HBx and c-MYC Cooperate to Induce URI1 Expression in HBV-Related Hepatocellular Carcinoma

Unconventional prefoldin RNA polymerase II subunit 5 interactor (URI1) has emerged as an oncogenic driver in hepatocellular carcinoma (HCC). Although the hepatitis B virus (HBV) represents the most common etiology of HCC worldwide, it is unknown whether URI1 plays a role in HBV-related HCC (HCC-B). In the present study, we investigated URI1 expression and its underlying mechanism in HCC-B tissues and cell lines. URI1 gene-promoter activity was determined by a luciferase assay. Human HCC-B samples were used for a chromatin immunoprecipitation assay. We found that c-MYC induced URI1 expression and activated the URI1 promoter through the E-box in the promoter region while the HBx protein significantly enhanced it. The positivity of URI1 expression was significantly higher in HCC-B tumor tissues than in non-HBV-related HCC tumor tissues, suggesting that a specific mechanism underlies URI1 expression in HCC-B. In tumor tissues from HCC-B patients, a significantly higher level of c-MYC was recruited to the E-box than in non-tumor tissues. These results suggest that HBx and c-MYC are involved in URI1 expression in HCC-B. URI1 expression may play important roles in the development and progression of HCC-B because HBx and c-MYC are well-known oncogenic factors in the virus and host, respectively

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner

Expression of DNA Methyltransferase (DNMT) 1, 3a and 3b Proteins in Human Hepatocellular Carcinoma

Alteration of aberrant DNA methylation is one of the most consistent epigenetic changes found in human cancers. DNA methylation is catalyzed by DNA methyltransferase (DNMT). In this study, we examined DNMT protein expression by immunohistochemistry in surgically resected hepatocellular carcinomas (HCCs). Sections of paraffin-embedded specimens were obtained from 95 patients with HCC between 1989 and 2002. The specimens were stained with anti-DNMTs (DNMT1, DNMT3a and DNMT3b) antibodies. There were statistically significant associations between DNMT protein expression and tumor differentiation (P < 0.05) and intrahepatic metastasis (P < 0.05). DNMT3a protein expression was significantly correlated with portal vein involvement of tumors (P < 0.05). The overall survival rates of patients with DNMT3a-positive HCCs and DNMT3b-positive HCCs were significantly lower than those of patients negative for these proteins (P < 0.005, respectively). To further evaluate the correlation between DNMT protein expression and patient survival, we classified patients into 3 groups: Group 1, DNMT1(+), 3a(–) and 3b(–); Group 2) DNMT1(+), 3a or 3b(+); and Group 3) DNMT1(+), 3a(+) and 3b(+). The overall survival rate of patients in Group 3 was significantly lower than those of patients in Groups 1 and 2 (P = 0.0009). In conclusion, the results of this study suggest that DNMT1, DNMT3a and DNMT3b are cooperatively involved in determining the extent of HCCs, and that DNMT protein overexpression in HCCs may be a predictive factor for poor survival

Prognostic Impact of Pre- and Post-operative P-CRP Levels in Pancreatic Cancer Patients

Background: C-reactive protein (CRP) levels reflect ongoing inflammation and/or tissue damage, and studies suggest that platelets play a role in tumor invasion and metastasis. P-CRP is defined as the multiplied product of serum CRP and platelet levels. Here the prognostic value of pre- and post-operative P-CRP levels in pancreatic cancer (PC) patients was assessed. Methods: This retrospective study used data from 107 consecutive PC patients who had undergone either pancreaticoduodenectomy or distal pancreatectomy. Clinicopathological parameters and pre/post-operative laboratory data derived from patient records were used for analyses. P-CRP was defined as the product of peripheral thrombocyte count (/uL) × serum CRP level (mg/dL) divided by 104; the optimal P-CRP cut-off value was defined using receiver operating characteristic curves. Results: PC patients were classified as either P-CRPLow (< 1.782; n = 49) or P-CRPHigh (≥ 1.782; n = 58), based on the cut-off value of 1.782. Univariate analysis revealed that performance status, clinical stage, pathological T and N stages, P-CRP, and carbohydrate antigen 19-9 (CA19-9) significantly affected overall survival (OS). Multivariate analysis revealed that independent risk factors for OS were pathological N stage, P-CRP, and CA19-9. Additionally, 103 PC patients for whom postoperative data were available were classified into four groups (P-CRPLow-Down, P-CRPLow-Up, P-CRPHigh-Down and P-CRPHigh-Up), based on preoperative P-CRP and postoperative trend of P-CRP, and we found that prognosis, in terms of OS, was significantly different among these groups (P = 0.012). Conclusion: Pre- and post-operative P-CRP values are a potential predictor of prognosis in PC patients

Utility and Limitation of Preoperative Neutrophil Lymphocyte Ratio as a Prognostic Factor in Hepatocellular Carcinoma

【Background】 The neutrophil lymphocyte ratio (NLR) has been proposed to be a surrogate marker of inflammation and immunological status and to have prognostic value in various malignancies. This study was conducted to clarify the prognostic significance of preoperative NLR in hepatocellular carcinoma (HCC). 【Methods】 We enrolled 135 patients with histologicallyproven HCC who underwent initial curative hepatectomy. Based on the median NLR values, patients were divided into: NLR ? 2.0 (NLR-high, n = 69) and NLR < 2.0 (NLR-low, n = 66). 【Results】 In univariate analysis, the 5-year overall survival (OS) rates were 59.8 % ± 6.7% and 75.6% ± 6.5% (P = 0.028) in the NLR-high and NLR-low groups, respectively. Furthermore, the 5-year disease specific survival rates were 68.6% ± 6.7%, and 81.2 ± 6.4% (P = 0.048) in the NLR-high and NLR-low groups, respectively. 【Conclusion】 Our results showed that high NLR was an independent predictor for OS in hepatectomy-treated HCC, suggesting that NLR may be a novel prognostic biomarker for HCC. On the other hand, NLR also has a limitation to predict postoperative prognosis of HCC patients by itself

The Combination of Prognostic Nutritional Indicator and Serum Carcinoembryonic Antigen is Useful in Predicting Postoperative Recurrence in Stage II Colorectal Cancer

[Background] The efficacy of adjuvant chemotherapy in stage II colorectal cancer (CRC) patients has not been clearly demonstrated. Therefore, identification of robust prognostic factors is crucial for the assessment of recurrence risk in stage II CRC and appropriate adjuvant treatment, in clinical practice. [Methods] We enrolled 135 colorectal adenocarcinoma patients who underwent proctocolectomies and had histologically diagnosed stage II CRC. [Results] Receiver operating characteristic (ROC) analysis, to evaluate the predictive ability of certain serum factors for CRC recurrence, indicated that the prognostic nutritional indicator (PNI), followed by serum carcinoembryonic antigen (CEA) level, were the strongest predictive metrics. Based on cutoff values from ROC analyses, patients were divided as follows; CEAHigh (≥ 4.55 ng/mL), CEALow (< 4.55 ng/mL), PNIHigh (≥ 47.72), and PNILow (< 47.72). The recurrence rates of patients with CEAHigh and PNILow, CEAHigh and PNIHigh, CEALow and PNILow, and CEALow and PNIHigh were 34.3%, 0%, 6.8%, and 2.6%, respectively (a significant difference at P < 0.0001). Logistic regression analysis revealed that the combination of serum CEA level and PNI was an independent predictive indicator of tumor recurrence after operation in stage II CRC patients. The 5-year disease specific survival rates of patients with CEALowPNIHigh, CEAHighPNIHigh, CEALowPNILow, CEAHighPNILow were 100%, 100%, 97.4%, and 77.5%, respectively (P < 0.0001). [Conclusion] The combination of CEA and PNI was useful in predicting postoperative recurrence in stage II CRC patients

Comparisons of Postoperative Complications and Nutritional Status After Proximal Laparoscopic Gastrectomy with Esophagogastrostomy and Double-Tract Reconstruction

[Background] The purpose of this study was to compare postoperative complications and nutritional status between esophagogastrostomy and double-tract reconstruction in patients who underwent laparoscopic proximal gastrectomy, and assess the advantages of both surgical procedures. [Methods] Between 2010 and 2018, 47 cases underwent proximal gastrectomy with esophagogastrostomy (n = 23) or double-tract reconstruction (n = 24) at our institution for the treatment of clinical T1N0 adenocarcinoma located in the upper third of the stomach. Patient clinical characteristics, short-term outcomes, nutrition status, and skeletal muscle index were compared among the two groups. [Results] There was no significant difference between esophagogastrostomy and double-tract reconstruction in terms of operation time, blood loss, and length of postoperative hospital stay. Reflux symptoms and anastomotic stenosis were significantly higher in the esophagogastrostomy group compared with the double-tract reconstruction group (P < 0.001 and P = 0.004, respectively). There was no significant difference in anastomotic leakage, surgical site infection, and pancreatic fistula. For the nutritional status, the decrease rate of cholinesterase was significantly higher in the esophagogastrostomy group compared with the double-tract reconstruction group at 6 months (P = 0.008) There was no significant difference in the decrease rate of skeletal muscle mass index at 1 year after surgery. [Conclusion] Compared with esophagogastrostomy, double-tract reconstruction tends to have better short-term nutritional status and postoperative outcomes in terms of preventing the occurrence of gastroesophageal reflux and anastomosis stenosis. These findings suggest that double-tract reconstruction may be a useful method in laparoscopic proximal gastrectomy

Comparative Study of Complications in CV Catheter Insertion for Pediatric Patients: Real-time Ultrasound-guided Versus Venography-guided Approach

[Background]Tunneled central venous catheters (CVC), called Broviac/Hickman catheter, are widely used in the long-term treatment of pediatric patients. Recently, the percutaneous approach for CVC insertion has become dominant as a less invasive intervention. In this study, we reviewed the mechanical and delayed complications according to different procedures of CVC insertion and assessed the risk factors for complications in CVC insertions for pediatric patients. [Methods]A total of 159 pediatric patients (85 males and 74 females) were included in this study. Primary reasons for indication of CVC settlement were hemato-oncologic disorders (66 cases, 42%), malignant solid tumors (30, 19%) and other benign diseases (63, 40%). CVC insertion was performed with surgical venous cutdown (CD) in 51 patients (32%), with real-time ultrasound-guided puncture (RTUS) in 57 (36%), and venography-guided puncture (VG) in 49 (31%). [Results]CD was dominantly selected and the frequency of venipuncture increased respective to the increased age of patients. RTUS was dominantly selected for one to four year old patients and VG was dominant in 5 to 15 year old patients. Some types of mechanical complication were observed in 4 of 159 (2.5%) and some delayed types were observed in 66 of 159 cases (42%). No mechanical complications occurred in cases with CD and RTUS; on the other hand, 3 (6%) of 49 insertions with VG were observed. However, we could not show any significant risk factors for the mechanical complications. In the meantime, delayed complications and premature removal were significantly observed in patients under 5 years old. [Conclusion]RTUS is superior to our conventional VG considering less frequent mechanical complications. High frequent delayed complication and premature removal should be considered, especially for patients under 5 years old