Prognosis Of Gastric Carcinoma Research Articles

Activation of CD3+ T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma

ABSTRACT Most of gastric carcinoma (GC) is attributed to infection by Helicobacter pylori (H. pylori) but there is increasing evidence that the positive H. pylori status correlates with better prognosis in GC. The H. pylori-induced cellular immune response may suppress cancer and in this work, recombinant pcDNA3 plasmids encoding various fragments of H. pylori virulence genes of cagA, vacA and babA are constructed and combined into groups to immunize BALB/c mice. The activated splenic CD3+ T cells are purified and the anticancer effects are investigated in vitro and in vivo. The H. pylori DNA vaccines induce a shift in the response from Th1 to Th2 that mimicks the immune status in patients of GC with chronic H. pylori infection. The stimulated CD3+ T cells inhibit the growth of human GC cells in vitro and adoptive transfusions of the CD3+ T cells suppress the growth of GC xenograft in vivo. The effects may be caused by the larger ratios of infiltrated CD8+/CD4+ T cells, reduced infiltration of regulatory FOXP3+ T cells, and enhanced apoptosis induced by upregulation of Caspase-9/Caspase-3 and downregulation of Survivin. Our results reveal the potential immunotherapeutic value of H. pylori vaccine-activated CD3+ T cells in those with advanced GC.

The effect of matrix metalloproteinases and adhesion molecules on the prognosis in gastric carcinoma

Background: Matrix metalloproteinases (MMPs), adhesion molecules, and receptors are needed in the process of cancer growth. This study aims to investigate the role of MMP-3, MMP-10, MMP-11, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in gastric cancer. Materials and Methods: Fifty-two gastric carcinoma cases who underwent gastrectomy were included in the study. The cases were inspected with regard to the presence/absence of lymph node and distant metastases. The selected paraffin blocks were immunohistochemically stained with MMP 3, MMP 10, MMP 11, ICAM (CD 54), and VCAM (CD 106). Results: Most of the cases (n: 50, 94%) with gastric cancer manifested cytoplasmic staining with MMP-11. MMP-10 expression was found in 45 of 52 (86.5%), MMP-3 staining was determined in 43 (82.6%) of gastric carcinomas. Different areas of differentiation within the tumor showed differences in MMP expression in terms of intensity and extensiveness. ICAM-1 expression was found in 47 of 52 (90.4%) cases and with VCAM-1, 46/52 (88.5%) of gastric cancers manifested positive staining. Its expression was found to be higher in the nonmetastatic group both in intestinal and diffuse types. VCAM-1 was diffusely expressed in gastric cancers. However, we did not determine a significant correlation concerning differentiation and lymph node and distant metastasis. Conclusions: MMP-3, MMP-10, MMP-11, ICAM-1, and VCAM-1 are expressed in gastric cancers and are thought to be involved in tumor development. Levels of expression that decrease in parallel to decreasing differentiation in areas of differentiation within tumor corroborate the idea that they are related to tumor progression. Due to its relationship with metastasis, ICAM-1 expression in noncohesive cells supports the idea that ICAM-1 is a significant factor involved in metastasis development in gastric cancers. Decreased MMP-10 and MMP-11 expression in metastases suggest that these enzymes may also be linked to the metastatic potential of gastric cancers.

The fasting blood glucose and long non-coding RNA SNHG8 predict poor prognosis in patients with gastric carcinoma after radical gastrectomy.

This prospective study sought to evaluate the prediction of fasting blood glucose and long non-coding RNA (lncRNA) SNHG8 for the risk of gastric carcinoma mortality. A total of 217 gastric carcinoma patients underwent radical gastrectomy were included during 2012-16. The final follow-up was finished in January 2017. The aggregate hazard ratio(HR) demonstrated that poor prognosis of gastric carcinoma was associated with fasting blood glucose (HR= 1.29, P=0.037), SNHG8 expression(HR = 1.10, P= 0.009), positive distant metastasis(HR = 2.99, P= 0.020), EBV positive (HR = 3.40, P=0.002), and tumor size more than 5.0 cm (HR = 3.36, P= 0.005). In survival analysis, elevated fasting blood glucose (P =0.007) and high SNHG8 expression (P =0.007) were significantly associated with shorter survival times in gastric cancer. Significant multiplicative interaction was shown between fasting blood glucose and SNHG8 expression (chi-squared=7.81, Pmultiplicative =0.005), without statistical additive interaction. Fasting blood glucose and SNHG8 expression could predict poor prognosis after radical gastrectomy. LncRNA SNHG8 could be applied as a novel epigenetic molecular target in gastric carcinoma.

Overexpression of ADAMTS-2 in tumor cells and stroma is predictive of poor clinical prognosis in gastric cancer

ADAMTS-2 is a member of the ADAMTS family and is a procollagen N-proteinase. The objective of our research is to explore the prognostic significance of ADAMTS-2 in gastric carcinoma. A total of 655 samples with full clinicopathological data were investigated in this study. Tissue microarray immunohistochemistry analysis was used to analyze the relationship between clinicopathological characteristics and ADAMTS-2 expression. Oncomine and Kaplan-Meier plotters were performed for the relationship analysis between prognosis and ADAMTS-2 expression in patients with gastric cancer. Compared with that of normal tissues, the ADAMTS-2 protein expression was remarkably higher in gastric cancer cells and fibroblast cells. The results of univariate analysis indicated that the expression of ADAMTS-2 in tumor cells and fibroblast cells, Laurén classification, TNM grade, and carcinoembryonic antigen level in gastric cancer were all correlated with overall survival. The results of multivariate analysis indicated that the high expression of ADAMTS-2 in gastric cancer cells and fibroblast cells both were independent prognostic factors. Therefore, ADAMTS-2 may be a potential biomarker for assessing the prognosis of gastric carcinoma.

Expression and significance of human ether-a-go-go-related gene protein and matrix metalloproteinase-9 in gastric cancers

Objective To investigate the expression of human ether-a-go-go-related gene (HERG1) protein and matrix metalloproteinase-9 (MMP-9) in gastric carcinoma and their correlation with prognosis of gastric carcinoma. Methods Reverse transcription and polymerase chain reaction (PCR) assay and Western blotting were used to detect the expression of HERG1 and MMP-9 in 80 cases of gastric carcinomas and corresponding normal gastric tissues, and the patients were followed up. Results The positive expression rate of HERG1 and MMP-9 was 60% and 55% respectively. There was significant correlation between the positive expression rate of MMP-9 with depth of invasion, TNM stage, differention, lymphatic and distant matastasis. The positive rate of HERG1 was correlated with lymphatic and distant metastasis. Conclusion HERG1 protein and MMP-9 expression in gastric carcinoma appears to be well-characterized indicators of prognosis and metastasis and may play an important role in the tumor invasion and metastasis. Key words: Gastric carcinoma; Human ether-a-go-go-related gene protein; Matrix metalloproteinase-9; Metastasis

Loss of ARID1A expression is associated with poor prognosis in patients with gastric cancer

Deletion of the frequently mutated AT-rich interacting domain-containing protein 1A (ARID1A), an SWI/SNF subunit, is associated with poor prognosis in various tumors. This study observed and analyzed ARID1A expression and its correlation with prognosis in gastric carcinoma. Postoperative sections of 98 patients with primary gastric cancer and 40 patients with gastric benign lesions were examined by immunohistochemistry. ARID1A deficiency was observed in 19.39% of gastric cancer tissues, 4.08% of matched paracancerous tissues, and 2.5% of normal gastric mucosa tissues. ARID1A expression was significantly down-regulated in gastric cancer tissues compared with paracancerous tissues (P = .001) and normal gastric mucosa tissues (P = .011). ARID1A deletion significantly correlated with tumor size (P = .022), lymph node metastasis (P = .030), and tumor differentiation (P = .009). In the 90 gastric cancer tissues with tumor stages II and III, the clinical outcome of the ARID1A-negative patients was significantly poorer than that of the ARID1A-positive patients (P = .005). Univariate analysis revealed that tumor invasion depth (P = .025), stage (P = .032), poor differentiation (P = .046), lymph node metastasis (P = .038), and ARID1A expression (P = .023) were significantly related to the overall survival of gastric cancer patients. Multivariate analysis demonstrated that tumor invasion depth (P = .029) and ARID1A expression (P = .031) were independent factors that indicate poor prognosis. In conclusion, the loss of ARID1A expression in gastric cancer patients significantly correlated with poor survival.

Expressions and clinical significances of CD68 and ABHD5 in gastric carcinoma

Objective To evaluate the expressions of CD68 and alpha/beta hydrolase domain-con-taining protein 5 (ABHD5) in gastric carcinoma and their interrelation, and the relationship with the clinicopathological features of gastric carcinoma. Methods The immunohistochemistry staining was used to determine the expressions of CD68 and ABHD5 in 60 cases of gastric carcinoma and 30 cases of adjacent normal tissues. The relationships between CD68, ABHD5 and clinicopathological features of gastric carcinoma, and the correlation of them were analyzed. Results The expressions of CD68 and ABHD5 in gastric carcinoma were significantly higher than those in adjacent normal tissues, and the positive expression rates were 65.00% vs. 26.67% (χ2=11.779, P=0.001) and 60.00% vs. 30.00% (χ2=7.200, P=0.007) respectively, with significant differences. The expression of CD68 was related to TNM stage (χ2=7.959, P=0.005), lymph node metastasis (χ2=6.901, P=0.009) and serosal invasion (χ2=5.833, P=0.016), but it was not associated with pathological grade (χ2=0.028, P=0.866), gender (χ2=0.533, P=0.465) and age (χ2=0.060, P=0.807). The expression of ABHD5 was related to pathological grade (χ2=4.318, P=0.038), TNM stage (χ2=4.051, P=0.044) and serosal invasion (χ2=5.275, P=0.022), but it was not associated with lymph node metastasis (χ2=0.545, P=0.460), gender (χ2=0.191, P=0.662) and age (χ2=1.358, P=0.244). Contingency correlation analysis showed that there was positive correlation between CD68 and ABHD5 in gastric cancer (c=0.328, P=0.010). Conclusion The expressions of CD68 and ABHD5 in gastric carcinoma are higher than those in adjacent normal tissues, which are correlated with the different clinicopathological features of gastric carcinoma. The expression of CD68 is positively correlated with the expression of ABHD5. The combined detection of CD68 and ABHD5 expressions in gastric carcinoma is helpful to evaluate the invasion, metastasis and prognosis of gastric carcinoma. Key words: Stomach neoplasms; Alpha/beta hydrolase domain-containing protein 5; CD68

Lyc-55716: A novel small-molecule RORγ agonist immuno-oncology agent: Rationale for tumor selection and clinical evaluation of gastric and esophageal carcinoma in phase 2a expansion.

67 Background: Type 17 effector T cell differentiation and function are regulated by the master transcription factor retinoic acid receptor–related orphan receptor γt (RORγ). Synthetic RORγ agonists, which modulate immune cell gene expression to enhance effector functions and decrease Treg and checkpoint pathways, have shown promise as mono- and combination therapy in syngeneic tumor models. Translational and bioinformatics assessments were performed during Phase 1 testing of the investigational RORγ agonist LYC-55716 to support inclusion of patients with gastric carcinoma (GC) and esophageal carcinoma (EC) in a Phase 2a expansion of clinical trial LYC-55716-1001 (NCT02929862). Methods: Transcriptional profiling of murine and human T cells treated ± RORγ agonists identified a gene signature. Using The Cancer Genome Atlas (TCGA), and other public datasets, data on GC and EC patients were evaluated to determine: (a) RORγ and RORγ-inducing cytokine expression; (b) signature genes associated with RORγ biology, surrogate biomarkers for endogenous RORγ ligands, and correlations with prognosis; (c) tumor microenvironment (TME) immune profiles. Results: Expression: In TCGA RNA sequencing data analysis, 50%-70% of GC and EC samples expressed moderate to high levels of RORγ, indicating infiltration of Type 17 T cells into the tumors. Furthermore, genes that support expression of RORγ were highly expressed in ~75% of GC and EC tumors. Biology: TCGA data showed that GC and EC tumors express low levels of sterol efflux genes, suggesting low levels of endogenous agonists in the TME. In analysis of public datasets, expression of the RORγ target gene IL17A correlated with a favorable prognosis for EC. In addition, some of the other RORγ signature genes also correlated with good prognosis in GC and EC. Immune profile: TCGA showed infiltration of T cells and a high mutational burden in GC and EC, which are positively associated with efficacy of immunotherapy. Conclusions: Bioinformatics assessments of RORγ expression, biology, and tumor immune profiles support the inclusion of GC and EC patients in an ongoing Phase 2 clinical trial of LYC-55716.

Definition of Prognosis Based on Lymph Node Metastasis and Elevation of Serum C-Reactive Protein for Patients with Gastric Carcinoma Treated with Curative Resection.

The aim of this study was to develop prognostic criteria based on the combination of nodal metastasis and preoperative elevation of serum C-reactive protein (CRP) for patients with gastric carcinoma that have been treated with curative resection. Three hundred and twenty patients with gastric carcinoma who had been treated with curative resection were enrolled. One point was provided for each incidence of nodal metastasis and preoperative elevation of serum CRP and we examined whether this cumulative score system could provide a strict stratification of survival. Significant differences regarding survival were observed both between patients with scores of 0 and 1 (P < 0.0001) and between patients with scores of 1 and 2 (P < 0.0001). Multivariate analysis showed that the cumulative score (P = 0.0003) and the depth of the tumor (P = 0.016) were independent prognostic indicators. Criteria for the prediction of prognosis in gastric carcinoma treated with curative resection based on tumor-related and host-related factors could provide a strict stratification. J. Med. Invest. 65:191-194, August, 2018.

DIMT1 overexpression correlates with progression and prognosis in gastric carcinoma

We investigated the expression of dimethyladenosine transferase 1 homolog (DIMT1) in human gastric carcinoma (GC) tissues, pericarcinoma histologically normal tissues, and normal gastric tissues and explored its clinical significance. Immunohistochemistry staining was used to detect the expression of DIMT1, and the findings were compared with clinicopathological features of patients with GC. The result also was ascertained by Western blotting. The Kaplan-Meier method and log-rank test were used to compare the overall survival rate and time in the DIMT1 low-level and high-level expression groups. Immunohistochemical staining indicated that the expression of DIMT1 in GC tissues (65/75; 86.7%) was significantly more common (P<.001) than that in pericarcinoma histologically normal tissues (14/75; 18.7%) and normal gastric tissues (2/12; 16.7%). High expression of DIMT1 correlated closely with differentiation (P=.023), invasion (P=.042), lymph node metastasis (P=.008), distant metastasis (P=.006), and TNM stage (P=.013). Western blotting showed that DIMT1 expression correlated positively with TNM stage and implied that more advanced TNM stage was accompanied by higher expression of DIMT1 (P<.001). Kaplan-Meier survival analysis showed that high DIMT1 expression correlated significantly (P<.001) with a poor prognosis. Our data suggest that DIMT1 is a useful molecular biomarker to predict tumor progression and prognosis in patients with GC.

The characteristics of c-MET and HER2 expression in gastric carcinoma and its correlation with clinical-pathological parameters.

e15566 Background: The aim of this study was to determine whether overexpression of c-MET or HER2 had an effect on the clinical-pathological parameters and / or the prognosis of gastric carcinoma, as well as a direct correlation among those parameters. Methods: 134 gastric resectates were archived between 2007-2012 and retrospectively examined for c-MET and HER2 expression via immunohistochemistry (IHC). The HER2 status IHC2 + was additionally verified by means of Chromogenic in situ hybridization (CISH). Statistical data analysis was performed on the basis of the parameters acquired in the prospective multicentre observation study QCGC'07 / 09. Results: A total of 71 patients (53%) were found to express c-MET low and 63 patients (47%) expressed c-MET high, 122 patients (91%) were found to be HER2 negative and 12 persons (9%) were HER2 positive. C-MET high was significantly more pronounced in the Lauren intestinal type (63.8%, p = 0.001) and moderately to poorly differentiated tumour tissue (G2 50.9%, G3 43.9%, p = 0.038) as well es tissue with lymph vessel infiltration (L1 59.1%, p = 0.039). HER2 showed no significant effect on the clinical-pathological parameters. The median overall survival was shown to be shortened for the c-MET high-expressing (c-MET low 56 months, SD: ± 24.67; 95% CI: 7.65-104.36 vs. c-MET high 32 months, SD: ± (median-OS HER2 negative 38 months, SD: ± 14.11, 95% CI: 10.35-65, p = 0.839), and HER2 negative, 65, median-OS HER2 positive not reached, p = 0.305) patients. 8/134 resectates (5.97%, p = 0.135) were high and positive in both expression patterns, showing no significant difference to the OS (p = 0.393). Conclusions: In our studies, c-MET high or HER2 negative expression was associated with a poorer OS. However, no direct correlation between HER2 and c-MET could be demonstrated

Regulation of CD44v6 expression in gastric carcinoma by the IL-6/STAT3 signaling pathway and its clinical significance.

As a cancer stem cell marker, CD44 variant 6 (CD44v6) has been implicated in carcinogenesis, tumor progression, and metastasis in a variety of human carcinomas. However, little is known about the expression of CD44v6 in Gastric Carcinoma (GC). Therefore we investigated CD44v6 expression in clinical specimen and further explore the underlying molecular mechanisms.In this study, we systemically investigated CD44v6 expression by immunohistochemistry in normal, premalignant gastric mucosa (low and high grade intraepithelial neoplasia), and GC at various stages. The correlation of CD44v6 expression with clinicopathological characteristics, and prognosis in GC was also analyzed. Next, we investigated cell proliferation, migration and invasion in GC cell lines. Furthermore, we explored a novel mechanism by which CD44V6 was upregulated in GC cell.The immunohistochemistry results showed that enhanced expression of CD44v6 was closely associated with tumor differentiation, lymph node metastasis, TNM stage and poor prognosis in GC patients. In gastric cancer cell lines, CD44v6 involved in cell proliferation, invasion and metastasis in Next, report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD44v6. RNA interference silencing of STAT3 resulted in decrease of CD44v6 levels. We also found that STAT3 inhibitor AG490 decrease expression of CD44v6 by blocking activation of STAT3, even in the presence of IL-6. Targeting STAT3-mediated CD44v6 up-regulation may represent a novel, effective treatment by eradicating the stomach tumor microenvironment.

Detection of digestive malignancies and post-gastrectomy complications via gastrointestinal fluid examination.

To date, gastric carcinoma (GC) is one of the common and fatal digestive malignancies worldwide. The prognosis of GC is not always satisfactory because of late diagnosis. Scholars are keen on discovering novel accurate and economical biomarkers in body liquids for GC screening to detect and evaluate the lesion before the results of imaging techniques are obtained. While traditional serum assays have limited sensitivity and specificity, gastrointestinal juice may provide relevant specific biomarkers because of its close contact with the tumor. Herein, the current progress in the relationship between gastrointestinal fluid analyses and GC is systematically and comprehensively reviewed. The detection of gastric juice pH, fluorescence spectrum, cytology, Helicobacter pylori-associated markers, nitrosamines, conventional tumor markers, amino acids, proteomics, microRNAs, long noncoding RNAs, protein-coding genes, vitamin C, etc., and combination tests of different category markers could provide important diagnostic and prognostic clues for gastrointestinal diseases. Particularly, early GC may be efficiently screened using gastric juice. Gastrointestinal fluid examination could also predict the adverse effects of postgastrectomy, such as pancreatic leakage, fistula, and abscess. Gastric fluid markers should be further studied to reveal the early predicators of malignancy and complications. The methods for obtaining the samples of gastrointestinal juice with minimum incision should also be comprehensively investigated.

Prognostic value of diffuse versus intestinal histotype in patients with gastric cancer: a systematic review and meta-analysis.

There are two distinct types of gastric carcinoma (GC), intestinal, more frequently sporadic and linked to environmental factors, and diffuse (undifferentiated) that is highly metastatic and characterized by rapid disease progression and a poor prognosis. However, there are many conflicting data in the literature concerning the association between histology and prognosis in GC. This meta-analysis was performed to provide demonstration if histology according to Lauren classification is associated with different prognosis in patients with GC. We searched PubMed, the Cochrane Library, SCOPUS, Web of Science, CINAHL, and EMBASE for all eligible studies. The combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) in terms of overall survival (OS) were evaluated. A total of 73 published studies including 61,468 patients with GC were included in this meta-analysis. Our analysis indicates that GC patients with diffuse-type histology have a worst prognosis than those with intestinal subgroup in all studies (HR 1.23; 95% CI, 1.17-1.29; P<0.0001), in both loco-regional confined (HR 1.21; 95% CI, 1.12-1.30; P<0.0001) and advanced disease (HR 1.25; 95% CI, 1.046-1.50; P=0.014), in Asiatic (HR 1.2; 95% CI, 1.14-1.27; P<0.0001) and Western patients (HR 1.3; 95% CI, 1.19-1.41; P<0.0001), and in those not exposed (HR 1.15; 95% CI, 1.07-1.24; P<0.0001) or exposed (HR 1.27; 95% CI, 1.17-1.37; P<0.0001) to (neo)adjuvant therapy. Our results indicated that histology might be a useful prognostic marker for both early and advanced GC patients, with intestinal-type associated with a better outcome. This information could be used for stratification purpose in future clinical trials.

High expression of Wls is associated with lymph node metastasis and advanced TNM stage in gastric carcinomas.

The roles of Wnt protein in carcinogenesis have been well documented in human cancers. Wls is a key modulator for the secretion of Wnt protein. We previously found that Wls was aberrantly expressed in colorectal carcinomas. Studies have revealed that dysregulation of Wnt signal transduction plays an important role in gastric carcinoma. We hypothesized that Wls may play a role in the development and progression of gastric carcinoma. In this study, three gastric cancer cell lines MGC-803, SGC-7901, and AGS, and a set of gastric carcinoma tissue specimens were subjected to immunohistochemistry. The relationship between the expression of Wls and clinicopathological parameters was analyzed. Wls was negatively detected in MGC-803, positively detected in SGC-7901 and AGS cell lines. Wls was weakly expressed in 9.7% (15/154), moderately in 33.1% (51/154), and strongly in 57.1% (88/154) of tested gastric carcinoma specimens. High expression of Wls was positively associated with well and moderately differentiated tumors (P = 0.035, rs = 0.170), lymph node metastasis (P = 0.001, rs = 0.276), and advanced TNM stage (P = 0.006, rs = 0.219). Our data suggest that Wls protein is related to tumor metastasis and advanced TNM stage, and may be used as a new marker for prognosis of gastric carcinoma.

Clinicopathological Implication of Insulin-like Growth Factor-II mRNA-Binding Protein 3 (IMP3) Expression in Gastric Cancer.

The clinicopathological significance of oncofetal mRNA-binding protein, human insulin-like growth factor II mRNA-binding protein 3 (IMP3), in gastric carcinoma (GC) is not fully understood. Tissue microarray blocks with specimens from 346 patients with GC were constructed to evaluate the clinicopathological role of IMP3 expression in GC. These results were validated with an online dataset of 876 patients from the Kaplan-Meier Plotter. Sera from 15 controls and 57 patients with GC were collected in order to compare the levels of serum IMP3 between groups. High expression of IMP3 was significantly associated with poor prognosis. Survival curves from the Kaplan-Meier Plotter showed that high IMP3 expression was significantly related to worse disease-free survival and overall survival. Tissue overexpression of IMP3 might be used as a predictor of advanced disease or lymph node metastasis, and is associated with poorer prognosis in GCs.

Low Expression of CDK10 Correlates with Adverse Prognosis in Gastric Carcinoma.

Background: Cyclin-dependent kinase (CDK) 10, is reported to play an essential role in the progression from the G2 to M phase of the cell cycle. Recently, reduced expression of CDK10 has been observed in several cancerous human tissue, suggesting that CDK10 is a tumor suppressor gene. However, data on its expression pattern and clinical relevance in gastric cancer are not sufficient. Therefore, this study aims to investigate CDK10 expression and its prognostic significance in primary gastric adenocarcinoma.Methodology/Principal Findings: The expression level of CDK10 was analyzed using qRT-PCR, western blotting, and immunohistochemistry on tissue samples from 189 post-resection gastric cancer patients. The expression of CDK10 mRNA was reduced in tumor tissue samples compared with matched adjacent non-tumor tissue samples (P=0.013); this finding was confirmed by western blot analysis (P=0.016). Immunohistochemistry data indicated that CDK10 expression was significantly decreased in 92 of 189 (48.7%) gastric cancer cases. Kaplan-Meier survival curves revealed that decreased expression of CDK10 was strongly associated with a poor prognosis in gastric cancer patients (P<0.001). Multivariate Cox analysis identified CDK10 expression as an independent prognostic factor for overall survival (P=0.011).Conclusions/Significance: Our data suggest that reduced CDK10 expression independently predicts a poor prognosis in patients with gastric cancer. CDK10 can may serve as a valuable prognostic marker and a potential target for gene therapy.

Prognostic significance and the role in TNM stage of extranodal metastasis within regional lymph nodes station in gastric carcinoma.

The role of extranodal metastasis (ENM) in TNM stage in gastric carcinoma (GC) is controversial. This study was aimed to make a detailed investigation of the prognostic significance and the role in TNM stage of ENM in GC. The patients with primary GC, who underwent gastrectomy with curative intention in West China Hospital from January 2005 to December 2011, were retrospectively enrolled. The prognosis and clinicopathological traits were compared between ENM positive (ENMP) and negative (ENMN) groups in all patients, TNM I-II, III and IV stages, respectively. The significance of the number and the role in TNM stage of ENM were also assessed. In our study, 1457 patients were enrolled, with 1324 (90.9%) in ENMN group and 133 (9.1%) in ENMP group. ENMP group had significantly more advanced GC and worse prognosis (all p<0.05) than ENMN group in all patients, TNM I-II stages and TNM III stage. ENM>2 subgroup had remarkably larger tumor size (p=0.002) and more advanced N stage (p=0.016) than ENM=1-2 subgroup. The number of ENM was an independent prognostic factor in ENMP group (p=0.029). The prognosis of ENM>2 in TNM I-III stages was significantly worse than ENMN patients in TNM III stage. The C-index of TNM stage plus the number of ENM was significantly higher than that of current TNM stage alone (p=0.005). In conclusion, the patients in ENMP subgroup had more advanced GC and worse prognosis than those in ENMN subgroup. It might be more reasonable to categorize ENM>2 into TNM IV stage.

Correlation of p53 overexpression with the clinicopathological prognostic factors in gastric adenocarcinoma

Background: Gastric cancer is one of the leading causes of cancer deaths. The etiology of gastric cancer is complex multistep process characterised by histopathologic precursor lesions and molecular genetic alterations involving APC, K-ras and p53 genes. Overexpression of p53 in gastric carcinoma is associated with bad prognosis. Aim: To establish correlation between p53 overexpression and clinicopathological features of gastric carcinoma. Materials and methods: A cross-sectional, descriptive hospital based study of clinical, histopathological and immunohistochemistry (IHC) features of gastric carcinoma was conducted on gastrectomy specimens received to the Department of Pathology from January 2008 to June 2013. The clinical features, tumour morphology and p53 status by immunohistochemistry, were evaluated in each case. Results: The most common histologic type of gastric carcinoma was of intestinal type and predominantly were grade III tumours (60%). Most (75%) of them presented with lymph node metastasis. Majority were in stage IIIA (27.5%) or stage IV (20.0%). Majority of gastric carcinomas (35%) had 1+ intensity of p53 expression but and it was not statistically significant. Majority of gastric adenocarcinomas showed p53 positivity in <5% tumour cells. Overall, 62.5% gastric adenocarcinomas showed p53 positivity and 10 out of 40 (25%) were intensely positive. There was no significant correlation between p53 status and age of patient, tumor site, tumor size, histological type, grade, lymph node status and TNM stage. Conclusion: Mutation in p53 plays a vital role in development of gastric carcinoma. However, a significant correlation between gastric carcinoma and clinicopathological parameters could not be established. A prolonged follow up study on a large number of cases can help to find out whether p53 overexpression by standard IHC could be a useful marker for prognosis of gastric carcinoma.

Abstract A25: microRNAs associated with chemoresistance in gastric cancer patients tumors treated with neoadjuvant chemoterapy

Abstract Abstract: Results of randomized controlled studies conducted to verify the effectiveness of neoadjuvant chemotherapy (NC) for gastric carcinoma (GC) have suggested that this treatment is therapeutically useful for the patients instead of surgery alone. However, in some patients with apparently the same molecular and histological tumor characteristics, the objective clinical response with NC is not achieved, and this lack of response may delay curative surgery and the toxicity induced by chemotherapy may increase surgical complications. Therefore, the main challenge for improving clinical outcomes is to understand the molecular mechanisms that may play essential roles in patients' responses of GC treatments. So, predictive novel molecules identification may be crucial for correct patients' selection. Emerging evidence suggested that some microRNAs (miRNAs) can have prognostic and diagnostic value in many types of cancer. Expression levels of several miRNAs have been found to be correlated with GC prognosis and could determine the clinical response for neoadjuvant chemotherapy. Objective: Our goal was to analyze the association between tumor miRNA expression and the pathological response grade of gastric carcinoma patients treated with neoadjuvant chemotherapy. Methods: A total of 52 paraffined samples were selected from a retrospective database of A.C. Camargo Cancer Center: From these samples, 34 were biopsy tumor samples (collected before chemotherapy) of GC patients treated with NC and 18 were normal gastric tissue (controls). The chemotherapy schemes used in NC were epirubicin, cisplatin and fluoracil, with adaptations using docetaxel, xeloda and oxaliplatin. All patients treated with NC received chemotherapy prior the surgery, and subsequently they were submitted to a complete resection (R0). To determine the tumor response of patients treated of neoadjuvant chemotherapy, we analyzed representative tumor slides stained with hematoxilin and eosine, and evaluated the percentage of viable tumor cells present in the gastric resection after NC. For trial analyses we used TLDA (Taqman® Low Density Array) qRT-PCR to determine the expression of 377 miRNAs. After that, validation of differentially expressed miRNAs was done by qRT-PCR using individual assays. Results: According to the percentage of viable tumor cells seen in microscopic analysis we established a graduation from 0% to 100% of viable tumor cells, being this relationship proportional inversely to treatment response. After evaluating the percentage of viable tumor cells present in gastric resection after NC, we categorized the samples in quartiles. After statistical analysis, the samples with a 100% of viable tumor cells after neoadjuvant treatment, showed us nine downregulated miRNAs. We performed qRT-PCR using individual assays, and confirmed downregulated expression of 3 miRNAs in biopsy tumor samples of patients treated with NC with 100% of viable tumor cells in gastric resection tumor. Conclusion: We found proteomic and expression profiles reports about the relationship of these 3 downregulated miRNAs with some genomic alterations involved in gastric cancer pathways and with some mechanisms of drugs resistance. These miRNA signature may be useful as potential biomarkers to predict response of gastric cancer patients to NC. Citation Format: Michelle Maccarini Barcelos-Baldoni, Claudia Malheiros Coutinho-Camillo, Renato David Puga, Maria Dirlei Ferreira-Begnami. microRNAs associated with chemoresistance in gastric cancer patients tumors treated with neoadjuvant chemoterapy. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A25.