Lui Wy

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma

Somatic mutations in mitochondrial DNA (mtDNA) have been detected in hepatocellular carcinoma (HCC). However, it remains unclear whether mtDNA copy number and mitochondrial biogenesis are altered in HCC. In this study, we found that mtDNA copy number and the content of mitochondrial respiratory proteins were reduced in HCCs as compared with the corresponding non-tumorous livers. MtDNA copy number was significantly reduced in female HCC but not in male HCC. Expression of the peroxisome proliferator-activated receptor γ coactivator-1 was significantly repressed in HCCs (P<0.005), while the expression of the mitochondrial single-strand DNA-binding protein was upregulated, indicating that the regulation of mitochondria biogenesis is disturbed in HCC. Moreover, 22% of HCCs carried a somatic mutation in the mtDNA D-loop region. The non-tumorous liver of the HCC patients with a long-term alcohol-drinking history contained reduced mtDNA copy number (P<0.05) and higher level of the 4977 bp-deleted mtDNA (P<0.05) as compared with non-alcohol patients. Our results suggest that reduced mtDNA copy number, impaired mitochondrial biogenesis and somatic mutations in mtDNA are important events during carcinogenesis of HCC, and the differential alterations in mtDNA of male and female HCC may contribute to the differences in the clinical manifestation between female and male HCC patients.

Heterotopic Pancreas: A Difficult Diagnosis

Heterotopic pancreas is a rare disease. We evaluated 17 patients treated surgically at our hospital. Epigastric pain (77%), abdominal fullness (30%), and tarry stools (24%) were the three most frequent symptoms and signs. The lesions were diagnosed as gastroduodenal tumors by gastroduodenoscopy (67%) or upper gastrointestinal series (71%). Among these, only one gastric submucosal tumor was considered to be heterotopic pancreas preoperatively. Three patients were found to have gastric tumor by abdominal ultrasound. Computed tomography, small-intestinal series, barium enema, endoscopic retrograde cholangiopancreatography, angiography, and cholescintigraphy did not help in disclosing lesion. In about half of the patients, the lesions were located at the stomach. Tumor size varied from 1 to 3 cm. Surgical excision relieved symptoms. These findings indicated heterotopic pancreas is still a difficult disease for diagnosis, regardless of the improvements of diagnostic tools and techniques.

Relation of number of positive lymph nodes to the prognosis of patients with primary gastric adenocarcinoma.

BACKGROUND--No nodal grouping category of gastric cancer has been universally accepted for the grading of the effectiveness of therapeutic regimens. AIMS--To establish an appropriate nodal grouping as a forecaster of distant disease and test its validity as a determinant in survival. PATIENTS--Five hundred and ten patients who underwent curative resections for gastric cancer were studied. METHODS--Retrospectively analyse the prognostic significance of the number of metastatic lymph nodes. RESULTS--A total of 17 176 lymph nodes with an average of 34 per specimen were removed, of which 2811 (16%) showed metastases. Among the 510 patients, 287 (56%) had lymph node metastases, with an average of 9.8 per metastatic case. The survival of all patients was related to their nodal status, an abrupt decrease in survival was seen between 0 and 1 and 4 compared with 5 or more modes while little difference in survival existed among 1, 2, 3, and 4, and among 5, 6, 7, and 8 positive nodes. Multivariate analysis showed that the number of positive nodes (1-4, 5-8 versus > or = 9; relative risk 2.2) and depth of cancer invasion (three levels; relative risk 1.9) were independently correlated with survival. The current nodal stage was not a prognostic factor. CONCLUSIONS--Gastric cancer patients with 0, 1 to 4, 5 to 8, and > 9 positive nodes may represent four appropriate prognostic groups and should be adopted for classification of nodal stage in gastric cancer.

Quality of Life of Patients with Gastric Adenocarcinoma after Curative Gastrectomy

Abstract. Quality of life (QOL) was evaluated in 162 patients having radical gastrectomy for cancer. The results showed that more than half of the patients had a good appetite; they consumed a normal diet and a normal volume of food. Approximately 60% of the patients had weight loss of more than 5 kg. Patients who underwent a total gastrectomy had poor tolerance of normal food and frequent eating and body weight loss versus those who had a subtotal gastrectomy. Patients who underwent Billroth II reconstruction after a distal subtotal gastrectomy lost more body weight than those with a Billroth I anastomosis. The extent of lymphadenectomy did not influence the QOL. Patients under 65 years of age had a better QOL. Nearly all patients had normal work and daily living activities. Some patients appeared to lack energy or had a period of anxiety or depression. These data indicate that radical gastrectomy can be performed with an acceptable QOL for a potentially curable gastric carcinoma.

Heme Oxygenase-1 Gene Promoter Polymorphism is Associated with Risk of Gastric Adenocarcinoma and Lymphovascular Tumor Invasion

PurposeHeme oxygenase-1 (HO-1) gene, which encodes an oxidative response protein, plays a role in cytoprotection. A (GT)n dinucleotide repeat in HO-1 promoter is polymorphic and modulates the transcriptional activity of the gene. A HO-1 gene promoter polymorphism was reported to be associated with the risks of lung adenocarcinoma and oral squamous cancer. In this study, the correlation between the HO-1 gene promoter polymorphism and the clinicopathological characteristics, along with the risk of gastric cancer, was analyzed.Experimental designWe examined the genotypic frequencies of (GT)n repeats in 183 gastric cancer patients and 250 control subjects by PCR-based genotyping and DNA sequencing. The length polymorphisms of (GT)n repeats were classified into short (S) component (n ≤ 25), medium (M) component (26 ≤ n ≤ 30) and long (L) component (n ≥ 31). The distribution of S, M and L components in patient and control groups were evaluated to determine the correlation with susceptibility and clinicopathological characteristics of gastric adenocarcinoma.ResultsHigher frequencies of L-allele, L-allele carrier (S/L, M/L, L/L) and S/L genotype were found in gastric cancer patients. The frequencies of M-allele, M-allele carrier (M/M, M/L, M/S) and M/M genotype were significantly lower in patients with gastric cancer than controls. Furthermore, the frequency of lymphovascular tumor invasion was significantly lower in M-allele carriers compared to non-M-allele carriers (S/S, S/L, L/L) (p = 0.009).ConclusionsThese findings suggest that the long (GT)n repeat of HO-1 gene promoter was associated with a higher frequency of gastric adenocarcinoma, and the medium (GT)n repeat might possess protective effect against gastric adenocarcinoma with a lower frequency of lymphovascular invasion in tumors.

Factors affecting recurrence in node-negative advanced gastric cancer.

Background and Aim:  Prognostic factors of lymph node‐negative gastric adenocarcinoma after curative resection have been discussed. Recurrent pattern of advanced lymph node‐negative gastric cancer after curative resection has rarely been described.

Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway

Hepatoma cells are known to be highly resistant to chemotherapy. Previously, we have found differential Taxol resistance in human and murine hepatoma cells. The aim of this study was to examine the effect of a multidrug resistance inhibitor, cyclosporin A in combination with Taxol on hepatoma in vitro and in vivo, and to identify the possible mechanism involved in Taxol resistance. Simultaneous treatment of cyclosporin A (0–10 μM) and Taxol (0.1 μM) inhibited cell growth in vitro. Cyclosporin A interfered with Taxol (0.1 μM)-induced AKT activation and BAD phosphorylation. Cyclosporin A combined with Taxol treatment augments caspase-9, -3 activation and loss of mitochondrial membrane potential in HepG2 cells. PI3 kinase inhibitor, wortmannin, or a dominant-negative AKT1 expression vector treatment partially enhanced Taxol-induced apoptosis indicating that PI3 kinase-AKT pathway was involved in Taxol-resistance pathway. Moreover, combination treatment reduced tumour growth in SCID and C57BL/6 mice as compared to either Taxol or cyclosporin A treatment. Our results indicate that the combination of cyclosporin A and Taxol is effective in the reversal of Taxol resistance through the inhibition of PI3 kinase-AKT1 pathway.

Hypercholesterolaemia in patients with hepatocellular carcinoma

Ninety‐one (11.4%) subjects with hypercholesterolaemia (serum cholesterol level more than 250 mg/dL) of 792 Chinese patients with hepatocellular carcinoma (HCC) were studied in Taiwan. All 91 patients had large tumours greater than 7 cm in diameter and a tumour volume greater than 50%; 56 (61%) of these patients manifested tumour involvement in both lobes of the liver. The HCC patients with hypercholesterolaemia had significantly higher mean serum levels of albumin, triglyceride and α‐fetoprotein (AFP) compared with age‐sex‐tumour volume matched HCC patients without hypercholesterolaemia. The associated incidence of hypoglycaemia in hypercholesterolaemic HCC patients was significantly higher than in HCC patients without hypercholesterolaemia (15/90 vs 4/90; P= 0.01). There was no significant difference in the survival analysis between HCC patients with and without hypercholesterolaemia. Eight and 11 of hypercholesterolaemic HCC patients had their tumours surgically resected and received transcatheter hepatic arterial chemoembolization (TAE), respectively. Serum cholesterol levels fell to the normal range after treatment and rose to abnormal levels again when tumours recurred after surgery or progressively enlarged after TAE. The change in pattern of serum cholesterol was parallel to the change in serum AFP. Serum cholesterol levels may serve as another marker in identifying tumour recurrence and the presence of a viable tumour mass in hypercholesterolaemic HCC patients who have received surgical resection or TAE.

HBsAg(+) Donor as a Kidney Transplantation Deceased Donor

BACKGROUND The organ shortage and high prevalence of hepatitis B (HB) infection in the general population are important issues in Taiwan. It is difficult for us to abandon HBsAg(+) donors. Hereby we present our experience transplanting kidneys from deceased donors with HB virus infection. METHODS From November 1977 to March 2007, 21 patients with end-stage renal disease received kidney grafts from 12 HBsAg(+) deceased donors (3.92% of 306 donors). One of the 12 donors was hepatitis Be antigen (HBeAg) (+), and 5 displayed antibody to hepatitis core antigen (anti-HBc) (+). Four of the 21 recipients were HBsAg(+) before transplantation. RESULTS Four HBsAg(+) recipients remained surface antigen positive after transplantation. One of them died of an intracranial hemorrhage. Two (11.76%) of the other 17 HBsAg(-) recipients became HBsAg(+), 1 of whom died of hepatic failure and the other of sepsis. The other 15 HBsAg(-) recipients (88.23%) remained HBsAg(-) after transplantation. They displayed normal serum levels of aspartate aminotransferase/alanine aminotransferase during the follow-up period. The 5-year patient and graft survivals were 85.15% and 61.14%, respectively. CONCLUSION Although the number of patients is relatively small, it does suggest that a kidney allograft from an HBsAg(+) deceased donor transplanted to an HBsAg(+) or (-) recipient is safe. This strategy shortens the waiting time. Additional prophylactic HB immunoglobulin and antiviral medications are also suggested. Frequent surveillance after transplantation is essential.

The increase of MICA gene A9 allele associated with gastric cancer and less schirrous change.

Since surgical resection is the principal treatment of gastric cancer, early detection is the only effective strategy against this disease at present. Recently, a new polymorphic gene family, the major histocompatibility complex class I chain-related (MIC) genes located about 40 kb centromeric to HLA-B gene has been proposed. This family consists of five genes (A, B, C, D and E). Among them, MICA has five various alleles (A4, A5, A5.1, A6 and A9), which can be used as a polymorphic marker for genetic mapping and for disease susceptibility. The MICA polymorphism was studied in our gastric cancer patients to see if there is any possible correlation with genetic predisposition and clinicopathological factors. Genomic DNA was extracted from fresh or frozen peripheral blood leukocytes in 107 patients with gastric adenocarcinoma who underwent gastrectomy in our hospital and 351 noncancer controls. MICA polymorphism was analysed by using PCR-based technique. The results showed both phenotypic and allele frequencies of allele A9 in patients with gastric cancer were significantly higher than controls (33 vs 17.6%, P=0.005; 17 vs 9.9%, P=0.02). Gastric adenocarcinoma with allele A9 was associated with less schirrous change than those without (P=0.014). MICA gene A9 allele might confer the risk of gastric cancer and associate with less schirrous change. The mechanisms among them deserve further investigation.