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To date, few reports have investigated the genetic alterations and clinicopathological features among gastric cancer (GC) patients with no tumor recurrence, early recurrence and late recurrence following curative surgery.A total of 473 GC patients undergoing curative surgery were included. The clinicopathological characteristics, patient prognosis, recurrence patterns, and genetic alterations were compared between GC patients with early recurrence and late recurrence.Among the 473 GC patients, 119 had early recurrence (2 years) and 45 had late recurrence (≥2 years). Patients with early recurrence had tumor size larger than 5 cm, fewer superficial-type tumors, more lymphovascular invasion, more advanced pathological T and N categories and TNM stages, and worse 5-year overall survival than patients with late recurrence and no recurrence. For intestinal-type GC, patients with no tumor recurrence had more Helicobacter pylori infection than patients with early recurrence and late recurrence; for diffuse-type GC patients, the frequency of PIK3CA amplification was the highest in early recurrence, followed with late recurrence and no recurrence. GC patients with single-site recurrence had more ARID1A mutations than those with multiple-site recurrence. Multivariate analysis demonstrated that age, tumor recurrence, and pathological N categories were independent prognostic factors.PIK3CA amplifications were more common in diffuse-type GC with early recurrence, while ARID1A mutations were more common in patients with single-site recurrence. Targeted therapy and immunotherapy might be helpful for these patients.

Supplementary Figure 6 from The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2

Supplementary Figures 1-5 from The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2

Supplementary Tables 1-2, Figure Legends 1-8 from The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2

Supplementary Figure 8 from The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2

Supplementary Figure 7 from The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2

To date, few reports have investigated the genetic alterations and clinicopathological features in gastric cancer (GC) according to sex. In total, 2673 GC patients receiving curative surgery were enrolled. Among the 2673 GC patients, 1979 (74.0%) patients were male. After propensity-score matching, 846 patients were enrolled for the analysis, including 423 males and 423 females. There was no significant difference in the clinicopathological features between the sexes. Regarding the initial recurrence pattern, the males were more likely to develop tumor recurrence and liver metastasis than the females, especially in stage III GC. Regarding the molecular analysis, the males had higher PD-L1 expression than the females, especially in stage III GC. In addition, the patients aged ≥ 65 years had higher PD-L1 expression than the patients younger than 65 years. The multivariate analysis demonstrated that sex was among the independent prognostic factors affecting overall survival (OS) and disease-free survival (DFS). Among the patients with liver metastases, PD-L1 expression was more common among the aged male patients. The males were associated with more tumor recurrence and higher PD-L1 expression than the females, especially in stage III GC. For GC patients with liver metastases, PD-L1 testing is recommended, especially among aged male patients.

Various reconstruction methods have been performed following distal gastrectomy; however, each reconstruction method has its own advantages and disadvantages. This study aims to compare the long-term outcomes between Billroth-I (B-I) and Roux-en-Y (RY) reconstruction after distal gastrectomy for gastric cancer. A total of 459 patients who underwent distal gastrectomy (B-I: 166, RY: 293) were included. Postoperative endoscopic findings and biliary tract stone formation were compared between the two groups. At 1 year and 2 years postoperatively, gastric residue was more common in the RY group, gastritis was similar between groups, and bile reflux was more common in the B-I group. At 5 years postoperatively, gastric residue was similar between the groups, while gastritis and bile reflux were more common in the B-I group. Gastroesophageal reflux was more common in the B-I group at 1 year postoperatively, but gastroesophageal reflux became not significantly different between the groups at 2 and 5 years postoperatively. Gallstone formation was more common in the RY group and in patients aged ≥ 65 years. During long-term follow-up, RY reconstruction was associated with lower incidence of bile reflux and gastritis, and higher incidence of gallstone formation than B-I reconstruction. The incidence of gastric residue was more common in the RY reconstruction group in the early postoperative period and became not significantly different between the two groups over time. For aged patients with RY reconstruction, cholecystectomy is recommended concurrently as gastrectomy.

Objective The Lauren classification is an important histologic classification of gastric cancer (GC) with different biological behaviors between histologic types. Background To date, there are few reports on the genetic alterations and survival differences between different histologic types according to the Lauren classification. Methods In total, 433 GC patients undergoing surgery were enrolled. The clinicopathologic features, prognoses, and genetic alterations of the different Lauren types were compared. Results Diffuse-type GC was associated with a younger age, female predominance, more Borrmann type 3 and 4 tumors, more advanced pathologic tumor (T) and node (N) categories, more tumor recurrences (especially peritoneal recurrence), and worse 5-year overall survival and disease-free survival rates than intestinal-type GC and mixed-type GC. Regarding genetic alterations, mixed-type GC was associated with more TP53 mutations than intestinal-type GC and diffuse-type GC. Multivariate analysis demonstrated the following independent prognostic factors: age, Lauren classification, and pathologic T and N categories. Regarding mixed-type GC, diffuse-type major tumors were associated with more lymphovascular invasion, a more advanced N category and tumor, node, metastasis stage, and fewer PI3K/AKT pathway mutations than intestinal-type major tumors. Conclusions Diffuse-type GC had unfavorable clinicopathologic features and a worse prognosis than intestinal-type GC. For mixed-type GC, the clinicopathologic features and genetic alterations were different between intestinal-type major tumors and diffuse-type major tumors.

Gastric stump (&ldquo, remnant&rdquo, ) cancer is the development of a malignancy related to previous gastric surgery. Prognosis in gastric stump cancer, compared with that in primary gastric cancer, is still controversial. From January 1988 to December 2012 at a single medical centre in Taiwan, 105 patients with gastric stump cancer, including 85 with previous peptic ulcer disease and 20 with previous gastric cancer, were analyzed for clinicopathologic characteristics and overall survival (os). The 5-year os rates for patients with gastric stump cancer and with primary gastric cancer were 51.2% and 54.5% respectively (p = 0.035). Analysis of clinicopathologic characteristics indicated that, compared with patients having primary gastric cancer, those with gastric stump cancer had more lymph node metastasis (p < 0.001) and had been diagnosed at a more advanced stage (p = 0.047). Multivariate analysis with os as an endpoint showed that age [p = 0.015, hazard ratio (hr): 2.300, 95% confidence interval (ci): 1.173 to 4.509], tumour size (p = 0.037, hr: 1.700, 95% ci: 1.031 to 2.801), stromal reaction (p = 0.021, hr: 1.802, 95% ci: 1.094 to 2.969), and pathologic N category (p = 0.001, hr: 1.449, 95% ci: 1.161 to 1.807) were independent predictors in gastric stump cancer. The os rates for patients with gastric stump cancer who previously had gastric cancer or peptic ulcer disease were 72.9% and 50.0% respectively (p = 0.019). The Borrmann classification was more superficial (p = 0.005), lymph node metastases were fewer (p = 0.004), and staging was less advanced (p = 0.025) in patients with gastric stump cancer who previously had gastric cancer than in their counterparts who previously had peptic ulcer disease. Survival is poorer in patients with gastric stump cancer who previously had peptic ulcer disease than in those who previously had primary gastric cancer. Patients with gastric stump cancer who previously had gastric cancer and could receive curative gastrectomy tended to have a better prognosis because of a more superficial Borrmann classification. Regular follow-up in patients who have undergone gastric surgery is recommended for the early detection of gastric stump cancer.

Simple Summary Immunotherapy is approved in selected cases of gastric cancer, and durable responses have been observed in exceptional responders. Several potential predictive biomarkers have been identified in gastric cancer, such as microsatellite instability-high (MSI-H), Epstein–Barr virus (EBV), and programmed death ligand 1 (PD-L1). We explored the real-world evidence of these biomarkers and their outcomes. When only combined positive score (CPS) ≥ 1 was used as the biomarker, the overall response rate (ORR) and progression-free survival (PFS) were not statistically significant. CPS ≥ 1 was commonly combined with MSI-H (75%) and Epstein–Barr encoding region (EBER) (80%). MSI-H and CPS ≥ 5 were prognostic biomarkers associated with better ORR and PFS. In patients with EBER, better ORR and PFS were observed only in patients with CPS ≥ 1. These results could transform clinical practice and can be used to formulate more precise treatment suggestions for patients with gastric cancer. Abstract Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers—microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein–Barr encoding region (EBER)—were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.

Background Mucinous gastric carcinoma (MGC) is rare and often associated with an advanced stage. The clinicopathological features and prognosis of MGC and non-MGC (NMGC) are controversial. Methods In total, 2637 gastric cancer (GC) patients receiving curative surgery were enrolled. The clinicopathological features and genetic alterations were compared between patients with MGC and NMGC. Results Among the 2637 GC patients, 92 (3.5%) had MGC. After propensity score matching, compared to patients with NMGC, patients with MGC had more poorly differentiated tumors, medullary stromal reaction-type tumors, tumors with infiltrating Ming's classification, diffuse-type tumors, more abnormal preoperative serum carbohydrate antigen 19-9 levels, and more advanced T categories. After propensity score matching, there were no significant differences between MGC and NMGC regarding the initial recurrence patterns, 5-year overall survival (OS), and disease-free survival (DFS) rates. Multivariate analysis demonstrated that the MGC cell type is not an independent prognostic factor of OS and DFS. No significant differences in microsatellite instability status, Epstein-Barr virus infection, Helicobacter pylori infection, or genetic mutations were observed between MGC and NMGC. The expression of programmed death-ligand 1 (PD-L1) was significantly higher in MGC than that in NMGC. MGC was diagnosed at a more advanced stage compared with NMGC. Conclusion MGC itself was not an independent prognostic factor of worse survival. MGC was correlated with higher PD-L1 expression than NMGC, which may have a clinical impact on the treatment of MGC in the future.

Background Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms. Methods The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients. Results We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin-332 through FAK-PI3K/AKT-GSB3β/β-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients. Conculsions These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment.

Chemotherapy is generally considered as the main treatment for metastatic gastric adenocarcinoma. The role of gastrectomy for metastatic gastric cancer without obvious symptoms is controversial. The objective of this study is to investigate survival outcomes of treatment modalities using a real-world data setting. A retrospective cohort study was designed using the Taiwan Cancer Registry database. We identified the treatment modalities and used Kaplan–Meier estimates and Cox regressions to compare patient survival outcomes. From 2008 to 2015, 5599 gastric adenocarcinoma patients were diagnosed with metastatic disease (M1). The median overall survival (OS) of patients with surgery plus chemotherapy had the longest survival of 14.2 months. The median OS of the patients who received chemotherapy alone or surgery alone was 7.0 and 3.9, respectively. Age at diagnosis, year of diagnosis, tumor grade, and treatment modalities are prognostic factors for survival. The hazard ratios for patients who received surgery plus chemotherapy, surgery alone, and supportive care were 0.47 (95% CI 0.44–0.51), 1.22 (95% CI 1.1–1.36), and 3.23 (95% CI 3.01–3.46), respectively, by multivariable Cox regression analysis when using chemotherapy alone as a referent. Chemotherapy plus surgery may have a survival benefit for some selected gastric adenocarcinoma patients with metastatic disease.

Various reconstruction methods have been performed following distal gastrectomy; however, each reconstruction method has its own advantages and disadvantages. This study aims to compare the long-term outcomes between Billroth-I (B-I) and Roux-en-Y (RY) reconstruction after distal gastrectomy for gastric cancer.A total of 459 patients who underwent distal gastrectomy (B-I: 166, RY: 293) were included. Postoperative endoscopic findings and biliary tract stone formation were compared between the two groups.At 1 year and 2 years postoperatively, gastric residue was more common in the RY group, gastritis was similar between groups, and bile reflux was more common in the B-I group. At 5 years postoperatively, gastric residue was similar between the groups, while gastritis and bile reflux were more common in the B-I group. Gastroesophageal reflux was more common in the B-I group at 1 year postoperatively, but gastroesophageal reflux became not significantly different between the groups at 2 and 5 years postoperatively. Gallstone formation was more common in the RY group and in patients aged ≥ 65 years.During long-term follow-up, RY reconstruction was associated with lower incidence of bile reflux and gastritis, and higher incidence of gallstone formation than B-I reconstruction. The incidence of gastric residue was more common in the RY reconstruction group in the early postoperative period and became not significantly different between the two groups over time. For aged patients with RY reconstruction, cholecystectomy is recommended concurrently as gastrectomy.

Background: Benign immunoglobulin G4 (IgG4)-related orbital disease (IgG4-ROD)&mdash, characterized as tumors mimicking malignant orbital lymphoma (OL)&mdash, responds well to steroids, instead of chemotherapy, radiotherapy and/or surgery of OL. The objective of this study was to report the differences in computed tomography (CT) features and- serum IgG4 levels of IgG4-ROD and OL. Methods: This study retrieved records for patients with OL and IgG4-ROD from a pathology database during an eight-year-and-five-month period. We assessed the differences between 16 OL patients with 27 lesions and nine IgG4-ROD patients with 20 lesions according to prebiopsy CT features of lesions and prebiopsy serum IgG4 levels and immunoglobulin G (IgG) levels This study also established the receiver-operating curves (ROC) of precontrast and postcontrast CT Hounsfield unit scales (CTHU), serum IgG4 levels, serum IgG levels and their ratios. Results: Significantly related to IgG4-ROD (all p &lt, 0.05) were the presence of lesions with regular borders, presence of multiple lesions&mdash, involving both lacrimal glands on CT scans&mdash, higher median values of postcontrast CTHU, postcontrast CTHU/precontrast CTHU ratios, serum IgG4 levels and serum IgG4/IgG level ratios. Compared to postcontrast CTHU, serum IgG4 levels had a larger area under the ROC curve (0.847 [95% confidence interval (CI): 0.674&ndash, 1.000, p = 0.005] vs. 0.766 [95% CI: 0.615&ndash, 0.917, p = 0.002]), higher sensitivity (0.889 [95% CI: 0.518&ndash, 0.997] vs. 0.75 [95% CI: 0.509&ndash, 0.913]), higher specificity (0.813 [95% CI: 0.544&ndash, 0.960] vs. 0.778 [95% CI: 0.578&ndash, 0.914]) and a higher cutoff value (&ge, 132.5 mg/dL [milligrams per deciliter] vs. &ge, 89.5). Conclusions: IgG4-ROD showed distinct CT features and elevated serum IgG4 (&ge, 132.5 mg/dL), which could help distinguish IgG4-ROD from OL.

Background: Epstein&ndash, Barr virus (EBV)-associated gastric cancer (GC) is one of four major gastric cancer types and is traditionally considered to be related to lymphoepithelioma-like GC. Few studies have investigated the clinical significance of EBV infection in intestinal/solid type, diffuse (poorly cohesive) type, and lymphoepithelioma-like GC. Methods: A total of 460 GC patients receiving curative surgery were enrolled. The clinicopathological features, genetic alterations and prognoses were compared between patients with and without EBV infection. Results: EBV-positive GC patients (n = 43) had more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like carcinoma, more lymphoid stroma, fewer Helicobacter pylori infections, and higher programmed death-ligand 1 (PD-L1) expression than EBV-negative GC patients. For intestinal/solid type GC, EBV-positive tumors were more likely to be located in the upper and middle stomach, have more lymphoid stroma, fewer Helicobacter pylori infections, higher PD-L1 expression, and more liver metastases than EBV-negative tumors. For diffuse (poorly cohesive) type GC, EBV-positive tumors were more likely to be located in the upper stomach, and have more lymphoid stroma than EBV-negative tumors. For lymphoepithelioma-like GC, EBV-positive tumors had more PI3K/AKT pathway mutations than EBV-negative tumors. Conclusions: Intestinal/solid type GC patients with EBV-positive tumors were associated with higher PD-L1 expression and more liver metastases, while lymphoepithelioma-like GC patients with EBV-positive tumors had more PI3K/AKT pathway mutations. Immunotherapy and targeted therapy may be beneficial for these groups of patients. Routine EBV survey is recommended in GC.

Background Helicobacter pylori (HP) can induce epithelial cells and intestinal metaplasia with genetic damage that makes them highly susceptible to the development of gastric cancer (GC). Materials and Methods Between 2005 and 2010, 356 patients with gastric cancer who received curative surgery were enrolled. Analysis of HP, Epstein-Barr virus (EBV) infection, PIK3CA amplification, and mutation analysis of 68 mutations in eight genes using a mass spectrometric single-nucleotide polymorphism genotyping technology was conducted. The clinicopathological characteristics of patients with or without HP infection were compared. Results Among the 356 patients, 185 (52.0%) had HP infection. For intestinal-type GC, patients with HP infection were more likely to be younger and had fewer PI3K/AKT pathway genetic mutations than those without HP infection. For diffuse-type GC, patients with HP infection were characterized by less male predominance, less lymphoid stroma, fewer microsatellite instability-high tumors, and fewer PI3K/AKT pathway genetic mutations than those without HP infection. Patients with HP infection had less tumor recurrence and a better 5-year overall survival (87.7% vs. 73.9%, p = .012) and disease-free survival (64.1% vs. 51.3%, p = .013) than those without HP infection, especially for intestinal-type GC. For EBV-negative GC, patients with HP infection had fewer PI3K/AKT pathway mutations and a better 5-year overall survival and disease-free survival than those without HP infection. Multivariate analysis demonstrated that HP infection was an independent prognostic factor regarding overall survival and disease-free survival. Conclusion Patients with GC with HP infection were associated with fewer PI3K/AKT pathway genetic mutations and better survival than those without HP infection, especially for EBV-negative and intestinal-type GC. Implications for Practice Patients with gastric cancer with Helicobacter pylori (HP) infection had fewer PI3K/AKT pathway genetic mutations, less tumor recurrence, and better survival than those without HP infection, especially for Epstein-Barr virus (EBV)-negative and intestinal-type gastric cancer. HP infection is an independent prognostic factor regarding overall survival and disease-free survival. Future in vivo and in vitro studies of the correlation among HP infection, PI3K/AKT pathway, and EBV infection in gastric cancer are required.

Objective: The tumor suppressor gene phosphatase and tensin homolog (PTEN) was reported to inhibit the growth and invasion of gastric cancer (GC) via the downregulation of focal adhesion kinase (FAK). To date, the clinical implication of PTEN and FAK expression in GC has not been well addressed. Methods: A total of 200 GC patients receiving curative surgery were enrolled. The clinicopathologic features according to the expression of PTEN and FAK protein using immunohistochemical staining were compared among patients. Results: Patients with high PTEN expression were more likely to have smaller tumor size, more well- and moderately differentiated tumors, a more superficial gross appearance, less scirrhous stromal reactions, more likely to have high FAK expression, and have less advanced pathologic tumor (T) category, node (N) category, and tumor, node, metastasis (TNM) stage and more distant metastases than patients with low PTEN expression. Multivariate analysis showed that PTEN/FAK expression status is an independent prognostic factor affecting overall survival (OS) and disease-free survival (DFS). Patients with PTEN(high)/FAK(low) had better OS and DFS, followed by those with PTEN(high)/FAK(high), those with PTEN(low)/FAK(low), and those with PTEN(low)/FAK(high) (OS: 83.3% versus 58.0% versus 46.2% versus 26.5%, respectively, P < 0.001; DFS: 83.3% versus 55.8% versus 30.8% versus 24.4%, respectively, P < 0.001). Conclusions: GC patients with high PTEN expression were more likely to have fewer tumor recurrences and a better prognosis than those with low PTEN expression. PTEN and FAK may have opposing effects on GC patient survival. Our results may have clinical impact on treatment of GC patients.

BACKGROUND Lymph node (LN) metastasis is one of the independent prognostic factors of gastric cancer (GC). The difference in survival rates and initial recurrence patterns in patients with node-positive GC with retrieved LN numbers greater than or less than 16 is worthy of further study. METHODS A total of 1314 patients with node-positive GC were enrolled. The clinicopathological characteristics, retrieved LN numbers, adjuvant chemotherapy, initial recurrence patterns, and survival differences between serosa-negative and serosa-positive GC were investigated. RESULTS For serosa-negative GC, patients with retrieved LN numbers ≥16 were associated with fewer tumor recurrences, locoregional recurrences, distant metastases, and better 5-year overall survival (OS) rates and disease-free survival (DFS) rates. For serosa-positive GC, patients with retrieved LN numbers ≥16 were associated with similar locoregional and distant metastasis and similar 5-year OS and DFS rates compared with those with retrieved LN numbers

Few reports have investigated different genetic alterations according to age in various cancers. In total, 1749 GC patients receiving curative surgery were enrolled. The clinicopathological features, and prognoses were compared between younger (

Background Caspase-3 acts as a major executioner protein in proteolytic degradation during apoptosis. The role of Caspase-3 in gastric cancer remains controversial. Methods A total of 366 gastric cancer patients who received curative surgery were enrolled. Caspase-3 expression in gastric tumors was examined by immunohistochemical staining. Correlations between Caspase-3 expression and the survival rates and between Caspase-3 expression and the clinicopathological parameters of the gastric cancer patients were analyzed. Results The 5-year overall survival rates of gastric cancer patients with and without Caspase-3 expression were 51.2% and 37.3%, respectively ( P = 0.030). The 5-year disease-free survival rates of gastric cancer patients with and without Caspase-3 expression were 49.2% and 34.6%, respectively ( P = 0.029). Analyses of the clinicopathological features showed that larger tumor size ( P = 0.030), more advanced Borrmann type ( P = 0.012), more aggressive stromal reaction ( P = 0.001), higher classification using Ming's infiltrating histology type ( P = 0.018), more lymph node involvement ( P = 0.019), and more lymphovascular involvement ( P = 0.045) were significantly correlated with a lack of Caspase-3 expression. The multivariate analysis showed that age ( P = 0.001), Borrmann classification ( P = 0.032), stromal reaction type ( P = 0.018), TNM pathological T category ( P = 0.002), TNM pathological N category ( P P = 0.041) were significantly correlated with the overall survival of gastric cancer patients. Conclusion Caspase-3 expression in gastric cancer patients is related to favorable clinicopathological features and a positive prognosis after curative surgery. Caspase-3 may act as a tumor suppressor in human gastric cancer.

Background: Although particular matter (PM) increases incidence and severity of idiopathic pulmonary fibrosis, the underlying mechanism remains elusive. Methods: The effects of PM were evaluated in a murine model of bleomycin-induced pulmonary fibrosis. Mice were divided into four groups, receiving: (1) Saline (control), (2) bleomycin, (3) PM, or (4) bleomycin plus PM (Bleo+PM). Additional groups of Bleo+PM mice were treated with sivelestat (an inhibitor of neutrophil elastase) or reparixin (a C-X-C motif chemokine receptor 2 antagonist), or were genetically modified with keratinocyte chemoattractant (KC) deletion. Results: Pulmonary fibrosis was not observed in the control or PM groups. Bleomycin induced pulmonary fibrosis within 14 days. The Bleo+PM group showed worse pulmonary fibrosis when compared to the bleomycin group. Analyses of immune cell profile and chemokine/cytokine concentrations at day 2-bronchoalveolar lavage fluid (BALF) revealed that the Bleo+PM group had increased neutrophil number and elastase level and KC concentration compared to the bleomycin group. Neutrophil elastase activated the Smad2/Smad3/&alpha, SMA pathway to induce collagen deposition, while sivelestat abrogated the increased severity of pulmonary fibrosis caused by PM. Chemotaxis assay revealed that BALF of the Bleo+PM group recruited neutrophil, which was dependent on KC. Further, genetic KC deletion or pharmaceutical inhibition of KC binding to CXCR2 with reparixin ameliorated the PM-induced increased severity of pulmonary fibrosis. Conclusions: These data provide evidence that the PM-induced increased severity of pulmonary fibrosis depends on KC-mediated neutrophil chemotaxis and give additional mechanic insight that will aid in the development of therapeutic strategies.

BACKGROUND Surgical resection offers an effective treatment for patients with hepatocellular carcinoma (HCC); however, it has high tumor recurrence rate. Clusterin is a highly conserved glycoprotein that enhances cell aggregation in vitro. It is upregulated in several types of cancers such as breast, ovarian, colon, prostate and kidney cancers and HCC. Clusterin overexpression is correlated with tumor metastasis. We evaluated the significance of clusterin expression levels in serum and resected tissues of patients with HCC. METHODS Serum, resected tumor tissue, and non-tumor tissue were collected from 140 patients with HCC undergoing hepatic resection. Serum clusterin levels were determined by enzyme-linked immunosorbent assay. Clusterin expression in resected tissue was evaluated by immunohistochemistry. Median follow-up time was 57.8 months. RESULTS Mean serum clusterin levels were found to be 130.0 ± 58.7 µg/mL (range, 10.1 µg/mL -366.6 µg/mL). Serum clusterin levels were independent of tumor stage and deterioration of liver function in patients. No significant difference was observed in the survival of patients with high (>130.0 ± 58.7 µg/mL) or low (≤130.0 ± 58.7 µg/mL) serum clusterin level. Clusterin was expressed in HCC tissues of 76 patients (54.3%) and non-tumor liver tissues of 53 patients (37.9%). No significant difference was observed in the survival of patients with positive or negative clusterin expression in HCC tissues. In non-tumor tissues, patients with positive clusterin expression were observed to have low post-operative disease-free survival rate (p = 0.001) compared to patients with negative clusterin expression. Multivariate analysis showed that tumor with macrovascular/microvascular invasion and clusterin expression in non-tumor tissues are independent prognostic factors following hepatic resection. CONCLUSION In HCC, clusterin expression in non-tumor tissue shows worse prognosis after hepatic resection. Clusterin can be a prognostic marker for patients with post-resection HCC.

Background Aberrant DNA methylation is involved in gastric carcinogenesis and may serve as a useful biomarker in the diagnosis and detection of gastric cancer (GC) recurrence. Results A total of 157 patients who received surgery for GC were enrolled in the present study. A genome-wide methylation analysis was performed in tumor and adjacent normal tissues for the discovery set of 16 GC patients; the top three hypermethylated CpG sites of DNA promoters were selected for validation in tissue and plasma samples for the validation set of 141 GC patients. The frequencies of the top three hypermethylated genes in available patient tissues (n = 141) and plasma samples (n = 106) were 41.8% and 38.7%, respectively, for ADAM19; 40.4% and 42.5%, respectively, for FLI1; and 56.7% and 50.9%, respectively, for MSC. In both tissue and plasma samples, FLI1 hypermethylation was associated with more advanced GC and liver and distant lymphatic metastasis, and ADAM19 hypermethylation was associated with more stage IV GC. In plasma samples, MSC hypermethylation was more common in non-superficial type GC than samples without MSC hypermethylation. In both tissue and plasma samples, patients with methylation of all the three genes had significantly more liver metastases, distant lymphatic metastases, and paraaortic lymph node metastases than patients with two or fewer hypermethylated genes. The survival analysis showed that only for stage III GC, patients with hypermethylation of two or three genes had a worse 5-year disease-free survival rate than those with hypermethylation of one or none of the three genes. Subgroup analysis showed that FLI1 hypermethylation in both tissue and plasma samples was associated with liver metastasis in MSI−/EBV− GC, and MSC hypermethylation in tissue samples was correlated with liver metastasis in MSI+ or EBV+ GC. Patients with FLI1 hypermethylation in plasma samples had a significantly worse 5-year disease-free survival rate than those without FLI1 hypermethylation in MSI−/EBV− GC. FLI1 hypermethylation was an independent prognostic factor affecting the overall survival and disease-free survival in both tissue and plasma samples. Conclusions DNA methylation is a useful biomarker for predicting tumor recurrence patterns and GC patient survival.

Aim. To determine the incidence, prognosis, and immunophenotypes (CK7, CK20, CDX2, and GCDFP-15) of primary or secondary perianal Paget’s diseases (PPDs). Methods. Twenty-three PPD patients were recruited, including 10 primary and 13 secondary PPDs. Immunophenotypes of PPD were analyzed. Results. In 23 PPD patients, 14 (60.9%) were male and the median age was 75 years. Three (13.0%, 2 primary and 1 secondary PPDs) had recurrence and two (8.7%, both primary PPDs) had invasive PPDs. The colorectal cancers (CRCs) in secondary PPD cases were located in anorectal area for 9 patients while 4 were located in the rectum; 5, 2, 4, and 2 were in stages I, II, III, and in uncertain stage, respectively. The distant metastasis rates of CRC in the secondary PPD patients during follow-up were 40% (2/5), 0% (0/2), and 50% (2/4) for stages I, II, and III, respectively. Other synchronous or metachronous malignancies included cholangiocarcinoma, urothelial carcinoma, anorectal small-cell carcinoma, and unknown hepatic malignancy. One primary PPD patient died from the metastases of invasive Paget’s disease while 3 secondary PPD patients died from the metastases of CRCs during follow-up. Immunohistochemical staining showed CK7 (7/10 and 6/13), CK20 (6/10 and 10/13), CDX2 (6/10 and 12/13), and GCDFP-15 (3/10 and 0/13) positivities in primary and secondary PPD patients, respectively. The immunophenotypes were not statistical significantly related to synchronous CRC (P=0.402, 0.650, 0.127, and 0.068 for CK7, CK20, CDX2, and GCDFP-15, respectively). Conclusions. The incidence of concurrent CRC in PPD patients is not low. An adequate survey for CRC should be considered for PPD patients at initial diagnosis. In this series of study, stage I CRC with PPD would have a higher metastatic rate, thus indicating aggressive treatment and follow-up. The CK7, CK20, CDX2, and GCDFP-15 immunostaining results for the PPD patients were not predictive of primary or secondary type.

Laparoscopic surgery has become increasingly popular in the management of gastric gastrointestinal stromal tumors (GISTs) in recent years. One hundred and forty-five patients underwent curative resections of primary gastric stromal tumors between September 2002 and March 2012 were assigned to either an open surgery group (n = 99) or a laparoscopic surgery group (n = 46). In the open surgery group, there was a significantly higher number of samples with a mitotic index ≥ 10 (16.1% vs. 0%), more tumors located in the gastric cardia (13.1% vs. 6.5%), greater operative blood loss (80 mL vs. 50 mL) and a longer postoperative hospital stay (10 days vs. 6 days) than in the laparoscopic group. The surgical morbidity and mortality were 6.1% and 0% in the open group, whereas no complication or mortality in the laparoscopic group. Ten patients in the open group had tumor recurrences and no recurrence in the laparoscopic group. Multivariate analysis showed that tumor size and mitotic index were two independent risk factors associated with tumor recurrence. The 3-year disease-free survival rates and 5-year overall survival rates were similar between the two groups. The laparoscopic approach is a safe alternative procedure for gastric GISTs.

Robot-assisted gastrectomy has been reported to be a safe alternative to both conventional laparoscopy and the open approach for treating early gastric carcinoma. Currently, there are a limited number of published reports on this technique in the literature. We assessed the current status of robotic and laparoscopic surgery in the treatment of gastric cancer and compared the operative outcomes, learning curves, and oncological outcome of the two approaches. Robotic gastrectomy offers benefits that include increased ease of performing D2 lymph node dissection and reduced blood loss compared with laparoscopic gastrectomy. However, the operative time is longer, and robotic gastrectomy is more costly for the patients. Regarding to the operative and oncological outcomes, there appears to be no significant differences between laparoscopic and robotic gastrectomies after the surgeon overcomes the associated learning curves. Sharing the available knowledge regarding laparoscopic and robotic gastrectomies could shorten these learning curves. For elder patients, minimally invasive surgery that decreases the postoperative recovery time should be considered the preferred treatment. Prospective randomized studies are required to compare the surgical and oncological outcomes among laparoscopic, robotic, and open surgeries for both early and advanced gastric cancer.