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Abstract Background This study was conducted to investigate the long-term outcomes of laparoscopic total gastrectomy (LTG) versus open total gastrectomy (OTG) in patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NACT). Methods Patients with AGC who received NACT before surgery were enrolled in either the LTG or OTG group. Propensity score matching (PSM) (1:2) was performed between the two groups based on the propensity score using a 0.15 calliper width. Three-year overall survival (OS) and disease-free survival (DFS) were compared between these two groups before and after PSM. OS and DFS rates were calculated by the Kaplan‒Meier method, and any differences in survival were evaluated with a log-rank test. Univariate and multivariate Cox proportional hazards analyses were used to estimate the simultaneous effects of prognostic factors on survival and the hazard ratio (HR) between LTG and OTG patients. Results A total of 144 patients completed the follow-up, with 24 patients in the LTG group and 120 patients in the OTG group. After a mean follow-up of 64.40 months, there were no significant differences in the 3-year OS or DFS rates between the two groups before (P = 0.453 and P = 0.362, respectively) or after PSM (P = 0.972 and P = 0.884, respectively). Multivariate Cox proportional hazards analysis indicated that ypN stage was an independent risk factor for worse OS (P = 0.013). Conclusions This study showed that LTG with D2 lymphadenectomy performed by an experienced surgical team resulted in comparable 3-year OS and DFS compared with OTG in patients with AGC after NACT. Trial registration This study is not registered.

Abstract Background Ubiquitin-specific protease 15 (USP15) exhibits amplifications in various tumors, including gastric cancer (GC), yet its biological function and mechanisms in GC progression remain elusive. Methods Here, we established stable USP15 knockdown or overexpression GC cell lines and explored the potential mechanism of USP15 in GC. Besides, we also identified interacting targets of USP15. Results USP15 knockdown significantly impeded cell proliferation, invasion, epithelial-mesenchymal transition, and distal colonization in xenograft models, while enhancing oxaliplatin's antitumor effect. USP15 was involved in ubiquitination modification of glycolytic regulators. Silencing of USP15 suppressed glycolytic activity and impaired mitochondrial functions. Interference with USP15 expression reversed tumor progression and distal colonization in vivo. HKDC1 and IGF2BP3 were found as core interacting targets of USP15, and HKDC1 was identified as a substrate for ubiquitination modification by USP15, whereby USP15 regulated glucose metabolism activity by inhibiting the ubiquitination degradation of HKDC1. Conclusions Our study unveiled aberrantly high expression of USP15 in GC tissues, correlating with malignant progression and nonresponse to neoadjuvant therapy. USP15 inhibitors, if developed, could be effective in promoting chemotherapy through glucose metabolism remodeling.

The role of the intratumoral microbiome in gastric cancer (GC) has not been comprehensively assessed. Here, we explored the relationship between the microbial community and GC prognosis and therapy efficacy. Several cancer-associated microbial characteristics were identified, including increased α-diversity, differential β-diversity, and decreased Helicobacter pylori abundance. After adjusting for clinical features, prognostic analysis revealed 2 phyla, 14 genera, and 5 species associated with the overall survival of patients with GC. Additionally, 2 phyla, 14 genera, and 6 species were associated with adjuvant chemotherapy (ACT) efficacy in patients with stage II – III GC. Furthermore, we classified GC microbiome structures into three microbial subtypes (MS1, MS2 and MS3) with distinguishing features. The MS1 subtype exhibited high immune activity and enrichment of microbiota related to immunotherapy and butyric acid-producing, as well as potential benefits in immunotherapy. MS2 featured the highest α-diversity and activation of the TFF pathway, MS3 was characterized by epithelial-mesenchymal transition and was associated with poor prognosis and reduced ACT efficacy. Collectively, the results of this study provide valuable insights into the microbial characteristics associated with GC prognosis and therapy efficacy.

Abstract. Background:. Gastric cancer is one of the most common malignant tumors in the digestive system in China. Few comprehensive practice guidelines for early gastric cancer in China are currently available. Therefore, we created the Chinese national clinical practice guideline for the prevention, diagnosis, and treatment of early gastric cancer. Methods:. This clinical practice guideline (CPG) was developed in accordance with the World Health Organization’s recommended process and with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) in assessing evidence quality. We used the Evidence to Decision framework to formulate clinical recommendations to minimize bias and increase transparency in the CPG development process. We used the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement and the Appraisal of Guidelines for Research and Evaluation II (AGREE II) as reporting and conduct guidelines to ensure completeness and transparency of the CPG. Results:. This CPG contains 40 recommendations regarding the prevention, screening, diagnosis, treatment, and follow-up of early gastric cancer based on available clinical studies and guidelines. We provide recommendations for the timing of Helicobacter pylori eradication, screening populations for early gastric cancer, indications for endoscopic resection and surgical gastrectomy, follow-up interval after treatment, and other recommendations. Conclusions:. This CPG can lead to optimum care for patients and populations by providing up-to-date medical information. We intend this CPG for widespread adoption to increase the standard of prevention, screening, diagnosis, treatment, and follow-up of early gastric cancer; thereby, contributing to improving national health care and patient quality of life.

Abstract Evidence from Europe shows that perioperative chemotherapy may be beneficial for the treatment of locally advanced gastric cancer, but reliable and robust data is lacking. To rectify this, the phase 3 RESONANCE trial investigated the efficacy and safety of S-1 plus oxaliplatin (SOX) as a perioperative chemotherapy regimen for gastric cancer. This randomized, open-label trial enrolled patients from 19 medical centers with stage II/III resectable gastric cancer who were centrally randomly assigned to either perioperative chemotherapy (PC) arm or adjuvant chemotherapy (AC) arm. Patients in the PC arm received two to four cycles of SOX followed by surgery and four to six cycles of SOX. Patients in the AC arm received upfront surgery and eight cycles of SOX. 386 patients in each group were enrolled and 756 (382 in PC and 374 in AC) were included in the mITT population. The three-year DFS rate was 61.7% in the PC arm and 53.8% in the AC arm (log-rank p = 0.019). The R0 resection rate in the PC arm was significantly higher than that in the AC arm (94.9% vs. 83.7%, p

Abstract Background Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance‐associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. Methods Our study utilized whole‐exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2‐24C > T (rs717620) point mutation and conducting dual‐luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss‐of‐function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. Results ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss‐of‐function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2‐high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2‐mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient‐derived organoids and patient‐derived tumor‐like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. Conclusions Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. Highlights ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.

Clinical guidelines for gastric cancer treatment recommend intraoperative peritoneal lavage cytology to detect free cancer cells. Patients with positive cytology require neoadjuvant chemotherapy instead of instant resection, and conversion to negative cytology results in improved survival. However, pathologists’ or artificial intelligence's accuracy of cytological diagnosis is disturbed by manually produced, unstandardized slides. In addition, the elaborate infrastructure makes cytology accessible to a limited number of medical institutes. This work develops CellGAN, a deep learning method that enables label‐free virtual peritoneal lavage cytology by producing virtual hematoxylin–eosin‐stained images with single‐color stimulated Raman scattering microscopy. A structural similarity loss is introduced to overcome the challenge of unsupervised virtual pathology techniques that cannot accurately present cellular structures. This method achieves a structural similarity of 0.820 ± 0.041 and a nucleus area consistency of 0.698 ± 0.102, indicating the staining fidelity outperforms the state‐of‐the‐art method. Diagnosis using virtually stained cells reaches 93.8% accuracy and substantial consistency with conventional staining. Single‐cell detection and classification on virtual slides achieve a mean average precision of 0.924 and an area under the receiver operating characteristic curve of 0.906, respectively. Collectively, this method achieves standardized and accurate virtual peritoneal lavage cytology and holds great potential for clinical translation.

Death receptor 5 (DR5) can inhibit malignant proliferation via tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in many cancers. Here we examined the expression and sublocalization of DR5 in gastric cancer, as well as its effects on clinical prognosis and cellular processes. Our analysis included a cohort of 240 gastric cancer patients. Bioinformatic analysis showed a significant correlation between DR5 and DNA replication, tumor mutation burden (TMB), and tumor stemness. Unlike death receptor 4 (DR4TRAIL‐R1), DR5 was expressed in the cytoplasm and nucleus, and was found to be positively correlated with lymphovascular invasion, lymph node metastasis, and TNM stage. Patients with positive DR5 had worse overall survival (OS) (P = 0.006). The multivariate Cox model showed that DR5 is an independent poor prognostic factor (hazard ratio = 1.693). Furthermore, knockdown of DR5 inhibited aggressive behaviors, including proliferation and metastasis in gastric cancer cells, and inhibited lung metastasis in vivo. In summary, nuclear localization of DR5 expression is a poor prognosis factor in gastric cancer and promotes growth, invasion, and metastasis of tumor cells in vitro and in vivo.

Abstract Background A major obstacle to the development of personalized therapies for gastric cancer (GC) is the prevalent heterogeneity at the intra-tumor, intra-patient, and inter-patient levels. Although the pathological stage and histological subtype diagnosis can approximately predict prognosis, GC heterogeneity is rarely considered. The extracellular matrix (ECM), a major component of the tumor microenvironment (TME), extensively interacts with tumor and immune cells, providing a possible proxy to investigate GC heterogeneity. However, ECM consists of numerous protein components, and there are no suitable models to screen ECM-related genes contributing to tumor growth and prognosis. We constructed patient-derived tumor xenograft (PDTX) models to obtain robust ECM-related transcriptomic signatures to improve GC prognosis prediction and therapy design. Methods One hundred twenty two primary GC tumor tissues were collected to construct PDTX models. The tumorigenesis rate and its relationship with GC prognosis were investigated. Transcriptome profiling was performed for PDTX-originating tumors, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to extract prognostic ECM signatures and establish PDTX tumorigenicity-related gene (PTG) scores. The predictive ability of the PTG score was validated using two independent cohorts. Finally, we combined PTG score, age, and pathological stage information to establish a robust nomogram for GC prognosis prediction. Results We found that PDTX tumorigenicity indicated a poor prognosis in patients with GC, even at the same pathological stage. Transcriptome profiling of PDTX-originating GC tissues and corresponding normal controls identified 383 differentially expressed genes, with enrichment of ECM-related genes. A robust prognosis prediction model using the PTG score showed robust performance in two validation cohorts. A high PTG score was associated with elevated M2 polarized macrophage and cancer-associated fibroblast infiltration. Finally, combining the PTG score with age and TNM stage resulted in a more effective prognostic model than age or TNM stage alone. Conclusions We found that ECM-related signatures may contribute to PDTX tumorigenesis and indicate a poor prognosis in GC. A feasible survival prediction model was built based on the PTG score, which was associated with immune cell infiltration. Together with patient ages and pathological TNM stages, PTG score could be a new approach for GC prognosis prediction.

Abstract Background We aimed to assess the performance of the risk assessment questionnaire and fecal immunochemical test (FIT) in a population-based colorectal cancer (CRC) screening program to provide timely evidence for tailored screening strategies in China. Methods This analysis was conducted using data from Beijing Cancer Screening Prospective Cohort Study (BCSPCS). A risk assessment questionnaire and FIT were selected as the primary screening methods, and participants with any positive results were referred to undergo a diagnostic colonoscopy. Results From 2015 to 2020, 148,636 Beijing residents aged 40–69 years were invited from designated communities, with 147,807 finishing the risk assessment questionnaire and 115,606 (78.2%) completing the FIT. Among the 42,969 (29.1%) high-risk CRC participants, 23,824 (55.4%) underwent colonoscopy. One year after enrollment, all subjects were linked to the Beijing Cancer Registry (BCR) database and 241 cases of CRC were confirmed. The CRC incidence rate was 58.2/100,000 for the low-risk arm and 418.9/100,000 for the high-risk arm. For participants who underwent colonoscopy, 91 CRC cases were detected, with a detection rate of 91.9% and 63.7% of them were early-stage cases. Furthermore, the sensitivities of utilizing the risk assessment questionnaire alone, FIT alone, combined risk assessment questionnaire and FIT were 75.7%, 50.1%, and 95.1%, and the specificities were 75.3%, 87.3%, and 70.7%, respectively. Conclusion The Beijing CRC screening program can effectively detect early-onset CRC; however, the compliance with colonoscopy still needs to be improved.

Abstract Background The prognosis of gastric cancer (GC) patients with positive peritoneal cytology (CY1) without other distant metastasis is poor, and there are no standard treatment strategies. Our study aimed to compare the survival outcomes of CY1 GC patients receiving chemotherapy or surgery as initial treatment. Methods From February 2017 to January 2020, clinical and pathological data of patients diagnosed with CY1 GC without other distant metastasis in the Peking University Cancer Hospital was reviewed. Patients were divided into two groups: chemotherapy-initial group and surgery-initial group. In chemotherapy-initial group, patients received preoperative chemotherapy initially. According to the treatment response, the patients were divided into three subgroups: conversion gastrectomy group, palliative gastrectomy group, and further systematic chemotherapy group. In surgery-initial group, patients underwent gastrectomy followed by postoperative chemotherapy. Results A total of 96 CY1 GC patients were included with 48 patients in each group. In chemotherapy-initial group, preoperative chemotherapy yielded an objective response rate of 20.8% and disease control rate of 87.5%. Conversion to CY0 after preoperative chemotherapy was obtained in 24 (50%) patients. The median overall survival was 36.1 months in chemotherapy-initial group and 29.7 months in surgery-initial group (p = 0.367). The median progression-free survival was 18.1 months in chemotherapy-initial group and 16.1 months in surgery-initial group (p = 0.861). The 3-year overall survival rates were 50.0% and 47.9%, respectively. In chemotherapy-initial group, twenty-four patients who converted to CY0 by preoperative chemotherapy and received surgery obtained a significantly better prognosis. The median overall survival was still not reached in these patients. Conclusion There was no significant difference in survival outcomes between chemotherapy-initial group and surgery-initial group. CY1 GC patients who converted to CY0 by preoperative chemotherapy and received radical surgery could obtain a favorable long-term prognosis. Further investigation should focus on preoperative chemotherapy to eliminate peritoneal cancer cell. Trial registration This study is retrospectively registered.

Abstract Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.

BackgroundThis study aimed to compare the clinical outcomes and patient benefits of uncut Roux-en-Y (URY) anastomosis and Billroth-II with Braun (BB) anastomosis after distal gastrectomy.MethodsWe retrospectively reviewed the data of patients who underwent URY or BB anastomosis after distal gastrectomy between March 2015 and December 2017. Clinical characteristics, survival data, postoperative recovery data, and long-term outcomes were recorded and compared between the two groups.ResultsA total of 231 patients were included, with 167 in the URY group and 64 in the BB group. Kaplan–Meier curves for overall survival showed no differences after propensity score matching (p = 0.488). Long-term postoperative quality of life evaluation also showed no significant differences. Compared to the BB group, patients in the URY group had a significantly shorter time to start a liquid diet after propensity score matching (67.6 h vs. 46.5 h, p = 0.003), and a lower occurrence of bile reflux on follow-up gastroscopy (p

Abstract Immune checkpoint blockade (ICB) offers a new opportunity for treatment for gastric cancer (G.C.). Understanding the upstream regulation of immune checkpoints is crucial to further improve the efficacy of ICB therapy. Herein, using the CRISPR-Cas9-based genome-wide screening, we identified TRIM28 as one of the most significant regulators of PD-L1, a checkpoint protein, in G.C. cells. Mechanistically, TRIM28 directly binds to and stabilizes PD-L1 by inhibiting PD-L1 ubiquitination and promoting PD-L1 SUMOylation. Furthermore, TRIM28 facilitates K63 polyubiquitination of TBK1, activating TBK1-IRF1 and TBK1-mTOR pathways, resulting in enhanced PD-L1 transcription. It was found that TRIM28 was positively correlated with PD-L1 in G.C. cells. Moreover, high TRIM28 expression suggests poor survival in a cohort of 466 patients with G.C., and this observation is consistent while analyzing data from publicly available databases. Ectopic TRIM28 expression facilitated tumor growth, increased PD-L1 expression, and suppressed T cell activation in mice. Administration of the PD-L1 or TBK1 inhibitor significantly alleviated the TRIM28-induced tumor progression. Furthermore, combining the TBK1 inhibitor with CTLA4 immune checkpoint blockade has synergistic effects on G.C., and provides a novel strategy for G.C. therapy.

Abstract Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated “tumor-normal interface” region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.

Abstract Background Laparoscopic gastrectomy (LG) for gastric cancer has rapidly developed and become more popular in recent decades. Additional high-quality randomized controlled trial (RCT) studies comparing LG versus open gastrectomy (OG) for gastric cancer (GC) have been published in recent years. An updated systematic review is warranted. The aim of our meta-analysis was to comprehensively evaluate the short- and long-term outcomes of LG versus OG for GC. Materials and methods The PubMed, Embase, Web of Science, and Cochrane Center Register of Controlled Trials databases were comprehensively searched to identify RCTs comparing LG versus OG for GC published between January 1994 and December 7, 2021. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines. All RCTs comparing the short- and long-term outcomes of LG with those of OG were included. A random effects model was adopted with significant heterogeneity (I 2 > 50%), while a fixed effects model was employed in all other cases (I 2 ≤ 50%). Results A total of 26 RCTs with 8301 patients were included in this meta-analysis. The results indicated that the intraoperative complication rate was comparable between the LG group and the OG group (OR=1.14, 95% CI [0.76, 1.70], I 2=0%, p=0.53). The LG group had fewer postoperative complications than the OG group (OR=0.65, 95% CI [0.57, 0.74], I 2=26%, p

Abstract Background The safety and short-term outcomes of gastrectomy after preoperative chemotherapy plus immunotherapy (PCIT) versus preoperative chemotherapy (PCT) in patients with advanced gastric cancer (AGC) remain unclear. This study was conducted to compare the safety and short-term efficacy of PCIT with those of PCT in patients with AGC. Methods We retrospectively reviewed the data of patients with AGC who received PCIT or PCT at Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center I between January 2019 and June 2021. The clinical characteristics were recorded, and short-term oncological outcomes were compared. Independent t tests, Mann‒Whitney U tests, chi-square tests, and Fisher’s exact tests were used to calculate differences. The correlation analyses were performed using Pearson correlation. All p values were two-sided, and a p value

Abstract Background Gastric cancer (GC) is among the most malignant tumors, yet the pathogenesis is not fully understood, especially the lack of detailed information about the mechanisms underlying long non‐coding RNA (lncRNA)‐mediated post‐translational modifications. Here, the molecular mechanisms and clinical significance of the novel lncRNA syndecan‐binding protein 2‐antisense RNA 1 (SDCBP2‐AS1) in the tumorigenesis and progression of GC were investigated. Methods The expression levels of SDCBP2‐AS1 in 132 pairs of GC and adjacent normal tissues were compared, and the biological functions were assessed in vitro and in vivo. RNA pull‐down and immunoprecipitation assays were conducted to clarify the interactions of SDCBP2‐AS1 and heterogeneous nuclear ribonucleoprotein (hnRNP) K. RNA‐sequencing, immunoprecipitation, immunofluorescence, and luciferase analyses were performed to investigate the functions of SDCBP2‐AS1. Results SDCBP2‐AS1 was significantly downregulated in GC tissues and predictive of poor patient prognosis. Silencing of SDCBP2‐AS1 promoted the proliferation and migration of GC cells both in vitro and in vivo. Mechanically, SDCBP2‐AS1 physically bound to hnRNP K to repress SUMOylation of hnRNP K and facilitated ubiquitination of hnRNP K and β‐catenin, thereby promoting the degradation of β‐catenin in the cytoplasm. Silencing of SDCBP2‐AS1 caused SUMOylation of hnRNP K and stabilized β‐catenin activity, which altered transcription of downstream genes, resulting in tumorigenesis and metastasis of GC. Moreover, the knockdown of hnRNP K partially abrogated the effects of SDCBP2‐AS1. Conclusions SDCBP2‐AS1 interacts with hnRNP K to suppress tumorigenesis and metastasis of GC and regulates post‐transcriptional modifications of hnRNP K to destabilize β‐catenin. These findings suggest SDCBP2‐AS1 as a potential target for the treatment of GC.

Abstract We elucidated the functional significance and molecular mechanisms of DUSP5P1 lncRNA (dual specificity phosphatase 5 pseudogene 1) in gastric carcinogenesis. We demonstrated that gastric cancer (GC) patients with high DUSP5P1 expression had shortened survival in two independent cohorts. DUSP5P1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Mechanistically, DUSP5P1 activated ARHGAP5 transcription by directly binding to the promoter of ARHGAP5 with a binding motif of TATGTG. RNA-seq revealed that ARHGAP5 activated focal adhesion and MAPK signaling pathways to promote GC metastasis. DUSP5P1 also dysregulated platinum drug resistance pathway. Consistently, DUSP5P1 overexpression in GC cells antagonized cytotoxic effect of Oxaliplatin, and shDUSP5P1 plus Oxaliplatin exerted synergistic effect on inhibiting GC metastasis in vitro and in vivo. DUSP5P1 depletion also suppressed the growth of platinum drug-resistant PDO models. In conclusion, DUSP5P1 promoted GC metastasis by directly modulating ARHGAP5 expression to activate focal adhesion and MAPK pathways, serves as therapeutic target for platinum drug resistant GC, and is an independent prognostic factor in GC.

Abstract Peritoneal metastasis (PM) is the mostcommon form of distant metastasis and one of the leading causes of death in gastriccancer (GC). For locally advanced GC, clinical guidelines recommend peritoneal lavage cytology for intraoperative PM detection. Unfortunately, current peritoneal lavage cytology is limited by low sensitivity (

Background Systemic Immune-inflammation Index (SII) and body composition parameters are easily assessed, and can predict overall survival (OS) in various cancers, allowing early intervention. This study aimed to assess the correlation between CT-derived body composition parameters and SII and OS in patients with advanced gastric cancer receiving dual programmed death-1 (PD-1) and human epidermal growth factor receptor 2 (HER2) blockade.Materials and methods This retrospective study enrolled patients with advanced gastric cancer treated with dual PD-1 and HER2 blockade from March 2019 to June 2022. We developed a deep learning model based on nnU-Net to automatically segment skeletal muscle, subcutaneous fat and visceral fat at the third lumbar level, and calculated the corresponding Skeletal Muscle Index, skeletal muscle density, subcutaneous fat area (SFA) and visceral fat area. SII was computed using the formula that total peripheral platelet count×neutrophil/lymphocyte ratio. Univariate and multivariate Cox regression analysis were used to determine the associations between SII, body composition parameters and OS.Results The automatic segmentation deep learning model was developed to efficiently segment body composition in 158 patients (0.23 s/image). Multivariate Cox analysis revealed that high SII (HR=2.49 (95% CI 1.54 to 4.01), p

Abstract Aim Much attention has been paid to conversion therapy for stage IV gastric cancer, however, its operative comorbidities and survival benefit have not yet been clarified. CONVO‐GC‐1, an international retrospective cohort study, was designed to investigate the role of conversion surgery in Japan, Korea, and China. Methods The rate of operative complications was the primary endpoint and the overall survival (OS), according to the four‐category criteria previously published (Gastric Cancer:19; 2016), was analyzed as the secondary endpoint. Results A total of 1206 patients underwent surgery after chemotherapy with curative intent. Operative complications were observed in 290 (24.0%) patients in all grades, including pancreatic fistula and surgical site infection. The median survival time (MST) of all resected patients was 36.7 mo (M) and those of R0, R1, and R2 resection were 56.6 M, 25.8 M, and 21.7 M, respectively. Moreover, the MST of R0 patients were 47.8 M, 116.7 M, 44.8 M in categories 1, 2, and 3, respectively, and not reached in category 4. Interestingly, the MST of P1 patients was as favorable as that of P0CY1 patients if R0 resection was achieved. The MST of patients with liver metastasis was also favorable regardless of the number of lesions, and the MST of patients with para‐aortic lymph node (LN) No 16a1/b2 metastasis was not inferior to that of patients with para‐aortic LN No 16a2/b1 metastasis. Conclusion Conversion therapy for stage IV gastric cancer is safe and could be a new therapeutic strategy to improve the survival of patients, especially those with R0 resection.

Abstract Rapid proliferation and metastasis of gastric cancer (GC) resulted in a poor prognosis in the clinic. Previous studies elucidated that long non-coding RNA (LncRNA) LINC00205 was upregulated in various tumors and participated in tumor progression. The aim of our study was to investigate the regulating role of LINC00205 in tumorigenesis and metastasis of GC. Both public datasets and our data showed that the LINC00205 was highly expressed in GC tissues and several cell lines. Notably, GC patients with high level of LINC00205 had a poor prognosis in our cohort. Mechanistically, knockdown of LINC00205 by shRNAs suppressed GC cells proliferation, migration, invasion remarkably, and induced cell cycle arrest. Based on bioinformatics prediction, we found that LINC00205 might act as a competitive endogenous RNA (ceRNA) through targeting miR-26a. The level of miR-26a had negatively correlated with LINC00205 expression and was decreased among GC cell lines, tissues, and serum samples. Our results for the first time confirmed that miR-26a was a direct target of LINC00205 and might have the potential to become a plasma marker for clinical tumor diagnosis. Indeed, LINC00205 knockdown resulted in the dramatic promotion of miR-26a expression as well as inhibition of miR-26a potential downstream targets, such as HMGA2, EZH2, and USP15. These targets were essential for cell survival and epithelial-mesenchymal transition. Importantly, LINC00205 was able to remodel the miR-26a-mediated downstream silence, which identified a new mechanism of malignant transformation of GC cells. In conclusion, this study revealed the regulating role of the LINC00205/miR-26a axis in GC progression and provided a new potential therapeutic strategy for GC treatment.

Summary: Recent evidence demonstrates that the reprogramming of energy metabolism can interact with the tumor immune microenvironment, thereby participating in the progression of cancer. In this study, multi-omics data of 2471 gastric cancer samples were used to identify tumor glycometabolism and its correlation with tumor immune microenvironment. A series of bioinformatic approaches were performed to establish a scoring system to predict the survival and response of chemotherapy and immunotherapy. Three glycometabolic subtypes and two immune clustering subgroups of gastric cancer were determined. We further established a Gluco-Immune Scoring system to quantify the cancer glycometabolic status and immune infiltration of individual patients. Patients with low Gluco-Immune Score were sensitive to adjuvant chemotherapy, while patients with high Gluco-Immune Score may benefit from immunotherapy. Our results indicate that in gastric cancer, the assessment of tumor glucose metabolism and immune microenvironment has application value for the prediction of curative effects and the formulation of combined treatment strategies.

N6-methyladenosine (m6A), the most prevalent RNA internal modification, is present in most eukaryotic species and prokaryotes. Studies have highlighted an intricate network architecture by which m6A epitranscriptome impacts on immune response and function. However, it was only until recently that the mechanisms underlying the involvement of m6A modification in immune system were uncovered. Here, we systematically review the m6A involvement in the regulation of innate and adaptive immune cells. Further, the interplay between m6A modification and anti-inflammatory, anti-viral and anti-tumour immunity is also comprehensively summarized. Finally, we focus on the future prospects of m6A modification in immune modulation. A better understanding of the crosstalk between m6A modification and immune system is of great significance to reveal new pathogenic pathways and to develop promising therapeutic targets of diseases.

Abstract Background The prognostic values of preoperative tumor markers (TMs) remain elusive in patients with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy treatment (NACT). This study aimed to assess and establish a novel scoring system incorporating carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4) to enhance prognostic accuracy for progression-free survival (PFS) and pathological response (pCR). Methods Patients' data were retrospectively analyzed from December 2006 to December 2017 in our center. The cutoff value of TMs was determined using the time-dependent receiver operating test characteristics method. These three TMs were allocated 1 point each for the post neoadjuvant chemotherapy combination of tumor markers (post-NACT CTM) scores. The training group comprised 533 patients, responsible for full analysis, and the validation group comprised 137 patients based on the selection protocol. Results Of 533 enrolled patients, 138, 233, 117, and 45 patients scored 0, 1, 2, 3 respectively. The 3-year PFS rate Multivariate analysis revealed that post-NACT CTM score was an independent predictor of PFS (0 vs. 1, HR: 1.34, 95% CI: 0.92–1.96, P = 0.128; 0 vs. 2, HR: 2.03, 95% CI: 1.35–3.05, P = 0.001; 0 vs. 3, HR: 2.98, 95% CI: 1.83–4.86, P

ObjectsThe aim of this study is to explore the epidemiological characteristics of peripheral T-cell lymphoma in Beijing.Methods All data were extracted from the Beijing Cancer Registry database from January 1, 2007, to December 31, 2018. Segi’s World Standard Population was used to estimate the age-standardized rate (ASR). Changes in trends were examined using joinpoint regression analysis. The observed survival was estimated by the Kaplan–Meier method. Relative survival was calculated using Ederer II and standardized using the Brenner method and International Cancer Survival Standard (ICSS) group 1 age structure. Stratified by gender, area, and histological type, incidence, mortality, and age of onset trends were observed in Beijing.Results In Beijing, there were 801 new cases and 463 deaths of T-cell lymphoma from 2007 to 2018. Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) was the most prevalent subtype (37.45%), followed by angioimmunoblastic T-cell lymphoma (AITL; 20.35%), NK/T-cell lymphoma (NK/TCL; 17.60%), and anaplastic large cell lymphoma (ALCL; 10.24%). The crude incidence and mortality rates were 0.52 and 0.30 per 100,000 person-years, respectively, whereas the age-standardized incidence and mortality rates (ASIR and ASMR) were 0.35 and 0.18 per 100,000 person-years, respectively. Both ASIR and ASMR were more prevalent in men (0.48 and 0.24 per 100,000) and urban area (0.38 and 0.19 per 100,000) than in women (0.22 and 0.11 per 100,000) and rural area (0.30 and 0.15 per 100,000). The average annual percentage change (AAPC) of ASIR and ASMR was 5.72% (95% confidence interval (CI): 1.79%–9.81%) and 4.35% (95% CI: −0.09%–8.99%), respectively. The age-specific incidence rate increased with age and peaked at the age groups of 10–14 and 80–84. The mean and median age of onset increased between 2007 and 2018. In addition, it decreased after the age of onset was age standardization (β = −0.41, P = 0.26). The 5-year age-standardized relative survival was 39.02% for all patients, 58.14% for NK/TCL, 57.60% for ALCL, 31.38% for AITL, and 29.18% for PTCL-NOS.Conclusions T-cell lymphoma incidence was rising, but survival was dismal in Beijing, indicating the need for improved early diagnosis and standardized treatment.

Abstract Background S100A11 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. The dysregulated expression of the S100A11 gene has been implicated in tumour metastasis. However, the role of S100A11 protein in tumour cell response to chemotherapeutic drugs has not been characterised. Methods Transcript levels of S100A11 in gastric cancer were evaluated using an in-house patient cohort. Protein expression of S100A11 in gastric cancer was estimated by immunohistochemistry of a tissue microarray. The stable gastric cancer cell lines were established using lentiviral shRNA vectors. The knockdown of S100A11 was validated by qRT-PCR, PCR, and Western blot. The cellular function of S100A11 was estimated by assays of cell adhesion, migration, and invasion. The cell cytotoxic assay was performed to investigate the response to chemotherapeutic drugs. An unsupervised hierarchical clustering and principal component analysis (HCPC) was applied to unveil the dimensional role of S100A11 among all S100 family members in gastric cancer. Results High expression of S100A11 is associated with poor survival of gastric cancer patients (p

Abstract Background Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. Methods RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. Discussion This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. Trial registration Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

Abstract Background Recently, artificial neural network (ANN) methods have also been adopted to deal with the complex multidimensional nonlinear relationship between clinicopathologic variables and survival for patients with gastric cancer. Using a multinational cohort, this study aimed to develop and validate an ANN‐based survival prediction model for patients with gastric cancer. Methods Patients with gastric cancer who underwent gastrectomy in a Chinese center, a Japanese center, and recorded in the Surveillance, Epidemiology, and End Results database, respectively, were included in this study. Multilayer perceptron neural network was used to develop the prediction model. Time‐dependent receiver operating characteristic (ROC) curves, area under the curves (AUCs), and decision curve analysis (DCA) were used to compare the ANN model with previous prediction models. Results An ANN model with nine input nodes, nine hidden nodes, and two output nodes was constructed. These three cohort's data showed that the AUC of the model was 0.795, 0.836, and 0.850 for 5‐year survival prediction, respectively. In the calibration curve analysis, the ANN‐predicted survival had a high consistency with the actual survival. Comparison of the DCA and time‐dependent ROC between the ANN model and previous prediction models showed that the ANN model had good and stable prediction capability compared to the previous models in all cohorts. Conclusions The ANN model has significantly better discriminative capability and allows an individualized survival prediction. This model has good versatility in Eastern and Western data and has high clinical application value.

Abstract Background Gastric neoplasms containing neuroendocrine carcinoma (NEC) components are rare malignancies with highly aggressive behavior and a poor prognosis and include pure NEC and mixed tumors containing NEC components. We aimed to investigate whether there is a distinct difference in overall survival (OS) between gastric neoplasms containing NEC components and gastric adenocarcinoma. Methods Surgically resected gastric neoplasms containing NEC components (n = 180) and gastric adenocarcinomas (n = 785) from January 2013 to December 2019 at Peking University Cancer Hospital were retrospectively analysed. Patients were categorized into a surgical group and a neoadjuvant group and adjusted using propensity score matching. In the two groups, gastric neoplasms containing NEC components were divided into pure NEC and mixed tumors with less than 30% ( 70% G-HMiNEN) neuroendocrine carcinoma components. OS was compared between these groups and the gastric adenocarcinoma group. Results The OS of gastric neoplasms containing neuroendocrine NEC components was poorer than that of gastric adenocarcinomas in the surgical group, regardless of whether the percentage of neuroendocrine cancer components was less than 30%, between 30 and 70%, more than 70% or 100%. Cox multivariable regression analysis suggested that tumor category (neoplasms containing NEC components or gastric adenocarcinoma) was an independent risk factor for prognosis. Interestingly, among patients receiving neoadjuvant therapy, the difference was not significant. Conclusions Gastric neoplasms containing any proportion of NEC components had poorer overall survival than gastric adenocarcinoma in patients treated with surgery directly, indicating that these neoplasms are more malignant than gastric adenocarcinoma. Among the patients receiving neoadjuvant therapy, the difference in overall survival was not significant, which was in sharp contrast with the results of the surgery group, suggesting that neoadjuvant therapy may have a good effect in the treatment of these neoplasms.

Abstract Background To investigate whether there is a distinct difference in prognosis between hepatoid adenocarcinoma of the stomach (HAS) and non-hepatoid adenocarcinoma of the stomach (non-HAS) and whether HAS can benefit from radical surgery. Methods We retrospectively reviewed 722 patients with non-HAS and 75 patients with HAS who underwent radical gastrectomy between 3 November 2009 and 17 December 2018. Propensity score matching (PSM) analysis was used to eliminate the bias among the patients in our study. The relationships between gastric cancer type and overall survival (OS) were evaluated by the Kaplan-Meier method and Cox regression. Results Our data demonstrate that there was no statistically significant difference in the OS between HAS and non-HAS {K-M, P = log rank (Mantel-Cox), (before PSM P = 0.397); (1:1 PSM P = 0.345); (1:2 PSM P = 0.195)}. Moreover, there were no significant differences in the 1-, 2-, or 3-year survival rates between patients with non-HAS and patients with HAS (before propensity matching, after 1:1 propensity matching, and after 1:2 propensity matching). Conclusion HAS was generally considered to be an aggressive gastric neoplasm, but its prognosis may not be as unsatisfactory as previously believed.

To address the increasing need for detecting and validating protein biomarkers in clinical specimens, mass spectrometry (MS)-based targeted proteomic techniques, including the selected reaction monitoring (SRM), parallel reaction monitoring (PRM), and massively parallel data-independent acquisition (DIA), have been developed. For optimal performance, they require the fragment ion spectra of targeted peptides as prior knowledge. In this report, we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples. To build the spectral resource, we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker. We then applied the workflow to generate DPHL, a comprehensive DIA pan-human library, from 1096 data-dependent acquisition (DDA) MS raw files for 16 types of cancer samples. This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer (PCa) patients. Thereafter, PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated. As a second application, the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma (DLBCL) patients and 18 healthy control subjects. Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM. These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery. DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.

Abstract Background Circular RNAs (circRNAs) are a new class of endogenous non-coding RNAs (ncRNAs) widely expressed in eukaryotic cells. Mounting evidence has highlighted circRNAs as critical regulators of various tumours. More importantly, circRNAs have been revealed to recruit and reprogram key components involved in the tumour microenvironment (TME), and mediate various signaling pathways, thus affecting tumourigenesis, angiogenesis, immune response, and metastatic progression. Main body of the abstract In this review, we briefly introduce the biogenesis, characteristics and classification of circRNAs, and describe various mechanistic models of circRNAs. Further, we provide the first systematic overview of the interplay between circRNAs and cellular/non-cellular counterparts of the TME and highlight the potential of circRNAs as prospective biomarkers or targets in cancer clinics. Finally, we discuss the biological mechanisms through which the circRNAs drive development of resistance, revealing the mystery of circRNAs in drug resistance of tumours. Short conclusion Deep understanding the emerging role of circRNAs and their involvements in the TME may provide potential biomarkers and therapeutic targets for cancer patients. The combined targeting of circRNAs and co-activated components in the TME may achieve higher therapeutic efficiency and become a new mode of tumour therapy in the future.

Background The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect.Methods In this study, tumor-associated immune cells (TAICs) infiltration in residual tumor after neoadjuvant chemotherapy (NAC) together with 1075 cases of treatment-naïve GC patients was analyzed first. Then we performed multiplex fluorescence staining of a panel of immune markers (CD3, CD4, CD8, FOXP3 and PDL1) and T cell receptor β-chain sequencing to phenotype and enumerate T cell subpopulations and clonal expansion in paired GC samples (prechemotherapy and postchemotherapy) from another cohort of 30 cases of stage II/III GC patients.Results Infiltration of CD68+ macrophages in residual tumors after NAC was significantly decreased compared with treatment-naïve GC patients, while no significant difference observed with respect to other immune markers. In residual tumors, post-NAC CD8 +T cells and CD68+ macrophages levels were significantly associated with chemotherapy response. Post-NAC CD8+ T cell levels remained as an independent predictor for favorable prognosis. Furthermore, when comparing the paired samples before and after NAC from 30 cases of stage II/III GC patients, we found FOXP3+ regulatory T cells proportion significantly decreased after chemotherapy. Pre-NAC FOXP3+ T reg cells level was much richer in the response group and decreased more significantly in the stromal compartment. CD8+ cytotoxic T lymphocytes levels were elevated after chemotherapy, which was more significant in the group treated with XELOX regimen and in patients with better response, consistent with the TCR diversity elevation.Conclusions These findings have deepened our understanding of the immune modulating effect of chemotherapy and suggest that the immune profile of specimens after standard chemotherapy should be considered for the personalized immunotherapy to ultimately improve clinical outcome in patients with GC.

BackgroundsPerioperative chemotherapy (PEC) and neoadjuvant chemotherapy (NAC) have become a vital part of locally advanced gastric cancer (LAGC) treatment, but the optimal duration of PEC has not been studied. The aim of this study was to demonstrate the possibility of duration reduction in PEC in the adjuvant chemotherapy (AC) phase for ypN0 patients.MethodsWe included LAGC patients who achieved ypN0 after NAC in our institution from 2005 to 2018. The risk/benefit of AC and other covariates were majorly measured by overall survival (OS) and progression-free survival (PFS). We developed a survival-tree-based model to determine the optimal PEC duration for ypN0 patients in different classes.ResultsA total of 267 R0 resection patients were included. There were 55 patients who did not receive AC. The 5-year OS was 74.34% in the non-AC group and 83.64% in the AC group with a significant difference (p = 0.012). Multivariate Cox regression revealed that both AC (AC vs. non-AC: HR, 0.49; 95%CI, 0.27–0.88; p = 0.018) and ypT stages (ypT3-4 vs. ypT0-2: HR, 2.00; 95%CI, 1.11–3.59; p = 0.021) were significant protective/risk factors on patients OS and PFS. A decision tree model for OS indicated an optimal four to six cycles of PEC, which was recommended for ypT0-2N0 patients, while a minimum of five PEC cycles was recommended for ypT3-4N0 patients.ConclusionAC treatment is still necessary for ypN0. The duration reduction could be applied for the ypT0-2N0 stage patients but may not be suitable for higher ypT stages and beyond. A multicenter-based study is required.

Background and Objectives: This study aims to explore the safety of preoperative chemotherapy and clarify whether preoperative chemotherapy with oxaliplatin + S-1 (SOX) regimen and its adverse events are associated with higher risks of postoperative complications.Methods: We included consecutive patients with gastric cancer who underwent gastrectomy in our department between July 1 2018, and January 31 2020. Patients with preoperative SOX regimen chemotherapy were included in the analysis.Results: In the 343 included patients, 77 cases underwent preoperative chemotherapy. In total, surgical complications were found in 117 patients (34.1%), and there was no significant difference between the patients with and without preoperative chemotherapy before and after propensity score matching (p > 0.05, respectively). Multivariate analysis showed that preoperative comorbidities (p = 0.026) and the preoperative cT4b (p = 0.028) were independent risk factors in postoperative complications. In patients with preoperative chemotherapy, neither the occurrence of adverse events nor their severity was associated with postoperative complications (p > 0.05). However, the patients who received five to six cycles were more prone to postoperative complications than those who received three to four cycles (62.5 vs. 27.9%, OR = 4.306, 95% Cl = 1.282–14.464, p = 0.018).Conclusions: Occurrence of postoperative complications was not influenced by preoperative SOX chemotherapy. However, increased cycles of chemotherapy may lead to higher incidence of postoperative complications.

Background: Previous studies have reported inverse associations between urban greenness and mortality. However, findings regarding contemporaneous and cumulative average greenness exposure are inconsistent. A potential explanation is the weak effects of greenness among the general population. This study assessed the associations between contemporaneous and cumulative average greenness exposure and survival in lung cancer patients. Methods: An open cohort consisting of lung cancer patients enrolled from 1 January 2001 was studied. The cohort was followed up until 31 December 2018. We evaluated contemporaneous and cumulative greenness exposure using the normalized difference vegetation index (NDVI) within a 250 m buffer of each patient’s geocoded residential address. The association between NDVI and mortality was evaluated using both time-fixed and time-varying Cox models. Their difference was compared either. Results: In time-fixed Cox models, a 0.1-unit increment in contemporaneous and cumulative average NDVI was associated with 17% (95% confidence interval [CI], 15–18%) and 7% (95% CI, 5–8%) reductions in mortality rate, respectively. Time-varying Cox models consistently revealed significant associations, but their magnitudes were lower, at 2% (95% CI, 1–3%) for both contemporaneous and cumulative average NDVI. Compared to the time-fixed models, the time-varying ones exhibited better fit for the proportional hazard assumption in Cox regressions with more conservative results. Conclusion: Urban greenness is positively associated with an increased chance of survival in lung cancer patients. Compared to time-fixed Cox models, the results of time-varying Cox models were more conservative. This study confirms the beneficial health effects of urban greenness, which may facilitate the improvement of public health by urban green space planning.

IntroductionSomatic copy number deletion (SCND) of CDKN2A gene is the most frequent event in cancer genomes. Whether CDKN2A SCND drives human cancer metastasis is far from clear. Hematogenous metastasis is the main reason of human gastric carcinoma (GC) death. Thus, prediction GC metastasis is eagerly awaited.MethodGC patients (n=408) enrolled in both a cross-sectional and a prospective cohorts were analysed. CDKN2A SCND was detected with a quantitative PCR assay (P16-Light). Association of CDKN2A SCND and GC metastasis was evaluated. Effect of CDKN2A SCND by CRISPR/Cas9 on biological behaviors of cancer cells was also studied.ResultsCDKN2A SCND was detected in 38.9% of GCs from patients (n=234) enrolled in the cross-sectional cohort. Association analysis showed that more CDKN2A SCND was recognized in GCs with hematogenous metastasis than those without (66.7% vs. 35.7%, p=0.014). CDKN2A SCND was detected in 36.8% of baseline pN0M0 GCs from patients (n=174) enrolled in the prospective study, the relationship between CDKN2A SCND and hematogenous metastasis throughout the follow-up period (62.7 months in median) was also significant (66.7% vs. 34.6%, p=0.016). Using CDKN2A SCND as a biomarker for predicting hematogenous metastasis of GCs, the prediction sensitivity and specificity were 66.7% and 65.4%. The results of functional experiments indicated that CDKN2A SCND could obviously downregulate P53 expression that consequently inhibited the apoptosis of MGC803 GC and HEK293T cells. This may account for hematogenous metastasis of GCs by CDKN2A SCND.ConclusionCDKN2A SCND may drive GC metastasis and could be used as a predictor for hematogenous metastasis of GCs.

BackgroundMammography-based breast cancer screening has been widely implemented in many developed countries. Evidence was needed on participation and diagnostic performance of population-based breast cancer screening using ultrasound in China.MethodsWe used data from the Cancer Screening Program in Urban China in Beijing from 2014 to 2019 and was followed up until July 2020 by matching with the Beijing Cancer Registry database. Eligible women between the ages of 45 and 69 years were recruited from six districts and assessed their risk of breast cancer through an established risk scoring system. Women evaluated to be at high risk of breast cancer were invited to undergo both ultrasound and mammography. Participation rates were calculated, and their associated factors were explored. In addition, the performance of five different breast cancer screening modalities was evaluated in this study.ResultsA total of 49,161 eligible women were recruited in this study. Among them, 15,550 women were assessed as high risk for breast cancer, and 7,500 women underwent ultrasound and/or mammography as recommended, with a participation rate of 48.2%. The sensitivity of mammography alone, ultrasound alone, combined of ultrasound and mammography, ultrasound for primary screening followed by mammography for triage, and mammography for preliminary screening followed by ultrasound for triage were19.2%, 38.5%, 50.0%, 46.2%, and 19.2%, and the specificity were 96.1%, 98.6%, 94.7%, 97.6%, 95.7%, respectively. The sensitivity of combined ultrasound and mammography, ultrasound for primary screening followed by mammography for triage, was significantly higher than mammography alone (p=0.008 and p=0.039). Additionally, ultrasound alone (48,323 RMB ($7,550)) and ultrasound for primary screening followed by mammography for triage (55,927 RMB ($8,739)) were the most cost-effective methods for breast cancer screening than other modalities.ConclusionsUltrasound alone and ultrasound for primary screening and mammography are superior to mammography for breast cancer screening in high-risk Chinese women.

BackgroundEpstein–Barr virus associated gastric cancer (EBVaGC) is a special subtype of gastric cancer. However, the perioperative treatment plan and the response to chemotherapy are still uncertain.MethodsWe retrospectively enrolled patients diagnosed with EBVaGC from March 2013 to July 2020 in Beijing Cancer Hospital. Clinicopathological characteristics were recorded. Disease-free survival (DFS) were then calculated, and variants affecting DFS were tested in a Cox proportional regression model.ResultsOne hundred sixty consecutive patients were finally included in our study. Of the patients, 96.9% had adenocarcinoma, while five had squamous cell carcinoma component. Most (70.9%) of them were poorly differentiated. Prevalent programmed death-ligand 1 (PD-L1) (69%) and minor HER-2 (3.8%) expression were noticed; all of the patients were MMR proficient (pMMR) or microsatellite stable (MSS). Among 33 patients who experienced neoadjuvant therapy, the number of tumor regression grade (TRG) 1, TRG 2, and TRG 3 was 5, 16, and 12, respectively. Patients with advanced tumor stage and T stage showed poorer response. Thirty-one patients experienced first-line chemotherapy; ORR was 33.3%, and DCR was 61.9%. One hundred forty-seven patients underwent surgery, and 27 of them showed disease recurrence; the 3-year DFS rate was 71.0%. Tumor stage, neoadjuvant chemotherapy, vascular invasion, and negative PD-L1 expression were associated with poorer DFS. Vascular invasion was the independent risk factor of DFS. Only seven patients reached OS with median follow-up time of 14 months.ConclusionEBVaGC exhibits unique clinicopathological characteristics. Neoadjuvant chemotherapy may not be suitable for EBVaGC, and EBVaGC exhibited relatively poor response to chemotherapy.

Abstract Background Limited information is available regarding the patient safety culture in Chinese hospitals. This study aims to assess the patient safety culture in Peking University Cancer Hospital and to identify opportunities for improving the organization’s safety culture. Methods A cross-sectional study was conducted in April 2018 and 2019, respectively. Data on patient safety culture were collected from clinical and administrative staffs using the Hospital Survey on Patient Safety Culture (HSOPSC). Results Twelve composite dimension variables were hierarchically clustered. Three highest positive response dimensions include ‘Organizational Learning and continuous improvement’ (92.9%), ‘Teamwork within units’ (89.7%), and ‘Hospital management support for patient safety’ (83.7%), while 3 lowest positive response dimensions included ‘Frequency of events reported’ (43.9%), ‘Non-punitive response to error’ (51.1%), ‘Communication openness’ (52.2%), and ‘Staffing’ (53.7%). Compared to the average scores of the United States, the scores of the Peking University Cancer Hospital was significantly lower on ‘Communication openness’ and ‘Frequency of events reported’. After targeted continuous improvement based on results in 2018, all 12 dimensions surprisingly increased in the safety culture conducted in 2019. Conclusion Inadequate feedback and communications about error and lack of communication openness are key challenges for patient safety in the delivery of care in this hospital. Results of this baseline survey indicate the need for a modified approach and attention to context when designing interventions aimed at improving the safety culture in this organization.

Summary: The diffuse-type gastric cancer (DGC) constitutes a subgroup of gastric cancer with poor prognosis and no effective molecular therapies. Here, we report a phosphoproteomic landscape of DGC derived from 83 tumors together with their nearby tissues. Based on phosphorylation, DGC could be classified into three molecular subtypes with distinct overall survival (OS) and chemosensitivity. We identified 16 kinases whose activities were associated with poor OS. These activated kinases covered several cancer hallmark pathways, with the MTOR signaling network being the most frequently activated. We proposed a patient-specific strategy based on the hierarchy of clinically actionable kinases for prioritization of kinases for further clinical evaluation. Our global data analysis indicates that in addition to finding activated kinase pathways in DGC, large-scale phosphoproteomics could be used to classify DGCs into subtypes that are associated with distinct clinical outcomes as well as nomination of kinase targets that may be inhibited for cancer treatments. : Biological Sciences; Cancer Systems Biology; Proteomics; Systems Biology Subject Areas: Biological Sciences, Cancer Systems Biology, Proteomics, Systems Biology