Hirofumi Sugita

Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer

Aberrant promoter hypermethylation (methylation) is an epigenetic change that silences the expression of crucial genes, thus inactivating the apoptotic pathway in various cancers. Inactivation of the apoptotic pathway has been considered to be associated with chemoresistance. The objective of the present study was to clarify the effect of the methylation of the apoptosis-related genes, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), on the response to chemotherapy in metastatic or recurrent gastric cancers. Tumor samples were obtained from 80 gastric cancer patients who were treated with fluoropyrimidine-based chemotherapy for distant metastatic or recurrent disease, after surgical resection of the primary tumor. The methylation status of the apoptosis-related genes, BNIP3 and DAPK, was investigated by methylation-specific PCR. Methylation in BNIP3 was detected in 31 tumors (39%) and in DAPK in 33 tumors (41%). There was no correlation between the methylation status of BNIP3 and that of DAPK. The response rate was significantly lower in patients with methylation of DAPK, than in those without (21 vs. 49% p=0.012). Progression-free survival time (PFS) was shorter in patients with methylation of DAPK than in those without (p=0.007). The overall survival time (OS) was shorter in patients with methylation of BNIP3 than in those without (p=0.031). The response rate was significantly lower in patients with methylation of either DAPK or BNIP3, or both, than in those without methylation (p=0.003). PFS and OS were significantly shorter in patients with methylation of either or both of these genes than in those without (p=0.002, p=0.001). The methylation of BNIP3 and DAPK can predict lower response to chemotherapy and poor prognosis in gastric cancer.

A prospective study of tumor suppressor gene methylation as a prognostic biomarker in surgically resected stage I to IIIA non-small-cell lung cancers.

Introduction: While retrospective analyses support an association between early tumor recurrence and tumor suppressor gene promoter methylation in early-stage non–small-cell lung cancers (NSCLCs), few studies have investigated this question prospectively. Methods: Primary tumor tissue from patients with resected pathologic stage I to IIIA NSCLCs was collected at the time of surgery and analyzed for promoter methylation via methylation-specific reverse transcriptase polymerase chain reaction (MethyLight). The primary objective was to determine an association between promoter methylation of 10 individual tumor suppressor genes (CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, SOCS3, and ADAMTS8) and recurrence-free survival (RFS), with the secondary objectives of determining association with overall survival (OS), and relation to clinical or pathologic features. Results: A total of 107 patients had sufficient tumor tissue for successful promoter methylation analysis. Majority of patients were former/current smokers (88%) with lung adenocarcinoma (78%) and pathologic stage I disease (62%). Median follow-up was 4 years. When controlled for pathologic stage, promoter methylation of the individual genes CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, and ADAMTS8 was not associated with RFS. Promoter methylation of the same genes was not associated with OS except for DAPK1 which was associated with improved OS (p = 0.03). The total number of genes with methylated promoters did not correlate with RFS (p = 0.89) or OS (p = 0.55). Conclusion: Contrary to data established by previous retrospective series, tumor suppressor gene promoter methylation (CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, and ADAMTS8) was not prognostic for early tumor recurrence in this prospective study of resected NSCLCs.

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.

BubR1 and AURKB overexpression are associated with a favorable prognosis in gastric cancer

The majority of human solid tumors exhibit aneuploidy caused by impairment of the mitotic checkpoint. Since the Mad2, BubR1 and Aurora kinase B (AURKB) proteins are involved in the mitotic checkpoint, we investigated Mad2, BubR1 and AURKB mRNA expression and its effect on clinicopathological parameters and prognosis in 100 consecutive patients who underwent surgical resection for gastric cancer. Mad2, BubR1 and AURKB mRNA expression levels in gastric cancer tissues and corresponding normal gastric mucosa were compared by real-time quantitative RT-PCR. The data were then correlated to clinicopathological parameters and prognosis. The expression of Mad2, BubR1 and AURKB mRNA was found to be significantly higher in cancer tissue compared to normal tissue. BubR1 and AURKB expression was significantly higher during the earlier stages of the disease. Patients with high BubR1 expression had improved relapse-free survival and overall survival compared to patients with low BubR1 expression. Multivariate analysis of stage II and III patients indicated that high expression of BubR1 and/or AURKB was associated with improved overall survival. We conclude that overexpression of BubR1 and AURKB is associated with a low risk of gastric cancer progression, and that overexpression of BubR1 and/or AURKB can therefore be used to identify gastric cancer patients with a favorable prognosis.

Clinical significance of platelet derived growth factor-C and -D in gastric cancer

Platelet-derived growth factor (PDGF)-C and PDGF-D are frequently upregulated in human cancers and play important roles in tumor progression, angiogenesis and metastasis. However, the distribution, frequency and prognostic value of PDGF-C and PDGF-D expression in gastric cancer have not been clarified. The present study evaluated the association between expression of PDGF-C and PDGF-D, clinicopathological factors and outcomes, in patients with gastric cancer. Gastric adenocarcinoma tumor samples were obtained from 204 patients who underwent curative gastrectomy between 2003 and 2007. The expression of PDGF-C and PDGF-D was analyzed by immunohistochemical staining. High expression of PDGF-C and PDGF-D was detected in 114 (56%) and 151 (74%) tumors, respectively. PDGF-D expression was significantly associated with tumor depth (P=0.039), histopathology (P<0.01), tumor stage (P=0.01) and recurrence (P<0.01), whereas PDGF-C expression correlated only with histopathology (P=0.05). High PDGF-D expression was also associated with significantly shorter relapse-free survival (RFS) time (P<0.01), whilst high PDGF-C expression was associated with marginally, but not significantly, shorter RFS (P=0.10). On multivariate analysis, high PDGF-D expression was determined to be an independent prognostic factor (hazard ratio, 3.3; 95% confidence interval, 1.20–9.4; P=0.02). These findings indicate that high PDGF-D expression is strongly associated with tumor progression, recurrence, distant metastasis and poor outcomes in patients with gastric cancer. PDGF-D may therefore be an independent prognostic factor and a novel therapeutic target.

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

Intraoperative pancreatic injury gives rise to severe postoperative pancreatic fistula: results of a review of unedited videos of the laparoscopic surgical procedures

Objective To examine risk factors for and causes of severe postoperative pancreatic fistula (sPOPF) after laparoscopic gastrectomy (LG) Summary of Background Data There are few reports on POPF after LG. Methods Between February 2012 and March 2014, we examined 86 patients who underwent LG comparing them with 33 patients who underwent open gastrectomy (OG) for gastric cancer. Risk factors for severe POPF (sPOPF) of Clavien-Dindo grade IIIa or higher were examined. To investigate causes of sPOPF, we reviewed unedited video recordings of laparoscopic surgical procedures. Results sPOPF occurred to 3 patients (3.5%) after LG and 1 patient (3.0%) after OG, indicating no significant difference (p=0.901). Univariate analysis showed no significant risk factors for sPOPF after LG. By reviewing video recordings, all 3 patients with sPOPF after LG had direct pancreatic injury by ultrasonically activated device (USAD) during peripancreatic lymphadenectomy. In 2 of them, pancreas was injured while the contour of pancre...