Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

Activin A/ACVR2A axis inhibits epithelial-to-mesenchymal transition in colon cancer by activating SMAD2.

Colorectal cancer is one of the most common malignancies worldwide. Liver metastasis is the major direct cause of colorectal cancer-related deaths. Although radical resection is the most effective treatment for colorectal cancer liver metastasis, several patients are not eligible for surgery. Therefore, there is a need to develop novel treatments based on the understanding of the biological mechanisms underlying liver metastasis in colorectal cancer. This study demonstrated that activin A/ACVR2A inhibits colon cancer cell migration and invasion, as well as suppresses the epithelial-to-mesenchymal transition of mouse colon cancer cells. This finding has been further validated in animal experiments. Mechanistic studies revealed that activin A binds to Smad2 (instead of Smad3) and activates its transcription. Analysis of the paired clinical samples further confirmed that the expression levels of ACVR2A and SMAD2 were the highest in adjacent healthy tissues, followed by primary colon cancer tissues and liver metastasis tissues, suggesting that ACVR2A downregulation may promote colon cancer metastasis. Bioinformatics analysis and clinical studies demonstrated that ACVR2A downregulation was significantly associated with liver metastasis and poor disease-free and progression-free survival of patients with colon cancer. These results suggest that the activin A/ACVR2A axis promotes colon cancer metastasis by selectively activating SMAD2. Thus, targeting ACVR2A is a potential novel therapeutic strategy to prevent colon cancer metastasis.

Small Nucleolar RNA Host Gene 1 (SNHG1) and Chromosome 2 Open Reading Frame 48 (C2orf48) as Potential Prognostic Signatures for Liver Cancer by Constructing Regulatory Networks.

BACKGROUND Liver cancer is a common malignant tumor with poor prognosis. The present study sought to identify potential signatures that can predict the prognosis of patients with liver cancer. MATERIAL AND METHODS The RNA sequencing (RNA-seq) and clinical information of liver cancer patients were obtained from the Cancer Genome Atlas (TCGA) database. Differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were identified between liver cancer and adjacent normal tissues. After predicting lncRNA-miRNA and miRNA-mRNA pairs using online databases, the competing endogenous RNA (ceRNA) networks were constructed. Furthermore, the prognostic value of these differentially expressed genes was evaluated using univariate and multivariate Cox regression analyses. RESULTS After constructing the ceRNA network, 2 lncRNAs small nucleolar RNA host gene 1 (SNHG1) and chromosome 2 open reading frame 48 (C2orf48) with the most nodes were identified. Correlation analysis revealed that SNHG1 was correlated with miR-195 and C2orf48 was correlated with miR-195 and miR-93. High expression of SNHG1, C2orf48, and miR-93 can contribute to poorer clinical outcomes compared to low expression. Furthermore, low miR-195 expression was correlated with shorter survival time than was high expression. SNHG1 and C2orf48 were closely associated with histology grade. Univariate and multivariate Cox regression analyses confirmed that SNHG1 and C2orf48 are risk factors for liver cancer. CONCLUSIONS Our findings revealed that SNHG1 and C2orf48 possess potential prognostic value and should be considered as possible biomarkers for predicting clinical outcomes for patients with liver cancer.

A kinase-interacting protein 1 may serve as a potential biomarker for deteriorative tumor features and poor prognosis in gastric cancer patients.

OBJECTIVE: This study aimed to explore the association of A kinase-interacting protein 1 (AKIP1) expression with clinicopathological characteristics and prognosis in gastric cancer patients. METHODS: Data of 260 gastric cancer patients were retrospectively reviewed. AKIP1 expression in tumor tissue and non-cancerous tissue specimens was detected by immunohistochemistry and semi-quantitatively scored according to the staining intensity and density. Moreover, the clinicopathological features were retrieved, and disease-free survival (DFS) and overall survival (OS) were calculated. RESULTS: A kinase-interacting protein 1 expression was increased in tumor tissues compared with non-cancerous tissues (P < .001). In terms of tumor features, tumor AKIP1 high expression correlated with elevated T stage (P < .001) and raised TNM stage (P = .042), while did not correlate with pathological grade (P > .999), tumor size (P = .060), N stage (P = .180), or tumor location (P > .999). Meanwhile, tumor AKIP1 was not associated with the non-tumor features either. Kaplan-Meier curves disclosed that AKIP1 high expression patients had shorter DFS (P = .004) and OS (P = .043) compared with AKIP1 low expression patients. Univariate Cox's regression showed that AKIP1 high expression correlated with shorter DFS (P = .005, hazard ratio [HR] = 1.635) and OS (P = .046, HR = 1.519), whereas multivariate Cox's regression displayed that AKIP1 did not independently predict worse DFS (P = .172, HR = 1.276) or shorter OS (P = .433, HR = 1.183). CONCLUSION: A kinase-interacting protein 1 may serve as a potential biomarker for deteriorative tumor features and poor prognosis in gastric cancer patients.

PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation.

Previous reports have suggested that human CD4(+) CD25(hi)FOXP3(+) T regulatory cells (Tregs) have functional plasticity and may differentiate into effector T cells under inflammation. The molecular mechanisms underlying these findings remain unclear. Here we identified the residue serine 422 of human FOXP3 as a phosphorylation site that regulates its function, which is not present in murine Foxp3. PIM1 kinase, which is highly expressed in human Tregs, was found to be able to interact with and to phosphorylate human FOXP3 at serine 422. T cell receptor (TCR) signaling inhibits PIM1 induction, whereas IL-6 promotes PIM1 expression in in vitro expanded human Tregs. PIM1 negatively regulates FOXP3 chromatin binding activity by specifically phosphorylating FOXP3 at Ser(422). Our data also suggest that phosphorylation of FOXP3 at the Ser(418) site could prevent FOXP3 phosphorylation at Ser(422) mediated by PIM1. Knockdown of PIM1 in in vitro expanded human Tregs promoted FOXP3-induced target gene expression, including CD25, CTLA4, and glucocorticoid-induced tumor necrosis factor receptor (GITR), or weakened FOXP3-suppressed IL-2 gene expression and enhanced the immunosuppressive activity of Tregs. Furthermore, PIM1-specific inhibitor boosted FOXP3 DNA binding activity in in vitro expanded primary Tregs and also enhanced their suppressive activity toward the proliferation of T effector cells. Taken together, our findings suggest that PIM1 could be a new potential therapeutic target in the prevention and treatment of human-specific autoimmune diseases because of its ability to modulate the immunosuppressive activity of human Tregs.

Nuclear-enriched abundant transcript 1 as a diagnostic and prognostic biomarker in colorectal cancer.

BACKGROUND: High expression of the long non-coding RNA nuclear-enriched abundant transcript 1 (NEAT1) in whole blood has been reported in colorectal cancer patients; however, its' clinical significance and origin are unclear. We evaluated the diagnostic and prognostic value, and origin of whole blood NEAT1 in colorectal cancer. METHODS: Expression of NEAT1 variants, NEAT1_v1 and NEAT1_v2 were determined using real-time quantitative PCR. The diagnostic value of whole blood NEAT1 expression was evaluated in test (n = 60) and validation (n = 200) cohorts of colorectal cancer patients and normal controls (NCs). To identify the origin of NEAT1, its expression was analyzed in blood, matched primary tumor tissues, para-tumor tissues, metastatic tissues, and also immune cells from patients or NCs. Function of NEAT1 in colorectal cell lines was also assessed. The correlation of NEAT1 expression with clinical outcomes was assessed in 191 patients. RESULTS: Whole blood NEAT1 expression was significantly higher in colorectal cancer patients than in NCs. NEAT1_v1 and NEAT1_v2 expression were highly accurate in distinguishing colorectal cancer patients from NCs (area under the curve: 0.787 and 0.871, respectively). Knockdown of NEAT1_v1 in vitro could inhibit cell invasion and proliferation, while knockdown of NEAT1_v2 promoted cell growth. However, whole blood expression was not correlated with matched tissues. An elevated expression was seen in neutrophils from CRC patients. Furthermore, high expression of NEAT1_v1 was correlated with worse overall survival. In contrast, high expression of NEAT1_v2 alone was correlated with better overall survival. CONCLUSION: Whole blood NEAT1 expression is a novel diagnostic and prognostic biomarker of overall survival in colorectal cancer. Elevated NEAT1 may derive from neutrophils.

Unfavorable effect of small tumor size on cause-specific survival in stage IIA colon cancer, a SEER-based study.

BACKGROUND: We sought to determine the prognostic role of tumor size on cause-specific survival (CSS) of patients with stage IIA colon cancer. METHODS: Surveillance, Epidemiology and End Results (SEER) database was utilized to identify patients with stage IIA colorectal cancer (examined lymph nodes ≥12) diagnosed from 1988 to 2003. The prognostic effect of tumor size on CSS was evaluated by univariate and multivariate analyses. RESULTS: A total of 8775 patients were enrolled in the analysis. The median follow-up time was 109 months. As determined by minimal P value method, tumor sizes of 2.5 and 6.0 cm were used as optimal cutoff value to divide the cohort. The 8-year CSS of colon cancer with tumor sizes ≤2.5, 2.6-6.0, and >6.0 cm was 81.6, 86.2, and 86.7% respectively (P = 0.003). In the multivariate analysis of colon cancer, using ≤2.5-cm tumors as reference, decreased hazard ratio (HR) of CSS was observed in 2.6-6.0 cm (HR, 0.736; 95% confidence interval (CI), 0.599-0.905; P = 0.004) and >6.0 cm (HR, 0.770; 95% CI, 0.619-0.958; P = 0.019) tumors. CONCLUSIONS: In stage IIA colon cancer, small tumor size represented a subset with decreased CSS. Further studies are merited to validate the unfavorable prognostic role of small tumor size in stage IIA colon cancer.

Feasibility and Safety of Laparoscopic Colon Surgery Performed Under Intravenous Sedation and Local Anesthesia Using Microinvasive (<3 mm) Instruments: An Acute and Survival Study on Porcine Model.

PURPOSE: The purpose of the study was to evaluate the feasibility and safety of performing laparoscopic intestinal surgery using local anesthesia and intravenous sedation with instruments <3 mm in diameter. METHODS: Porcine model with acute (n = 2) and the survival studies (n = 8): all female pigs, weight (median 36.4 kg, range 33.2-38.4 kg). Surgeries were performed using only intravenous sedation with ketamine-midazolam and local anesthetic infiltration at the sites of trocar insertion, with airway protection. CO2 pneumoperitoneum was maintained using pressure of 3 to 5 mm Hg. Commercially available instruments, sizes <3 mm in diameter were used. Surgical steps were as follows: (a) exploration of all quadrants of the abdomen and pelvis, (b) "running" the entire length of small bowel, (c) dissection of bowel attachments to the peritoneal sidewall, and (d) creating a 2.5 cm enterotomy in the colon and suture repair of this defect. RESULTS: All 10 surgeries were completed successfully. Animals tolerated the procedure well, with no requirement of intubation. There were no decrements in vital signs during pneumoperitoneum or surgery. Despite spontaneous respiration movements, all planned surgical maneuvers were feasible. The median length of operations was 74 minutes (range 56-165 minutes). All survival animals had an uneventful recovery; there were no infectious complications, oral intake and bowel function returned within 24 hours. CONCLUSIONS: It appears feasible and safe to perform simple laparoscopic intestinal procedures using instruments <3 mm in diameter and low CO2 insufflation pressure under local anesthesia and intravenous sedation. This methodology holds promise in the development of new approaches to intestinal surgery and disease diagnosis.

Higher FOXP3-TSDR demethylation rates in adjacent normal tissues in patients with colon cancer were associated with worse survival.

BACKGROUND: The influence of natural regulatory T cells (nTregs) on the patients with colon cancer is unclear. Demethylated status of the Treg-specific demethylated region (TSDR) of the FOXP3 gene was reported to be a potential biomarker for the identification of nTregs. METHODS: The demethylation rate of the TSDR (TSDR-DMR) was calculated by using methylation-specific quantitative polymerase chain reaction (MS-qPCR) assay. The expression of TSDR-DMR and FOXP3 mRNA was investigated in various colorectal cancer cell lines. A total of 130 colon carcinoma samples were utilized to study the DMR at tumor sites (DMRT) and adjacent normal tissue (DMRN). The correlations between DMRs and clinicopathological variables of patients with colon cancer were studied. RESULTS: The TSDR-DMRs varied dramatically among nTregs (97.920 ± 0.466%) and iTregs (3.917 ± 0.750%). Significantly, DMRT (3.296 ± 0.213%) was higher than DMRN (1.605 ± 0.146%) (n = 130, p = 0.000). Higher DMRN levels were found in female patients (p = 0.001) and those with distant metastases (p = 0.017), and were also associated with worse recurrence-free survival in non-stage IV patients (low vs. high, p = 0.022). However, further Cox multivariate analysis revealed that the FOXP3-TSDR status does not have prognostic value. CONCLUSION: MS-qPCR assays of FOXP3-TSDR can efficiently distinguish nTregs from non-nTregs. Abnormal recruitment of nTregs occurs in the local tumor microenvironment. Infiltration of tissue-resident nTregs may have a negative role in anti-tumor effects in patients with colon cancer; however, this role is limited and complicated.

Metastatic lymph node ratio can further stratify prognosis in rectal cancer patients treated with preoperative radiotherapy: a population-based analysis.

Recent studies have shown that it is not only the absolute number of involved lymph nodes (LNs) but also the ratio of metastatic lymph node that confers prognostic information. However, the impact of the lymph node ratio (LNR) on the prognosis of rectal cancer treated with preoperative radiotherapy is still not fully studied. In this study, Surveillance, Epidemiology, and End Results (SEER)-registered rectal cancer patients treated with preoperative radiotherapy (preop-RT) with LN metastasis were evaluated using multivariate Cox regression analysis to determine the prognostic role of the LNR. LNR optimal cutoff was identified by X-tile. The rationale of yielding pathological node stage (yp-N stage) and yielding pathological lymph node ratio stage (yp-rN stage) (LNR stage) was further combined for analysis. For the results, X-tile program determined 0.28 and 0.68 as optimal cutoff values in terms of survival in 1,872 rectal cancer patients treated with preoperative radiotherapy. yp-rN was significantly associated with 5-year rectal cancer cause-specific survival (RCSS) (P < 0.001). In a multivariate analysis, yp-rN was a significant independent prognostic factor for RCSS (hazard ratios, 1.277 and 1.631; P < 0.001). yp-rN had a prognostic impact on RCSS in patients with yp-N1 and yp-N2 subgroup. yp-N stage also had influenced on RCSS in all yp-rN stage. The yp-rN stage can be used together with the yp-N stage to select high-risk patients for postoperative treatment.

Characterize molecular signatures and establish a prognostic signature of gastric cancer by integrating single-cell RNA sequencing and bulk RNA sequencing.

Gastric cancer is a significant global health concern with complex molecular underpinnings influencing disease progression and patient outcomes. Various molecular drivers were reported, and these studies offered potential avenues for targeted therapies, biomarker discovery, and the development of precision medicine strategies. However, it was posed that the heterogeneity of the disease and the complexity of the molecular interactions are still challenging. By seamlessly integrating data from single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq), we embarked on characterizing molecular signatures and establishing a prognostic signature for this complex malignancy. We offered a holistic view of gene expression landscapes in gastric cancer, identified 226 candidate marker genes from 3 different dimensions, and unraveled key players' risk stratification and treatment decision-making. The convergence of molecular insights in gastric cancer progression occurs at multiple biological scales simultaneously. The focal point of this study lies in developing a prognostic model, and we amalgamated four molecular signatures (COL4A1, FKBP10, RNASE1, SNCG) and three clinical parameters using advanced machine-learning techniques. The model showed high predictive accuracy, with the potential to revolutionize patient care by using clinical variables. This will strengthen the reliability of the model and enable personalized therapeutic strategies based on each patient's unique molecular profile. In summary, our research sheds light on the molecular underpinnings of gastric cancer, culminating in a powerful prognostic tool for gastric cancer. With a firm foundation in biological insights and clinical implications, our study paves the way for future validations and underscores the potential of integrated molecular analysis in advancing precision oncology.

CXCL1 promotes colon cancer progression through activation of NF-κB/P300 signaling pathway.

BACKGROUND: The upregulated expression of CXCL1 has been validated in colorectal cancer patients. As a potential biotherapeutic target for colorectal cancer, the mechanism by which CXCL1 affects the development of colorectal cancer is not clear. METHODS: Expression data of CXCL1 in colorectal cancer were obtained from the GEO database and verified using the GEPIA database and the TIMER 2.0 database. Knockout and overexpression of CXCL1 in colorectal cancer cells by CRISPR/Cas and "Sleeping Beauty" transposon-mediated gene editing techniques. Cell biological function was demonstrated by CCK-8, transwell chamber and Colony formation assay. RT-qPCR and Western Blot assays measured RNA and protein expression. Protein localization and expression were measured by immunohistochemistry and immunofluorescence. RESULTS: Bioinformatics analysis showed significant overexpression of CXCL1 in the colorectal cancer tissues compared to normal human tissues, and identified CXCL1 as a potential therapeutic target for colorectal cancer. We demonstrate that CXCL1 promotes the proliferation and migration of colon cancer cells and has a facilitative effect on tumor angiogenesis. Furthermore, CXCL1 elevation promoted the migration of M2-tumor associated macrophages (TAMs) while disrupting the aggregation of CD4+ and CD8+ T cells at tumor sites. Mechanistic studies suggested that CXCL1 activates the NF-κB pathway. In the in vivo colon cancer transplantation tumor model, treatment with the P300 inhibitor C646 significantly inhibited the growth of CXCL1-overexpressing colon cancer. CONCLUSION: CXCL1 promotes colon cancer development through activation of NF-κB/P300, and that CXCL1-based therapy is a potential novel strategy to prevent colon cancer development.

[Advantage of perisplenic hilar lymph node dissection by laparoscopy-assisted total gastrectomy (D2) over conventional open total gastrectomy for advanced gastric cancer].

OBJECTIVE: To compare the number of harvested perisplenic hilar lymph nodes by laparoscopy-assisted total gastrectomy (LATG) and conventional open total gastrectomy (OTG) for advanced upper and middle gastric cancer. METHODS: Three hundred twelve patients with advanced gastric cancer treated in a single institution between Sept 2008 and Jan 2011 were included in this study. They were divided into two groups: the LATG group and OTG (D2) group. All the surgical operations were performed by one surgeon or under his supervision. The lymph node clearance outcomes of the patients treated by those two surgical procedures were analyzed. RESULTS: The harvested lymph node numbers of the two groups were (29.57 ± 9.62) and (29.38 ± 11.22) respectively, statistically with no significant difference (P = 0.875). The numbers of lymph node dissected around the splenic area in the LATG group and OTG group (Section 10, 11 group) were (2.01 ± 1.34) and (1.33 ± 1.11), respectively, indicating a significant difference (P = 0.000). The numbers of lymph nodes dissected around the celiac region (Section 7, 8, 9, 11p and 12a(2) group) were (7.90 ± 3.41) and (7.22 ± 2.65), respectively, with a non-significant difference (P = 0.050). There were also no significant differences while comparing with the numbers of lymph nodes dissected in the cardiac area (group 1, 2), pyloric region (5, 6 group) and the greater and lesser omentum area (group 3 and 4) between the two groups (P = 0.605, P = 0.248, P = 0.262). CONCLUSION: Short-term results of this study indicate that laparoscopy-assisted total gastrectomy (D2) is better than conventional open surgery in perisplenic hilar lymph node dissection.

Clinical Perspectives on Liquid Biopsy in Metastatic Colorectal Cancer.

Liquid biopsy, which generally refers to the analysis of biological components such as circulating nuclear acids and circulating tumor cells in body fluids, particularly in peripheral blood, has shown good capacity to overcome several limitations faced by conventional tissue biopsies. Emerging evidence in recent decades has confirmed the promising role of liquid biopsy in the clinical management of various cancers, including colorectal cancer, which is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. Despite the challenges and poor clinical outcomes, patients with metastatic colorectal cancer can expect potential clinical benefits with liquid biopsy. Therefore, in this review, we focus on the clinical prospects of liquid biopsy in metastatic colorectal cancer, specifically with regard to the recently discovered various biomarkers identified on liquid biopsy. These biomarkers have been shown to be potentially useful in multiple aspects of metastatic colorectal cancer, such as auxiliary diagnosis of metastasis, prognosis prediction, and monitoring of therapy response.

A Pipeline to Call Multilevel Expression Changes between Cancer and Normal Tissues and Its Applications in Repurposing Drugs Effective for Gastric Cancer.

Differential gene analyses on gastric cancer usually focus on expression change of single genes between tumor and adjacent normal tissues. However, besides changes on single genes, there are also coexpression and expression network module changes during the development of gastric cancer. In this study, we proposed a pipeline to investigate various levels of changes between gastric cancer and adjacent normal tissues, which were used to repurpose potential drugs for treating gastric cancer. Specifically, we performed a series of analyses on 242 gastric cancer samples (33-normal, 209-cancer) downloaded from the cancer genome atlas (TCGA), including data quality control, differential gene analysis, gene coexpression network analysis, module function enrichment analysis, differential coexpression analysis, differential pathway analysis, and screening of potential therapeutic drugs. In the end, we discovered some genes and pathways that are significantly different between cancer and adjacent normal tissues (such as the interleukin-4 and interleukin-13 signaling pathway) and screened perturbed genes by 2703 drugs that have a high overlap with the identified differentially expressed genes. Our pipeline might be useful for understanding cancer pathogenesis as well as gastric cancer treatment.

Association between the expression of carbonic anhydrase II and clinicopathological features of hepatocellular carcinoma.

The present study aimed to examine the molecular marker associated with the therapy and prognosis of hepatocellular carcinoma (HCC), and further investigate the association between its expression and the clinicopathological features of HCC. To select the core genes closely associated with HCC, differentially expressed genes (DEGs) were analyzed and screened from Gene Expression Omnibus datasets (GSE 36376) using a bioinformatics approach. Tumor and adjacent tissues were collected form 112 patients of HCC who were treated by radical resection. The expression levels of carbonic anhydrase II (CA2) in the tumor and adjacent tissues were determined using reverse transcription-quantitative polymerase chain reaction analysis and immunohistochemistry. The χ2 test was applied for observing the association between the expression of CA2 and clinicopathological features of patients with HCC. The effects of the expression of CA2 on the patients' overall survival (OS) and disease-free survival (DFS) were examined via Kaplan-Meier analysis. A total of 83 DEGs were screened and analyzed using gene network analysis, among which CA2 had direct interactions with more than one disease gene of HCC. The results of immunohistochemistry showed that CA2 was expressed at a lower level in the tumor tissues compared with the adjacent tissues (t=3.012, P=0.010). Single factor analysis revealed that the mRNA expression of CA2 was able to predict the recurrence of HCC, and was significantly associated with α-fetoprotein (AFP), microvascular invasion, tumor-node-metastasis (TNM) staging, and recurrence (P<0.05). The expression levels of AFP, CA2 and TNM staging were confirmed to be independent prognostic factors of HCC (P<0.05). Kaplan-Meier analysis demonstrated that the group with a high expression of CA2 showed increased DFS and OS, compared with the low expression group (P<0.05). These findings indicated that elevated CA2 increased DFS and OS of HCC, which suggested that CA2 may be a potential target for HCC therapy.

Chemokine (C-X-C motif) ligand 1 is associated with tumor progression and poor prognosis in patients with colorectal cancer.

Chemokine (C-X-C motif) ligand 1 (CXCL1) is a chemotactic cytokine known to regulate cancer progression and invasion. However, the prognostic significance of CXCL1 expression in colorectal cancer (CRC) has not been fully characterized. The present study explored the clinicopathological significance and potential role of CXCL1 in the carcinogenesis and progression of CRC. The protein expression of CXCL1 was measured immunohistochemically in tissue microarrays constructed from 276 CRC patients. CXCL1 expression levels and their associations with clinicopathological characteristics and patient survival were evaluated. The effect of CXCL1 on glycolysis was also examined. High CXCL1 expression was detected in 165 (59.8%) cases. CXCL1 expression was correlated with tumor diameter (P=0.002), T stage (P=0.044), N stage (P=0.005), M stage (P=0.001), lymphovascular invasion (P=0.010), and carcinoembryonic antigen status (P=0.019). High CXCL1 expression was validated as an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) by both univariate and multivariate Cox regression analyses (both P<0.05). Experimentally, expression of CXCL1 was knocked down by stable transfected short hairpin RNA, resulting in a significantly decreased rate of glycolysis both in in vitro assays and in patients' samples (P<0.05). Silencing the expression of CXCL1 decreased the levels of the glycolytic enzymes GLUT1, HK2, and LDHA. In conclusion, by inducing glycolysis, CXCL1 plays a crucial role in both cancer progression and metastasis in CRC patients. The CXCL1 expression level is an independent prognostic factor for both OS and DFS. Moreover, CXCL1 may serve as a new biomarker and potential therapeutic target for CRC treatment.

Downregulation of Activin A Receptor Type 2A Is Associated with Metastatic Potential and Poor Prognosis of Colon Cancer.

Aims: Activin A receptor type 2A (ACVR2A) is a membrane receptor in the transforming growth factor- beta (TGF-ß signaling pathway, which is involved in the regulation of cell proliferation, migration, and apoptosis. The aim of this study was to examine the expression profiles and biological functions of ACVR2A in colon cancer. Methods: ACVR2A expression was investigated using the GSE39582 database and two validation cohorts. An in vitro study of cell proliferation and migration of human colon cell lines was also performed. Results: In the GSE39582 database (n= 497), expression of ACVR2A mRNA was identified as a prognostic factor by linear regression analysis. In one validation cohort of 15 patients with stage IV cancer, the mRNA expression of ACVR2A was significantly reduced in metastatic lesions and primary tumors compared with adjacent normal controls (P = 0.001). In another validation cohort of tissue microarray (TMA) consisting of 193 cases, reduced ACVR2A protein expression correlated with advanced N stage (P = 0.001) and positive lymphovascular invasion (P = 0.005). Strong correlations between low ACVR2A mRNA or protein expression and worse survival were also observed in the GSE39582 database and the TMA validation cohort (all P < 0.05). Moreover, our in vitro studies showed a remarkable increase in cell migration in ACVR2A knockdown cells. Conclusions: Our findings indicate that loss of ACVR2A has an important role in cancer progression and distant metastasis and may serve as a prognostic marker in patients with colon cancer.

Negative lymph node count is a significant prognostic factor in patient with stage IV gastric cancer after palliative gastrectomy.

Negative lymph node (NLN) count has been validated as a protective predictor in various cancers after radical resection. However, the prognostic value of NLN count in the setting of stage IV gastric cancer patients who have received palliative resection has not been investigated. Surveillance, Epidemiology, and End Results Program (SEER)-registered gastric cancer patients were used for analysis in this study. Kaplan-Meier survival curves and multivariate Cox proportional hazards model were used to assess the risk factors for patients' survivals. The results showed that NLN count and N stage were independently prognostic factors in patients with stage IV gastric cancer after palliative surgery (P< 0.001). X-tile plots identified 2 and 11 as the optimal cutoff values to divide the patients into high, middle and low risk subsets in term of cause-specific survival (CSS). And NLN count was proved to be an independently prognostic factor in multivariate Cox analysis (P< 0.001). The risk score of NLN counts demonstrated that the plot of hazard ratios (HRs) for NLN counts sharply increased when the number of NLN counts decreased. Collectively, our present study revealed that NLN count was an independent prognostic predictor in stage IV gastric cancer after palliative resection. Standard lymph node dissection, such as D2 lymphadectomy maybe still necessary during palliative resection for patients with metastatic gastric cancer.

[Study on the clinicopathologic characteristics and prognostic difference of gastric stump cancer between non-anastomotic site and anastomotic site].

OBJECTIVE: To evaluate the clinicopathologic characteristics and prognostic difference of gastric stump cancer between non-anastomotic site and anastomotic site. METHODS: Clinicopathologic data of 149 patients with gastric stump cancer undergoing operation (radical resection and palliative resection) in our department from January 1999 to June 2015 were analyzed retrospectively. Gastric stump cancer was defined as a primary carcinoma detected in the remnant stomach more than 5 years after subtotal gastrectomy for a benign disease(87 cases) or over 10 years after radical subtotal gastrectomy for a malignant disease (62 cases). Patients were divided into the anastomotic site group (72 cases) and the non-anastomotic site group (77 cases) according to tumor sites within the remnant stomach. Clinicopathologic characteristics, operative data, lymph node metastasis and prognosis were compared between the two groups. RESULTS: Compared with non-anastomotic site group, the T stage, N stage and TNM stage were later in the anastomotic site group. Number of case of T1, T2, T3, and T4 stage in anastomotic site group was 1(1.4%), 2 (2.8%), 17(23.6%) and 52(72.2%), while such number in non-anastomotic site group was 8(10.4%), 10(13.0%), 27(35.1%) and 32(41.6%) respectively(χ2=17.665, P=0.001). Number of case of N0, N1, N2, and N3 in anastomotic site group was 28 (38.9%), 10 (13.9%), 23 (31.9%) and 11 (15.3%), while such number in non-anastomotic site group was 55 (71.4%), 10 (13.0%), 7 (9.1%) and 5 (6.5%) respectively(χ2=19.421, P=0.000). Number of case of stage I(, II(, III( and IIII( in anastomotic site group was 3(4.2%), 10(13.9%), 47(65.3%) and 12(16.7%), while such number in non-anastomotic site group was 16(20.8%), 40 (51.9%), 15(19.5%) and 6(7.8%) respectively(χ2=45.294, P=0.000). The histology and Borrmann classification were worse in anastomotic site group. Anastomotic site group had 19 cases(26.4%) of good differentiation and 53 cases(73.6%) of bad differentiation, while non-anastomotic site group had 43 cases (55.8%) of well-differentiated and 34 cases (44.2%) of poorly-differentiated tumors respectively(χ2=13.287, P=0.000). Anastomotic site group had 3 cases (4.2%) of Borrmann I(, 17 cases (23.6%) of Borrmann II(, 47 cases(65.3%) of Borrmann III( and 5 cases (6.9%) of Borrmann IIII(, while non-anastomotic site group had 18 cases (23.4%) of Borrmann I(, 16 cases (20.8%) of Borrmann II(, 34 cases (50.6%) of Borrmann III( and 4 cases (5.2%) of Borrmann IIII( respectively(χ2=11.445, P=0.010). Compared with non-anastomotic site group, anastomotic site group had a lower curative resection rate [63.9% (46/72) vs. 89.6% (69/77), χ2=13.977, P=0.000], a higher combined organ resection rate [33.3% (24/72) vs. 16.9% (13/77), χ2=5.394, P=0.020] and a more metastatic lymph nodes (4.3±4.9 vs. 1.9±3.6, t=3.478, P=0.000). The lymph node metastasis rates of No.4, No.10 and jejunal mesentery root lymph node in anastomotic site group and non-anastomotic site group were 15.3% (11/72) and 5.2% (4/77)(χ2=4.178, P=0.041), 9.7% (7/72) and 1.3% (1/77) (χ2=5.196, P=0.023), and 25.0% (18/72) and 3.9% (3/77)(χ2=13.687, P=0.000), respectively. Median followed up of all the patients was 37(2 to 154) months and the overall 5-year survival rate was 44.1%. The 5-year survival rate was 33.1% in anastomotic site group and 55.2% in non-anastomotic site group, and the difference was statistically significant between two groups (P=0.015). In the subgroup analysis according to the histology differentiation, the 5-year survival rate of patients with well-differentiation was not significantly different between two groups (43.7% vs. 56.2%, P=0.872), but the 5-year survival rate of patients with bad differentiation in anastomotic site group was significantly lower than that in non-anastomotic site group(29.8% vs. 53.8%, P=0.029). CONCLUSION: Gastric stump cancer locating in anastomotic site indicates worse differentiation histology, higher lymph node metastasis rate, lower curative resection rate and poorer prognosis.