Lymphocyte-C-reactive Protein Ratio as Promising New Marker for Predicting Surgical and Oncological Outcomes in Colorectal Cancer.

BACKGROUND: Systemic inflammation via host-tumor interactions is currently recognized as a hallmark of cancer. The aim of this study was to evaluate the prognostic value of various combinations of inflammatory factors using preoperative blood, and to assess the clinical significance of our newly developed inflammatory score in colorectal cancer (CRC) patients. METHOD: In total 477 CRC patients from the discovery and validation cohorts were enrolled in this study. We assessed the predictive impact for recurrence using a combination of nine inflammatory markers in the discovery set, and focused on lymphocyte-C-reactive protein ratio (LCR) to elucidate its prognostic and predictive value for peri-operative risk in both cohorts. RESULTS: A combination of lymphocytic count along with C-reactive protein levels demonstrated the highest correlation with recurrence compared with other parameters in CRC patients. Lower levels of preoperative LCR significantly correlated with undifferentiated histology, advanced T stage, presence of lymph node metastasis, distant metastasis, and advanced stage classification. Decreased preoperative LCR (using an optimal cut-off threshold of 6000) was an independent prognostic factor for both disease-free survival and overall survival, and emerged as an independent risk factor for postoperative complications and surgical-site infections in CRC patients. Finally, we assessed the clinical feasibility of LCR in an independent validation cohort, and confirmed that decreased preoperative LCR was an independent prognostic factor for both disease-free survival and overall survival, and was an independent predictor for postoperative complications and surgical-site infections in CRC patients. CONCLUSION: Preoperative LCR is a useful marker for perioperative and postoperative management of CRC patients.

Identification of Predictors of Recurrence in Patients with Lower Rectal Cancer Undergoing Neoadjuvant Chemotherapy: A Direct Comparison of Short-Course and Long-Course Chemoradiotherapy.

OBJECTIVE: This study aimed to investigate clinicopathological responses and oncological outcome in patients receiving short- or long-course chemoradiotherapy (CRT) and to assess the predictive factor for recurrence in each treatment. METHODS: A total of 118 rectal cancer patients receiving preoperative CRT were enrolled. Clinicopathological responses and oncological outcome in patients receiving short- or long-course CRT were investigated. RESULTS: Despite there being no significant differences in the prognosis of disease-free survival (DFS) based on TNM stage classification in patients receiving long-course CRT, patients with advanced stage demonstrated poor DFS after short-course CRT. The presence of lymph node metastasis was a predictor of poor DFS in short-course CRT, whereas poor pathological response was a predictor of recurrence in long-course CRT. CONCLUSIONS: Distinct predictors of recurrence depending on the CRT course might be needed to discriminate candidates from rectal cancer patients receiving preoperative CRT who might benefit from more intensive adjuvant therapy after surgery.

Clinical Implications of Pretreatment: Lymphocyte-to-Monocyte Ratio in Patients With Rectal Cancer Receiving Preoperative Chemoradiotherapy.

BACKGROUND: Despite advances in local control of rectal cancer, recurrence in distant organs is still one of the main causes of mortality. Prognostic biomarkers would be valuable for the treatment of patients who have rectal cancer. OBJECTIVE: The aim of our study was to investigate the prognostic impact of lymphocyte-to-monocyte ratio in patients with rectal cancer receiving preoperative chemoradiotherapy, and to clarify the clinical significance of lymphocyte-to-monocyte ratio. DESIGN: Prospectively maintained data of patients with rectal cancer were retrospectively evaluated to clarify the clinical relevance of the lymphocyte-to-monocyte ratio. SETTING: This study was conducted at a single expert center. PATIENTS: A total of 119 consecutive patients with rectal cancer through chemoradiotherapy followed by total mesorectal excision at our institute were enrolled in this study. Eight patients were excluded because of a lack of laboratory data, and finally 111 patients were assessed in this study. MAIN OUTCOME MEASURES: The primary outcome measured was the clinical relevance of the lymphocyte-to-monocyte ratio in patients with rectal cancer receiving chemoradiotherapy. RESULTS: Patients with a low pretreatment lymphocyte-to-monocyte ratio showed poor prognosis significantly both in overall survival and disease-free survival of those with rectal cancer receiving chemoradiotherapy. Multivariate analyses showed that low pretreatment lymphocyte-to-monocyte ratio level, presence of pathological lymph node metastasis (ypN(+)), and high pretreatment serum C-reactive protein level were independent prognostic factors of overall survival and disease-free survival. In addition, time-to-event analysis divided into 2 groups by ypN status showed that low pretreatment lymphocyte-to-monocyte ratio was correlated with poor overall survival and disease-free survival not only in group ypN(-) but also in group ypN(+). LIMITATIONS: The present study had several limitations, including that it was a retrospective observational and single institutional study with Japanese patients. CONCLUSIONS: The combination of lymphocyte-to-monocyte ratio and ypN status can be a predictive marker of poor prognosis and recurrence among patients with rectal cancer undergoing preoperative chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/A780.

Proteomics analysis of differential protein expression identifies heat shock protein 47 as a predictive marker for lymph node metastasis in patients with colorectal cancer.

The discovery of biomarkers to predict the potential for lymph node (LN) metastasis in patients with colorectal cancer (CRC) is essential for developing improved strategies for treating CRC. In the present study, they used isobaric tags for relative and absolute quantitation to conduct a proteomic analysis designed to identify novel biomarkers for predicting LN metastasis in patients with CRC. They identified 60 differentially expressed proteins specifically associated with LN metastasis in CRC patients and classified the molecular and functional characteristics of these proteins by bioinformatic approaches. A literature search led them to select heat shock protein 47 (HSP47) as the most suitable candidate biomarker for predicting LN metastasis. Validation analysis by immunohistochemistry showed that HSP47 expression in patients with CRC and the number of HSP47-positive spindle cells in the tumor stroma were significantly higher compared with those in adjacent normal colonic mucosa, and the number of the latter cells increased with tumor progression. Further, the number of HSP47-positive spindle cells in stroma was a more informative marker for identifying LN metastasis than HSP47expression. Multivariate analysis identified spindle cells that expressed elevated levels of HSP47 as an independent predictive biomarker for CRC with LN metastasis. Moreover, these cells served as an independent marker of disease-free and overall survival of patients with CRC. Their data indicate that the number of HSP47-positive spindle cells in the stroma of CRC may serve as a novel predictive biomarker of LN metastasis, early recurrence and poor prognosis.

Inflammation-based prognostic scores as indicators to select candidates for primary site resection followed by multimodal therapy among colorectal cancer patients with multiple metastases.

BACKGROUND: Although patients with metastatic colorectal cancer (CRC) are often unable to undergo treatment after resection of primary tumors, identifying such patients before surgery is not easy. In this study, we evaluated the association among clinicopathological findings, survival outcomes, and ability to undergo multimodal therapy after primary tumor resection in patients with Stage IV CRC. METHODS: We collected clinicopathological findings and preoperative laboratory data, including carcinoembryonic antigen (CEA) and systemic inflammatory response markers for 92 patients who were treated for Stage IV CRC between 2005 and 2014. We used multivariate analysis on factors that affect prognosis and ability to undergo postoperative treatment. RESULTS: Postoperative multimodal therapy improved overall survival (OS) significantly. Among serum markers, elevated CEA, neutrophil-to-lymphocyte ratio, and modified Glasgow prognosis score (mGPS) were significant indicators of shorter OS. In multivariate analysis, low performance status (P = 0.003), undifferentiated histology type (P = 0.019), and elevated mGPS (P = 0.042) were independent predictors of worse prognosis; and older age (P = 0.016), right-sided colon cancer (P = 0.043), and elevated mGPS (P = 0.031) were independent risk factors for difficulty of introducing postoperative multimodal therapy. CONCLUSIONS: Preoperative mGPS is a useful objective indicator for CRC patients with multiple metastases who are able to undergo primary site resection followed by postoperative multimodal therapy.

miRNA-503 Promotes Tumor Progression and Is Associated with Early Recurrence and Poor Prognosis in Human Colorectal Cancer.

OBJECTIVES: MicroRNA (miR)-503 is downregulated in several cancers and plays a tumor-suppressive role in carcinogenesis. However, the miR-503 expression pattern, its clinical significance and its molecular mechanism in colorectal cancer (CRC) have not been investigated. METHODS: We analyzed miR-503 expression in normal mucosa (n = 20), adenoma (n = 27) and CRC (n = 20). We quantified miR-503 expression in an independent cohort (n = 191) and investigated the clinical significance of miR-503 in CRC. CRC cell lines were transfected with anti-miR-503 to assess its function and target gene. RESULTS: miR-503 expression increased according to the adenoma-carcinoma sequence. High miR-503 expression was significantly associated with large tumor size, serosal invasion, lymphatic and venous invasion as well as lymph node metastasis. CRC patients with high miR-503 expression had significantly earlier relapse and poorer prognosis than those with low expression. miR-503 was an independent recurrence marker in stage I/II CRC. In vitro, attenuated miR-503 expression resulted in inhibition of proliferation, invasion and migration and acquisition of anoikis of CRC cells. The putative target gene (calcium-sensing receptor) was significantly upregulated after miR-503 attenuation. CONCLUSIONS: miR-503 acts as an 'onco-miR' in CRC. High miR-503 expression is associated with early recurrence and poor prognosis in CRC.

Circulating microRNA-203 predicts metastases, early recurrence, and poor prognosis in human gastric cancer.

BACKGROUND: Metastasis is a major cause of death in patients with gastric cancer (GC). MicroRNAs (miRNAs) relating to the epithelial-mesenchymal transition (EMT) control GC progression and metastasis. The aim of this study was to evaluate serum EMT-associated miRNAs for metastatic and prognostic noninvasive biomarkers in GC. METHODS: In the first step of this study (preliminary experiments), we selected candidate miRNAs associated with metastasis by analyzing the expression of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) and miR-203 in serum samples from stage I (n = 12) and stage IV (n = 12) GC patients. The second phase involved the independent validation of candidate miRNAs in serum specimens from 130 patients with GC and 22 controls. RESULTS: Based on the preliminary experiments, miR-203 was selected as the candidate serum miRNA that was most closely associated with metastasis. Validation analysis revealed that serum miR-203 levels were significantly lower in stage IV than stage I-III GC patients. Serum miR-203 expression was significantly lower in GC patients with a higher T stage, vessel invasion, and lymph node, peritoneal, and distant metastases. Low expression of serum miR-203 was significantly associated with poor disease-free and overall survival. Multivariate analysis revealed that low serum miR-203 expression was an independent predictive marker for lymph node, peritoneal, and distant metastases and a poor prognosis in patients with GC. CONCLUSIONS: Serum miR-203 has the potential to serve as a noninvasive biomarker for prognosis and to predict metastasis in patients with GC.

Prognostic relevance of stromal CD26 expression in rectal cancer after chemoradiotherapy.

BACKGROUND: CD26 is a transmembrane glycoprotein whose role in various types of malignancies, along with the potential therapeutic and diagnostic targets, has been evaluated. Preoperative chemoradiotherapy (CRT) is an effective tool for local control of rectal cancer, but the rate of disease recurrence remains high. The aim of this study was to clarify the association between CD26 expression and rectal cancer after preoperative CRT. METHODS: A total of 85 patients with rectal cancer who had undergone preoperative CRT were enrolled in this study. We investigated CD26 expression in residual tumors and the surrounding stromal tissue using immunohistochemistry. Additionally, stromal CD26 gene expression was assessed by real-time quantitative polymerase chain reaction. RESULTS: Patients with high CD26 expression in cancer tissue more frequently had serosal invasion, vascular invasion, and a poor pathological response. High expression of CD26 in the tumor stroma was significantly correlated with histology and tumor recurrence. High CD26 expression in the stroma, but not the tumor itself, was significantly correlated with a poor prognosis. Patients expressing CD26 in the tumor stroma, based on transcriptional analysis, also had a significantly poorer prognosis than those without the expression. In multivariate analysis, lymph node metastasis and high stromal CD26 expression were identified as independent prognostic factors in patients with rectal cancer after neoadjuvant CRT. CONCLUSION: Stromal CD26 expression after preoperative CRT was significantly associated with tumor recurrence and prognosis in rectal cancer patients. Our data suggest that stromal CD26 plays an important role and is a potential therapeutic target in tumor relapse.

Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) regulates immune responses through interaction with its receptor. PD-L1 is not only a predictor of poor prognosis but also a new therapeutic target in several malignancies. Neoadjuvant chemoradiotherapy (CRT) is an effective tool for local control of rectal cancer, but the disease recurrence rate remains high. The aim of this study was to retrospectively evaluate the correlation between PD-L1 expression and clinicopathological variables in rectal cancer after neoadjuvant CRT. MATERIALS AND METHODS: A total of 90 rectal cancer patients who underwent neoadjuvant CRT were enrolled in this study. We evaluated PD-L1 expression using immunohistochemistry. Moreover, we investigated the correlation between PD-L1 expression and tumor-infiltrating T cells, and between CD8- and Foxp3-positive cells. RESULTS: Patients with high PD-L1 expression more frequently had vascular invasion and tumor recurrence compared to patients with low PD-L1 expression (P = 0.0225 and P = 0.0051). High PD-L1 expression was significantly associated with poor recurrence-free and overall survival (P = 0.0027 and P = 0.0357). Multivariate analysis revealed lymph node metastasis and high PD-L1 expression as independent risk factors for tumor recurrence (P = 0.0102 and P = 0.0374). Numbers of infiltrating CD8-positive cells in patients with high PD-L1 expression were significantly lower than in patients with low PD-L1 expression (P = 0.0322). CONCLUSION: Our data suggest that inhibition of PD-L1 may be a new immunotherapeutic strategy to reduce tumor recurrence and improve prognosis in patients with rectal cancer after neoadjuvant CRT.

RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.

Rac GTPase-activating protein (RacGAP) 1 plays a key role in controlling various cellular phenomena including cytokinesis, transformation, invasive migration and metastasis. This study investigated the function and clinical significance of RacGAP1 expression in colorectal cancer (CRC). The intrinsic functions of RacGAP1 in CRC cells were analyzed using small interfering RNA (siRNA). We analyzed RacGAP1 mRNA expression in surgical specimens from 193 CRC patients (Cohort 1) by real-time PCR. Finally, we validated RacGAP1 protein expression using formalin-fixed paraffin-embedded samples from 298 CRC patients (Cohort 2) by immunohistochemistry. Reduced RacGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration and invasion. In Cohort 1, RacGAP1 expression in CRC was significantly higher than in adjacent normal mucosa and increased according to tumor node metastasis stage progression. High RacGAP1 expression in tumors was significantly associated with progression and prognosis. In Cohort 2, RacGAP1 protein was overexpressed mainly in the nuclei of CRC cells; however, its expression was scarcely observed in normal colorectal mucosa. RacGAP1 protein expression was significantly higher in CRC patients with higher T stage, vessel invasion and lymph node and distant metastasis. Increased expression of RacGAP1 protein was significantly associated with poor disease-free and overall survival. Multivariate analyses revealed that high RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence and poor prognosis in CRC. Our data provide novel evidence for the biological and clinical significance of RacGAP1 as a potential biomarker for identifying patients with lymph node metastasis and poor prognosis in CRC.

Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients.

Chronic inflammation of gastric mucosa by Helicobacter pylori infection can initiate gastric carcinogenesis. As angiopoietin-like protein 2 (ANGPTL2) mediates inflammation and inflammation-associated carcinogenesis, we investigated the functional and clinical significance of ANGPTL2 in human gastric cancer (GC). SiRNA knockdown studies were performed for the functional assessment of ANGPTL2 in GC cell lines. ANGPTL2 expression was evaluated immunohistochemically in 192 tissue specimens from GC patients. In addition, we screened serum ANGPTL2 levels from 32 GC patients and 23 healthy controls; and validated these results in 194 serum samples from GC patients and 45 healthy controls by ELISA. ANGPTL2 knockdown caused anoikis and inhibited proliferation, invasion and migration in GC cells. ANGPTL2 expression was upregulated in GC tissues compared to normal gastric mucosa; and high ANGPTL2 expression was significantly associated with tumor progression, early recurrence (P = 0.003) and poor prognosis (P = 0.007). Serum ANGPTL2 in GC patients was significantly higher than for healthy controls (P < 0.05), and accurately distinguished GC patients from healthy control (AUC = 0.865). The validation step confirmed significantly higher serum ANGPTL2 levels in GC patients than healthy controls (P < 0.0001). Receiver operating characteristic curves yielded robust AUC value (0.831) accompanied by high sensitivity (73.0%) and specificity (82.2%) in distinguishing GC patients from healthy controls. High serum ANGPTL2, rather than its expression in matched tissues, was significantly associated with tumor progression, and emerged as an independent marker for recurrence (HR: 5.05, P = 0.0004) and prognosis (HR: 3.6, P = 0.01). Serum ANGPTL2 expression is a potential noninvasive biomarker for diagnosis, early recurrence and prognosis of GC patients.

Angiopoietin-Like Protein 2 Acts as a Novel Biomarker for Diagnosis and Prognosis in Patients with Esophageal Cancer.

BACKGROUND: Angiopoietin-like protein 2 (ANGPTL2) mediates chronic inflammation. Tumor cell-derived ANGPTL2 promotes tumor invasion and angiogenesis. Overexpression of ANGPTL2 in tumor cells is associated with tumor progression and has been recognized in lung, breast, colon, and gastric cancer. However, to our knowledge the functional and clinical significance of ANGPTL2 expression has not been investigated in patients with esophageal cancer (EC). METHODS: First, in vitro assays were performed for functional analysis of ANGPTL2 using small interfering RNA. Next, ANGPTL2 expression in EC tissues (n = 71) was evaluated by immunohistochemistry (IHC in patients with EC (n = 71). Finally, serum ANGPLT2 levels from patients with EC (n = 71) and healthy controls (n = 35) were evaluated using enzyme-linked immunosorbent assay. RESULTS: Knockdown of ANGPTL2 expression decreased the proliferative, invasive, and migration capacity in EC cell lines. ANGPTL2 expression in EC tissues was significantly elevated in patients with a high T stage, squamous cell carcinoma, and high TNM stage. Patients with high ANGPTL2 expression had significantly poorer overall and disease-free survival than those with low expression. Furthermore, high ANGPTL2 expression in EC tissues was an independent predictive marker for a poor prognosis. On the other hand, the serum ANGPTL2 level in patients with EC was significantly higher than that in healthy controls, and allowed for highly accurate discrimination between patients with and without EC. However, no significant association between serum ANGPTL2 levels and clinicopathological findings was observed in patients with EC. CONCLUSIONS: We have demonstrated novel evidence for the clinical significance of ANGPTL2 as a biomarker in patients with EC.

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer.

BACKGROUND: Rac GTPase activating protein 1 (RacGAP1) plays a regulatory role in cell growth, transformation and metastasis. The aim of this study was to clarify the association between RacGAP1 expression and clinical outcome in patients with gastric cancer. METHODS: A total of 232 gastric cancer patients in our institute who underwent surgery without preoperative treatments were enrolled in this study. We investigated RacGAP1 expression using immunohistochemistry (IHC) and evaluated IHC scores calculated by the percentage of positive cells and intensity and its expression at the invasive front. RACGAP1 expression was also assessed. RESULTS: RacGAP1 expression was observed in the nuclei of gastric cancer cells. Evaluation by IHC score showed no significant correlations with clinicopathological variables except for histological differentiation. In transcriptional analyses, RACGAP1 expression was elevated in diffuse type gastric cancer than intestinal type without a significant difference. We observed significant correlations of RacGAP1 protein expression at the invasive front with older age, tumor size, lymph node metastasis, lymphatic invasion, vascular invasion and advanced stage. Patients with RacGAP1 protein expression at the invasive front had significantly poorer prognosis than those without it (P < 0.0001). In multivariate analysis, lymph node metastasis, distant metastasis and positive RacGAP1 expression at the invasive front were independent prognostic factors (lymph node metastasis: P = 0.0106; distant metastasis: P = 0.0012; RacGAP1: P = 0.0011). CONCLUSIONS: RacGAP1 expression at the invasive front in gastric cancer was significantly correlated with factors reflecting tumor progression and poor prognosis. Our data suggest that RacGAP1 might play important roles in the progression of gastric cancer.

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenograft model of gastric cancer using two-photon laser scanning microscopy.

BACKGROUND: We previously visualized in vivo responses to chemotherapy in a colorectal liver metastatic xenograft model using in vivo real-time and time-series intravital two-photon laser scanning microscopy (TPLSM). In this study, we established the method for evaluating the response of peritoneal xenografts to chemotherapy of metastatic gastric cancer using intravital TPLSM. METHODS: Red fluorescent protein-expressing gastric cancer cells (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein nude mice. RESULTS: Laparotomy revealed that 2 weeks after inoculation, macroscopic peritoneal metastatic nodules were formed. The first intravital TPLSM session revealed that they were composed of red tumor cell clusters and green surrounding stroma. Paclitaxel was administered intraperitoneally after the first TPLSM three times a week for 7 days in the treatment group. At the second laparotomy, there were significantly fewer and smaller nodules in the treated mice than in the controls. The second intravital TPLSM session showed tumor cell fragmentation, swelling, and nuclear condensation in the metastatic nodules--a response to chemotherapy. There were multinuclear tumor cells in the paclitaxel-treated living mice. CONCLUSIONS: Our method may become a powerful tool for evaluating the efficacy of novel anti-gastric cancer drugs in a preclinical murine model with minimum interindividual variation.

Short- and long-term outcomes of laparoscopic gastrectomy in elderly patients with gastric cancer.

BACKGROUND: Elderly patients are regarded as being at increased risk during major abdominal surgery because of a lack of functional reserve and an increased number of comorbidities. The aim of this study was to compare short- and long-term outcomes of laparoscopic gastrectomy between elderly and young gastric cancer patients. METHODS: Two-hundred ten patients who underwent laparoscopic gastrectomy for gastric cancer at our institution between January 2001 and December 2011 were included in this retrospective study. Patients were divided into two age groups (younger than 70 years and older than 70 years) and were evaluated with respect to postoperative morbidity, quality of life (QOL), and survival. RESULTS: Postoperative morbidity was similar in elderly and young groups (18.3 vs. 21.6 %; P = 0.718). Overall survival of the elderly group was significantly worse than that of the young group (P < 0.001). However, disease-specific survival was not significantly different between the two groups. Longitudinal postoperative change in QOL in the elderly group showed a recovery similar to that in the young group. CONCLUSIONS: Laparoscopic gastrectomy can be performed as safely in elderly patients as in young patients, with comparable postoperative results and long-term outcomes, including QOL, although the life expectancy of elderly patients is shorter.

Systemic Analysis of Predictive Biomarkers for Recurrence in Colorectal Cancer Patients Treated with Curative Surgery.

BACKGROUND: Preoperative serum systemic inflammatory response (SIR) in patients with colorectal cancer (CRC) has been reported to be a predictive biomarker of early recurrence. The molecular status of CRC, including microsatellite instability (MSI), BRAF and KRAS mutations, and tumor-infiltrating lymphocytes (TILs), has also been associated with recurrence in CRC patients treated with curative surgery. AIM: We investigated the impacts of SIR status, TILs, and MSI on recurrence in curative CRC patients. METHODS: In this retrospective study, we enrolled 157 patients with stage I-III CRC undergoing curative surgery, for whom preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and C-reactive protein (CRP) data were available as indicators of SIR status. Molecular status was evaluated by counting TILs as the numbers of intratumoral Foxp3- and CD8-positive T cells by immunohistochemistry. MSI status was determined using five mononucleotide repeat microsatellite markers. RESULTS: Kaplan-Meier analysis of SIR indicators revealed that higher CRP, NLR, and PLR were associated with significantly poorer disease-free survival (DFS). Low levels of infiltrating CD8-positive T cells in CRC tissue was a significant predictor of poor DFS. Multivariate analysis showed that few infiltrating CD8-positive T cells and high serum CRP levels were independent predictive factors for recurrence. Furthermore, the combination of high CRP and few infiltrating CD8-positive T cells increased the predictive accuracy in these patients. CONCLUSIONS: The results of this study suggest that both CRP levels in preoperative serum and CD8 T cells in CRC tissue are useful biomarkers for predicting early relapse in CRC patients treated with curative surgery.

Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis.

The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia.

Identification of prognostic factors and surgical indications for metastatic gastric cancer.

BACKGROUND: The treatment of metastatic gastric cancer is not uniform, and the prognostic factors and indications for surgery are currently unclear. This retrospective study aimed to identify the prognostic factors and clinical indications for surgery in patients with metastatic gastric cancer. METHODS: A total of 123 consecutive patients with gastric cancer and synchronous distant metastasis treated between January 1999 and December 2011 were reviewed. Patient, tumor, laboratory, surgical, and chemotherapy factors were analyzed, with overall survival as the endpoint. Univariate analyses were performed using the log-rank test, multivariate analyses were performed using the Cox proportional hazards model, and Kaplan-Meier curves were used to estimate survival. Significance was set at p<0.05. RESULTS: The median overall survival time was 13.1 months. Ninety-eight patients received chemotherapy. Twenty-eight patients underwent gastrectomy with metastasectomy and 55 underwent gastrectomy without metastasectomy. The median overall survival time for patients who underwent gastrectomy with metastasectomy, gastrectomy without metastasectomy, and no surgical intervention was 21.9 months, 12.5 months, and 7.2 months, respectively (p<0.001). Multivariate analysis identified gastrectomy with or without metastasectomy, performance status (PS) ≥ 3, neutrophil-to-lymphocyte ratio (NLR) >3.1, and carbohydrate antigen 19-9 (CA19-9) level >37 U/mL as predictors of poor survival. NLR and CA19-9 level were also independent prognostic factors in the group of patients who underwent surgery. CONCLUSIONS: High pretreatment NLR, CA19-9 level, and PS are predictors of poor prognosis in patients with metastatic gastric cancer. In selected patients, gastrectomy can be performed safely, and may be associated with longer survival.

Increased expression of Slug and Vimentin as novel predictive biomarkers for lymph node metastasis and poor prognosis in colorectal cancer.

Slug and Vimentin genes play a critical role in regulating epithelial-mesenchymal transition (EMT) via downregulation of epithelial markers and upregulation of mesenchymal markers. The present study evaluated the clinical significance of Slug and Vimentin expression as potential disease biomarkers in colorectal cancer (CRC). At first, the biological role of Slug in CRC was assessed by RNA interference in CRC cell lines to assess tumor progression, invasion and migration. Next, we analyzed Slug and Vimentin expression in surgical tissue specimens from 181 CRC patients (Cohort 1) by quantitative real-time reverse transcription-PCR and 208 patients (Cohort 2) by immunohistochemistry. Knockdown of Slug using small interfering RNA in CRC cell lines resulted in inhibition of EMT, reduced cell proliferation, invasion and migration in CRC cells. Interestingly, Slug and Vimentin expression in cancer tissues was significantly higher in patients with higher T stage, lymph node involvement, liver metastasis and advanced tumor node metastasis stages. A significant correlation was observed between Slug and Vimentin expression in CRC (messenger RNA: ρ = 0.546, protein: ρ = 0.405), and increased expression of Slug and Vimentin was significantly associated with poor prognosis. Furthermore, increased expression of Slug emerged as an independent prognostic factor and a predictive marker of lymph node metastasis in CRC patients. Our data provide novel evidence for the biological and clinical significance of Slug and Vimentin expression as potential predictive biomarkers for identifying patients with lymph node metastasis or poor prognosis in CRC.

Identification of patients with developing ulcerative colitis-associated neoplasia by nitrative DNA damage marker 8-nitroguanin expression in rectal mucosa.

GOAL: To clarify whether the expression of nitrative and oxidative DNA damage markers in the rectal mucosa of patients with ulcerative colitis (UC) could be used to predict UC-associated neoplasia. BACKGROUND: A longer duration of UC can increase the risk of developing UC-associated cancer (UCAC). Effective diagnostic markers are being sought to provide more selective screening and treatment strategies for patients with long-standing UC. STUDY: A total of 141 patients with UC who underwent a proctocolectomy were enrolled in this study. The expression of 8-nitroguanine (8-NG), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and inducible nitric oxide synthase (iNOS) in the rectal mucosa were evaluated using immunohistochemistry (IHC) and assessed relative to the pathogenesis of UC-associated neoplasia. RESULTS: Eighteen patients (12.8%) had UC-associated neoplasia including low-grade or high-grade dysplasia and UCAC. IHC scores of 8-NG in UC-associated neoplasia group was significantly higher than in non-neoplasia group (P<0.0001). In contrast, IHC score of 8-oxodG in non-neoplasia group was significantly decreased compared with UC-associated neoplasia group (P=0.0028). In logistic regression analysis, duration of disease >8 years, high IHC scores of 8-NG, and low 8-oxodG in the rectal mucosa were significantly associated with the development of UC-associated neoplasia (P<0.01). The expression of 8-NG was more frequently observed in patients with UCAC than in patients with sporadic colorectal cancer (P<0.01). CONCLUSION: These results suggest that evaluating the expression levels of 8-NG in the rectal mucosa may be a useful biomarker for detecting patients with UC-associated neoplasia.