m6A methylation-mediated regulation of LncRNA MEG3 suppresses ovarian cancer progression through miR-885-5p and the VASH1 pathway.

BACKGROUND: Ovarian cancer poses a serious threat to women's health. Due to the difficulty of early detection, most patients are diagnosed with advanced-stage disease or peritoneal metastasis. We found that LncRNA MEG3 is a novel tumor suppressor, but its role in tumor occurrence and development is still unclear. METHODS: We investigated the expression level of MEG3 in pan-cancer through bioinformatics analysis, especially in gynecological tumors. Function assays were used to detect the effect of MEG3 on the malignant phenotype of ovarian cancer. RIP, RNA pull-down, MeRIP-qPCR, actinomycin D test were carried out to explore the m6A methylation-mediated regulation on MEG3. Luciferase reporter gene assay, PCR and Western blot were implemented to reveal the potential mechanism of MEG3. We further confirmed the influence of MEG3 on tumor growth in vivo by orthotopic xenograft models and IHC assay. RESULTS: In this study, we discovered that MEG3 was downregulated in various cancers, with the most apparent downregulation in ovarian cancer. MEG3 inhibited the proliferation, migration, and invasion of ovarian cancer cells. Overexpression of MEG3 suppressed the degradation of VASH1 by negatively regulating miR-885-5p, inhibiting the ovarian cancer malignant phenotype. Furthermore, we demonstrated that MEG3 was regulated at the posttranscriptional level. YTHDF2 facilitated MEG3 decay by recognizing METTL3­mediated m6A modification. Compared with those injected with vector control cells, mice injected with MEG3 knockdown cells showed larger tumor volumes and faster growth rates. CONCLUSION: We demonstrated that MEG3 is influenced by METTL3/YTHDF2 methylation and restrains ovarian cancer proliferation and metastasis by binding miR-885-5p to increase VASH1 expression. MEG3 is expected to become a therapeutic target for ovarian cancer.

Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer.

Gastric cancer (GC) represents a significant burden of cancer-related mortality worldwide, underscoring an urgent need for the development of early detection strategies and precise postoperative interventions. However, the identification of non-invasive biomarkers for early diagnosis and patient risk stratification remains underexplored. Here, we conduct a targeted metabolomics analysis of 702 plasma samples from multi-center participants to elucidate the GC metabolic reprogramming. Our machine learning analysis reveals a 10-metabolite GC diagnostic model, which is validated in an external test set with a sensitivity of 0.905, outperforming conventional methods leveraging cancer protein markers (sensitivity < 0.40). Additionally, our machine learning-derived prognostic model demonstrates superior performance to traditional models utilizing clinical parameters and effectively stratifies patients into different risk groups to guide precision interventions. Collectively, our findings reveal the metabolic landscape of GC and identify two distinct biomarker panels that enable early detection and prognosis prediction respectively, thus facilitating precision medicine in GC.

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy.

Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.

Prognostic importance of the preoperative New-Naples prognostic score for patients with gastric cancer.

BACKGROUND: The wide applicability of the Naples prognostic score (NPS) is still worthy of further study in gastric cancer (GC). This study aimed to construct a New-NPS based on the differences in immunity and nutrition in patients with upper and lower gastrointestinal tumors to help obtain an individualized prediction of prognosis. METHODS: This study retrospectively analyzed patients who underwent radical gastrectomy from April 2014 to September 2016. The cutoff values of the preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), serum albumin (Alb), and total cholesterol (TC) were calculated by ROC curve analysis. ROC and t-ROC were used to evaluate the accuracy of the prognostic markers. The Kaplan-Meier method and log-rank test were used to analyze the overall survival probability. Univariate and multivariate analyses based on Cox risk regression were used to show the independent predictors. The nomogram was made by R studio. The predictive accuracy of nomogram was assessed using a calibration plot, concordance index (C-index), and decision curve. RESULTS: A total of 737 patients were included in training cohort, 411 patients were included in validation cohort. ROC showed that the New-NPS was more suitable for predicting the prognosis of GC patients. NPS = 2 indicated a poor prognosis. Multivariate analysis showed that CEA (P = 0.026), Borrmann type (P = 0.001), pTNM (P < 0.001), New-NPS (P < 0.001), and nerve infiltration (P = 0.035) were independent risk factors for prognosis. CONCLUSION: The New-NPS based on the cutoff values of NLR, LMR, Alb, and TC is not only suitable for predicting prognosis but can also be combined with clinicopathological characteristics to construct a nomogram model for GC patients.

Artificial intelligence for colorectal neoplasia detection during colonoscopy: a systematic review and meta-analysis of randomized clinical trials.

Background: The use of artificial intelligence (AI) in detecting colorectal neoplasia during colonoscopy holds the potential to enhance adenoma detection rates (ADRs) and reduce adenoma miss rates (AMRs). However, varied outcomes have been observed across studies. Thus, this study aimed to evaluate the potential advantages and disadvantages of employing AI-aided systems during colonoscopy. Methods: Using Medical Subject Headings (MeSH) terms and keywords, a comprehensive electronic literature search was performed of the Embase, Medline, and the Cochrane Library databases from the inception of each database until October 04, 2023, in order to identify randomized controlled trials (RCTs) comparing AI-assisted with standard colonoscopy for detecting colorectal neoplasia. Primary outcomes included AMR, ADR, and adenomas detected per colonoscopy (APC). Secondary outcomes comprised the poly missed detection rate (PMR), poly detection rate (PDR), and poly detected per colonoscopy (PPC). We utilized random-effects meta-analyses with Hartung-Knapp adjustment to consolidate results. The prediction interval (PI) and I2 statistics were utilized to quantify between-study heterogeneity. Moreover, meta-regression and subgroup analyses were performed to investigate the potential sources of heterogeneity. This systematic review and meta-analysis is registered with PROSPERO (CRD42023428658). Findings: This study encompassed 33 trials involving 27,404 patients. Those undergoing AI-aided colonoscopy experienced a significant decrease in PMR (RR, 0.475; 95% CI, 0.294-0.768; I2 = 87.49%) and AMR (RR, 0.495; 95% CI, 0.390-0.627; I2 = 48.76%). Additionally, a significant increase in PDR (RR, 1.238; 95% CI, 1.158-1.323; I2 = 81.67%) and ADR (RR, 1.242; 95% CI, 1.159-1.332; I2 = 78.87%), along with a significant increase in the rates of PPC (IRR, 1.388; 95% CI, 1.270-1.517; I2 = 91.99%) and APC (IRR, 1.390; 95% CI, 1.277-1.513; I2 = 86.24%), was observed. This resulted in 0.271 more PPCs (95% CI, 0.144-0.259; I2 = 65.61%) and 0.202 more APCs (95% CI, 0.144-0.259; I2 = 68.15%). Interpretation: AI-aided colonoscopy significantly enhanced the detection of colorectal neoplasia detection, likely by reducing the miss rate. However, future studies should focus on evaluating the cost-effectiveness and long-term benefits of AI-aided colonoscopy in reducing cancer incidence. Funding: This work was supported by the Heilongjiang Provincial Natural Science Foundation of China (LH2023H096), the Postdoctoral research project in Heilongjiang Province (LBH-Z22210), the National Natural Science Foundation of China's General Program (82072640) and the Outstanding Youth Project of Heilongjiang Natural Science Foundation (YQ2021H023).

Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy.

BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, BET inhibitors represent a novel form of epigenetic anticancer treatment. Although preliminary clinical trials have shown the anticancer potential of BET inhibitors, it appears that these drugs have limited effectiveness when used alone. Therefore, given the limited monotherapeutic activity of BET inhibitors, their use in combination with other drugs warrants attention, including the meaningful variations in pharmacodynamic activity among chosen drug combinations. In this paper, we review the function of BET proteins, the preclinical justification for BET protein targeting in cancer, recent advances in small-molecule BET inhibitors, and preliminary clinical trial findings. We elucidate BET inhibitor resistance mechanisms, shed light on the associated adverse events, investigate the potential of combining these inhibitors with diverse therapeutic agents, present a comprehensive compilation of synergistic treatments involving BET inhibitors, and provide an outlook on their future prospects as potent antitumor agents. We conclude by suggesting that combining BET inhibitors with other anticancer drugs and innovative next-generation agents holds great potential for advancing the effective targeting of BET proteins as a promising anticancer strategy.

Laparoscopic versus open gastrectomy for gastric cancer: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Laparoscopic gastrectomy (LG) has been widely used for advanced gastric cancer (GC), and its resection extent is not limited to distal gastrectomy. However, the superiority of this minimally invasive approach remains controversial. This study aimed to evaluate the benefits and risks of LG on the short- and long-term outcomes compared with open gastrectomy (OG) for GC. MATERIALS AND METHODS: A systematic literature search was performed to identify randomized controlled trials (RCTs) comparing LG and OG for treatment of GC. The primary outcomes were adverse events, recurrence, mortality, and the quality of life. The secondary outcomes included operation-relevant outcomes and postoperative recovery outcomes. We employed random-effects meta-analyses to pool results with Hartung-Knapp adjustment. The prediction interval (PI) was used to quantify the between-study heterogeneity. Meta-regression and subgroup analyses were performed to examine the potential sources of heterogeneity. RESULTS: Twenty-eight studies involving 7643 patients were included. Most studies (22 out of 28) reported results from experienced surgeons. Compared to OG, LG was found to have the advantages of less blood loss, fewer postoperative complications, and faster recovery, but at the expense of lesser proximal resection margin length, longer operation time, and fewer retrieved lymph nodes. There were no significant differences for anastomosis-related complications, recurrence and survival and other outcomes between LG and OG. Significant between-study heterogeneity was observed. Body mass index (BMI) and age were two major sources of heterogeneity. CONCLUSIONS: For experienced surgeons, LG is an alternative approach to OG for patients with GC. Patients with lower BMI and older age may benefit most from LG. Future studies are needed to confirm our findings in low-volume hospitals and for less-experienced surgeons. Future trials focusing on patient-important outcomes are warranted for clinical decision-making.

Development and Validation of an Age-Related Gastric Cancer-Specific Immune Index.

Background: Aging has a negative impact on the immune function of patients. The purpose of this study was to construct an age-related specific immune index according to the immune aging phenomenon of gastric cancer (GC) and explore its prognostic value. Methods: This study retrospectively analyzed patients who underwent radical GC surgery in the Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Harbin Medical University, from August 2014 to December 2016 and divided them into a training cohort and a validation cohort. A new immune score, the GC-specific immune index (GSII), was developed as a series of lymphocyte subsets associated with the prognosis of patients with GC. Then, the receiver operating characteristic (ROC) curve was used to compare the prediction performance. The Kaplan‒Meier method and Log rank test were used to analyze the overall survival of patients. Cox hazard regression models were used to identify independent risk factors associated with prognosis. Finally, a nomogram model was constructed by combining the GSII and clinicopathological characteristics, and the calibration chart, consistency index, and decision curve were used to test the performance of the model. Results: Aging did not significantly affect CD8 cell counts but decreased CD4 and CD19 cell counts. Based on the Cox analysis, the GSII of patients ≤60 years old was 0.079×lg CD4+0.348×lg CD19, and the GSII of patients >60 years old was 0.058×lg CD4. A decreased GSII was indicative of a poor prognosis and was an independent risk factor associated with patient outcomes. The nomogram constructed based on the GSII and clinicopathological features accurately predicted patient prognosis. Furthermore, the GSII was well validated in the validation cohort. Conclusion: The GSII constructed for the special immune aging phenomenon of GC can accurately predict patient prognosis.

Metastatic lymph nodes and prognosis assessed by the number of retrieved lymph nodes in gastric cancer.

BACKGROUND: The prognostic value of quantitative assessments of the number of retrieved lymph nodes (RLNs) in gastric cancer (GC) patients needs further study. AIM: To discuss how to obtain a more accurate count of metastatic lymph nodes (MLNs) based on RLNs in different pT stages and then to evaluate patient prognosis. METHODS: This study retrospectively analyzed patients who underwent GC radical surgery and D2/D2+ LN dissection at the Cancer Hospital of Harbin Medical University from January 2011 to May 2017. Locally weighted smoothing was used to analyze the relationship between RLNs and the number of MLNs. Restricted cubic splines were used to analyze the relationship between RLNs and hazard ratios (HRs), and X-tile was used to determine the optimal cutoff value for RLNs. Patient survival was analyzed with the Kaplan-Meier method and log-rank test. Finally, HRs and 95% confidence intervals were calculated using Cox proportional hazards models to analyze independent risk factors associated with patient outcomes. RESULTS: A total of 4968 patients were included in the training cohort, and 11154 patients were included in the validation cohort. The smooth curve showed that the number of MLNs increased with an increasing number of RLNs, and a nonlinear relationship between RLNs and HRs was observed. X-tile analysis showed that the optimal number of RLNs for pT1-pT4 stage GC patients was 26, 31, 39, and 45, respectively. A greater number of RLNs can reduce the risk of death in patients with pT1, pT2, and pT4 stage cancers but may not reduce the risk of death in patients with pT3 stage cancer. Multivariate analysis showed that RLNs were an independent risk factor associated with the prognosis of patients with pT1-pT4 stage cancer (P = 0.044, P = 0.037, P = 0.003, P < 0.001). CONCLUSION: A greater number of RLNs may not benefit the survival of patients with pT3 stage disease but can benefit the survival of patients with pT1, pT2, and pT4 stage disease. For the pT1, pT2, and pT4 stages, it is recommended to retrieve 26, 31 and 45 LNs, respectively.

Patient-Level DNA Damage Repair Pathway Profiles and Anti-Tumor Immunity for Gastric Cancer.

DNA damage repair (DDR) comprises the detection and correction of alterations in the chemical structure of DNA. The dysfunction of the DDR process has been determined to have important implications for tumor carcinogenesis, malignancy progression, treatment resistance, and prognosis assessment. However, the role of the DDR process in gastric cancer (GC) remains to be fully understood. Thus, a total of 2,019 GC samples from our hospital (Harbin Medical University Cancer Hospital in china) and 12 public data sets were included in our study. In this study, single-sample gene set enrichment analysis (ssGSEA) was used to generate the DDR pathway activity profiles of 8 DDR sub-pathways and identify a DDR pathway signature by combining the DDR sub-pathway gene sets. The DDR pathway profiling's impacts on the clinical outcomes, biological functions, genetic variants, immune heterogeneity, and treatment responses were analyzed through multidimensional genomics and clinical data. The results demonstrate that the DDR pathway profiling was clearly distinguished between tumor and normal tissues. The DDR pathway profiling reveals patient-level variations, which may contribute to explaining the high heterogeneity of human GC for the biological features and treatment outcomes. Thus, tumors with low DDR signature scores were independently correlated with shorter overall survival time and significantly associated with mesenchymal, invasion, and metastasis phenotypes. The statistical model integrating this DDR pathway signature with other clinical predictors outperforms each predictor alone for predicting overall survival in discrimination, calibration, and net clinical benefit. Moreover, low DDR signature scores were tightly associated with genome stability, characterized by low tumor mutational burden (TMB) and low fractions of genome alteration. Furthermore, this study confirms that patients with low DDR pathway signature scores might not benefit from adjuvant chemotherapy and a monoclonal antibody directed against programmed cell death-1 ligand 1 (anti-PD1) therapy. These findings highlighted that the DDR pathway profiling confers important implications for patients with GC and provides insights into the specific clinical and molecular features underlying the DDR process, which may help to facilitate clinical management.

Comprehensive Characterization of Tumor Purity and Its Clinical Implications in Gastric Cancer.

Solid tumour tissues are composed of tumour and non-tumour cells, such as stromal cells and immune cells. These non-tumour cells constitute an essential part of the tumour microenvironment (TME), which decrease the tumour purity and play an important role in carcinogenesis, malignancy progression, treatment resistance and prognostic assessment. However, the implications of various purity levels in gastric cancer (GC) remain largely unknown. In the present study, we used an in-silico approach to infer the tumour purity of 2,259 GC samples obtained from our hospital and 12 public datasets based on the transcriptomic data. We systematically evaluated the association of tumour purity with clinical outcomes, biological features, TME characteristics and treatment response in GC. We found that tumour purity might be a patient-specific intrinsic characteristic of GC. Low tumour purity was independently correlated with shorter survival time and faster recurrence and significantly associated with mesenchymal, invasive and metastatic phenotypes. Integrating GC purity into a clinical prognostic nomogram significantly improved predictive validity and reliability. In addition, low tumour purity was strongly associated with immune and stromal cell functions. Fibroblasts, endothelial cells and monocytes were markedly enriched in low-purity tumours, serving as robust indicators of a poor prognosis. Moreover, patients with low GC purity may not benefit more from adjuvant chemotherapy. Our findings highlight that tumour purity confers important clinical, biological, microenvironmental and treatment implications for patients with GC. Therefore, a comprehensive evaluation of tumour purity in individual tumours can provide more insights into the molecular mechanisms of GC, facilitate precise classification and clinical prediction and help to develop more effective individualised treatment strategies.

Comprehensive Characterization of RNA Processing Factors in Gastric Cancer Identifies a Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses.

RNA processing converts primary transcript RNA into mature RNA. Altered RNA processing drives tumor initiation and maintenance, and may generate novel therapeutic opportunities. However, the role of RNA processing factors in gastric cancer (GC) has not been clearly elucidated. This study presents a comprehensive analysis exploring the clinical, molecular, immune, and drug response features underlying the RNA processing factors in GC. This study included 1079 GC cases from The Cancer Genome Atlas (TCGA, training set), our hospital cohort, and two other external validation sets (GSE15459, GSE62254). We developed an RNA processing-related prognostic signature using Cox regression with the least absolute shrinkage and selection operator (LASSO) penalty. The prognostic value of the signature was evaluated using a multiple-method approach. The genetic variants, pathway activation, immune heterogeneity, drug response, and splicing features associated with the risk signature were explored using bioinformatics methods. Among the tested 819 RNA processing genes, we identified five distinct RNA processing patterns with specific clinical outcomes and biological features. A 10-gene RNA processing-related prognostic signature, involving ZBTB7A, METTL2B, CACTIN, TRUB2, POLDIP3, TSEN54, SUGP1, RBMS1, TGFB1, and PWP2, was further identified. The signature was a powerful and robust prognosis factor in both the training and validation datasets. Notably, it could stratify the survival of patients with GC in specific tumor-node-metastasis (TNM) classification subgroups. We constructed a composite prognostic nomogram to facilitate clinical practice by integrating this signature with other clinical variables (TNM stage, age). Patients with low-risk scores were characterized with good clinical outcomes, proliferation, and metabolism hallmarks. Conversely, poor clinical outcome, invasion, and metastasis hallmarks were enriched in the high-risk group. The RNA processing signature was also involved in tumor microenvironment reprogramming and regulating alternative splicing, causing different drug response features between the two risk groups. The low-risk subgroup was characterized by high genomic instability, high alternative splicing and might benefit from the immunotherapy. Our findings highlight the prognostic value of RNA processing factors for patients with GC and provide insights into the specific clinical and molecular features underlying the RNA processing-related signature, which may be important for patient management and targeting treatment.

Development and validation of an individual alternative splicing prognostic signature in gastric cancer.

Gastric cancer (GC) is a heterogeneous disease with different clinical manifestations and prognoses. Alternative splicing (AS) is a determinant of gene expression and contributes to protein diversity from a rather limited gene transcript in metazoans. AS events are associated with different aspects of cancer biology, including cell proliferation, apoptosis, invasion, etc. Here, we present a comprehensive analysis of the prognostic AS profile in GC. GC-specific AS (GCAS) events were analyzed, and overall survival-associated GCAS (OS-GCAS) events were verified among the genome-wide AS events identified in The Cancer Genome Atlas (TCGA) database. In total, 1,287 GCAS events of 837 genes and 173 OS-GCAS events of 130 genes were identified. The parental genes of OS-GCAS events were significantly enriched in the development of GC. Protein-protein interaction (PPI) and OS-GCAS-associated splicing factor (SF) interaction networks were constructed. Multivariate Cox regression analysis with least absolute shrinkage and selection operator (LASSO) penalty was performed to establish a prognostic risk formula, representing 23 OS-GCAS events. The low-risk group had better OS than the high-risk group and lower immune and stromal scores. Cox proportional hazard regression was applied to generate an AS-clinical integrated prognostic model with a considerable area under the curve (AUC) value in both the training and validation datasets. Our study provides a profile of OS-GCAS events and an AS-clinical nomogram to predict the prognosis of GC.

The landscape of alternative splicing reveals novel events associated with tumorigenesis and the immune microenvironment in gastric cancer.

Alternative splicing (AS), contributing to vast protein diversity from a rather limited number of genes in eukaryotic transcripts, has emerged as an important signature for tumor initiation and progression. However, a systematic understanding of its functional impact and relevance to gastric cancer (GC) tumorigenesis is lacking. Differentially expressed AS (DEAS) was verified among GC-associated AS events based on RNA-seq profiles from the TCGA database. Functional enrichment analysis, unsupervised clustering analysis and prognostic models were used to infer the potential roles of DEAS events and their molecular, clinical and immune features. In total, 12,225 AS events were detected from 5,199 genes, among which 314 AS events were identified as DEAS events in GC. The parental genes of the DEAS events were significantly enriched in the regulation of GC-related processes. The splicing correlation network suggested a significant relationship between DEAS events and splicing factors (SFs). Three clusters of DEAS events were identified to be different in prognosis, cancer-specific signatures and immune features between distinct clusters. Univariate and multivariate analyses regarded 3 DEAS events as independent prognostic indicators. Profiling of the AS landscape in GC elucidated the functional roles of the splicing network in GC and might serve as a novel prognostic indicator and therapeutic target.

The Ratio of the Hemoglobin to Red Cell Distribution Width Combined with the Ratio of Platelets to Lymphocytes Can Predict the Survival of Patients with Gastric Cancer Liver Metastasis.

BACKGROUND: Hemoglobin/red cell distribution width (HR) and platelet/lymphocyte (PLR) ratios are considered effective prognostic markers in various cancers. We have proposed a new prognostic parameter: HR+PLR. The aim of this study is to explore the prognostic value of the HR+PLR scoring system in patients with gastric cancer liver metastasis. METHODS: This study retrospectively analyzed the clinical data of 306 patients with gastric cancer liver metastases admitted to our hospital from 2007 to 2014. According to the size of HR value and PLR value, we will divide the patients into three groups, namely, HR+PLR: (1) 0 points: HR > 1.02 and PLR < 128; (2) 1 point: HR > 1.02 and PLR > 128 and HR < 1.02 and PLR < 128; and (3) 2 points: HR < 1.02 and PLR > 128. RESULTS: The HR+PLR score was statistically different from age (P = 0.049), T stage (P < 0.001), N stage (P = 0.017), number of liver metastases (P = 0.018), gastrectomy (P < 0.001), hepatectomy (P = 0.001), peritoneal metastasis (P = 0.012), prognostic nutritional index (PNI) (P = 0.028), and neutrophil/lymphocyte ratio (NLR) (P = 0.045). The HR+PLR scoring system has a higher area under the ROC curve (AUC value) than PNI, PLR, HR, and PLR (AUC = 0.798, P < 0.001). In multivariate analysis, gastrectomy (P = 0.001), hepatectomy (P < 0.001), chemotherapy (P = 0.014), and HR+PLR score (P < 0.001) were considered independent prognostic factors. CONCLUSION: For patients with gastric cancer liver metastasis, the HR+PLR score is a simple, reliable, and economic prognostic marker.

Impact of CD144 gene expression on outcomes in stage III gastric cancer patients.

CD144 has been shown to promote tumour angiogenesis, invasion and metastasis in malignant tumours. The purpose of the present study was to investigate the clinical prognostic significance of CD144 in advanced gastric cancer (GC) to complement the American Joint Committee on Cancer (AJCC) 8th Edition convention. We established that CD144 was highly related to angiogenesis using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) public databases. We randomly selected 173 stage III GC patients who received curative gastrectomy. The expression level of CD144 was assessed by immunohistochemistry and Image-Pro Plus software. After survival analysis, nomograms were created to predict the risk of stage III gastric cancer patients' 5-years survival. In this study, the median value of the CD144 positive area/total area under the microscope was 5.6%, and this was defined as the cut-off value. The expression of CD144 assisted further subgrouping of stage Ⅲa, Ⅲb, and Ⅲc GC patients. To evaluate the disease-free survival (DFS) and overall survival (OS) of patients, univariate and multivariate analysis was performed, which showed that the expression of CD144 was an independent predictor for DFS, and Borrmann type and expression of CD144 were independent predictors for OS (p<0.05). Nomograms were used to evaluate the risk of stage III GC by combining Borrmann type and the expression level of CD144. In advanced GC patients, the expression level of CD144 is a useful prognostic indicator in evaluating the risk of disease prognosis.

Changing trends of clinicopathologic features and survival duration after surgery for gastric cancer in Northeast China.

BACKGROUND: Through analyzing the data from a single institution in Northeast China, this study revealed the possible clinicopathologic characteristics that influence the prognosis of patients with gastric cancer (GC). AIM: To evaluate the changing trends of clinicopathologic features and survival duration after surgery in patients with GC in Northeast China, which is a high-prevalence area of GC. METHODS: The study analyzed the difference in clinicopathologic features and survival duration after surgery of 5887 patients who were histologically diagnosed with GC at the Harbin Medical University Cancer Hospital. The study mainly analyzed the data in three periods, 2000 to 2004 (Phase 1), 2005 to 2009 (Phase 2), and 2010 to 2014 (Phase 3). RESULTS: Over time, the postoperative survival rate significantly increased from 2000 to 2014. In the past 15 years, compared with Phases 1 and 2, the tumor size was smaller in Phase 3 (P < 0.001), but the proportion of high-medium differentiated tumors increased (P < 0.001). The proportion of early GC gradually increased from 3.9% to 14.4% (P < 0.001). A surprising improvement was observed in the mean number of retrieved lymph nodes, ranging from 11.4 to 27.5 (P < 0.001). The overall 5-year survival rate increased from 24% in Phase 1 to 43.8% in Phase 3. Through multivariate analysis, it was found that age, tumor size, histologic type, tumor-node-metastasis stage, depth of invasion, lymph node metastasis, surgical approach, local infiltration, radical extent, number of retrieved lymph nodes, and age group were independent risk factors that influenced the prognosis of patients with GC. CONCLUSION: The clinical features of GC in Northeast China changed during the observation period. The increasing detection of early GC and more standardized surgical treatment effectively prolonged lifetimes.

Prognostic significance of Borrmann type combined with vessel invasion status in advanced gastric cancer.

BACKGROUND: Borrmann classification (types I-IV) for the detection of advanced gastric cancer has been accepted worldwide, and lymphatic and/or blood vessel invasion (LBVI) status is related to the poor prognosis after gastric cancer. AIM: To evaluate the significance of Borrmann type combined with LBVI status in predicting the prognosis of advanced gastric cancer. METHODS: We retrospectively studied the clinicopathological characteristics and long-term survival data of 2604 patients who were diagnosed with advanced gastric adenocarcinoma at Harbin Medical University Cancer Hospital from January 2009 to December 2013. Categorical variables were evaluated by the Pearson's χ 2 test, the Kaplan-Meier method was used to identify differences in cumulative survival rates, and the Cox proportional hazards model was used for multivariate prognostic analysis. RESULTS: A total of 2604 patients were included in this study. The presence of LVBI [LBVI (+)] and Borrmann type (P = 0.001), tumor location (P < 0.001), tumor size (P < 0.001), histological type (P < 0.001), tumor invasion depth (P < 0.001), number of metastatic lymph nodes (P < 0.001), and surgical method (P < 0.001) were significantly correlated with survival. When analyzing the combination of the Borrmann classification and LBVI status, we found that patients with Borrmann type III disease and LBVI (+) had a similar 5-year survival rate to those with Borrmann IV + LBVI (-) (16.4% vs 13.1%, P = 0.065) and those with Borrmann IV + LBVI (+) (16.4% vs 11.2%, P = 0.112). Subgroup analysis showed that the above results were true for any pT stage and any tumor location. Multivariate Cox regression analysis showed that Borrmann classification (P = 0.023), vascular infiltration (P < 0.001), tumor size (P = 0.012), pT stage (P < 0.001), pN stage (P < 0.001), and extent of radical surgery (P < 0.001) were independent prognostic factors for survival. CONCLUSION: Since patients with Borrmann III disease and LBVI (+) have the same poor prognosis as those with Borrmann IV disease, more attention should be paid to patients with Borrmann III disease and LBVI (+) during diagnosis and treatment, regardless of the pT stage and tumor location, to obtain better survival results.

Parathyroid hormone analogues for fracture healing: protocol for a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Fracture healing is a complex physiological process. Impaired healing will increase the need for care and cause serious complications. Thus, identifying strategies to accelerate the rate of healing, preventing delayed unions and non-unions, is essential. Parathyroid hormone (PTH) is a key systemic regulator of calcium and phosphate metabolism. It has been determined that intermittent administration of PTH and its analogue can exert anabolic effect on bone, increase bone mass and reduce bone loss, leading to an increase in bone formation. Owing to their anabolic effect, there is an increasing interest in its potential in promoting the process of fracture healing. However, in clinical studies, the results are in conflict. This objective of this study is to determine the role of PTH analogues for fracture healing in adults. METHODS AND ANALYSIS: MEDLINE, EMBASE and Cochrane databases will be searched to identify all randomised controlled trials (RCTs) and quasi-RCTs that compare the different effects between PTH analogues and any other treatments in adults with any type of fracture. The primary outcome is the functional recovery. And the secondary outcomes are fracture union and adverse events. The meta-analysis will be performed using a random effects model. Heterogeneity will be assessed by the P values and I² statistic. And subgroup analyses and sensitivity analyses will be used to explore the heterogeneity. Risk of bias will be assessed using the Cochrane tool and the quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Ethical approval is not required because this proposed systematic review and meta-analysis is based on published data, without including confidential personal data or data on interventions on patients. The findings of this study will be published in a peer-reviewed journaland presented at a relevant conference. PROSPERO REGISTRATION NUMBER: CRD42017062093.

Effect of low-intensity pulsed ultrasound on distraction osteogenesis: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fractures and non-unions, but its efficacy for bone distraction osteogenesis remains uncertain. This study aims to determine whether LIPUS can effectively and safely reduce the associated treatment time for patients undergoing distraction osteogenesis. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched until May 1, 2018, without language restriction. Studies should be randomized controlled trials (RCTs) or quasi-RCTs of LIPUS compared with sham devices or no devices in patients who undergo distraction osteogenesis. The primary outcome was the treatment time. The secondary outcome was the risk of complications. Treatment effects were assessed using mean differences, standardized mean differences, or risk ratios using a random-effects model. The Cochrane risk-of-bias tool was used to assess the risk of bias. The I2 statistic was used to assess the heterogeneity. The GRADE system was used to evaluate the evidence quality. RESULTS: A total of 7 trials with 172 patients were included. The pooled results suggested that during the process of distraction osteogenesis, LIPUS therapy did not show a statistically significant reduction in the treatment time (mean difference, - 8.75 days/cm; 95% CI, - 20.68 to 3.18 days/cm; P = 0.15; I2 = 72%) or in the risk of complications (risk ratio, 0.90 in favor of LIPUS; 95% CI, 0.65 to 1.24; I2 = 0%). Also, LIPUS therapy did not show a significant effect on the radiological gap fill area (standardized mean difference, 0.48 in favor of control; 95%CI, - 1.49 to 0.52; I2 = 0%), the histological gap fill length (standardized mean difference, 0.76 in favor of control; 95%CI, - 1.78 to 0.27; I2 = 0%), or the bone density increase (standardized mean difference, 0.43 in favor of LIPUS; 95%CI, - 0.02 to 0.88; I2 = 0%). CONCLUSIONS: Among patients undergoing distraction osteogenesis, neither the treatment time nor the risk of complications could be reduced by LIPUS therapy. The currently available evidence is insufficient to support the routine use of this intervention in clinical practice. TRIAL REGISTRATION: CRD 42017073596.