A Proposal of a Personalized Surveillance Strategy for Gastric Cancer: A Retrospective Analysis of 9191 Patients.

BACKGROUND: In gastric cancer, various surveillance strategies are suggested in international guidelines. The current study is intended to evaluate the current strategies and provide more personalized proposals for personalized cancer medicine. MATERIALS AND METHODS: In the aggregate, 9191 patients with gastric cancer after gastrectomy from 1998 to 2009 were selected from the Surveillance, Epidemiology, and End Results database. Disease-specific survival was analyzed by Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analyses were used to confirm the independent prognostic factors. As well, hazard ratio (HR) curves were used to compare the risk of death over time. Conditional survival (CS) was applied to dynamically assess the prognosis after each follow-up. RESULTS: Comparisons from HR curves on different stages showed that earlier stages had distinctly lower HR than advanced stages. The curve of stage IIA was flat and more likely the same as that of stage I while that of stage IIB is like that of stage III with an obvious peak. After estimating CS at intervals of three months, six months, and 12 months in different periods, stages I and IIA had high levels of CS all along, while there were visible differences among CS levels of stages IIB and III. CONCLUSIONS: The frequency of follow-up for early stages, like stages I and IIA, could be every six months or longer in the first three years and annually thereafter. And those with unfavorable conditions, such as stages IIB and III, could be followed up much more frequently and sufficiently than usual.

Structure activity relationships of chrysoeriol and analogs as dual c­Met and VEGFR2 tyrosine kinase inhibitors.

Vascular endothelial growth factor receptor 2 (VEGFR2) and c­Met are tyrosine kinases, which are involved in the tumorigenesis of various types of cancer. Previous studies have demonstrated that the elevated activation of c­Met is associated with the drug resistance of VEGFR2 inhibitors. Therefore, dual c­Met and VEGFR2 kinase inhibitors are expected to overcome VEGFR2 inhibitor resistance and subsequently lead to a superior therapeutic outcome to regular VEGFR2 inhibitors. In the present study, it was found that chrysoeriol, which can be extracted from several natural plants, was a potential dual c­Met and VEGFR2 kinase inhibitor. The results of docking experiments revealed that chrysoeriol was able to efficiently bind in the active site cavity of c­Met and VEGFR2. The results of enzymatic assays showed relatively high binding affinities of chrysoeriol to c­Met (Kd=12 µM) and VEGFR2 (Kd=11 µM). The structure activity relationships (SARs) of chrysoeriol and its analogs were investigated using pharmacological and molecular docking experiments. To the best of our best knowledge, the present study is the first to report a natural product with both c­Met and VEGFR2 inhibitory profiles, and provides insights into future dual c­Met and VEGFR2 kinase inhibitor development.

Development of a risk-scoring system to evaluate the serosal invasion for macroscopic serosal invasion positive gastric cancer patients.

BACKGROUND: The status of serosal invasion is often discordance between pathological and intraoperative evaluation. Our study sought to develop a risk-scoring system (RSS) to predict the probability of pT4a for macroscopic serosal invasion (MSI) positive patients and reevaluate the serosal invasion status. PATIENTS AND METHODS: A total of 1301 pT3/pT4a gastric cancer patients with curative surgery were reviewed. We constructed the RSS to predict the probability of pT4a and assigned MSI-positive patients into different risk groups based on the risk scores. The prognostic significance of these risk groups was also evaluated. RESULTS: Univariate and multivariate analyses identified that tumor location, Lauren type, Borrmann type, tumor size, lymphovascular invasion and pN stage were risk factors related to pT4a. Survival analyses showed that pT3 MSI-positive patients in high-risk group had similar survival with pT4a patients. We incorporated these two groups into one stage and proposed a novel revised-T stage. Two-step multivariate analyses indicated that the revised-T stage showed better prediction ability for prognosis and peritoneal recurrence assessment than original pT stage and MSI status. CONCLUSIONS: In our present study, we developed a RSS to predict the probability of pT4a for MSI-positive patients. Based on our RSS, we proposed a treatment algorithm to reevaluate the tumor invasion for MSI-positive patients in clinical practice. Future studies should include other preoperative predictors to improve the clinical utility of our model.

Old drug new tricks: Chlorhexidine acts as a potential allosteric inhibitor toward PAK1.

This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor.

Alcohol drinking and gastric cancer risk: a meta-analysis of observational studies.

BACKGROUND: Many studies investigated the association between alcohol drinking and gastric cancer risk, but the results were controversial. We performed a meta-analysis of observational studies to explore the association. MATERIALS AND METHODS: We searched PubMed to identify the relevant studies that reported the association between alcohol drinking and gastric cancer risk up to December 31, 2016. We pooled relative risks (RRs) in random effects model and performed dose-response analysis to quantify the association. Cochran Q test and I2 analyses were used to evaluate the heterogeneity. Meta-regression, subgroup, sensitivity and publication bias analyses were also performed. RESULTS: 75 studies were included in our study. The pooled RR of high vs low total alcohol drinking was 1.25 (95% CI, 1.15-1.37, P < 0.001), and a nonlinear association was further observed. Subgroup analysis showed that alcohol drinking significantly associated with the risk of gastric noncardia cancer (RR, 1.19; 95% CI, 1.01-1.40, P = 0.033), but not with the risk of gastric cardia cancer (RR, 1.16; 95% CI, 0.98-1.39, P = 0.087). Notably, the pooled RRs of high vs low analyses were 1.13 (95% CI, 1.03-1.24, P = 0.012) for beer drinking, 1.22 (95% CI, 1.06-1.40, P = 0.005) for liquor drinking, and 0.99 (95% CI, 0.84-1.16, P = 0.857) for wine drinking. CONCLUSIONS: Our meta-analysis found a nonlinear association between alcohol drinking and gastric cancer risk, and heavy drinking level was strongly related to gastric cancer risk. Beer and liquor had significant positive associations with gastric cancer risk, while wine drinking would not increase gastric cancer risk. These results need to be verified in future research.

A Nomogram for Predicting Overall Survival of Gastric Cancer Patients with Insufficient Lymph Nodes Examined.

Insufficient number of examined lymph nodes (eLNs) was considered to increase significantly the risk of stage migration in gastric cancer patients. The aim of our study is to establish a nomogram predicting the overall survival (OS) for patients with an insufficient number of eLNs. A total of 872 gastric cancer patients with extended lymphadenectomies were assigned randomly (2:1) to the development cohort and the validation cohort. The nomogram was established based on the Cox regression model using the development cohort. The concordance index (C-index) was used to evaluate the discriminative ability. We also compared our model with two other staging systems. Using multivariate analysis, age, sex, tumor location, depth of invasion, macroscopic type, lymphovascular invasion, the number of eLNs, and metastatic lymph nodes were selected and incorporated into the nomogram. The C-index of the nomogram was 0.742 and 0.743 in development and validation cohorts, respectively, which were significantly superior to the C-indices (range 0.705-0.712, all P < 0.001) of American Joint Committee on Cancer (AJCC) seventh edition and lymph node ratio staging systems in both cohorts. We established a nomogram which could predict accurately OS for gastric cancer patients with insufficient number of eLNs.

Rare upper gastrointestinal hemorrhage of cetuximab: A case report.

RATIONALE: cetuximab, an epidermal growth factor receptor inhibitor, is a targeted therapeutic regimen of colorectal cancers. Several common adverse effects have been found, such as cutaneous or gastrointestinal toxicity. However, according to the articles had been published, upper gastrointestinal bleeding (UGIB) is considered to be rare and its mechanism remains unclear. PATIENT CONCERNS: In this report, we presented a 42-year-old male patient with advanced recto-sigmoid cancer. After palliative operation, the patient suffered from complete upper gastrointestinal (GI) obstruction, which was induced by extensive abdominal metastasis of the tumor. Considering his poor condition, we chose the targeted drug, cetuximab, as his further treatment. But after the application of cetuximab, the UGIB immediately happened twice in this patient. DIAGNOSIS: UGIB, as a rare complication of cetuximab, occured to the patient. INTERVENTIONS: We stopped the bleeding with thrombin, hemocoagulase and somatostatin and suspended the subsequent treatment plan of cetuximab. At the same time, anti-shock treatment was given immediately. OUTCOMES: He was died of respiratory and circulatory failure caused by UGIB and advanced tumor eventually. LESSONS: UGIB should be considered as a rare but severe complication of cetuximab. When cetuximab is applied for patients with advanced colon tumors, more cautions should be required if the patients are accompanied by upper gastrointestinal obstruction. In addition, for those patients who suffered from UGIB recently, cetuximab should be prohibited if the Rockall score ranged > 5 points.

Gastric cancer cell supernatant causes apoptosis and fibrosis in the peritoneal tissues and results in an environment favorable to peritoneal metastases, in vitro and in vivo.

BACKGROUND: In this study, we examined effects of soluble factors released by gastric cancer cells on peritoneal mesothelial cells in vitro and in vivo. METHODS: HMrSV5, a human peritoneal mesothelial cell line, was incubated with supernatants from gastric cancer cells. Morphological changes of HMrSV5 cells were observed. Apoptosis of HMrSV5 cells was observed under a transmission electron microscope and quantitatively determined by MTT assay and flow cytometry. Expressions of apoptosis-related proteins (caspase-3, caspase-8, Bax, bcl-2) were immunochemically evaluated. RESULTS: Conspicuous morphological changes indicating apoptosis were observed in HMrSV5 cells 24 h after treatment with the supernatants of gastric cancer cells. In vivo, peritoneal tissues treated with gastric cancer cell supernatant were substantially thickened and contained extensive fibrosis. CONCLUSIONS: These findings demonstrate that supernatants of gastric cancer cells can induce apoptosis and fibrosis in HMrSV5 human peritoneal mesothelial cells through supernatants in the early peritoneal metastasis, in a time-dependent manner, and indicate that soluble factors in the peritoneal cavity affect the morphology and function of mesothelial cells so that the resulting environment can become favorable to peritoneal metastases.

Prognostic significance of tumor deposits in gastric cancer patients who underwent radical surgery.

BACKGROUND: To investigate the prognostic significance of tumor deposits (TDs) in gastric cancers patients who underwent radical surgery. METHODS: Clinicopathologic and prognostic data from 2998 gastric cancer patients who underwent R0 surgery with D2/D3 lymphadenectomy were retrospectively reviewed. A TD was defined as discrete foci of tumor found in the perigastric fat or in adjacent ligament away from the leading edge of the tumor and showing no evidence of residual lymph node tissue, but within the lymph drainage area of the primary carcinoma. RESULTS: TDs were detected in 17.8% of patients. TDs were more frequently observed in cancers of larger size, of Borrmann type 4, with lymphovascular invasion, deeper in depth of invasion, and with extended lymph node metastasis. Multivariate analysis confirmed the presence of TDs as 1 of independent factors predicting a poorer outcome. When stratified by pN category, significant differences in survival were observed between patients with and without TDs for those in pN0/pT1-3, pN1/pT3, pN2/pT1-3 and pN3/pT2-3 category, but not for those in pT4a and pT4b category. Moreover, for cancers in each pN category, the prognosis for patients with TDs in pT1-4a category was similar with that of those without TDs in pT4a category, but significantly better than that of those with or without TDs in pT4b category. A revised pT category and a revised pTNM system were proposed, in which all the cancers with TDs in pT1-4a category were incorporated into those without TDs in pT4a category according to the pN category. Further analysis revealed the revised pT category and the revised pTNM system had better homogeneity, discriminatory ability, and monotonicity of gradients than the American Joint Committee on Cancer (AJCC) pT category and the AJCC pTNM system, respectively, representing optimum prognostic stratification. CONCLUSION: TDs significantly correlated with gastric cancer patients' survival. It might be more suitable for TDs to be treated as a form of serosal invasion. Consequently, en bloc resection of the primary carcinoma is crucially important, and adjuvant chemotherapy should always be considered if TDs have been detected.

Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination.

BACKGROUND: Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. However, the role of CTGF in gastric cancer remains largely unknown. RESULTS: In this study, we showed that CTGF was highly expressed in gastric cancer tissues compared with matched normal gastric tissues. The CTGF expression in tumor tissue was associated with histologic grade, lymph node metastasis and peritoneal dissemination (P < 0.05). Patients with positive CTGF expression had significantly lower cumulative postoperative 5 year survival rate than those with negative CTGF expression (22.9% versus 48.1%, P < 0.001). We demonstrated that knockdown of CTGF expression significantly inhibited cell growth of gastric cancer cells and decreased cyclin D1 expression. Moreover, knockdown of CTGF expression also markedly reduced the migration and invasion of gastric cancer cells and decreased the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Animal studies revealed that nude mice injected with the CTGF knockdown stable cell lines featured a smaller number of peritoneal seeding nodules than the control cell lines. CONCLUSIONS: These data suggest that CTGF plays an important role in cell growth and invasion in human gastric cancer and it appears to be a potential prognostic marker for patients with gastric cancer.

Clinicopathologic characteristics and prognosis of signet ring cell carcinoma of the stomach: results from a Chinese mono-institutional study.

BACKGROUND: Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics, and its clinicopathologic characteristics and prognosis are still controversial. METHODS: A retrospective analysis was under taken for 2,315 patients with gastric cancer who had undergone gastrectomy from 1980 to 2004. Among them, 211 patients had SRC and were compared with 2,104 patients with non-signet ring cell carcinoma (NSRC). RESULTS: Significant differences were noted in age, gender, and depth of tumor invasion between patients with SRC and NSRC of early gastric carcinoma. There were statistically significant differences in age, gender, macroscopic appearance, tumor size, depth of tumor invasion, peritoneal dissemination, and curability between patients with SRC and NSRC of advanced gastric carcinoma. In early gastric carcinoma, patients with SRC had a significantly better survival rate than those with NSRC, and the signet ring cell histology was an independent predictive factor. In advanced gastric carcinoma, there was no significant difference of survival rate between SRC and NSRC, and the signet ring cell histology was not an independent predictive factor. CONCLUSIONS: SRC is a distinct type of gastric carcinoma in terms of clinicopathologic characteristics and prognosis.

Clinicopathological analysis and prognostic significance of peritoneal cytology in Chinese patients with advanced gastric cancer.

BACKGROUND: The influence of peritoneal cytology on survival of patients with gastric cancer has not been consistent. This study was to identify risk factors for positive peritoneal cytology and to evaluate the predictive value of positive cytology among Chinese patients with advanced gastric cancer. METHODS: The study included 139 patients with gastric cancer macroscopically invading the serosa, who underwent gastrectomy and intra-operative peritoneal cytological examination. In these patients, the relationship between cytological positivity and various clinicopathological features was analysed, and survival analysis was performed to identify independent prognostic factors of significance. RESULTS: Thirty-eight (27.3%) of 139 patients had positive peritoneal cytology. Although tumour size, lymphovascular invasion, depth of tumour invasion, lymph node metastasis and peritoneal metastasis were correlated with positive cytology, multivariate analysis revealed the depth of tumour invasion and peritoneal metastasis as the independent features affecting the cytology. Patients with a positive cytology result were confirmed to have a greater risk for recurrence in the pattern of peritoneal carcinomatosis and a significant inferior prognosis. Multivariate analysis indicated that positive peritoneal cytology was an independent prognostic factor among the curatively resected patients with advanced gastric cancer and was the prognostic factor most predictive of death for these patients (risk ratio = 2.74). CONCLUSIONS: Positive peritoneal cytology correlated with advanced features of gastric cancer. It is an independent poor prognostic factor, and it may serve as a guide for adjuvant therapeutic options to improve the survival of gastric cancer.

Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis.

BACKGROUND: Peritoneal dissemination is one of the main causes of death in gastric cancer patients. Transforming growth factor-beta1 (TGF-ß1), one of the most potent fibrotic stimuli for mesothelial cells, may play a key role in this processing. The purpose of this study is to elucidate the effects of TGF-ß1 on regulation of gastric cancer adhesion to mesothelial cells. METHODS: Peritoneal tissues and peritoneal wash fluid were obtained for hematoxylin and eosin staining or ELISA to measure fibrosis and TGF-ß1 levels, respectively. The peritoneal mesothelial cell line, HMrSV5, was used to determine the role of TGF-ß1 in regulation of gastric cancer cell adhesion to mesothelial cells and expression of collagen, fibronectin, and Smad 2/3 by using adhesion assay, western blot, and RT-PCR. RESULTS: The data showed that TGF-ß1 treatment was able to induce collagen III and fibronectin expression in the mesothelial cells, which was associated with an increased adhesion ability of gastric cancer cells, but knockdown of minimal sites of cell binding domain of extracellular matrix can partially inhibit these effects. CONCLUSION: Peritoneal fibrosis induced by TGF-ß1 may provide a favorable environment for the dissemination of gastric cancer.

Clinicopathologic characteristics and prognosis of gastric cancer invading the subserosa.

BACKGROUND: The clinicopathologic characteristics and prognosis for gastric cancer invading subserosa (SS) are still not clear. METHODS: A retrospective analysis was under taken of 1,201 patients with advanced gastric cancer (pT2, pT3, and pT4a) who had undergone gastrectomy from 1980 to 2001. Clinicopathologic characteristics and prognosis of gastric cancer invading SS were compared with those of cancers invading muscularis propria (MP) and serosa (Se). RESULTS: Patients with cancers invading SS had larger tumors and more frequent lymphovascular invasion, lymph node and peritoneal metastasis than those with cancers invading MP. Yet, they had smaller tumors and less frequent lymphovascular invasion, lymph node and peritoneal metastasis than those with cancers invading Se. Postoperative survival with cancers invading SS was intermediate between that with cancers invading MP and Se at pN0, pN1, pN2, and pN3 stages. Multivariate analysis indicated lymph node metastasis, type of resection, curability, peritoneal metastasis, and hepatic metastasis were independent prognostic factors for patients with cancers invading SS. CONCLUSIONS: Clinicopathologic characteristics and prognosis of gastric cancer invading SS are intermediate between those of gastric cancers invading MP and Se.

Transforming growth factor beta1 produced in autocrine/paracrine manner affects the morphology and function of mesothelial cells and promotes peritoneal carcinomatosis.

Human peritoneal mesothelial cells (HPMCs) in intact mesothelium have been demonstrated to protect against tumor peritoneal metastasis. We have previously reported that gastric cancer cells can induce peritoneal apoptosis, lead to damage of peritoneum integrity, and therefore promote peritoneal metastasis. In this study, we investigated the effects of TGF-beta1 on tumor-mesothelial interaction. Briefly, the levels of various soluble factors, in particular TGF-beta1, were measured. HMrSV5 cells, a human peritoneal mesothelial cell line, were co-incubated with TGF-beta1, gastric cancer cells, or gastric cancer cells and TGF-beta1 receptor inhibitor SB431542. The expressions of smad 2/3 and phosphorylated smad 2/3, indicator of TGF-beta/Smads pathway activation, were evaluated. Then the morphological changes of HPMCs were observed. The cell damage was quantitatively determined by fluorescent microscopy and flow cytometry. Tumor-mesothelial cell adhesion was also examined. Results showed a significant elevation of TGF-beta1 expression, which is companied by dramatically increased phosphorylated-smad 2/3 levels, after mesothelial cell co-culture with the gastric cancer cell line. In addition, mesothelial cells exposed to gastric cancer cells or TGF-beta1 became exfoliated and exhibited signs of injury, while blocking TGF-beta1 can partially inhibit these effects. These results indicate that soluble factors, such as TGF-beta1, produced in autocrine/paracrine manner in the peritoneal cavity, affect the morphology and function of mesothelial cells so that the resulting environment becomes favorable for peritoneal metastases.

Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression.

Curcumin (diferuloylmethane), is a natural chemopreventive agent known to inhibit the proliferation of several cancer cell lines. It has been previously demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR) tyrosine kinase, but its inhibitive effect on p21-activated kinase 1 (PAK1), a downstream protein of EGFR, has not been defined. In this paper we found that curcumin repressed the expression of HER2 and inhibited the kinase activity of PAK1 without affecting its expression. Silencing HER2 in gastric cancer cells showed that even if PAK1 activity was transiently strengthened by EGF, curcumin still had a strong inhibitive effect. It should be emphasized that kinase assay in vitro showed that curcumin could act as an ATP-competitive inhibitor, which was supported by computer-aided molecular modeling. Curcumin also downregulated the mRNA and the protein expression of cyclin D1 and suppressed transition of the cells from G(1) to S phase. Therefore, curcumin inhibited the proliferation and invasion of gastric cancer cells. Overall, these results provided novel insights into the mechanisms of curcumin inhibition of gastric cancer cell growth and potential therapeutic strategies for gastric cancer.

Astragalus extract inhibits destruction of gastric cancer cells to mesothelial cells by anti-apoptosis.

AIM: To determine the inhibitory effect of Astragalus memebranaceushas on gastric cancer cell supernatant-induced apoptosis of human peritoneal mesothelial cells. METHODS: Human peritoneal mesothelial cell (HPMC) line HMrSV5 was co-incubated with gastric cancer cell supernatant (MKN45) and/or Astragalus memebranaceushas. Morphological changes in gastric cancer cells were observed under phase-contrast microscope. Quantitative cell damage was determined by MTT assay. Apoptosis was determined under transmission electron microscope and quantified by detecting acridine orange/ethidium bromide-stained (AO/EB) condensed nuclei under fluorescent microscope or by flow cytometry. Expressions of Bcl-2 and Bax were evaluated with immunostaining. RESULTS: Morphological changes and exfoliation occurred and naked areas appeared in cultured HMrSV5 cells 24 h after they were treated with gastric cancer cell supernatant. Cell supernatant from MKN45 gastric cancer cells induced apoptosis of HMrSV5 cells in a time-dependent manner. Obvious morphological changes were observed in cell apoptosis, such as condensation of chromatin, nuclear fragmentations and apoptotic bodies. Astragalus memebranaceus could partly suppress these changes and regulate the expressions of Bcl-2 and Bax in HMrSV5 cells. CONCLUSION: Gastric cancer cells induce apoptosis of HPMCs through the supernatant. Astragalus memebranaceushas inhibits this phenomenon and can be used an adjuvant chemothera-peutic agent in gastric cancer therapy.