Xin-Zu Chen

Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients

Gastric cancer is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate. To date, there is a lack of efficient therapeutic protocols for gastric cancer. Recent studies suggest that cancer stem cells (CSCs) are responsible for tumor initiation, invasion, metastasis, and resistance to anticancer therapies. Thus, therapies that target gastric CSCs are attractive. However, CSCs in human gastric adenocarcinoma (GAC) have not been described. Here, we identify CSCs in tumor tissues and peripheral blood from GAC patients. CSCs of human GAC (GCSCs) that are isolated from tumor tissues and peripheral blood of patients carried CD44 and CD54 surface markers, generated tumors that highly resemble the original human tumors when injected into immunodeficient mice, differentiated into gastric epithelial cells in vitro, and self-renewed in vivo and in vitro. Our findings suggest that effective therapeutic protocols must target GCSCs. The capture of GCSCs from the circulation of GAC patients also shows great potential for identification of a critical cell population potentially responsible for tumor metastasis, and provides an effective protocol for early diagnosis and longitudinal monitoring of gastric cancer.

Short-term evaluation of laparoscopy-assisted distal gastrectomy for predictive early gastric cancer: a meta-analysis of randomized controlled trials.

Background: In recent decade, laparoscopy-assisted distal gastrectomy (LADG) has been introduced to treatment of early gastric cancer (EGC). Previous meta-analyses included the randomized controlled trial (RCT) apparently contaminated with advanced gastric cancer. Besides, more RCTs enrolling the predictive EGC are available. The present meta-analysis was aimed to compare LADG with open distal gastrectomy (ODG) by updating the literature search and repooling the RCTs of only predictive EGC with improved methodology. Methods: Comprehensive search of PubMed, EmBase, and multiple websites of clinical trials registration and oncologic groups were performed. Only short-term outcomes measures were considered to meta-analysis. The RevMan 5.0 was used for pooled estimates. Results: Six RCTs of 629 patients totally were included for meta-analysis. Comparing LADG to ODG, results found less postoperative early morbidity (risk ratios=0.61, P=0.01), similar mortality (risk diffrence=0.01, P=0.32), prolonged operation time [mean difference (MD)=86.64 min, P<0.00001], decreased intraoperative blood loss (MD=−108.33 mL, P=0.001), decreased number of harvested lymph nodes (MD=−4.88, P<0.00001), forwarded time to oral intake (MD=−0.48 d, P=0.32), and shortened hospital stay (MD=−2.03 d, P=0.14). Conclusions: LADG could bring the patients with EGC slight benefits by decreasing intraoperative blood loss and postoperative early morbidity, but unfavorably, might increase the operation time and decease the number of harvested lymph nodes. The long-term survival benefit is still eager to be proven by further outcomes of RCTs.

Prognostic value of cancer stem cell marker CD133 expression in gastric cancer: a systematic review.

Objective To investigate the correlation between CD133-positive gastric cancer and clinicopathological features and its impact on survival. Methods A search in the Medline and Chinese CNKI (up to 1 Dec 2011) was performed using the following keywords gastric cancer, CD133, AC133, prominin-1 etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Outcomes included overall survival and various clinicopathological features. Results A total of 773 gastric cancer patients from 7 studies were included. The median rate of CD133 expression by immunohistochemistry (IHC) was 44.8% (15.2%–57.4%) from 5 studies, and that by reverse transcription polymerase chain reaction (RT-PCR) was 91.3% (66.7%–100%) from 4 studies. The accumulative 5-year overall survival rates of CD133-positive and CD133-negative patients were 21.4% and 55.7%, respectively. Meta-analysis showed that CD133-positive patients had a significant worse 5-year overall survival compared to the negative ones (OR = 0.20, 95% CI 0.14–0.29, P<0.00001). With respect to clinicopathological features, CD133 overexpression by IHC method was closely correlated with tumor size, N stage, lymphatic/vascular infiltration, as well as TNM stage. Conclusion CD133-positive gastric cancer patients had worse prognosis, and was associated with common clinicopathological poor prognostic factors.

Tumor-Infiltrating Immune Cells Are Associated With Prognosis of Gastric Cancer

AbstractImmune cells contribute to determining the prognosis of gastric cancer. However, their exact role is less clear.We determined the prognostic significance of different immune cells in intratumoral tissue (T), stromal tissue (S), and adjacent normal tissue (N) of 166 gastric cancer cases and their interactions, including CD3+, CD4+, CD8+, CD57+, CD68+, CD66b+, and Foxp3+ cells, and established an effective prognostic nomogram based on the immune reactions.We found high densities of TCD3+, TCD4+, TCD8+, SCD3+, SCD4+, SCD57+, SCD66b+, and NFoxp3+ cells, as well as high TCD8+/SCD8+ ratio, TCD68+/SCD68+ ratio, TCD3+/TFoxp3+ ratio, TCD4+/TFoxp3+ ratio, TCD8+/TFoxp3+ ratio, SCD3+/SFoxp3+ ratio, and SCD4+/SCD8+ ratio were associated with better survival, whereas high densities of TCD66b+, TFoxp3+, SFoxp3+ and NCD66b+ cells as well as high TCD57+/SCD57+ ratio, TCD66b+/SCD66b+ ratio, SCD8+/SFoxp3+ ratio, and TFoxp3+/NFoxp3+ ratio were associated with significantly worse outcome. Multivariate analysis indicated that tumor size, longitudinal tumor location, N stage, TCD68+/SCD68+ ratio, TCD8+/TFoxp3+ ratio, density of TFoxp3+ cells, and TCD66b+/SCD66b+ ratio were independent prognostic factors, which were all selected into the nomogram. The calibration curve for likelihood of survival demonstrated favorable consistency between predictive value of the nomogram and actual observation. The C-index (0.83, 95% CI: 0.78 to 0.87) of our nomogram for predicting prognosis was significantly higher than that of TNM staging system (0.70).Collectively, high TCD68+/SCD68+ ratio and TCD8+/TFoxp3+ ratio were associated with improved overall survival, whereas high density of TFoxp3+ cells and TCD66b+/SCD66b+ ratio demonstrated poor overall survival, which are promising independent predictors for overall survival in gastric cancer.

Total vs. proximal gastrectomy for proximal gastric cancer: a systematic review and meta-analysis.

BACKGROUND/AIMS To compare effectiveness between total gastrectomy (TG) and proximal gastrectomy (PG) for proximal gastric cancer. METHODOLOGY PubMed, Embase, Cochrane library and Chinese CNKI databases were searched to select eligible studies comparing TG to PG for proximal gastric cancer. Outcome measures included overall survival, recurrence, mortality and morbidity rates, as well as nutritional states. Meta-analyses were performed by RevMan 5.0. RESULTS One randomized controlled trial and 7 retrospective studies involving 1077 patients were included. Meta-analysis showed no significant difference of 5-year overall survival rate (OR=0.89, p=0.53). However, TG achieved a lower recurrence rate (Peto OR=0.53, p=0.004). PG experienced higher morbidity risk (OR=0.11, p<0.00001), concerning higher risks of reflux esophagitis (OR=0.04, p<0.00001) and anastomotic stenosis (OR=0.14, p<0.00001) in a short period. TG performed longer operation time (p=0.002) and more blood loss (p<0.00001). Operative mortality and nutritional states were comparable without significant differences. CONCLUSIONS Based on current retrospective evidences, TG and PG had similar overall survival outcome for proximal gastric cancer, but TG showed lower recurrence rate. PG with gastroesophagostomy had higher incidence of reflux esophagitis and anastomotic stenosis. TG can be recommendation for proximal gastric cancer, although more high-quality trials are still expected.

Docetaxel, Cisplatin and Fluorouracil (DCF) Regimen Compared with Non-Taxane-Containing Palliative Chemotherapy for Gastric Carcinoma: A Systematic Review and Meta-Analysis

Background Gastric carcinoma (GC) is one of the highest cancer-mortality diseases with a high incidence rate in Asia. For surgically unfit but medically fit patients, palliative chemotherapy is the main treatment. The chemotherapy regimen of docetaxel, cisplatin and 5-fluorouracil (DCF) has been used to treat the advanced stage or metastatic GC. It is necessary to compare effectiveness and toxicities of DCF regimen with non-taxane-containing palliative chemotherapy for GC. Methods PubMed, EmBase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure databases were searched to select relative randomized controlled trials (RCTs) comparing DCF to non-taxane-containing chemotherapy for patients with palliatively resected, unresectable, recurrent or metastatic GC. Primary outcome measures were 1-year and 2-year overall survival (OS) rates. Secondary outcome measures were median survival time (MST), median time to progression (TTP), response rate and toxicities. Results Twelve RCTs were eligible and 1089 patients were analyzed totally (549 in DCF and 540 in control). DCF regimen increased partial response rate (38.8% vs 27.9%, p = 0.0003) and reduced progressive disease rate (18.9% vs 33.3%, p = 0.0005) compared to control regimen. Significant improvement of 2-year OS rate was found in DCF regimen (RR = 2.03, p = 0.006), but not of 1-year OS rate (RR = 1.22, p = 0.08). MST was significantly prolonged by DCF regimen (p = 0.039), but not median TTP (p = 0.054). Both 1-year OS rate and median TTP had a trend of prolongation by DCF regimen. Chemotherapy-related mortality was comparable (RR = 1.23, p = 0.49) in both regimens. In grade I-IV toxicities, DCF regimen showed a major raise of febrile neutropenia (RR = 2.33, p<0.0001) and minor raises of leucopenia (RR = 1.25, p<0.00001), neutropenia (RR = 1.19, p<0.00001), and diarrhea (RR = 1.59, p<0.00001), while in other toxicities there were no significant differences. Conclusion DCF regimen has better response than non-taxane containing regimen and could potentially improve the survival outcomes. The chemotherapy-related toxicity of DCF regimen is acceptable to some extent.

The Impact of Body Mass Index on the Surgical Outcomes of Patients With Gastric Cancer: A 10-Year, Single-Institution Cohort Study.

Abstract This study aimed to investigate the impact of body mass index (BMI) on the short-term and long-term results of a large cohort of gastric cancer (GC) patients undergoing gastrectomy. Recently, the “obesity paradox” has been proposed, referring to the paradoxically “better” outcomes of overweight and obese patients compared with nonoverweight patients. The associations between BMI and surgical outcomes among patients with GC remain controversial. A single-institution cohort of 1249 GC patients undergoing gastrectomy between 2000 and 2010 were categorized to low-BMI (<18.49 kg/m2), normal-BMI (18.50–24.99 kg/m2), and high-BMI (≥25.00 kg/m2) groups. The postoperative complications were classified according to the Clavien-Dindo system, and their severity was assessed by using the Comprehensive Complication Index (CCI). The impact of BMI on the postoperative complications and overall survival was analyzed. There were 908, 158, and 182 patients in the normal-BMI, low-BMI, and high-BMI groups, respectively. The overall morbidity in the high-BMI group (24.7%) was higher than that in either the low-BMI or the normal-BMI group (20.9% and 15.5%, respectively; P = 0.006), but the mean CCI in the low-BMI group was significantly higher (8.32 ± 19.97) than the mean CCI in the normal-BMI and high-BMI groups (3.76 ± 11.98 and 5.58 ± 13.07, respectively; P < 0.001). The Kaplan–Meier curve and the log-rank test demonstrated that the low-BMI group exhibited the worst survival outcomes compared with the normal-BMI group, whereas the high-BMI group exhibited the best survival outcomes (P < 0.001). In multivariate analysis, BMI was identified as an independent prognostic factor. In the stage-specific subgroup analysis, a low BMI was associated with poorer survival in the cases of stage III–IV diseases. Low BMI was associated with more severe postoperative complications and poorer prognosis. Despite a higher risk of mild postoperative complications, the high-BMI patients exhibited paradoxically “superior” survival outcomes compared with the normal-BMI patients. These findings confirm the “obesity paradox” in GC patients undergoing gastrectomy.

D2 plus para-aortic lymphadenectomy versus standardized D2 lymphadenectomy in gastric cancer surgery

PurposeTo evaluate the survival benefits and safety of D2 plus para-aortic lymphadenectomy (D2 + PALD) for gastric carcinoma.MethodsPatients with gastric carcinoma, who agreed to undergo D2 + PALD between February 2001 and December 2003, were allocated to the D2 + PALD group, and compared with a control group who underwent D2 lymphadenectomy. Patients were followed up until August 2007.ResultsSixty-two patients were allocated to the D2 + PALD group, and a concurrent 55 patients were allocated to the D2 group. The mean follow-up period was 57.6 (range 43.0—77.6) months, with 11.1% lost to follow-up. The morbidity and mortality rates were 24.2% and 0% in the D2 + PALD group, and 27.3% and 1.8% in the D2 group, respectively. The overall 3- and 5-year survival rates were 77.5% and 65.8% in the D2 + PALD group, and 73.2% and 66.1% in the D2 group, respectively, without a significant difference. The frequency of metastasis to the para-aortic lymph nodes (PALN) was 8.1%. The logistic regression revealed that PALN metastasis was correlated to metastasis of No. 8a and No. 9 lymph nodes (P = 0.021 and P = 0.030, respectively).ConclusionAlthough D2 + PALD can be performed safely with an acceptable incidence of complications when performed by well-trained gastrointestinal surgeons, its survival benefits are not significantly greater than those of D2 lymphadenectomy. Therefore, routine D2 + PALD should not be recommended.

Long-term survival outcomes of laparoscopic versus open gastrectomy for gastric cancer: a systematic review and meta-analysis.

AbstractMany meta-analyses have confirmed the technical feasibility and favorable short-term surgical outcomes of laparoscopic gastrectomy (LG) for gastric cancer patients, but the long-term survival outcome of LG remains controversial compared with open gastrectomy (OG).This study aimed to compare the 5-year overall survival (OS), recurrence, and gastric cancer–related death of LG with OG among gastric cancer patients.PubMed was searched to February 2014.The resectable gastric cancer patients who underwent curative LG or OG were eligible. The studies that compared 5-year OS, recurrence, or gastric cancer–related death in the LG and OG groups were included.A meta-analysis, meta-regression, sensitivity analysis, subgroup analysis, and stage-specific analysis were performed to estimate the survival outcome between the two groups and identify the potential confounders. Quality assessment was based on a tailored comparability scoring system.Twenty-three studies with 7336 patients were included. The score of comparability between two groups and the extent of lymphadenectomy were two independent confounders. Based on the well-balanced studies, the 5-year OS (OR = 1.07, 95% CI 0.90–1.28, P = 0.45), recurrence (OR = 0.83, 95% CI 0.68–1.02, P = 0.08), and gastric cancer–related death (OR = 0.86, 95% CI 0.65–1.13, P = 0.28) rates were comparable in LG and OG. Several subsets such as the publication year, study region, sample size, gastrectomy pattern, extent of lymphadenectomy, number of nodes harvested, and proportion of T1–2 or N0–1 did not influence the estimates, if they were well balanced. Particularly, the stage-specific estimates obtained comparable results between the two groups.Randomized controlled trials comparing LG with OG remain sparse to assess their long-term survival outcomes.The major contributions of this systematic review compared with other meta-analyses are a comprehensive collection of available long-term survival outcomes within a much larger number of observations and a more precise consideration of confounders. Current knowledge indicates that the long-term survival outcome of laparoscopic gastric cancer surgery is comparable to that of open surgery among early or advanced stage gastric cancer patients, and LG is acceptable with regard to oncologic safety.

Is CD133 a biomarker for cancer stem cells of colorectal cancer and brain tumors? A meta-analysis

Background CD133 has been used to identify normal and cancer stem cells from several different tissues. Nowadays some researchers have reported that CD133 expression was not restricted to cancer stem cells (CSCs) of colorectal cancer and brain tumors, and CD133-negative subsets could also initiate tumors. We therefore performed a meta-analysis to assess the value of CD133 as a biomarker of CSCs for colorectal cancer and brain tumors. Methods A Medline search was performed to identify relevant studies for the analysis. The meta-analysis was done using RevMan 5.0 software. Outcome measures were colony formation rate and xenotransplanted tumor formation rate. Results Fifteen identified studies were available for analysis. For in vitro tests, there were no significant differences in the colony formation rates between CD133-positive and CD133-negative cells for colorectal cancer and brain tumors. For in vivo tests, the xenotransplanted tumor formation rate showed a significant difference between CD133-positive cells and CD133-negative cells in colorectal cancer only, corresponding to a risk difference of 0.40 (95%CI: 0.07, 0.73). Samples (cell lines versus tissues), applied biomarkers (combined versus single), and injection site were included as factors in sensitivity analyses, but the results were very inconsistent. Conclusions CD133 may not be suitable as a universe biomarker in identifying CSCs of colorectal cancer and brain tumors. Additional studies are necessary to further delineate its role.