A vicinal oxygen chelate protein facilitates viral infection by triggering the unfolded protein response in Nicotiana benthamiana.

Vicinal oxygen chelate (VOC) proteins are members of an enzyme superfamily with dioxygenase or non-dioxygenase activities. However, the biological functions of VOC proteins in plants are poorly understood. Here, we show that a VOC in Nicotiana benthamiana (NbVOC1) facilitates viral infection. NbVOC1 was significantly induced by infection by beet necrotic yellow vein virus (BNYVV). Transient overexpression of NbVOC1 or its homolog from Beta vulgaris (BvVOC1) enhanced BNYVV infection in N. benthamiana, which required the nuclear localization of VOC1. Consistent with this result, overexpressing NbVOC1 facilitated BNYVV infection, whereas, knockdown and knockout of NbVOC1 inhibited BNYVV infection in transgenic N. benthamiana plants. NbVOC1 interacts with the basic leucine zipper transcription factors bZIP17/28, which enhances their self-interaction and DNA binding to the promoters of unfolded protein response (UPR)-related genes. We propose that bZIP17/28 directly binds to the NbVOC1 promoter and induces its transcription, forming a positive feedback loop to induce the UPR and facilitating BNYVV infection. Collectively, our results demonstrate that NbVOC1 positively regulates the UPR that enhances viral infection in plants.

The role of alternative polyadenylation in epithelial-mesenchymal transition of non-small cell lung cancer.

The metastatic non-small cell lung cancer (NSCLC) is one of the cancers with high incidence, poor survival, and limited treatment. Epithelial-mesenchymal transition (EMT) is the first step by which an early tumor converts to an invasive one. Studying the underlying mechanisms of EMT can help the understanding of cancer metastasis and improve the treatment. In this study, 1013 NSCLC patients and 123 NSCLC cell lines are deeply analyzed for the potential roles of alternative polyadenylation (APA) in the EMT process. A trend of shorter 3'-UTRs (three prime untranslated region) is discovered in the mesenchymal samples. The identification of EMT-related APA events highlights the proximal poly(A) selection of CARM1. It is a pathological biomarker of mesenchymal tumor and cancer metastasis through losing miRNA binding to upregulate the EMT inducer of CARM1 and releasing miRNAs to downregulate the EMT inhibitor of RBM47. The crucial role of this APA event in EMT also guides its effect on drug responses. The patients with shorter 3'-UTR of CARM1 are more benefit from chemotherapy drugs, especially cisplatin. A stratification of NSCLC patients based on this APA event is useful for chemotherapy design in future clinics.

Comparative Transcriptome Analysis Reveals the Effect of the DHN Melanin Biosynthesis Pathway on the Appressorium Turgor Pressure of the Poplar Anthracnose-Causing Fungus Colletotrichum gloeosporioides.

Anthracnose of poplar caused by Colletotrichum gloeosporioides is a leaf disease that seriously affects poplar growth. The pathogen invades the host in the form of adherent cells, which generate turgor pressure through the metabolism of intracellular substances prior to penetrating the epidermis of poplar leaves. In this study, the expansion-related pressure of the mature appressorium of the wild-type C. gloeosporioides was approximately 13.02 ± 1.54 MPa at 12 h, whereas it was 7.34 ± 1.23 MPa and 9.34 ± 2.22 MPa in the melanin synthesis-related gene knockout mutants ΔCgCmr1 and ΔCgPks1, respectively. The CgCmr1 and CgPks1 genes were highly expressed at 12 h in the wild-type control, implying that the DHN melanin biosynthesis pathway may play an important role in the mature appressorium stage. The transcriptome sequencing analysis indicated that the upregulated melanin biosynthesis genes in C. gloeosporioides, such as CgScd1, CgAyg1, CgThr1, CgThr2, and CgLac1, are involved in specific KEGG pathways (i.e., fatty acid biosynthesis, fatty acid metabolism, and biotin metabolism). Therefore, we speculate that the melanin synthesis-related genes and fatty acid metabolism pathway genes contribute to the regulation of the turgor pressure in the mature C. gloeosporioides appressorium, ultimately leading to the formation of infection pegs that enter plant tissues. These observations may reflect the co-evolution of C. gloeosporioides and its host.

The Potential Regulation of A-to-I RNA Editing on Genes in Parkinson's Disease.

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD's transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) abolish existing miRNA binding sites, which allows miRNAs to regulate other genes; (2) create new miRNA binding sites that may sequester miRNAs from regulating other genes; or (3) occur in the miRNA seed regions and change their targets. The first two processes are also referred to as miRNA competitive binding. In our study, we found 8 RNA editing events that may alter the expression of 1146 other genes via miRNA competition. We also found one RNA editing event that modified a miRNA seed region, which was predicted to disturb the regulation of four genes. Considering the PD-related functions of the affected genes, 25 A-to-I RNA editing biomarkers for PD are proposed, including the 3 editing events in the EIF2AK2, APOL6, and miR-4477b seed regions. These biomarkers may alter the miRNA regulation of 133 PD-related genes. All these analyses reveal the potential mechanisms and regulations of RNA editing in PD pathogenesis.

New insight on the correlation of immune landscapes with immune markers expression in different risk classification of gastrointestinal stromal tumors.

BACKGROUND: The immune landscapes of gastrointestinal stromal tumors (GISTs) are still unclear. We aimed to explore the immune status of GISTs with different recurrence risks and sought potential immunotherapeutic targets. METHODS: Immune cell infiltration and the expression of 93 tumor markers of 65 GISTs with different recurrence risks from public datasets were analyzed via bioinformatic methods. Infiltrating immune cell and OX40L expression of 417 patients from the Zhongshan cohort were analyzed by immunohistochemistry and immunofluorescence. The clinicopathological data of the patients were collected and the prognostic factors were analyzed by univariate and multivariate methods. RESULTS: Macrophages, T cells and NK cells were the most abundant immune cells in tumor microenvironment. OX40L was the only differentially expressed marker in high- and low-risk patients, as well as in patients with primary and recurrent GIST. The positive rate of OX40L in GIST was 54%. OX40L was highly expressed in patients with no metastasis, low mitotic index and relapse risk. The amount of CD68 + macrophages was the independent factor of OX40L expression. The OX40L expression was positively correlated with M2 and resting mast cells. OX40L co-located with CD4 + T cells, M2 and activated mast cells. Patients with high OX40L levels experienced more prolonged relapse-free survival (RFS). CONCLUSIONS: We first reported that GIST cells could express OX40L, patients with high OX40L experienced longer RFS. The colocalization of OX40L with immune cells indicates that OX40L could be a promising potential target for immunotherapy in GIST.

Validation of the IMPROVE bleeding risk assessment model in surgical patients: Results from the DissolVE-2 Study.

INTRODUCTION: IMPROVE Bleeding Risk Score (BRS) is known to be validated and widely accepted in medical patients. However, its relevance in surgical patients has so far not been explored. External validation of the IMPROVE BRS on bleeding in surgical patients can hopefully improve clinical practice (for surgical patients). METHODS: Data from 6986 surgical patients were collected from the DissolVE-2 cohort. The Kaplan-Meier method was used to assess the incidences of major bleeding and any bleeding among surgical patients within 14 days of admission. A cut-off value of BRS ≥7 indicated a higher risk of bleeding. Risk factors associated with major and any bleeding were analysed by the Cox regression method. Model discrimination was evaluated by area under the receiver operator characteristic curves (AUC). Calibration curves and Hosmer-Lemeshow χ2 statistics were used to measure the difference between predicted and observed bleeding risks. RESULTS: A total of 6399 surgical patients were included in the final validation cohort. The cumulative incidence rate of any bleeding was 3.9 % (95 % confidence interval [CI], 3.4-4.5), of which the incidence rate of major bleeding was 1.2 % (95 % CI, 0.9-1.6). Among patients with a BRS of ≥7, 16.3 % reported any bleeding, and 26.3 % reported major bleeding. The IMPROVE BRS had a better discriminative power (AUC = 0.69) and excellent goodness of fit (Hosmer-Lemeshow test, P = 0.208) for the prediction of major bleeding events as compared with any bleeding (AUC = 0.55; Hosmer-Lemeshow test, P = 0.004). The calibration plot suggested a more accurate prediction for major bleeding events. Moreover, the IMPROVE BRS had a higher AUC value of 0.83 and better goodness of fit (P = 0.2616) for major bleeding in patients undergoing abdominal surgery than other surgery types. CONCLUSION: The IMPROVE BRS is a simple and practical technique that can help in predicting the risk of major bleeding in surgical patients, improving functional and safety outcomes of hospitalized patients with surgery.

RNA m5C regulator-mediated modification patterns and the cross-talk between tumor microenvironment infiltration in gastric cancer.

The effect of immunotherapy strategy has been affirmed in the treatment of various tumors. Nevertheless, the latent role of RNA 5-methylcytosine (m5C) modification in gastric cancer (GC) tumor microenvironment (TME) cell infiltration is still unclear. We systematically explore the m5C modification patterns of 2,122 GC patients from GEO and TCGA databases by 16 m5C regulators and related these patterns to TME characteristics. LASSO Cox regression was employed to construct the m5Cscore based on the expression of regulators and DEGs, which was used to evaluate the prognosis. All the GC patients were divided into three m5C modification clusters with distinct gene expression characteristics and TME patterns. GSVA, ssGSEA, and TME cell infiltration analysis showed that m5C clusters A, B, and C were classified as immune-desert, immune-inflamed, and immune-excluded phenotype, respectively. The m5Cscore system based on the expression of eight genes could effectively predict the prognosis of individual GC patients, with AUC 0.766. Patients with a lower m5Cscore were characterized by the activation of immunity and experienced significantly longer PFS and OS. Our study demonstrated the non-negligible role of m5C modification in the development of TME complexity and inhomogeneity. Assessing the m5C modification pattern for individual GC patients will help recognize the infiltration characterization and guide more effective immunotherapy treatment.

Incidence and risk factors for postoperative pancreatic fistula in 2089 patients treated by radical gastrectomy: A prospective multicenter cohort study in China.

OBJECTIVE: To determine the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) following radical gastrectomy and to identify independent risk factors of CR-POPF. BACKGROUND: CR-POPF and its sequelae are potential complications following radical gastrectomy. The reported incidence of CR-POPF was quite different across various regions, and no consensus was reached. METHODS: Between December 2017 to November 2018, patients who underwent radical gastrectomy from 22 centers across 13 regions in China were prospectively recruited. The primary endpoint was the occurrence of CR-POPF, defined by the International Study Group of Pancreatic Fistula (ISGPF) in 2016. Clinically relevant change and short-term outcomes were recorded to diagnose and grade the POPF. Multivariate regression analyses were performed to identify independent risk factors of clinically relevant postoperative pancreatic fistula (CR-POPF). RESULTS: A total of 2089 cases were analyzed. The incidence of biochemical leakage (BL) and CR-POPF were 19.6% and 1.1% respectively. All CR-POPF patients recovered well after appropriate treatment and no Grade C POPF were recorded. Logistic regression analysis showed pTNM III (OR, 2.940; 95% CI 1.180-7.325; P = 0.021) and LigaSure usage (OR, 6.618; 95% CI 1.847-23.707; P = 0.004) were independent risk factors of CR-POPF. LigaSure usage (OR, 4.817; 95% CI 1.184-19.598; P = 0.028), the drain amylase content (D-AMY) on postoperative day 3 (POD3) ≥5 times the upper limit of normal amylase (OR, 3.476; 95% CI 1.240-9.744; P = 0.018) and open surgery (OR, 2.463; 95% CI 1.003-6.050; P = 0.049) were independent predictors for identifying CR-POPF from BL. CONCLUSION: In rich-experienced gastric cancer centers, there is high prevalence of BL secondary to radical gastrectomy without clinical impact. Fewer patients suffered Grade B POPF, and Grade C POPF was less common. The patients with pTNM III or LigaSure usage were prone to suffer CR-POPF. Surgery procedure, LigaSure usage combined with D-AMY measurement on POD3 are promising for early identification of CR-POPF.

Clinical and Prognostic Significance of Tumor-Infiltrating CD8+ T Cells and PD-L1 Expression in Primary Gastrointestinal Stromal Tumors.

PURPOSE: Immunotherapy for gastrointestinal stromal tumors (GISTs) remains a clinical challenge. The present study aimed to explore the clinical and prognostic significance of immune cell infiltration and PD-L1 expression in GISTs. METHODS: A total of 507 clinical tissue specimens of primary GISTs were collected for immunohistochemical analysis of immune cell infiltration and PD-L1 expression. Influencing factors of survival were evaluated by Kaplan-Meier analysis. Univariate and multivariate analyses were performed using the Cox regression model. RESULTS: There were significant differences in sex, tumor location, size, mitotic index, NIH risk grade, and cell morphology between different gene mutation types of GISTs. Immune cell infiltration in GISTs mainly involved macrophages and T cells. PD-1 was expressed in 48.5% of the tissue specimens, and PD-L1 expression was detected in 46.0% of the samples. PD-L1 expression was negatively correlated with the tumor size and mitotic index but positively correlated with the number of CD8+ T cells. There were significant differences in the number of CD8+ T cells between different gene mutation types. Wild type-mutant GISTs were enriched with CD8+ T cells as compared with KIT- and PDGFRA-mutant GISTs. The number of CD8+ T cells was higher in non-gastric GISTs. PD-L1 and CD8+ T cells were independent predictors for better relapse-free survival of GISTs. CONCLUSIONS: PD-L1 expression is a predictive biomarker for better prognosis of GISTs. Non-gastric GIST patients with wild-type mutations may be the beneficiaries of PD-1/PD-L1 inhibitors.

Effect of stroke screening survey on intravenous thrombolysis and long-term outcomes in acute ischemic stroke patients: the real-world evidence from Shanghai, China.

BACKGROUND: The stroke screening survey (SSS) is an essential strategy for stroke prevention. However, previous studies rarely discussed the effect of SSS on the acute phase treatment procedure for acute ischemic stroke (AIS) and the long-term prognosis outcomes. This study aims to investigate the effect of SSS on intravenous thrombolysis and long-term outcomes in AIS patients. METHODS: The stroke patients included were collected from Jiading Residences Community Health Records and Shanghai Stroke Service System database, from January 2017 to December 2019. Patients were divided into two groups, according to whether they have been screened before the event (onset and death). Demographic characteristics and treatment information of patients in the two groups were compared by the Mann-Whitney test and Chi-square test. The demographic differences between groups were adjusted with Propensity Score Matching (PSM) to evaluate the effect of SSS on door-to-needle time (DNT). The Kaplan-Meier survival curve with a log-rank test and multiple Cox regression model were used to evaluate the effect of SSS on long-term lifetime. RESULTS: A total of 1,236 patients with AIS were collected, including 468 (37.86%) female, 126 (10.19%) patients with intravenous thrombolysis, 241 (23.30%) patients died from all-cause mortality by January 8, 2020. A total of 124 (10.03%) patients have been screened before AIS onset, and 261 (21.17%) patients had undergone SSS after AIS onset. The baseline information indicated that patients with previous screening were older than the patients without at the time of onset [75 (70, 83) vs. 73 (65, 82), P=0.017], as well as more likely to have a history of hypertension (90.32% vs. 78.51%, P=0.002) and diabetes (50.00% vs. 25.81%, P<0.001). PSM results showed that patients with previous screening were associated with less severe onset situation [3 (1, 9) vs. 3 (1, 5), P=0.001] and shorter DNT [30 (24, 49) vs. 44 (31.5, 49), P=0.037] when compared to patients without. Additionally, patients with SSS had a lower hazard ratio of 0.567 (95% CI: 0.380-0.847, P=0.006) on all-cause mortality. CONCLUSIONS: For AIS patients, the SSS is associated with less severe onset situation, shorter DNT, and longer long-term lifetime.

The long non-coding RNA DKFZp434J0226 regulates the alternative splicing process through phosphorylation of SF3B6 in PDAC.

BACKGROUND: Long noncoding RNAs (lncRNAs), a type of pervasive genes that regulates various biological processes, are differentially expressed in different types of malignant tumors. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we investigated the role of the lncRNA DKFZp434J0226 in PDAC. METHODS: Aberrantly expressed mRNAs and lncRNAs among six PDAC and paired non-tumorous tissues were profiled using microarray analysis. Quantitative real-time polymerase chain reaction was used to evaluate DKFZp434J0226 expression in PDAC tissues. CCK-8 assay, wound-healing assay, soft agar colony formation assay, and transwell assay were performed to assess the invasiveness and proliferation of PDAC cells. Furthermore, RNA pull-down, immunofluorescence, RNA immunoprecipitation, and western blotting assays were performed to investigate the association between DKFZp434J0226 and SF3B6. Tumor xenografts in mice were used to test for tumor formation in vivo. RESULTS: In our study, 222 mRNAs and 128 lncRNAs were aberrantly expressed (≥ twofold change). Of these, 66 mRNAs and 53 lncRNAs were upregulated, while 75 lncRNAs and 156 mRNAs were downregulated. KEGG pathway analysis and the Gene ontology category indicated that these genes were associated with the regulation of mRNA alternative splicing and metabolic balance. Clinical analyses revealed that overexpression of DKFZp434J0226 was associated with worse tumor grading, frequent perineural invasion, advanced tumor-node-metastasis stage, and decreased overall survival and time to progression. Functional assays demonstrated that DKFZp434J0226 promoted PDAC cell migration, invasion, and growth in vitro and accelerated tumor proliferation in vivo. Mechanistically, DKFZp434J0226 interacted with the splicing factor SF3B6 and promoted its phosphorylation, which further regulated the alternative splicing of pre-mRNA. CONCLUSIONS: This study indicates that DKFZp434J0226 regulates alternative splicing through phosphorylation of SF3B6 in PDAC and leads to an oncogenic phenotype in PDAC.

BOP1 Silencing Suppresses Gastric Cancer Proliferation through p53 Modulation.

Block of proliferation 1 (BOP1) is a key protein involved in ribosome maturation and affects cancer progression. However, its role in gastric cancer (GC) remains unknown. This study aimed to explore the expression of BOP1 in GC and its potential mechanisms in regulating GC growth, and the relationship between BOP1 level in cancer tissues and survival was also analyzed. The expression of BOP1 was examined by immunohistochemistry (IHC) in a cohort containing 387 patients with primary GC. Cultured GC cells were treated by siRNA to knock down the BOP1 expression, and examined by CCK-8 assay and plate clone formation to assess cell proliferation in vitro. Apoptotic rate of cultured GC cells was detected by flow cytometry with double staining of AnnxinV/PI. The xenografted mouse model was used to assess GC cell proliferation in vivo. Western blot and IHC were also performed to detect the expression levels of BOP1, p53 and p21. Patients with higher level of BOP1 in cancer tissues had significantly poorer survival. BOP1 silencing significantly suppressed GC cell proliferation both in vitro and in vivo. It blocked cell cycle at G0/G1 phase and led to apoptosis of GC cells via upregulating p53 and p21. BOP1 silencing-induced suppression of cell proliferation was partly reversed by pifithrin-α (a p53 inhibitor). Our study demonstrated that BOP1 up-regulation may be a hallmark of GC and it may regulate proliferation of GC cells by activating p53. BOP1 might be considered a novel biomarker of GC proliferation, and could be a potential indicator of prognosis of GC patients. BOP1 might also be a potential target for the treatment of GC patients if further researched.

Pattern of No. 12a lymph node metastasis in gastric cancer.

OBJECTIVE: The current standard D2 lymphadenectomy for gastric cancer (GC) includes dissection of lymph nodes (LNs) along the proper hepatic artery (No. 12a), however, the survival benefit remains controversial. The purpose of this study was to evaluate the pattern of No. 12a LN metastasis (LNM) in GC and explore the indications for No. 12a LN dissection. METHODS: Medical records of 413 consecutive GC patients who underwent curative surgery in Zhongshan Hospital, Fudan University between January 2015 and December 2018 were enrolled and reviewed retrospectively. The correlation between No. 12a LNM and clinicopathologic characteristics of patients was analyzed. RESULTS: The overall incidence of No. 12a LNM was 2.67% (11/413). Tumor location (P=0.012), depth of tumor infiltration (P<0.01) and N stage (P=0.018) were significant factors associated with No. 12a LNM. All the tumors with No. 12a LNM involved the lower third of the stomach and were in T3-4 stages. Patients with No. 12a LNM had extensive LNM than those without (20.91±4.25vs. 5.0±0.54, P<0.001). For advanced GC patients (stage III/IV) with tumors involving the lower third of the stomach, the incidence of No. 12a LNM increased to 10.7% (11/103). Patients with No. 12a LNM had a significantly poorer recurrence-free survival (RFS) (P=0.005) and overall survival (OS) (P=0.017). According to the result of multivariable Cox regression, No. 12a LNM was not an independent impact factor on RFS and OS. CONCLUSIONS: The overall incidence of No. 12a LNM was low but it was much higher in GC patients who had very advanced tumors involving the lower third of the stomach. No. 12a LN dissection should be considered for these patients to improve the survival outcomes.

Immune Cell Infiltration and the Expression of PD-1 and PD-L1 in Primary PDGFRA-Mutant Gastrointestinal Stromal Tumors.

PURPOSE: To characterize the immune cell profile and expression of PD-1, PD-L1, and IDO in PDGFRA-mutant gastrointestinal stromal tumors (GISTs). METHODS: The clinicopathological data of PDGFRA-mutant GIST patients who received surgical resection in Zhongshan Hospital between January 2013 and August 2019 were reviewed retrospectively. The specimens of tissue chips were detected for immune cell infiltration and the expression of PD-1, PD-L1, and IDO by immunohistochemical staining. RESULTS: CD3+, CD8+, and CD68+ cells were the main infiltrating immune cells in the 42 patients included in this study. In addition, CD4+, CD56+, Foxp3+, and CD20+ cells were also observed. A higher CD8+ T cell count was associated with smaller tumor size and PDGFRA D842V mutation (P = 0.047, P = 0.005). A higher CD3+ and CD68+ cell count was associated with a higher mitotic index (P = 0.022, P = 0.006). CD4+ and CD20+ cell count was associated with tumor morphology (P = 0.002, P = 0.045). PD-1 expression was present in 37 (88%) samples. Eighteen samples were positive for PD-L1 expression, and it was higher in small vs. large tumors (P = 0.012) and epithelioid and mixed cell type vs. spindle cell type GISTs (P = 0.046). IDO expression was positive in all 42 patients. The number of CD4+ cells was significantly greater in the specimens with high IDO expression (P = 0.012). CONCLUSION: There were abundant infiltrating immune cells in PDGFRA-mutant GISTs. PD-L1 expression was negatively associated with tumor size. The immunotherapy targeting PD-1/PD-L1 checkpoint and IDO may be valuable.

Preoperative Hepatic and Regional Arterial Chemotherapy in Patients Who Underwent Curative Colorectal Cancer Resection: A Prospective, Multi-center, Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting. SUMMARY OF BACKGROUND DATA: Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients. METHODS: A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877). RESULTS: A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms. CONCLUSIONS: The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00643877.

Shanghai international consensus on diagnosis and comprehensive treatment of colorectal liver metastases (version 2019).

The liver is the most common anatomical site for hematogenous metastases from colorectal cancer. Therefore effective treatment of liver metastases is one of the most challenging elements in the management of colorectal cancer. However, there is rare available clinical consensus or guideline only focusing on colorectal liver metastases. After six rounds of discussion by 195 clinical experts of the Shanghai International Consensus Expert Group on Colorectal Liver Metastases (SINCE) from 29 countries or regions, the Shanghai Consensus has been finally completed, based on current research and expert experience. The consensus emphasized the principle of multidisciplinary team, provided detailed diagnosis approaches, and guided precise local and systemic treatments. This Shanghai Consensus might be of great significance to standardized diagnosis and treatment of colorectal liver metastases all over the world.

International consensus on natural orifice specimen extraction surgery (NOSES) for gastric cancer (2019).

At present, natural orifice specimen extraction surgery (NOSES) has attracted more and more attention worldwide, because of its great advantages including minimal cutaneous trauma and post-operative pain, fast post-operative recovery, short hospital stay, and positive psychological impact. However, NOSES for the treatment of gastric cancer (GC) is still in its infancy, and there is great potential to improve its theoretical system and clinical practice. Especially, several key points including oncological outcomes, bacteriological concerns, indication selection, and standardized surgical procedures are raised with this innovative technique. Therefore, it is necessary to achieve an international consensus to regulate the implementation of GC-NOSES, which is of great significance for healthy and orderly development of NOSES worldwide.

Validation of the IMPROVE bleeding risk score in Chinese medical patients during hospitalization: Findings from the dissolve-2 study.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis remains suboptimal in China due to the bleeding risk associated with pharmacologic prophylaxis. We used data from the DissolVE-2 study to report the risk factors for bleeding and validated the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding risk score (BRS). METHODS: In-hospital major bleeding incidence in medical patients from the DissolVE-2 study were assessed by Kaplan-Meier method. Risk factors associated with clinically relevant bleeding (CRB) were analysed using Cox regression model. Sensitivity, specificity, positive predictive value, negative predictive value and receiver-operating characteristic (ROC) curve was used to compute the diagnostic accuracy of IMPROVE BRS in the study cohort. FINDINGS: Of the 6623 medical patients, 5076 patients with all relevant clinical details were included for the validation cohort. Overall, 127 CRB events (38 major and 89 clinically relevant non-major bleeding events) occurred in this cohort, with a cumulative incidence rate of 2.6% (95% confidence interval [CI], 2.3-3.4). Application of IMPROVE BRS revealed significantly higher hazards of CRB (hazard ratio [HR]: 7.17, 95% CI, 5.05-10.18) and major bleeding (HR: 13.95, 95% CI, 7.28-26.73) in patients with IMPROVE BRS ≥7. Comparison of predictive parameters revealed higher sensitivity (44.1 vs 35.9) and positive predictive value (10.9 vs 2.6) for CRB in our study than the IMPROVE study, which was substantiated by the area under the curve (0.73, p<0.0001) from the ROC curve analysis. INTERPRETATION: IMPROVE BRS is a simple model for estimating bleeding risk in Chinese medical patients and could be used in conjunction with VTE risk assessment models to decide prophylactic treatment for VTE. FUNDING: This study and the additional data analysis were funded by Sanofi (Beijing) Pharmaceutical Co, Ltd by the Fund of The National Key Research and Development Program of China [Grant 2016YFC0905600] and by CAMS Innovation Fund for Medical Sciences (CIFMS) (No.2018-I2M-1-003).

Prevention and control strategies of general surgeons under COVID-19 pandemic.

The novel coronavirus SARS-CoV-2 and the disease caused by it, COVID-19, have spread to virtually all countries worldwide within just a few months. The economic and sanitary impact has been enormous. In March 2020, the World Health Organization declared COVID-19 a pandemic. How to effectively prevent and control SARS-CoV-2 transmission while providing care to surgical patients during the pandemic is a crucial topic. In order to minimize the risk of cross-infection between patients and physicians, many hospitals have taken measures to limit outpatient services, elective hospitalizations, and the number of operations. Based on the prevention and control measures stipulated by major medical institutions in China, this overview provides recommendations for surgeons from three aspects: outpatient treatment, ward management and perioperative protection. Telemedicine should be encouraged as a means of social distancing. Outpatient examination should be selected. Reasonable spatial arrangement and effective environmental disinfection are important for ward management. Patient selection for surgery and timing of operations should be carefully discussed within multi-disciplinary teams. Appropriate personal protective equipment should be worn adapted to the situational risk. On December 31, 2019, China reported to the WHO Country Office a pneumonia of unknown cause detected in Wuhan [1], [3]. Subsequently, the disease later named COVID-19 affected a substantial proportion of the population in Wuhan and spread to other areas of China. Relying on a nationwide shutdown and mandatory quarantine, China has effectively curtailed the domestic outbreak. However, due to the high transmissibility of SARS-Cov-2 and the mobility of people, COVID-19 spread to the rest of the world. Many hospitals worldwide were faced with confirmed and suspected SARS-Cov-2 infections, putting a huge strain on the safety of patients and employees. Consequently, surgical patients who seek medical care during the COVID-19 pandemic present significant challenges. This paper summarizes medical care and infection prevention and control in general surgery patients during the COVID-19, pandemic in the light of the current situation in China. It provides reference for surgeons and decision makers in health care in other countries suffering from the COVID-19 pandemic.

Predictive And Prognostic Value Of Hepatic Steatosis In Conversion Therapy For Colorectal Liver-limited Metastases: A Propensity Score Matching Analysis.

PURPOSE: To evaluate the role of hepatic steatosis (HS) in patients with synchronous colorectal liver-limited metastases (CLLMs) undergoing conversion therapy. PATIENTS AND METHODS: From March 2013 to March 2017, a total of 406 patients with initially unresectable CLLMs accepted conversion therapy in multidisciplinary team (MDT). Before the implementation of conversion therapy, all patients underwent CT scan to assess the presence of hepatic steatosis and divided into the HS group (n = 124) and the non-HS group (n = 282). After using propensity score matching (PSM) to eliminate the potential confounding bias of the two groups, the conversion hepatectomy rate and long-term oncological survival in two groups were compared. RESULTS: After 1:1 PSM, no significant difference was observed at baseline between patients in the HS group (n = 119) and the non-HS group (n = 119). Patients in the HS group had higher conversion hepatectomy rate from MDT evaluation (31.1% vs 18.5%, P = 0.029) and actual hepatectomy rate (30.2% vs 18.5%, P = 0.030), when compared with patients in the non-HS group, respectively. In addition, the HS group achieved better progression-free survival (PFS, P = 0.047) and overall survival (OS, P = 0.035) than that of the non-HS group. Multivariate logistic analysis confirmed that pretreatment HS was an independent predictor for conversion hepatectomy rate (OR, 2.393; 95% CI, 1.463-4.315, P = 0.001), and multivariate Cox analysis revealed that HS was an independent prognostic factor for PFS (HR, 0.493, 95% CI 0.281-0.866, P = 0.014) and OS (HR, 0.559, 95% CI 0.398-0.785, P = 0.001). CONCLUSION: For CLLM patients who underwent conversion therapy, hepatic steatosis could be an effective predictor for conversion hepatectomy rate and an independent prognostic factor for PFS and OS.