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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

This study aimed to evaluate the protein expression of glutathione peroxidase 4 (GPX4) in resected non-small cell lung cancer (NSCLC). The clinical relevance and prognostic significance of GPX4 expression were analyzed. We reviewed patients with resected NSCLCs at Taipei Veterans General Hospital between September 2002 and January 2018. Available paraffin-embedded specimens were retrieved for immunohistochemistry (IHC) staining to detect GPX4 expression. The cutoff value for defining GPX4 positivity was determined according to the percentage of tumor stained in the microscopic field. The correlation between immune expression, clinicopathologic data, overall survival (OS), and disease-free survival (DFS) were analyzed. A total of 265 NSCLC specimens were retrieved for IHC staining. GPX4 expression positive was in 192 (72.5%) according to a cutoff value of 5%. GPX4 was a significant prognostic factor for OS and DFS on multivariate analysis at both 5% and 25% cutoff values. GPX4 expression was associated with poor OS and DFS, especially in lung adenocarcinoma (p = 0.008, and 0.027, respectively). In conclusions, IHC analysis revealed that GPX4 expression was associated with poor survival outcomes in patients with resected lung adenocarcinoma. Further research is needed to understand the role of GPX4 in tumorigenesis and the underlying mechanism responsible for survival outcomes in patients with resected lung adenocarcinoma.

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.

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma.

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.

Background: ARID1A is a key component of the SWI/SNF chromatin remodeling complex, which has been identified in various cancers. Loss of ARID1A expression is correlated with poor prognosis in gastric cancer (GC); however, the clinical relevance of ARID1A mutations in GC has not yet been reported. Materials and Methods: A total of 518 GC patients receiving gastrectomy were enrolled. The analysis of 13 mutations of the ARID1A gene using mass spectrometric single-nucleotide polymorphism genotyping technology was conducted. The clinicopathological features of GC with and without ARID1A mutations were compared. Results: Among the 518 GC patients, 59 (11.4%) had ARID1A mutations. For diffuse-type GC, patients with ARID1A-mutated tumors were older and had fewer poorly differentiated tumors, fewer incidence of Epstein–Barr virus infection, a higher likelihood of ARID1A expression loss, more microsatellite instability-high tumors, a lower prevalence of peritoneal recurrence, and better survival rates than those with ARID1A nonmutant tumors. For intestinal-type GC, patients with ARID1A-mutant tumors had more PI3K/AKT pathway genetic mutations than patients with ARID1A nonmutant tumors. Multivariate analysis showed that ARID1A mutations are an independent prognostic factor in diffuse-type GC. Conclusion: ARID1A mutations are associated with a better prognosis in diffuse-type GC.

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.

BackgroundTo date, few reports have investigated genetic alterations and clinicopathological features in cardia and noncardia gastric cancer (GC).MethodsIn total, 435 GC patients receiving curative surgery were included. The clinicopathological features, recurrence patterns, prognoses and genetic alterations were compared between cardia and noncardia GC patients.ResultsAmong the 435 enrolled patients, 47 (10.8%) had cardia GC. Compared with noncardia GC, cardia GC was associated with more intestinal-type tumors and similar initial recurrence patterns and 5-year overall survival (OS; 50.8% vs. 50.5%, P = 0.480) and disease-free survival (DFS; 48.6% vs. 48.9%, P = 0.392) rates. For both intestinal-type GC and diffuse-type GC, the clinicopathological features and 5-year OS and DFS rates were not significantly different between the cardia and noncardia GC patients. Multivariable analysis showed that cardia GC was not an independent prognostic factor. Compared with noncardia GC, cardia GC was associated with increased PIK3CA amplification than in patients with intestinal-type GC and was associated with increased HER2 expression in patients with diffuse-type GC.ConclusionsCardia GC is not an independent prognostic factor. In cardia GC patients with intestinal-type GC, PIK3CA amplification was more common, and in those with diffuse-type GC, HER2 expression was more common. Targeted therapy may be beneficial for these patient subgroups.

Background Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. Results In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. Conclusions These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.

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.

Background: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. Methods: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. Results: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown&ndash, induced cell migration and invasion of gastric cancer cells. Conclusions: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.

Rationale Paragangliomas (PGLs) are rare neuroendocrine tumors that are strongly influenced by genetics, and succinate dehydrogenase-deficient PGLs appear to constitute one of the most important categories. Interestingly, somatic PGLs only possess genomic alterations involving the SDHB and SDHD subunits, and no SDHA alterations have been described. Here, we are presenting the clinical and genetic analyses of 2 cases with the first somatic SDHA variant identified in PGLs. Patient concerns Here, we reported 2 family members with the diagnosis of PGL. Patient 1 is a 55-year-old woman with a functionally perigastric PGL that co-occurred with a gastric gastrointestinal stromal tumor (GIST), and patient 2 is a 43-year-old woman with a nonfunctionally pericardial PGL, who was the younger sister of the first patient. Diagnoses Imaging surveys of the 2 cases depicted the presence of a perigastric and a pericardial mass, respectively. A diagnosis of paragangliomas was established by immunohistochemistry (IHC). Interventions Both patients underwent single-stage resection of the lesion after preoperative oral α-adrenoceptor therapy for 2 weeks. We later performed comprehensive genomic profiling on the tumor samples, including PGL and GIST from patient 1 and PGL from patient 2, and searched for novel actionable mutations, including in all succinate dehydrogenase subunits, as the IHC results were negative for SDHB. Outcomes Both patients had an uneventful recovery after surgery and the sequencing showed a novel somatic variant in the SDHA gene on chromosome 5q11 (c.1945_1946delTT). Regular follow-up with biochemical testing and image studies showed no evidence of recurrence after a year for patient 1 and 6 years for patient 2. Lessons PGLs often lead to considerable diagnostic difficulty due to their multiple anatomical locations and variable symptoms, as presented by our cases. The comprehensive use of images and plasma/urine catecholamine measurement can aid the diagnosis of PGLs. In addition, our findings also demonstrate the usefulness and importance of genetic analysis of SDHA mutations in patients exhibiting SDHB IHC-negative PGL. Additional studies utilizing comprehensive genomic profiling are needed to identify the group of PGLs harboring this SDHA genomic alteration.

Signet-ring cell carcinoma (SRC) in advanced gastric cancer (GC) is often associated with more invasiveness and a worse prognosis than other cell types. The genetic alterations associated with gastric carcinogenesis in SRC are still unclear. In this study, 441 GC patients receiving curative surgery for GC between 2005 and 2013 were enrolled. The clinicopathological characteristics and genetic alterations of GC patients with and without SRC were compared. Among the 441 GC patients, 181 had SRC. For early GC, patients with SRC had more tumors located in the middle and lower stomach, more infiltrating tumors and better overall survival (OS) rates than those without SRC. For advanced GC, patients with SRC had more scirrhous type tumors, more PIK3CA amplifications, fewer microsatellite instability-high (MSI-H) tumors, more peritoneal recurrences and worse 5-year OS rates than those without SRC. For advanced GC with SRC, patients with peritoneal recurrence tended to have PD-L1 expression. For advanced GC without SRC, patients with liver metastasis tended to have PD-L1 expression, PI3K/AKT pathway mutations, TP53 mutations and MSI-H tumors. For advanced GC, PD-L1 expression was associated with peritoneal recurrence in SRC tumors, while non-SRC tumors with liver metastasis were likely to have PI3K/AKT pathway mutations, TP53 mutations and PD-L1 expression, immunotherapy and targeted therapy may be beneficial for these patients.

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.

Even with the advance of diagnosis and the treatment, the 5-year survival rate for esophageal cancer patients is still poor. The checkpoint protein inhibition provides another choice to improve the survival. The expression of the programmed death ligand-1 (PD-L1) was reported but the clinical relevance remained inconsistent in esophageal cancer. Besides, there were few references about the other ligand, programed death ligand-2 (PD-L2). In this study, we evaluated the expressions of PD-L1 and PD-L2 in patients with esophageal squamous cell carcinoma (ESCC) and assessed their clinical relevance.From 1996 to 2011, 150 patients undergone complete surgical resection for ESCC were enrolled. Clinical data were recorded. Expression of PD-L1 and PD-L2 on cytoplasm in paraffin embedded tumor samples were analyzed by immunohistochemistry staining and scored with a semi-quantitative method.Of the patients, 96 (64.0%) patients had PD-L1 overexpression and 63 (42.0%) had PD-L2 overexpression. There was a correlation between the expression of PD-L1 and PD-L2 (P0.001). Patients without overexpression of PD-L1, pathological T1-2 and N0 status, pathological stage I-II and no post-operative adjuvant treatment had a better disease free survival (DFS). In multivariate analysis, PD-L1 expression and pathological stage were the independent prognostic factors for DFS. The expression of PD-L2 did not influence the DFS. Although not statistically significant, patients without overexpression of PD-L1 and PD-L2 seem to have a better overall survival (OS).The overexpression of PD-L1 on cytoplasm, not PD-L2, is an independent prognostic factor for DFS in patients with ESCC undergone esophagectomy. However, there is a trend which suggested that patients without overexpression of PD-L1 and PD-L2 had a better OS.

In recent decades, research concerning gastric carcinogenesis has rapidly progressed. It is evident that hepatocyte growth factor (HGF) is clinically related to gastric cancer progression and metastasis. In addition, previous studies have found that expression of Notch ligand Jagged1 is correlated with the poor prognosis of gastric cancer. However, the interaction between the HGF/c-Met and Notch1 signaling pathways remains unknown. In the present study, we found that gastric cancer patients with positive c-Met expression exhibited poorer overall survival than patients without c-Met expression (P=0.043) and that Jagged1 expression was significantly correlated with c-Met expression (r=0.301; P=0.004) in human gastric cancer specimens. In addition, Jagged1 activity increased after HGF stimulation, which in turn increased the downstream expression of cyclooxygenase 2 (COX-2) in a time-dependent manner. After knockdown of Notch1 intracellular domain (N1IC), HGF was found to increase the proliferation and migration ability in human gastric cancer cells. However, overexpression of N1IC still had no effect after HGF stimulation. Our study found a feedback loop between HGF/c-Met and Jagged1/Notch1 signaling. Furthermore, both HGF/c-Met and Notch1 signaling triggered COX-2 activity. These results suggest that gastric cancer progression is not associated with a unique signaling pathway and that a feedback loop may exist between the HGF/c-Met and Notch1 signaling pathways, which may result in therapeutic resistance. Therefore, multi-modality therapies should be considered for treating gastric cancer.

Objective The purpose of this study was to determine clinical and ultrasonographic characteristics of male breast tumors. Methods The medical records of male patients with breast lesions were retrieved from an electronic medical record database and a pathology database and retrospectively reviewed. A total of 112 men (125 breast masses) with preoperative breast ultrasonography (US) were included (median age, 59.50 years; age range, 15–96 years). Data extracted included patient age, if the lesions were bilateral, palpable, and tender, and the presence of nipple discharge. Breast lesion features on static US images were reviewed by three experienced radiologists without knowledge of physical examination or pathology results, original breast US image interpretations, or surgical outcomes. The US features were documented according to the BI-RADS (Breast Imaging-Reporting and Data System) US lexicons. A forth radiologist compiled the data for analysis. Results Of the 125 breast masses, palpable tender lumps and bilateral synchronous masses were more likely to be benign than malignant (both, 100% vs 0%, P < 0.05). Advanced age and bloody discharge from nipples were common in malignant lesions (P

With the progression of molecular techniques, the detection of circulating plasma DNA (cpDNA) is clinically feasible. However, the role of the cpDNA levels in gastric cancer is not well understood. This study assessed the mutational profile in primary tumors and clarified the clinical utility of quantitative and qualitative cpDNA alterations in 277 patients with advanced gastric cancer. The concentrations of cpDNA were measured by TaqMan qPCR, and 68 mutations in 8 genes were studied for cpDNA mutations. The median cpDNA concentrations in patients with stages I, II, and III gastric cancer were 3979, 3390 and 4278 copies/mL, respectively, and increased to 11,380 copies/mL in patients with Stage IV gastric cancer (p < 0.001). Among the 35 patients harboring cpDNA mutations, Stage IV patients (100%) were more likely to display high cpDNA levels than were Stage I (33.3%), II (75%) and III patients (66.7%) (p = 0.037). Patients displaying high cpDNA levels were more likely to experience peritoneal recurrence and exhibited significantly lower 5-year overall survival rates (39.2% vs. 45.8%, p = 0.039) than did patients displaying low cpDNA levels. Only for late stage (Stages III or IV) gastric cancer, patients harboring cpDNA mutations were more likely to experience vascular invasion (20% vs. 2.4%, p = 0.036) and exhibited a lower 5-year overall survival rate than did those lacking cpDNA mutations (5.6% vs. 31.5%, p = 0.028). High cpDNA levels are associated with peritoneal recurrence and poor prognosis in patients with advanced gastric cancer; harboring cpDNA mutations is associated with poor prognosis among patients with late stage gastric cancer.

// Wen-Liang Fang 1, 2 , Kuo-Hung Huang 1, 2, 3 , Yuan-Tzu Lan 2, 4 , Chien-Hsing Lin 5 , Shih-Ching Chang 2, 4, * , Ming-Huang Chen 2, 6 , Yee Chao 2, 6 , Wen-Chang Lin 7, 8 , Su-Shun Lo 2, 9 , Anna Fen-Yau Li 2, 10 , Chew-Wun Wu 1, 2 , Shih-Hwa Chiou 3, 11, 12 , Yi-Ming Shyr 1, 2, * 1 Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan 2 School of Medicine, National Yang-Ming University, Taipei City, Taiwan 3 Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei City, Taiwan 4 Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan 5 Genome Research Center, National Yang-Ming University, Taipei City, Taiwan 6 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 7 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 8 Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan 9 National Yang-Ming University Hospital, Yilan City, Taiwan 10 Department of Pathology, Taipei Veterans General Hospital, Taipei City, Taiwan 11 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei City, Taiwan 12 Institute of Pharmacology, National Yang-Ming University, Taipei City, Taiwan * These authors have contributed equally to this work Correspondence to: Shih-Ching Chang, e-mail: changsc@vghtpe.gov.tw Yi-Ming Shyr, e-mail: ymshyr@vghtpe.gov.tw Keywords: PI3K/AKT pathway, PIK3CA amplifications, recurrence pattern, diffuse-type, prognosis Received: August 08, 2015 Accepted: December 05, 2015 Published: December 17, 2015 ABSTRACT Mutations in genes involved in the PI3K/AKT pathway and amplifications of the PIK3CA gene in gastric cancer and their associations with clinicopathological characteristics and EBV infection were analyzed in this study. A total of 431 patients with gastric adenocarcinomas were enrolled, and 39 mutation hotspots were evaluated in these patients using MALDI-TOF mass spectrometry were analyzed. PIK3CA amplifications were analyzed using real-time quantitative PCR. Regarding patients with intestinal-type gastric cancer, those with mutations in PI3K/AKT pathway genes were also more likely to have tumors located in the lower-third of the stomach than were those without mutations. Regarding patients with diffuse-type gastric cancer, those with PI3K/AKT pathway mutations were more likely to have tumors located in the upper-third of the stomach and to have more hematogenous metastases, particularly in the liver and lungs, than were patients without such mutations (22.2% vs. 4.5%). No significant survival difference was observed between patients with vs. without PI3K/AKT pathway mutations. Mutations in PI3K/AKT pathway genes were associated with hematogenous metastasis in patients with diffuse-type gastric cancer. Only when the tumors were located in the middle-third of stomach, tumor with mutations of the PIK3CA gene or mutations of the PI3K/AKT pathway genes were associated with more EBV infection than those without mutations. Patients with PIK3CA amplifications were more likely to have diffuse-type and poorly differentiated gastric cancers and were more likely to experience peritoneal recurrence compared with those without PIK3CA amplifications. Even upon subgroup analysis, PI3KCA amplifications were found to not affect the patients’ outcomes.

Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is an effective alternative treatment for early gastric cancer. However, a major concern is the likelihood of lymph node metastasis. From December 1987 to December 2006, 391 patients who underwent curative surgery for gastric cancer with mucosal (T1a, n = 265) or submucosal (T1b, n = 126) invasion and a retrieved lymph node number ≧ 15 were enrolled. The frequency and risk factors of lymph node metastasis were analyzed. The frequency of lymph node metastasis was 4.9 % in T1a lesions and 21.4 % in T1b lesions. Although the depth of submucosal tumor invasion was2 mm, there was a 28.6 % chance of lymph node metastasis. A T1b lesion, i.e., the width of the submucosal tumor invasion was5 mm, resulted in fewer lymph node metastases than lesions5 mm in width. Multivariate analysis demonstrated that Lauren's diffuse type and lymphatic invasion were independent risk factors for lymph node metastasis in T1a lesions, while lymphatic invasion was the strongest risk factor for lymph node metastasis in T1b lesions. EMR/ESD is a good alternative for T1a intestinal type adenocarcinoma without lymphatic invasion. Surgical resection is necessary for patients with T1b gastric cancer with lymphatic invasion.

Signet ring cell adenocarcinoma is a histological classification based on the WHO classification. The presence of this specific histological type is associated with a worse pathological appearance. The prognosis of signet ring cell adenocarcinoma in gastric cancer patients after curative surgery is still under debate. From January 1988 to December 2012, a total of 2971 patients, including 819 early and 2152 advanced gastric cancer patients underwent curative resection for gastric cancer. Among them, there were 185 cases of signet ring cell adenocarcinoma in early gastric cancer patients, while there were 570 cases in advanced gastric cancer patients. The overall incidence of signet ring cell adenocarcinoma was 25.4%. Our results showed that the 5-year overall survival rates of early gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 90.7 and 83.2%, respectively (P = 0.001). The 5-year disease-free survival rates of early gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 87.4 and 81.6%, respectively (P = 0.003). The 5-year overall survival rates of advanced gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 32.1 and 37.9%, respectively (P = 0.041). The 5-year disease-free survival rates of advanced gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 28.6 and 35.2%, respectively (P = 0.037). Signet ring cell adenocarcinoma was an independent predictor for overall survival in advanced gastric cancer (P = 0.017). The clinical features and prognosis of signet ring cell adenocarcinoma are different between early and advanced gastric cancer. Signet ring cell adenocarcinoma is a poor prognostic factor in advanced gastric cancer after curative resection.

Adenosquamous carcinoma of the stomach is a very rare disease, consisting of less than 0.4 % of all stomach cancer. From 1991 to 2013, a total of 2800 patients received gastrectomy for gastric cancer at Taipei Veterans General hospital. Among them, seven patients (0.25 %) diagnosed as adenosquamous carcinoma were enrolled. The clinicopathologic characteristics and prognosis were analyzed. The mean age of the seven patients was 62.3 years-old. There were 5 males and 2 females. Six patients were stage III disease and one patient was stage IV disease. Four patients finally died of gastric cancer. Only one patient had no recurrence until death. Among the seven patients, adenocarcinoma component comprises the majority of the metastatic lymph node in 6 patients (85.7 %). The only one patient with major squamous cell carcinoma component in metastatic lymph node had no tumor recurrence till death. Adenosquamous carcinoma of stomach is a rare disease and is associated with a poor prognosis. The component of adenocarcinoma and squamous cell carcinoma in the metastatic lymph node may influence the prognosis.