DeepRisk network: an AI-based tool for digital pathology signature and treatment responsiveness of gastric cancer using whole-slide images.

BACKGROUND: Digital histopathology provides valuable information for clinical decision-making. We hypothesized that a deep risk network (DeepRisk) based on digital pathology signature (DPS) derived from whole-slide images could improve the prognostic value of the tumor, node, and metastasis (TNM) staging system and offer chemotherapeutic benefits for gastric cancer (GC). METHODS: DeepRisk is a multi-scale, attention-based learning model developed on 1120 GCs in the Zhongshan dataset and validated with two external datasets. Then, we assessed its association with prognosis and treatment response. The multi-omics analysis and multiplex Immunohistochemistry were conducted to evaluate the potential pathogenesis and spatial immune contexture underlying DPS. RESULTS: Multivariate analysis indicated that the DPS was an independent prognosticator with a better C-index (0.84 for overall survival and 0.71 for disease-free survival). Patients with low-DPS after neoadjuvant chemotherapy responded favorably to treatment. Spatial analysis indicated that exhausted immune clusters and increased infiltration of CD11b+CD11c+ immune cells were present at the invasive margin of high-DPS group. Multi-omics data from the Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) hint at the relevance of DPS to myeloid derived suppressor cells infiltration and immune suppression. CONCLUSION: DeepRisk network is a reliable tool that enhances prognostic value of TNM staging and aid in precise treatment, providing insights into the underlying pathogenic mechanisms.

Effectiveness of oncology nurse navigator on the incidence of postoperative pulmonary complications in gastric cancer patients undergoing radical gastrectomy.

BACKGROUND: Management of postoperative pulmonary complications (PPCs) can be challenging in gastric cancer patients undergoing radical gastrectomy and is always associated with poor prognosis. Even though oncology nurse navigator (ONN) provide effective and critical individualized care to patients, little is known about their impact on the occurrence of PPCs in gastric cancer patients. This study aimed to determine whether ONN decreases the incidence of PPCs in gastric cancer patients. METHODS: This was a retrospective review in which data for gastric cancer patients at one centre was evaluated before and after an ONN hired. An ONN was introduced to patients at their initial visit to manage pulmonary complications throughout treatment. The research was conducted from 1 August 2020 to 31 January 2022. The study participants were divided into the non-ONN group (from 1 August 2020 to 31 January 2021) and the ONN group (from 1 August 2021 to 31 January 2022). The incidence and severity of PPCs between the groups were then compared. RESULTS: ONN significantly decreased the incidence of PPCs (15.0% vs. 9.8%) (OR = 2.532(95% CI: 1.087-3.378, P = 0.045)), but there was no significant difference in the components of PPCs including pleural effusion, atelectasis, respiratory infection, and pneumothorax. The severity of PPCs was also significantly higher in the non-ONN group (p = 0.020). No significant statistical difference was observed for the major pulmonary complications ([Formula: see text] 3) between the two groups (p = 0.286). CONCLUSIONS: Role of ONN significantly decrease the incidence of PPCs in gastric cancer patients undergoing radical gastrectomy.

Neoadjuvant apatinib combined with oxaliplatin and capecitabine in patients with locally advanced adenocarcinoma of stomach or gastroesophageal junction: a single-arm, open-label, phase 2 trial.

BACKGROUND: Adding anti-angiogenics to neoadjuvant chemotherapy for localized gastric cancer is recognized as a promising strategy, but its clinical value remains to be defined. METHODS: This single-center, single-arm, phase 2 trial included patients with locally advanced (cT3/4aN+M0) adenocarcinoma of the stomach or gastroesophageal junction (GEJ) who received three cycles of intravenous oxaliplatin (135 mg/m2 on day 1), oral capecitabine (1000 mg/m2 twice daily on days 1 to 14), and oral apatinib for 21 days (250 mg once daily in the first two cycles, and further increased to 500 mg daily in the third cycle based on whether any adverse event of grade 3 or worse occurred), and an additional cycle of oxaliplatin plus capecitabine, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was the proportion of patients who achieved an objective response according to RECIST version 1.1. RESULTS: Between April 28, 2017, and October 23, 2019, 37 patients were screened and 35 participants were included. Of the 32 patients assessable for efficacy and safety, objective responses were achieved in 25 (78.1%; 95% confidence interval [CI], 60.0% to 90.7%) patients. Thirty-one (96.9%) patients received R0 resection, two (6.3%) patients achieved pathological complete response, and 11 (34.4%) patients achieved pathological response. At the data cutoff date (September 30, 2021), the median event-free survival was 42.6 (95% CI, 16.2 to not reached) months, and the median overall survival was not reached. The most common grade 3 or 4 treatment-emergent adverse events were hypertension (9/32, 28.1%), thrombocytopenia (7/32, 21.9%), and neutropenia (5/32, 15.6%). Seven (21.9%) patients developed surgical complications, and the most common one was intra-abdominal abscess (4/32, 12.5%). CONCLUSIONS: The concomitant use of apatinib, oxaliplatin, and capecitabine as neoadjuvant therapy showed promising efficacy and manageable safety profile in patients with locally advanced adenocarcinoma of the stomach or GEJ, and further phase 3 study is warranted. TRIAL REGISTRATION: This study was registered with ClinicalTrial.gov ( NCT03229096 ).

G3BP1 interacts with YWHAZ to regulate chemoresistance and predict adjuvant chemotherapy benefit in gastric cancer.

BACKGROUND: A large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure. Stress granules (SGs) play a self-defence role for tumour cells in inhibiting chemotherapy-induced apoptosis. As an SG assembly effector, G3BP1 (Ras-GTPase-activating protein SH3 domain-binding protein) has been reported to be overexpressed in gastric cancer; thus, here we aim to explore its potent roles in gastric cancer chemoresistance. METHODS: Kaplan-Meier analysis was used to compare survival rates in gastric cancer patients with different G3BP1 expression. The influence of G3BP1 on gastric cancer cell chemoresistance and apoptosis were evaluated by in vitro and in vivo approaches. The interaction between G3BP1 and YWHAZ was assessed by immunohistochemistry, immunoprecipitation and immunofluorescence. RESULTS: G3BP1 was associated with the poor outcome of gastric cancer patients who received adjuvant chemotherapy. G3BP1 knockdown significantly increased the sensitivity of gastric cancer cells to chemotherapy drugs. Mechanically, cell apoptosis and pro-apoptotic-associated molecules were significantly elevated upon G3BP1 depletion. Gene co-expression network analyses identified YWHAZ as the critical interlayer of G3BP1; as a result, G3BP1 interacted with YWHAZ to sequester Bax into the cytoplasm. Clinically, G3BP1highYWHAZhigh gastric cancer patients displayed the worst outcome compared with other patients after chemotherapy. CONCLUSIONS: The expression of G3BP1 and YWHAZ could predict the adjuvant chemotherapy benefit in gastric cancer patients.

Stemness-related LncRNA pair signature for predicting therapy response in gastric cancer.

OBJECTIVE: As a critical feature of cancers, stemness is acknowledged as a contributor to the development of drug resistance in gastric cancer (GC). LncRNAs have been revealed to participate in this process. In this study, we tried to develop a stemness-related lncRNA pair signature as guidance for clinical decisions. METHODS: The analysis was initiated by collecting stemness-related lncRNAs in TCGA cohort. The differentially expressed stemness-related lncRNAs between normal and tumor tissues in GC patients from TCGA datasets were further collected to establish the signature based on Lasso and Cox regression analyses. The predictive efficacy of the signature for chemotherapy and immunotherapy was also tested. The practicality of this signature was also validated by Zhongshan cohort. RESULTS: A 13-DEsrlncRNA pair-based signature was established. The cutoff point acquired by the AIC algorithm divided the TCGA cohort into high and low risk groups. We found that the low-risk group presented with better survival (Kaplan-Meier analysis, p < 0.001). Cox regression analyse was also conducted to confirm the signature as an independent risk factor for GC {p < 0.001, HR = 1.300, 95% CI (1.231-1.373)]}. As for the practicality of this signature, the IC50 of cytotoxic chemotherapeutics was significantly higher in the high-risk group. The low-risk group also presented with higher immunophenoscore (IPS) in both the "CTLA4+ PD1+" (Mann-Whitney U test, p = 0.019) and "CTLA4- PD1+" (Mann-Whitney U test, p = 0.013) groups, indicating higher sensitivity to immunotherapy. The efficacy of the signature was also validated by Zhongshan cohort. CONCLUSIONS: This study could not only provide a stemness-related lncRNA signature for survival prediction in GC patients but also established a model with predictive potentials for GC patients' sensitivity to chemotherapy and immunotherapy.

Reevaluation of lymphovascular invasion in gastric cancer using endothelial markers D2-40 and EVG: Enhanced detection, better predictor of lymph node metastasis and biological aggressiveness.

BACKGROUND AND OBJECTIVES: The diagnosis of lymphovascular invasion (LVI) is often inaccurate with routine histology. This study aimed to evaluate the use of immunohistochemistry (IHC) in detecting LVI and reevaluate the clinical implications of LVI in gastric cancer. METHODS: This prospective unrandomized cohort study analyzed the rates of LVI positivity and its relevance with other clinicopathologic features. RESULTS: Between November 2017 and April 2018, 558 patients undergoing curative gastrectomy were enrolled and assigned to the IHC group (n = 285) and hematoxylin-eosin group (n = 273). The use of IHC increased the rates of LVI positivity (60.8% vs. 43.3%, p < .001) and decreased the rates of undetermined LVI subtype (7.7% vs. 27.1%, p < .001). The LVI-negative patients identified by IHC had fewer lymph node metastases (16.8% vs. 34.6%, p = .002) and earlier pathological stage (p = .004) than those identified by routine histology. The LVI-positive patients identified by IHC had a higher percentage of perineural invasion (p = .019). CONCLUSIONS: The use of endothelial markers significantly enhanced the detection of LVI. The LVI detected by IHC could be a better predictor of lymph node metastasis and biological aggressiveness in gastric cancer.

Reduced expression of the chromatin remodeling gene ARID1A enhances gastric cancer cell migration and invasion via downregulation of E-cadherin transcription.

The chromatin remodeling gene AT-rich interactive domain-containing protein 1A (ARID1A) encodes the protein BAF250a, a subunit of human SWI/SNF-related complexes. Recent studies have identified ARID1A as a tumor suppressor. Here, we show that ARID1A expression is reduced in gastric cancer (GC) tissues, which are significantly associated with local lymph node metastasis, tumor infiltration and poor patient prognosis. ARID1A silencing enforces the migration and invasion of GC cells, whereas ectopic expression of ARID1A inhibits migration. The adhesive protein E-cadherin is remarkably downregulated in response to ARID1A silencing, but it is upregulated by ARID1A overexpression. E-cadherin overexpression significantly inhibits GC cell migration and invasion, whereas CDH1 (coded E-cadherin) silencing promotes migration. Restored expression of CDH1 in ARID1A-silenced cell lines restores the inhibition of cell migration. Luciferase reporter assays and chromatin immunoprecipitation indicate that the ARID1A-associated SWI/SNF complex binds to the CDH1 promoter and modulates CDH1 transcription. ARID1A knockdown induces evident morphological changes of GC cells with increased expression of mesenchymal markers, indicating an epithelial-mesenchymal transition. ARID1A silencing does not alter the level of ß-catenin but induces a subcellular redistribution of ß-catenin from the plasma membrane to the cytoplasm and nucleus. Immunohistochemical studies demonstrate that reduced expression of E-cadherin is associated with local lymph node metastasis, tumor infiltration and poor clinical prognosis. ARID1A and E-cadherin expression show a strong correlation in 75.4% of the analyzed GC tissues. They are synergistically downregulated in 23.5% of analyzed GC tissues. In conclusion, ARID1A targets E-cadherin during the modulation of GC cell migration and invasion.

Prognostic value of stromal cell-derived factor 1 expression in patients with gastric cancer after surgical resection.

Aberrant chemokine stromal cell-derived factor 1 (SDF-1) expression has been shown to be involved in the development and progression of various malignancies. Our present study aims to investigate the clinical and prognostic value of SDF-1 expression and improve risk stratification in patients with gastric cancer. Peritumoral and intratumoral SDF-1 levels were assessed in 220 retrospectively enrolled gastric cancer patients, and their relations with clinicopathological features and clinical outcomes were evaluated. A predictive nomogram was created to refine risk stratification for overall survival of gastric cancer patients. Compared with peritumor tissues, tumor tissues showed decreased SDF-1 expression levels according to TNM stage progression in gastric cancer specimens. Peritumoral SDF-1 expression correlated positively with tumor invasion depth and lymph node metastasis, whereas intratumoral SDF-1 expression associated negatively with tumor size, tumor differentiation, tumor invasion depth, lymph node metastasis, and clinical TNM stage. Moreover, both low peritumoral SDF-1 expression and high intratumoral SDF-1 expression indicated favorable overall survival, and SDF-1 risk derived from the peritumoral/intratumoral SDF-1 expression signature could stratify prognosis of patients with gastric cancer. After backward elimination, SDF-1 risk was identified as an independent prognostic factor for survival. Finally, a predictive nomogram was generated with identified independent prognosticators to assess patient survival at 3 and 5 years following surgery. Conclusively, SDF-1 risk, an identified independent prognostic factor, could be developed into a nomogram with tumor invasion depth, lymph node involvement, and distant metastasis to refine predictive accuracy for survival in patients with gastric cancer after surgical resection.

Development and validation of an individualized nomogram for gastric cancer patients treated with perioperative chemotherapy followed by radical surgery.

Background: Prognostic factors are complicated and changeable for locally advanced gastric cancer (GC) patients. This study aimed to perform a novel prognostic model on survival for locally advanced GC patients who have received neoadjuvant chemotherapy and radical surgery. Methods: The locally advanced GC patients with neoadjuvant chemotherapy were included in this study from Zhongshan Hospital, Fudan University. A nomogram was developed based on independent prognostic factors identified through a multivariable Cox regression model. Model performance was evaluated in training and independent external cohorts in terms of calibration, discrimination, and clinical usefulness. Results: A total of 273 patients received radical resections. The median progression-free survival (PFS) and overall survival (OS) for all patients were 43.8 and 61.2 months, respectively. Nomogram showed that Lauren type made the greatest contribution to prognosis, followed by ypN. The prognostic nomogram had excellent discriminative ability, with a C-index of 0.689 [95% confidence interval (CI): 0.661-0.716], and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.778, 0.746, and 0.725 for 3-, 5- and 10-year OS, respectively. Similar results were obtained in the external validation cohort. Based on the nomogram, the whole cohort was divided into high-risk and low-risk groups. And risk group classification was significantly associated with clinical characteristics, and produced an AUC value of 0.781, 0.748, and 0.727 for 3-, 5- and 10-year OS, respectively. Furthermore, compared with the tumor-node-metastasis (TNM) staging system (8th edition), Japanese criteria, and German criteria, the decision curve analysis (DCA) graphically demonstrated that the new model had more optimal net benefits in predicting the 3-, 5-, and 10-year OS for GC patients. Both C-index and time-dependent ROC curve demonstrated that the nomogram had a stronger capability for accurately predicting prognosis compared with the other staging system. Conclusions: The nomogram model is an effective support tool to predict OS in GC patients undergoing perioperative chemotherapy followed by radical surgery.

Clinical and prognostic implications of ß1, 6-N-acetylglucosaminyltransferase V in patients with gastric cancer.

Aberrant ß1, 6-N-acetylglucosaminyltransferase V (MGAT5) expression in malignant tissues has been reported to be involved in the development of various cancers and their progression, through altering N-glycan branching. We aimed to investigate the clinical and prognostic values of MGAT5 and improve the risk stratification in patients with gastric cancer. MGAT5 expression was retrospectively analyzed by immunohistochemistry in three independent sets comprising 313 patients from China with gastric adenocarcinoma. Results were assessed for association with clinical features and overall survival using Kaplan-Meier analysis. Prognostic values of MGAT5 expression and clinical outcomes were evaluated by Cox regression analysis. A molecular prognostic stratification scheme incorporating MGAT5 expression was determined in patients with late-stage gastric cancer by using receiver operating characteristic analysis. The results show that low intratumoral MGAT5 density, which was associated with poor differentiation, N classification, TNM stage, and Kiel stage, was an independent prognosticator for poor overall survival. The combination of intratumoral MGAT5 expression and TNM or Kiel staging systems had a better predictive power for overall survival. Applying the prognostic value of intratumoral MGAT5 density to TNM stage III+IV and Kiel stage IIIB+IV groups showed a better risk stratification for overall survival in patients with late-stage gastric cancer. In conclusion, integrating intratumoral MGAT5 density that was recognized as an independent prognostic marker into current clinical staging systems significantly improved prognostic stratification of patients with late-stage gastric cancer. This refined risk stratification scheme might aid in appropriate therapeutic options and ultimately improve the outcomes of patients with advanced-stage disease.

Multiplex immune profiling reveals the role of serum immune proteomics in predicting response to preoperative chemotherapy of gastric cancer.

Responses toward preoperative chemotherapy are heterogeneous in patients with gastric adenocarcinoma. Existing studies in the field focus heavily on the tumor microenvironment (TME), whereas little is known about the relationship between systemic immunity and chemotherapy response. In this study, we collect serum samples from patients with gastric adenocarcinoma before, on, and after preoperative chemotherapy and study their immune proteomics using an antibody-based proteomics panel. We also collect surgically resected tumor samples and incorporate multiple methods to assess their TME. We find that both local and systemic immune features are associated with treatment response. Preoperative chemotherapy induces a sophisticated systemic immune response indicated by dynamic serum immune proteomics. A pretreatment serum protein scoring system is established for response prediction. Together, these findings highlight the fundamental but largely underestimated role of systemic immunity in the treatment of gastric cancer, suggesting a patient stratification strategy based on pretreatment serum immune proteomics.

Predictors of mortality in patients with acute small-bowel perforation transferred to ICU after emergency surgery: a single-centre retrospective cohort study.

Background: Although small-bowel perforation is a life-threatening emergency even after immediate surgical intervention, studies have rarely investigated surgical outcomes due to its relatively low incidence. This study aimed to investigate the outcomes of emergency surgery for patients with small-bowel perforation transferred to the intensive care unit (ICU) and the risk factors for mortality. Methods: Consecutive patients with small-bowel perforation who were confirmed via emergency surgery and transferred to the ICU in Zhongshan Hospital, Fudan University (Shanghai, China) between February 2011 and May 2020 were retrospectively analysed. Medical records were reviewed to determine clinical features, laboratory indicators, surgical findings, and pathology. Results: A total of 104 patients were included in this study, among whom 18 (17.3%), 59 (56.7%), and 27 (26.0%) underwent perforation repair, segmental resection with primary anastomosis, and small-bowel ostomy, respectively. Malignant tumours were the leading cause of perforation in these patients (40.4%, 42/104). The overall post-operative complication rate and mortality rates were 74.0% (77/104) and 19.2% (20/104), respectively. Malignant tumour-related perforation (odds ratio [OR], 4.659; 95% confidence interval [CI], 1.269-17.105; P = 0.020) and high post-operative arterial blood-lactate level (OR, 1.479; 95% CI, 1.027-2.131; P = 0.036) were identified as independent risk factors for post-operative mortality in patients with small-bowel perforation transferred to the ICU. Conclusions: Patients with small-bowel perforation who are transferred to the ICU after emergency surgery face a high risk of post-operative complications and mortality. Moreover, those patients with malignant tumour-related perforation and higher post-operative blood-lactate levels have poor prognosis.

The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction.

The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m2 twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m2 (day 1) plus capecitabine 1000 mg/m2 twice daily (days 1-14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6-51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3-4 adverse event was decreased lymphocyte count (27 [75.0%]). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.

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

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

PRICKLE1 promotes gastric cancer metastasis by activating mTOR signaling.

Lymph node metastasis confers an unfavorable prognosis in gastric cancer (GC). Transcriptomic sequencing has been used to explore the molecular changes in metastatic cancers, but the changes of expression profiling of metastatic GC in lymph nodes remain largely unknown. To identify the potential driver genes, we performed whole transcriptomic sequencing (RNA-seq) on five pairs of gastric adenocarcinoma specimens with metastatic lymph nodes confirmed by pathology. We identified six genes associated with lymph node metastasis and predicted poor prognosis in GC patients. Finally, we focused on PRICKLE1, a cell polarity protein, which dramatically upregulated in several GC cell lines from metastatic lesions compared with those from the primary tumor. Loss and gain of function assay in vitro showed that the migration and invasion capability of GC cells were limited by downregulating and upregulating PRICKLE1 expression. Mechanically, we found PRICKLE1 might modulate tumor metastasis through mTOR signaling pathway. Inhibition of mTOR significantly reduced GC cell migration and invasion in vitro. In summary, we identified and validated PRICKLE1 as a novel gene involved in GC metastasis. This study provided a valuable insight into the mechanisms of GC metastasis and developed a potential therapeutic target to prevent GC cell dissemination.

Integrated Analysis of Stemness-Related LncRNAs Helps Predict the Immunotherapy Responsiveness of Gastric Cancer Patients.

The immune microenvironment plays a critical role in tumor biology. As a critical feature of cancers, stemness is acknowledged as a contributor to the development of drug resistance in gastric cancers (GCs). Long non-coding RNAs (lncRNAs) have been revealed to participate in this process. In this study, we aimed to develop a stemness-related lncRNA signature (SRLncSig) with guiding significance for immunotherapy. Three cohorts (TCGA, Zhongshan, and IMvigor210) were enrolled for analysis. A list of stemness-related lncRNAs (SRlncRNAs) was collected by co-expression strategy under the threshold of coefficient value >0.35 and p-value < 0.05. Cox and Lasso regression analysis was further applied to find out the SRlncRNAs with prognosis-predictive value to establish the SRLncSig in the TCGA cohort. IPS and TIDE algorithms were further applied to predict the efficacy of SRLncSig in TCGA and Zhongshan cohorts. IMvigor210 was composed of patients with clinical outcomes of immunotherapy. The results indicated that SRLncSig not only was confirmed as an independent risk factor for GCs but also identified as a robust indicator for immunotherapy. The patient with a lower SRLncSig score was more likely to benefit from immunotherapy, and the results were highly consistent in three cohorts. In conclusion, our study not only could clarify the correlations between stemness and immunotherapy in GC patients but also provided a model to guide the applications of immunotherapy in clinical practice.

Predictive values profiling of interleukin-2, interleukin-8, tumor necrosis factor-α, procalcitonin, and C-reactive protein in critical gastrointestinal cancer patients.

BACKGROUND: The prognostic values of serum cytokines in cancer have not yet been fully determined. The objective of this study was to identify potential biomarkers associated with clinical outcomes in critical gastrointestinal (GI) cancer patients. METHODS: A retrospective analysis was performed to quantify serum interleukin (IL)-2, IL-8, tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and C-reactive protein (CRP) for correlation with clinical outcomes in GI cancer patients. The patients were divided into tertiles or quartiles based on the cytokine levels: Q1, Q2, and Q3, or Q1, Q2, Q3, and Q4. Receiver operating characteristic (ROC) curves were drawn to determine the optimal cutoff values of the cytokines. RESULTS: Trend analysis showed that IL-2, IL-8, TNF-α, PCT, and CRP levels had significant positive correlations with mortality in GI cancer patients (all P-values were lower than 0.05). The significance was observed in Q3 vs. Q1 in IL-2 (P=0.026), Q3 vs. Q1 in IL-8 (P=0.003), Q2 and Q3 vs. Q1 in TNF-α (P=0.012 and P=0.002, respectively), Q4 vs. Q1 in PCT (P=0.031), Q3 and Q4 vs. Q1 in CRP (P=0.011 and P=0.001, respectively). The area under curve (AUC) of IL-2, IL-8, TNF-α, PCT, and CRP were 0.706, 0.729, 0.743, 0.769, and 0.736, and the optimal cutoff points were determined at 838 U/mL, 46.15 pg/mL, 11.95 pg/mL, 0.77 pg/mL, and 109.38 mg/L, respectively. Under these critical values, the sensitivity was 73.3%, 66.7%, 80.0%, 93.3%, and 86.7%, and the specificity was 64.9%, 72.0%, 60.4%, 61.8%, and 68.9%, respectively. CONCLUSIONS: In GI cancer patients, serum IL-2, IL-8, TNF-α, PCT, and CRP levels can provide potential prognostic values for predicting clinical outcomes. The results may facilitate the exploration of cancer-related cytokine networks and development of novel therapy for GI cancer patients.

Establishment of an Immune Cell Infiltration Score to Help Predict the Prognosis and Chemotherapy Responsiveness of Gastric Cancer Patients.

The immune microenvironment plays a critical role in tumor biology. The molecular profiles of immune components and related genes are of tremendous value for the study of primary resistance to immune checkpoint blockers (ICBs) for gastric cancer (GC) and serve as prognostic biomarkers to predict GC survival. Recent studies have revealed that tumor immune cell infiltration (ICI) is an indicator of the survival and responsiveness to chemotherapy in GC patients. Here, we describe the immune cell landscape based on the ESTIMATE and CIBERSORT algorithms to help separate GC into 3 ICI clusters using the unsupervised clustering method. Further in-depth analyses, such as differential expression gene (DEG) analysis and principal component analysis (PCA), help to establish an ICI scoring system. A low ICI score is characterized by an increased tumor mutation burden (TMB). The combination of the ICI score and TMB score better predicts the survival of GC patients. Analyses based on public and our own database revealed that the ICI scoring system could also help predict the survival and chemotherapy responsiveness of GC patients. The present study demonstrated that the ICI score may be an effective prognostic biomarker and predictive indicator for chemotherapy and immunotherapy.

Quantitative proteomics study of breast cancer cell lines isolated from a single patient: discovery of TIMM17A as a marker for breast cancer.

The proteins involved in breast cancer initiation and progression are still largely elusive. To gain insights into these processes, we conducted quantitative proteomic analyses with 21T series of breast cell lines, which include a normal, primary tumor and a metastatic tumor that were isolated from a single patient. Stable isotope labeling of amino acid in cell culture followed by LC-MS/MS analysis was performed and deregulated proteins were identified using statistical analysis. Gene ontology analysis revealed that proteins involved in metabolic processes were the most deregulated in both tumorigenesis and metastasis. Interaction network analysis indicated that ERBB2 signaling played a critical role in tumorigenesis. In addition to known markers such as ERBB2 and E-cadherin, novel markers, including BRP44L, MTHFD2 and TIMM17A, were found to be overexpressed in 21T breast cancer cells and verified in additional breast cell lines. mRNA expression analysis as well as immunohistochemistry analysis in breast cancer tissues indicated that expression level of TIMM17A was directly correlated with tumor progression, and survival analysis suggested that TIMM17A was a powerful prognosis factor in breast cancer. More interestingly, overexpression and siRNA knockdown experiments indicated an oncogenic activity of TIMM17A in breast cancer. Our study provides a list of potential novel markers for breast cancer tumorigenesis and metastasis using a unique cell model. Further studies on TIMM17A as well as other markers on the list may reveal mechanisms that result in more effective therapeutics for cancer treatment.