Mutational and transcriptional profile predicts the prognosis of stage IV gastric cancer - Prognostic factors for metastatic gastric cancer.

BACKGROUND AND STUDY AIMS: The clinicopathological risk factors in the prognosis of stage IV gastric cancer have been comprehensively studied. However, the influencing factors of stage IV gastric cancer prognosis at genomic and transcriptional levels have not been well defined. PATIENTS AND METHODS: The mutational and transcriptional data, along with demographic, clinicopathological and prognostic information of 44 stage IV gastric cancer patients were downloaded from the TCGA database. Univariate and multivariate analyses were performed to identify the significant risk factors and a Nomogram model was established to predict the patient prognosis. RESULTS: TTN, TP53, FLG, LRP1B, SYNE1 and ARID1A were among the top mutated genes without hot-spot mutations. The mutational status of AHNAK2, ASCC3, DNAH3, DOP1A, MYLK, SIPA1L1, SORBS2, SYNE1 and ANF462 significantly stratified the patient prognosis. The transcription of several genes, such as AQP10, HOXC8/9/10, COL10A1/COL11A1, WNT7B, KRT17 and KLK6 was significantly up-regulated or down-regulated. Enrichment analysis on mutations and transcription revealed cell skeleton and membrane function, extracellular matrix function, HPV infection, and several cancer-related pathways as the main aberrancies. Univariate analyses revealed a series of significant factors stratifying patient prognosis, mainly including cancer location, several mutated genes and many up- or down-regulated genes. However, subsequent multivariate analysis revealed SYNE1 mutation, DNAH3 mutation, COMMD3 transcription level, and cancer location as the independent risk factors. A Nomogram model has been established with these significant risk factors to predict the patient prognosis. Further validation is needed to ensure the effectiveness of the model in real clinical practice. CONCLUSIONS: Cancer location, along with the mutational status of SYNE1 and DNAH3 and the transcriptional level of COMMD3 were independent risk factors of stage IV gastric cancer. A Nomogram model was established with these factors for prognosis prediction.

GRIK5 stimulates colon cancer growth and metastasis through cAMP/PKA/CADM3 signaling.

Glutamate receptor, ionotropic, kainate 5 (GRIK5) is a member of glutamate receptors participating, and the kainate receptor family has been proved to regulate cell proliferation and transformation. Our study aimed at exploring the role of GRIK5 in colon tumor progression. Three hundred and ninety eight colon cancer patients in The Cancer Genome Atlas Program (TCGA) data set and 26 clinical colon cancer patients were included for GRIK5 expression and prognosis analysis. GRIK5 overexpressed HCT116 and CT26 cell lines were established for cell proliferation and Transwell assay. Western blot analysis and immunostaining assay was conducted to evaluate the activation of activation of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cell adhesion molecular 3 (CADM3) signaling in cell lines and tumor tissues. Subcutaneous CT26-bearing mice model was established to examine GRIK5-induced tumor growth and metastasis in vivo. Our study identified GRIK5 to be upregulated in patients with colon cancer, and higher GRIK5 levels correlated with the poor overall survival in patients. In vitro, GRIK5 overexpression markedly enhanced the proliferative properties and aggressive behaviors of colon cancer cells. Mechanistically, GRIK5 induced the activation of cAMP/PKA signaling, proceeded with augmented CADM3 expression, eventually resulting in sustained tumor growth. GRIK5 was a crucial scaffold in enabling colon cancer growth and metastasis, which offered a promising target for therapeutic manipulation of colon cancer.

Prevalence and Spectrum of Predisposition Genes With Germline Mutations Among Chinese Patients With Bowel Cancer.

Background: Bowel cancer is the third-most common cancer and the second leading cause of cancer-related death worldwide. Bowel cancer has a substantial hereditary component; however, additional hereditary risk factors involved in bowel cancer pathogenesis have not been systematically defined. Materials and Methods: A total of 573 patients with bowel cancer were enrolled in the present study, of whom 93.72% had colorectal cancer (CRC). Germline mutations were integrated with somatic mutation information via utilizing target next-generation sequencing. Results: Pathogenic/Likely Pathogenic (P/LP) germline alterations were identified in 47 (8.2%) patients with bowel cancer and the ratio of the number of these patients with family history was significantly higher in the P/LP group than that noted in the non-pathogenic (Non-P) group. Certain rare germline alterations were noted, such as those noted in the following genes: FANCD2, CDH1, and FLCN. A total of 32 patients (68.1%) had germline alterations in the DNA-damage repair (DDR) genes and homologous recombination (HR) accounted for the highest proportion of this subgroup. By comparing 573 patients with bowel cancer with reference controls (China_MAPs database), significant associations (p < 0.01) were observed between the incidence of bowel cancer and the presence of mutations in APC, ATM, MLH1, FANCD2, MSH3, MSH6, PMS1, and RAD51D. Somatic gene differential analysis revealed a marked difference in 18 genes and a significant difference was also noted in tumor mutation burden (TMB) between germline mutation carriers and non-germline mutation subjects (p < 0.001). In addition, TMB in DDR mutation groups indicated a dramatic difference compared with the non-DDR mutation group (p < 0.01). However, no statistically significant differences in TMB were noted among detailed DDR pathways for patients with bowel cancer, irrespective of the presence of germline mutations. Moreover, a significantly higher level (p < 0.0001) of mutation count was observed in the DDR group from The Cancer Genome Atlas (TCGA) database and the DDR and non-DDR alteration groups displayed various immune profiles. Conclusion: Chinese patients with bowel cancer exhibited a distinct spectrum of germline variants, with distinct molecular characteristics such as TMB and DDR. Furthermore, the information on somatic mutations obtained from TCGA database indicated that a deeper understanding of the interactions among DDR and immune cells would be useful to further investigate the role of DDR in bowel cancer.

[Impact of preoperative oral liquid carbohydrate on postoperative insulin resistance in gastric cancer patients and its associated study].

OBJECTIVE: To investigate the impact of preoperative oral liquid carbohydrate on postoperative insulin resistance (IR) in gastric cancer patients undergoing elective resection, and to examine the association of IR index (homeostasis model assessment, HOMA-IR) with tumor necrosis factor-α (TNF-α). METHODS: Between January 2013 and September 2013, 35 patients undergoing elective resection for gastric cancer were prospectively enrolled and randomized into two groups. Patients in trial group (n=18) received oral 500 ml of 10% glucose solution two hours before surgery. Patients in control group (n=17) were asked to fast for 8-12 hours before operation. About 300 mg of rectus abdominis and subcutaneous fatty tissues was removed before the closure of abdominal wall. Blood samples were collected to measure the serum concentration of TNF-α with double antibody sandwich ELISA in perioperative period (3-hour before operation, end of operation, 1-day and 3-day after operation). HOMA-IR was calculated on preoperative 3-hour and postoperative 1-day. Western blotting was used to detect protein expression of TNF-α. Correlation of HOMA-IR with TNF-α was examined. RESULTS: HOMA-IR on the first day after surgery was not different from that at 3-hour before surgery in trial group (P=0.090), which was significantly lower than that in control group (P=0.000). In trial group, serum TNF-α at the end of operation was higher than that at 3-hour before surgery, which declined rapidly on the first day after surgery and had no significant difference compared with that on the third day after surgery. In control group, serum TNF-α at the end of operation was also higher than that before surgery, which rose to the peak on the first day after surgery and was still higher than that at 3-hour before surgery. The TNF-α protein expression in muscle tissues of trial group was higher than that of control group (P=0.001), while no significant difference was observed between two groups in adipose tissues (P=0.987). Correlation analysis showed that HOMA-IR was positively correlated with TNF-α on the first day after surgery (r=0.832, P=0.000). CONCLUSION: Oral intake of liquid carbohydrate 2 hours before surgery can reduce the level of TNF-α, which is likely to improve the postoperative insulin resistance.

Paired design study by real-time PCR: miR-378* and miR-145 are potent early diagnostic biomarkers of human colorectal cancer.

BACKGROUND: Although microRNAs offer great potential as cancer biomarkers, effective clinical dignostics and tumor maker have not been verified to diagnose with colorectal cancer (CRC). The purpose of our study is to systematically assess the expression of miRNAs in matched cancer and normal tissue samples to identify promising diagnostic microRNA (miRNA) biomarkers for CRC. METHODS: In our study, we examined by Real-Time PCR the expression levels of 96 mature miRNA in 32 CRC patients with differently expressed tumors versus normal colon tissues. Using enter and stepwise variable selection methods separately, conditional logistic regression was conducted to identify miRNAs associated with CRC. The classification performance of these indicators was assessed under the Fisher discriminant analysis. Receiver operating characteristic curve analyses were applied to obtain diagnostic utility of the differentially expressed miRNAs. RESULTS: In this study, we confirmed 11 overexpressed miRNAs with no less than twofold difference, and 85 downexpressed miRNAs with up to 0.5-fold difference in CRC from 96 aberrantly expressed miRNAs being identified by real-time PCR. Conditional logistic regression results confirmed that miRNA-378 and miRNA-145 expression profile was statistically significant. The error diagnosis rate of these two miRNAs are 0.194 and 0.113, separeately, showing by discriminant analysis. CONCLUSIONS: MiRNA-145 and miRNA-378* are potential biomarkers for early detection of CRC, which may help in diagnosing CRC in early period.

[Preliminary experiences of application of sentinel lymph node navigation technique in early gastric cancer].

OBJECTIVE: To investigate the feasibility and clinical significance of sentinel lymph node (SLN) navigation limited surgery in early gastric cancer (EGC). METHODS: Thirty-nine patients confirmed with EGC between January 2002 and December 2006 were randomly divided into tailored surgery group (20 cases) and conventional surgery group (19 cases). By combining the mapping agents of (99m)Tc labeled sulfur colloid solution and blue violet, SLN biopsy was conducted in tailored surgery group, in which a limited gastric resection with D0-D1 lymphadenectomy was performed in 17 cases with negative SLN examined by routine HE staining during operation; standard radical gastrectomy with lymphadenectomy (D2) was conducted in the other 3 cases with positive SLN and in all the cases of conventional surgery group. The diagnostic accuracy and false-negative rate of SLN status were calculated respectively. The operation outcome and postoperative complication and survival rate were compared between the two groups. RESULTS: SLNs were detected in all 20 patients with a successful detection rate of 100% in tailored surgery group. The number of detected SLNs ranged from 1 to 3, with a mean of 2.2 per case. The diagnostic accuracy and false-negative rate was 95% and 5%, respectively. The hospital stay and recovery time of gastrointestinal functions in patients undergoing limited surgery were significantly shorter than in conventional surgery group and with similar postoperative survival and less complications. CONCLUSIONS: SLN biopsy may provide an accurate diagnostic procedure for detecting lymph node metastasis in EGC. Patients with node-negative EGC receiving limited surgery are likely to benefit from minimally invasive approach with the similar survival as standard radical surgery.

[Minimally invasive surgical treatment for venous leg ulcer].

OBJECTIVE: To evaluate therapeutic effects of endovenous laser treatment (ELT) and subfascial endoscopic perforator surgery (SEPS) in the treatment of venous leg ulcer (VLU). METHODS: ELT and SEPS were performed in 10 patients with VLU (involving 10 legs). Among them, external valvuloplasty was performed in 4 legs with deep venous valve insufficiency. RESULTS: Ulcer of the 10 legs healed within 10-60 days after the operation, and follow-up study ranging from 2 to 8 months with the average of 6 months revealed no recurrences. CONCLUSION: ELT combined with SEPS provides an effective approach for VLU treatment with minimal invasion, and when combined with external valvuloplasty, this approach may effectively reduce ulcer recurrence.