Gastric Carcinoma Patients Research Articles

3243 Unusual Presentation of Gastric Adenocarcinoma and Ascites

INTRODUCTION: Approximately 3-6% of patients with gastric carcinoma (GC) present with ascites at their initial presentation of GC. Many studies suggest that GC patients with ascites have poor prognosis due to ascites-related complications, like spontaneous bacterial peritonitis (SBP). CASE DESCRIPTION/METHODS: A 69 year-old Asian female active smoker presented with worsening abdominal pain and 10 lbs weight loss for 1 month. She reported one episode of coffee ground emesis. Physical examination revealed reticulated abdominal skin discoloration, right upper quadrant tenderness, and hypoactive bowel sounds. Laboratory studies: Hgb: 12.4 g/dL; MCV 92.3 fL; WBC: 14.2 K/mcL, Lactate: 1.3 mmol/L, BUN 13 mg/dL, Cr < 0.46 mg/dL. CT abdomen revealed distended small bowel loops, moderate ascites, omental caking and gastric thickening greatest at the gastric body with surrounding fat infiltration and tiny nodes. Paracentesis drained 3.8 L of cloudy yellow ascites fluid with a WBC of 385. The patient was started on treatment for SBP. Esophagogastroduodenoscopy was performed revealing a partially obstructing, ulcerating mass at the gastric cardia and gastric body (A). Biopsy confirmed the diagnosis of gastric adenocarcinoma (B). DISCUSSION: We present a patient who initially presented with symptoms suggestive of malignancy. Her labs revealed SBP although her presentation was asymptomatic. With only 3-6% of patients with gastric carcinoma (GC) presenting with ascites at their initial presentation of GC, ascites-related complications, like SBP, is associated with poorer prognosis. For this reason, current treatment for GC with ascites is palliation and prevention of ascites-related symptoms.

Molecular Profiles and Metastasis Markers in Chinese Patients with Gastric Carcinoma

The goal of this work was to investigate the molecular profiles and metastasis markers in Chinese patients with gastric carcinoma (GC). In total, we performed whole exome sequencing (WES) on 74 GC patients with tumor and adjacent normal formalin-fixed, paraffin-embedded (FFPE) tissue samples. The mutation spectrum of these samples showed a high concordance with TCGA and other studies on GC. PTPRT is significantly associated with metastasis of GC, suggesting its predictive role in metastasis of GC. Patients carrying BRCA2 mutations tend not to metastasize, which may be related to their sensitivity to chemotherapy. Mutations in MACF1, CDC27, HMCN1, CDH1 and PDZD2 were moderately enriched in peritoneal metastasis (PM) samples. Furthermore, we found two genomic regions (1p36.21 and Xq26.3) were associated with PM of GC, and patients with amplification of 1p36.21 and Xq26.3 have a worse prognosis (P = 0.002, 0.01, respectively). Our analysis provides GC patients with potential markers for single and combination therapies.

Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.

Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation-44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T-TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration-approved drug preventing Y/T-TEAD interaction, on gastric CSC tumorigenic properties. Y/T-TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient-derived GC and cell lines. Verteporfin effects on Y/T-TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient-derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T-TEAD molecular signature was enriched in CD44+ patient-derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T-TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere-forming CD44+ /aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T-TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ-TEAD activity could be a promising CSC-based strategy for the treatment of GC.

MiR-29c suppresses cell invasion and migration by directly targeting CDK6 in gastric carcinoma.

Gastric carcinoma (GC) is one common malignant tumor with high morbidity and mortality rates all over the world. Recently, numerous studies have showed that the microRNAs (miRNAs) dysregulation was implicated in GC carcinogenesis. This research aimed to explore the potential associations between miR-29c and cyclin-dependent kinase 6 (CDK6) in GC. GC tissues and corresponding normal tissues were collected from 54 GC patients who underwent surgery at the Second Hospital of Anhui Medical University between 2015 and 2017. We measured the expressions of CDK6 and miR-29c in GC tissues using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). We next investigated the functions of miR-29c in GC cells by performing transwell assays. To further determine the correlation between miR-29c and CDK6 in GC cell invasion and migration, the rescue experiments were performed by co-transfecting miR-29c inhibitor and CDK6 siRNA into AGS cells. MiR-29c expressions were significantly declined in GC tissues and cells. Additionally, functional assays showed that the miR-29c over-expression suppressed the invasion and migration capacities of GC cells. According to TargetScan and dual-luciferase reporter assays, CDK6 was identified as a new miR-29c target. Moreover, the knockout of CDK6 had similar effects as the miR-29c over-expression in GC cells. The current research indicated that miR-29c over-expression could inhibit tumor behaviors in GC partially via down-regulating CDK6. We revealed that miR-29c down-regulated in GC tissues and cells. MiR-29c over-expression effectively suppressed the GC cell invasion and migration. Moreover, CDK6 was identified as a direct functional target of miR-29c in GC. The current study provides new insights for the GC treatment and suggests that miR-29c/CDK6 axis is a therapeutic candidate target for GC patients.

Survival benefit of palliative gastrectomy followed by chemotherapy in stage IV gastric signet ring cell carcinoma patients: A large population‐based study

BackgroundStage IV gastric signet ring cell carcinoma (SRCC) is a type of malignant gastric cancer (GC) with poorer survival compared to metastatic non‐SRCC gastric cancer (NOS). However, chemotherapy alone was unable to maintain long‐term survival. This study aimed to evaluate survival benefit of palliative gastrectomy plus chemotherapy (PG+C) for metastatic gastric SRCC.MethodsWe obtained data on gastric cancer patients between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Statistical methods included χ 2 tests, Kaplan‐Meier curves, COX models, propensity score matching (PSM) and subgroup analysis.ResultsAmong 27 240 gastric cancer patients included, 4638 (17.03%) were SRCC patients. The proportion of patients with younger age, female gender, poorly differentiated grade and M1 stage was higher in SRCC than in NOS (P < .001). Multivariate analysis revealed that multiple metastatic sites (HR = 1.39, 95% CI: 1.14‐1.69, P = .001) was associated with increased mortality risk in metastatic SRCC. Median survival time was improved in metastatic SRCC receiving PG+C compared to PG/C alone (13 vs 7 months, P < .001). Notably, in subgroup analysis, 13 of 17 groups of metastatic SRCC patients with PG+C had prolonged overall survival compared to chemotherapy alone, especially for those with only one metastatic site (HR = 0.61, 95% CI: 0.51‐0.73, P < .001).ConclusionsOur results suggested that there exists at least a selective group of stage IV gastric SRCC patients, who could benefit from palliative gastrectomy followed by chemotherapy compared to chemotherapy alone. Further prospective trials are needed to support our conclusion.

E2F6-mediated lncRNA CASC2 down-regulation predicts poor prognosis and promotes progression in gastric carcinoma

AimsTo investigate the potential biological role of E2F6 and its underlying molecular mechanism in gastric carcinoma (GC) progression. Main methodsThe expressions of cancer susceptibility candidate 2 (CASC2), E2F6 and matrix metalloprotein-2 (MMP-2) were measured by quantitative real-time polymerase chain reaction and western blotting. The inhibitory effect of E2F6 on CASC2 was evaluated using luciferase reporter assay. Cell growth was assessed by colony formation assay and cell counting kit-8. Cell invasion and apoptosis were measured by transwell assay and flow cytometry assay, respectively. In vivo tumorigenicity was assessed by tumor xenografts in nude mice. Key findingsOur data revealed that CASC2 was downregulated while E2F6 was upregulated in GC tissues and cell lines. Remarkably, lower expression of CASC2 was associated with poor survival in GC patients. E2F6 inhibited the expression of CASC2. Subsequently, reliable data showed that downregulation of E2F6 suppressed the proliferation and invasion, and promoted the apoptosis of GC cells. Furthermore, downregulation of E2F6 decreased the expression of MMP-2 and increased the activity of caspase-3. However, these changes triggered by E2F6 knockdown could be reversed by inhibition of CASC2. Moreover, we also proved that downregulation of CASC2 reverses the effect of E2F6 knockdown on tumor growth in vivo. SignificanceOur data demonstrated that E2F6 could regulate the proliferation, invasion and apoptosis of GC cells via inhibiting the expression of CASC2, suggesting that E2F6/CASC2 axis is another regulator of GC progression.

Abstract 3177: KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor

Abstract Background: Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related death, particularly in China. Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer. Mutations in KRAS are detected in many types of human tumors and have been proved to be associated with development and progression of cancer. In this study, we sought to explore the role of KRAS in signet-ring cell carcinoma. Patients and methods: Genomic data from 393 GC samples from The Cancer Genome Atlas (TCGA) was extracted to analyze mutation status of KRAS. Sanger sequencing for KRAS was applied in 234 FFPE SRCC patient samples. Immunohistochemical(IHC) and Fluorence in situ hybridization(FISH) were performed to detect KRAS expression level and KRAS amplification status in FFPE samples. Patients were evaluated in terms of survival and clinicopathological characteristics, as well as KRAS mutation and expression status in TCGA and in our cohort, respectively. We also explored KRAS mutation and expression level in 4 SRCC cell lines. Drug inhibition rate of MEK/mTOR inhibitors was evaluated by cell viability assay. Results: Thirty-one patients (0.079%) and thirty-seven GC patients (0.094%) in TCGA harbored point mutations and copy number variation (CNV), respectively. Patients with KRAS point mutations and CNV showed higher mRNA level compared to non-mutant cases (P = 0.003 and P &amp;lt; 0.001). No survival difference was observed between KRAS different gene status in TCGA cohort. In our 234 in-house SRCC samples, 15 samples harbored KRAS mutations. We further did analysis on the 75 patients which had enough FFPE samples. Eight patients showed KRAS mutations and two patients showed KRAS amplification. The median overall survival (OS) was 12.5 months for patients with KRAS mutation, and 19.5 months for patients without KRAS mutation (P = 0.045). The majority of SRCC patients are positive with KRAS detected by IHC, which is higher than our intestinal cohort (80% vs 38.6%, P&amp;lt;0.001). However, no difference of overall survival was observed between different KRAS expression level. We further explore the correlation between KRAS status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored KRAS mutation, were hypersensitive to MEK inhibition. However, mTOR inhibitor showed no preference on SRCC cell lines in terms of KRAS status. Conclusion: These data demonstrate the status of KRAS gene in SRCC and uncover the therapeutic potential for targeting of these tumors through MEK inhibition in SRCC. Citation Format: Nandie Wu, Ying Huang, Xiangshan Fan, Yang Yang, Qin Liu, Lixia Yu, Rafael Rosell, Baorui Liu, Jia Wei. KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3177.

Abstract 2030: Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma

Abstract Cancer-associated fibroblasts (CAF) are a major component of tumor stroma and their effect on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. The aim of this study was to investigate the effect of an AXL inhibitor on CAF-induced GC progression. We examined growth arrest specific factor 6 (GAS6) expression and phosphorylation of AXL in various cell lines, including GC cells and non-cancerous cells, by qPCR, western blot, and immunocytochemistry. We investigated the role of CAF-derived GAS6 on the migration and proliferation of GC cells using migration and cell survival assays. The effect of the AXL inhibitor, Bemcentinib, on the CAF-induced aggressive phenotype of GC cells was also investigated. Finally, we performed immunohistochemistry to measure the phosphorylation of AXL in a tissue microarray composed of 175 GC tissues, and evaluated its correlation with the prognosis of GC patients. qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was inhibited in GC cells, the effect of CAF was reduced. In addition, Bemcentinib, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, P-AXL positively correlated with the expression of vimentin (P &amp;lt; 0.001) and high levels of P-AXL were significantly associated with poor overall survival (P = 0.022).These findings suggest that CAF is a major source of GAS6 in the GC microenvironment and actively promotes an aggressive phenotype in GC cells through AXL activation. We conclude that an AXL inhibitor may be a novel agent for GC treatment. Citation Format: Dagyoeng Lee, Jongsu Woo, Cheong A Bae, In-Hye Ham, Hye Jung Oh, Sang-Yong Son, Sang-Uk Han, Tae-Min Kim, Jung Hwan Yoon, Won Sang Park, Hoon Hur. Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2030.

Abstract 4876: Clinical significance of diffuse-type histological type coexistence in Stage II/III gastric cancer

Abstract Background: Signet ring cell carcinoma (sig) and non-solid poorly differentiated adenocarcinoma (por2) are the histological forms of gastric cancer called diffuse type. They are considered to be a tissue type with a poor prognosis. Adjuvant chemotherapy using S-1 is standard therapy for stage II/III gastric cancer in Japan, however, clinical relevance of histological type to outcome of adjuvant therapy remains unclear. Purpose: The purpose of the present study was to examine the impact of the coexistence of diffuse type on the prognosis of stage II/III gastric cancer. Patients and Methods: We retrospectively analyzed the clinicopathologic data of 935 gastric carcinoma patients who underwent gastrectomy between 2007 and 2015 at our department. Results: We observed that there were 62 cases (17%) with sig mixed (dominant 12 cases, inferiority 50 cases) and 104 cases (30%) with por 2 mixed (dominant 19 cases, inferiority 85 cases). The patients with por2 or sig had more peritoneum dissemination compared with intestinal types. In Stage III, the recurrence rate was high in the case with sig mixed, the 3-year relapse-free survival rate was 36% in the mixed case and 55% in the non-mixed case. However, we found no correlation of sig mixture to prognosis of patients with Stage II. Among the patient who received the S-1 adjuvant chemotherapy, the prognosis of sig mixture was relatively poor. Conclusion: In the case of stage III gastric cancer in which there was mixed signet ring cell carcinoma in the tissue, the recurrence rate was high and the prognosis was poor. Our findings suggested that it should be needed to treat sig mixed cases as a high risk group in the future postoperative adjuvant chemotherapy for gastric cancer. Citation Format: Hiroaki Tanaka, Kazuya Muguruma, Tatsuro Tamura, Takahiro Toyokawa, Masatsune Shibutani, Tatsunari Fukuoka, HIsashi Nagahara, Masaichi Ohira. Clinical significance of diffuse-type histological type coexistence in Stage II/III gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4876.

High expression of MRE11 correlates with poor prognosis in gastric carcinoma

BackgroundMRE11, a protein known to play a vital role in DNA double-strand break repair, is associated with the prognosis of a variety of tumours, but there are few studies regarding the role of MRE11 in gastric carcinoma (GC). The present study aimed to explore the clinicopathological significance and prognostic value of MRE11 expression in GC.MethodsData from the TCGA, GEO and Oncomine databases were analysed to assess MRE11 mRNA levels in GC. The prognostic role of the level of MRE11 mRNA was examined via the Kaplan-Meier plotter. MRE11 protein expression in tumour tissues from 155 GC patients was analysed by immunohistochemistry. Relationships between MRE11 expression and clinicopathological characteristics, overall survival (OS) and recurrence-free survival (RFS) were evaluated by Cox proportional hazards regression models and Kaplan-Meier survival curves.ResultsThe results of bioinformatics analysis showed that MRE11 mRNA levels in GC tissues were higher than those in normal tissues (P < 0.01). Tissue microarray analysis showed that MRE11 protein expression was increased in GC tissues (P < 0.001), and MRE11 overexpression in GC tissues was significantly related to lymph node metastasis (P < 0.05), distant metastasis (P < 0.05) and tumour-node-metastasis stage (P < 0.05). Kaplan-Meier analyses showed that patients with GC who exhibited MRE11 overexpression had worse OS and RFS. According to Cox proportional hazards analyses, MRE11 overexpression was an independent prognostic factor for OS and RFS in these GC patients.ConclusionsMRE11 overexpression is significantly associated with poor prognosis, and MRE11 may serve as a prognostic biomarker in GC patients.

Prospective observation: Clinical utility of plasma Epstein-Barr virus DNA load in EBV-associated gastric carcinoma patients.

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.

LncRNA NR027113 promotes malignant progression of gastric carcinoma via EMT signaling pathway.

The aim of this study was to explore the characteristics of long noncoding RNA (lncRNA) NR027113 in gastric carcinoma, and to further investigate whether it could promote the development of gastric carcinoma via epithelial mesenchymal transition (EMT) signaling pathway. Quantitative Real-time polymerase chain reaction (qRT-PCR) was performed to analyze the expression of NR027113 in 68 paired of gastric carcinoma and para-carcinoma tissues. Subsequently, the relationship between NR027113 expression and clinical indexes of gastric carcinoma as well as the prognosis of patients was analyzed. NR027113 expression in gastric carcinoma cells was detected by qRT-PCR as well. NR027113 knockdown model was constructed by lentivirus transfection in gastric carcinoma cells (including AGS and SGC-7901). Meanwhile, the effects of NR027113 on the biological functions of gastric carcinoma cells were analyzed by cell counting kit-8 (CCK-8), wound healing, transwell invasion and migration assay, respectively. Furthermore, the correlation between NR027113 and EMT signaling pathways was studied. QRT-PCR results showed that the expression level of NR027113 in gastric carcinoma tissues was significantly higher than that of para-carcinoma tissues. Compared with patients with low expression of NR027113, the incidence of lymph node metastasis and distant metastasis was significantly higher in patients with high NR027113 expression. Meanwhile, the survival rate of patients with low NR027113 expression was significantly lower. Compared with control group, the invasion and migration abilities of cells in NR027113 knockdown group were significantly decreased. Subsequent qRT-PCR results demonstrated that the expression of EMT signaling pathway-related proteins was significantly changed after transfection of sh-NR027113. The above finding indicated that NR027113 could inhibit the malignant progression of gastric carcinoma. Moreover, the addition of transforming growth factor-β (TGF-β) cytokines synergistically promoted the malignant progression of gastric carcinoma with NR027113. NR027113 expression was significantly increased in gastric carcinoma. Meanwhile, it was positively correlated with lymph node metastasis, distant metastasis and poor prognosis of gastric carcinoma patients. Furthermore, NR027113 could accelerate the invasion and migration abilities of gastric carcinoma cells via EMT signaling pathway.

Toxicity syndromes, patient-related clinical indicator of toxicity burden induced by intensive triplet chemotherapy-based regimens in metastatic gastrointestinal cancers.

e15013 Background: Cancer treatments induce symptoms and signs superimposing on clinical and cancer-related status of individual patient, defining heterogenous toxicity syndromes (TS). We reviewed intensive first line triplet chemotherapy-based regimens developed in fit metastatic gastro-intestinal cancers (mGI), based on FIr/FOx schedule including fluorouracil and weekly alternating irinotecan and oxaliplatin. Methods: Metastatic colorectal (mCRC), pancreatic ductal adenocarcinoma (mPDAC), gastric carcinoma (mGC) patients were enrolled by careful decision-making in real life phase II studies: FIr-B/FOx, adding bevacizumab (BEV), in overall, and FIr-C/FOx-C, adding cetuximab (CET), in KRAS/NRAS wild-type mCRC, respectively; FIr/FOx in mPDAC; FD/FOx, adding docetaxel (D), in mGC. Toxicity, and individual limiting toxicity syndromes (LTS), classified as limiting toxicity alone (LTS-single site, LTS-ss) or associated to other limiting or G2 toxicities (LTS-multiple sites, LTS-ms) were evaluated and compared by chi-square test. Results: FIr-B/FOx and FIr-C/FOx-C in mCRC, FIr/FOx in mPDAC, FD/FOx in mGC, respectively reported activity, efficacy and limiting toxicities similar to other triplet chemotherapy-based regimens. Reported LTS: FIr-B/FOx in mCRC 44%, LTS-ms 24% and LTS-ss 20%, in young elderly (yE) 46%, LTS-ms significantly increased vs LTS-ss; FIr-C/FOx-C in KRAS/NRAS wild-type mCRC 65.5%, significantly increased LTS-ms vs LTS-ss, in yE 83%; FIr/FOx in mPDAC 27.5%, mostly LTS-ms, in yE 38.4% all LTS-ms; FD/FOx in mGC 30%, all LTS-ms, in yE 25%. Conclusions: LTS meet the need of an innovative clinical parameter of patient-related toxicity burden, indicating global and individual tolerability, including differential spectrum and intensities of TS related to cancer treatment and according to clinical status of the individual patient. LTS integrated with conventional toxicity evaluation may help properly select patients fit for intensive medical treatments in mGI cancers.

Expression of HER2/c-erbB-2, EGFR Protein in Gastric Carcinoma and its Clinical Significance.

ObjectiveTo investigate the HER2/c-erbB-2, epidermal growth factor receptor (EGFR) protein expression in gastric cancer and association with patients’ clinical pathology characteristics and prognosis.MethodsHER2/c-erbB-2 and EGFR protein expression was examined by immunohistochemical assay in gastric cancer tissue and corresponding paired normal gastric tissue of 67 patients of gastric carcinoma. The HER2/c-erbB-2, EGFR protein positive expression rate in cancer tissue and normal gastric tissue were compared. The correlation between HER2/c-erbB-2, EGFR protein positive expression and patients’ clinical pathology characteristics and survival was evaluated.ResultsThe positive expression rate of HER2/c-erbB-2 in the cancer and paired normal gastric tissues were 32.8% (22/67) and 4.5% (3/67), respectively with statistical difference (p<0.05). And the positive expression rate of EGFR in cancer and paired normal gastric tissues were 41.8% (28/67) and 5.9 (4/67), respectively, with statistical difference (p<0.05). HER2/c-erbB-2 positive expression in cancer tissue was significant correlated with the pathology grading (p<0.05), tumor invasion depth (p<0.05) and local regional lymph node metastasis (p<0.05); EGFR positive expression in cancer tissue was significant correlated with the tumor invasion depth (p<0.05) and local regional lymph node metastasis (p<0.05). The median survival time was 13.14 and 23.6 months respectively for HER2/c-erbB-2 positive and negative expression groups respectively with statistical difference ( HR=2.26, 9%CI:1.06-4.80, p<0.05). However, the median survival time was 15.47 and 22.87 months for EGFR positive and negative expression groups respectively, without statistical difference (HR=1.78, 9%CI:0.96-3.29, p>0.05).ConclusionPositive expression of HER2/c-erbB-2 and EGFR proteins in cancer tissue was significant higher than normal gastric tissue and have significant correlation with prognosis.

Metaproteomics of fecal samples of Crohn's disease and Ulcerative Colitis

Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic inflammatory bowel diseases (IBD) of the gastrointestinal tract. This study used non-invasive LC-MS/MS to find disease specific microbial and human proteins which might be used later for an easier diagnosis.Therefore, 17 healthy controls, 11 CD patients and 14 UC patients but also 13 Irritable Bowel Disease (IBS) patients, 8 Colon Adenoma (CA) patients, and 8 Gastric Carcinoma (GCA) patients were investigated. The proteins were extracted from the fecal samples with liquid phenol in a ball mill. Subsequently, the proteins were digested tryptically to peptides and analyzed by an Orbitrap LC-MS/MS. For protein identification and interpretation of taxonomic and functional results, the MetaProteomeAnalyzer software was used.Cluster analysis and non-parametric test (analysis of similarities) separated healthy controls from patients with CD and UC as well as from patients with GCA. Among others, CD and UC correlated with an increase of neutrophil extracellular traps and immune globulins G (IgG). In addition, a decrease of human IgA and the transcriptional regulatory protein RprY from Bacillus fragilis was found for CD and UC. A specific marker in feces for CD was an increased amount of the human enzyme sucrose-isomaltase. SignificanceCrohn's Disease and Ulcerative Colitis are chronic inflammatory diseases of the gastrointestinal tract, whose diagnosis required comprehensive medical examinations including colonoscopy. The impact of the microbial communities in the gut on the pathogenesis of these diseases is poorly understood. Therefore, this study investigated the impact of gut microbiome on these diseases by a metaproteome approach, revealing several disease specific marker proteins. Overall, this indicated that fecal metaproteomics has the potential to be useful as non-invasive tool for a better and easier diagnosis of both diseases.

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 impact of neoadjuvant chemoradiation versus chemotherapy on short and long-term outcomes among gastric carcinoma patients.

78 Background: There is little consensus on the use of neoadjuvant chemoradiation (NCRT) versus neoadjuvant chemotherapy (NCT) in gastric carcinoma (GC) patients. We sought to compare the outcomes of these two approaches in a large national data base. Methods: National Cancer Data Base PUF (2004-2014) of GC patients who underwent NCRT/NCT followed by resection were included. Primary outcome was overall survival (OS), secondary outcomes were pathological complete response (pCR), R0 resection and postoperative mortality. Results: A total of 4204 GC patients with NCT were included, 62% of them had additional neoadjuvant radiotherapy (NRT). NCRT had higher pCR and R0 rates [551/2613 (21%), 2314/2561 (90%)] than NCT group [148/1573 (9%), 1242/1543 (80%)], p &lt; 0.0001. Multivariate logistic regression showed similar higher odds of pCR (OR 2.8, 95% CI 1.65-4.60, p &lt; 0.0001) and R0 (OR 1.5, 95% CI 1.14-1.99, p = 0.004) among NCRT versus NCT. There was no significant difference in length of hospital stay, 30-day readmission rate, 30- and 90-day postoperative mortality. Median, 3- and 5-year OS for NCRT versus NCT were: (20.4 months, 24% and 11%) versus (18.3 months, 19% and 6%), p &lt; 0.001. Univariate cox regression analysis showed superior OS with NRT (HR 0.9, 95% CI 0.80-0.91, p &lt; 0.001). After adjusting for confounding variables, pCR (HR 0.2, 95% CI 0.18-0.24, p &lt; 0.001) and R0 (HR 0.7, 95% CI 0.61-0.75, p &lt; 0.001) had better OS, while NRT was not. Conclusions: NRT improved pCR and R0 rates in GC without increase in surgical morbidity/mortality. The long-term OS benefit of NRT is likely secondary to higher pCR and R0 resection.

Impact of enhanced recovery after surgery on postoperative rehabilitation, inflammation, and immunity in gastric carcinoma patients: a randomized clinical trial.

We determined the effects of enhanced recovery after surgery (ERAS) in patients undergoing radical surgery for gastric carcinoma. Sixty patients undergoing radical gastrectomy for gastric carcinoma in Lishui Hospital between March and October 2016 were randomized to receive either ERAS (30 patients) or conventional care (30 patients, controls). Clinical, economic, and laboratory indices were analyzed. ERAS patients showed faster recovery and shorter postoperative hospital stays than the controls (P<0.05). Some clinical indices (i.e., time to first flatus and defecation, time to removal of drainage tubes, time to resumption of oral feeding, time to postoperative mobilization, and postoperative complications) were significantly better in ERAS patients than in controls. Duration of postoperative infusion was lower in ERAS patients than in controls (P<0.05). In ERAS patients, serum albumin and prealbumin were higher on postoperative day 7, C-reactive protein was lower on postoperative days 3 and 7, and neutrophil count was lower on postoperative day 3 compared to the values in controls (P<0.05 for all). IgM levels were higher in ERAS patients on postoperative days 3 and 7 (P<0.05), while IgG levels were higher on postoperative day 3 (P<0.05). Total T lymphocytes were higher in ERAS patients on postoperative day 3, while helper T cells and CD4+/CD8+ ratio were higher on postoperative days 3 and 7 (P<0.05 for all). In gastric carcinoma patients, ERAS may reduce perioperative inflammation, improve immunity and postoperative nutrition, shorten hospitalization, and enhance rehabilitation.

Immunohistochemical evaluation of P53 and Ki67 in biopsy samples of gastritis and gastric cancer patients

Background: Chronic gastritis (CG) is an inflammatory process that can lead to gastric cancer and Helicobacter Pylori (H. Pylori). In this study, immunohistochemical evaluation of P53 and Ki67 in biopsy samples of CG and gastric carcinoma patients with and without H. Pylori infection was investigated. Methods: From 82 archived paraffin blocks, 42 blocks were selected for CG group and 40 as the gastric cancer group. All CG and gastric cancer cases were subdivided into H. Pylori positive and negative subgroups. Monoclonal antibodies specific for Ki67 and P53 were used for immunohistochemical staining. Results: The results showed that differences of Ki67 and P53 expressions were statistically significant among patients with CG gastritis and gastric cancer (P 0.05). Conclusions: The present study proposed that P53 and Ki67 expressions changed in gastric cancer compared to the CG specimens. It seems that overexpression of these biomarkers probably has important roles in the route of carcinogenesis. Our results suggested that these overexpressions were not associated with H. Pylori infection. Further studies with larger sample size are needed in this field.

Distal gastrectomy for gastric carcinoma in patients with diabetes mellitus: impact of reconstruction type on glucose tolerance.

Current evidence regarding metabolic surgery suggests that different types of digestive tract reconstruction can result in differences in postoperative glucose tolerance. This study evaluated the impact of Billroth I (B-I), Billroth II (B-II), and Roux-en-Y (R-Y) procedures on peri-operative glucose tolerance in patients with gastric carcinoma who had diabetes mellitus. A single-institution, retrospective cohort study was conducted using data from patients who underwent totally laparoscopic distal gastrectomy. These patients were grouped according to the type of reconstruction (B-I, B-II, or R-Y). After the operation, we addressed the changes in glucose tolerance-including changes in HbA1c levels, remission of diabetes, and overall effects of the treatment. We studied 57 patients (B-I, n=32; B-II, n=17; R-Y, n=8). B-II and R-Y reconstruction improved HbA1c levels more than B-I. Notably, R-Y improved tolerance the most (B-I vs. B-II, p<0.001; B-I vs. R-Y, p<0.001; B-II vs. R-Y, p<0.001). The type of reconstruction (B-II and R-Y vs. B-I) and a pre-operative HbA1c ≥7% were the two significant independent contributing factors determining postoperative improvement in HbA1c, with odds ratio (OR) 8.437, 95% confidence interval (CI) 1.635-43.527, p=0.011; OR 16.5, 95% CI 3.361-81.011, p=0.001, respectively. Either R-Y or B-II should be considered the primary option for patients with gastric carcinoma and diabetes when glycemic control is insufficient.