The efficient circulating immunoscore predicts prognosis of patients with advanced gastrointestinal cancer.

BACKGROUND: Immunoscore from tumor tissues was initially established to evaluate the prognosis of solid tumor patients. However, the feasibility of circulating immune score (cIS) for the prognosis of advanced gastrointestinal cancers (AGC) has not been reported. MATERIAL AND METHODS: Peripheral venous blood was collected from 64 untreated AGC patients. We utilized flow cytometry to determine several immune cell subpopulations, including CD8+ and CD4+ T cells, NK cells, and CD4 + CD25 + CD127low Tregs. The circulating immune score 1 (cIS1) was assessed according to the proportions of CD4+, CD8+ T cells, and NK cell, whereas circulating immune score 2 (cIS2) was derived from the proportions of CD4+, CD8+ T cell, and CD4 + CD25 + CD127low Tregs. The prognostic role of cIS for progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier curves and Cox multivariate models. Receiver operating characteristic (ROC) curves were depicted to compare the prognostic values of cIS1 and cIS2. RESULTS: AGC patients with high cIS1(≥ 2) and cIS2(≥ 2) had significantly longer PFS (cIS1: median PFS, 11 vs. 6.7 months, P = 0.001; cIS2: 12 vs. 5.8 months, P < 0.0001) and OS (cIS1: median OS, 12 vs. 7.9 months, P = 0.0004; cIS2: 12.8 vs. 7.4 months, P < 0.0001) than those with low cIS1 and low cIS2. The areas under ROC curves (AUROCs) of cIS1 and cIS2 for OS were 0.526 (95% confidence interval; 95% CI 0.326-0.726) and 0.603 (95% CI 0.427-0.779, P = 0.332), whereas AUROC of cIS2 for PFS was larger than that of cIS1 0.735 (95% CI 0.609-0.837) vs 0.625 (95% CI 0.495-0.743) (P = 0.04)). CONCLUSION: The cIS can be applied to predict the prognosis of untreated AGC patients. Compared with cIS1, cIS2 displayed superior prognostic value for PFS prediction.

DFT study on the gold(I)-catalyzed cycloaddition and rearrangement reactions of allene-containing allylic silyl ether.

The DFT calculation at the B3LYP/B3LYP-D3(BJ) level was carried out to explore the reaction mechanism of the synthesis of spirocyclo[4,5]decane skeleton by gold-catalyzed allenyl compounds. The more accurate energy under the CH3CN solvent in the experiment is calculated by the single-point energy of the SMD model. Computational studies have shown that the reaction consists of three main steps: intramolecular cycloaddition of the end group carbon atoms of allenyl and vinyl groups, the semipinacol rearrangement process in which the four-membered ring is reconstructed into the five-membered ring, the elimination reaction releases the catalyst and obtains the product. The calculation results show that Zheng et al. reported that the gold-catalyzed synthesis reaction can easily occur under the experimental conditions due to its low activation free energy (12.07-15.49 kcal/mol). Furthermore, it was found that the MOMO(CH2)2 substituent has higher reactivity than the corresponding reactant of the phenyl substituent.

An Efficient Prognostic Immune Scoring System For Colorectal Cancer Patients With Peritoneal Metastasis.

Immunoscore can accurately predict the prognosis of patients with stage I-III colorectal cancer. However, whether it can be used to predict the prognosis of colorectal cancer peritoneal metastases (CRCPM) remains to be validated. We analyzed peritoneal and ovarian metastases in 68 patients with CRCPM. The immunoscore (IS) was based on the infiltration level of CD3+ and CD8+ T cells, whereas the TBM score was derived from the infiltration level of CD3+, CD8+, CD20+ and CD163+ cells to tumor microenvironment (TME). The predictive value of IS and TBM scores for relapse-free survival (RFS) and overall survival (OS) of patients with CRCPM was analyzed using Kaplan Meier curve and Cox multivariate models. Significant difference in the infiltration levels of different immune cell subtypes in primary lesions, peritoneal metastasis and ovarian metastasis were compared using t-test.CRCPM patients with high IS (>1), high TBM1 score (≥2) or high TBM2 score (≥2) had a significantly longer OS (IS: median OS, not reached vs 23 months, p = .0078; TBM1: not reached vs 21.5 months, p = .013; TBM2: 39.3 months vs 15.2 months, p = .001). On the other hand, patients with high IS had a trend of improved RFS (13.4 months vs 11.0 months, p = .067). However, TBM1 and TBM2 score has no predictive utility for RFS. Multivariate analysis revealed that IS, TBM1 and TBM2 can accurately predict OS, but not RFS. Finally, the infiltration level of CD3+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophage was significantly higher in peritoneal metastatic tissue and ovarian metastatic tissue, relative to primary tumor tissues.The IS and TBM score of peritoneal metastases could effectively predict OS of patients with CRCPM. Peritoneal metastasis of colorectal cancer decreased the infiltration level of T and B cells.

Molecular Alterations in Metastatic Ovarian Cancer From Gastrointestinal Cancer.

Reports indicate that most metastatic ovarian cancer (MOC) originates from gastrointestinal cancer (GIC). Notably, GICs metastasize to the ovary frequently via 3 main routes including hematogenous spread, lymphogenous spread, and transcoelomic spread. Nonetheless, the mechanism of the progression remains unknown, and only a handful of literature exists on the molecular alteration implicated in MOC from GIC. This work collected existing evidence and literature on the vital molecules of the metastatic pathway and systematically analyzed them geared toward exploring the mechanism of the metastatic pathway of MOC. Further, this review described dominating molecular alteration in the metastatic process from cancer cells detaching away from lesions to arrive at the ovary, including factors for regulating signaling pathways in epithelial-interstitial transformation, invading, and surviving in the circulatory system or abdominal cavity. We interrogated the basis of the ovary as a distant metastatic site. This article provides new insights into the metastatic pathway and generates novel therapeutic targets for effective treatment and satisfactory outcomes in GIC patients.

Impact of permissive hypercapnia on regional cerebral oxygen saturation and postoperative cognitive function in patients undergoing cardiac valve replacement.

BACKGROUND: Cardiac valve replacement (CVR) is currently the main surgical treatment for patients with valvular heart diseases (VHD). Postoperative cognitive dysfunction (POCD) is one of the most serious complications of cardiac surgery. Permissive hypercapnia (PHC), an important lung-protective ventilation strategy, has protective effects on vital organs, including the heart, lungs, and central nervous system (CNS). The main objective of this study is to assess the effect of the PHC ventilation strategy on rSO2 and postoperative cognitive function in patients undergoing CVR. METHODS: A total of 66 patients undergoing CVR were included and randomly divided into the PHC ventilation group (Group H, n=33) and conventional ventilation group (Group C, n=33). Patients of both groups were subjected to conventional ventilation before cardiopulmonary bypass (CPB). patients in Group H were subjected to the PHC ventilation strategy to keep the partial pressure of carbon dioxide (PaCO2) at 46-60 mmHg. RESULTS: (I) Group H had a lower HR at T0 and T1 (P<0.05) and higher CO at T3 and T4 (P<0.05) than Group C. (II) Group H had higher rSO2 at T4 (P<0.05), lower pH and lactate (Lac) at T4 (P<0.05), higher PaCO2 at T3 and T4 (P<0.05), and lower PaO2 at T3 and T4 (P<0.05). (III) Compared to 1 d before surgery, the MMSE scores of both groups were lower 24 h after surgery (P<0.05). CONCLUSIONS: PHC can increase the rSO2 of patients undergoing CVR, increase cerebral blood flow, improve the cerebral oxygen supply/consumption balance, and play a protective role in the brain. It has no significant impact on the incidence of POCD.

Factors Prognostic for Peritoneal Metastases from Colorectal Cancer Treated with Surgery.

PURPOSE: To analysis factors prognostic for peritoneal metastases (PM) from colorectal cancer (CRC) treated with surgery using data from two sources and investigate the origin and effective treatment of ovarian metastases (OM). PATIENTS AND METHODS: Data from CRC patients with PM who had undergone surgery were collected from the Surveillance, Epidemiology, and End Results (SEER) database (n = 639) and a single Chinese institution (n = 60). Cumulative survival was evaluated by Kaplan-Meier analysis. Factors associated with overall survival (OS) and progression-free survival (PFS) prognosis were assessed using Cox's proportional hazard regression models. RESULTS: Median OS values for patients who underwent surgery were 19 and 32 months in the SEER database and Chinese center, respectively. Age was an independent predictor of OS in both datasets. Signet-ring cell cancer and perineural invasion were independent predictors of inferior OS only in the SEER dataset, while completeness of cytoreduction (CC) and peritoneal carcinomatosis index were independent predictors for OS and PFS only in the Chinese center. Median OS was 24 months in CRC patients with PM alone and 36 months in those with both PM and OM (p = 0.181). Further, median PSF in patients with PM alone was 10 months, while that in individuals with both PM and OM was 20 months (p = 0.181). CONCLUSION: Surgical treatment of the primary and metastatic sites is effective and safe for CRC patients with PM. CC-0 is recommended for improved prognosis. Moreover, OM should be recognized as a feature of PM, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is beneficial for CRC patients with OM.

The prognostic effect of TTF-1 expression in the Chinese population of patients with advanced lung adenocarcinomas.

BACKGROUND: Thyroid transcription factor 1 (TTF-1), which is usually expressed by lung adenocarcinomas and small cell carcinomas, is usually used to distinguish adenocarcinoma and small cell carcinoma from cells of another type of lung cancer. We examined the association between TTF-1 expression and overall survival between patients with stage IV pulmonary adenocarcinoma to investigate the role of TTF-1 as a predictive and/or prognostic tumor marker in patients with advanced lung adenocarcinomas. METHODS: Analysis of the clinicopathologic features, treatment regimens, and overall survival of 209 lung adenocarcinoma patients who had been detected for TTF-1 expression and received consecutive treatments in the Affiliated Hospital of Qingdao University. RESULTS: TTF-1 expression was positive in 166 (79%) and negative in 43 (21%) patients who were reviewed. Moreover, there was no significant difference between the clinicopathologic features of TTF-1 positive and TTF-1 negative tumors. In the multivariable review, the overall survival of TTF-1 positive tumor patients was significantly longer than that of TTF-1 negative tumor patients [22.7 vs. 11.8 months (P<0.0001)], increasing the prognostic effect of Karnofsky performance status and receiving first-line chemotherapy or targeted therapy. Positive TTF-1 and negative TTF-1 patients receiving pemetrexed-based chemotherapy improved the duration of treatment compared to those receiving non-pemetrexed chemotherapy. CONCLUSIONS: TTF-1 expression was associated with an improved survival in patients with advanced lung adenocarcinomas. Both patients, either TTF-1 positive or negative, could benefit from the first-line chemotherapy or pemetrexed treatment option. However, as discovered by our investigation, TTF-1 cannot forecast a portion of the lung adenocarcinomas that had a selective sensitivity to pemetrexed.

Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer.

BACKGROUND: The role of tumour-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remains controversial. This is especially so because the prognostic significance and clinicopathological relevance of different subtypes of TAMs in the immune microenvironment of CRC have not yet been established. OBJECTIVE: To assess the clinicopathological and prognostic value of pan-macrophages, M1-macrophages or M2-macrophages in patients with CRC. METHODS: Comprehensive searched on the Medline/PubMed, Web of Science (WoS) and Google Scholar databases was conducted to identify relevant studies published up to April 2019. The association between overall survival (OS), cancer-specific survival (CSS) or disease-free survival (DFS) and TAMs was analysed by meta-analysis. RESULTS: A total of 3749 patients from 17 studies were included. The pooled hazard ratios (HRs) indicated that high-density pan-macrophages improved OS (HR 0.67, P = 0.02). The pooled HR for M2-macrophages showed that high M2-macrophages infiltration was significantly associated with shorter OS (HR 2.93, P < 0.0001) and DFS (HR 2.04, P = 0.02). The pooled odds ratios (ORs) revealed that high-density TAMs was associated with high CD8+ T cell infiltration (OR 2.04, P = 0.007), no distant metastasis (NDM) (OR 0.38, P < 0.0001), microsatellite instability-high (MSI-H) (OR 0.38, P = 0.001), no lymph node metastasis (NLNM) (OR 0.54, P = 0.0002) and non-mucinous cancer (OR 0.39, P < 0.00001). CONCLUSIONS: Unlike other solid tumours, high-density CD68+ macrophage infiltration can be a good prognostic marker for CRC. However, when macrophages act as targets of combination therapy in CRC treatment, this might be more effective for CRC patients with high CD8+ T cell infiltrate, NDM, MSI-H, NLNM and non-mucinous cancer.

The prognostic value of tumor-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: a systematic review and meta-analysis.

PURPOSE: In colorectal cancer (CRC), whether the immune score can be used to predict the clinical prognosis of the patient has not been completely established. Besides, the prognostic values of tumor-infiltrating lymphocytes (TILs) in different anatomical locations, counting sites, and subtypes have been controversial. The purpose of this meta-analysis is to analyze and determine the prognostic value of TILs indices including TIL subsets, infiltrating sites, and anatomical sites. METHODS: Relevant literature was obtained by searching PubMed and Google Scholar. The pooled hazard ratio (HR) of the overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) was computed to investigate the prognostic significance of CD3+, CD8+, CD45RO+, and FOXP3+ T cells. RESULTS: A total of 22 studies involving 5108 patients were included in the meta-analysis. In CC, based on T cell subtypes analysis, the final results indicated that CD8+ and FOXP3+ infiltrating cells, but not CD3+ T cells were prognostic markers for DFS and OS. In addition, with regard to the counting location of TILs, subgroup analysis revealed that only high FOXP3+ infiltrates in the tumor stroma (ST) were significantly associated with OS (HR = 0.38, 95% confidence interval (CI) = 0.22-0.67, P = 0.0007), whereas in invasive margin (IM), high density of CD3+ infiltrating cells indicated increased DFS (HR = 0.76, 95% CI = 0.62-0.93, P = 0.008). At the tumor center (TC), high CD8+ T cells infiltration was associated with improved DFS (HR = 0.50, 95% CI = 0.38-0.65, P < 0.00001). In RC, whether CSS or OS, high-density TIL was associated with improved prognosis. CONCLUSION: In a single counting site, high-density TILs reflect favorable prognostic value in CC or RC. For CC, more prospective studies are needed to verify whether different anatomical sites affect the distribution of TILs and thus the prognosis of patients. For RC, further studies should analyze the prognostic value of the immune score.

Squalene epoxidase promotes the proliferation and metastasis of lung squamous cell carcinoma cells though extracellular signal-regulated kinase signaling.

BACKGROUND: The biological function of squalene epoxidase (SQLE), an important rate-limiting enzyme in downstream cholesterol synthesis, is to convert squalene to 2-3 oxacin squalene. The expression of SQLE in lung cancer is abnormal. We conducted this study to investigate the effect of SQLE expression on lung squamous cell carcinoma (SCC) proliferation, migration, and invasion and its role in extracellular signal-regulated kinase (ERK) signaling. METHODS: Cell Counting Kit 8, wound healing, and Transwell assays; Western blotting; and quantitative real-time PCR were used to investigate the effect of SQLE in a lung SCC H520 cell line. Kaplan-Meier analysis was used to identify the prognostic significance of SQLE. RESULTS: Overexpression of SQLE promoted lung SCC cell proliferation, migration and invasion, whereas knockdown of SQLE expression showed the opposite effect. SQLE can interact with ERK to enhance its phosphorylation. SQLE may contribute to the pathogenesis of lung cancer by modulating ERK signaling. Further survival analysis indicated that high expression of SQLE indicated poor prognosis in lung SCC. CONCLUSION: Our study presents novel evidence of potential biomarkers or therapeutic targets for lung SCC therapy and prognosis.

Cancer Immunotherapies Targeting Tumor-Associated Regulatory T Cells.

Tumor-associated regulatory T cells (Tregs) are important effectors in the tumor microenvironment (TME), acting as accomplices in the promotion of tumor progression. Currently, the importance of removing the immunosuppressive activity in the TME has received its due attention, and Tregs have been focused on. The cytokine-receptor axes are among the essential signaling pathways in immunocytes, and tumor-associated Tregs are no exception. Therefore, manipulating cytokine-receptor pathways may be a promising effective strategy for treating various malignancies. Here, we summarize the classification, immunosuppressive mechanisms, existing immunotherapies, and potential biomarkers related to tumor-infiltrating Tregs to guide the development of effective cancer immunotherapies.

[Incidence and risk factors of postoperative cognitive dysfunction in patients underwent coronary artery bypass grafting surgery].

OBJECTIVE: To investigate the incidence rate and the risk factors for postoperative cognitive dysfunction (POCD) in patients underwent coronary artery bypass grafting surgery. METHODS: A total of 147 patients underwent elective coronary artery bypass grafting (CABG) surgery between January to July 2013 were included in this study. POCD was diagnosed using a neuropsychological test battery. All enrolled patients were interviewed on the day before surgery, the seventh day and 3 months after surgery, respectively, by the same researcher, and were divided into two groups based on the results: the POCD group and the non-POCD group. The information, including age, sex, body mass index, educational status, comorbidities, history of smoking and drinking, ASA grade, left ventricular ejection fraction, operation method, duration of operations, regional cerebral oxygen saturation, the lowest haemoglobin concentrations and the haemoglobin concentration decline rate during the operation, tracheal catheter retention time, postoperative pain on visual analogue scales (VAS) and systemic inflammatory response syndrome score (SIRS score), were recorded based on a schedule of survey. Multivariate logistic regression was used to analyze the risk factors for POCD. RESULTS: A total of 101 patients finished this study. On 7 days and 3 months after surgery, 38 and 21 cases showed POCD, with an incidence rate at 37.6% and 20.8%, respectively. Interestingly, there was no significant difference in incidence of POCD between CABG and OPCABG group on both 7 days and 3 months after surgery (P>0.05). The logistic stepwise regression analysis indicated that the risk factors for POCD included advanced age (OR=1.177, 95%CI 1.071-1.292, P=0.001), the haemoglobin concentration decline rate (OR=1.334, 95%CI 1.152-1.545, P<0.05) and SIRS score (OR=2.815, 95%CI 1.014-7.818, P=0.047). CONCLUSION: The incidence rate of POCD was 37.6% and 20.8% on 7 days and 3 months after surgery respectively. Advanced age, the haemoglobin concentration decline rate and SIRS score are independent risk factors for POCD in patients underwent coronary artery bypass grafting surgery.

[18F-FDG imaging by coincidence circuit SPECT with low-dose CT in preoperative assessment of pulmonary lesions].

OBJECTIVE: To assess the clinical diagnostic value of 18F-FDG imaging by coincidence circuit SPECT with low-dose CT in differential diagnosis of pulmonary lesions and mediastinal lymph node involvement, which can not be definitely diagnosed based on regular CT image in patients with non-small-cell lung cancer (NSCLC). METHODS: By using GE-Millennium VG with Hawkeye, 18F-FDG imaging was carried out in 48 patients with suspected lung cancer. Clinical value of 18F-FDG imaging for diagnosing malignancy was evaluated through comparison with the final pathological results. Mediastinal lymph node involvement was also assessed through lesion-by-lesion comparison with pathologic results in 74 lymph node regions from 24 patients. RESULTS: Final pathologic diagnoses of these patients were 36 malignancies consisting of 20 adenocarcinomas, 12 squamous cell carcinomas, 3 small cell carcinomas and I large cell carcinoma; 12 benign tumors including 6 pneumonias, 2 tuberculosis, 2 hamatomas, 1 cyst and 1 neurofibroma. Of 48 patients, uptake of 18F-FDG in the chest was found to be abnormal in 40. Correct diagnosis were made in 34 malignancies and 6 false positive lesions were excluded based on morphology and 18F-FDG uptake status of the lesion. There were 6 false positive and 2 false negative cases. Furthermore, extrathoracic metastases which were not showed on previous CT image in 4 patients including one in the adrenal gland and 3 in the bone were detected by 18F-FDG imaging. The sensitivity, specificity and accuracy of the 18F-FDG imaging for differentiating malignant tumor from benign was 94.4%, 50.0% and 83.3%, respectively. Squamous cell carcinoma was found to uptake more FDG than adenocarcinoma. For determination of mediastinal lymph node involvement, the sensitivity, specificity and accuracy of 18F-FDG imaging was 57.9% , 90.9% and 82.4%, respectively through lesion-by-lesion comparison; whereas, which was 61.5%, 81.8% and 70.8%, respectively, based on case-by-case comparison. CONCLUSION: 18F-FDG imaging by coincidence circuit SPECT with low-dose CT is quite helpful in differential diagnosis for patient with undetermined lesion on regular CT image, but it is limited for staging of lung cancer in the patients with non-small cell lung cancer.