[Show abstract][Hide abstract]ABSTRACT: Background:
Early gastric cancer is defined as a lesion confined to the mucosa or submucosa, regardless of the size or lymph node metastasis. Treatment methods include endoscopic mucosal resection or endoscopic submucosal dissection, wedge resection, laparoscopically assisted gastrectomy and open gastrectomy. Lymph node metastasis is strong related with survival and recurrence. Therefore, the likelihood of lymph node metastasis is one of the most important factors when determining the most appropriate treatment.
We retrospectively analyzed 597 patients who underwent D2 gastrectomy for early gastric cancer. The relationship between lymph node metastasis and clinicopathological features was analyzed. Using multivariate logistic regression analyses, we created a nomogram to predict the lymph node metastasis probability for early gastric cancer. Receiver operating characteristic analyses was performed to assess the predictive value of the model.
In the present study, 58 (9.7 %) early gastric cancer patients were histologically shown to have lymph node metastasis. The multivariate logistic regression analysis demonstrated that the age at diagnosis, differentiation status, the presence of ulcers, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in early gastric cancer. Additionally, the tumor macroscopic type, size and histology type significantly correlated with these important independent factors. We constructed a predictive nomogram with these factors for lymph node metastasis in early gastric cancer patients, and the discrimination was good with the AUC of 0.860 (95 % CI: 0.809-0.912).
We developed an effective nomogram to predict the incidence of lymph node metastasis for early gastric cancer patients.
[Show abstract][Hide abstract]ABSTRACT: Several studies have evaluated the efficacy of neoadjuvant treatment using oxaliplatin and fluoropyrimidines in advanced gastric cancer (GC). However, preoperative biomarkers predictive of clinical outcome remain lacking. We examined polymorphisms in the MTHFR, DPYD, UMPS, ABCB1, ABCC2, GSTP1, ERCC1, and XRCC1 genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 103 GC patients treated with preoperative chemotherapy. DNA was extracted from peripheral blood cells, and the genotypes were analyzed using a SNaPShotTM assay, polymerase chain reaction amplification, and sequencing. The ABCC2-24C > T (rs717620) genotype was associated with pathologic response to neoadjuvant chemotherapy. Patients with the TT and TC genotypes responded to neoadjuvant chemotherapy 3.80 times more often than those with the CC genotype (95% CI: 1.27-11.32). Patients with the CC genotype also had poorer outcomes than those with other genotypes. Thus, ABCC2-24C > T polymorphism may help to predict the response to preoperative chemotherapy in GC patients.
[Show abstract][Hide abstract]ABSTRACT: Background
To compare the safety and efficacy of laparoscopic distal gastrectomy (LDG) versus open distal gastrectomy (ODG) in treating locally advanced distal gastric cancer after neoadjuvant chemotherapy (NACT).
Forty-four patients with locally advanced distal gastric cancer were enrolled. The patients received neoadjuvant chemotherapy before undergoing surgery. Twenty patients were allocated into LDG after NACT group and 24 patients into ODG after NACT group. Radicalness of oncological resection, surgical safety and recovery were measured and compared.
All operations were successfully performed without severe postoperative complications. There were no significant differences in blood loss, mean operation time, complications, distal and proximal resection margin, and number of retrieved lymph nodes between LDG and ODG groups, but LDG group had shorter length of incision and the first aerofluxus time.
Laparoscopic distal gastrectomy after NACT has comparable results with open distal gastrectomy in safety and efficacy in the short term.
[Show abstract][Hide abstract]ABSTRACT: Background: Various human epithelial origin cancers produce cytoplasmic immunoglobulin (Ig) G. Recent studies have elucidated that it was related with the tumorigenesis. This study was aimed to identify relationship between the cancer cell-derived IgG expression level and clinical parameters in gastric cancer (GC). Methods: Cancer cell-derived IgG expression was assessed using immunohistochemistry analysis in 231 primary GC tissues. The role of cancer cell-derived IgG on cell proliferation, migration and invasion were assessed. Results: Our results indicated that IgG was overexpressed in GC tissues (42.2%, 46/109) than in adjacent tissues (11.0%, 12/109, P<0.0001). Positive IgG expression was more frequently detected in patients with TNM III + IV stages when compared with those with TNM I + II stages in GC (48.6% vs. 37.2%, respectively). Upon univariate analysis, IgG positive group had significantly lower 5-year overall survival than the negative group (P=0.0361). Multivariate analysis showed IgG expression was an independent prognostic indicator for 5-year overall survival of patients with GC (P=0.018). Furthermore, knockdown of IgG by short interfering RNA (siRNA) resulted in reducing proliferation, migration and invasion of GC cell. Conclusions: Our results showed that cancer cell-derived IgG overexpression might be correlated with GC progression, and would be a novel biomarker to predict the prognosis of patients with GC.
Article · Jun 2016 · Translational Cancer Research
[Show abstract][Hide abstract]ABSTRACT: Background: Early screening and monitoring of the stage of colorectal cancer (CRC) is crucial for successful treatment and patient survival. Our purpose was to identify that evaluating methylated oncostatin M receptor (mOSMR) and Septin 9 (mSEPT9) in plasma DNA could be a feasible method for CRC diagnosis. Methods: Plasma samples (40 samples have matched cancer and adjacent non-cancer tissues) were collected from 187 patients with CRC, 25 patients with polyps and 109 healthy controls. qRT-PCR assay was used to analyze SEPT9 and OSMR mRNA levels. DNA bisulfite treatment, the levels of mSEPT9 and mOSMR in CRC tissues and plasma samples were evaluated by using fluorescence-based real-time PCR assay (MethyLight). mSEPT9 and mOSMR levels in plasma were compared before and after curative resection. Serum CEA, CA19-9, CA72-4 and CA242 were also measured and analyzed in parallel. Results: SEPT9 and OSMR mRNA levels were significantly lower in CRC tissues compared with those in their adjacent noncancerous tissues (P=0.006 and 0.002, respectively). mSEPT9 and mOSMR were significantly higher in CRC tissues compared with those in their adjacent non-cancerous tissues (P < 0.0001). Plasma mSEPT9 (cut-off value: 0.777) and mOSMR (0.796) had a sensitivity of 62.6% and 74.9% for CRC, and a specificity of 91.7% and 86.2%, respectively. mSEPT9 and mOSMR were positive in 12.0% and 20.0% in polyps, respectively. Moreover, combined mSEPT9 and mOSMR (77.0%) showed a higher sensitivity than CEA (32.9%), CA72.4 (20.4%), CA199 (13.9%) and CA242 (23.9%), and these blood biomarkers together had a higher sensitivity (83.0%) compared with these individual blood biomarkers. Conclusions: OSMR methylation (mOSMR) in plasma is useful for diagnosis of CRC as a new biomarker, and the panel of tests to analyze mSEPT9, mOSMR, CEA, CA19-9, CA72-4 and CA242 appears to be feasible and convenient for the diagnosis of CRC.
Article · Apr 2016 · Translational Cancer Research
[Show abstract][Hide abstract]ABSTRACT: Background:
To combine clinicopathological characteristics associated with lymph node metastasis for submucosal gastric cancer into a nomogram.
We retrospectively analyzed 262 patients with submucosal gastric cancer who underwent D2 gastrectomy between 1996 and 2012. The relationship between lymph node metastasis and clinicopathological features was statistically analyzed. With multivariate logistic regression analysis, we made a nomogram to predict the possibility of lymph node metastasis. Receiver operating characteristic (ROC) analysis was also performed to assess the predictive value of the model. Discrimination and calibration were performed using internal validation.
A total number of 48 (18.3%) patients with submucosal gastric cancer have pathologically lymph node metastasis. For submucosal gastric carcinoma, lymph node metastasis was associated with age, tumor location, macroscopic type, size, differentiation, histology, the existence of ulcer and lymphovascular invasion in univariate analysis (all P<0.05). The multivariate logistic regression analysis identified that age ≤50 years old, macroscopic type III or mixed, undifferentiated type, and presence of lymphovascular invasion were independent risk factors of lymph node metastasis in submucosal gastric cancer (all P<0.05). We constructed a predicting nomogram with all these factors for lymph node metastasis in submucosal gastric cancer with good discrimination [area under the curve (AUC) =0.844]. Internal validation demonstrated a good discrimination power that the actual probability corresponds closely with the predicted probability.
We developed a nomogram to predict the rate of lymph node metastasis for submucosal gastric cancer. With good discrimination and internal validation, the nomogram improved individualized predictions for assisting clinicians to make appropriated treatment decision for submucosal gastric cancer patients.
Article · Jan 2016 · Chinese Journal of Cancer Research
[Show abstract][Hide abstract]ABSTRACT: Purpose:
Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of anti-angiogenic agents in gastric cancer.
A systematic search of PubMed, Embase and conference databases is performed to identify clinical trials with specific anti-angiogenic agents in gastric cancer treatment RESULTS: The risk of disease progression (37-52%) and death (19-22%) with ramucirumab as second-line treatment decreas in phase III trials in advanced gastric cancer. No significant improvements in overall survival(OS) with the addition of bevacizumab to chemotherapy is shown. Bevacizumab or ramucirumab combined with traditional chemotherapy is associated with higher adverse event rate compared to chemotherapy alone. Except for apatinib, phase II trials of other tyrosine kinase inhibitors (TKIs) may improve overall response rate, but no significant improvements in OS and progression-free survival(PFS) when combined with chemotherapy.
Phase III trials in advanced gastric cancer have demonstrated improved outcome with ramucirumab as second-line treatment. Most of other studies on anti-angiogenic agents in gastric cancer have reported improvement in response rate but not in OS compared to chemotherapy alone. Future research is expected in optimizing the anti-angiogenic therapy combined with traditional treatment.
[Show abstract][Hide abstract]ABSTRACT: Genome-wide association studies (GWAS) have reported a number of loci harboring common variants that influence risk of colorectal cancer (CRC) in European descent. But all the SNPs identified explained a small fraction of total heritability. To identify more genetic factors that modify the risk of CRC, especially Chinese Han specific, we conducted a three-stage GWAS including a screening stage (932 CRC cases and 966 controls) and two independent validations (Stage 2: 1,759 CRC cases and 1,875 controls; Stage 3: 943 CRC cases and 1,838 controls). In the combined analyses, we discovered two novel loci associated with CRC: rs12522693 at 5q23.3 (CDC42SE2-CHSY3, OR = 1.31, P = 2.08 × 10-8) and rs17836917 at 17q12 (ASIC2-CCL2, OR = 0.75, P = 4.55 × 10-8). Additionally, we confirmed two previously reported risk loci, rs6983267 at 8q24.21 (OR = 1.17, P = 7.17 × 10-7) and rs10795668 at 10p14 (OR = 0.86, P = 2.96 × 10-6) in our cohorts. These results bring further insights into the CRC susceptibility and advance our understanding on etiology of CRC.
[Show abstract][Hide abstract]ABSTRACT: Systemic chemotherapy is the key treatment for advanced gastric cancer. The benefit of adjuvant surgery following preoperative chemotherapy in gastric cancer with liver metastasis has not been well established.
Forty-nine gastric cancer patients diagnosed with synchronous liver metastasis initially treated with chemotherapy were categorized into the following two groups: surgery group: 25 patients who underwent gastrectomy and subsequently received postoperative chemotherapy and control group: 24 patients who received chemotherapy alone.
The median overall survival of patients in the surgery group and control group was 20.5 and 9.1 months, respectively, (P = 0.006). The median progression-free survival in the surgery group was 10.9 months, with statistical significance when compared with 5.0 months in the control group (P = 0.001). Multivariate analysis demonstrated that response to chemotherapy was the only independent factor in predicting prognosis. The survival of patients who achieved partial response (PR) was prolonged if they received adjuvant surgery (P = 0.024). No significant difference in the survival of patients underwent combined hepatic resection when compared with patients performed gastrectomy only.
For gastric cancer with synchronous liver metastasis, adjuvant gastrectomy followed by chemotherapy might be beneficial for survival comparing with chemotherapy alone, especially in patients response to initial preoperative chemotherapy.
Full-text Article · Jul 2015 · World Journal of Surgical Oncology
[Show abstract][Hide abstract]ABSTRACT: Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood.
We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants.
We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab.
Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options.
Full-text Article · Apr 2015 · Journal of Translational Medicine
[Show abstract][Hide abstract]ABSTRACT: Background:
Lysosome-associated transmembrane protein 4β-35 (LAPTM4B-35), a member of the mammalian 4-tetratransmembrane spanning protein superfamily, has been reported to be overexpressed in several cancers. However the expression of LAPTM4B-35 and its role in the progression of gastric cancer (GC) remains unknown. The aim of this study was to investigate LAPTM4B-35 expression in GC, its potential relevance to clinicopathologic parameters and role of LAPTM4B-35 during gastric carcinogenesis.
In the present study, paraffin-embedded specimens with GC (n = 240, including 180 paired specimens) and 24 paired fresh frozen tissues were analyzed. qRT-PCR and immunohistochemistry (IHC) were used to analyze the expression of LAPTM4B-35 in GC. The effects of LAPTM4B-35 on GC cell proliferation, migration and invasion were determined by overexpression and knockdown assays.
IHC showed that LAPTM4B-35 was expressed in 68.3% (123/180) of GC tissues, while in 16.1% (29/180) of their paired adjacent noncancerous gastric tissues (P = 0.000). LAPTM4B-35 mRNA levels in GC tissues were also significantly elevated when compared with their paired adjacent noncancerous tissues (P = 0.017). Overexpression of LAPTM4B-35 was significantly associated with degree of differentiation, depth of invasion, lymphovascular invasion and lymph node metastasis (P<0.05). Kaplan-Meier survival curves revealed that patients with LAPTM4B-35 expression had a significant decrease in overall survival (OS) in stages I-III GC patients (P = 0.006). Multivariate analysis showed high expression of LAPTM4B-35 was an independent prognostic factor for OS in stage I-III GC patients (P = 0.025).
These findings indicate that LAPTM4B-35 overexpression may be related to GC progression and poor prognosis, and thus may serve as a new prediction marker of prognosis in GC patients.