Molecular insights into the development of hepatic metastases in colorectal cancer: a metastasis prediction study.

OBJECTIVE: Colorectal cancer is presently the third most commonly diagnosed cancer in the United States. In this study, we identified molecular differences between hepatic and non-hepatic metastases in colorectal cancer and evaluated their prognostic significance. MATERIALS AND METHODS: We downloaded primary data from the NCBI Gene Expression Omnibus (GSE6988, GSE62321, GSE50760, and GSE28722). To identify the molecular differences, we used the Significance Analysis of Microarray method. We selected nine prognostic genes (SYTL2, PTPLAD1, CDS1, RNF138, PIGR, WDR78, MYO7B, TSPAN3, and ATP5F1) with hepatic metastasis prediction score in colorectal cancer (hereafter referred to as LASSO Score). We confirmed the prognostic significance of the LASSO Score by using Kaplan-Meier survival analysis, multivariate analysis, the time-dependent area under the curve (AUC) of Uno's C-index, and the AUC of the receiver operating characteristic curve at 1-5 years. RESULTS: Survival analysis revealed that a high LASSO Score is associated with a poor prognosis in colorectal cancer patients with hepatic metastases (p = 0). Analysis of C-indices and AUC values from the receiver operating characteristic curve further supported this prediction by the LASSO Score. Multivariate analysis confirmed the prognostic significance of the LASSO Score (p = 1.13e-06). CONCLUSIONS: This study reveals the biological mechanisms underlying hepatic metastases in colorectal cancer and will help in developing targeted therapies for colorectal cancer.

Association between immunotherapy biomarkers and glucose metabolism from F-18 FDG PET.

OBJECTIVE: To assess associations between parameters derived from F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and mRNA expression levels of immune checkpoint biomarkers such as programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Integrated data were downloaded from Genomic Data Common Data Portal. Clinical, mRNA-seq, and whole exome-seq data of lung adenocarcinoma and squamous cell carcinoma from The Cancer Genome Atlas (TCGA) database were analyzed. TMB was defined as the total number of somatic missense mutations per megabase of the genome examined. Expression levels of PD-1, PD-L1, CTLA4 mRNA and TMB were collected. Correlations between imaging parameters of glucose metabolism and the expression levels of genomic biomarkers from cancers were evaluated. Bonferroni correction (adjusted p<0.0027) was applied to reduce type 1 error. RESULTS: Of 31 NSCLC cases, 11 cases were adenocarcinoma (LUAD) and 20 were squamous cell carcinoma (LUSC). In linear regression analysis, texture parameters such as low gray-level run emphasis (LGRE, R2=0.48, p<0.0001), short run low gray-level emphasis (SRLGE, R2=0.45, p<0.0001) and long run low gray-level emphasis (LRLGE, R2=0.41, p=0.0001) derived from gray-level run length matrix (GLRLM) showed remarkable correlation with PD-L1 mRNA expression. Expression of PD-1, CTLA-4, and TMB failed to show any significant correlation with parameters of the F-18 FDG PET/CT. CONCLUSIONS: Texture parameters derived from PET, known to indicate glucose uptake distribution, were correlated with expression of PD-L1 mRNA but not with expression of PD-1, CTLA-4 and TMB. Thus, tumoral heterogeneity could be a surrogate marker for the identification of PD-L1 level in NSCLC.

Intravenous stem cell dose and changes in quantitative lung fibrosis and DLCO in the AETHER trial: a pilot study.

OBJECTIVE: Our purpose was to compare quantitative CT-derived changes in lung fibrosis with pulmonary function, including DLCO, in human subjects with idiopathic pulmonary fibrosis who received an injection of one of two different intravenous doses of human bone-marrow-derived mesenchymal stem cells. PATIENTS AND METHODS: Two three-subject cohorts from the AETHER trial (Allogeneic Human Cells in subjects with Idiopathic Pulmonary Fibrosis via Intravenous Delivery) underwent high-resolution CT and clinical testing at baseline, 24 weeks, and 48 weeks after injection. Cohort 1 received 2x107 stem cells, and cohort 2 received 1x108 stem cells. CT scans were quantitatively analyzed for lung fibrosis using 510K cleared validated software. The percent predicted DLCO and other pulmonary function studies were obtained. RESULTS: The cohorts were well matched in lung fibrosis at baseline as assessed by CT scan and lung function. The mean QLF in cohort 1 increased from 13.1% at baseline to 17.1% at 48 weeks, while mean QLF in cohort 2 increased from 15.4% at baseline to 16.5% at 48 weeks. The subjects in cohort 2 progressed more slowly in whole lung fibrosis by a mean of 2.87% compared with cohort 1 (p=0.001 with adjustment of baseline covariates) during the baseline to the 48-week interval. The baseline DLCO was lower in cohort 2 than in cohort 1 (p<0.0001). Over 48 weeks of the study, cohort 2 subjects demonstrated a mean DLCO decline of only 2% compared with a decline of 17% in cohort 1 subjects (p=0.02). CONCLUSIONS: In this pilot study, the subjects receiving 1x108 stem cells demonstrated slower progression in quantitative lung fibrosis and a smaller decrease in DLCO than subjects receiving 2x107 stem cells.

Development of an E-learning System for the Endoscopic Diagnosis of Early Gastric Cancer: An International Multicenter Randomized Controlled Trial.

BACKGROUND: In many countries, gastric cancer is not diagnosed until an advanced stage. An Internet-based e-learning system to improve the ability of endoscopists to diagnose gastric cancer at an early stage was developed and was evaluated for its effectiveness. METHODS: The study was designed as a randomized controlled trial. After receiving a pre-test, participants were randomly allocated to either an e-learning or non-e-learning group. Only those in the e-learning group gained access to the e-learning system. Two months after the pre-test, both groups received a post-test. The primary endpoint was the difference between the two groups regarding the rate of improvement of their test results. FINDINGS: 515 endoscopists from 35 countries were assessed for eligibility, and 332 were enrolled in the study, with 166 allocated to each group. Of these, 151 participants in the e-learning group and 144 in the non-e-learning group were included in the analysis. The mean improvement rate (standard deviation) in the e-learning and non-e-learning groups was 1·24 (0·26) and 1·00 (0·16), respectively (P<0·001). INTERPRETATION: This global study clearly demonstrated the efficacy of an e-learning system to expand knowledge and provide invaluable experience regarding the endoscopic detection of early gastric cancer (R000012039).

Efficacy and complications of enteral feeding tube insertion after liver transplantation.

BACKGROUND: Adequate nutritional support for patients undergoing major surgery significantly affects postoperative recovery. Data on enteral feeding after liver transplantation (LT) are scarce. The aim of this work was to determine the efficacy and complications of feeding tubes inserted with the use of fluoroscopic assistance, endoscopic assistance, or transperitoneal jejunostomy in patients who underwent LT. METHODS: From January 2008 to August 2013, 2,058 LTs were performed at Asan Medical Center, Seoul, Korea. Enteral feeding tubes were inserted in 155 patients (7.5%) after LT: with the use of fluoroscopic placement in 81 (52%), endoscopic placement in 49 (32%), and transperitoneal jejunostomy in 25 (16%). We retrospectively analyzed the efficacy and complications of enteral feeding tubes. RESULTS: The median age was 55 years (interquartile range [IQR] 49-60). Enteral feeding indications were a high risk of gastric aspiration (n = 90), gastric stasis (n = 27), pneumonia (n = 23), gastrointestinal bleeding (n = 12), and bowel rest (n = 3). Median enteral feeding durations were 14.5 days (IQR 8.0-30.7) for fluoroscopic placement, 20.0 days (IQR 8.0-40.0) for endoscopic placement, and 37.5 days (IQR 18.2-86.2) for transperitoneal jejunostomy. Times to establishment of oral feeding were 13.0 days (IQR 6.2-25.7) for fluoroscopic placement, 24.0 days (IQR 10.5-43.5) for endoscopic placement, and 37.0 days (IQR 17.0-64.2) for transperitoneal jejunostomy. After tube insertion, tube dislocation and blockage occurred in 34 patients (22%) and 16 patients (25%), respectively. CONCLUSIONS: Enteral feeding tube insertion in patients who can not maintain a nasogastric tube or start oral intake for a long time is important for nutritional support after LT. Proper feeding method selection according to patient condition can help patients by improving nutritional support after major operations such as LT.

Serpin peptidase inhibitor clade A member 1 is a biomarker of poor prognosis in gastric cancer.

BACKGROUND: In a previous study, we reported that serpin peptidase inhibitor clade A member 1 (serpinA1) is upregulated in Snail-overexpressing gastric cancer. Although serpinA1 has been studied in several types of cancer, little is known about its roles and mechanisms of action. In this study, we examined the role of serpinA1 in the migration and invasion of gastric cancers and determined its underlying mechanism. METHODS: Expression levels were assessed by western blot analyses and real-time PCR. Snail binding to serpinA1 promoter was analysed by chromatin immunoprecipitation (ChIP) assays. The roles of serpinA1 were studied using cell invasion and migration assays. In addition, the clinicopathologic and prognostic significance of serpinA1 expression were validated in 400 gastric cancer patients using immunohistochemical analysis. RESULTS: Overexpression of Snail resulted in upregulation of serpinA1 in gastric cancer cell lines, AGS and MKN45, whereas knockdown of Snail inhibited serpinA1 expression. Chromatin immunoprecipitation analysis showed that overexpression of Snail increased Snail recruitment to the serpinA1 promoter. Overexpression of serpinA1 increased the migration and invasion of gastric cancer cells, whereas knockdown of serpinA1 decreased invasion and migration. Moreover, serpinA1 increased mRNA levels and release of metalloproteinase-8 in gastric cancer cells. Serpin peptidase inhibitor clade A member 1 was observed in the cytoplasm of tumour cells and the stroma by immunohistochemistry. Enhanced serpinA1 expression was significantly associated with increased tumour size, advanced T stage, perineural invasion, lymphovascular invasion, lymph node metastases, and shorter overall survival. CONCLUSIONS: Serpin peptidase inhibitor clade A member 1 induces the invasion and migration of gastric cancer cells and its expression is associated with the progression of gastric cancer. These results may provide a potential target to prevent invasion and metastasis in gastric cancer.

15-Deoxy-Δ(12,14)-prostaglandin J2 prevents oxidative injury by upregulating the expression of aldose reductase in vascular smooth muscle cells.

The omega-6 fatty acid derivative 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) is believed to play a role in cellular protection against oxidative stress in diverse cell systems. However, the cellular mechanisms by which protection is afforded by 15d-PGJ2 are not fully elucidated in vascular smooth muscle cells (VSMCs). In this study, we report the finding that 15d-PGJ2 elicited a time and concentration- dependent increase in aldose reductase (AR) expression. This induction was independent of the activation of peroxisome proliferator- activated receptor γ. Inhibition of phosphatidylinositol 3-kinase (PI3K) significantly suppressed the increase in expression and promoter activity of AR induced by 15d-PGJ2. Luciferase reporter assays demonstrated that 15d-PGJ2 targets the multiple stress response regions comprising the antioxidant response element in the promoter of the AR gene. 15d-PGJ2-mediated induction of AR promoter activity was potentiated in the presence of nuclear factor-erythroid 2-related factor 2 (Nrf2), but not in cells expressing dominant negative Nrf2. Cells treated with 15d-PGJ2 were resistant to oxidant-induced apoptotic cell death by inhibiting production of reactive oxygen species. These effects were significantly attenuated in the presence of an AR inhibitor or small interfering RNA against AR, indicating that AR plays a protective role against oxidative injury. Taken together, these findings demonstrate that activation of PI3K by 15d-PGJ2 increases the expression of AR through Nrf2, and increased AR activity may function as an important cellular response against oxidative injury.

Management of gastric epithelial neoplasia in patients requiring esophagectomy for esophageal cancer.

Esophageal squamous cell carcinoma is occasionally associated with malignancies located in other regions of the alimentary tract, as well as in the head, neck, and upper respiratory tract. The stomach is most commonly used for reconstruction of the alimentary tract after esophagectomy for esophageal cancer. When synchronous tumors are located in the stomach, it is often unsuitable for use in esophageal reconstruction. In such cases, an invasive procedure involving anastomosis between the esophagus and the colon must be performed. However, this procedure is associated with a high incidence of mortality and morbidity. Seven patients with synchronous esophageal cancer and gastric epithelial neoplasia were encountered. First, endoscopic submucosal dissection (ESD) was performed for the gastric epithelial neoplasia. Then, following successful ESD, Ivor-Lewis esophagectomy for esophageal cancer was planned 1 to 2 weeks later. A total of 11 gastric epithelial lesions were found in seven patients. En bloc resection by ESD was possible in all 11 lesions and histologically complete resection was achieved in all 11 lesions. Follow-up endoscopy was done 1-2 weeks after ESD; six patients with well-healing ulcers underwent esophagectomy the next day (8 or 15 days after ESD). In one patient with a poorly healed ulcer, a second follow-up endoscopy was done 1 week later and then esophagectomy was performed the next day (22 days after ESD). Post-surgical complications related to ESD, such as bleeding or mediastinal leak, were not seen in any of the seven patients. In patients with synchronous esophageal cancer and gastric epithelial neoplasia, ESD for gastric epithelial neoplasia followed by Ivor-Lewis esophagectomy 1 to 2 weeks later is an effective choice of treatment.

Cu(II)-induced molecular and physiological responses in the brown-rot basidiomycete Polyporales sp. KUC9061.

AIM: A potentially safe disposal method for copper-containing waste wood is bioremediation using brown-rot fungi. However, the mechanisms regulating brown-rot fungi copper tolerance are poorly understood. The objective of this study was to better understand the molecular and physiological changes in Polyporales sp. KUC9061 in response to Cu(II) using GeneFishing technology. METHODS AND RESULTS: The presence of Cu(II) in the malt extract agar (MEA) media decreased the brown-rot fungi's growth rate in a concentration-dependent manner, but the fungal biomass was significantly increased in part for the biosorption of Cu(II). Increased expression of the genes encoding for the GIS2 DNA-binding protein and the 40S ribosomal protein S3A appears to be involved in this process. Oxalic acid is not used as a defence mechanism against high copper exposure, and ATP citrate lyase is not directly involved in oxalic acid production in this fungus. Several Cu(II)-sensitive proteins showed stable gene expression, suggesting that mechanisms that do not rely on these genes are responsible for the Cu(II) tolerance of the fungus. CONCLUSIONS: Polyporales sp. KUC9061 does not use oxalic acid to chelate excess Cu(II) and potentially has other mechanisms, including the increased production of mycelia, to regulate Cu(II) biosorption. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first effort to examine Cu(II)-induced differential gene expression and the related physiological changes in the brown-rot fungus, a potential degrader of copper-containing waste wood. The results of this study will help with using this fungus to safely dispose of waste wood safe.

Endoscopic submucosal resection of esophageal subepithelial lesions using band ligation.

Subepithelial lesions (SELs) are occasionally found in the esophagus during upper endoscopy. Sometimes endoscopic resection is needed for accurate diagnosis or in the rare cases of malignant transformation of SELs. In this case series, we evaluated the usefulness of endoscopic submucosal resection with a ligation device (ESMR-L) in esophageal SELs. Twenty-three patients with 25 esophageal SELs that were no larger than 13 mm and were localized within the muscularis mucosae or submucosa were enrolled. ESMR-L was successfully performed in all 25 SELs. The en bloc resection rate was 100% (25/25), and histologically complete resection was achieved in 24 lesions (24/25, 96%). After resection of the lesion by snare, minor immediate bleeding occurred in four cases, but there was no delayed bleeding or perforation.

A case of a giant mucocoele of the appendiceal stump presented with a palpable mass in the right thigh: pre-operative diagnosis based on characteristic multidetector CT findings.

The pre-operative diagnosis of a mucocoele of the appendiceal stump (MAS) may be difficult owing to rarity and non-specific clinical presentation. However, a pre-operative diagnosis of a MAS is important to prevent widespread dissemination by inadvertent spillage of mucous contents. We describe a case of a MAS presenting with a palpable mass in the right thigh in which a pre-operative diagnosis was made by characteristic multidetector CT (MDCT) findings.

Interleukin-18, transforming growth factor-ß, and vascular endothelial growth factor gene polymorphisms and susceptibility to primary glomerulonephritis.

Several studies have showed an association of gene polymorphisms with the development of glomerulonephritis (GN). We investigated the effects of gene polymorphisms on the development of GN by analyzing polymorphisms in the interleukin (IL)-18, transforming growth factor (TGF)-ß, and vascular endothelial growth factor (VEGF) genes in Korean patients with primary GN. The study included 146 normal subjects (controls) and 100 patients diagnosed with primary GN by kidney biopsy. The gene polymorphisms A-607C and G-137C in IL-18, C-509T and T869C in TGF-ß1, and C-2578A and C405G in VEGF were investigated in DNA extracted from peripheral blood. Significant differences were observed between the GN and control groups in the genotype and allele frequencies of A-607C IL-18 and C405G VEGF. The frequencies of the IL-18-607CC genotype [P = 0.001, odds ratio (OR) = 2.473] and the VEGF 405GG genotype (P = 0.001, OR = 2.473) were significantly increased in the GN group. The combination of IL-18-607CC+ and VEGF 405GG+ genotypes had a higher risk for developing GN in comparison with the combination of IL-18-607CC- and VEGF 405GG- genotypes (P < 0.001, OR = 8.642). In the haplotype analysis of the IL-18 gene, the CG haplotype was significantly more frequent in the GN group than the control group (61.5% vs 46.9%, P = 0.002). These results show that the -607CC genotype of the IL-18 gene and the 405GG genotype of the VEGF gene are associated with susceptibility to and the development of primary GN.

Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells.

BACKGROUND: Stathmin1 is a microtubule-regulating protein that has an important role in the assembly and disassembly of the mitotic spindle. The roles of stathmin1 in carcinogenesis of various cancers, including prostate and breast cancer, have been explored. However, its expression and roles in gastric cancer have not yet been described. METHODS: Stathmin1 expression in paraffin-embedded tissue sections from 226 patients was analysed by immunohistochemistry. Roles of stathmin1 were studied using a specific small interfering RNA (siRNA). RESULTS: The expression of stathmin1 was positively correlated with lymph node metastasis, TNM stages and vascular invasion, and negatively with recurrence-free survival, in the diffuse type of gastric cancer. The median recurrence-free survival in patients with a negative and positive expression of stathmin1 was 17.0 and 7.0 months, respectively (P=0.009). When the expression of stathmin1 was knocked down using siRNA, the proliferation, migration and invasion of poorly differentiated gastric cancer cells in vitro were significantly inhibited. Moreover, stathmin1 siRNA transfection significantly slowed the growth of xenografts in nude mice. CONCLUSION: These results suggest that stathmin1 can be a good prognostic factor for recurrence-free survival rate and is a therapeutic target in diffuse-type gastric cancer.

Does propofol and alfentanil-induced sedation cause periodic apnoea in chronic renal failure patients?

AIMS: There is evidence suggesting that the respiratory response to sedation is different in patients with sleep apnoea, which is common in patients with chronic renal failure (CRF). This study examined the respiratory response of sedation with propofol and alfentanil, whose pharmacokinetics are not affected by the renal function, in CRF patients. METHODS: Chronic renal failure patients who underwent arteriovenous-fistular surgery (CRF group) and patients who underwent chemoport insertion (control group) were enrolled in this study. Sedation was induced by infusing propofol 1.5 micro/ml and alfentanil 0.2 micro/kg/min continuously in both groups. In the desaturation study, the respiratory rate and peripheral oxygen saturation in room air were checked. In the apnoea-hypopnoea study, the patient's sedation (Observer's Assessment of Alertness/Sedation) score, apnoea-hypopnoea index (AHI) was recorded using a portable ventilation effort recorder (microMesam) while applying 5 l/min of oxygen through a facial mask. RESULTS: The desaturation event was more common (21.5/h vs. 2/h, p = 0.001) in the CRF patients. Apnoea and hypopnoea (AHI: 13.0 vs. 1.6, p = 0.012, per cent of patients with an AHI > 5: 53.3% vs. 7.1%, p = 0.014) occurred more frequently in the CRF patients but the sedation score was not different. CONCLUSION: Chronic renal failure patients have a higher risk of developing apnoea and hypopnoea during sedation, which highlights the need for careful monitoring and management in these patients.

Investigation of the association between CT detection of early gastric cancer and ultimate histology.

AIM: To evaluate the association between computed tomography (CT) detection of early gastric cancer (EGC) and various parameters, including the depth of invasion, lesion extent, morpholgical type, location, and histological type. MATERIALS AND METHODS: One hundred and ten patients with 114 EGCs were preoperatively examined using multidetector CT (MDCT). All patients received 500 ml water as an oral contrast agent approximately 15 min before the examination and an additional 500 ml immediately prior to the study. Portal venous phase, contrast-enhanced, helical scans with multiplanar reformation were obtained. All patients underwent surgery. For location and size of tumour, the CT findings were compared with the histopathological results. The association between CT detection of EGC and various parameters were assessed. In addition, we performed a stepwise forward logistic regression to identify which variables significantly increased the CT detection rate of EGC. RESULTS: The detection rate of all EGCs using MDCT was 36.4%. The detection rate for EGCs confined to the superficial layer (mucosa or SM1) was 14.3%, whereas the detection rate for EGCs that involved the deep layer (SM2 or more than SM2) was 86.5%. All three of the protruded lesions and five of the six excavated lesions were readily detected using CT. Stepwise forward logistic regression showed that the best parameter for CT detection of EGCs was the depth of invasion; more EGCs were detected when the lesion was deep. CONCLUSION: MDCT has advantages in acceptable evaluation of the depth invasion of EGCs. EGC that is undetectable using CT suggests an EGC confined to the superficial layer, whereas EGC detectable using CT suggests deep lesions.

Evaluation of the biliary tract: the value of performing magnetic resonance cholangiopancreatography in conjunction with a 3-D spoiled gradient-echo gadolinium enhanced dynamic sequence.

The 3-D gradient-echo (GRE) sequence allows thinner sections and better resolution of biliary obstruction. When the presence of biliary obstruction is identified using magnetic resonance cholangiopancreatography, the addition of the 3-D GRE sequence may be helpful for diagnosing biliary obstruction. By showing the changes in the bile duct wall, within the duct lumen and around the bile duct, this technique can be helpful for distinguishing benign from malignant stricture as well as a stone from an enhancing intraluminal mass.

Analysis of allograft biopsy specimens in renal transplants with proteinuria: is proteinuria a culprit of graft loss?

It has been proposed that proteinuria occurring after renal transplantation may be not only a marker but also a culprit of allograft dysfunction. We retrospectively analyzed the data from 55 patients who underwent transplant renal biopsy for proteinuria and/or azotemia occurring beyond 1 year after transplantation. Proteinuria was considered as significant when > or = 30 mg/dL, and the results of transplant biopsy were categorized according to the Banff 97 classification. Logistic regression was used to estimate odds ratios (OR) for graft loss associated with proteinuria and transplant pathology. The patients were followed for 86.0 +/- 32.8 months after transplantation, and transplant biopsy was performed at 54.1 +/- 31.0 months. Proteinuria at 1 year after transplantation noted in 29.1% of patients was not significantly associated with graft loss (OR = 1.94, 95% CI from 0.59 to 6.41). In addition, proteinuria at the time of transplant biopsy was not significantly associated with graft loss. Chronic allograft nephropathy was the most frequent transplant pathology. Only glomerulonephritis was significantly associated with proteinuria at the time of the transplant biopsy. On the other hand, graft loss was significantly associated with the presence of proteinuria both at 1 year after transplant biopsy and at the final follow-up. These results suggest that posttransplantation proteinuria is an important marker of graft dysfunction, but is not predictive of graft loss in biopsy-proven cases. Appropriate management guided by the results of a transplant biopsy may improve the outcome.