Yasuaki Hirooka

Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma.

Suppression of apoptosis is important for carcinogenesis and tumor growth. Recent studies revealed that survivin not only inhibited apoptosis but also accelerated cancer cell proliferative activity. To investigate the prognostic role of expression of the antiapoptosis gene, survivin, in hepatocellular carcinoma (HCC), the authors analyzed the correlation between the expression pattern of survivin messenger RNA (mRNA) and clinicopathologic findings of patients. Tissues were obtained by surgical resection of livers from 51 patients with HCC and 6 patients without HCC. Expression of survivin mRNA was evaluated using reverse transcription-polymerase chain reaction in 51 tumors, 51 adjacent histologically noncancerous livers, and 6 normal livers. Survivin protein expression was evaluated using Western blotting, and apoptotic cancer cells were detected by immunostaining with polyclonal rabbit anti-single-stranded DNA. Survivin mRNA expression was detected in 21 of 51 (41%) tumors, 2 of 51 (4%) noncancerous livers, and none of the 6 normal livers. Survivin mRNA expression did not correlate with tumor size or stage of HCC. Percentage of apoptotic cancer cells of 30 survivin mRNA-negative tumors (5.2 ± 3.4%) was significantly higher than that of 21 survivin mRNA-positive tumors (2.2 ± 2.3%, P = 0.0019). The disease-free 5-year survival rate of 21 patients positive for survivin mRNA (19%) was significantly poorer than that of 30 patients negative for survivin mRNA (39%, P = 0.0148). Survivin mRNA was detected in 57% (17/30) patients with HCC recurrence but in only 19% (4/21) of patients without recurrence (P = 0.0072). These results indicated that survivin mRNA expression could be used as an independent prognostic factor for patients with HCC after hepatectomy.

Relaitonship between area of serosal invasion and prognosis in patient with gastric carcinoma

We examined the relationship between the spatial extent of invasion of the gastric serosa in patients with gastric carcinoma and their postoperative 5‐year survival rate. At the time of surgical resection of gastric patients with gross evidence of serosal invasion. Examination of the relaitonship between the presence of with an area of serosal invasion 10 cm2 or less were positive for free cancer cells, but such cells were found in 72% of cases with an area of serosal invasion greaer than 20 cm2. The 5‐year survival rate was 31% in patients iwht ana area of serosal invasion of less than 10 cm2, whereas the rate was only 8% in patients witha n area of serosal invasion greawter than 20 cm2. Not only the presence of serosal invaison by a tumor but also the spatial extent of the invasion are significant factors that ainfluence the prognosis of patients wiht gastric carcinoma.

Postoperative delirium following gastrointestinal surgery in elderly patients

Postoperative delirium is a common complication which can interfere with the surgical treatment and recovery of elderly patients, and is likely to prolong their hospitalization. Unfortunately, there is as yet no completely effective pre- and/or post operative technique of patient care to reduce or prevent postoperative delirium. In this study, 36 patients aged over 70 years undergoing gastrointestinal operations were assessed to examine the relationships between the preoperative cognitive state, the postoperative sleep cycle, and the occurrence of postoperative delirium. All patients were evaluated preoperatively using the revised version of Hasegawas dementia scale (HDS-R). We correlated those test results and assessed the sleep-wakefulness disturbance postoperatively, to obtain a clinical DMS-III diagnosis of postoperative delirium. The incidence of postoperative delirium was 17% (6/36). The patients who developed postoperative delirium demonstrated preoperative cognitive impairment, and had a short sleep period during the night and a long sleep period during the day. Postoperatively, these results suggest that HDS-R is a useful method of evaluating preoperative cognition in elderly patients. Considering that sleep deficiency is likely to predispose elderly patients to postoperative delirium, techniques to prevent sleep deprivation may be of considerable value in minimizing the incidence of postoperative delirium.

Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma

PurposeKiSS-1 has been cloned as a human metastasis suppressor gene and an orphan G-protein-coupled receptor (hOT7T175) identified as the endogenous receptor of the KiSS-1 product. In the present study, we evaluated the clinical importance of KiSS-1 and hOT7T175 gene expression in hepatocellular carcinoma (HCC).MethodsThe expression levels of KiSS-1, hOT7T175 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger RNAs (mRNAs) were analyzed quantitatively by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 60 surgically resected HCCs. The KiSS-1/GAPDH and hOT7T175/GAPDH ratios of tumors were compared with clinicopathological findings.ResultsLoss of KiSS-1 mRNA expression was not detected in HCCs. The mean KiSS-1/GAPDH ratio did not change between non-cancerous cirrhotic livers and carcinomas. On the other hand, the average hOT7T175/GAPDH ratios increased from non-cancerous livers (0.08) to carcinomas (0.48). Overexpression of KiSS-1 and hOT7T175 genes was recognized in 6 tumors, which were in an advanced stage and showed poor survival.ConclusionOverexpression of KiSS-1 and hOT7T175 genes was frequently observed and correlated with HCC progression; thus, the possibility that overexpressed KiSS-1 and hOT7T175 peptides mediate growth signals into cancer cells in HCCs is suggested.

Serum human telomerase reverse transcriptase messenger RNA as a novel tumor marker for hepatocellular carcinoma

Purpose: We previously reported the usefulness of a qualified highly sensitive detection method for human telomerase reverse transcriptase (hTERT) mRNA in serum with 89.7% sensitivity for hepatocellular carcinoma (HCC). In this study, we developed a quantitative detection method for serum hTERT mRNA and examined the clinical significance in HCC diagnosis. Experimental Background: In 64 patients with HCC, 20 with liver cirrhosis, 20 with chronic hepatitis, and 50 healthy individuals, we measured serum hTERT mRNA by using the newly developed real-time quantitative reverse transcription-PCR with SYBR Green I. We examined its sensitivity and specificity in HCC diagnosis, clinical significance in comparison with other tumor markers, and its correlations with the clinical variables by using multivariate analyses. Results: Serum hTERT mRNA showed higher values in patients with HCC than those with chronic liver diseases. hTERT mRNA expression was shown to be independently correlated with clinical variables such as tumor size, number, and degree of differentiation (P < 0.001, each). The sensitivity/specificity of hTERT mRNA and alpha;-fetoprotein (AFP) mRNA in HCC diagnosis were 88.2%/70.0% for hTERT and 71.6%/67.5% for AFP, respectively. hTERT mRNA proved to be superior to AFP mRNA, AFP, and des-γ-carboxy prothrombin in HCC diagnosis. Furthermore, hTERT mRNA in serum was associated with that in HCC tissue. Conclusions: The usefulness of hTERT mRNA expression in HCC diagnosis and its superiority to conventional tumor markers were shown. Therefore, serum hTERT mRNA is a novel and available marker for HCC diagnosis.

Complications of radiofrequency ablation for hepatocellular carcinoma in a multicenter study: An analysis of 16 346 treated nodules in 13 283 patients

Aim:  We surveyed multiple centers to identify types and frequency of complications and mortality rate associated with radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC).

Quantitative analysis of apoptosis-related gene expression in hepatocellular carcinoma

The suppression of apoptosis is an important factor in tumor progression in hepatocellular carcinoma (HCC). However, to the authors knowledge the clinicopathologic importance of the expression of apoptosis‐related genes (bcl‐2, bax, and survivin) in HCC remains unclear. In the current study, the authors investigated the correlation between expression of apoptosis‐related genes and the occurrence of spontaneous apoptosis in HCC. In addition, the prognostic significance of the expression of apoptosis‐related genes in patients with HCC was analyzed.

Expression of 8-hydroxy-2'-deoxyguanosine in chronic liver disease and hepatocellular carcinoma.

Abstract: Reactive oxygen species may be involved in the progression of chronic liver disease and the occurrence of hepatocellular carcinoma (HCC). To clarify whether clinicopathological findings in liver diseases are related to oxidative DNA damage, hepatic expression of the 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) was examined in 75 liver disease patients, which included 32 chronic hepatitis (CH), 13 liver cirrhosis (LC) and 30 HCC patients. The CH patients had higher 8‐OHdG‐positive hepatocytes than LC (P<0.05). In CH and LC, the number of 8‐OHdG‐positive hepatocytes was correlated with alanine aminotransferase and asparate aminotransferase (P<0.01 and P<0.05, respectively). Of 30 HCC cases, 25 cases (83%) showed stronger immunoreactivity than non‐cancerous counterparts. The patients with poorly differentiated HCC had a larger tumor size and higher levels of AFP, and exhibited higher labeling indices of PCNA‐, TUNEL‐ and 8‐OHdG‐positive cells than those with well and moderately differentiated HCC. Our findings suggest that oxidative DNA damage is increased in association with necroinflammation in chronic liver disease and determination of 8‐OHdG is useful in assessing high‐grade malignancy in HCC.

Interferon alpha inhibits intrahepatic recurrence in hepatocellular carcinoma with chronic hepatitis C: a pilot study.

The aim of the present study is to evaluate whether interferon alpha (IFNalpha) therapy can inhibit intrahepatic recurrence after the curative treatment of small HCC with underlying chronic hepatitis C. Forty patients were enrolled in this study. They had solitary, small HCC</=3 cm in diameter, underlying chronic hepatitis C, and were </=70 years old. Of the patients, 18 were treated with IFNalpha for 6 months after the treatment of HCC, and 22 patients who did not receive IFNalpha therapy were used as controls. Six (33%) patients in the IFN group showed sustained response. The incidence of local recurrence was not different in the IFN and non-IFN groups (6 vs. 9%). The cumulative incidences of distant recurrence in the non-IFN and IFN groups were 9 and 6% at 1 year, 27 and 11% at 2 years, 63 and 18% at 3 years, 76 and 28% at 4 years, and 82 and 28% at 5 years; they were significantly different (P<0.01). Six (27%) patients in the non-IFN group died from the progression of HCC, but all IFN-treated patients were alive (P<0.05). The pilot study demonstrates that IFNalpha therapy after the curative treatment of small HCC can inhibit intrahepatic recurrence in the remnant liver and improve the prognosis of hepatitis C virus-related HCC.

Loss of heterozygosity of the retinoblastoma gene in liver cirrhosis accompanying hepatocellular carcinoma

Carcinogenesis is a multistep process. Most hepatocellular carcinoma (HCC) is preceded by liver cirrhosis, but the genetic changes involved in cirrhosis are not known well. The present study was conducted to evaluate aberration of the retinoblastoma (RB) gene in HCC and adjacent non-tumorous liver using 22 patients with chronic liver damage accompanying HCC. The specimens obtained by microdissection from paraffinembedded tissues were analyzed using an assay based on the polymerase chain reaction for highly polymorphic nucleotide sequences of microsatellites in theRB gene. Out of 22 cases, 15 showed constitutional heterozygosity for the microsatellite markers. In 11 (73.3%) of these 15 informative cases, the primary HCC foci showed loss of heterozygosity (LOH). In 8 of these 11 doubly informative (informative and LOH-positive in primary HCC) cases, LOH was found in 20 (64.5%) of 31 microdissected non-tumorous foci. All of the non-tumorous foci showingRB loss were cirrhotic lesions but there were no foci of chronic hepatitis. The remaining 4 cases without LOH in HCC foci showed no LOH in non-tumorous lesions. In our study, LOH of theRB gene was frequently observed in liver cirrhosis surrounding tumor.