Zhi Zhu

Evaluation of the seventh edition of American Joint Committee on Cancer TNM staging system for gastric cancer: results from a Chinese monoinstitutional study.

BackgroundTo investigate the validity of the 7th edition of American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer with special attention paid to pT2/pT3, pN1/pN2, and pN3a/pN3b category.Materials and MethodsClinicopathologic data of 1998 patients underwent R0 surgery for histologically proven gastric cancers with >15 lymph nodes retrieved were retrospectively reviewed.ResultsPrognoses were significantly different between pT2 and pT3 categories, between pN1 and pN2 categories, or between pN3a and pN3b categories. Each stage in the 6th edition was divided into the 7th edition stage with different survival rates. Moreover, stage IIIA, IIIB, and IIIC in the 7th edition system was divided into the 6th edition stage with different survival rates. Prognoses for patients in 7th edition T4aN1M0/T3N2M0/T2N3aM0, T4bN0-1M0/T4aN2M0/T3N3aM0, and T4aN3aM0/T4bN2M0 were similar to that of patients in T1N3bM0, T2N3bM0, and T3N3bM0, respectively, but significantly better than that of patients in T2N3bM0, T3N3bM0, and T4aN3bM0, respectively. However, no significant difference could be observed among patients in T4bN3aM0, T4aN3bM0, T4bN3bM0, and stage IV. A revised TNM system was proposed, in which T1N3bM0 was incorporated into stage IIIA, T2N3bM0 into stage IIIB, T3N3bM0 into stage IIIC, T4bN3aM0/T4aN3bM0/T4bN3bM0 into stage IV. Further analyses revealed the revised TNM system had better homogeneity, discriminatory ability, and monotonicity of gradients than the 6th and the 7th edition system.ConclusionsIt is reasonable to subclassify the 6th edition pT2 category and pN1 category into the 7th edition pT2/pT3 category and pN1/pN2 category, respectively. However, for better prognostic stratification, it might be more suitable for pN3a and pN3b categories to be considered individual determinants of the 7th edition TNM staging system.

Expression of Legumain Correlates with Prognosis and Metastasis in Gastric Carcinoma

Objective Legumain, a novel asparaginyl endopeptidase, has been observed to be highly expressed in several types of tumors, which may play a vital role in carcinogenesis. However, there is no study investigating the relationship among Legumain expression, clinicopathologic, biological variables and patient prognosis in gastric carcinoma. Methods In this study, a tissue microarray (TMA) containing 282 samples of primary gastric cancer was assessed for Legumain expression by immunohistochemistry. The TMA included 98 lymph node metastasis samples. The protein expression levels of Legumain were evaluated by Western blot analysis. Results Cytoplasmic immunoreactivity of Legumain was over-expressed in gastric cancer compared with paired normal gastric mucosa. Increased Legumain levels were significantly correlated with clinical stage, presence of distant metastasis. Legumain was significantly over-expressed in primary gastric cancer with metastasis than without metastasis. Patients with Legumain-positive localized tumors had lower 5-year overall survival (OS) than those with Legumain-negative tumors. Multivariate survival analysis showed that Legumain was an independent prognostic marker for OS (HR 1.459, 95% CI 1.251–1.703, P = 0.007). Conclusions Legumain expression could serve as a prognostic biomarker in patients at risk of developing metastasis or recurrence with gastric carcinoma.

Flotillin2 Expression Correlates with HER2 Levels and Poor Prognosis in Gastric Cancer

Objective Flotillin gene is known as a tumor promoter or suppressor, depending on the tumor type or tumor stage. We aimed to investigate the clinical significance of flotillin2 protein expression in gastric cancer. Methods We examined flotillin2 and erbB2 levels in tissue microarray of 282 gastric cancer samples and analyzed the association between flotillin2 levels, clinicopathologic factors and prognosis. The regulation of erbB2 by flotillin2 was examined with flotillin2 siRNA–transfected gastric cancer cells. Results Flotillin2 partially co-localized with erbB2 at the plasma membrane as detected by confocal microscopy, levels of erbB2 were reduced after flotillin knockdown in SGC-7901 cancer cells, and the expression of flotillin2 was positively correlated with that of erbB2. In non-neoplastic gastric mucosa, flotillin2 was not expressed in the epithelial compartment. In gastric cancer, positive staining of flotillin2 was shown in 129 (45.7%) of 282 cases, also, it was significantly associated with a Lauren grade, histologic type, lymphovascular invasion and tumor location. Moreover, survival analysis showed that flotillin2 expression was an independent prognostic factor of poor survival (p<0.001). Conclusions These results indicate that a positive correlation exists between flotillin2 and erbB2 expression levels, flotillin2 maybe involved in the stabilization of erbB2 at the plasma membrane, flotillin2 is significantly correlated with cancer progression and poor prognosis in gastric cancer.

Comparison Different Methods of Intraoperative and Intraperitoneal Chemotherapy for Patients with Gastric Cancer: A Meta-analysis

PURPOSE To investigate the efficacy and safety of intraperitoneal chemotherapy (IPC) for patients with gastric cancer and to compare effects between different regimens of IPC. METHOD Randomized controlled trials comparing the effects of surgery plus intraperitoneal chemotherapy with surgery alone or comparing the efficacy between different regimens of intraperitoneal chemotherapy were searched for in Medline, Embase, Pubmed, the Cochrane Library and the Chinese BioMedical Disc and so on by two independent reviewers. After quality assessment and data extraction, data were pooled for meta-analysis using RevMan5.16 software. Tests of interaction were used to test for differences of effects among subgroups grouped according to different IPC regimens. RESULTS Fifteen RCTs with a total of 1713 patients with gastric cancer were included for quality assessment and data extraction. Ten studies were judged to be of fair quality and entered into meta-analysis. Hyperthermic intraoperative intraperitoneal chemotherapy (HR=0.60, P<0.01), hyperthermic intraoperative intraperitoneal chemotherapy plus postoperative intraperitoneal chemotherapy (HR=0.47, P<0.01) and normothermic intraoperative intraperitoneal chemotherapy (HR=0.70, P=0.01) were associated with a significant improvement in overall survival. Tests of interaction showed that hyperthermia and additional postoperative intraperitoneal chemotherapy did not impact on its effect. Further analysis revealed that intraperitoneal chemotherapy remarkably decrease the rate of postoperative hepatic metastasis by 73% (OR=0.27, 95% CI=0.12 to 0.67, P<0.01). However, intraperitoneal chemotherapy increased risks of marrow depression (OR=5.74, P<0.01), fever (OR=3.67, P=0.02) and intra-abdominal abscess (OR=3.57, P<0.01). CONCLUSION The present meta-analysis demonstrates that hyperthermic intraoperative intraperitoneal chemotherapy and normothermic intraoperative intraperitoneal chemotherapy should be recommended to treat patients with gastric cancer because of improvement in overall survival. However, it is noteworthy that intraperitoneal chemotherapy can increase the risks of marrow depression, intra-abdominal abscesses, and fever.

Macroscopic Serosal Classification Predicts Peritoneal Recurrence for Patients with Gastric Cancer Underwent Potentially Curative Surgery

BackgroundPrevious studies revealed serosal invasion as one of the most important predictors of peritoneal micrometastasis. However, even for cancers with serosal invasion, the macroscopic serosal appearance is highly heterogeneous. The aim of the present study was to propose a macroscopic serosal classification (MSC) and to investigate the validity of this classification as a predictor of peritoneal recurrence.Materials and MethodsClinicopathologic features including MSC of 1528 patients with pT3/pT4a stage gastric cancers who underwent potentially radical surgery were retrospectively reviewed. MSC was classified as reactive type, nodular type, tendonoid type, and color-diffused type according to the macroscopic serosal appearance.ResultsThere were significant differences in tumor size, location, Bormann type, Lauren grade, lymphatic and/or blood vessels invasion (LBVI), width of serosa changes, depth of invasion, number of nodes metastasis, lymph node metastasis ratio, pN stage, and peritoneal cytology between patients with different types of serosa. Multivariate analysis revealed MSC, as well as depth of invasion, Lauren grade, and pN stage, significantly predicted the presence of peritoneal-free cancer cells. Both MSC and peritoneal cytology significantly correlated with patient survival. However, only MSC significantly predicted peritoneal recurrence on multivariate analysis, but peritoneal cytology did not, indicating MSC was more sensitive than cytologic examination. Further investigation suggested MSC and pN stage were also independent predictors of peritoneal recurrence for patients with negative peritoneal cytology.ConclusionsThe MSC sensitively predicts the presence of peritoneal micrometastasis for pT3/pT4a-stage gastric cancer patients who underwent potentially radical surgery. Consequently, it might be considered a good indicator to guide perioperative adjuvant therapy for patients with high risk of peritoneal recurrence.

Splenic hilar lymph node metastasis independently predicts poor survival for patients with gastric cancers in the upper and/or the middle third of the stomach

Effectiveness of splenectomy for advanced gastric cancers occupying the upper and/or the middle third of the stomach is still in debate. The aim of the present study is to elucidate the impact of splenectomy on patient survival by investigating the pathological characteristics and prognostic significance of splenic hilar lymph node metastasis.

Clinicopathological Significance and Prognostic Value of Lactate Dehydrogenase A Expression in Gastric Cancer Patients

Introduction LDH-A, the enzyme responsible for transforming pyruvate into lactate, has been demonstrated to be up-regulated in many types of cancer and to give rise to more aggressive behavior by regulating proliferation and anti-apoptosis. However, its expression in gastric cancer (GC) has not been characterized thoroughly. The purpose of this study was to clarify the expression and potential impact of LDH-A in GC. Methods We examined LDH-A expression by immunohistochemistry on GC tissue microarray (TMA) and using Western blot on fresh GC tissues and cell lines. Prognostic value and correlation with other clinicopathologic factors were evaluated. We transfected siRNA into GC cells against LDH-A. LDH-A was analyzed by Western blotting and real-time RT-PCR. Cell growth was evaluated in vitro and in vivo. Lactate and ATP production by cells were determined. Results There was significantly higher LDH-A expression in carcinoma than in non-neoplastic mucosa (NNM). There was a positive correlation of LDH-A expression with age, histological type and Lymph node metastases. Survival analysis demonstrated that high expression of LDH-A in GC was associated with lower overall survival (OS). When stratified by Lauren grade and histological classification, significance appeared in diffuse type and undifferentiated type GC. In multivariate analysis, the LDH-A expression in GC was an independent prognostic risk factor for OS (hazard ratio = 1.829, 95%CI 1.375–2.433,P<0.0001). Specific siRNA against LDH-A in GC cell line retarded cell growth both in vitro and in mouse models. LDH-A knockdown also reduced lactate and ATP production in GC cells. Conclusions Our study indicated the oncogenic role of LDH-A in GC. LDH-A expression is an independent prognostic risk factor in GC patients and up-regulated expression of LDH-A could be predictive of poor outcomes in diffuse type and undifferentiated type GC. Our results suggested that LDH-A might be a potential therapeutic target in gastric cancer.

The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster as a therapeutic suicide gene of breast cancer cells.

The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm‐dNK) was investigated for its broader substrate specificity and higher catalytic rate as a suicide gene in a combined gene/chemotherapy of cancer.

Expression of BAMBI and its combination with Smad7 correlates with tumor invasion and poor prognosis in gastric cancer

Bone morphogenetic proteins and activin membrane-bound inhibitor (BAMBI) and drosophila mothers against decapentaplegic protein 7 (Smad7) are known to negatively regulate the transforming growth factor-β (TGF-β) signaling and play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of BAMBI alone or in combination with Smad7 is associated with the progression of gastric cancer. In the present study, we investigated the expression of BAMBI and Smad7 in 276 cancer tissues and 263 tumor-adjacent tissues from gastric cancer patients, using tissue-microarray-based immunohistochemistry. The expression of BAMBI and Smad7 was significantly higher in cancer tissues than in tumor-adjacent tissues. The expression of BAMBI was significantly correlated with increased depth of invasion (P = 0.010), lymphatic invasion (P < 0.001), lymph node metastasis (P = 0.001), TNM stage (P = 0.008), and decreased differentiation (P = 0.046). The expression of BAMBI was associated with a significantly shorter overall survival (OS) (P = 0.006) and disease-free survival (DFS) (P = 0.011). The combined expression of BAMBI and Smad7 was associated with more invasion and metastasis as well as less survival time in gastric cancer patients. The univariate analysis showed that the expression of BAMBI alone or in combination with Smad7 was significantly associated with the OS and DFS. These findings suggest that BAMBI and Smad7 may cooperatively inhibit the TGF-β signaling, and thus promote the progression of gastric cancer.

Synergistic therapeutic effect in gastric cancer cells produced by oncolytic adenovirus encoding Drosophila melanogaster deoxyribonucleoside kinase

Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK), a novel suicide kinase, was applied as a cancer gene therapeutic approach. To improve the antitumor effect of Dm-dNK and its substrate with the selectivity and safety control in consideration, the conditionally replicative gene-viral system ZD55-dNK, which includes the replicationselective adenovirus ZD55 armed with the Dm-dNK, was used to further explore the potential of this approach. When ZD55-dNK was combined with BVDU it produced a synergistic inhibitive effect of adenovirus replication in vitro while maintaining specific cancer cell killing activity. From a clinical standpoint, this approach is promising for its considerably low toxic side effects.