Wei-Han Zhang

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.

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.

5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages

5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.

Comparison on Clinicopathological Features and Prognosis Between Esophagogastric Junctional Adenocarcinoma (Siewert II/III Types) and Distal Gastric Adenocarcinoma: Retrospective Cohort Study, a Single Institution, High Volume Experience in China

AbstractThe incidence of the EGJA is rapidly increasing. The clinicopathological features have not yet been elucidated. The aim of this study was to analyze the differences in clinicopathological features and prognosis between patients with esophagogastric junctional adenocarcinoma (EGJA) and distal gastric adenocarcinoma (DGA).In this retrospective study, 1230 patients who underwent gastrectomy between January 2006 and December 2010 in West China Hospital were enrolled. Patients were divided into 2 groups based on tumor location. Clinicopathological characteristics, postoperative complications, and survival outcomes were compared. Univariate and multivariate analysis were also used to evaluate the prognostic factors of DGA and EGJA.Patients with gastric adenocarcinoma were divided into 2 study groups according to tumor location: 321 EGJA (26.1%) and 909 DGA (73.9%). Tumors with larger diameter, more advanced pT and pN stage were more common in EGJA. Significant differences were revealed in 3-year overall survival rate (3-YS) between 2 groups: EGJA (57.5%) and DGA (65.5%) (P = 0.001), and further analysis indicate that there was also significant difference on 3-YS between EGJA (76.9%) and DGA (84.2%) (P = 0.012) in stage II. From our multivariate analysis, we found that there were different independent prognostic indicators for DGA and EGJA.The clinicopathological features of EGJA were strikingly different from DGA and patients with EGJA showed a worse prognosis when compared with DGA. The pT stage, pN stage, pM stage, tumor size, age, and radical degree were determined to be independent factors of prognosis for DGA, while only combined organ resection, pN stage, and pM stage were independent prognostic factors for EGJA.

Prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet in patients with gastric carcinoma: a retrospective cohort study

Nutritional and immune status is important to the prognosis of patients with gastric carcinoma (GC). Here, we evaluated the prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) in patients with GC. From January 2005 to December 2011, 1332 patients with GC who underwent gastrectomy were randomly divided into the training (n = 888) and the validation sets (n = 444) by X-tile according to the sample size ratio 2:1. The cut-point of HALP was 56.8 and the patients were subsequently subdivided into HALP < 56.8 and HALP ≥ 56.8 groups in both two sets. Multivariate analysis revealed that gender (p < 0.001, p < 0.001), tumor size (p = 0.003, p = 0.035) and T stage (p < 0.001, p = 0.044) were independently related to HALP both in the training and the validation sets. Kaplan-Meier (p < 0.001, p = 0.003) and Cox regression (p = 0.043, p = 0.042) showed that the prognosis of HALP ≥ 56.8 group was significantly better than that of HALP < 56.8 group both in two sets (p < 0.001, p < 0.001). Nomograms of these two sets based on HALP was more accurate in prognostic prediction than TNM stage alone. Our findings suggested that HALP was closely associated with clinicopathological features and was an independent prognostic factor in GC patients. Nomogram based on HALP could accurately predict the prognosis of GC patients.

The Value of Palliative Gastrectomy for Gastric Cancer Patients With Intraoperatively Proven Peritoneal Seeding.

AbstractThe aim of this study was to evaluate the survival benefit of palliative gastrectomy for gastric cancer patients with peritoneal seeding proven intraoperatively and to identify positive predictive factors for improving survival.The value of palliative resection for gastric cancer patients with peritoneal metastasis is controversial.From 2006 to 2013, 267 gastric cancer patients with intraoperatively identified peritoneal dissemination were retrospectively analyzed. Patients were divided into resection group and nonresection group according to whether a palliative gastrectomy was performed. Clinicopathologic variables and survival were compared. Subgroup analyses stratified by clinicopathologic factors and multivariable analysis for overall survival were also performed.There were 114 patients in the resection group and 153 in nonresection group. The morbidities in the resection and nonresection groups were 14.91% and 5.88%, respectively (P = 0.014). There, however, was no difference in mortality between the 2 groups. The median survival time of patients in the resection group was longer than in nonresection group (14.00 versus 8.57 months, P = 0.000). The median survivals among the patients with different classifications of peritoneal metastasis were statistically significant (P = 0.000). Patients undergoing resection followed by chemotherapy had a significantly longer median survival, compared with that of patients who had chemotherapy alone, those who had resection alone, or those who had not received chemotherapy or resection (P = 0.000). Results of subgroup analyses showed that except for P3 patients and patients with multisite distant metastases, overall survival was significantly better in patients with palliative gastrectomy, compared with the nonresection group. In multivariate analysis, P3 disease (P = 0.000), absence of resection (P = 0.000), and lack of chemotherapy (P = 0.000) were identified as independently associated with poor survival.Palliative gastrectomy might be beneficial to the survival of gastric cancer patients with intraoperatively proven P1/P2 alone, rather than P3. Postoperative palliative chemotherapy could improve survival regardless of operation and should be recommended.

Survival benefit and safety of no. 10 lymphadenectomy for gastric cancer patients with total gastrectomy.

Abstract This study was aimed to evaluate the survival benefit and safety of No. 10 lymphadenectomy for gastric cancer patients with total gastrectomy. Splenic hilar lymph nodes (LNs) are required to be dissected in total gastrectomy with D2 lymphadenectomy. However, there has still not been a consensus in aspects of survival and safety on No. 10 LN resection. From January 2006 to December 2011, 453 patients undergoing total gastrectomy for gastric cancer were retrospectively analyzed. Patients were grouped according to No. 10 lymphadenectomy (10D+/10D−). Clinicopathologic characteristics were compared between the 2 groups. These patients had undergone a follow-up until January 2014. The overall survival, morbidity, and mortality rate were analyzed. Subgroup analyses which were stratified by the sex, age, tumor location, lymphadenectomy extent, curative degree, differentiation, tumor size, and TNM staging (ie, stages of tumor) were performed. There were 220 patients in 10D+ group, whereas 233 in 10D− group. In terms of prognosis, the baseline features between the 2 groups were almost comparable. The incidence of No. 10 LN metastasis was 11.82%. There was no difference in morbidity and mortality between the 2 groups. Significantly more LNs were harvested from patients in 10D+ group (P = 0.000). The estimated overall 5-year survival rates were 46.44% and 37.43% in 10D+ group and 10D− group respectively, which is not statistically significant (P = 0.3288). Although no statistical significance was found in the estimated 5-year survival rate, these data were obviously higher in patients with age >60 years, Siewert II/ III tumors, N1 status, or IIIa/IIIc stages when No. 10 lymphadenectomies were performed. Although the differences were obvious, the 5-year survival rates between the 2 groups did not reach statistical significances, which was probably caused by too small patient samples. High-quality studies with larger sample sizes are needed before stronger statement can be done. Until then, the No. 10 LNs’ resection might be recommended in total gastrectomy with D2 lymphadenectomy with an acceptable incidence of complications.

Prognostic significance of preoperative serum CA125, CA19-9 and CEA in gastric carcinoma

The prognostic significance of preoperative serum CA125, CA19-9 and CEA in gastric carcinoma (GC) has been widely reported and is still under debate. Here, we evaluated the prognostic significance of preoperative serum CA125, CA19-9 and CEA in patients with GC. 1692 patients with GC who underwent gastrectomy were divided into the training (from January 2005 to December 2011, n = 1024) and the validation (from January 2012 to December 2013, n = 668) cohorts. Positive groups of CA125 (> 13.72 U/ml), CA19-9 (> 23.36 U/ml) and CEA (> 4.28 ng/ml) were significantly associated with more advanced clinicopathological traits and worse outcomes than that of negative groups (all P < 0.01). In Cox regression analysis, tumor size (P < 0.001, P = 0.005), pTNM stage (P < 0.001, P < 0.001) and CA125 (P = 0.026, P = 0.005) were independent prognostic factors both in two cohorts. Nomograms of these two cohorts based on the number of positive serum tumor markers (NPTM) were more accurate in prognostic prediction than TNM stage alone. Our findings suggested that elevated preoperative serum CA125, CA19-9 and CEA were associated with more advanced clinicopathological traits and less favorable outcomes. In addition, CA125 as an independent prognostic factor should be further investigated. Nomogram based on NPTM could accurately predict the prognosis of GC patients.

Necessity of harvesting at least 25 lymph nodes in patients with stage N2-N3 resectable gastric cancer: a 10-year, single-institution cohort study.

AbstractA minimum of 15 lymph nodes (LNs) has been recommended as an adequate number for radical gastrectomy for gastric cancer (GC). This study aimed to investigate whether the harvesting of at least 25 LNs was a better criterion for stage N2–3 GC based on the 10-year experience of a high-volume hospital.A total of 1363 patients who underwent radical gastrectomy for gastric cancer between 2000 and 2010 were included in this study. The relationship between the number of lymph nodes examined during gastrectomy and overall survival (OS) was analyzed.In multivariate analysis, the numbers of LNs examined (P = 0.001) and N stage were confirmed as 2 of the independent prognostic factors. A larger proportion of N2/N3a/N3b patients was observed in the group with ≥20 LNs examined. The cutoff of ≥25 LNs examined exhibited a significantly lower hazard ratio (HR) than other LN cutoffs among N2–N3 diseases, but the cutoff was not significantly superior to other cutoffs in patients with N0 and N1 disease (HR, 0.64, 0.62, and 0.53 for N2, N3a, and N3b, respectively). The 5-year OS rates were 58.59% and 32.77% for N2 and N3 diseases, respectively, with ≥25 LNs examined, which represents a significant improvement over 15–24 LNs examined (52.48% and 21.67% for N2 and N3 stages, respectively).Among patients with stage N2–N3 GC, harvesting at least 25 LNs may represent a superior cutoff for radical gastrectomy and could yield better survival outcomes.

A difficulty in improving population survival outcome of gastric cancer in mainland China: low proportion of early diseases

In Medical Oncology, a Chinese high-volume hospital’s experience typically represented the changes of surgical management for gastric cancer in mainland China [1]. Since the interim of first decade of twenty-first century, several Chinese surgeon communities of gastric cancer, such as gastric cancer committee in Chinese Anti-Cancer Association (CACA), made a great effort to spread standard gastric cancer surgery and advance the quality of radical D2 surgery in mainland China. Consequently, we found a dramatic increase in proportion of D2 surgery between two periods 2000–2005 and 2006–2010 [1]. Likewise, the average of harvested lymph nodes was obviously increased along with the promotion of technical quality [1]. Similar changes could be seen in other Chinese high-volume medical institutes nationwide, and the standard D2 surgery became the preferred treatment for resectable gastric cancer, including early gastric cancer (EGC). The promising alteration led to improvement in overall outcome of surgical patients with gastric cancer in mainland China. In Japan and Korea, also high-incidence countries of gastric cancer, standard D2 surgery is generally advocated. However, their overall survival outcome of gastric cancer appears superior to that in China, although the stage-specific survival rates are not apparently different [1]. Based on Globocan 2012 data set from International Agency for Research on Cancer (IARC), mortality-to-prevalence ratios (MPRs) are 0.04, 0.07 and 0.33 in Japan, Korea and China, respectively. MPR is a sensitive epidemiological parameter to estimate the difference in overall survival outcome among populations [2]. The high MPR in China indicates that the global efficacy of screening and management of gastric cancer is still weak, despite the likely comparability of surgical technique to Japan and Korea. Therefore, the shortage in overall survival outcome in China has to largely attribute to the lower proportion of EGC among all gastric cancer patients. According to Japanese and Korean reports, the proportion of EGC has been 50–60% among surgical patients, and additionally many eligible EGC patients are selected for endoscopic treatment, especially in Japan. In contrast, our experience in the Chinese high-volume hospital mentioned above demonstrates that the proportion of EGC was only 8–11% during 1994–2001 and 11–19% during 2002–2012, respectively (Fig. 1a). The average of EGC proportion is still very limited (14.5%) in west China, although it has already increased to some extent (Fig. 1b). Among surgical patients with EGC, 22.1% of them had lymph node metastasis, who were unfit for endoscopic treatment. It is the reason why endoscopic treatment cannot become popular in mainland China by now. Additionally, 30.8% of those patients with node-positive EGC had no less than 3 metastatic nodes, as unfit for limited surgery and sentinel node navigation despite of superficial infiltration. Most Chinese gastrointestinal surgeons personally prefer standard D2 surgery for EGC yet. The lower proportion of EGC and relatively advanced status of EGC make either surgical or endoscopic treatment pattern different between China and Japan or Korea. Factually, high mortality of gastric cancer has been a great part of increasing healthcare burden for 40 years in mainland X.-Z. Chen (&) W.-H. Zhang J.-K. Hu (&) Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu 610041, Sichuan Province, China e-mail: chen_xz_wch_scu@126.com