Single-cell analysis revealed a potential role of T-cell exhaustion in colorectal cancer with liver metastasis.

Liver metastasis (LM) is an important factor leading to colorectal cancer (CRC) mortality. However, the effect of T-cell exhaustion on LM in CRC is unclear. Single-cell sequencing data derived from the Gene Expression Omnibus database. Data were normalized using the Seurat package and subsequently clustered and annotated into different cell clusters. The differentiation trajectories of epithelial cells and T cells were characterized based on pseudo-time analysis. Single-sample gene set enrichment analysis (ssGSEA) was used to calculate enrichment scores for different cell clusters and to identify enriched biological pathways. Finally, cell communication analysis was performed. Nine cell subpopulations were identified from CRC samples with LM. The proportion of T cells increased in LM. T cells can be subdivided into NK/T cells, regulatory T cells (Treg) and exhausted T cells (Tex). In LM, cell adhesion and proliferation activity of Tex were promoted. Epithelial cells can be categorized into six subpopulations. The transformation of primary CRC into LM involved two evolutionary branches of Tex cells. Epithelial cells two were at the beginning of the trajectory in CRC but at the end of the trajectory in CRC with LM. The receptor ligands CEACAM5 and ADGRE5-CD55 played critical roles in the interactions between Tex and Treg cell-epithelial cell, which may promote the epithelial-mesenchymal transition process in CRC. Tex cells are able to promote the process of LM in CRC, which in turn promotes tumour development. This provides a new perspective on the treatment and diagnosis of CRC.

miR-182 controls cell growth in gastrointestinal stromal tumors by negatively regulating CYLD expression.

Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the digestive tract. MicroRNAs (miRNAs) are short non-coding RNAs, which control gene expression at a post-transcriptional level. Dysregulated miRNAs are involved in various types of human disease, including cancer. In the present study, it was revealed that miRNA-182 (miR-182) expression was significantly upregulated in human GISTs compared with adjacent normal tissues. Overexpression of miR-182 enhanced GIST-T1 cell growth, with increased proliferation and decreased apoptosis. miR-182 upregulation also promoted colony formation and migration of GIST-T1 cells. In addition, cylindromatosis (CYLD) was identified as a direct target of miR-182. Overexpression of miR-182 suppressed CYLD expression and enhanced downstream nuclear factor (NF)-κB activation. It was also determined that the expression of CYLD was downregulated in association with upregulated miR-182 in human GISTs. In conclusion, these results demonstrated that miR-182 promoted GIST cell growth by negatively regulating CYLD expression. These findings indicated that miR-182 antagonist may be a promising therapeutic strategy for the treatment of human GIST.

FBXW7 expression is associated with prognosis and chemotherapeutic outcome in Chinese patients with gastric adenocarcinoma.

BACKGROUND: FBXW7, a component of the Skp-Cullin1-F-box, mediates target protein recognition. It is a tumor suppressor gene that plays a role in the regulation of cell cycle exit and reentry via c-Myc, c-Jun and Notch degradation. There are few studies, particularly involving a large patient cohort, that have evaluated FBXW7 during gastric cancer progression. METHODS: Our study aimed to evaluate the value of FBXW7 as a clinical marker in gastric adenocarcinoma (GC) patients including a subset treated with postoperative chemotherapy. Quantitative reverse transcription PCR (qRT-PCR) assay was used to measure FBXW7 transcript levels in tumors paired with normal gastric tissue in 24 gastric adenocarcinoma patients. Subsequently, 546 additional GC samples were evaluated from patients that underwent radical gastrectomy, including 118 early stage cases(Stage I) and 428 advanced stage cases (Stages II or III). Amongst the advanced stage patient cases evaluated, 347 received postoperative adjuvant chemotherapy. All 546 gastric adenocarcinoma cases were then evaluated by tissue microarray and immunohistochemistry (IHC) for FBXW7 expression. Clinicopathological features and diagnoses were confirmed by histopathologic evaluation and review of clinical data. Overall survival (OS) was then evaluated in the 546 gastric cancer patients. RESULTS: By immunohistologic evaluation, low expression of FBXW7 in primary gastric cancer significantly correlated with poor differentiation of tumor cells. Moreover, low FBXW7 expression was associated with worse survival as well as worse adjuvant chemotherapy response. CONCLUSION: Our findings suggest that FBXW7 may serve as an important predictor in chemotherapeutic responses.

The surgical treatment of gastric cancer in the era of minimally invasive surgery.

Minimally invasive surgery is regarded as an alternative to conventional open surgery in gastric cancer. More and more surgeons devote their efforts to reduce surgical incision and acquire better recovery. Nowadays, laparoscopic distal gastrectomy has been the standard method for early stage cancer with remarkable advantage in short-term outcomes and is widely accepted by patients. The indication of laparoscopic gastrectomy has been extended to local advanced gastric cancer. However, the oncological safety has long been debated. Therefore, large scale randomized controlled clinical trials are ongoing to confirm the feasibility and safety in more advanced gastric cancer. With the accumulation of surgical experience and development of instrument, several advanced techniques, such as function preserving surgery, total laparoscopic anastomosis, sentinel node navigation surgery, robotic assisted surgery and reduced port laparoscopic gastrectomy have also been explored and applied to gastric cancer patient. All these techniques could modify the extent of surgery, reduce the risk of perioperative complications and generate potential better results in quality of life. Although recent studies have confirmed the feasibility and safety of each procedure, more evidence is required for further popularization of the newly technique. Herein we describe the current status and evidence for surgical treatment of gastric cancer in the era of minimally invasive surgery.

A novel molecular and clinical staging model to predict survival for patients with esophageal squamous cell carcinoma.

Current prognostic factors fail to accurately determine prognosis for patients with esophageal squamous cell carcinoma (ESCC) after surgery. Here, we constructed a survival prediction model for prognostication in patients with ESCC. Candidate molecular biomarkers were extracted from the Gene Expression Omnibus (GEO), and Cox regression analysis was performed to determine significant prognostic factors. The survival prediction model was constructed based on cluster and discriminant analyses in a training cohort (N=205), and validated in a test cohort (N=207). The survival prediction model consisting of two genes (UBE2C and MGP) and two clinicopathological factors (tumor stage and grade) was developed. This model could be used to accurately categorize patients into three groups in the test cohort. Both disease-free survival and overall survival differed among the diverse groups (P<0.05). In summary, we have developed and validated a predictive model that is based on two gene markers in conjunction with two clinicopathological variables, and which can accurately predict outcomes for ESCC patients after surgery.

Current status of surgical treatment of gastric cancer in the era of minimally invasive surgery in China: Opportunity and challenge.

Gastric cancer is one of the most common cancers in China. In the past decade, with the developments in surgical instruments and technologies, minimally invasive surgery has rapidly become an accepted treatment for gastric cancer in China. Many Chinese surgeons and researchers have contributed to the rapid evolution of minimally invasive surgery for gastric cancer. Their efforts have transformed into unique laparoscopic technique, workshops, academic communications, education and international communications in China. Meanwhile, many retrospective comparative trials and randomized controlled trials have revealed the advantages in minimally invasive surgery for gastric cancer. However, multicenter randomized controlled trials are still needed to delineate significantly quantifiable differences between laparoscopic and open gastrectomy. With more and more experience has accumulated, laparoscopic gastrectomy has been performed on older and overweight patients. Moreover, advanced minimally invasive techniques, such as modified laparoscopic spleen-preserving splenic hilum lymphadenectomy, various laparoscopic gastric reconstruction methods and robotic gastrectomy have been developed. It seems that China owns the potential to keep up with her neighbor, Japan and Korea, to become one of leading countries utilizing minimally invasive surgery for gastric cancer.

Impact of ABO blood group on the prognosis of patients undergoing surgery for esophageal cancer.

BACKGROUND: ABO blood type is an established prognostic factor in several malignancies, but its role in esophageal cancer (EC) is largely unknown. The aim of this study is to determine whether ABO blood group is associated with survival after esophagectomy for EC. METHODS: A total of 406 patients who underwent surgery for EC were enrolled. The associations of ABO blood group with clinical and pathological variables were assessed using chi-square test. Associations of ABO blood group with the survival were estimated using univariable and multivariable Cox proportional hazards regression models. RESULTS: The ABO blood group proportionally associated with the grade of EC tumor (P = 0.049). The ABO blood group status did not correlate with disease-free survival (DFS) in univariable analysis or multivariable analysis (P > 0.05). And there was no significant relationship between the ABO blood group and overall survival (OS) in univariable analysis or multivariable analysis (P > 0.05). CONCLUSIONS: Our results suggested that no association between ABO blood group and the survival was observed in patients undergoing surgery for EC.

Turning left or right? A comparative analysis in adenocarcinomas of the esophagogastric junction according to the seventh AJCC TNM classification for cancers of the esophagus and stomach: experience in a Chinese single institution.

The seventh AJCC TNM classification defines rules for classifying adenocarcinomas of esophagogastric junction (AEG II and III) as a part of esophageal cancer. But there are still many controversies over the classification system. The study aims to evaluate and compare whether AEG should be classified as cancers of esophagus or stomach. A single-center cohort of patients with AEG or proximal third gastric adenocarcinoma underwent surgical resection with curative intent in Shanghai from November 2004 to July 2011. We compared the clinicopathologic features between AEG (n=291) and proximal third gastric adenocarcinoma (n=176) and analyzed overall survival probabilities of AEG using the latest seventh AJCC TNM classification for cancers. Patients with AEG not only show more advanced diseases, but also have a significantly worse 5-year survival rate than those with proximal third gastric adenocarcinoma (P=0.027). In 291 patients with AEG, the gastric T classification is monotone but indistinct except for pT2 versus pT3 (P=0.001) and pT4a versus pT4b (P=0.012). The esophageal T classification is neither monotone nor distinct. For the N classification, both schemes are monotone and distinct. The gastric scheme is indistinctive for stages IA versus IB (P=0.428), for IIA versus IIB (P=0.376), for IIB versus IIIA (P=0.086), for IIIA versus IIIB (P=0.087), and for IIIC versus IV (P=0.928). The esophageal scheme is indistinct only except for IIIB versus IIIC (P=0.002). The gastric scheme includes one heterogeneous stage group (stage IIIC, P<0.001), whereas all stage groups are homogeneous in the esophageal scheme. Although AEG shows different clinicopathological features and surgical outcomes of patients, the current seventh AJCC TNM classification which stages the AEG in the esophageal scheme does not demonstrate the advantages in the assessment of the patient prognosis. We propose a revised staging system to clarify the AEG with esophageal invasion.

Preoperative imatinib treatment in patients with advanced gastrointestinal stromal tumors: patient experiences and systematic review of 563 patients.

Preoperative IM therapy for GIST is now a research focus. Due to the low incidence of the disease, there are few RCTs on the preoperative treatment for advanced GIST, let alone relevant meta-analysis. Efficacy of this therapy and targeting population are still undetermined. Therefore, the first part of this article is composed of a controlled retrospective study and demonstrates that preoperative therapy with IM can significantly improve the outcome of advanced GIST. In the second part of the paper, we further investigated what portion of advanced GIST patients benefit more from the therapy, based on a meta-analysis. As the disease is relatively rare, we involved 563 cases in the meta-analysis, much higher than in the controlled clinical studies (51 cases). The objective of this paper is to investigate effects of surgical resection on imatinib-treated advanced GIST. Twenty-two consecutive advanced GIST patients (Group A) with preoperative IM treatment were compared to 29 patients (Group B) who underwent initial tumor resection during the same period. Subsequently, a systematic review of 563 patients was applied to identify the benefit of the advanced GIST patients receiving imatinib before surgery. Compared with Group B, less patients in Group A underwent multivisceral resection (18.2% versus 48.3%, P = 0.026) or suffered tumor rupture at time of surgery (0% versus 17.2%, P = 0.04). The 3-year estimated progression-free survival of Group A (94.4%) was also superior to that of Group B (61.4%; P = 0.045). Subsequent meta-analysis indicated that primarily unresectable patients had higher complete resection and 2-year PFS rates than recurrent/metastasis patients (P = 0.005 and 0.20, respectively); (b) stable disease (SD) patients had better outcome in resection including resectability rate (P < 0.0001), PFS (P < 0.00001) and OS (P = 0.0008) than progressive disease (PD) patients; (c) in recurrent/metastatic PD patients, surgery played a minor role, because they had a higher bulky residual disease rate (P = 0.0005) and higher progression risk (P < 0.00001) within 2 years after surgery. Preoperative IM treatment improves prognosis of advanced GISTs. Among recurrent/metastatic patients, postimatinib surgery may benefit those who have SD after IM treatment but not those resistant to IM.

HER4 is a novel prognostic biomarker in gastrointestinal stromal tumor specifically originated from stomach.

HER family has been implicated in a number of malignant tumors for predicting prognosis and potential targeted therapy purposes, however, the prognostic roles of HER family in GISTs have not been elaborated yet. Our study aims to fully evaluate the prognostic value of HER family in GIST patients and efficacy of imatinib adjuvant therapy. For HER family expression detection, qPCR were used in 33 flesh GIST specimens, and then, 453 GIST samples (405 GISTs with operation only and 48 with imatinib adjuvant therapy after radical surgery) were collected for tissue microarrays construction and immunohistochemistry (IHC). Clinicopathological data were confirmed by pathological diagnosis and clinical recorders, recurrence-free survivals (RFS) were evaluated in 453 GIST patients. With qPCR and IHC performed, EGFR, HER2 and HER4 are focused on examining prognostic value in remainder of our study by high positive expression rates in GISTs. In high-risk GISTs with or without imatinib adjuvant therapy, EGFR negative expression are associated with decreased RFS when compared to positive cases. HER2 present no relationship with GIST patients' prognosis. HER4 positive expression significantly associated with disease recurrence in GISTs. Further subgroup studies revealed HER4 was an independent prognostic indicator especially for gastric GISTs, and also for gastric high-risk GISTs. In our study, detection of EGFR expression helps to precisely subdivide high-risk GISTs for different prognosis and probably predict outcomes for imatinib treatment. HER4 is a novel independent prognostic biomarker for gastric GISTs specifically, which could be potential therapeutic target in GISTs originated from stomach.

Endoscopic management for the assessment and treatment of anastomotic bleeding in laparoscopic anterior resection for rectal cancer.

OBJECTIVE: To evaluate the impact of routine intraoperative endoscopy (IOE) on postoperative anastomotic bleeding of laparoscopic anterior resection (LAR) for rectal cancer, and to investigate the value of the IOE in terms of prevention and treatment of postoperative anastomotic bleeding. METHODS: Medical records of the 279 cases of LAR from January 2006 to December 2011 were retrospectively analyzed, of which postoperative anastomotic bleeding occurred in 18. Univariate analysis was taken to determine the possible influencing factors of the bleeding. Then related influencing factors were put into the multivariate logistic regression analysis to ultimately determine the independent influencing factors of anastomotic bleeding. The efficacy of treatments to the anastomotic bleeding was also evaluated. RESULTS: The incidence of anastomotic bleeding after LAR is 6.5% (18/279).The rates of anastomotic bleeding in lower tumor location group and upper tumor location group were 9.2% (16/173) and 1.9% (2/106), respectively, as in intraoperative colonoscopy and nonintraoperative colonoscopy group were 3.3% (5/151), and 10.2% (13/128), respectively. Comparing the location of the tumor, the coefficient of regression and relative risk value for lower tumor were 1.564 and 4.776. Comparing the intraoperative colonoscopy and nonintraoperative colonoscopy group, the value for intraoperative colonoscopy group were -1.085 and 0.338. Sex, age, tumor stage, pathologic type, and preventive ileostomy had no relevance with the anastomotic bleeding. In 18 cases of the anastomotic bleeding, 7 received conservative treatments, 9 underwent endoscopic treatment, and 2 underwent reoperation. All the 18 cases had reached hemostasis. CONCLUSION: IOE is an independent protective factor of anastomotic bleeding after LAR. Endoscopic hemostasis is recommended for an anastomotic bleeding after LAR for rectal cancer with a stapling technique.

Oncological superiority of extralevator abdominoperineal resection over conventional abdominoperineal resection: a meta-analysis.

PURPOSE: The oncological superiority, i.e., lower circumferential resection margin (CRM) involvement, lower intraoperative perforation (IOP), and local recurrence (LR) rates, of extralevator abdominoperineal resection (EAPR) over conventional abdominoperineal resection (APR) for rectal cancer is inconclusive. This meta-analysis systematically compared the rates of CRM involvement, IOP, and LR of rectal cancer patients treated by EAPR and APR, respectively. METHODS: An electronic literature search of MEDLINE, EMBASE, and Cochrane Library through May 2013 was performed by two investigators independently to identify studies evaluating the CRM involvement, IOP, and LR rates of EAPR and APR, and search results were cross-checked to reach a consensus. Data was extracted accordingly. A Mantel-Haenszel random effects model was used to calculate the odds ratio (OR) with 95 % confidence intervals (95 % CI). RESULTS: Six studies with a total of 881 patients were included. Meta-analysis of CRM involvement and IOP data from all six studies demonstrated significant lower CRM involvement (OR, 0.36; 95%CI, 0.23-0.58; P < 0.0001) and IOP (OR, 0.31; 95%CI, 0.12-0.80; P = 0.02) rates of EAPR. Data from four studies also showed that EAPR was associated with a lower LR rate than APR (OR, 0.27; 95%CI, 0.08-0.95; P = 0.04). No differences of between-study heterogeneity or publication bias were seen in any of the meta-analyses. CONCLUSIONS: Extralevator abdominoperineal resection could achieve better CRM involvement outcome and lower IOP and LR rates, demonstrating an oncological superiority over conventional abdominoperineal resection.

Somatostatin receptors in gastrointestinal stromal tumors: new prognostic biomarker and potential therapeutic strategy.

Somatostatin receptors (SSTRs) already act as important roles in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high expression levels for prognosis predicting and octreotide LAR treatment purposes but less noticed in gastrointestinal stromal tumors (GISTs). Our study aims to fully evaluate the expression levels and prognostic values of SSTRs in GIST patients. For SSTRs expression detection, qPCR were used in 25 fresh GIST specimens, and then, 453 GIST samples (405 GISTs with operation only and 48 with imatinib adjuvant therapy after surgery) were collected for tissue microarrays (TMAs) construction and confirmed by immunohistochemistry (IHC). Clinicopathological data were confirmed by pathological diagnosis and clinical recorders, recurrence-free survivals (RFS) were evaluated in 453 GIST patients. With IHC performed, SSTR1 and SSTR2 present high positive proportion (81.9% and 87.6%) in 453 GISTs in our study, and positive expression rates of SSTR3, SSTR4 and SSTR5 are 56.1%, 8.8% and 47.2%, respectively. SSTR2 and SSTR5 negative expression are associated with decreased RFS when compared to positive cases by Kaplan-Meier survival analyses with log-rank test and univariate analysis in GISTs, furthermore, SSTR2 was an independent prognostic indicator for GISTs by multivariate analysis. In our study, detection of SSRT2 and SSTR5 expression helps to predict different prognosis in GIST patients. SSTR2 is a novel independent prognostic biomarker for GISTs. With high expression performance of SSTRs in GISTs, new therapeutic strategies such as octreotide or pasireotide LAR could be taken into consideration in selected advanced GIST patients.

Completely medial versus hybrid medial approach for laparoscopic complete mesocolic excision in right hemicolon cancer.

OBJECTIVE: To explore the feasibilities between operational approaches for laparoscopic complete mesocolic excision (CME) to right hemicolon cancer. METHODS: This prospective randomized controlled trial included patients admitted to a Shanghai minimally invasive surgical center to receive laparoscopic CME from September 2011 to January 2013 randomized into two groups: hybrid medial approach (HMA) and completely medial approach (CMA). The feasibilities and strategies of the two techniques were studied and compared. Furthermore, the operation time and vessel-related complications were designed to be the primary end points, and other operational findings, including the classification of the surgical plane and postoperative recovery, were designed to be the secondary end points for this study. RESULTS: After screening, 50 cases were allocated to the HMA group and 49 to the CMA group. Within the HMA group, there were 48 cases graded with mesocolic plane and 2 with intramesocolic plane. For the CMA group, there were 42 cases graded with mesocolic plane and seven with intramesocolic plane. The differences between the two were insignificant, as were the number of lymph nodes retrieved. The mean±standard deviation total operation time for the CMA group was 128.3 ± 36.4 min, which was significantly shorter than that for the HMA group, 142.6 ± 34.8 min. For the CMA group, the time involved in central vessel ligations and laparoscopic procedures was 58.5 %, 14.1 and 81.2 ± 23.5 min, respectively, which were shorter than the HMA group. The vessel-related complication rate was significantly higher in the HMA group. CONCLUSIONS: Laparoscopic CME via the total medial approach is technically feasible after the precise identification of the surgical planes and spaces for the right hemicolon. The procedure has a shorter operation time and fewer vessel-related complications.

Feasibility of incremental laparoscopic inguinal hernia repair development in China: an 11-year experience.

BACKGROUND: Our objective was to investigate the feasibility of laparoscopic inguinal hernia repair during its developmental phases in China. STUDY DESIGN: The clinical data of 2,056 patients (2,473 hernias) who underwent laparoscopic inguinal hernia repair at Shanghai Minimally Invasive Surgery Center between January 2001 and December 2011 were analyzed retrospectively. The operation priority was used to divide the patients into 7 groups for analysis of the learning curve. RESULTS: There were 1,005 transabdominal preperitoneal patch plastic repairs (TAPP), 1,458 total extraperitoneal repairs (TEP), and 10 intraperitoneal onlay mesh repairs performed on 874, 1,175, and 7 patients, respectively. Median follow-up period was 60 months. The operation time and postoperative hospital stay for TEP were considerably shorter than those for TAPP. The complication rate for TEP, especially seroma, was considerably lower. Transabdominal preperitoneal patch plastic repair was performed in 81.4% of the recurrent inguinal hernias. Seven patients underwent unilateral intraperitoneal onlay mesh repair and 3 others underwent unilateral intraperitoneal onlay mesh repair and TAPP on the opposite. Most of patients with grade I and II hernias underwent TEP. The learning curve has demonstrated that more obstacles occurred in the earlier phase of the laparoscopic inguinal hernia repair training, supported by findings such as fewer cases performed annually, longer operation time, and higher incidence of complications and recurrence. These findings have improved as experience is accumulated through more operations. In addition, the ratios of TEP to TAPP and mesh nonfixation to fixation also evolved throughout the course of the study. CONCLUSIONS: Laparoscopic inguinal hernia repair is a feasible technique that can be popularized in China.

Laparoscopic complete mesocolic excision (CME) with medial access for right-hemi colon cancer: feasibility and technical strategies.

OBJECTIVE: This study was designed to investigate the feasibility and technical strategies of laparoscopic complete mesocolic excision (CME) for right-hemi colon cancer. METHODS: The clinical and pathological findings of 64 patients with right-hemi colon cancer who underwent laparoscopic CME between March 2010 and September 2011 were collected retrospectively. Among them, 35 cases were eligible for the final analysis through various screening factors. The quality of surgery also was assessed by reviewing the recorded video obtained through the operations in terms of specimen anatomic planes and completeness of the excised mesocolon. RESULTS: Laparoscopic CME is focused on applying the concept of enveloped visceral and parietal planes during the operations. Laparoscopic approach proceeds with medial access where the dissection starts at ileocolic vessel before proceeds along with the superior mesenteric vessel. The access also emphasized en bloc resection of mesocolon without defections to the planes. Besides, lymph node resections at the root of ileocolic; right colic and middle colic vessels are necessary for ileocecum cancer. Cancers at the hepatic flexure requires further dissection of subpyloric lymph nodes and of greater omentum that is within 15 cm of the tumor and along the greater curvature. Thirty-five cases were evaluated as good plane. The median total number of central lymph nodes retrieved was 19 (range, 15-25) and central lymph node metastasis was found in 5 of all stage III cases. The median operation time was 2.6 h and the blood loss was 80 mL. The median time for passage of flatus and hospitalization were 2 and 12 days respectively. Complications were observed in three cases. CONCLUSIONS: CME is a novel concept for colon cancer surgery and might be a standard for the procedure. Laparoscopic CME with medial access is technically feasible and randomized trials are needed to evaluate its long-term outcomes.