Sho Otsuki

Vimentin expression is associated with decreased survival in gastric cancer.

Gastric cancer rich in stromal tissue, such as diffuse-type disease, carries a poor prognosis. In some cancers, expression of vimentin, a mesenchymal maker, is associated with poor survival. The expression of mesenchymal markers such as vimentin is observed after epithelial-mesenchymal transition (EMT), an important initial behavioral change related to the adhesion and migration properties of tumor cells that is required for local tumor invasion. A hallmark of EMT is the loss of E-cadherin. EMT-inducing regulators, including SIP1, Slug, and Twist, repress E-cadherin transcription by interacting with E-cadherin promoter. We investigated the expression of vimentin and EMT-related genes, including SIP1, Slug, and Twist, in frozen cancer tissues and normal tissues by real-time quantitative reverse-transcriptase polymerase chain reaction. Tumor samples were obtained from 106 patients with gastric adenocarcinomas who underwent a gastrectomy. The relation of the expression of these genes to clinicopathological factors and outcomes was studied. Vimentin mRNA was significantly higher in diffuse type compared to intestinal type according to Laurens classification (p=0.048) and was significantly elevated in patients with recurrent or distant metastatic disease (p=0.049). Immunohistochemically, however, vimentin was detected only in cancer stroma. Twist mRNA expression significantly correlated with tumor depth (p=0.042) and advanced tumor stage (I-II vs. III-IV, p=0.030). E-cadherin immunohistochemical expression was significantly associated with Laurens histopathological type (p<0.001). Univariate analysis of relapse-free survival showed that tumor depth, lymph node metastasis, Laurens histopathological type, and vimentin mRNA expression were significant prognostic factors (p<0.001, p=0.013, p=0.011, and p=0.019). On multivariate analysis, vimentin mRNA expression was an independent prognostic factor [hazard ratio (HR)=2.1; 95% confidence interval (CI), 1.0-4.4; p=0.036], coming after tumor depth (HR=9.7; 95%CI, 3.7-24; p<0.001). Vimentin mRNA expression is associated with recurrence or distant metastasis and decreased survival in gastric cancer.

Therapeutic Targeting of Fibroblast Growth Factor Receptors in Gastric Cancer

Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2) have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR) play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs), including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.

Clinical significance of MET in gastric cancer

Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC. Hepatocyte growth factor and its receptor, c-MET (MET), play key roles in tumor growth through activated signaling pathways from receptor in GC cells. Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC. Preclinical studies in animal models have shown that MET antibodies or small-molecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells. These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC.

Impact of comorbidities on postoperative complications in patients undergoing laparoscopy-assisted gastrectomy for gastric cancer.

BackgroundComorbidity is a predictor of postoperative complications (PCs) in gastrectomy. However, it remains unclear which comorbidities are predictors of PCs in patients who undergo laparoscopy-assisted gastrectomy (LAG). Clinically, insufficient lymphadenectomy (LND) is sometimes performed in high-risk patients, although the impact on PCs and outcomes remains unclear.MethodsWe retrospectively studied 529 patients with gastric cancer (GC) who underwent LAG. PCs were defined as grade 2 or higher events according to the Clavien-Dindo classification. We evaluated various comorbidities as risk factors for PCs and examined the impact of insufficient LND on PCs in patients with risky comorbidities.ResultA total of 87 (16.4%) patients had PCs. There was no PC-related death. On univariate analysis, heart disease, central nervous system (CNS) disease, liver disease, renal dysfunction, and restrictive pulmonary dysfunction were significantly associated with PCs. Both liver disease and heart disease were significant independent risk factors for PCs on multivariate analysis (odds ratio [OR] = 3.25, p = 0.022; OR = 2.36, p = 0.017, respectively). In patients with one or more risky comorbidity, insufficient LND did not significantly decrease PCs (p = 0.42) or shorten GC-specific survival (p = 0.25).ConclusionIn patients who undergo LAG for GC, the presence of heart disease or liver disease is an independent risk factor for PC. Insufficient LND (for example, D1+ for advanced GC) might be permissible in high-risk patients, because although it did not reduce PCs, it had no negative impact on GC-specific survival.

TPX2 expression is associated with poor survival in gastric cancer

BackgroundTargeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein required for microtubule formation in human cells. Several studies have demonstrated that TPX2 is overexpressed in multiple tumor types and promotes tumor growth and metastasis. However, there have been few reports regarding its role in gastric cancer. In this study, we evaluated TPX2 expression and investigated its correlations with gastric cancer clinicopathological features and prognosis.MethodsTumor samples were obtained from 290 patients with gastric adenocarcinoma who had undergone gastrectomy. The expression of TPX2 protein was examined using immunohistochemical staining. TPX2 messenger RNA (mRNA) levels were evaluated using real-time quantitative reverse transcription PCR in 19 of the gastric cancer tumors and adjacent normal tissues.ResultsThe mRNA levels of TPX2 were significantly higher in gastric cancer tissues than in matched adjacent normal tissues (p = 0.004). In the immunohistochemical analysis, TPX2 overexpression was found in 123 (42.4%) of 290 patients. High TPX2 expression was positively associated with age, type of histology, depth of tumor, lymph node metastasis, stage, and remote metastasis or recurrence. High TPX2 expression was significantly associated with poorer disease-specific survival (p = 0.004) and relapse-free interval (p = 0.013).ConclusionsOur results indicated that high TPX2 expression was associated with tumor progression and poor survival in gastric cancer.

Prognostic significance of PAK4 expression in gastric cancer

Aims p-21 activated kinase (PAK) 4, part of the six PAK families, plays an important role in growth factor signalling, cytoskeletal remodelling, gene transcription, cell proliferation and oncogenic transformation. However, the clinical significance of PAK4 in gastric cancer has yet to be fully elucidated. PAK4 expression was evaluated, and the correlations of PAK4 expression with clinicopathological features and outcomes in gastric cancer were examined. Methods Gastric adenocarcinomas obtained from 217 patients who underwent gastrectomy were analysed. PAK4 expression was evaluated using immunohistochemical staining. Results PAK4 overexpression was found in 95 (43.8%) of 217 tumours . High PAK4 expression was significantly correlated with clinicopathological variables related to tumour progression, including depth of invasion, metastatic lymph nodes, pathological stage, distant metastasis or recurrent disease. High PAK4 expression was significantly associated with poorer disease-specific survival (DSS) (p<0.001) and relapse-free survival (RFS) (p<0.001). On multivariable analysis, PAK4 was an independent prognostic factor for DSS (HR 2.5 (95% CI 1.4 to 4.7), p=0.003) and RFS (HR 2.8 (95% CI 1.4 to 5.6), p=0.004). Even in stage II and III disease, PAK4 was an independent prognostic factor for RFS (HR 2.2 (95% CI 1.1 to 4.5), p=0.029). Conclusions PAK4 may become a new prognostic factor in patients with gastric cancer.

Relationship between expression of IGFBP7 and clinicopathological variables in gastric cancer

Aims Insulin-like growth factor binding protein 7 (IGFBP7) is reported to have tumour suppressor function through an IGF-dependent pathway in various malignant tumours. However, the expression of IGFBP7 in adenocarcinoma and its relationship with tumour progression and survival differs among studies. Our aims were to investigate the relationship between the expression of IGFBP7 and clinicopathological variables and outcomes of patients with gastric cancer. Methods Tumour samples were obtained from 219 patients with gastric cancer who underwent gastrectomy. The expression of IGFBP7 protein was examined by immunohistochemical staining. IGFBP7 mRNA levels were analysed using real-time quantitative reverse-transcriptase PCR in 24 of the gastric cancer tumours and in adjacent non-tumour tissues. Correlation of IGFBP7 expression with clinicopathological features was analysed. Results The protein expression of IGFBP7 was positively correlated with depth of invasion, lymph node metastasis, distant metastasis or recurrence and pathological stage. High expression of IGFBP7 protein was associated with a significantly worse disease-specific survival (p<0.001) and was an independent prognostic factor in multivariable analysis (HR, 4.8; 95% CI 2.1 to 10.6; p<0.001). The IGFBP7 mRNA level was significantly higher in advanced gastric cancer than in early gastric cancer, in tumours with lymph node metastasis than in tumours without lymph node metastasis, and in tumours with distant metastasis or recurrence than in tumours without distant metastasis or recurrence. Conclusions Overexpression of IGFBP7 was associated with tumour progression and poor survival in gastric cancer. IGFBP7 may play a role in tumour progression in gastric cancer.

Different clinical significance of FGFR1–4 expression between diffuse-type and intestinal-type gastric cancer

BackgroundReceptor tyrosine kinases promote tumor progression in many cancers, although oncologic activation differs between diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC). Fibroblast growth factor receptor (FGFR) is one RTK, and we previously reported the clinical significance of FGFR1, 2, 3, and 4 in gastric cancer. The aim of the present study was to reevaluate the clinical significance of FGFR1–4 expression separately in DGC and IGC.MethodsTumor samples, including 109 DGCs and 100 IGCs, were obtained from patients who underwent gastrectomy between 2003 and 2007 in our institution. The expression levels of FGFR1, 2, 3, and 4 were measured in the tumors by immunohistochemical analysis.ResultsIn DGC, high expression of FGFR1, FGFR2, or FGFR4 was significantly associated with the depth of invasion, lymph-node metastasis, pathological stage, and distant metastasis or recurrent disease. Patients with high expression of FGFR1, FGFR2, or FGFR4 had significantly poorer disease-specific survival (DSS) (p = 0.009, p = 0.001, and p = 0.023, respectively). In IGC, only FGFR4 expression was significantly associated with factors relative to tumor progression and with shorter DSS (p = 0.012).ConclusionIn conclusion, high FGFR4 expression correlated with tumor progression and survival in both DGC and IGC, whereas high expression of FGFR1 and 2 correlated with tumor progression and survival in only DGC.

Assessment of Serum Copper State after Gastrectomy with Roux-en-Y Reconstruction for Gastric Cancer

Background: Some recent reports have noted that copper deficiency can occur in obese patients who have undergone bariatric surgery, such as Roux-en-Y (RY) gastric bypass or biliopancreatic diversion, or in patients who receive enteral nutrition through a jejunostomy. No reports appear to have assessed the serum copper state of patients following gastrectomy with RY reconstruction for gastric cancer. Methods: A cross-sectional study was conducted from June 2013 to December 2014. Serum copper levels (SCLs) in 242 out-clinic patients who underwent curative gastrectomy were obtained. Patients were classified into an RY group (n = 208) and a non-RY group (n = 34). Results: Hypocupremia was identified in 3 patients in the RY group (1.4%), and 2 patients in the non-RY group (5.9%; p = 0.146), but none experienced any symptoms caused by hypocupremia. No significant difference in the mean SCL was seen between the RY group (105.8 ± 21.2 µg/dl) and non-RY group (107.9 ± 22.7 µg/dl; p = 0.499). In the RY group, the mean SCL was significantly lower in younger patients, patients with follow-up period <3 years, and male patients. Conclusion: Some patients developed hypocupremia after gastrectomy with RY reconstruction, but the number is acceptably low, and physical symptoms were unusual.

Long-Term Effectiveness of Preserved Celiac Branch of Vagal Nerve After Roux-en-Y Reconstruction in Laparoscopy-Assisted Distal Gastrectomy

Background: The aim of this retrospective cohort study was to clarify the effectiveness of preserving the celiac branch (CB) of the vagal trunk after the Roux-en-Y (R-Y) reconstruction in laparoscopy-assisted distal gastrectomy (LADG). Methods: One hundred twenty patients with pathological stage I gastric cancer underwent R-Y reconstruction after LADG with D1 + F lymphadenectomy between January 2004 and March 2009 and were followed up for 5 years. The patients were divided into 2 groups: the preservation group (P-CB) and the resection group (R-CB). Evaluated variables included symptoms, endoscopic findings, nutritional status, and gallstone formation at 5 years after gastrectomy. Results: Gallstone formation was significantly less common in P-CB than in R-CB (16 vs. 33%, p = 0.035). One patient (2%) in P-CB and 4 (7%) in R-CB underwent surgery for symptomatic gallstones. On multivariate analysis of gallstone formation, R-CB was an independent risk factor for gallstone formation (odds ratio = 2.5, 95% confidential interval: 1.0-6.1, p = 0.049). Symptoms and endoscopic findings did not differ significantly between the groups. Relative values of body weight, serum albumin level, and total cholesterol level also did not significantly differ between the groups. Conclusion: Preserving the CB independently contributes to the prevention of gallstone formation during long-term follow-up after R-Y reconstruction following LADG. i 2014 S. Karger AG, Basel