BACKGROUND: Various treatments for hepatocellular carcinoma (HCC) are utilized in clinical practice; however, the prognosis is still poor on account of high recurrence rates. DNA methylation levels of CpG islands around promoters (promoter CpGis) inversely regulate gene expression and closely involved in carcinogenesis. As a new strategy, several chemicals globally inhibiting DNA methylation have been developed aiming at reducing DNA methylation levels and maintaining the expression of tumor suppressor genes. On the other hand, since these drugs nonspecifically modify DNA methylation, they can cause serious adverse effects. In order to ameliorate the methods by targeting specific CpGs, information of cancer-related genes that are regulated by DNA methylation is required. METHODS: We searched candidate genes whose expressions were regulated by DNA methylation of promoter CpGi and which are involved in HCC cases. To do so, we first identified genes whose expression were changed in HCC by comparing gene expressions of 371 HCC tissues and 41 non-tumor tissues using the Cancer Genome Atlas (TCGA) database. The genes were further selected for poor prognosis by log-rank test of Kaplan-Meier plot and for cancer relevance by Pubmed search. Expression profiles of upregulated genes in HCC tissues were assessed by Gene Ontology (GO) analysis. Finally, using DNA methylation data of TCGA database, we selected genes whose promoter DNA methylation levels were inversely correlated with gene expression. RESULTS: We found 115 genes which were significantly up- or downregulated in HCC tissues and were associated with poor prognosis and cancer relevance. The upregulated genes were significantly enriched in cell division, cell cycle, and cell proliferation. Among the upregulated genes in HCC, we identified hypomethylation of CpGis around promoters of FANCB, KIF15, KIF4A, ERCC6L, and UBE2C. In addition, TCGA data showed that the tumor suppressor gene P16 is unexpectedly overexpressed in many types of cancers. CONCLUSIONS We identified five candidate genes whose expressions were regulated by DNA methylation of promoter CpGi and associate with cancer cases and poor prognosis in HCC. Modification of site-specific DNA methylation of these genes enables a different approach for HCC treatment with higher selectivity and lower adverse effects.
Carcinoma, Hepatocellular ; genetics ; metabolism ; Cell Proliferation ; CpG Islands ; genetics ; DNA Methylation ; Databases as Topic ; Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms ; genetics ; metabolism ; Promoter Regions, Genetic

The patient was a six-month-old girl with an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). She had fever and visited a family physician at 5 months of age. Because of poor oxygenation, she was referred to our pediatric department and intubated soon after hospitalization. Echocardiography showed that the orifice of left coronary artery was just above pulmonary commissure, the left ventricular ejection fraction was 9%, and the level of mitral regurgitation was moderate. Right coronary angiography showed that the left coronary artery contrasted against the collateral arteries. The left coronary artery originated from the left side of the pulmonary trunk. After recovery of the general condition with medical therapy, the patient underwent coronary artery reconstruction by the modified spiral cuff technique on the 21st day of hospitalization. The temporary detachment of pulmonary valve and its commissure for making a margin around the left coronary artery enabled us to make the spiral cuff in almost the usual manner. She was moved to the intensive care unit with the support of extracorporeal membrane oxygenation (VA-ECMO) and was successfully weaned off the VA-ECMO 5 days after the surgery. The postoperative course was good, and she was discharged from our hospital 3 months after the surgery. The echocardiogram one year after the surgery showed a left ventricular ejection fraction of 30%, mild mitral regurgitation, and mild pulmonary regurgitation. Our experience indicates that the spiral cuff technique is a useful coronary reconstruction method for the treatment of ALCAPA, especially in cases presenting a considerable distance between the origin of the left coronary artery and the transplantation site. There are few reports regarding the surgical treatment of infantile ALCAPA showing reduced left ventricular function. Coronary artery reconstruction using the spiral cuff method and planned VA-ECMO are useful surgical procedures in such cases. Our experience also suggests that the establishment of a treatment strategy including mechanical support is essential to improve the results in severe ALCAPA cases.

A 17-days-old-girl with pulmonary artery (PA) sling, patent ductus arteriosus (PDA), and persistent left superior vena cava was admitted to our hospital. Despite good respiratory status just after birth, the respiratory status gradually worsened, and tracheal intubation was performed on 13th day after birth. Emergency division of the PDA was conducted on day 16. Although preoperative computed-tomography did not demonstrate tracheal stenosis, bronchoscopy after tracheal intubation revealed progression of tracheal stenosis with difficulty for stable anesthetic management. Therefore, operation was postponed to re-evaluate tracheal stenosis. Bronchoscopy and computed-tomography revealed the worsening of tracheal stenosis. Eventually, we performed total correction of the PA sling and tracheal stenosis on day 17. Cardiopulmonary bypass was established after median sternotomy. After transection of the PDA, the left PA originating from the right PA was also transected, and transplanted to the main PA. Then, sliding tracheoplasty was performed following the division of the tracheal stenotic region. Her respiratory condition improved after operation, and postoperative computed-tomography showed successful correction of tracheal stenosis. Although few such cases were reported for neonatal PA sling requiring concomitant tracheoplasty, this case suggests that total correction of PA sling and tracheal stenosis is feasible and useful surgical procedure for such cases.

A five-year-old boy with a univentricular heart, inferior vena cava interruption, and azygos connection was admitted to our hospital to undergo a staged Fontan-type procedure. Pectus excavatum had developed after he underwent total cavopulmonary shunt at the age of three years. Computed tomography revealed that the hepatic vein was just behind the recessed sternum. We performed simultaneous Nuss and Fontan-type procedures because we were afraid of the compression of the Fontan pathway from the hepatic vein to the pulmonary artery by the recessed sternum. A cardiopulmonary bypass was established and the hepatic vein and pulmonary artery were bypassed with a 16-mm expanded polytetrafluoroethylene graft. After removing the cardiopulmonary bypass, the Nuss procedure was performed. Although the bilateral thoracic cavities were diffusely and densely adhered, adhesiotomy was safely performed under direct visualization. The postoperative course was uneventful. Postoperative computed tomography showed that the pectus excavatum was well repaired and the Fontan pathway was not compressed by the sternum. Although there are few reports of Fontan-type and Nuss procedures being simultaneously performed, this method is useful for securing the space of the Fontan pathway and for preserving good Fontan circulation in the long term.

Liver metastases from colorectal carcinoma commonly form nodular lesions in the liverparenchyma. We report a case of liver metastasis from rectal adenocarcinoma that extendedpredominantly into the bile duct. A 62-year-old Japanese man underwent low anteriorresection for rectal adenocarcinoma 9 years ago. Approximately 3 years later, he underwentradiofrequency ablation therapy for a metastatic liver tumor. Nine years after surgery, atumor in liver segment III exhibiting intrabiliary extension was discovered; it wasunclear if this was a metastatic liver tumor or intrahepatic cholangiocarcinoma.Accordingly, we performed a left hepatectomy with lymph node dissection. The tumor wasnegative for cytokeratins 7 and 20, and was histologically similar to the primary rectaladenocarcinoma; it was diagnosed as rectal carcinoma metastasis. The patient has survivedfor 3 years after the hepatic surgery, for 9 years after radiofrequency ablation therapy,and for 12 years after the primary surgery. This case shows that liver metastasis fromcolorectal carcinoma can present as a predominantly intrabiliary growth that mimicsintrahepatic cholangiocarcinoma on imaging. Moreover, our case provides evidence for thesuperiority of anatomical hepatectomy over partial hepatectomy for metastatic liver tumorswith intrabiliary growth arising from rectal adenocarcinomas.

Objective : Transarterial or transapical aortic valve replacement (TAVR) procedures have been performed for high-risk patients with severe aortic valve stenosis (AS) in western countries. A high-risk patient is defined as having an STS score greater than 10%. In Japan, aortic valve replacement (AVR) with cardiopulmonary bypass (CPB) is standard care for AS, even if the patient is at high risk of developing complications. We calculated an expected operative risk of patients using a JAPAN score established by Japanese Adult Cardiovascular Surgery Database (JACVSD). Patients and Methods : Patients were divided into three groups : score less than 5%, low risk (LR) ; score 5-10%, moderate risk (MR) ; score more than 10%, high risk (HR). We also evaluated the efficacy of conventional AVR in each group. Between January 2002 and May 2011, we performed conventional AVR in our hospital and 116 patients who underwent AVR for symptomatic AS were enrolled in this study. Results : There were 79 patients in the LR group, 30 patients in the MR group and 7 patients in the HR group. The mean score was 2.6±1.1% in the LR group, 6.8±1.4% in the MR group and 23.3±16.8% in the HR group respectively. The mean follow-up period was 7.6±0.3 years. Preoperative co-morbidity was not statistically significant among three groups, however more octogenarians were found in the HR group. The aortic valve area and left ventricular ejection fraction (LVEF) were significantly smaller in the HR group. There were 4 cancer patients. The HR group had significantly longer operation and CPB times than the LR group. The operative mortality in all cases was 1.6%. Overall survival at 5 years was 78%. Actual survival at 5 years was 77% in the LR group, 82% in the MR group and 71% in the HR group. The major adverse cardiac and cerebrovascular event (MACCE)-free ratio at 5 years was 85%. Absence of death caused by MACCE at 5 years was 93%. All cancer patients died after AVR due to advancement in cancer. Conclusion : The results of conventional AVR with CPB were satisfactory in each group. Cancer patients may be good candidates for TAVR in the future.

Objective: Early life events connected with the risk of later disease can occur not only in utero, but also in infancy. In study of the developmental origins of health and disease, the relationship between infantile growth patterns and adolescent body mass index and blood pressure is one of the most important issues to verify.
Materials and Methods: We analyzed the correlation of current body mass index and systolic blood pressure of 168 female college students with their growth patterns in utero and in infancy.
Results: Body mass index and systolic blood pressure in adolescence showed positive correlations with changes in weight-for-age z scores between 1 and 18 months but not with those between 18 and 36 months. Stepwise multiple regression analysis showed that both change in weight-for-age z scores from 1 to 18 months and body mass index at 1 month were significantly and independently associated with systolic blood pressure in adolescence. Body mass index at 36 months was positively correlated with body mass index in adolescence, while body mass index at birth was negatively correlated with body mass index in adolescence.
Conclusion: Our findings shows that restricted growth in utero and accelerated weight gain in early infancy are associated with the cardiovascular risk factors of high systolic blood pressure and high body mass index in adolescence. In Japan, an increasing proportion of low birth weight infants and accelerated catch-up growth after birth have been observed in recent decades. This might be an alarming harbinger of an increase in diseases related to the developmental origins of health and disease in Japan.

Androgens play a central role in prostate cancer pathogenesis, and hence most of the patients respond to androgen deprivation therapies. However, patients tend to relapse with aggressive prostate cancer, which has been termed as hormone refractory. To identify the proteins that mediate progression to the hormone-refractory state, we used protein-chip technology for mass profiling of patients' sera. This study included 16 patients with metastatic hormone-refractory prostate cancer who were initially treated with androgen deprivation therapy. Serum samples were collected from each patient at five time points: point A, pre-treatment; point B, at the nadir of the prostate-specific antigen (PSA) level; point C, PSA failure; point D, the early hormone-refractory phase; and point E, the late hormone-refractory phase. Using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, we performed protein mass profiling of the patients' sera and identified a 6 640-Da peak that increased with disease progression. Target proteins were partially purified, and by amino acid sequencing the peak was identified as a fragment of apolipoprotein C-I (ApoC-I). Serum ApoC-I protein levels increased with disease progression. On immunohistochemical analysis, the ApoC-I protein was found localized to the cytoplasm of the hormone-refractory cancer cells. In this study, we showed an increase in serum ApoC-I protein levels in prostate cancer patients during their progression to the hormone-refractory state, which suggests that ApoC-I protein is related to progression of prostate cancer. However, as the exact role of ApoC-I in prostate cancer pathogenesis is unclear, further research is required.
Aged ; Amino Acid Sequence ; Antineoplastic Agents, Hormonal ; therapeutic use ; Apolipoprotein C-I ; analysis ; blood ; isolation & purification ; Blotting, Western ; Cell Line ; Disease Progression ; Drug Resistance, Neoplasm ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Molecular Sequence Data ; Prognosis ; Prostatic Neoplasms ; drug therapy ; metabolism ; Protein Array Analysis ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Hepatitis ; metabolism ; pathology ; Humans ; Liver Regeneration