Akira Togawa

Enhanced polyadenosine diphosphate‐ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma

Aim: The aim of this study is to assess the poly ADP‐ribosylation activity in human hepatocellular carcinoma (HCC) and in liver cirrhosis (LC) as compared to the activity in normal livers (NL).

Identification of novel immunohistochemical tumor markers for primary hepatocellular carcinoma; clathrin heavy chain and formiminotransferase cyclodeaminase

Early diagnosis of hepatocellular carcinoma (HCC) greatly improves its prognosis. However, the distinction between benign and malignant tumors is often difficult, and novel immunohistochemical markers are necessary. Using agarose two‐dimensional fluorescence difference gel electrophoresis, we analyzed HCC tissues from 10 patients. The fluorescence volumes of 48 spots increased and 79 spots decreased in tumor tissues compared with adjacent nontumor tissue, and 83 proteins were identified by mass spectrometry. Immunoblot confirmed that the expression of clathrin heavy chain (CHC) and Ku86 significantly increased, whereas formiminotransferase cyclodeaminase (FTCD), rhodanese, and vinculin decreased in tumor. The protein expression in tumor and nontumor tissues was further evaluated by immunostaining. Interestingly, CHC and FTCD expression was strikingly different between tumor and nontumor tissues. The sensitivity and specificity of individual markers or a combination for the detection of HCC were 51.8% and 95.6% for CHC, 61.4% and 98.5% for FTCD, and 80.7% and 94.1% for CHC+FTCD, respectively. Strikingly, the sensitivity and specificity increased to 86.7% and 95.6% when glypican‐3, another potential biomarker for HCC, was used with FTCD. Moreover, CHC and FTCD were useful to distinguish early HCC from benign tumors such as regenerative nodule or focal nodular hyperplasia, because the sensitivity and specificity of the markers are 41.2% and 77.8% for CHC, 44.4% and 80.0% for FTCD, which is comparable with those of glypican‐3 (33.3% and 100%). The sensitivity significantly increased by combination of these markers, 72.2% for CHC+FTCD, and 61.1% for CHC+glypican‐3 and FTCD+glypican‐3, as 44.4% of glypican‐3 negative early HCC were able to be detected by either CHC or FTCD staining. Conclusion: Immunostaining of CHC and FTCD could make substantial contributions to the early diagnosis of HCC. (HEPATOLOGY 2008.)

Enhancement of poly‐adenosine diphosphate‐ribosylation in human hepatocellular carcinoma

Background : Poly‐adenosine diphosphate (ADP)‐ribosylation, catalysed by poly(ADP‐ribose) polymerase (PARP), is a post‐translational modification of nuclear proteins and is involved in a wide range of biological processes including DNA repair, cell proliferation and malignant transformation. Alteration of this reaction in human hepatocellular carcinoma (HCC) is of interest, but has not yet been explored. The aim of this study was to evaluate poly‐ADP‐ribosylation and to compare the expression of PARP in HCC and adjacent non‐tumour tissues.

Apolipoprotein C-1 maintains cell survival by preventing from apoptosis in pancreatic cancer cells

Pancreatic cancer still remains one of the most lethal diseases and establishment of new therapy is needed. The purpose of this study is to find novel factors involved in pancreatic cancer progression by proteomic approach. We compared pre- and postoperative serum protein profiling obtained from pancreatic cancer patients who had curative pancreatectomy using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The peak intensity levels of both 6630 and 6420 Da were significantly higher in the preoperative serum than in the postoperative serum (P<0.002). Sequential amino acid analysis identified these proteins to be apolipoprotein C-1 (ApoC-1). The high level of ApoC-1 in preoperative serum significantly correlated with poor prognosis. Furthermore, ApoC-1 was abundantly expressed in pancreas neoplastic epithelium, and was detected in the culture medium of the pancreatic cancer cell line in vitro, which suggests that cancer cells secrete ApoC-1. Inhibition of ApoC-1 expression by short interfering RNA suppressed cell proliferation and induced apoptosis of pancreatic cancer cells. The specific expression of ApoC-1 and its role in preventing from spontaneous apoptosis in pancreatic cancer cells suggest that ApoC-1 contributes to the aggressiveness of pancreatic cancer and will be useful as a new therapeutic target.

Inhibition of Hepatic Regeneration after 70% Partial Hepatectomy by Simultaneous Resection of the Bowel in Rats

This study was aimed to evaluate bow simultaneous resection of the bowel influences hepatic regeneration after partial hepatectomy (HTX). Two hundred and sixty-four rats underwent 70% partial HTX, ileocecal resection (ICR), transverse colon resection (TR), colon amputation and simulatenous resection of the liver and the bowel (HTX+ICR, HTX+TR). Hepatic DNA synthesis was remarkably suppressed by simultaneous resection compared with the 70% HTX group (p < 0.01). In simultaneous resection groups, delayed enhanced hepatic protein synthesis (HPS) was observed after the operation as compared with the 70% HTX group, which showed an early postoperative peak of HPS. Postoperative anastomosis leakage occurred more frequently and survival rates were significantly lower in simultaneous resection groups. Higher plasma endotoxin levels of the portal and the peripheral veins were found in simultaneous resection groups as compared with other groups (p < 0.01-0.001). This study suggested that simultaneous resection of the bowel with partial HTX might inhibit hepatic regeneration and result in the increased risk of anastomosis leakage and high surgical mortality rate by increased plasma endotoxin levels and delayed enhanced HPS.

A randomized phase II trial of adjuvant chemotherapy with uracil/tegafur and gemcitabine versus gemcitabine alone in patients with resected pancreatic cancer†‡§

There have been few randomized studies of adjuvant chemotherapy using gemcitabine (GEM) in patients with resected pancreatic cancer.

Treatment with an oral fluoropyrimidine, S-1, plus cisplatin in patients who failed postoperative gemcitabine treatment for pancreatic cancer: a pilot study

BackgroundThis study set out to evaluate, in patients with gemcitabine-resistant pancreatic cancer, the response rate and toxicity of S-1 plus cisplatin (CDDP).MethodsSeventeen patients with histologically diagnosed invasive ductal pancreatic cancer were enrolled in this study. All patients had growing recurrent pancreas cancer despite the administration of gemcitabine. Thirteen patients underwent pancreatectomy, and 2 underwent choledochojejunostomy and gastrojejunostomy without pancreatectomy. S-1 (80 mg/m2 per day) was orally administered for 21 consecutive days, followed by a 14-day rest period. CDDP (40 mg/m2) in 500 ml saline was administered by intravenous drip on day 8. This schedule was repeated every 5 weeks until the occurrence of disease progression, unacceptable toxicities, or the patients refusal to continue.ResultsFive (29.4%) patients achieved a partial response and 2 (11.8%) had stable disease. In 5 of 15 patients (33.3%) who had elevated serum carbohydrate antigen (CA)19-9 levels at the start of treatment the CA19-9 was reduced by more than 50%. The median survival time was 10 months (range, 20 months), with 63.7% and 31.9% of patients alive at 6 and 12 months, respectively. Major adverse reactions in the 15 patients included gastrointestinal toxicities of grade 1 or 2. Only one patient (5.9%) developed grade 3 leucopenia.ConclusionS-1 with CDDP has a promising effect against gemcitabine-resistant pancreatic cancer, with easily manageable toxicities. Further investigation of this regimen is warranted in patients with pancreatic cancer, especially in comparison with gemcitabine.

Reduced hemoglobin and increased C-reactive protein are associated with upper gastrointestinal bleeding

AIM To investigate the early upper gastrointestinal endoscopy (endoscopy) significantly reduces mortality resulting from upper gastrointestinal (GI) bleeding. METHODS Upper GI bleeding was defined as 1a, 1b, 2a, and 2b according to the Forrest classification. The hemoglobin (Hb), and C-reactive protein (CRP) were examined at around the day of endoscopy and 3 mo prior to endoscopy. The rate of change was calculated as follows: (the result of blood examination on the day of endoscopy - the results of blood examination 3 mo prior to endoscopy)/(results of blood examination 3 mo prior to endoscopy). Receiver operating characteristic curves were created to determine threshold values. RESULTS Seventy-nine men and 77 women were enrolled. There were 17 patients with upper GI bleeding: 12 with a gastric ulcer, 3 with a duodenal ulcer, 1 with an acute gastric mucosal lesion, and 1 with gastric cancer. The area under the curve (AUC), threshold, sensitivity, and specificity of Hb around the day of endoscopy were 0.902, 11.7 g/dL, 94.1%, and 77.1%, respectively, while those of CRP were 0.722, 0.5 mg/dL, 70.5%, and 73%, respectively. The AUC, threshold, sensitivity, and specificity of the rate of change of Hb were 0.851, -21.3%, 76.4%, and 82.6%, respectively, while those of CRP were 0.901, 100%, 100%, and 82.5%, respectively. CONCLUSION Predictors for upper GI bleeding were Hb < 11.7 g/dL, reduction rate in the Hb > 21.3% and an increase in the CRP > 100%, 3 mo before endoscopy.

Establishment of gemcitabine-resistant human pancreatic cancer cells and effect of brefeldin-a on the resistant cell line.

To date, no therapy has been found to which pancreatic cancer responds with the exception of surgical resection in early stages. Recently, gemcitabine has become the standard of care for chemotherapy in those patients with advanced disease. Most pancreatic tumors however, develop resistance to gemcitabine. The aim of this study is to clarify the mechanism of resistance to gemcitabine in human pancreatic cells. Using a cell selection method, a human pancreatic cancer cell line resistant to gemcitabine was established. Cellular proliferation and viability were determined by MTT assay. The cell line with acquired resistance was also found to have cross resistance to fluorouracil. Brefeldin-A (BFA) has been used as a tool for studies of intracellular protein traffic, rather than as an anticancer drug. BFA displays the same effects on wild type cells and those with acquired resistance. Gemcitabine combined with BFA in low doses is significantly more effective than gemcitabine alone against MIA PaCa-2 cell line. Our data suggest that the gemcitabine-resistant and 5-FU-resistant pathways may partially overlap each other. In short, BFA may be used as a modulator of gemcitabine.

Reduced Hepatic Functional Reserve in Cirrhosis and Obstructive Jaundice with Special Reference to Histological Morphometric Analysis and Galactose Elimination Capacity

To evaluate liver dysfunction in patients with obstructive jaundice (OJ), morphological and functional hepatic mass was analyzed in comparison with cirrhosis (LC). Total hepatic parenchymal ratio (THPR) was estimated by morphometric analysis and hepatic functional mass by galactose tolerance test (GaTT) in 30 patients who underwent hepatectomy. The value of GaTT in patients with LC was remarkably depressed compared to those with normal liver function (p < 0.001). It was also depressed in OJ (p < 0.05 vs. normal liver), but less than in LC (p < 0.05). However, THPR decreased only in LC (p < 0.05 vs. either normal liver or OJ). A significant correlation between the value of GaTT and THPR was revealed in patients with LC, but not in OJ. These results suggested that liver dysfunction in OJ was independent of the decreased number of hepatocytes, differing from LC.