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Background: Novel therapeutic targets are needed to improve the poor prognosis of patients with advanced gastric cancer. The aim of this study was to identify a novel therapeutic target for the treatment of GC and to investigate the potential therapeutic value of an antibody raised against the target. Methods: We identified gamma-aminobutyric acid type A receptor subunit delta as a candidate therapeutic target by differential transcriptome analysis of metastatic GC tissue and adjacent nontumor tissues. GABRD mRNA levels were analyzed in 230 pairs of gastric tissue by quantitative reverse-transcription polymerase chain reaction. GABRD function was assessed in proliferation, invasion, and apoptosis assays in human GC cell lines expressing control or GABRD-targeting small interfering RNA (siRNA). Mouse anti-human polyclonal GABRD antibodies were generated and assessed for inhibition of GC cell growth in vitro and in a mouse xenograft model of peritoneal GC dissemination. Results: High GABRD mRNA expression level in primary human GC tissue was associated with poor prognosis. Expression of siGABRD in GC cell lines significantly decreased cell proliferation and invasion and increased apoptosis compared with control siRNA expression. Anti-GABRD polyclonal antibodies inhibited GC cell proliferation in vitro and decreased peritoneal tumor nodule size in the mouse xenograft model. Conclusion: We identified GABRD as novel regulator of GC cell growth and function. GABRD is upregulated in GC tissue and is associated with poor prognosis, suggesting that it may be a potential therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Background: The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. Methods: We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes. Results: ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048). Conclusion: These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: The albumin–bilirubin (ALBI) score was originally developed to assess the severity of liver dysfunction in patients with hepatocellular carcinoma and has subsequently been used as a prognostic marker for that disease. Here, we examined the value of the preoperative ALBI score as a prognostic marker for patients with esophageal squamous cell carcinoma (ESCC) after radical esophagectomy. Methods: We retrospectively analyzed data from 449 patients who underwent curative resection for ESCC. The ALBI score was calculated as (log10 serum bilirubin [μmol/l] × 0.66) + (serum albumin [g/l] × − 0.0852). Receiver operating characteristic curve analysis was used to define a preoperative modified ALBI (mALBI) score for patient stratification. Results: Of the 449 ESCC patients, 232 and 217 were assigned to mALBI Grade 1 or Grade 2 groups based on preoperative ALBI scores of ≤ − 3.33 or > − 3.33, respectively. Preoperative mALBI grade was significantly associated with age, excessive alcohol consumption, squamous cell carcinoma antigen level, and clinical disease stage. The mALBI Grade 2 group had significantly shorter disease-specific and recurrence-free survival than the mALBI Grade 1 group. Multivariate analysis demonstrated that mALBI Grade 2 was an independent prognostic factor for disease-specific survival (hazard ratio 1.86, 95% confidence interval 1.18–2.93, P = 0.0074). In most subgroup analyses, mALBI Grade 2 was associated with a greater risk of disease-specific death. Conclusions: mALBI grade serves as a simple and useful prognostic marker for disease-specific survival in patients with ESCC after radical esophagectomy. [ABSTRACT FROM AUTHOR]

Background: The expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC). Methods: SLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters. Results: The expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence. Conclusions: SLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients. [ABSTRACT FROM AUTHOR]

Background: Reports show miR-23b to be a cancer-related biomarker in various cancer types. Interestingly, it has a dual role of oncogenic and tumor-suppressive functions, depending on the cancer type. This study focused on the unknown association of miR-23b-3p with hepatocellular carcinoma (HCC). Methods: Expression of miR-23b-3p was measured in nine HCC cell lines and 125 resected human HCC samples by TaqMan microRNA assays. To detect its downstream target, miR-23b-3p mimic and inhibitor constructs were transfected and analyzed. Results: HepG2, a high miR-23b-3p-expressing cell line, was transfected with a miR-23b-3p inhibitor construct, whereas SK-Hep1, a low miR-23b-3p-expressing cell line, was transfected with a mimic construct. Proliferation of HCC cells was activated by miR-23b-3p overexpression and diminished by its knockdown. Then, 125 clinical HCC samples were examined to measure miR-23b-3p expression. Tumor expression of miR-23b-3p was upregulated in 48 cases (38%) and downregulated in 77 cases (62%). The upregulated cases were correlated with elderly patients (P = 0.015). These patients also showed significantly poor overall survival [hazard ratio (HR), 3.10; 95% conflidence interval (CI), 1.57–6.29; P = 0.001] in a multivariate analysis. Furthermore, mitochondrial metabolism-related genes (MICU3 and AUH) were detected as specific binding targets. Conclusion: The study showed that miR-23b-3p functions as an oncogenic microRNA in HCC cell lines. Its overexpression in resected HCC tissues was a significant prognostic factor of overall survival. Both MICU3 and AUH may be candidate gene targets of miR-23b-3p. [ABSTRACT FROM AUTHOR]

Background: The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC. Methods: Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated. Results: Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY−). The mutant allele frequency was significantly higher in the CY+ patients than in the CY− patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY− and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity. Conclusions: As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY. [ABSTRACT FROM AUTHOR]

Objectives: Postoperative pancreatic fistula (POPF) is the most threatening complication after pancreatectomy. This study aimed to directly assess pancreatic fatty infiltration with preoperative computed tomography (CT) imaging and to investigate whether a preoperative analysis of patient variables, including CT characteristics and clinical factors, can predict POPF. Methods: We enrolled 150 consecutive patients who underwent curative pancreatectomy. Radiographic factors, including pancreatic fat volume, were measured using preoperative CT imaging and the predictive factors were explored using univariate and multivariate analyses. Results: POPF developed in 30 patients (20.0%). The ratio of pancreatic fat (RPF) ≥ 4.83% was associated with a risk of POPF, high body mass index (BMI), and obese body habitus. Patients with POPF were significantly more likely to have high BMI (≥ 25 kg/m2), obese body habitus, and an RPF ≥ 4.83% than patients without POPF. In the multivariate analysis, visceral fat area/skeletal muscle index (VFA/SMI) ≥ 1.94 (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.43–12.9, p = 0.0095) was the sole independent predictive factor for POPF. For patients with a soft pancreas, VFA/SMI ≥ 1.94 (OR 5.67, 95% CI 2.05–15.7, p = 0.0008) was again the sole independent predictive factor for POPF. Conclusion: Preoperative CT images can examine pancreatic fatty infiltration, and patients who had POPF were significantly associated with a high RPF. Among several parameters, VFA/SMI was the only independent predictive factor for clinically relevant POPF. Preoperative evaluation of these body composition variables and the pancreatic configuration could be useful for predicting POPF. [ABSTRACT FROM AUTHOR]

Background: Recurrence after radical resection of esophageal squamous cell carcinoma (ESCC) is common. Limited evidence is available about the differences in clinical characteristics, risk factors, and prognostic significance between nodal and distant recurrence of thoracic ESCC. Patients and Methods: We retrospectively analyzed 341 patients who underwent radical resection of thoracic ESCC and experienced (1) initial recurrence only in lymph nodes (n = 39), (2) recurrence only at distant organs (n = 57), or (3) no recurrences (n = 245) after follow-up ≥ 24 months. Clinicopathological characteristics, survival times, and risk factors were compared between the nodal and distant recurrence groups. Results: The median follow-up time was 57.8 months. Metastasectomy as initial treatment for the recurrence was performed for six (15.4%) patients in the nodal recurrence group and one patient in the distant recurrence group. Compared with the nodal recurrence group, patients with distant recurrence had significantly shorter disease-free survival [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.10–2.57, P = 0.0169], postrecurrence survival (HR 1.77, 95% CI 1.01–3.10, P = 0.0476), and overall survival (HR 1.98, 95% CI 1.12–3.51, P = 0.0193). The distant recurrence group had significantly larger macroscopic tumor size and more advanced pathological T stage than the nodal recurrence group, whereas preoperative treatment, tumor location, number of fields dissected, tumor differentiation, lymphatic involvement, and vessel invasion were not significantly different between the two groups. Conclusions: Survival times and recurrence risk factors differed between patients with nodal and distant recurrence after radical resection of thoracic ESCC. [ABSTRACT FROM AUTHOR]

Background: β-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC). Patients and Methods: Expression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts. Results: B4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level. Conclusions: B4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients. [ABSTRACT FROM AUTHOR]

Background: We aimed to clarify the role of potassium voltage-gated channel subfamily J member 15 (KCNJ15) in esophageal squamous cell carcinoma (ESCC) cells and its potential as a prognosticator in ESCC patients. Methods: KCNJ15 transcription levels were evaluated in 13 ESCC cell lines and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with KCNJ15. The biological functions of KCNJ15 in cell invasion, proliferation, migration, and adhesion were validated through small interfering RNA-mediated knockdown experiments. Cell proliferation was further evaluated through the forced expression experiment. KCNJ15 expression was detected in 200 ESCC tissues by quantitative real-time reverse transcription PCR (qRT-PCR) and analyzed in 64 representative tissues by immunohistochemistry. Correlations between KCNJ15 expression levels and clinicopathological features were also analyzed. Results: The KCNJ15 expression levels varied widely in ESCC cell lines and correlated with COL3A1, JAG1, and F11R. Knockdown of KCNJ15 expression significantly repressed cell invasion, proliferation, and migration of ESCC cells in vitro. Furthermore, overexpression of KCNJ15 resulted in increased cell proliferation. Patients were stratified using the cut-off value of KCNJ15 messenger RNA (mRNA) levels in 200 ESCC tissues using receiver operating characteristic curve analysis; the high KCNJ15 expression group had significantly shorter overall and disease-free survival times. In multivariable analysis, high expression of KCNJ15 was identified as an independent poor prognostic factor. Staining intensity of in situ KCNJ15 protein expression tended to be associated with KCNJ15 mRNA expression levels. Conclusions: KCNJ15 is involved in aggressive tumor phenotypes of ESCC cells and its tissue expression levels may be useful as a prognosticator of patients with ESCC. [ABSTRACT FROM AUTHOR]

Background: Liver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome. Objective: In this study, we aimed to identify novel genes associated with liver metastasis of GC. Methods: Global expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis. Results: Among 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R. Conclusions: PRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the impact of serum tumor markers on survival for patients with pancreatic cancer (PC) who received initial systemic therapy (IST) followed by surgery. Methods: Between April 2010 and July 2018, 285 consecutive patients who underwent curative intent surgery for PC were enrolled in the study. The relation between carbohydrate antigen 19-9 and duke pancreatic monoclonal antigen type 2 (DUPAN-2) after IST was analyzed as well as PC prognosis. Results: The study identified 95 patients who underwent systemic chemotherapy with or without radiotherapy as IST from the our prospectively maintained database at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan. Survival analysis of the 95 patients showed significant differences in recurrence-free survival (RFS) and overall survival (OS) between the DUPAN-2-normalized (D-normalized) and DUPAN-2-unnormalized (D-unnormalized) groups (median RFS, 24.1 vs. 14.2 months, p = 0.003; median OS, not reached vs. 29.6 months, p = 0.003). In addition, a tendency of differences in survival was observed between the D-normalized and D-unnormalized groups with borderline resectable PC (RFS, 20.1 vs. 14.2 months, p = 0.052; OS, not reached vs. 29.6 months, p = 0.081), and significant differences in survival were observed between the D-normalized and D-unnormalized groups with unresectable PC (RFS, 25.1 vs. 12.1 months, p < 0.001; OS, not reached vs. 11.4 months, p < 0.001). Furthermore, multivariate analysis demonstrated that normalized DUPAN-2 independently predicted survival of resected PC [RFS: hazard ratio (HR) 2.180; 95% confidence interval (CI) 1.16–4.08, p = 0.015; OS: HR 2.806; 95% CI 1.19–6.62, p = 0.018]. Conclusions: During IST, DUPAN-2 normalization may potentially predict prolonged survival for PC patients and optimal timing for conversion surgery in IST. [ABSTRACT FROM AUTHOR]

Background: Squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA) are widely used in clinical practice to predict the prognosis of patients with esophageal squamous cell carcinoma (ESCC). However, their predictive values for prognosis are controversial. This study determined optimal cutoff values of serum SCC-Ag and CEA concentrations for predicting postoperative recurrence of ESCC, which enabled selection of high-risk patients. Methods: The study retrospectively analyzed 427 patients who underwent curative resection for ESCC. The optimal cutoff values of preoperative SCC-Ag and CEA concentrations for predicting postoperative recurrence were determined using combined analysis of hazard ratios and sensitivities for recurrence. Using the optimal cutoff value, the study evaluated survival, recurrence patterns, and temporal changes in marker concentrations. Results: The preoperative SCC-Ag concentration of 1.1 ng/ml was the optimal cutoff value for predicting postoperative recurrence, whereas precise cutoff values could not be determined for preoperative CEA concentrations. High preoperative SCC-Ag concentrations (> 1.1 ng/ml), which were significantly associated with more aggressive tumor phenotypes and shorter disease-free survival, were identified as an independent prognostic factor in the multivariable analysis. High preoperative SCC-Ag concentrations were significantly associated with greater prevalence of lung/pleura and local recurrences. Normalization of serum SCC-Ag concentrations after neoadjuvant treatment or esophagectomy was not associated with a decreased risk of postoperative recurrence. Conclusions: The optimal cutoff value of preoperative SCC-Ag concentrations that predicted recurrence of ESCC was 1.1 ng/ml, illuminating the utility of serum SCC-Ag concentrations as an easily measurable tool for selecting a perioperative management strategy. [ABSTRACT FROM AUTHOR]

Background: Nutritional and immunological statuses are attracting increasing attention for their ability to predict surgical outcomes in various cancers. The Naples prognostic score (NPS) consists of the serum albumin level, total cholesterol level, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio and could be useful for predicting survival. Patients and Methods: We retrospectively analyzed 196 patients with pancreatic cancer who underwent curative R0/R1 resection with a surgery-first strategy between June 2003 and August 2016. The NPS of the patients was calculated from preoperative data, and the patients were then divided into three groups based on their NPS. Clinicopathological characteristics, surgical outcomes, and long-term survival were compared, and multivariate analysis of overall survival was conducted. Results: Of a total of 196 patients, 22 were classified into group 0 (NPS 0), 113 into group 1 (NPS 1 or 2), and 61 into group 2 (NPS 3 or 4). Median survival time was 103.4 months in group 0, 33.3 months in group 1, and 21.3 months in group 2. Significant survival differences were observed among the 3 groups (group 1 vs. 2, group 0 vs. 2, P = 0.0380, P = 0.0022, respectively). On multivariate analysis, NPS was identified as an independent prognostic factor [hazard ratio (HR) = 1.78; P = 0.0131]; however, there were no significant differences in the incidence of postoperative morbidity among the NPS groups. Conclusions: The NPS could be an easy scoring system and an independent preoperative predictor of survival. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic gastrectomy (LG) is a standard approach for patients with clinical stage I gastric cancer in East Asia; however, following surgery, these patients may be pathologically diagnosed with stage II or III cancer. The prognosis of patients with gastric cancer migration from clinical stage I to pathological stage II or III after LG has not been completely clarified. Methods: To compare the prognosis following LG and open gastrectomy (OG) in patients with pathological stage II or III gastric cancer who were preoperatively diagnosed with stage I cancer, we conducted a retrospective analysis using a multicenter dataset comprising details of 3480 patients who underwent gastrectomy between 2010 and 2014 at nine participating institutions. We used propensity score matching to reduce selection bias. Results: After propensity score matching, 146 patients were finally selected. There were no significant differences in the number of dissected lymph nodes. Morbidity rates, length of postoperative hospital stay, and time between surgery and initiation of adjuvant chemotherapy were comparable between the two groups. Moreover, there were no significant differences in the overall, disease-specific, and relapse-free survival rates between the LG and OG groups. The LG group tended to have more patients with hematogenous recurrence, whereas the OG group tended to have more patients with peritoneal recurrence. Conclusions: Our multicenter dataset analysis indicated that the prognosis of patients with gastric cancer migration from clinical stage I to pathological stage II or III was independent of the surgical approach. [ABSTRACT FROM AUTHOR]

Background: Inflammation plays a critical role in the development and progression of cancers. We evaluated the clinical significance of the preoperative modified systemic inflammation score (mSIS) to predict long-term outcomes of patients with esophageal squamous cell carcinoma (ESCC). Methods: We included 443 patients who underwent curative resection of ESCC. The mSIS was formulated according to the serum albumin level (ALB) and lymphocyte-to-monocyte ratio (LMR) as follows: mSIS 0 (ALB ≥ 4.0 g/dL and LMR ≥ 3.4), mSIS 1 (ALB < 4.0 g/dL or LMR < 3.4), and mSIS 2 (ALB < 4.0 g/dL and LMR < 3.4). Results: Patients were categorized into preoperative mSIS 0 (n = 165), mSIS 1 (n = 183), and mSIS 2 (n = 95) groups. Preoperative mSIS was significantly associated with age, preoperative body mass index, and pathological disease stage. The disease-specific survival times of patients in preoperative mSIS 0, 1, and 2 sequentially shortened (P = 0.009), and mSIS 2 was identified as an independent prognostic factor (hazard ratio 2.63, 95% confidence interval 1.33–5.27, P = 0.0053). In most patient subgroups, the mSIS was associated with greater risk of disease-specific death. A stepwise increase in the prevalence of hematogenous recurrences was directly proportion to the mSIS. When patients were subdivided by mSIS before neoadjuvant treatment, there were no significant differences in disease-specific survival. Conclusions: Our findings demonstrate that the preoperative mSIS may serve as a powerful prognosticator of ESCC that definitively stratifies clinical outcomes as well as a tool for selecting treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing subtotal esophagectomy for esophageal cancer frequently experience postoperative pneumonia. Development of preoperatively determined predictors for postoperative pneumonia will facilitate identifying high-risk patients and will assist with informing patients about their risk of postoperative pneumonia, enabling physicians to estimate with greater accuracy, will result in tailoring perioperative management. Methods: Postoperative pneumonia was defined according to the revised Uniform Pneumonia Score. We analyzed the data for 355 patients to compare 32 potential predictive variables associated with postoperative pneumonia after subtotal esophagectomy. Results: Forty-one patients (11.5%) had postoperative pneumonia. Preoperative cholinesterase (ChE) concentrations demonstrated the greatest area under the curve value (0.662) to predict postoperative pneumonia (optimal cutoff value = 217 IU/l). Univariate analysis identified a continuous value of preoperative ChE concentration as a significant risk factor for postoperative pneumonia (P = 0.0014). Multivariable analysis using factors potentially relevant to pneumonia revealed that preoperative ChE concentration was one of independent risk factors for pneumonia after esophagectomy (P = 0.008). Patients with low ChE concentrations were at increased risk of postoperative pneumonia in most patient subgroups. Moreover, the odds ratios of low ChE concentrations were highest in patients undergoing neoadjuvant treatment. A combination of preoperative serum ChE concentrations and Brinkman index stratified patients into low, intermediate, and high risk of postoperative pneumonia. Conclusions: Our findings indicate that preoperative ChE concentrations, particularly in combination with Brinkman index, may serve simply as a determined predictor of pneumonia after subtotal esophagectomy and may facilitate physicians' efforts to reduce the incidence of postoperative pneumonia. [ABSTRACT FROM AUTHOR]

Background: The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa. Methods: Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer. Results: PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis. Conclusions: Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy. [ABSTRACT FROM AUTHOR]

Background: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer.Methods: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA.Results: DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells.Conclusions: Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the predictive value of the preoperative Controlling Nutritional Status (CONUT) score, which comprehensively reflects protein and lipid metabolism as well as the immunocompetence among patients with stage 2 or 3 gastric cancer.Methods: From a retrospective database of 3484 patients who underwent gastrectomy for gastric cancer at nine Japanese institutions between 2010 and 2014, data for 626 patients with stage 2 or 3 cancer were retrieved. The study evaluated the significance of the associations between the optimal CONUT score cutoff values with the prognosis and the incidence of postoperative complications.Results: The study determined that 2 was the optimal CONUT score cutoff value for predicting mortality 2 years after surgery. The patients with a CONUT score of 2 or higher (CONUT-high group) were significantly older and had a worse Eastern Cooperative Oncology Group performance status, lower body mass index, and more advanced tumor-node-metastasis stage than the patients with a CONUT score lower than 2 (CONUT-low group). Overall, the survival time was significantly shorter in the CONUT-high group than in the CONUT-low group [hazard ratio (HR) 1.97; P < 0.0001]. A multivariable analysis showed that the CONUT score was an independent prognostic factor of overall survival. The CONUT score more significantly reflected the overall survival for patients who underwent postoperative adjuvant chemotherapy than for those who underwent surgery alone. Additionally, a high preoperative CONUT score was significantly associated with an increased incidence of postoperative pneumonia and prolonged hospitalization.Conclusions: The study results suggest that the preoperative CONUT score may be a useful predictor of postoperative short- and long-term outcomes for patients with stage 2 or 3 gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Although peritoneal metastasis is a serious concern in patients with gastric cancer, no acceptable and specific biomarker is available. We aimed to identify a candidate biomarker to predict peritoneal metastasis of gastric cancer.Methods: Metastatic pathway-specific transcriptome analysis was conducted by comparison of patient groups with no recurrence and with peritoneal, hepatic, and nodal recurrence. Fifteen cell lines and 262 pairs of surgically resected gastric tissues were subjected to messenger RNA (mRNA) expression analysis. Polymerase chain reaction array analysis was performed to explore coordinately expressed cancer-related genes. To evaluate the in situ protein localization and expression patterns, immunohistochemical staining was performed.Results: From transcriptome data, troponin I2 (TNNI2) was identified as a candidate molecule specifically overexpressed in gastric cancer prone to peritoneal metastasis. TNNI2 mRNA was expressed at differential levels, independent of differentiated phenotype of cell lines. Epithelial to mesenchymal transition-related genes, tumor inhibitor of metalloproteinase 1 (TIMP1), and vacuolar protein sorting 13 homolog A (VPS13A) were expressed with TNNI2 at correlation coefficient > 0.7. The optimal cutoff of TNNI2 expression was determined as 0.00017. High TNNI2 expression was significantly and specifically associated with peritoneal metastasis and served as an independent risk marker for peritoneal recurrence after curative gastrectomy. Prevalence of peritoneal recurrence increased in parallel with staining intensity of TNNI2.Conclusions: TNNI2 expression in gastric tissues may serve as a specific biomarker for prediction of peritoneal metastasis of gastric cancer and contribute to improvement of patient management. [ABSTRACT FROM AUTHOR]

Background: Challenges to our understanding the molecular mechanisms of the progression of gastric cancer (GC) must be overcome to facilitate the identification of novel biomarkers and therapeutic targets. In this article, we analyzed the expression of the gene encoding F-box-only 50 (FBXO50) and determined whether it contributes to the malignant phenotype of GC. Methods: FBXO50 messenger RNA (mRNA) levels and copy numbers of the FBXO50 locus were determined in 10 GC cell lines and a nontumorigenic epithelial cell line. Polymerase chain reaction array analysis was performed to identify genes coordinately expressed with FBXO50. The effects of inhibiting FBXO50 on GC cell proliferation, adhesion, invasiveness, and migration were evaluated using a small interfering RNA targeted to FBXO50 mRNA. To evaluate the clinical significance of FBXO50 expression, we determined the levels of FBXO50 mRNA in tissues acquired from 200 patients with GC. Results: The levels of FBXO50 mRNA were increased in five GC cell lines and positively correlated with those of ITGA5, ITGB1, MMP2, MSN, COL5A2, GNG11, and WNT5A. Copy number gain of the FBXO50 locus was detected in four GC cell lines. Inhibition of FBXO50 expression significantly decreased the proliferation, adhesion, migration, and invasiveness of GC cell lines. In clinical samples, high FBXO50 expression correlated with increased pT4, invasive growth, lymph node metastasis, and positive peritoneal lavage cytology. Patients with high FBXO50 expression had a significantly higher prevalence of recurrence after curative gastrectomy and were more likely to experience shorter overall survival. Conclusions: FBXO50 may represent a biomarker for GC phenotypes and as a target for therapy. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) relapse can occur even if curative resection is achieved. Biomarkers predicting recurrence are needed to provide appropriate postoperative surveillance and perioperative therapeutic strategy. Methods: A global expression profiling was performed using tissues from GC patients with synchronous liver-confined metastasis. Family with sequence similarity 46, member C ( FAM46C), was identified as a candidate biomarker. mRNA expression analysis, direct nucleotide sequencing, bisulfite sequencing and copy number assays for FAM46C were performed with eleven GC cell lines. Expression levels of FAM46C in primary GC tissues from 129 patients who underwent curative GC resection were determined and correlated with clinicopathological factors, including postoperative outcome. Results: Levels of FAM46C mRNA differed among GC cell lines. Point mutations in FAM46C were detected in five GC cell lines accompanied with reduced FAM46C transcription. No hypermethylation was found in the promoter region of FAM46C. Copy number alterations were found in six GC cell lines with differing FAM46C transcription levels. Reduced FAM46C mRNA expression levels were detected in 117 (91 %) GC specimens compared with adjacent noncancerous tissues. Low FAM46C expression levels were significantly associated with larger macroscopic GC tumor sizes. The low FAM46C expression group was likely to have shorter disease-free survival than the high group and low FAM46C level was identified as an independent risk factor for recurrence after curative resection. FAM46C expression levels were low in all cases that were later found to have hepatic recurrence. Conclusions: Reduced GC expression of FAM46C is a potential biomarker to predict hepatic recurrence after curative gastrectomy. [ABSTRACT FROM AUTHOR]

Background: The administration of fluid irradiated with non-equilibrium atmospheric pressure plasma (NEAPP) has attracted much interest as a novel therapeutic method for cancer. The authors previously reported on the efficacy of plasma-activated medium (PAM) for treating cancer cell lines through the induction of apoptosis. In this study, the therapeutic effect of PAM was evaluated in vivo using a peritoneal metastasis mouse model. Methods: Two gastric cancer cell lines were used in proliferation assays performed to optimize the production of PAM by changing the distance between the plasma source and the medium surface and by altering the volume of irradiated medium. Wound-healing and adhesion assays were conducted to determine the effect of PAM therapy on cell migration and adhesion capacity in vitro. Finally, a mouse model established by the intraperitoneal injection of enhanced green fluorescent protein-tagged gastric cancer cells was used to explore the efficacy of PAM administered intraperitoneally in inhibiting peritoneal metastasis formation. Results: Shorter distances between the plasma source and the medium surface and smaller volumes of treated medium increased the anti-tumor effect of PAM. The PAM treatment attenuated gastric cancer cell migration and adhesion in vitro. The intraperitoneal administration of PAM decreased the formation of peritoneal metastatic nodules by 60% in the mouse model, and no adverse events were observed. Conclusions: Plasma-activated liquids may represent a novel therapeutic method for the treatment of peritoneal metastases in gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM. Methods: A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS). Results: Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively. Conclusions: Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection. [ABSTRACT FROM AUTHOR]

Background: Systemic hemostasis and thrombosis activation has been implicated in tumor progression and metastasis. This study aimed to investigate the use of coagulation factors as a novel prediction method for postoperative outcomes after curative gastrectomy in patients with stage II/III gastric cancer (GC). Methods: Overall, 126 patients with stage II/III GC who underwent gastrectomy between May 2003 and February 2016 were eligible for inclusion in the study. We retrospectively evaluated the predictive value of preoperative platelet count and plasma fibrinogen and d-dimer levels, and coagulation score (0: fibrinogen and d-dimer both below upper limits; 1: either fibrinogen or d-dimer over upper limits; 2: both fibrinogen and d-dimer over upper limits) for short- and long-term outcomes. Results: Postoperative complications were significantly more frequent in patients with elevated preoperative d-dimer levels compared with those with normal d-dimer levels (26 vs. 10 %; p = 0.032). The prevalence of postoperative complications showed a stepwise increase in proportion to the coagulation score. Patients with a coagulation score of 2 had significantly larger tumors ( p = 0.013) and significantly greater intraoperative blood loss ( p = 0.004) than those who scored 0 or 1. Coagulation score showed the highest values distinguished high-risk patients in overall and disease-free survival, and a coagulation score of 2 was an independent prognostic factor for recurrence. Patients with a coagulation score of 2 experienced a significantly higher prevalence of liver metastasis as an initial recurrence than those who scored 0 or 1 ( p = 0.019). Conclusions: The coagulation score is a simple and promising predictor for postoperative complications and recurrence after gastrectomy in stage II/III GC patients. [ABSTRACT FROM AUTHOR]

Background: Identification of novel molecules implicated in the malignancy of gastric cancer (GC) is key to the development of personalized treatments and the improvement of patient outcome. Neurotrophin receptor-interacting melanoma antigen-encoding protein ( NRAGE) regulates apoptosis and metastasis via interactions with various genes. This study aimed to evaluate the function and clinical significance of NRAGE in GC. Methods: The expression of NRAGE and its putative interacting genes apoptosis antagonizing transcription factor ( AATF), p75 neurotrophin receptor ( p75NTR), and proliferating cell nuclear antigen ( PCNA) were determined in GC cell lines using reverse transcription-polymerase chain reaction (RT-PCR). The effect of NRAGE knockdown by small interfering RNA (siRNA) on GC cell behavior also was evaluated. In addition, NRAGE expression was determined in 179 pairs of resected gastric tissues. Results: Expression of NRAGE mRNA positively correlated with that of AATF, and NRAGE knockdown significantly decreased the proliferation, migration, and invasion of GC cells. The mean level of NRAGE mRNA expression was significantly higher in GC tissues than in corresponding adjacent normal tissues. The expression patterns of NRAGE mRNA and protein were closely correlated. A stepwise elevation in NRAGE mRNA expression in GC tissues was observed with increasing Union for International Cancer Control (UICC) stage. High NRAGE expression in GCs was associated with shortened recurrence-free survival and identified as an independent prognostic factor (hazard ratio, 1.83; 95 % CI, 1.12-3.02, p = 0.017). Conclusions: The results indicate that NRAGE represents a putative oncogene associated with a malignant phenotype of GC. In GC, NRAGE may serve as a predictive biomarker and a target of molecular therapy. [ABSTRACT FROM AUTHOR]

Background: In East Asia, the tumor infiltrative pattern (INF) has been routinely evaluated by hematoxylin and eosin-stained sections as a pathologic characteristic of surgically resected specimens. Methods: The infiltrative pattern of gastric cancer (GC) has been histopathologically classified as INFa (expansive growth), INFb (intermediate type) and INFc (infiltrative growth) according to the Japanese Classification of Gastric Carcinoma. The prognostic value and characteristics of the disease recurrence pattern for each INF type were assessed in 785 patients with various stages of GC and also in 243 patients with stages 2 and 3 GC. Results: Comparison of the overall survival experienced by patients independently of stage showed that INF was significantly associated with prognosis. Specifically, peritoneal metastasis was present in 91 % of stage 4 patients in the INFc group, whereas hepatic metastasis was present in 39 % of stage 4 patients in the INFa and INFb group. After curative gastrectomy of patients with stages 2 or 3 GC, INF was not significantly associated with survival. The prevalence of peritoneal recurrence was significantly higher in the INFc group than in the INFa and INFb group, whereas the prevalence of hepatic recurrence was significantly higher in the INFa and INFb group than in the INFc group. Multivariate analysis identified INFc as an independent risk factor for peritoneal recurrence after curative gastrectomy. The association of the INF type with the incidence of peritoneal recurrence was observed with all disease stages regardless whether the patient was given adjuvant chemotherapy or not. Conclusions: Evaluation of the INF type shows promise for its role as a predictor of postoperative recurrence sites in patients with GC. [ABSTRACT FROM AUTHOR]

Background: Sensitive biomarkers are necessary for risk classification of patients with gastric cancer (GC), especially ones at risk of distant metastases. Melanoma-associated antigen (MAGE)-D2 has been reported to play a role in the process of cell adhesion and metastatic potential of tumor cells in colorectal cancer. The purpose of this study was to identify a novel clinically relevant biomarker of GC. Methods: Expression analysis of MAGE-D2 was conducted in GC cell lines and clinical samples (surgical specimen and serum) in both mRNA and protein level. Correlations between MAGE-D2 expression status and clinicopathological factors were evaluated. Results: MAGE-D2 mRNA expression levels were similar between GC tissues and the corresponding normal adjacent tissues and were independent of GC differentiation or subtype. In 101 (45 %) of 225 patients, the expression level of MAGE- D2 mRNA was increased in GC tissues compared with the corresponding normal adjacent tissues. Increased expression of MAGE- D2 mRNA in GC tissues was associated with distant metastasis and early recurrence and was an independent prognostic factor (hazard ratio 2.27, 95 % confidence interval 1.39-3.74, P = 0.001). There was a stepwise increase in serum MAGE- D2 level going from healthy volunteers to patients with localized GC and then to those with extended GC (stage IV). Patients with preoperative serum MAGE- D2 levels >130 pg/ml had a more unfavorable prognosis than those with levels ≤130 pg/ml. Conclusion: MAGE- D2 was associated with metastatic potential of GC and may represent a promising biomarker, both in gastric tissues and serum samples, for malignant behavior of GC. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the prognostic relevance of subcarinal lymph node dissection in patients with esophageal squamous cell carcinoma (ESCC) and to identify a subset of patients in whom subcarinal lymph node dissection can be omitted. Methods: We retrospectively analyzed 342 consecutive patients with thoracic ESCC who underwent R0 subtotal esophagectomy. All patients underwent subcarinal lymph node dissection. The efficacy index (frequency of metastasis to a particular lymph node station multiplied by the 5-year disease-specific survival rate of patients with metastasis to the station) was calculated for the subcarinal lymph node station, and the prognostic impact of dissecting this station was estimated with reference to the main tumor location. Independent predictive factors for pathological subcarinal lymph node metastasis were analyzed using a proportional hazards model. Results: The overall frequency of metastasis to the subcarinal lymph nodes was 7.0 % (2.4, 8.9, and 5.8 % in patients with upper, middle, and lower thoracic ESCC, respectively). The efficacy index for the middle thoracic esophagus was 2.9, and that for the upper and lower thoracic esophagus was 0.0. The 5-year disease-free survival rate was significantly lower in patients with pathological subcarinal lymph node metastasis than those without (23.1 vs. 67.5 %, respectively; log-rank p < 0.0001). In multivariate analysis, clinical T stage (T2-T4) was the independent predictive factor for pathological subcarinal lymph node metastasis ( p = 0.021). Conclusions: Subcarinal lymph node dissection might have little value in patients with upper and lower thoracic ESCC and could be omitted, especially for superficial carcinoma. [ABSTRACT FROM AUTHOR]

Background: Identification of molecular markers for sensitive detection of hepatocellular carcinoma (HCC) is required to achieve efficacious personalized therapy. Methods: We focused here on SAM domain, SH3 domain, and nuclear localization signals 1 ( SAMSN1) and investigated expression and methylation status of SAMSN1 in HCC cell lines and 144 pairs of surgical specimens. Results: SAMSN1 was expressed at significantly lower levels in tumor tissue compared with the corresponding noncancerous tissues of patients with HCC. Analysis of HCC cell lines revealed that hypermethylation of the SAMSN1 promoter correlated with decreased expression of SAMSN1 mRNA. Furthermore, treating cells with a DNA-demethylating drug increased SAMSN1 transcription. The levels of SAMSN1 mRNA in noncancerous liver were not affected by background liver inflammation or fibrosis. Moreover, the levels of SAMSN1 mRNA in HCC tissues inversely correlated with tumor size and preoperative levels of proteins induced by vitamin K absence. The clinical significance of SAMSN1 was further indicated by the correlation between its decreased expression in patients with HCC and their shorter overall and recurrence-free survival as well as recurrence following initial resection. Moreover, multivariate analysis identified SAMSN1 as an independent prognostic factor of HCC progression. The expression pattern of SAMSN1 correlated significantly with that of SAMSN1 mRNA, making it possible to use PCR techniques to readily quantitate SAMSN1 expression in tumors. Conclusions: Our findings indicate that inhibition of SAMSN1 transcription through DNA hypermethylation may influence the progression of HCC and thus represent a novel biomarker of the phenotype of HCC cells. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) frequently recurs after curative resection. Therefore, the availability of sensitive biomarkers for progression and recurrence is essential for managing patients' clinical course. Adherens junctions associated protein 1 ( AJAP1) may serve this purpose, because it mediates activities of tumor cells. Methods: AJAP1 mRNA levels and those of genes encoding potential interacting proteins, such as SRC in HCC cell lines, and 144 pairs of resected liver tissues were determined as well as the methylation status of the AJAP1 promoter and copy number changes at AJAP1 locus. The expression pattern of AJAP1 protein was evaluated using immunohistochemistry. Results: AJAP1 mRNA levels varied among nine HCC cell lines, and AJAP1 expression was reactivated after demethylation of its promoter. AJAP1 mRNA levels correlated inversely with those of SRC in HCC cell lines and tissues. AJAP1 mRNA levels were suppressed in HCC tissues. The expression pattern of AJAP1 correlated significantly with that of AJAP1 mRNA. Low levels of AJAP1 mRNA in patients with HCC associated significantly with elevated levels of tumor markers, larger tumor size, serosal infiltration, vascular invasion, hypermethylation of the AJAP1 promoter, and copy number loss at AJAP1 locus. Patients with low levels of AJAP1 expression were more likely to experience shorter disease-free survival (DFS), and multivariate analysis identified low AJAP1 expression as an independent factor for predicting DFS. Conclusions: AJAP1 may function as a key regulatory molecule associated with the recurrence of HCC. Hypermethylation of the AJAP1 promoter is a key regulatory mechanism controlling AJAP1 expression. [ABSTRACT FROM AUTHOR]

Background: The usefulness of enteral nutrition via a nasointestinal tube for patients who develop postoperative pancreatic fistula (POPF) after miscellaneous pancreatectomy procedures has been reported. However, no clear evidence regarding whether oral intake is possible during management of POPF after pancreatoduodenectomy (PD) is currently available. We investigated the effects of oral food intake on the healing process of POPF after PD by a multi-institutional randomized controlled trial. Methods: Patients who developed POPF were randomly assigned to the dietary intake (DI) group ( n = 30) or the fasted group [no dietary intake (NDI) group] ( n = 29). The primary endpoint was the length of drain placement. Results: No significant differences were found in the length of drain placement between the DI and NDI groups [27 (7-80) vs. 26 (7-70) days, respectively; p = .8858]. POPF progressed to a clinically relevant status (grade B/C) in 20 patients in the DI group and 19 patients in the NDI group ( p = .9257). POPF-related intra-abdominal hemorrhage was found in 2 patients in the NDI group, but in no patients in the DI group ( p = .1434). There were no significant differences in POPF-related intra-abdominal hemorrhage, the incidence of other complications, or the length of the postoperative hospital stay between the 2 groups. Conclusion: Food intake did not aggravate POPF and did not prolong the length of drain placement or hospital stay after PD. There may be no need to avoid oral dietary intake in patients with POPF. [ABSTRACT FROM AUTHOR]

Purpose: Morphological subtypes of intraductal papillary mucinous neoplasm (IPMN) have been established. Invasive IPMNs include colloid carcinoma and tubular carcinoma. Few studies have explored the association between the morphological and invasive subtypes in a large population. Clinical relevance of the morphological subtypes remains unclear. Methods: One hundred sixty-nine consecutive patients who underwent curative resection of IPMN were enrolled. The intraductal components were classified into four distinct epithelial subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The invasive components were classified as colloid or tubular. Results: The numbers of patients with gastric, intestinal, pancreatobiliary, and oncocytic subtypes were 123, 42, 3, and 1, respectively. Fifty-six patients had invasive cancer (tubular type, 42; colloid type, 14). The proportions of gastric type IPMN within each histological grade were 88 % among adenomas, 43 % among noninvasive carcinomas, 41 % among minimally invasive carcinomas, and 74 % among invasive carcinomas. Gastric subtype was more commonly associated with branch duct type and intestinal subtype with main duct type, and these tendencies were statistically significant ( P = 0.0131). Furthermore, there was a strong correlation between gastric and tubular types and between intestinal and colloid types ( P < 0.0001). The 5-year survival rate among the 56 invasive cancers was 52.7 % for gastric type and 89.7 % for intestinal type, which was statistically significant ( P = 0.030). Conclusions: Gastric type IPMN is mostly derived from branch duct IPMN and often demonstrates benign behavior, as seen with adenomas. However, once gastric type IPMN develops into invasive carcinoma, the survival rate is significantly lower than other types. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) often recurs and multicentric occurrence is more common than intrahepatic metastases after surgery. Prognostic prediction is insufficient when considering only factors in resected primary tumor. Methods: Control samples, termed supernormal (SN) liver, were taken from 11 cases of metastatic secondary malignancies of the liver. We selected adjacent nonneoplastic liver tissue from a patient with HCC and liver cirrhosis by hepatitis C (CN) for comparison. Expression profiling and methylation arrays were performed. We identified genes showing differences in both arrays. Prognosis was predicted for 179 cases of HCC based on gene expression. Results: Expression profiling showed that expression of thimet oligopeptidase ( THOP1) gene was decreased 4.119-fold in CN. Methylation array showed a higher value for CN (0.869) than SN (0.488). We studied THOP1 gene expression by real-time reverse transcriptase polymerase chain reaction. The average expression level of THOP1 ( THOP1 value × 10/ GAPDH) decreased in matching normal tissue (14.53 ± 10.14) relative to SN (78.14 ± 44.50). The group with higher than average THOP1 expression ( n = 74) showed significant correlations with prolonged survival ( P = 0.0383). Strongly reduced THOP1 expression (<3.0, n = 50) was shown to be an independent prognostic factor by multivariate analysis ( P = 0.0024). Conclusions: Expression of the THOP1 gene in the background liver of HCC is likely to be a good biomarker for risk of HCC development. When assessing HCC, it is important to extract prognostic factors from background liver tissue as well as considering malignant factors of the primary cancer lesion. [ABSTRACT FROM AUTHOR]

Background: There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models. Methods: The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival. Results: HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group. Conclusions: Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers. [ABSTRACT FROM AUTHOR]

Background: Pylorus-preserving pancreatoduodenectomy (PPPD) has replaced conventional pancreatoduodenectomy with a distal gastrectomy (cPD) as the most commonly performed procedure. However, there has been no evidence from prospective studies to indicate the overwhelming superiority of PPPD over cPD. A recent report revealed that resection of the pyloric ring reduced the incidence of delayed gastric emptying (DGE) in a randomized controlled trial. Methods: In 158 patients with pancreatic head cancer, the perioperative outcomes and long-term nutritional consequences were retrospectively compared among three types of pancreatoduodenectomy: cPD; PPPD; and subtotal stomach-preserving pancreatoduodenectomy (SSPPD), in which the pyloric ring and duodenum were removed and more than 90% of the stomach was preserved. Results: The incidence of DGE was significantly higher in the PPPD group than in the cPD and SSPPD groups (27.3 vs. 5.8 and 5.4%, respectively; P = 0.0012). The serum albumin concentration and total lymphocyte count at 1 year postoperatively were significantly higher in the SSPPD group than in the PPPD group ( P = 0.0303 and P = 0.0203, respectively). The patients in the SSPPD group showed longer survival times than the patients in the cPD and PPPD groups (median survival times, 21.3, 17.1, and 17.7 months, respectively), although the differences did not reach statistical significance. Conclusions: Our results suggest that preservation of the pyloric ring without vagal innervation has little significance, and that SSPPD with better perioperative and long-term outcomes is more suitable as a standard procedure for patients with pancreatic head cancer. [ABSTRACT FROM AUTHOR]

Background: The negative impact of anastomotic leakage on cancer-specific survival and recurrence patterns has been recognized in colorectal cancer. In pancreatic cancer, pancreatic fistula (PF) is a serious morbidity, but its negative effect on long-term outcome remains to be elucidated. The aim of this study was to determine the impact of PF on pancreatic cancer recurrence. Methods: The medical records of 184 patients with curative pancreatectomy for pancreatic cancer were reviewed. PF was scored on the basis of the International Study Group of Pancreatic Fistula classification. Overall and disease-free survivals and recurrence patterns were analyzed. Grade A PF was excluded because the negative effects can be negligible. Results: PF occurred in 51 of the 184 patients (27.7%). The mortality related to PF was 0.5% (1 of 184). PF was an independent risk factor for peritoneal recurrence (hazard ratio 3.974; 95% confidence interval 1.345-11.737; P = 0.013). According to the analysis of disease-free survival in patients with peritoneal recurrence, time to recurrence was shorter and the survival rate was worse in patients with PF than in those without PF (5.6 vs. 8.2 months; 6-month survival, 40 vs. 71%; 1-year survival, 7 vs. 19%; P = 0.053). PF was an independent prognostic factor after multivariate analysis (hazard ratio 3.257; 95% confidence interval 1.201-8.828; P = 0.020). Conclusions: PF was statistically significantly related to peritoneal recurrence, and patients with PF developed peritoneal recurrence earlier than those without PF. With regard to the development of peritoneal recurrence, PF may be considered to be a negative prognostic factor. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the world's top five causes of cancer-related deaths. Current treatments available ameliorate HCC; however, current therapy fails to completely treat and prevent HCC, as shown by its high recurrence rate. Recently developed genome-wide gene-expression profile analyses can now robustly detect many candidate genes that are modified by HCC. Here we attempt to identify novel genes displaying altered gene expression profiles when comparing healthy tissue with HCC by means of a double-combination array previously developed. Methods: Double-combination array analysis of gene expression profiles and single nucleotide polymorphism arrays were performed on each HCC tissue sample. Subsequently, samples from 48 HCC patients were subjected to quantitative real-time reverse transcription polymerase chain reaction and methylation-specific polymerase chain reaction. Results: The reelin ( RELN) gene was detected as a pertinent tumor suppressor gene by means of this method. Of the 48 clinical samples obtained, 34 (79.2%) displayed reduced RELN expression in tumor tissue, and the expression level of tumor tissues clearly reduced compared with that of corresponding normal tissues ( P = 0.002). Eighteen (37.5%) of 48 tumor tissues were found to be hypermethylated on the RELN gene promoter. Moreover, analysis of clinical data revealed an inverse correlation between RELN expression and HCC recurrence. Conclusions: The present study indicates that our in-house double-combination array is an effective and convenient technique in detecting novel genes with altered expression in disease. We suggest RELN is a key regulatory gene associated with the recurrence of HCC. [ABSTRACT FROM AUTHOR]