Tuanjie Li

Immunoscore Signature: A Prognostic and Predictive Tool in Gastric Cancer

Objective: We postulated that the ImmunoScore (IS) could markedly improve the prediction of postsurgical survival and chemotherapeutic benefits in gastric cancer (GC). Summary Background Data: A prediction model for GC patients was developed using data from 879 consecutive patients. Methods: The expression of 27 immune features was detected in 251 specimens by using immunohistochemistry, and a 5-feature-based ISGC was then constructed using the LASSO Cox regression model. Testing and validation cohorts were included to validate the model. Results: Using the LASSO model, we established an ISGC classifier based on 5 features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. Significant differences were found between the high-ISGC and low-ISGC patients in the training cohort in 5-year disease-free survival (45.0% vs. 4.4%, respectively; P <0.001) and 5-year overall survival (48.8% vs. 6.7%, respectively; P <0.001). Multivariate analysis revealed that the ISGC classifier was an independent prognostic factor. A combination of ISGC and tumor, node, and metastasis (TNM) had better prognostic value than TNM stage alone. Further analysis revealed that stage II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. Finally, we constructed 2 nomograms to predict which patients with stages II and III GC might benefit from adjuvant chemotherapy after surgery. Conclusions: The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value of the TNM staging system. Moreover, the ISGC might be a useful predictive tool to identify stage II and III GC patients who would benefit from adjuvant chemotherapy.

Interleukin-17-producing neutrophils link inflammatory stimuli to disease progression by promoting angiogenesis in gastric cancer.

Purpose: Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking. Experimental Design: A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivo. Results: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17+ neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer. Conclusions: These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment. Clin Cancer Res; 23(6); 1575–85. ©2016 AACR.

Gastric cancer cells inhibit natural killer cell proliferation and induce apoptosis via prostaglandin E2

ABSTRACT Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we showed, in detailed studies of NK cells from 235 untreated patients with gastric cancer (GC), the NK cell density in GC tissues could predict improved survival of patients. However, NK cells were significantly decreased in number with advanced-stage GC. A multivariate Cox analysis revealed that the intratumoral NK cell density was an independent prognostic factor for overall survival and disease-free survival in the GC patients. Most of the intratumoral NK cells exhibited a normal phenotype and secreted normal levels of cytokines, but the expression of Ki67 was decreased compared with NK cells from nontumoral regions. Moreover, the levels of intratumoral NK cells were negatively correlated with the intratumoral expression of cyclooxygenase-2. Furthermore, we found that PGE2 derived from GC cells suppressed NK cell proliferation and increased apoptosis in vitro. These data reveal that tumor-derived PGE2 is critical for inducing NK cell dysfunction in GC and demonstrate that an extensive infiltration of NK cells predicts a good prognosis in patients with GC. Our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression.

Prognostic and Predictive Value of p21-activated Kinase 6 Associated Support Vector Machine Classifier in Gastric Cancer Treated by 5-fluorouracil/Oxaliplatin Chemotherapy

To determine whether p21-activated Kinase (PAK) 6 is a prognostic and predictive marker in gastric cancer (GC) and to construct a classifier that can identify a subset of patients who are highly sensitive to 5-fluorouracil/oxaliplatin chemotherapy. We retrospectively analyzed the expression levels of PAK6, cyclooxygenase 2, p21WAF1, Ki-67, excision repair cross-complementing gene 1, and thymidylate synthase in 242 paraffin-embedded GC specimens of the training cohort by immunohistochemistry. Then, we used support vector machine (SVM)–based methods to develop a predictive classifier for chemotherapy (chemotherapy score – CS-SVM classifier). Further validation was performed in an independent cohort of 279 patients. High PAK6 expression was associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy. The CS-SVM classifier distinguished patients with stage II and III GC into low- and high-CS-SVM groups, with significant differences in the 5-year disease-free survival (DFS) and overall survival (OS) in chemotherapy patients. Moreover, chemotherapy significantly prolonged the DFS and OS of the high CS-SVM patients in the training and validation cohorts. In conclusion, PAK6 was an independent prognostic factor and increased chemoresistance. The CS-SVM classifier distinguished a subgroup of stage II and III patients who would highly benefit from chemotherapy, thus facilitating patient counseling and individualizing the management.

Short-Term Outcomes of Single-Incision Versus Conventional Laparoscopic Surgery for Colorectal Diseases: Meta-Analysis of Randomized and Prospective Evidence

BackgroundConventional laparoscopic surgery (CLS) has been established as an alternative to open surgery for colorectal diseases (CRDs); simultaneously, single-incision laparoscopic surgery (SILS) is gaining popularity.ObjectiveThe aim of this study was to compare the short-term efficacy and safety of SILS with CLS for CRDs.MethodsMEDLINE, EMBASE, and the Cochrane Library were searched for relevant randomized and prospective studies. Reference lists of relevant articles and reviews, conference proceedings, and ongoing trial databases were also screened. Outcome measures included surgical parameters, postsurgical recovery, pain, and adverse events. Meta-analysis was conducted where appropriate, comparing items using weighted mean differences (WMDs) and risk ratios (RRs) according to data type.ResultsA total of nine prospective (three randomized and six non-randomized) researches published from 2011 to 2015 were identified. The overall pooled results showed compared to CLS, SILS was associated with fewer blood transfusions, shorter incision length, and slighter postoperative pain, but more extra ports. All the other parameters were comparable. Randomized evidence supported SILS was associated with less blood loss, and shorter hospital stay, but longer operative time. For only colectomy cases, SILS was associated with more conversions to open surgery. SILS was associated with longer surgical time for Easterners, but not for Westerners. The detected differences were clinically insignificant.ConclusionsThe results based on randomized and prospective evidence provide convincing support for the clinical similarity that SILS is basically as applicable, effective, and safe as CLS when dealing with colorectal lesions, but not for superiority.

Prognostic impact of lymph node skip metastasis in stage III colorectal cancer

The aim of this study was to evaluate the prognostic impact of lymph node skip metastasis (LNSM) in patients with Stage III colorectal cancer.

Sericin nanomicelles with enhanced cellular uptake and pH-triggered release of doxorubicin reverse cancer drug resistance

Abstract Drug resistance is the major challenge facing cancer chemotherapy and nanoscale delivery systems based on natural materials, such as sericin, are a promising means of overcoming drug resistance. Yet, no attempt of introducing synthetic poly(γ-benzyl-L-glutamate) (PBLG) onto sericin polypeptide to fabricate a facile biocompatible and biodegradable micelle has been tried. Here, we prepared a polypeptide-based amphiphilic polymer containing hydrophilic sericin polypeptide backbone and PBLG side chains via ring-opening polymerization (ROP) strategy. The introduction of PBLG side chains remarkably enhances the stability of sericin micelles in water. Meanwhile, the micelles exhibited a high loading capacity and pH-responsive release ability for antitumor drug doxorubicin (DOX), called sericin-PBLG-DOX. Owing to the excellent cell membrane penetration of sericin-PBLG, the cellular uptake of DOX when loaded into micelles was improved. Subsequently, sericin-PBLG-DOX was transferred into perinuclear lysosomes, where the release rate of DOX was accelerated. Compared to the same dose of DOX, sericin-PBLG-DOX could induce a more efficient anti-tumor effect both in vitro and in vivo, and these micelles have promise for future clinical applications in overcoming cancer drug resistance with good biosafety, enhanced cellular uptake, pH-triggered drug release, efficient anti-tumor effects, and minimized systemic toxicity.

Vitamin-B12-conjugated sericin micelles for targeting CD320-overexpressed gastric cancer and reversing drug resistance

AIM Our previous research has introduced sericin micelles to reverse drug resistance. However, these micelles could not selectively bind to gastric cancer (GC) cells. We developed vitamin B12 (VB12) conjugated sericin micelles for targeted GC therapy. MATERIALS & METHODS We used VB12, sericin, synthetic poly(γ-benzyl-L-glutamate) (PBLG) and paclitaxel (PTX) to develop VB12-conjugated and PTX-loaded micelles (VB12-sericin-PBLG-PTX). Then we explored their physicochemical properties, cellular uptake and antitumor mechanism. RESULTS VB12-sericin-PBLG-PTX micelles were proved to be of appropriate particle size, have good dispersion and are bio-safe. Following transcobalamin II (CD320)-receptor-mediated endocytosis, these swallowed micelles with GC-targeting and enhanced cellular uptake abilities, alter mitochondrial transmembrane potential/apoptosis pathway and reverse drug resistance. CONCLUSION VB12-sericin-PBLG-PTX micelles are promising materials for GC-targeted clinical applications.

Superiority of the 8th edition of the TNM staging system for predicting overall survival in gastric cancer: Comparative analysis of the 7th and 8th editions in a monoinstitutional cohort

The present study was performed to evaluate the predictive capacity of the 8th edition vs. the 7th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for overall survival (OS) of patients with gastric cancer. Data of eligible patients with gastric cancer in our institution between June 2004 and June 2014 were retrospectively reviewed. A total of 1,506 patients were followed up to July 2016, among whom 1,484 patients with complete stage information were included in the TNM staging analysis. A total of 339 (22.8%) patients presented stage migration, including 325 (21.9%) migrating to a lower tier and 14 (0.9%) to a higher tier. All patients with stage migration to a lower tier were in stage III, including 177 (54.5%) patients migrating from stage IIIB to IIIA, and 148 (45.5%) from stage IIIC to IIIB. Patients migrating from IIIB to IIIA yielded a median OS time and 5-year OS rate closer to those remaining in stage IIIA. Similarly, patients migrating from IIIC to IIIB yielded a median OS time and 5-year OS rate closer to those remaining in stage IIIB. The 7th edition of the staging system exhibited prognostic discrepancy in discriminating stage IIIA from IIIB on survival curves, which was improved in the 8th edition. The 8th edition had a better predictive capability of survival, as evidenced by a smaller value of -2log likelihood in the Cox proportional regression model (7th edition 4738.859 vs. 8th edition 4736.683). Therefore, the present study demonstrated that the 8th edition of the AJCC TNM staging system is superior to the 7th edition in predicting the OS of patients with gastric cancer.

Morbidity and mortality of elderly patients with advanced gastric cancer after laparoscopy-assisted or open distal gastrectomy: a randomized–controlled trial

Abstract Laparoscopy-assisted distal gastrectomy (LDG) combined with D2 lymphadenectomy may be safely performed in patients with advanced gastric cancer (AGC) by experienced surgeons at specialized high-volume institutions as shown in the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS)-01. However, studies focusing on the use of LDG in patients with gastric cancer older than 65 years are rare. This study was designed to investigate the morbidity and mortality of elderly patients with gastric cancer who underwent laparoscopic-assisted or open distal gastrectomy (ODG). In this prospective, randomized, open, parallel controlled trial, patients older than 65 years with tumor located at the middle or lower part of the stomach will be enrolled in this study. Patients will be randomly divided into a laparoscopic group and an open surgery group. The early post-operative complications, intra-operative complications and post-operative recovery will be compared between the two groups. This trial will provide valuable clinical evidence for the objective assessment of the feasibility, short-term safety, and potential benefits of LDG compared with ODG for gastric cancer in the elderly patients. This trial has been registered on ClinicalTrials.gov. (Identifier: NCT02246153.) in September 22, 2014.