Effect of vitamin K2 on the recurrence of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.     

Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer

Mutations in mitotic checkpoint genes have been detected in several human cancers, and these cancers exhibit chromosomal instability. Aneuploid stem cells seem to result from chromosomal instability and have been reported in many lung cancers. To determine whether alteration of mitotic checkpoint regulators is involved in carcinogenesis and tumor progression in primary lung cancer, we screened the genomic DNA sequence of 30 human lung cancer cell lines and 30 primary lung cancer tumors for a mutation in the hBUB1 mitotic checkpoint gene. First, we designed 26 sets of intron-based primers to amplify each of the 25 exons of the hBUB1 gene to examine the entire coding region of the hBUB1 gene. Using these primers, we performed polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis as well as direct sequencing in the mutation analysis of the hBUB1 gene. Three different nucleotide substitutions were detected in the coding region of the hBUB1 gene in some of the cancer cell lines and primary tumors as follows. The hBUB1 gene of one adenocarcinoma tumor contained a somatic missense mutation, a cytosine-to-guanine substitution in codon 51 of exon 5 that resulted in a histidine-to-aspartic acid amino acid substitution. The hBUB1 gene of three lung cancer cell lines contained a thymine-to-cytosine substitution in codon 430 of exon 12, which did not result in an amino-acid substitution. We were unable to determine whether the nucleotide substitution in exon 12 was a polymorphism or a silent mutation because matched normal tissue was not available. A polymorphism in codon 93 of exon 4, a guanine-to-thymine substitution, in hBUB1 was found in one lung cancer cell line and one primary lung tumor. This is the first report of a somatic missense mutation of a gene involved in a mitotic checkpoint in primary lung cancer. The presence of a point mutation in the hBUB1 gene is consistent with the hypothesis that alteration of mitotic checkpoint genes is involved in the development of primary lung cancers. Because the frequency of hBUB1 gene mutations was low, future studies should focus on other mechanisms of inactivation of the hBUB1 gene as well as mutation analysis of other mitotic checkpoint genes in lung cancers.     

Lower optimal dose of amrubicin for relapsed small-cell lung cancer: a retrospective study

International Journal of Clinical Oncology - Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose...     

The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice

It has been demonstrated the involvement of branched-chain amino acids (BCAA) on obesity and related metabolic disorder. We investigated the effects of branched-chain amino acids (BCAA) on obesity and on glucose/fat homeostasis in mice fed on a high-fat (45%) diet. BCAA was dissolved in 0.5% methylcellulose and added to the drinking water (BCAA-treated group). A high-fat diet was provided for 6 weeks and BCAA was given for 2 weeks. The BCAA-treated group gained almost 7% less body weight and had less epididymal adipose tissue (WAT) mass than the control group (p<0.05). BCAA supplementation also reduced the hepatic and skeletal muscle triglyceride (TG) concentrations (p<0.05). The hepatic levels of PPAR-alpha and uncoupling protein (UCP) 2, and the level of PPAR-alpha and UCP3 in the skeletal muscle were greater in the BCAA-treated group than in the control mice (p<0.05). These results demonstrate that the liver and muscle TG concentration are less in BCAA-treated group. BCAA affects PPAR-alpha and UCP expression in muscle and liver tissue.     

Data mining reveals complex interactions of risk factors and clinical feature profiling associated with the staging of non‐hepatitis B virus/non‐hepatitis C virus‐related hepatocellular carcinoma

Aim: Non‐hepatitis B virus/non‐hepatitis C virus‐related hepatocellular carcinoma (NBNC‐HCC) is often detected at an advanced stage, and the pathology associated with the staging of NBNC‐HCC remains unclear. Data mining is a set of statistical techniques which uncovers interactions and meaningful patterns of factors from a large data collection. The aims of this study were to reveal complex interactions of the risk factors and clinical feature profiling associated with the staging of NBNC‐HCC using data mining techniques. Methods: A database was created from 663 patients with NBNC‐HCC at 20 institutions. The Milan criteria were used as staging of HCC. Complex associations of variables and clinical feature profiling with the Milan criteria were analyzed by graphical modeling and decision tree algorithm methods, respectively. Results: Graphical modeling identified six factors independently associated with the Milan criteria: diagnostic year of HCC; diagnosis of liver cirrhosis; serum aspartate aminotransferase (AST); alanine aminotransferase (ALT); α‐fetoprotein (AFP); and des‐γ‐carboxy prothrombin (DCP) levels. The decision trees were created with five variables to classify six groups of patients. Sixty‐nine percent of the patients were within the Milan criteria, when patients showed an AFP level of 200 ng/mL or less, diagnosis of liver cirrhosis and an AST level of less than 93 IU/mL. On the other hand, 18% of the patients were within the Milan criteria, when patients showed an AFP level of more than 200 ng/mL and ALT level of 20 IU/mL or more. Conclusion: Data mining disclosed complex interactions of the risk factors and clinical feature profiling associated with the staging of NBNC‐HCC.     

Risk factors for deterioration of long-term liver function after radiofrequency ablation therapy

AIM:To identify factors that influence long-term liver function following radiofrequency ablation(RFA)in patients with viral hepatitis-related hepatocellular carcinoma.METHODS:A total of 123 patients with hepatitis B virus-or hepatitis C virus-related hepatocellular carcinoma(HCC)(n=12 and n=111,respectively)were enrolled.Cumulative rates of worsening Child-Pugh(CP)scores(defined as a 2-point increase)were examined.RESULTS:CP score worsening was confirmed in 22patients over a mean follow-up period of 43.8±26.3mo.Multivariate analysis identified CP class,platelet count,and aspartate aminotransferase levels as significant predictors of a worsening CP score(P=0.000,P=0.011 and P=0.024,respectively).In contrast,repeated RFA was not identified as a risk factor for liver function deterioration.CONCLUSION:Long-term liver function following RFA was dependent on liver functional reserve,the degreeof fibrosis present,and the activity of the hepatitis condition for this cohort.Therefore,in order to maintain liver function for an extended period following RFA,suppression of viral hepatitis activity is important even after the treatment of HCC.     

Prognostic implications of nasal cavity and cleft morphology in secondary bone grafting.

OBJECTIVE: To examine the prognostic significance of the skeletal morphology around the nasal cavity and the alveolar cleft in secondary bone grafting (SBG). DESIGN AND SETTING: Fifty-one alveolar clefts in 41 patients (10 bilateral and 31 unilateral cleft lips and palates) registered in the Tokushima University Dental Hospital were examined in this study. METHOD: Evaluation of the bony bridge after SBG using dental radiographs at 1 year after surgery. The clefts were divided into two groups: group I (54.9%) in which the upper border of the bony bridge was preferably maintained on or above the horizontal reference line (RL) constructed at the level of the root apex of the upper central incisor adjacent to the cleft, and group II (45.1%) in which the bone level was lower than the RL. Presurgical cleft width was determined by the dental radiographs. The cleft/nasal cavity ratio; the value of the cleft width divided by the nasal cavity width on the cleft side, which was analyzed by frontal cephalograms before the SBG; and the cleft/apertura piriformis ratio, the value analyzed by computed tomography, were used. RESULTS AND CONCLUSION: The age, sex, and eruptive stage of the canine teeth at the time of the SBG showed no significant difference between groups. The presurgical cleft width also showed no significant difference between group I (6.6 +/- 3.1 mm) and group II (7.9 +/- 3.3 mm). The cleft/nasal cavity ratio showed a significant difference between groups I and II (0.42 +/- 0.14, 0.75 +/- 0.25; p < .05). Furthermore, the cleft/apertura piriformis ratio also showed a significant difference between groups I and II (0.32 +/- 0.12, 0.65 +/- 0.26; p < .05). These results suggested that measurements of the skeletal morphology around the nasal cavity and alveolar cleft might aid in predicting the stability of the bony bridge after SBG.     

Sitagliptin add-on to low dosage sulphonylureas: efficacy and safety of combination therapy on glycaemic control and insulin secretion capacity in type 2 diabetes

Aims:  To assess the efficacy and safety of combination therapy with sitagliptin and low dosage sulphonylureas on glycaemic control and insulin secretion capacity in Japanese type 2 diabetes. Methods: Eighty‐two subjects were sequentially recruited for the 52‐week, prospective, single arm study. Sitagliptin was added on to sulphonylureas (glimepride or gliclazide) with or without metformin. The primary endpoint was a change in A1C. The secondary endpoints were changes in BMI, insulin secretion capacity, blood pressure and urinary albumin excretion, unresponsive rate, and hypoglycaemia. Insulin secretion capacity was evaluated by glucagon loading test. Results:  Change in A1C was ?0.80% (95% CI ?0.90 to ?0.68) (p < 0.001). Change in BMI, systemic and diastolic blood pressure, and urinary albumin excretion were ?0.38 kg/m² (95% CI ?0.72 to ?0.04) (p < 0.05), ?6.7/?3.6 mmHg (95% CI ?10.0 to ?3.4/?4.8 to ?2.4) (p < 0.001), and ?43.2 mg/gCr (95% CI ?65.7 to ?20.8) (p < 0.001) respectively. Mild hypoglycaemia was observed in three cases. The unresponsive rate was 6.1%. Glucagon loading test showed that 0‐min and 6‐min CPR at baseline and 52‐week were not significantly changed: 0‐min CPR, 1.58 ± 0.58–1.71 ± 0.73 ng/ml; 6‐min CPR, 3.48 ± 1.47–3.58 ± 1.21 ng/ml. Insulin secretion capacity, CPI and SUIT index at baseline did not predict the efficacy of the combination therapy. The final dosages of glimepiride and gliclazide were 1.44 ± 0.90 mg and 34.5 ± 15.3 mg respectively. The dosage of sitagliptin was increased from 50 mg to 69.0 ± 24.5 mg in 52‐week. Conclusions:  The combination therapy with sitagliptin and low dosage sulphonylureas was safe and effective for glycaemic control. Glucagon loading test indicated that 1 year administration of sitagliptin and sulphonylureas preserved insulin secretion capacity.     

Unchanged frequency of loss of heterozygosity and size of the deleted region at 8p21-23 during metastasis of lung cancer.

The genetic mechanisms involved in lung cancer development and progression are beginning to be understood. Many studies have documented frequent loss of heterozygosity (LOH) at specific chromosomal regions in cancer cells; this implies that tumor suppressor genes (TSG) are usually present in those regions. Recently, it has been reported that LOH or chromosomal deletions at chromosome 8p21-23 represent early events frequently occurring in lung cancer. In addition, the size of these chromosome 8 deletions, as well as their frequency, was also reported to increase during lung cancer progression. To determine the spectrum and frequency of alterations of chromosome 8p21-23 in human lung cancer and whether these increase with progression of the tumors, we performed LOH analysis of chromosome 8p and 3p in the genomic DNA from cells from primary and metastatic sites of lung cancer, as well as from normal lung. We studied 35 subjects with primary lung cancer including 30 tumors with distant metastasis. Detection of allelic deletion utilized a PCR-based approach of microsatellite polymorphism analysis, which was performed using the microsatellite markers D8S1130, D8S1106, D8S511, D8S1827, D8S549, D8S261, LPL, D8S258, D8S136, NEFL, D3S1295, D3S1313, D3S1234, D3S1300, D3S1351, D3S1339, and D3S1340. The overall allelic deletion rates were 10 of 28 (35.7%) at 8p and 13 of 33 (39.4%) at 3p. The allelic deletions in the primary cancer and its metastatic sites were in each case identical in both frequency and size of the deleted regions. In our analysis, 8p21-23 deletions were not always associated with 3p deletions in primary lung cancer. These results therefore suggest that allelic deletion at chromosome 8p21-23 is an early and frequent event in the carcinogenesis and development of lung cancer, independent of chromosome 3p deletion. However, a continuing increase in the frequency of LOH at 8p21-23 and in the size of the deleted region rarely occurs during the process of metastasis.