Tomoe Beppu

The Significance of p53 Mutations as an Indicator of the Biological Behavior of Recurrent Hepatocellular Carcinomas

The significance of p53 mutations in the primary lesion for recurrent hepatocellular carcinoma (HCC) was evaluated. Mutations of p53 were examined using non-radioisotopic (nonRI)-polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) in 98 resected HCCs. Of the 98 cases, 25 (26%) had a p53 mutation. In 83 patients who survived surgery, the presence of a p53 mutation was associated with a shortened overall survival (P<0.001) and a shortened cancer-free survival (P<0.05). In 43 patients who developed recurrence, there was no statistically significant correlation between the status of p53 in the primary lesion and the clinical features of recurrent HCCs examined, i.e., extrahepatic metastasis, the number of recurrent tumors, extent of recurrent tumors, and treatment for recurrent tumors. However, postrecurrence survival was significantly lower in patients in whom a p53 mutation had been detected in the primary lesion (P<0.01). A multivariate analysis for prognostic value after recurrence revealed that the p53 mutation was a useful independent prognostic factor affecting survival after recurrence (P<0.01). In conclusion, our findings suggest that HCCs with p53 mutations have a high malignant potential based on their poor prognosis. Therefore, a p53 mutation in the primary lesion is useful as an indicator of the biological behavior of recurrent HCCs.

Role of Preoperative Transcatheter Arterial Chemoembolization for Resectable Hepatocellular Carcinoma: Relation between Postoperative Course and the Pattern of Tumor Recurrence

The effects of preoperative transcatheter arterial chemoembolization (TACE) were retrospectively evaluated in patients with resectable hepatocellular carcinoma (HCC). A total of 227 patients who underwent hepatectomy for HCC were studied (146 underwent preoperative TACE and 81 did not). We compared operative outcome, mortality, and disease-free survival between TACE and non-TACE groups. We also compared the pattern of recurrence and postrecurrence survival between subgroups according to staging. Of the 227 patients, 105 with tumor stage I-II were assigned to group A (group A/TACE, n = 69; group A/non-TACE, n = 36), and the remaining 122 with tumor stage III-IV were assigned to group B (group B/TACE, n =77; group B/non-TACE, n =45). Complete necrosis was found to be more frequent in the TACE group (p < 0.01). Operating time, blood loss, and mortality did not differ between those who did and did not undergo preoperative TACE. TACE did not significantly improve disease-free survival within either the entire TACE group or group A/TACE. In contrast, in group B/TACE the disease-free survival rates were significantly higher than in group B/non-TACE. Furthermore, both extrahepatic metastasis and diffuse intrahepatic metastasis were significantly more frequent in group B/non-TACE than in group B/TACE. The preoperative TACE also improved the postrecurrence survival in group B. We speculate that preoperative TACE reduced tumor recurrence and that it might confer a survival advantage after surgery, particularly in patients with advanced HCC. In addition, it is expected that this procedure may improve the pattern of tumor recurrence when it does occur.

Correlation of Thymidine Phosphorylase Staining and the Ki-67 Labeling Index to Clinicopathologic Factors and Hepatic Metastasis in Patients with Colorectal Cancer

AbstractPurpose. Our aim was to investigate the thymidine phosphorylase (TdRPase) expression and Ki-67 labeling index (LI) of primary tumors of colorectal cancer and hepatic metastases immunochemically and to evaluate the relationship of these parameters to various clinicopathologic factors and hepatic metastasis. Methods. We performed immunochemical studies in 74 patients with colorectal cancer, using anti-TdRPase antibody and MIB-1 antibody. Results. TdRPase expression and a Ki-67 LI ≧30% in primary lesions were significantly more common in patients with lymphatic invasion (ly), venous invasion (v), lymph node involvement (n), and hepatic metastasis. A Ki-67 LI ≧ 30% of the primary tumor was associated with a significantly higher frequency of metachronous liver metastasis. In the same patients, the mean Ki-67 LI was 24.3 ± 17.9 for primary lesions and 5.0 ± 4.2 for hepatic metastases, this difference being significant. Conclusions. These results indicate that TdRPase expression and the Ki-67 LI are related to various clinicopathologic factors, suggesting their usefulness as indices of tumor malignancy. We suggest that the Ki-67 LI of primary colorectal cancer could be an important predictor of the future development of metachronous liver metastasis.

Long-Term prognosis of non-shunt operation for idiopathic portal hypertension

Abstract: This report presents 46 Japanese patients with idiopathic portal hypertension (IPH) in whom non-shunt operation was performed for the management of esophageal varices. Non-shunt operation included transthoracic esophageal transection (Sugiuras procedure) in 37 patients, transabdominal esophageal transection (TAET) in 3 patients, and Hassabs procedure in 6 patients. Rates of postoperative variceal eradication were: 78.4% by Sugiuras procedure; 100% by TAET; and 50% by Hassabs procedure. The cumulative rates for recurrent varices and recurrent bleeding were 3.9%, and 5.1%, respectively, at 5 years, and 8.9% and 9.8% at both 10 and 15 years. Only 3 patients required additional endoscopic injection sclerotherapy to treat recurrent varices. Although 3 patients developed upper gastrointestinal bleeding, the source of hemorrhage was esophageal varices in 1, and portal hypertensive gastropathy in 2; none of the patients died from bleeding. Actuarial survival for all patients was 87.5% at 5 years, 77.9% at 10 years, and 58.8% at 15 years. There were no deaths within the first 30 days after surgery. These results show that non-shunt operation is useful in preventing bleeding from esophageal varices in patients with IPH.

Early Diagnosis of Postoperative Infection : Assessment of Whole Blood Chemiluminescence

Abstract: Whole blood chemiluminescence (CL), which allows for the evaluation of both the oxygen radical release by phagocytes and the serum opsonin activity using very small amounts of blood, is considered to be a useful means of assessing the host defense against infection. We measured the whole blood chemiluminescence in 59 patients before and after open surgery (surgery by a laparotomy) for gastrointestinal disease. Early postoperative infection was detected in 12 (20.3%) of the 59 patients. These 12 patients all had significantly higher white blood cell counts compared with the noninfected patients on the third and subsequent days after surgery ( P < 0.01). The peak CL in the early postoperative infected group was also significantly higher than that in the noninfected group on the day of surgery ( P < 0.0001), 1 day after surgery ( P <≧0.0001), and 3 days after surgery ( P < 0.01). Whole blood CL may therefore be a useful modality for the early detection of postoperative infection in the future.

Hemodynamics in extrahepatic portal vein obstruction and its changes during long-term follow-ups

Thirty-six patients with extrahepatic portal vein obstruction (EHO) were studied. Twenty-one patients, whose age at onset was under 20 years old, were thought to be primary EHO. Ten of 15 patients over 21 years old, had a history of abdominal diseases, and were thus considered to be secondary EHO; only 5 were primary EHO. EHO was classified into three categories, based on selective celiac-superior mesenteric arteriography, and intraoperative trans-splenic and superior mesenteric venography: the hilar obstruction of portal vein, the portal trunk obstruction, and the portal trunk-splenic vein obstruction. Both primary and secondary EHO cases were found to have extended their obstructed region over time by progressing from hepatic hilum to portal trunk obstruction followed by splenic vein obstruction. On the other hand, based on retrograde portography, EHO was classified into the absence of intrahepatic portal obstruction (portal trunk type) and the intrahepatic obstruction (portal branch type) and the portal branch type tended to predominate. Changes of intra- and extra-hepatic portal obstruction were examined by comparing various angiographies of the 14 patients available for between 1 and 26 years of long-term follow-up. While EHO tended to progress with time, no patient showed progress of a intrahepatic portal vein obstruction. From these results, EHO patients are expected to show continuous progression of EHOs during long-term follow-ups, and to have high recurrence rates of gastrointestinal varices after various treatments due to the persistent portal hypertension. However, effective hepatic flow is likely to be maintained because collateral circulation to the liver develops, and intrahepatic portal vein obstruction does not progress, resulting in a good prognosis for EHO.

Numerical chromosomal abnormality in gastric MALT lymphoma and diffuse large B-cell lymphoma.

Background: We investigated numerical chromosomal abnormalities, using the fluorescence in situ hybridization (FISH) method, in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBL). We also compared the histopathological findings, including the presence or absence of Helicobacter pylori infection, with the analytical results. Methods: Sixteen patients who underwent operation for malignant gastric lymphoma in our department were divided into three groups: patients with low-grade gastric MALT lymphoma (l-MALT; n = 5), those with high-grade gastric MALT lymphoma (h-MALT; n = 8), and those with DLBL (n = 3). Numerical abnormalities of chromosomes 8, 9, 12, and 17 were investigated by the FISH method, and the presence or absence of H. pylori infection was microscopically examined. Results: Numerical abnormality was observed in chromosome 12 in 11 patients (68.8%), in chromosome 8 in 10 (62.5%), and in chromosome 17 in 5 (31.3%), showing a high frequency. H. pylori infection was detected in 80% and 50% of patients with l-MALT and h-MALT, respectively, but no H. pylori infection was observed in patients with DLBL. Conclusions: A new biological characteristic of gastric MALT lymphoma was obtained, i.e., a high frequency of numerical abnormalities of chromosomes 12, 8, and 17. There was no correlation between the numerical chromosomal abnormalities and the clinicopathological findings.

Prognostic implication and intratumoral heterogeneity of p53, Ki-67, CEA and CA19-9 expressions in cholangiocellular carcinoma

Abstract Background: Cholangiocellular carcinoma (CCC) is known to be associated with poor prognosis even when surgical treatment is applied, and few studies of its biological behavior have been conducted because of the relatively low incidence (about 2.7% of primary liver cancer cases in Japan according to the Liver Cancer Study Group of Japan, 1994). Methods: We analyzed 41 specimens from 17 resected CCC tumors to assess the biological behavior using immunohistochemical staining for the tumor suppressor protein, p53; the cell proliferation marker, Ki-67; and two tumor antigens, CEA and CA19-9. Results: In the central and marginal regions, 15 of 17 tumors demonstrated immunoreactivity for p53, and all 17 immunoreactivity for Ki-67. All tumors were immunostained for CEA and CA19-9. A significant difference between the central and marginal regions was found in p53 and Ki-67 staining intensity but not in CEA and CA19-9 staining intensity. There was a significant relationship with survival for the p53 and Ki-67 labeling index (LI) in the marginal region, and a significant correlation was also found between the marginal p53 and Ki-67 LI. The survival of patients with the stromal type of CEA staining pattern was significantly shorter than those with other types. Conclusions: We conclude that immunohistochemical investigations using p53, Ki-67 and CEA offer prognostic value in CCC. Furthermore, consideration of the regional heterogeneity is of great importance in the evaluation of the biological behavior of CCC, and more aggressive features are found in the marginal region.

Bile acid profile and decrement rate of serum total bilirubin after biliary drainage

SummaryNon-esterified (non-sulfated and non-glucuronidated) bile acid profile in the serum and bile was assessed using mass fragmentation spectrometry in relation to the decrement rate of the serum total bilirubin after relief of the biliary obstruction by external biliary drainage in fourteen patients. Biliary excretion of the total bile acid was decreased and the serum ratio of cholic to cenodeoxycholic acid was low in the patients with refractory jaundice. An unusual bile acid, 3β,7α-dihydroxy-5β-cholan-24-oic acid, was detected in the sera of all patients early after biliary drainage. Disappearance of this bile acid from the serum was delayed in refractory jaundice. These findings suggested that extremely prolonged jaundice after biliary drainage resulted from profound liver cell damage secondary to biliary obstruction.

Serum alpha-glutathione S-transferase: a new marker of hepatocellular damage associated with hepatectomy

Serum concentrations of alpha-glutathione S-transferase (alphaGST) were determined before and after hepatectomy to examine the clinical usefulness of alphaGST as a marker of hepatocellular damage compared with the conventional liver function tests. Prior to hepatectomy, serum alphaGST concentrations correlated significantly with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In patients who had a good postoperative course, serum alphaGST concentrations rose significantly to a peak immediately after surgery, followed by a rapid fall to the normal range within 1 week, yielding a monophasic pattern. Serum alphaGST concentrations reached a peak earlier than other parameters of liver function, and peak serum alphaGST concentrations correlated with peak serum concentrations of AST and ALT. The mean decrease rate of serum alphaGST concentration from peak values was significantly more rapid than that of serum AST and ALT, indicating an early return of alphaGST concentrations to the normal range. These findings suggest that serum alphaGST may be a more sensitive marker of hepatocellular damage than transaminases and may therefore be useful for rapid monitoring of the extent and persistence of liver injury after hepatectomy.