonembolized lobe of patients with either normal or abnormal liver parenchyma and its effect upon portal pressure were examined to identify the patient population for whom this approach is most suited., Methods: The study population included 43 patients undergoing major hepatectomy after PVE. Patients were divided into 2 groups according to their liver parenchyma: 17 patients with normal liver parenchyma (N group) and 26 patients with damaged liver parenchyma due to viral hepatitis (D group). We calculated the correlation between volumetric increases in the nonembolized (left) lobe after PVE (hypertrophic ratio = post-PVE left lobe volume/pre-PVE left lobe volume) using computed tomography volumetry before and 2 weeks after PVE. Clinical parameters also were examined to identify those parameters modifying the hypertrophic ratio in each group, and changes in portal pressure by PVE and the subsequent hepatectomy were recorded. Finally, by comparing patients with or without postoperative liver failure after hepatectomy, the influence of the hypertrophic ratio and portal pressure on the outcome of subsequent hepatectomy was examined., Results: The hypertrophic ratio was 1.34 +/- 0.23 in the N group, and 1.25 +/- 0.21 in the D group. This difference was not significant. Multiple regression analysis revealed that the parenchymal volumetric rate of the right lobe (PVR) in the D group and both PVR and prothrombin time in the N group were independent parameters predicting the hypertrophic ratio. The portal pressure increased immediately after PVE and was similar in both groups to levels after hepatectomy. Six patients in the D group experienced postoperative liver dysfunction. In 5 of these 6 patients, the hypertrophic ratio was below 1.2, and the portal pressure was higher than that in patients without liver dysfunction., Conclusions: PVE induces hypertrophy of the nonembolized lobe of both abnormal and normal liver parenchyma, and the effect was predictable. Postoperative liver failure appeared to be more severe in patients having a lower hypertrophic ratio and higher portal pressure in abnormal liver parenchyma, however. PVE also may have diagnostic use in predicting portal pressure after hepatectomy, which may be associated with surgical outcome.

Background: The impact of the use of preoperative portal vein embolization (PVE) on long-term survival after surgery was evaluated by retrospective analysis of prognostic factors in patients with advanced-stage hepatocellular carcinoma (HCC) who had undergone hepatic resection with or without PVE., Methods: The portal embolization group (Group P) consisted of 26 patients who had undergone major hepatectomy (more extensive than right hepatectomy) with PVE, and the nonembolized group (Group N) consisted of 43 patients who had undergone major hepatectomy without PVE. All patients were diagnosed with advanced HCC graded as Stage III or IV according to the International Union Against Cancer TNM classification system. Patient survival rates, recurrence rates, and recurrence sites after surgery in the two groups were evaluated and compared., Results: The 1-year, 3-year, and 5-year cumulative disease specific survival rates in patients with TNM Stage III HCC, respectively, were 96.0%, 64.4%, and 52.7% in Group N and 92.9%, 57.1%, and 45.7% in Group P, whereas the corresponding values in patients with Stage IV HCC were 53.5%, 40.1%, and 26.8% in Group N and 63.5%, 50.8%, and 19.1% in Group P. There were no statistically significant differences in survival rates between Group P and Group N. Multivariate analysis showed that PVE was not a significant prognostic factor. The 1-year, 3-year, and 5-year cumulative recurrence rates for patients with both stages of disease combined were 44.1%, 80.2%, and 86.8% in Group N, respectively, and 39.9%, 72.2%, and 72.2% in Group P, respectively, with no statistically significant differences between the two groups. To date, 35 patients in Group N and 16 patients in Group P have had tumor recurrences in the liver remnant; of these, 27 patients in Group N and 12 patients in Group P had multiple recurrence foci in the liver remnant. No significant difference was seen between the two groups; however, 10 of 16 patients in Group P (62.5%) had remote organ metastasis in addition to recurrence in the liver remnant compared with only 6 of 35 patients in Group N (17.1%): This difference was significant statistically (P = 0.012)., Conclusions: PVE during major hepatic resection neither improves nor worsens long-term prognosis but allows resection in a patient group that, otherwise, is considered as unresectable. Remote metastasis involving the lung, bone, or stomach was seen more frequently postoperatively in Group P compared with Group N, raising a possibly important issue regarding the use of this approach for the treatment of patients with hepatic malignancies, especially HCC., (Copyright 2001 American Cancer Society.)

Total hepatic vascular exclusion and venovenous bypass are frequently used surgical procedures when concomitant resection of the inferior vena cava is required during surgery of liver cancer involving the retrohepatic inferior vena cava close to the hepatic veins. However, the duration of total hepatic vascular exclusion is limited due to the risk of hepatic ischemia. Three patients presented with severely compressed inferior vena cava and/or hepatic veins due to liver cancer. The surgical procedure involved initial taping of the inferior vena cava just below the hepatic veins by extrahepatic division and taping of the hepatic veins. After taping the inferior vena cava, hepatectomy with caval resection was performed by simply clamping the retrohepatic inferior vena cava, without the need for total hepatic vascular exclusion or venovenous bypass. In all patients the retrohepatic inferior vena cava were safely replaced with a prosthetic graft under stable hemodynamics. Duration of the inferior vena cava clamping was 31, 66, 75 minutes, respectively. No graft-related complications occurred, but 2 of the 3 patients showed temporal renal dysfunction associated with renal congestion postoperatively. The surgical procedure described herein is effective for the treatment of retrohepatic inferior vena cava in some patients. However, when the case is complicated by chronic nephropathy or simultaneous nephrectomy is required, venovenous bypass should be performed.

beta-Catenin has multiple functions both in intercellular adhesion and in signal transduction. As a signaling molecule, mutations in exon 3 of the beta-catenin gene stabilize this protein in the cytoplasm. Subsequently, accumulated beta-catenin protein translocates to nuclei with T-cell factor-4, and upregulates transcriptional activity of the target genes involved in carcinogenesis. Mutations in exon 3 of the beta-catenin gene have been detected in various carcinomas. We examined immunolocalization of beta-catenin protein and mutations in the beta-catenin and adenomatous polyposis coli (APC) genes in papillary carcinoma (25 cases), follicular carcinoma (two cases), and benign thyroid tumor (29 cases). We detected no mutation in exon 3 of the beta-catenin gene in both malignant and benign thyroid tumors by polymerase chain reaction (PCR) and direct sequencing. No mutations in the mutation cluster region of APC were found in any tumor samples analyzed. Immunohistochemically, beta-catenin showed membranous localization in most specimens. These results suggest that mutations of the beta-catenin and APC genes are rare and that activation of the Wnt signaling pathway may not contribute to pathogenesis in human papillary and follicular thyroid carcinomas.

We describe the rare case of a patient with esophageal small cell carcinoma who was completely cured. A 77-year-old man had small cell carcinoma of the esophagus with extensive lymph node metastases. Treatment comprised a subtotal esophagectomy and extended lymph node dissection. He has survived for more than 7 years with no evidence of recurrent disease. We suggest that radical operations should be considered for future patients if curative resection can be expected.

A 32-year-old man admitted for treatment of a left atrial myxoma showed a 76 x 25 mm tumor in the left atrium originating in the interatrial septum upon echocardiography. The myxoma was surgically removed using a mini sternotomy and the superior transseptal approach. The hospital course was unremarkable. In the 2 years since operation, the patient has remained asymptomatic and tumor-free. The superior transseptal approach is thus useful in surgical removal of left atrial myxoma because it can be excised with minimum manipulation despite the mini sternotomy and small skin incision.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play an important role in tumor invasion and metastasis. There have been only a few studies on the protein expression of MMPs and TIMPs in thyroid carcinomas. Therefore, we investigated the protein expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 in 86 papillary thyroid carcinomas using immunohistochemistry, semiquantitative scoring morphometry of immunohistochemistry, gelatin zymography, and western blotting. We also examined the correlations between the immunohistochemical scores and several clinicopathological parameters. The immunoreactivities of MMP-2, MMP-9, TIMP-1, and TIMP-2 were largely located in the tumor cells or non-tumor follicular cells and to a much lesser extent in the fibroblasts and endothelial cells in the tumor and non-tumor regions. Compared with non-tumor regions, these four proteins tended to be overexpressed in the tumor cells; the overexpression was found in 64 of 86 (74%), 80 of 86 (93%), 79 of 86 (92%), and 64 of 86 (74%) cases for MMP-2, MMP-9, TIMP-1, and TIMP-2, respectively. Gelatin zymography showed distinct bands of MMP-2 and MMP-9 in tumor extracts but vague bands in non-tumor extracts. Western blotting revealed the specific bands of MMP-2 and MMP-9 in both tumor and non-tumor extracts. Morphometric scoring revealed that high expression of these proteins significantly correlated with large tumor size, presence of lymph node metastasis, high clinical stage, high intrathyroidal invasion, and high vascular invasion. These data suggest that MMP-2, MMP-9, TIMP-1, and TIMP-2 proteins and activities are increased in tumors cells of papillary thyroid carcinomas and that they play an important role in the invasion and metastasis of papillary thyroid carcinomas.

Objective: We tested the hypothesis that occlusion of the superior mesenteric artery induces late preconditioning against myocardial infarction and examined the effects of pharmacological modifiers of inducible nitric oxide synthase activity on the late preconditioning in anesthetized rats., Methods: Rats underwent an intestinal ischemia preconditioning protocol (30 min occlusion of the superior mesenteric artery) or were sham-operated. They were subjected to a sustained 30 min of coronary occlusion and 180 min of reperfusion 24 h later., Results: In rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was 72+/-4% and 31+/-2%, respectively, in sham-operated rats, and these were significantly reduced to 44+/-4% and 23+/-2% (P<0.01) 24 h after intestinal ischemia preconditioning. Myeloperoxidase activity was significantly reduced by intestinal ischemia preconditioning. Administration of aminoguanidine (300 mg/kg, s.c.) or S-methylisothiourea sulfate (3 mg/kg, i.v.), both relative inducible NO synthase inhibitors, 60 or 30 min before sustained myocardial ischemia not only abolished the late preconditioning afforded by intestinal ischemia, but also inhibited the ability of intestinal ischemia preconditioning to significantly reduce neutrophil infiltration. A change in inducible NO synthase activity was not observed in normal myocardium 24 h after intestinal ischemia, but 30 min of coronary occlusion significantly increased the inducible NO synthase activity in the preconditioned group, which was abolished by aminoguanidine or S-methylisothiourea sulfate., Conclusions: These data provide pharmacological evidence that induction of inducible nitric oxide synthase, following intestinal ischemia, is associated with increased myocardial tolerance to infarction 24 h later.

We evaluated the changes in hepatic arterial and portal perfusion in nonembolized as well as in embolized lobes after portal venous branch embolization (PVE) with dynamic helical computed tomography (CT). Six patients with hepatic malignancies, who underwent PVE prior to a subsequent hepatectomy, were the subjects of this study. We performed CT examinations before PVE and 2 weeks after PVE to make a volumetric analysis. At the same time, we performed single-location dynamic sequences after the injection of a 50-ml bolus of contrast medium, and we then created time-density curves from circular regions of interest drawn over the aorta, parenchyma of the right and left lobe of the liver, and spleen. We calculated the arterial perfusion index (ml/min per ml of tissue) and the portal perfusion index by dividing the maximum rate of enhancement of the liver before and after the splenic peak by the peak aortic enhancement. We then calculated the arterial and portal flows (ml/min) from the perfusion index and values of CT volumetry. In the right lobe, where the portal flow was occluded, the arterial perfusion index and flow increased significantly after PVE. In contrast, the arterial perfusion index and flow both decreased in the left lobe after PVE in a reverse response to the increase in the portal perfusion index and flow. The total arterial flow of the liver thus seemed to slightly increase; however, the change was not significant. By performing PVE an increased arterial perfusion was induced in the embolized lobe, with a concomitant decrease in arterial perfusion in the nonembolized lobe.

Expression of p53 protein and MDM2 was evaluated in paraffin-embedded tissue from 78 patients with papillary carcinomas of the thyroid (PCT), in order to elucidate the relationship between them and their correlations with some clinicopathologic features implicated in tumor progression. These proteins were expressed in nuclei of tumor cells, but not in non-tumor cells. Staining was defined as positive when 10% or more of tumor cells expressed these proteins. The number of cases positive for p53 protein was 21/78 (27%), and that positive for MDM2 was 26/78 (33%). Co-overexpression of p53 protein and MDM2 was observed in 12/78 cases (15%). A significant positive relationship was found between them (P < 0.01); p53-positive cases tended to be also positive for MDM2 and vice versa. Statistical analysis revealed that overexpression of p53 protein significantly correlated with large tumor size (P = 0.0271) and the presence of capsular invasion (P = 0.04). There were significant positive correlations between tumor size and intrathyroidal invasion and between tumor size and capsular invasion in PCT, suggesting that p53 protein overexpression is associated only with tumor progression (tumor size). However, we could not find any significant correlations between MDM2 expression and clinicopathologic features. Our findings suggest that overexpression of p53 protein and MDM2 in papillary carcinoma of the thyroid is associated with the progression of the tumors, and that p53 may be a marker of the progression of PCT.

Insertion of a rigid mitral prosthesis impairs the function of the mitral annulus and induces systolic narrowing of the left ventricular outflow tract (LVOT). To study this mechanism, we investigated dynamic changes in the left ventricular (LV) base, which consists of the mitral annulus and LVOT orifice. In seven patients with mechanical mitral valve prostheses and eight normal subjects, the image of the LV base was reconstructed three-dimensionally and its dynamic change during systole was studied. In the patients, the rigid prosthetic valve (=mitral annulus) tilted toward the left ventricle with a hinge point at the posterior mitral annulus during systole. The left ventricular base exhibited contraction, but the size of the prosthetic valve was constant. As a consequence, the prosthetic valve occupied more of the left ventricular base, which resulted in narrowing of the LVOT. In the normal subjects, the mitral annulus did not interfere with the region of the LVOT orifice during systole as the mitral annulus underwent both dorsiflexion and contraction. Thus, fixation of the mitral annulus induces an anti-physiologic motion of the annulus. Conscious preservation of annular flexibility in mitral valve surgery is important in avoiding potential dynamic LVOT obstruction.

A total of 18 patients (13: colon cancer, 5: gastric cancer) with multiple liver metastases (H3) underwent hepatic arterial infusion chemotherapy (HAI) using an implanted arterial port with portable syringe pumps in our outpatient clinic. Clinical perspective: overall response rate was 22.2% (CR: 1 case, PR: 3 cases (1 case: hepatectomy after HAI), NC: 12 cases, PD: 2 cases), however, 7 of 12 cases of NC were long NC (more than 6 months). No major complications with HAI were experienced. Patient Perspective: After HAI in our outpatient clinic, the 50% survival was 341 days, 50% hospital free days were 319 days and home stay rate was 92.9%. Societal Perspective: cost and hospital stay days were significantly reduced. Home anti-cancer chemotherapy using HAI for gastrointestinal cancer patients with multiple liver metastases was safe and efficient from the viewpoint of medical outcomes.

Midkine (MK) is a novel heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. We immunohistochemically examined 90 thyroid papillary carcinomas (85 invasive type and five encapsulated type), using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK in archival paraffin sections. The thyroid tumors exhibited an intense reaction in the cytoplasm. Most of the papillary carcinomas (77/90), had tumor cells that expressed MK. These were classified into the following two types: invasive type (76/85) and encapsulated type (1/5). Notably, the intensity of MK was stronger at the invading border area of the tumors than in the center. In tissues adjacent to the cancer tissues, normal follicular epithelial cells expressed MK very faintly or not at all. The in situ hybridization analysis revealed that the signals of MK transcripts were found in the cytoplasm of the cancer cells. In the noncancerous follicular epithelial cells adjacent to neoplasm the signals of MK transcripts were detected very weakly or not at all. The distribution and localization of the MK-transcript signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. We conclude that thyroid papillary carcinoma strongly expresses MK protein and messenger RNA, and that this overexpression may relate to the development and invasion of these carcinomas.

Background: Preoperative portal vein embolization successfully reduces the incidence of postoperative hepatic failure in which endotoxin is postulated to be involved. To identify the mechanism of this preventive effect, the relationship of endotoxin-induced liver injury with tumour necrosis factor (TNF) alpha and nitric oxide production in the peripheral blood, liver and spleen of rats subjected to preoperative portal vein branch ligation (PVL) was compared with that in rats undergoing sham operation., Methods: Rats with PVL and those that underwent sham operation were subjected to resection of ligated liver lobes (PVL-Hx rats) and two-thirds hepatectomy (noPVL-Hx rats) respectively at day 5, followed by intravenous administration of endotoxin 200 microgram/kg body-weight at day 7. At various time intervals after endotoxin injection, the peripheral blood, liver and spleen tissues were harvested and analysed for TNF-alpha and nitric oxide production., Results: The survival rates of noPVL-Hx and PVL-Hx rats at 48 h after endotoxin administration were 40 and 100 per cent respectively. The former rats showed more extensive liver injury as represented by higher serum aminotransferase and hyaluronate levels than the latter. Plasma concentrations of TNF-alpha at 1.5 h after endotoxin treatment were significantly higher in noPVL-Hx rats (mean(s.e.m.) 22 125(2175) pg/ml; n = 6) than PVL-Hx rats (8344(4076) pg/ml; n = 6) (P < 0.01). Consistent with this, expression of TNF-alpha messenger RNA in the liver and spleen was suppressed in PVL-Hx rats. In two-thirds hepatectomized rats, plasma TNF-alpha concentrations after endotoxin administration at 1, 2 and 3 days (14 350(2186), 26 375(2478) and 23 000(3745) pg/ml respectively; n = 6 each) were significantly higher than that before operation (9067(1559) pg/ml; n = 6) (P < 0.05), whereas those at 5 and 7 days (10 102(3616) and 8580(1427) pg/ml respectively; n = 6 each) showed no significant increase. Furthermore, nitric oxide production in peripheral blood and liver was suppressed by preoperative PVL., Conclusion: Prevention of endotoxin-induced liver failure by preoperative PVL is associated with reduced production of TNF-alpha in the later phase of liver regeneration.

N-Aminoazaaromatics were found to react with nitric oxide in the presence of oxygen to afford deaminated products in high yields. The reaction proceeded almost instantaneously in various solvents including water, and one to two equivalent of NO was consumed depending upon the amount of oxygen coexisted, and 1 equivalent of N2O was released in the reaction. In addition, N-aminoazoles were deaminated by potassium superoxide to give parent azoles in good yields. Two equivalents of superoxide was consumed, and about half equivalents of both nitrite and nitrate ion were released. The results demonstrated that N-aminoazoles have ability to protect the biological system against the oxidation promoted by radicals such as nitrogen oxides and superoxide.

There have been no reports evaluating double-stranded RNA-activated protein kinase (PKR) in thyroid carcinomas. Therefore, we investigated the protein expression of PKR and its correlations with several pathologic parameters and Ki-67 labeling in 86 thyroid carcinomas, using a semiquantitative scoring method. Western blot analysis showed a specific band of 68 kDa corresponding to PKR molecular weight in 9 selected fresh samples. In immunohistochemistry of archival samples, PKR was expressed in 77 of 86 (90%) cases. The positive rate and PKR score were significantly higher in papillary carcinoma (75 of 80, 94%, PKR score = 4.47 +/- 2.17) than in nonpapillary carcinomas (2 of 6, 33%, PKR score = 1.50 +/- 2.81). Nontumorous thyroid showed no or faint "baseline" PKR expression. There were no significant differences between the PKR score and tumor size, tumor invasion, capsular invasion, or lymph node metastasis. However, there were significant differences between the PKR score and vascular invasion or presence of satellite tumor nodules, the PKR score being higher in cases with more vascular invasion and in cases with satellite tumor nodules than in cases without them. Ki-67 labeling showed a reverse correlation with the PKR score, being the highest in cases with low PKR scores. These results suggest that follicular cells newly express PKR during thyroid carcinogenesis, that PKR is more expressed in papillary carcinoma than in nonpapillary carcinoma, that PKR expression may be associated with high vascular invasion and satellite nodules, and that PKR expression is linked to low cell proliferative activity.

1. The present study was planned to: (i) determine whether the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) was attenuated during reperfusion of short-term ischaemic myocardium; and (ii) study whether blockade of prostaglandin synthesis with indomethacin reversed the inhibitory baroreflex. 2. Arterial pressure was lowered with intravenous sodium nitroprusside before coronary occlusion and 3 min after release of a 5 min occlusion of the left circumflex coronary artery in anaesthetized rabbits. The protocol was repeated 20 min after indomethacin (5 mg/kg, i.v.) or indomethacin vehicle (50 mmol/L tris(hydroxymethyl)aminomethane buffer, pH 8.4) treatment. In addition, this study was performed in a group of vagotomized rabbits. 3. Before indomethacin treatment, the slope of the mean arterial pressure (MAP)-RSNA relationship decreased from -3.3+/-0.77 to -2.01+/-0.69% change in RSNA/mmHg (P < 0.05) during reperfusion of ischaemic myocardium in intact rabbits. The decrease in the slope was reversed by administration of indomethacin. However, the decrease in the slope was not reversed by indomethacin vehicle. Furthermore, the reduction in the slope of the MAP-RSNA relationship during reperfusion of ischaemic myocardium was abolished in vagotomized rabbits. However, there was no inhibition of the slope of the MAP-HR relationship during reperfusion of ischaemic myocardium in either intact or vagotomized rabbits. 4. In conclusion, our data suggest that prostaglandins released by ischaemic myocardium can attenuate the baroreflex-mediated response of RSNA to lowered arterial pressure via vagal afferents during reperfusion of short-term ischaemic myocardium.

Sixteen patients who involved in chest wall disease underwent major chest wall resection between April 1995 and January 1999. The underlying diseases were 6 recurrence of breast cancers, 4 direct invasion by primary lung cancer, 2 metastatic chest wall tumor, one direct invasion by metastatic lung tumor, one direct invasion by metastatic mediastinal tumor, one radio-induced-necrosis of the chest wall, and one chest wall infection. In 9 patients, the thoracic cage reconstruction was performed using double sheets of absorbable mesh (Dexon mesh), cross string sutures and autologous ribs grafts. None of the patients had major respiratory failure and chest wall unstability. No late complications including infections, pains, recurrence and others related to reconstruction materials have been observed.

Serum hyaluronate can be used as an index of hepatic sinusoidal endothelial cell function. This study was designed to evaluate its application as a predictor of liver failure after major hepatectomy. Thirty-six patients who underwent right liver lobectomy after percutaneous transhepatic right branch portal vein embolization were divided into two groups based on their postoperative clinical course (groups 1 and 2, with and without postoperative liver failure, n = 6 and n = 30, respectively). We serially measured serum hyaluronate levels using a sandwich binding protein assay system before and after hepatectomy and determined relations with progression of the underlying chronic liver disorder, portal venous pressure, and liver growth of the left lobe after portal embolization. Serum hyaluronate levels were significantly elevated, in line with the degree of severity of the underlying chronic liver disorder, and correlated well with the portal venous pressure and the hypertrophic ratio of the left lobe subsequent to portal embolization. Serum hyaluronate levels in group 1 were significantly higher than those in group 2 before surgery and increased steeply during the early period after hepatectomy. These results suggest that the serum hyaluronate reflects the hepatic functional reserve, and serial measurement of this parameter after hepatectomy can serve as a simple indicator for early detection of posthepatectomy liver failure.

We report a rare case of rectal epithelioid leiomyosarcoma with osteoclast-like giant cells. A 71-year-old Japanese man was admitted to a hospital with melena. Results of a colonoscopy test revealed a polypoid tumor in the rectum, and a biopsy specimen from the lesion showed a sarcoma; the patient underwent rectosigmoidectomy. At gross inspection, the tumor measured 8 x 7 x 4 cm and was polypoid with ulcerations. Necrotic and hemorrhagic foci were scattered. Microscopically, the tumor consisted of 2 cell types: malignant tumor cells with epithelioid features and benign-appearing osteoclast-like giant cells. The tumor cells were polygonal and epithelioid in shape and had eosinophilic or clear cytoplasms, with scattered giant tumor cells. Immunohistochemical examination revealed that the tumor cells were positive for vimentin, muscle actin, alpha-smooth muscle actin, and desmin, whereas the osteoclast-like giant cells were positive for CD68, leukocyte common antigen, and lysozymes. We diagnosed this case as epithelioid leiomyosarcoma with osteoclast-like giant cells. To the best of our knowledge, this is the first case of rectal epithelioid leiomyosarcoma with osteoclast-like giant cells.

Effectiveness and present problems of video-assisted thoracic surgery (VATS) for metastatic lung tumor were investigated by comparing 14 cases (16 operations) of VATS with 16 cases (19 operations) of conventional thoracotomy during the same period. VATS was favorably selected in the solitary metastasis. The cases who had small tumor diameter less than 3 cm and shorter distance from viseral pluera to the tumor surface than tumor diameter were advantageous for only thoracoscopic procedure to do the safe and sure resection. Regarding to the tumor number, we detected another tumor intraoperatively in 2 of 16 cases (12.5%) of VATS and 6 of 19 cases (31.6%) of thoracotomy. Multiple metastases had the tendency to have the differences of the tumor number between preoperation and intraoperation. Prognosis is very good until now, but the recurrence rate was high (64.5%) and one case had the recurrence at the surgical margin. VATS for metastatic tumor is very effective, but it is important not to hesitate to do the mini-thoracotomy and convert to conventional thoracotomy for safe and sure resection.

The extent of cancerous invasion of the inferior vena cava (IVC) determined from resected liver cancer was examined pathologically. Ten patients presenting with liver cancer (metastatic liver cancer, five patients; hepatocellular carcinoma, three; and cholangiocellular carcinoma, two) were diagnosed with positive IVC invasion using preoperative imaging techniques of extracorporeal ultrasonography, computed tomography, magnetic resonance imaging, and vena cavography. The diagnostic criterion for positive IVC invasion by preoperative imaging was longitudinal IVC compression measuring over 50 mm, or transverse IVC compression extending to more than half the circumference of the IVC, or the presence of lesions protruding into the IVC lumen, or the presence of developed collateral veins. All patients underwent combined resection of the IVC. However, pathology results revealed that four of the ten patients had no cancerous invasion of the IVC, and that the extent of invasion along both the longitudinal and transverse axes of the IVC was much smaller than the compression shown by imaging results. We believe that detailed preoperative assessment, using a more precise imaging technique, as well as further intraoperative examination, is required to predict the full pathological extent of cancerous invasion of the IVC.

Background: Criteria for selection of patients for portal vein embolization (PVE) before major hepatectomy for advanced-stage hepatocellular carcinoma (HCC) have not been clarified in detail. This study was aimed at defining those benefiting from this therapy in a retrospective fashion., Patients and Methods: Firstly, to determine liver functional criteria for applying this approach 26 patients with stage III (17 patients) or IV (9 patients) disease, who underwent major hepatectomies after PVE, were divided into those without major complications (20 patients) and a postoperative liver failure group (6 patients). Clinical, analytical, and hemodynamic parameters obtained before and after PVE were compared between the groups. Secondly, to define the application of this approach with regard to tumor progression survival rates of patients were also obtained, taking into account factors which affect tumor development, i.e. lesion size, intrahepatic metastasis and vascular invasion., Results: With regard to liver function 4 nonindications were obtained: (1) a portal pressure measured right after PVE >25 cm H(2)O; (2) post-PVE serum hyaluronate >200 ng/ml; (3) pre-PVE serum cholinesterase <150 U/l; (4) post-PVE serum cholinesterase <150 U/l. In view of the tumor progression in patients with HCCs featuring intrahepatic metastasis spread to more than 3 segments (IM3) 1-, 3- and 5-year survival rates were low (42.9, 28.6 and 0%) with a statistical significance, compared to those in patients with intrahepatic metastasis limited in the same lobe (76.9, 46.2 and 24.6%)., Conclusions: When laboratory data fulfill 3 or more of the criteria, the extent of hepatic resection may have to be carefully reconsidered. Patients with HCCs featuring IM3 intrahepatic metastasis may not benefit from the aggressive approach described here., (Copyright 2000 S. Karger AG, Basel.)

The effect of warm ischemia on lidocaine-metabolizing activity was examined in vivo. Total liver ischemia was produced for 1 hr in Sprague-Dawley rats by clamping the portal vein and hepatic artery at the hilum. Livers were then reperfused, and liver microsomes were prepared before and 0, 2, 6, and 24 hr, and 3, 6, and 10 days after reperfusion. Microsomal lidocaine-metabolizing activity and cytochrome P-450 content were examined. Lidocaine N-deethylase activity was decreased from 2.25 +/- 0.33 to 0.97 +/- 0.21 nmol/mg protein/min (mean +/- SD) 24 hr after reperfusion. This inhibition was prolonged, and activity gradually recovered after 10 days. The cytochrome P-450 content showed the same tendency. On the other hand, serum levels of alanine aminotransferase increased significantly 2 hr after reperfusion and returned to control levels 3 days after reperfusion. Liver blood flow recovered rapidly after unclamping and reached baseline levels within 6 hr. Our results suggest that after warm ischemia, prolonged hepatic dysfunction in drug metabolism, which cannot be detected by evaluating serum enzymes or liver blood flow, exists at the microsomal level.

We report an autopsy case of mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome. A 38-year-old Japanese male was found to have Zollinger-Ellison syndrome and pancreatic gastrinoma, and gastrectomy and resection of the pancreatic tumor were performed. However, hypergastrinemia persisted, and the patient died of disseminated carcinomatosis at 62 years of age, 24 years after the onset of Zollinger-Ellison syndrome. At autopsy, the main tumor was present in the residual pancreas, and metastases were noted in many organs. In the pancreas and other organs, ductal and endocrine carcinoma areas were mixed and there was a gradual transition between the two. No acinar differentiation was noted. The ductal elements were positive for mucins and carcinoembryonic antigen but negative for neuroendocrine markers, while endocrine elements were positive for chromogranin A and synaptophysin and to a lesser extent for gastrin, but negative for mucins and carcinoembryonic antigen. The ductal elements comprised about 30% of the tumor cells, and endocrine elements 70%. According to the revised World Health Organization classification, our case was diagnosed as mixed ductal-endocrine carcinoma. Our case is rare because the tumor manifested as gastrinoma with Zollinger-Ellison syndrome and the patient survived for 24 years. To the best of our knowledge, no such case has been reported. Our case suggests that pancreatic endocrine tumors may evolve into mixed ductal-endocrine carcinomas.

We report, herein, on the first case of a mesenteric desmoid tumor with multiple peritoneal dissemination. A 73 year-old Japanese woman, who had a history of uterine cancer that was treated with hysterectomy followed by a high dose of irradiation 25 years ago, had an unknown stenosis of the sigmoid colon, which was treated with partial resection of the stenosed colon 6 years ago, and then resulted in multiple small bowel obstructions due to the recurrence of mesenteric desmoids. The clinical behavior of this tumor is considered to be unpredictable. We emphasize that mesenteric desmoid tumors should be considered as one of the causes of stenosis of the colon and small bowel, and patients should receive careful follow-up after unknown stenosis.

We report an autopsy case of reactive hemophagocytic syndrome with peculiar liver histology. A 71-year-old female was diagnosed as having acute myelogenous leukemia and treated with chemotherapy. During her course, methicillin-resistant Staphylococcus aureus (MRSA) was noted in blood culture and she was diagnosed as having MRSA sepsis. She died of respiratory failure 5 months after the onset of leukemia and 10 days after the MRSA sepsis. Ante-mortem liver function tests were within normal ranges. At autopsy, myeloblastic leukemia cells positive for CD13 were present in the bone marrow and, to a much lesser extent, in the spleen and liver. Numerous histiocytes of a bland appearance with erythrophagocytosis were noted in the bone marrow and spleen. The histiocytes were positive for CD68, but negative for S-100 and lysozymes. In the liver, many histiocytes of bland appearance with erythrophagocytosis and CD68 positivity were present in the portal tracts with no Kupffer cell hyperplasia. There were no hepatocellular degeneration, fatty changes or sinusoidal dilations. We consider that this histiocytosis was associated with MRSA infection and diagnosed this as infection-associated hemophagocytic syndrome. In previously reported cases, hemophagocytosis in hyperplastic Kupffer cells was the main liver change of reactive hemophagocytic syndrome. The present case suggests that marked histiocytosis in portal tracts only may be a main feature of liver changes in reactive hemophagocytic syndrome and that such cases may not show abnormal liver function tests.

Background: Prostaglandin E1 (PGE1) has protective effects experimentally and clinically in individual models of hepatic ischaemia-reperfusion injury and of partial hepatectomy. The present study investigated the effects of intraportal administration of PGE1 on hepatic blood flow, systemic arterial pressure and long-term animal survival after 60 min of total liver ischaemia followed by 70 per cent partial hepatectomy in rats., Methods: Total liver ischaemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE1 0.5 microg per kg per min was infused intraportally for 15 min before inducing ischaemia and for 120 min after ischaemia in the treatment group. Normal saline was infused in the control group. During ischaemia 70 per cent partial hepatectomy was performed. Portal venous flow (PVF), peripheral tissue blood flow (PTBF) and hepatic artery flow were measured before and after ischaemia. Serum biochemical analysis was carried out at 1, 3 and 24 h, and 7 and 14 days; and liver histology at 1 and 24 h, and 7 days after reperfusion. Survival was followed for 1 year., Results: Intraportal infusion of PGE1 significantly improved PVF and PTBF without affecting the systemic arterial pressure. Long-term survival was significantly higher in the PGE1 group. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels decreased significantly, and 2-h bile flow was significantly improved, in the PGE1 group. Histological examination revealed significant portal venous congestion, sinusoidal congestion, fatty degeneration and tissue necrosis 24 h and 7 days after reperfusion in the control group., Conclusion: PGE1 has a protective effect against liver damage when the liver is injured by warm ischaemia and reperfusion followed by partial resection.

Renal sympathetic nerve activity (RSNA) responses to acute cardiac tamponade were studied in conscious rabbits with all reflexes intact (Int) or after either surgical sinoaortic denervation (SAD) or administration of intrapericardial procaine (ip-Pro) or intravenous procaine (iv-Pro). In Int rabbits, the mean arterial pressure (MAP) remained relatively constant until the pericardial volume reached 7. 7 ml, whereas the RSNA increased to 226% [compensated cardiac tamponade (CCT)], then, at a pericardial volume of 9.3 ml, the MAP fell sharply and RSNA decreased to 34% [decompensated cardiac tamponade (DCT)]; 1 min after cessation of pericardial infusion, an intravenous injection of naloxone resulted in increases in both MAP and RSNA. In SAD rabbits, RSNA did not alter throughout CCT and DCT, but increased on injection of naloxone. In ip-Pro rabbits, RSNA increased during CCT but did not decrease during DCT, whereas, in iv-Pro rabbits, the RSNA response was similar to that in Int rabbits. These results indicate that RSNA responses to cardiac tamponade are biphasic, with an increase during CCT and a decrease during DCT. Sinoaortic baroreceptors are involved in mediating the increase in RSNA, whereas cardiac receptors may be involved in mediating the decrease in RSNA. An endogenous opioid may be responsible for the decrease in RSNA seen during DCT.

To investigate the roles of calcium-binding proteins in degranulation, we used three anti-allergic drugs, amlexanox, cromolyn and tranilast, which inhibit IgE-mediated degranulation of mast cells, as molecular probes in affinity chromatography. All of these drugs, which have different structures but similar function, scarcely bound to calmodulin in bovine lung extract, but bound to the same kinds of calcium-binding proteins, such as the 10-kDa proteins isolated in this study, calcyphosine and annexins I-V. The 10-kDa proteins obtained on three drug-coupled resins and on phenyl-Sepharose were analysed by reversed-phase HPLC. It was found that two characteristic 10-kDa proteins, one polar and one less polar, were bound with all three drugs, although S100A2 (S100L), of the S100 family, was bound with phenyl-Sepharose. The cDNA and deduced amino acid sequence proved our major polar protein to be identical with the calcium-binding protein in bovine amniotic fluid (CAAF1, S100A12). The cDNA and deduced amino acid sequence of the less-polar protein shared 95% homology with human and mouse S100A13. In addition, it was demonstrated that the native S100A12 and recombinant S100A12 and S100A13 bind to immobilized amlexanox. On the basis of these findings, we speculate that the three anti-allergic drugs might inhibit degranulation by binding with S100A12 and S100A13.

To investigate whether nitric oxide (NO) in the central nervous system is involved in the decrease in renal sympathetic nerve activity (RSNA) during acute cardiac tamponade in conscious rabbits, we examined the effect of 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase in vivo, on RSNA during acute cardiac tamponade in chronically installed conscious rabbits. Cardiac tamponade was produced by intrapericardial infusion of physiological saline at 2 ml/30 s. Mean arterial pressure (MAP) remained constant initially but RSNA increased to 218+/-24% when we started injection of physiological saline into the pericardial space. Concomitantly after MAP fell to 51+/-1 mm Hg by subsequent injection of the saline into the pericardial space, RSNA decreased to 45+/-6%. If 7-NI (50 mg/kg) was administered intraperitoneally 35 min before the beginning of cardiac tamponade, the decline in RSNA caused by cardiac tamponade was markedly counteracted. Brain nitric oxide synthase (NOS) activity in the cerebral cortex and medulla oblongata, assessed by the conversion of labelled arginine to citrulline, was inhibited by 48% and 44% after the intraperitoneal administration of 7-NI. These results indicate that acute cardiac tamponade elicits a biphasic effect on RSNA, which rises during non-hypotensive period and then falls during hypotension in conscious rabbits. The decrease in RSNA was abolished by treatment with 7-NI, suggesting that the abrupt decrease in RSNA during hypotension induced by acute cardiac tamponade is mediated by NO in the central nervous system.

Percutaneous transhepatic portal vein embolization (PTPE) has been used to decrease the risk of hepatic failure after hepatectomy in patients with poor liver function. The effect of PTPE on hepatic drug-metabolizing activities is not clear. Therefore we examined the effect of portal vein branch ligation, a model of PTPE, on hepatic drug-metabolizing activities in Sprague-Dawley rats. Ligated and nonligated lobes were harvested separately. Drug-metabolizing activities and concentrations of components of the microsomal cytochrome P-450 monooxygenase system were examined. In ligated lobes, drug-metabolizing activities (lidocaine and aminopyrine) and enzymatic concentrations of the microsomal cytochrome P-450 monooxygenase system gradually decreased over 10 days. In nonligated lobes these functions were depressed rapidly to 60% of those before PBL but then recovered 10 days after PBL. From the viewpoint of drug metabolism, hepatic dysfunction occurred in both ligated and nonligated lobes.

We describe herein the case of a 21-year-old woman in whom Castleman disease of the pararenal retroperitoneum was successfully resected. The patient was referred to our hospital from another hospital for investigation of a retroperitoneal mass in the right middle abdomen. Ultrasonography, computed tomography, and magnetic resonance imaging demonstrated a large retroperitoneal mass with heterogeneous imaging characteristics. An aortogram showed arterial feeding to this mass from a few lumbar arteries. Although a definitive preoperative diagnosis could not be made, surgical excision was performed and histopathological examination confirmed a diagnosis of the hyaline type of Castleman disease. The patient had an uneventful postoperative course and was discharged 14 days after her operation. She now leads an active social life without any signs of sequelae or recurrence 14 months later. To the best of our knowledge, only 2% (6/315) of all reported cases of Castleman disease have been located in the pararenal and retroperitoneal area.

Aims: The c-erbB-2 proto-oncogene encodes a transmembrane protein which is highly homologous to epidermal growth factor receptor. Overexpression of this c-erbB-2 protein has been reported in many human carcinomas, including breast carcinoma. However, there have been few studies of the expression of c-erbB-2 in cholangiocarcinoma and hepatolithiasis, a condition occasionally associated with cholangiocarcinoma., Methods and Results: In this study, we evaluated immunoreactivity for the c-erbB-2 protein in human cholangiocarcinomas (n = 47), hepatolithiasis (n = 20), fetal livers (n = 36) and normal adult livers (n = 6). In normal adult livers and fetal livers, expression of c-erbB-2 protein could not be detected in hepatocytes or intrahepatic biliary cells. In hepatolithiasis, there was overexpression of c-erbB-2 in 15/20 (75%). The expression was found with a membranous pattern on the proliferated intrahepatic bile ducts and proliferated intrahepatic peribiliary glands around the bile ducts containing stones. Hepatocytes were negative for c-erbB-2 protein. Moreover, the biliary cell expression of the c-erbB-2 protein correlated significantly with Ki67 labelling index. On the other hand, aberrant expression of c-erbB-2 was found in 33/47 (70%) cholangiocarcinomas. The c-erbB-2 expression in cholangiocarcinomas did not correlate with Ki67 labelling index or p53 expression., Conclusions: These results indicate that aberrant expression of c-erbB-2 protein is found in cholangiocarcinoma and also in noncancerous biliary proliferative lesions such as hepatolithiasis. These findings also suggest that c-erbB-2 oncogene participates not only in cholangiocarcinogenesis but also in biliary cell proliferation in non-neoplastic conditions.