Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown.Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA).Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo.LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC. 

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LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer

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One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients.

Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact.

Ferroptosis, a novel regulated cell death induced by iron-dependent lipid peroxidation, plays an important role in tumor development and drug resistance. Long noncoding RNAs (lncRNAs) are associated with various types of cancer. However, the precise roles of many lncRNAs in tumorigenesis remain elusive. Here we explored the transcriptomic profiles of lncRNAs in primary CRC tissues and corresponding paired adjacent non-tumor tissues by RNA-seq and found that LINC00239 was significantly overexpressed in colorectal cancer tissues. Abnormally high expression of LINC00239 predicts poorer survival and prognosis in colorectal cancer patients. Concurrently, we elucidated the role of LINC00239 as a tumor-promoting factor in CRC through in vitro functional studies and in vivo tumor xenograft models. Importantly, overexpression of LINC00239 decreased the anti-tumor activity of erastin and RSL3 by inhibiting ferroptosis. Collectively, these data suggest that LINC00239 plays a novel and indispensable role in ferroptosis by nucleotides 1-315 of LINC00239 to interact with the Kelch domain (Nrf2-binding site) of Keap1, inhibiting Nrf2 ubiquitination and increasing Nrf2 protein stability. Considering the recurrence and chemoresistance constitute the leading cause of death in colorectal cancer (CRC), ferroptosis induction may be a promising therapeutic strategy for CRC patients with low LINC00239 expression. 

https://www.nature.com/articles/s41419-022-05192-y.pdf

Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2

Sensing gastric cancer exosomes with MoS2-based SERS aptasensor.

Gastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.

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The role and application of small extracellular vesicles in gastric cancer

Background With the increasing prevalence of Siewert type Ⅱ adenocarcinoma of the esophagogastric junction (EGJ), the optimal surgical treatment is not universally agreed. This meta-analysis compares the safety and efficacy between the transhiahtal (TH) approach and the transthoracic (TT) approach. Methods A systematic and electronic search of several databases was performed up to June 2020. The Newcastle-Ottawa scale was used to evaluate article quality and funnel plots were created to identify potential publication bias. The random-effects model was used when significant heterogeneity was identified. Results In total, nine retrospective studies and two randomized controlled trials (RCTs) involving 2331 patients were included. Decreased intraoperative blood loss, shorter hospital stay, lower incidence of pulmonary complications, and longer 3-year overall survival were observed in the TH group. There were no significant differences concerning duration of surgery, R0 resection rate, number of dissected lymph nodes, perioperative mortality and morbidity rate, abdominal complication rate, or anastomotic leak rate. With regard to 5-year overall survival, a potential benefit may be achieved with the TH approach, which requires further confirmation. Conclusion In terms of surgery-related and long-term outcomes, the TH approach may be more appropriate for Siewert type Ⅱ adenocarcinoma of EGJ, especially for esophagus invasion ≤4 cm.

https://www.tandfonline.com/doi/pdf/10.1080/17474124.2020.1806710

Transhiatal versus transthoracic surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction: a meta-analysis.

A novel multidimensional inflammatory and nutritional assessment system named the Naples prognostic score could serve as an independent prognostic indicator. However, its significance in patients with high- and intermediate-risk gastrointestinal stromal tumours remains unclear.We performed this retrospective cohort study based on a prospectively collected database of gastrointestinal stromal tumours (GISTs) between March 2010 and December 2019. The Kaplan-Meier method and log-rank test were used for survival analyses. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression analysis was used for univariate and multivariate analyses. Time-dependent receiver operating characteristic curves were generated to evaluate the discriminatory ability of the prognostic scoring systems. Differences in the areas under the curve were further compared.A total of 405 patients with regular follow-up were included and analysed in this study. Significant differences in progression-free survival and overall survival were observed between the groups (P < 0.001). Multivariate analysis demonstrated that the NPS was a significant predictor of poor progression-free survival (1 vs 0, HR = 4.622, P = 0.001; 2 vs 0, HR = 12.770, P < 0.001) and overall survival (2 vs 0, HR = 5.535, P = 0.002). Furthermore, time-dependent AUC analyses showed that the NPS was more accurate than other haematologic prognostic systems.The present study demonstrates that the NPS could independently predict disease progression and survival among patients with high- and intermediate-risk GISTs. The NPS might be regarded and applied as one of the most convenient and effective preoperative risk stratification tools in the future, which should be validated by large-scale multicentre prospective cohort studies. 

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Naples prognostic score, a novel prognostic score for patients with high- and intermediate-risk gastrointestinal stromal tumours after surgical resection

Background Multiple gastrointestinal stromal tumors (MGISTs) are specific and rare. Little is known about the impact of MGISTs on the survival of patients with gastrointestinal stromal tumors (GIST). The diagnosis, treatment and follow-up strategies of MGISTs is not specifically described in guidelines. Aim To compare the clinicopathological characteristics and prognosis of MGISTs and solitary GISTs (SGISTs). Methods Patients diagnosed with primary GISTs from March 2010 to January 2020 were included. Due to the inhomogeneous distribution of several baseline characteristics and uneven MGIST and SGIST group sizes, propensity score matching was performed according to comorbidities, body mass index, tumor location, mitotic index, sex, age and American Society of Anesthesiologists score. Differences in clinicopathological characteristics and prognosis between patients with MGISTs and patients with SGISTs were compared. Results Among the entire cohort of 983 patients, the incidence of MGISTs was 4.17%. Before matching, patients with MGISTs and those with SGISTs had disparities in body mass index, surgical approach, tumor size and mitotic index. After 1:4 ratio matching, the clinical baseline data were comparable. The 5-year progression-free survival rate was 52.17% in the MGIST group and 75.00% in the SGIST group (P = 0.031). On multivariate analysis, tumor location, tumor size, mitotic index, imatinib treatment and MGISTs (hazard ratio = 2.431, 95% confidence interval = 1.097-5.386, P = 0.029) were identified as independent prognostic factors of progression-free survival. However, overall survival was similar between the SGIST and MGIST groups. Conclusion Patients with MGISTs had poorer progression-free survival than patients with SGISTs. Risk criteria and diagnostic and treatment strategies should be developed to achieve personalized precision therapy and maximize the survival benefit.

Clinicopathological characteristics and longterm survival of patients with synchronous multiple primary gastrointestinal stromal tumors: A propensity score matching analysis

Background. The management of 2-5 cm gastric gastrointestinal stromal tumours (GISTs) is still debated between surgeons and endoscopists. We aimed to investigate short-term and long-term outcomes between surgical resection (SR) and endoscopic resection (ER). Methods. This study included 67 and 215 patients between 2010 and 2020 who underwent ER and SR, respectively. After propensity score matching, the clinical outcomes were compared. Individual patient information that requires special instructions is also summarized. Results. After matching, the operation time (P=0.005) and postoperative hospital stay (P=0.005) were significantly longer in the SR group than in the ER group. However, there were no significant differences in blood loss (P=0.741), resection margin (P=1.000) or time to liquid diet (P=0.055). Statistical differences were also seen in en bloc resection (P<0.001) and adverse events (P=0.027). The recurrence rate did not differ significantly between the two techniques, and the mitotic index and ulceration were identified as independent prognostic factors of progression-free survival. Conclusions. ER might be comparable to SR for the treatment of 2-3 cm gastric GISTs. SR is still considered the standard treatment for 3-5 cm gastric GISTs, while the intraoperative and postoperative information of ER should be recorded in detail and closely evaluated. Surgical resection is recommended if the tumour has a high mitotic index or mucosal ulceration.

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Surgical Resection Is Still Better Than Endoscopic Resection for Patients With 2-5 cm Gastric Gastrointestinal Stromal Tumours: A Propensity Score Matching Analysis.

Mengdi Fu

Papers

The role and application of small extracellular vesicles in gastric cancer

Transhiatal versus transthoracic surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction: a meta-analysis.

Naples prognostic score, a novel prognostic score for patients with high- and intermediate-risk gastrointestinal stromal tumours after surgical resection

Clinicopathological characteristics and longterm survival of patients with synchronous multiple primary gastrointestinal stromal tumors: A propensity score matching analysis

Surgical Resection Is Still Better Than Endoscopic Resection for Patients With 2-5 cm Gastric Gastrointestinal Stromal Tumours: A Propensity Score Matching Analysis.