Predicting response to immunotherapy in gastric cancer via assessing perineural invasion-mediated inflammation in tumor microenvironment.

BACKGROUND: The perineural invasion (PNI)-mediated inflammation of the tumor microenvironment (TME) varies among gastric cancer (GC) patients and exhibits a close relationship with prognosis and immunotherapy. Assessing the neuroinflammation of TME is important in predicting the response to immunotherapy in GC patients. METHODS: Fifteen independent cohorts were enrolled in this study. An inflammatory score was developed and validated in GC. Based on PNI-related prognostic inflammatory signatures, patients were divided into Clusters A and B using unsupervised clustering. The characteristics of clusters and the potential regulatory mechanism of key genes were verified by RT-PCR, western-blot, immunohistochemistry and immunofluorescence in cell and tumor tissue samples.The neuroinflammation infiltration (NII) scoring system was developed based on principal component analysis (PCA) and visualized in a nomogram together with other clinical characteristics. RESULTS: Inflammatory scores were higher in GC patients with PNI compared with those without PNI (P < 0.001). NII.clusterB patients with PNI had abundant immune cell infiltration in the TME but worse prognosis compared with patients in the NII.clusterA patients with PNI and non-PNI subgroups. Higher immune checkpoint expression was noted in NII.clusterB-PNI. VCAM1 is a specific signature of NII.clusterB-PNI, which regulates PD-L1 expression by affecting the phosphorylation of STAT3 in GC cells. Patients with PNI and high NII scores may benefit from immunotherapy. Patients with low nomogram scores had a better prognosis than those with high nomogram scores. CONCLUSIONS: Inflammation mediated by PNI is one of the results of tumor-nerve crosstalk, but its impact on the tumor immune microenvironment is complex. Assessing the inflammation features of PNI is a potential method in predicting the response of immunotherapy effectively.

Laparoscopic versus open surgery for colonoscopic perforation: A systematic review and meta-analysis.

BACKGROUND: The efficacy of laparoscopic surgery (LS) for the treatment of colonoscopic perforation is still controversial. The purpose of this meta-analysis was to evaluate the effectiveness and safety of LS versus open surgery (OS) for colonoscopic perforation. METHODS: All clinical trials that compared laparoscopic with OS for colonoscopic perforation published in English were identified in PubMed, EMBASE, Web of Science, and Cochrane Library searches. A modified scale was used to assess the quality of the literature. We analyzed the age, sex ratio, aim of colonoscopy, history of abdominopelvic surgery, type of procedure, size of perforation, operation time, postoperative fasting time, hospital stay, postoperative complication morbidity, and postoperative mortality. Meta-analyses were performed using weighted mean differences for continuous variables, and odds ratios for dichotomous variables. RESULTS: No eligible randomized trials were identified, but eleven nonrandomized trials were analyzed. In the pooled data of 192 patients who underwent LS and 131 OS, there were no significant differences in age, sex ratio, aim of colonoscopy, history of abdominopelvic surgery, perforation size, and operative time between the groups. LS group had shorter time of hospital stay and postoperative fasting time, less postoperative complication morbidity, but there were no significant difference in postoperative mortality rate between LS group and OS group. CONCLUSIONS: Based on the current meta-analysis, we conclude that LS is a safe and efficacious technique for colonoscopic perforation, with fewer postoperative complications, less hospital mortality, and faster recovery compared with OS.

Neurotransmitters: promising immune modulators in the tumor microenvironment.

The tumor microenvironment (TME) is modified by its cellular or acellular components throughout the whole period of tumor development. The dynamic modulation can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Hence, the focus of cancer research and intervention has gradually shifted to TME components and their interactions. Accumulated evidence indicates neural and immune factors play a distinct role in modulating TME synergistically. Among the complicated interactions, neurotransmitters, the traditional neural regulators, mediate some crucial regulatory functions. Nevertheless, knowledge of the exact mechanisms is still scarce. Meanwhile, therapies targeting the TME remain unsatisfactory. It holds a great prospect to reveal the molecular mechanism by which the interplay between the nervous and immune systems regulate cancer progression for laying a vivid landscape of tumor development and improving clinical treatment.

Comparison of high or modified low tie of the inferior mesenteric artery in laparoscopic rectal cancer surgery: A meta-analysis.

OBJECTIVE: The purpose of this study was to perform a meta-analysis comparing the oncological, intraoperative and safety outcomes in laparoscopic rectal cancer surgery with and without preservation of the left colic artery (LCA). METHOD: We searched several databases including PubMed, Web of Science, Cochrane Library, and Embase databases. This meta-analysis included randomized clinical trials, prospective, and retrospective comparative studies regarding high- or modified low-tie ligation of the inferior mesenteric artery in laparoscopic rectal cancer surgery. RESULTS: Of 641 potentially eligible articles, 16 studies with 3050 participants met the eligibility criteria and were included in the meta-analysis. There was no significant difference in estimated blood loss (WMD -2.63, 95% CI -5.69 to 0.43; P = .09), the number of harvested lymph nodes (WMD -0.35, 95% CI -1.60 to 0.20; P = .50), the number of apical lymph node yield (WMD -0.19, 95% CI -0.52 to 0.13; P = .24), the number of apical lymph node metastasis (OR 0.76, 95% CI 0.40 to 1.45; P = .40), rate of conversion to open surgery (OR 0.74, 95% CI 0.50 to 1.09; P = .513), rate of urinary dysfunction (OR 1.39, 95% CI 0.71 to 2.74; P = .34), rate of recurrence and metastasis (OR 1.10, 95% CI 0.75 to 1.61; P = .64), 5-year survival rate (OR 0.89, 95% CI 0.67 to 1.18; P = .42). However, this meta-analysis demonstrated a statistically significant difference in operating time (WMD -9.92, 95% CI -15.49 to -5.84; P = .0005), rate of diverting stom (OR 1.42, 95% CI 1.06 to 1.92; P = .02), rate of anastomotic leakage (OR 2.673, 95% CI 1.91 to 3.62; P < .00001), time to first flatus (WMD 0.29, 95% CI 0.11 to 0.48; P = .002), time of hospitalization (WMD 0.64, 95% CI 0.14 to 1.15; P = .01) between the 2 surgical techniques. COCLUSION: The available evidence suggests that preserving the left colic artery is a safe, effective technique for patients with laparoscopic rectal cancer. nique for patients with laparoscopic rectal cancer.

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer.

Pancreatic cancer is a lethal malignancy with a 5-year survival rate of about 10% in the United States, and it is becoming an increasingly prominent cause of cancer death. Among pancreatic cancer patients, pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all cases and has a very poor prognosis with an average survival of only 1 year in about 18% of all tumor stages. In the past years, there has been an increasing interest in cancer-associated fibroblasts (CAFs) and their roles in PDAC. Recent data reveals that CAFs in PDAC are heterogeneous and various CAF subtypes have been demonstrated to promote tumor development while others hinder cancer proliferation. Furthermore, CAFs and other stromal populations can be potentially used as novel prognostic markers in cancer. In the present study, in order to evaluate the prognostic value of CAFs in PDAC, CAF infiltration rate was evaluated in 4 PDAC datasets of TCGA, GEO, and ArrayExpress databases and differentially expressed genes (DEGs) between CAF-high and CAF-low patients were identified. Subsequently, a CAF-based gene expression signature was developed and studied for its association with overall survival (OS). Additionally, functional enrichment analysis, somatic alteration analysis, and prognostic risk model construction was conducted on the identified DEGs. Finally, oncoPredict algorithm was implemented to assess drug sensitivity prediction between high- and low-risk cohorts. Our results revealed that CAF risk-high patients have a worse survival rate and increased CAF infiltration is a poor prognostic indicator in pancreatic cancer. Functional enrichment analysis also revealed that "extracellular matrix organization" and "vasculature development" were the top enriched pathways among the identified DEGs. We also developed a panel of 12 genes, which in additional to its prognostic value, could predict higher chemotherapy resistance rate. This CAF-based panel can be potentially utilized alone or in conjunction with other clinical parameters to make early predictions and prognosticate responsiveness to treatment in PDAC patients. Indeed, it is necessary to conduct extensive prospective investigations to confirm the clinical utility of these findings.

LAP+CD4+T cells regulate the anti-tumor role of CIK cells in colorectal cancer through IL-10 and TGF-ß.

The rate of colorectal cancer (CRC) is increasing. Adoptive immune cell therapy (ACT) is a research hotspot in CRC treatment, and the common adoptive cells are cytokine-induced killer cells (CIK). The problem of ACT is that some regulatory T cells (Treg) will affect the efficacy. Latent associated polypeptide (LAP)+CD4+T is a new Treg, and its immunosuppressive effect is much higher than that of traditional Tregs. This research mainly explored the influence of LAP+CD4+T cells on anti-tumor lethality of CIK cells, so as to fill this gap. The LAP+CD4+T CIK cells and LAP-CD4+T CIK cells were sorted by immunomagnetic beads. LAP+CD4+T cells were expanded in vitro, and high expression cytokine genes were screened by RT-qPCR. LAP+CD4+T and LAP-CD4+T CIK cells were co-cultured to test cyto-activity. Transplanted tumor models of CRC were established in nude mice, which were randomized into a control group (CG), CIK group, LAP (-) group, LAP (+) group, IL-10 siRNA group, and TGF-siRNA group, and the tumor growth in each group was observed. The research results revealed that interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß) were highly expressed in LAP+CD4+T cells. LAP+CD4+T could effectively suppress CIK cell proliferation and activity. LAP-CD4+T could suppress IL-10 and TGF-ß, and inhibit CIK cell apoptosis, proliferation, and tumor growth, thus improving their anti-tumor lethality. LAP+CD4+T cells regulate the anti-tumor role of CIK cells in CRC through IL-10 and TGF-ß.

Prediction of Survival Rate and Chemotherapy Effect by an Immune Score Model in Colorectal Cancer.

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths. Immune cells in the tumor microenvironment play an important role in the development of tumors. In this study, CIBERSORT was used to estimate the subset of the immune cells using bulk gene expression data (i.e., TCGA, GEO, and cBioPortal databases). 1,087 samples were included in the analysis. The results revealed that among the 22 immune cell subsets that were evaluated, resting and activated NK cells, macrophage M1 and M2, and resting mast cells are associated with significant improvements in patient survival of colorectal cancer. The 15-year survival rates for the training cohort showed 49.1% and 32.5%, respectively, for the low- and high-risk groups. Likewise, the validation and entire cohorts showed 77.3% versus 47.2% and 65.3% versus 46.5%, respectively, for the low- and high-risk groups. Also, the prognostic immune score in predicting the chemotherapy effects showed that the low-risk group had a better survival superiority over the high-risk group, whether patients received chemotherapy or not. The gene set enrichment analysis showed that the low-risk group was highly enriched in pathways or processes related to immune response. The immune checkpoint assessment revealed significantly higher mRNA expressions of CTLA4 in the lower risk group than in the higher risk group. Altogether, this study offers information that could improve the prognosis of colorectal cancer.

GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Abundant metabolic fuels have been implicated as potential drivers of CRC. However, it remains unclear whether fructose, an ample sugar in daily diets, is essential for CRC growth. In the present study, we found that glucose levels were always insufficient in human CRC tissues. Compensating for this, fructose was flexibly utilized by tumor cells as an alternative energy source to maintain proliferation and exert chemotherapy resistance in vitro by upregulating GLUT5, a major fructose transporter encoded by SLC2A5. Mechanistically, in glucose-deprived but fructose-rich environments, GLUT5 could interact with ketohexokinase and inhibit its autophagy-dependent degradation, thus trapping fructose into glycolysis and tricarboxylic acid cycle for the malignant growth of CRC cells. In addition, reducing dietary fructose or pharmacological blockade of fructose utilization significantly reduced CRC growth and sensitized CRC cells to chemotherapy in vivo. Taken together, our findings highlight the role of elevated fructose utilization mediated by the GLUT5-KHK axis in governing CRC growth and imply that efforts to refine fructose intake or inhibit fructose-mediated actions may serve as potential therapeutic strategies.

A retrospective cohort study of clinical value of PRL-3 in stage III human colorectal cancer.

ABSTRACT: The aim of this study was to investigate the expression of phosphatase of regenerating live-3 (PRL-3) in human stage III colorectal cancer (CRC) and to evaluate its correlation with metachronous liver metastasis (MLM) and prognosis.The retrospective cohort study included 116 stage III CRC primary tumors and 60 normal colorectal tissues. PRL-3 expression was measured by immunohistochemistry. We investigated the correlation of PRL-3 with clinicopathologic features by the chi-square test. The association of PRL-3 expression with MLM was assessed by binary logistic regression. Overall survival (OS) and disease-free survival (DFS) between patients with positive PRL-3 expression and those with negative PRL-3 expression were compared by the Kaplan-Meier method and Cox proportional hazards regression model.We found that 32.8% of stage III CRC primary tumors were PRL-3 positive, and 15.0% of normal colorectal epithelia showed high PRL-3 expression (P = .012). Seventeen tumors (47.2%) among 36 cases that developed MLM were PRL-3 positive, and only 21 tumors (26.3%) in the 80 cases that did not develop MLM had positive PRL-3 expression (P = .026). PRL-3 expression was associated with MLM (P = .028). Patients with positive expression of PRL-3 showed a significantly shorter OS (40.32 ±â€Š3.97 vs 53.96 ±â€Š2.77 months, P = .009) and DFS (34.97 ±â€Š4.30 vs 44.48 ±â€Š2.89 months, P = .036). A multivariate analysis indicated that PRL-3 expression was an independent unfavorable prognostic factor for OS (P = .007).Our study suggested that high PRL-3 expression is an independent risk factor for MLM and poor prognosis. PRL-3 is expected to be a promising biomarker for predicting the incidence of MLM and prognosis in patients with stage III CRC.

Secreted phosphoprotein-1 accelerates the progression of human colorectal cancer through activating ß-catenin signaling.

Colorectal cancer (CRC) is a common malignant tumor of the digestive tract and one of the leading causes of cancer-associated mortality. Secreted phosphoprotein-1 (SPP-1) is overexpressed in CRC and promotes cancer progression, but the underlying mechanisms underlying SPP-1 function remain unclear. The present study aimed to explore the effects of Wnt/ß-catenin signaling in SPP-1-induced CRC progression. The expression patterns of SPP-1 in CRC tissues were examined using reverse transcription-quantitative (RT-q)PCR, western blotting and immunohistochemistry. SPP-1 expression in cells was assessed using RT-qPCR and western blotting. Cell-Counting Kit-8, flow cytometry and tumor-burdened mice experiments were used to determine cell proliferation, apoptosis and in vivo tumor formation abilities. The results showed that SPP-1 expression was markedly elevated in CRC tissues and cells compared with that in normal colorectal tissues and cells. High expression of SPP-1 was associated with advanced clinical process and low overall survival rate in patients with CRC. Besides, SPP-1 could interact with ß-catenin and positively regulated ß-catenin protein expression, and enhanced its nuclear accumulation. Moreover, SPP-1-upregulation significantly enhanced cell proliferation and in vivo tumor formation ability, and reduced apoptosis, whereas these effects were all abolished when ß-catenin was silenced. Overall, the present study revealed that SPP-1 promoted the progression of CRC in a ß-catenin-dependent manner.

[Enhanced recovery after preserving the left colonic artery during laparoscopic anterior resection for rectal cancer].

OBJECTIVE: To evaluate the postoperative outcomes of preserving the left colonic artery during laparoscopic anterior resection for rectal cancer. METHODS: The clinicopathologic data of 91 rectal cancer patients (pathologic Stage II) undergoing laparoscopic anterior resection was retrospectively analyzed. During the surgeries, the left colonic artery was preserved in 40 patients (preserved group) and ligated in 51 patients (unpreserved group). The operating time, intraoperative blood loss, time to first flatus and defecation, duration of postoperative abdominal distension and pain, number of retrieved lymph nodes, ileum fistulation and anatomical leakage rate were compared between the two groups. RESULTS: The surgeries were completed in all the 91 patients laparoscopically without conversion. There was no intraoperative complications including rectal perforation, injury to vessel or ureter in either group. The operating time, blood loss and number of retrieved lymph nodes were similar between the groups (P>0.05). Three patients in preserved group and 5 in ligation group received preventive ileum fistulation due to low rectal cancer. Anatomical leakage occurred in three patients of unpreserved group. The average duration of postoperative abdominal distension and pain was 2.14∓0.35 days in preserved group and 3.15∓0.42 days in ligation group. The time to first flatus and defecation was 37.15∓12.62 h and 3.16∓0.52 days in preserved group and 62.25∓11.75 h and 4.25∓0.75 days in ligation group. Postoperative hospital stay was 4.54∓0.42 days in preserved group and 6.23∓0.51 days in ligation group. Total hospitalization cost in the two groups was 34 525.32∓1206.36 Yuan and 41 215∓1051.32 Yuan, respectively. Significant differences were found the in duration of postoperative abdominal distension and pain, postoperative hospital stay, and total cost between the two groups (P<0.05). CONCLUSION: During laparoscopic anterior resection for rectal cancer, preserving the left colonic artery effectively ensures the blood supply to the anastomosis and the remaining descending colon to promote the recovery of the patients after surgery.

Efficacy of Laparoscopic Primary Repair in the Treatment of Colonic Perforation After Colonoscopy: A Review of 40,127 Patients.

BACKGROUND: In recent years, increasing colonoscopy use increases the incidence of colonic perforation. Colonic perforation during colonoscopy is a rare but extremely serious complication. Traditionally, the management of colonic perforation is explorative laparotomy with bowel resection. Treatment using laparoscopic approach is a novel approach, and has been reported in some recent literatures. Nowadays, the using of laparoscopic primary repair in treatment of colonoscopic perforations has not been confirmed. This study retrospectively reviewed our experiences in treating colonoscopic perforations by laparoscopic primary repair. OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of the laparoscopic primary repair in the treatment of colonic perforations during colonoscopy. METHODS: Between January 2003 and December 2014, data were collected retrospectively on all patients who underwent colonoscopy and compared the recovery parameters and morbidity of patients who underwent laparoscopic primary repair versus those who had open surgery. RESULTS: A total of 40,127 colonoscopies were performed during the study period. There were 24 patients who underwent primary repair [13 underwent laparoscopic surgery (LS) and 8 underwent open surgery (OS)]. There were no demographic differences between the LS and OS groups (P>0.05). Compared with OS group, patients who underwent laparoscopic repair had a significantly shorter incision length (LS: 3.15±0.35 mm vs. OS: 12.60±2.87 mm, P=0.000), fewer blood loss (LS: 28.54±10.82 mL vs. OS: 159.25±46.90 mL, P=0.000), shorter postoperative hospital stay (LS: 8.31±1.93 d vs. OS: 12.38±1.41 d, P=0.000), and shorter postoperative fasting time (LS: 3.38±0.7 d vs. OS: 5.25±0.71 d, P=0.000). The operative time of LS group was a little longer than OS group, but there were no significant differences (LS: 86.31±22.22 min vs. OS: 75.125 ±14.24 min, P=NS). CONCLUSIONS: Laparoscopic primary repair is safe and effective in resolving colonic perforation due to colonoscopy, and it might offer benefits over the open approach.