Postoperative recurrence remains common in patients with Siewert type II/III gastroesophageal junction adenocarcinoma (AEG), and conventional TNM staging provides limited individualized prognostic information. This study aimed to develop and validate a composite Nutritional Risk Index and Hemoglobin-to-Platelet Ratio (NRI-HPR) score for predicting recurrence and survival. A total of 270 patients who underwent curative gastrectomy between 2011 and 2015 were included as the training cohort, and 117 patients treated between 2020 and 2023 were enrolled as an independent validation cohort. Patients were stratified into three NRI-HPR score groups according to predefined cutoffs. Survival outcomes and recurrence patterns were analyzed using Kaplan–Meier and Cox regression analyses. Prognostic nomograms incorporating NRI-HPR were constructed and validated. In the training cohort, 5-year recurrence-free survival (RFS) rates were 79.6

Bioadhesives represent promising alternatives to sutures towards gastric perforation management, however, significant challenges persist concerning instant wet adhesion and durable stability in gastric perforation sealing, particularly in direct contacting with acidic gastric fluids on large perforation injuries. Here we report an injectable acid-tolerant hydrogel composed of FDA-approved components for sutureless repair of large gastric defects. The hydrogel displays rapid in situ gelation, instant wet adhesion, and high burst pressure for efficient sealing despite excessive mechanical challenges, tissue irregularities and gastric juices. The enhanced hydrogen bonding interactions among amide-linked skeleton enable robust acid-tolerant interfaces to accommodate durable adhesion under the fluidically, chemically and mechanically dynamic in-vivo environments. A larger-scale porcine gastric perforation is applied to validate the sealing efficacy via a combined laparoscopic-endoscopic technique. The negligible postoperative adhesion, suppressed inflammation and interference-free transcriptome and microbiome verify the therapeutic outcomes. The proposed bioadhesives hold great promise for clinical treatment of digestive diseases.

Despite recent advances in surgical adhesives as promising alternatives to sutures or staplers for colonic defects and gastrointestinal management, significant challenges persist regarding to excellent biocompatibility, injectability operation, robust tissue adhesion and durable stability in colon environments due to the growing popularity of minimally invasive laparoscopy. In this work, we reported an in situ injectable hydrogel bioadhesive (OSG) consisting of FDA-approved Octa-armed poly (ethylene glycol) succinimidyl glutarate (Octa-PEGSG) and Octa-armed poly (ethylene glycol) amine (Octa-PEG-NH2) polymers for sutureless repair of large colonic defects. The OSG hydrogel was advantageous to rapid injection to cover the whole irregular surfaces via the formation of uniform networks and chemical interface binding, and capable of instant adhesion, high burst pressure, secure sutureless closure and durable compliance in the ex vivo porcine colonic injury models, thus enabling robust wet adhesion interfaces even in direct contact with intestinal fluids and constant colonic peristalsis. In terms of excellent biocompatibility and suitable degradability after a comprehensive evaluation from in vivo and in vitro studies, OSG hydrogel was validated with efficient sutureless colonic repair in a rat-injured model without causing postoperative adhesion, long-term inflammatory response and colonic transcriptome and microbiome interference. Innovatively, we further established large-size (3 cm) of porcine colonic defect models by minimally invasive technique, and verified its therapeutic effect under laparoscopic technology. Overall, the proposed OSG bioadhesive offers a promising clinical alternative to sutures for the treatment of colonic defects.

Interactions between the microbiota and host have been proven to be critical regulators of homeostasis, and pain perception is no exception. Emerging evidence has identified the mechanisms by which microbiota dysbiosis contributes to hyperalgesia and revealed the potential value of microbiota-associated therapies in pain management. Herein, the authors introduce the basic knowledge of pain and microbiota for readers who are not simultaneously majoring in these two fields. The clarified mechanisms underlying the regulation of pain by the microbiota are outlined in terms of three ways. This review summarizes the current advancements in pain management and microbiology research for clinicians who wish to focus on this area. Probiotics, fecal microbiota transplantation, and other methods of microbiota modulation for pain management have entered clinical translation. The authors further propose the present limitations and prospects for high-quality development of preclinical and clinical investigations. Importantly, despite the large amount of attention given to gut bacteria, this review also puts forward great expectations on the role of nongut and nonbacterial microbiota in pain sensation. Efforts to decipher the mechanisms of microbiota functions will help to promote achievements in pain management from bench to bedside.

A fasting mimic diet (FMD) has been proven to be a potential therapeutic regimen for gastric cancer (GC) patients. However, the intolerance of energy restriction and limited efficacies hinder wide application of FMD. To identify critical targets mediating resistance against glucose starvation and explore novel approaches to GC therapy, proteomics profiling was performed to depict the landscape of protein expression changes in cells under glucose deprivation. MZT1 was found to be greatly upregulated. We next investigated potential clinical value and regulatory functions of MZT1. Compared to adjacent normal tissues, MZT1 was upregulated in GC specimens and associated with unfavorable patient prognosis. Both in vitro and in vivo experiments indicated that downregulation of the MZT1 level inhibited GC proliferation, migration, invasion, glycolysis and sensitized cells to glucose starvation. Mechanistically, MZT1 functioned as an oncogenic factor by inhibiting NEDD1 ubiquitination and increasing its expression. In conclusion, during glucose starvation, MZT1 is upregulated in GC cells, which promotes resistance by directly suppression of NEDD1 ubiquitination. Our findings unveil the novel mechanisms by which MZT1 can promote GC malignancy. The potential clinical value of MZT1 as GC biomarkers has been first revealed. Suppression of MZT1 may become a promising approach to improve FMD efficacy, which require further validation by future investigations.

BACKGROUND:Chronic psychological stress is a critical oncogenic factor of gastric cancer (GC). However, the mechanisms underlying stress-induced malignant progression remain largely unknown. Gut microbiota dysregulation is tightly associated with cancer development and metabolism. MATERIALS AND METHODS:Chronic unpredictable mild stress (CUMS) modeling was used to prepare mice suffering from chronic psychological stress. 16s rRNA sequencing and Q300 targeted metabolite quantification were jointly conducted to depict landscapes of gut microbiome and metabolomics of CUMS mice. Fecal microbiota transplantation was employed to investigate the functions of gut microbial communities in regulating CUMS-mediated GC growth. Drug affinity responsive target stability, surface plasmon resonance and molecular docking assays were performed to screen direct target proteins of 5Z-dodecenoic acid. The interactions between RIOK2 and BYSL were verified with co-immunoprecipitation and GST pull-down and fluorescent co-localization analysis. A series of experiments for malignant behaviors and glycolysis and subcutaneous tumor transplantation were employed to detect alterations of GC cell phenotypes ex vivo and in vivo, respectively. RESULTS:Microbiome and metabolomics collectively demonstrated disrupted gut microbial communities and metabolic patterns. Particularly, Blautia coccoides-derived 5Z-dodecenoic acid was predominately declined by CUMS. Supplementation with Blautia coccoides or 5Z-dodecenoic acid effectively mitigated the negative effects of CUMS on glycolysis and malignancy. Mechanistically, 5Z-dodecenoic acid directly inhibits the functions of RIOK2, which maintained ectopic glycolysis and malignant behaviors. RIOK2 further interacted with BYSL and maintained its properties of potentiation of GC progression and metabolism. CONCLUSION:Our findings advance the insights of Blautia coccoides-derived 5Z-dodecenoic acid implicated in chronic psychological stress-induced GC progression and provide novel strategies for dampening GC progression.

BACKGROUND AND OBJECTIVES:The occurrence of anastomotic leakage (AL) and gastroparesis syndrome (GS), common and severe complications after laparoscopic radical gastrectomy, significantly impacts the prognosis of patients. The objective of this study was to investigate the risk factors associated with AL after laparoscopic radical gastrectomy and GS after laparoscopic distal gastrectomy. METHODS:In this retrospective cohort study, 3779 patients who underwent laparoscopic radical gastrectomy and met the inclusion criteria were included. Of the 3779 patients, 85 (2.2%) were diagnosed with AL. The diagnosis of GS was made in 35 (2.4%) patients who underwent laparoscopic distal gastrectomy. Subsequently, univariate and multivariate logistic regression analyses were performed to determine the risk factors associated with AL and GS. RESULTS:The presence of hypoalbuminemia [odds ratio (OR)=2.437, 95% CI: 1.416-4.196, P =0.001] and intraoperative blood loss >150 ml (OR=1.712, 95% CI: 1.073-2.731, P =0.024) could be used as independent risk factors for AL. Total gastrectomy (OR=0.461, 95% CI: 0.264-0.805, P =0.006) and distal gastrectomy (OR=0.488, 95% CI: 0.276-0.863, P =0.014) were identified as the protective factors for AL. The presence of smoking history (OR=2.022, 95% CI: 1.022-4.001, P =0.043), pyloric obstruction (OR=3.748, 95% CI: 1.476-9.518, P =0.005), and Roux-en-Y anastomosis (OR=4.432, 95% CI: 1.292-15.206, P =0.018) were proved to be independently associated with GS for patients who underwent laparoscopic distal gastrectomy. CONCLUSIONS:This study delineates distinct risk factors for AL and GS after laparoscopic gastrectomy. Contrary to preservation paradigms, total gastrectomy reduced AL risk versus proximal gastrectomy, challenging current proximal tumor management strategies.

Objective: This study aimed to analyze the prognostic risk factors for hepatoid adenocarcinoma of the stomach (HAS) and construct two nomogram-based clinical prediction models to predict overall survival (OS) and recurrence-free survival (RFS) in patients with HAS. Methods: Data were retrospectively collected from 82 patients (64 males, 18 females; mean age 60.3 ± 9.4 years) who underwent radical gastrectomy and were pathologically diagnosed with gastric hepatoid adenocarcinoma at the First Medical Center of the PLA General Hospital between February 2006 and September 2023. Statistical analyses were conducted using SPSS 25.0 and R 4.3.2. Survival analyses were performed using the Kaplan-Meier method, and univariate analyses were used to identify clinical and pathological factors associated with prognosis. Variables with P<0.05 in the univariate analysis were included in multivariate Cox regression models to identify independent risk factors for OS and RFS. These factors were incorporated into the prediction models to construct nomograms. The discriminatory power of the models was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC) analyses, while calibration curves, decision curve analysis (DCA), and comparisons with the 8th edition of the TNM staging system of the American Joint Committee on Cancer (AJCC) were employed to evaluate model performance. Results: Among the 82 patients, 36 (43.9%) exhibited vascular infiltration, 61 (74.4%) had nerve infiltration, and lymph node metastasis was observed in 60 cases (73.2%). Pathological stages I, II, III, and IV were distributed as 11 (13.4%), 26 (31.7%), 44 (53.7%), and 1 (1.2%) cases, respectively. Inflammatory markers included neutrophil-to-lymphocyte ratio (NLR) ≥ 4.33 in 22 cases (26.8%), platelet-to-lymphocyte ratio (PLR) ≥ 142.2 in 50 cases (61.0%), monocyte-to-lymphocyte ratio (MLR) ≥ 0.411 in 22 cases (26.8%), α-fetoprotein (AFP) ≥ 2.48 µg/L in 64 cases (78.0%), and C-reactive protein (CRP) ≥ 7.506 mg/L in 12 cases (14.6%). Among the 82 patients, 3 cases (3.6%) were lost to follow-up. The median follow-up time was 52 (range: 8-147) months, with a median OS of 61(2-147) months. The 1-year and 3-year OS rates were 78.5% and 58.5%, respectively, while the 1-year and 3-year RFS rates were 77.3% and 60.3%, respectively. Multivariate analysis identified several independent risk factors influencing OS in patients with HAS: advanced pathological stage, MLR ≥ 0.411, AFP ≥ 2.545 µg/L, and CRP ≥ 7.51 mg/L. The hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: 5.218 (1.230-22.143), 2.610 (1.287-5.294), 2.950 (1.013-8.589), and 2.594 (1.145-5.877), respectively (all P < 0.05). For RFS, advanced pathological stage, PLR ≥ 152.0, and MLR ≥ 0.411 were independent risk factors, with HRs (95% CIs) of 4.735 (1.080-20.760), 3.759 (1.259-11.226), and 2.714 (1.218-6.048), respectively (all P < 0.05). The AUC values for OS prediction at 1 year, 3 years, and 5 years were 0.7765, 0.7525, and 0.7702, respectively. For RFS, the AUC values were 0.7304, 0.8137, and 0.8307 at 1 year, 3 years, and 5 years, respectively. The calibration curves demonstrated strong agreement between nomogram- predicted outcomes and observed survival data. DCA indicated that both TNM staging and the nomogram-based clinical prediction models provided a net positive benefit in predicting OS and RFS in HAS patients, with the nomogram model demonstrating superior performance. Conclusion: The nomogram-based clinical prediction models developed in this study demonstrated robust performance in predicting long-term OS and RFS in patients with HAS.

Fructose-1,6-bisphosphatase (FBPase) serves as the rate-limiting enzyme in gluconeogenesis and can be categorized into two subtypes: FBP1 and FBP2. FBP1 has been reported to exhibit reduced expression and impaired function in various malignant tumors. However, there is limited research investigating the role of FBP2 in tumorigenesis. Our results showed that the expression level of FBP2 in gastric cancer (GC) tissues was reduced compared to that in adjacent non-tumor tissues. Low FBP2 expression was correlated with adverse clinicopathological characteristics and unfavorable prognosis. Overexpression of FBP2 in GC cells resulted in a decreased expression level of hypoxia inducible factor-1α (HIF-1α), enhanced oxidative phosphorylation, and a modest reduction in glycolytic activity. Notably, the FBP2 has been shown to elevate the expression level of hexokinase domain-containing protein-1 (HKDC1). Both cellular and animal studies demonstrated that the overexpression of FBP2 or the knockdown of HKDC1 could attenuate the malignant biological behavior of GC. Moreover, the synergistic effect of these two approaches exerted a more potent anti-tumor response. Overall, the synergistic effect of FBP2 and HKDC1 can suppress the progression of GC through the promotion of oxidative phosphorylation and inhibition of glycolysis. FBP2 and HKDC1 are anticipated to serve as novel molecular markers for the diagnosis, targeted therapy, and prognosis of GC.

Abstract Background The effect of neoadjuvant immunotherapy on minimally invasive gastrectomy (MIG) in older patients with gastric cancer remains controversial. This study aimed to evaluate the safety, and efficacy of MIG for older patients who underwent neoadjuvant chemotherapy and immunotherapy (NICT). Methods The clinical data of 726 older patients aged over 65 years who underwent upfront MIG or MIG after NICT in the Department of General Surgery, Chinese PLA General Hospital First Medical Center between Jan 2020 and Nov 2023 were retrospectively analyzed. Propensity score-matched (PSM) analysis at a ratio of 1:2 was performed to reduce bias from confounding patient-related variables, short- and long-term outcomes were compared between the two groups. Results The baseline characteristics were comparable between 61 patients in the NICT-MIG group and 114 patients in the MIG group after PSM (P > 0.05). The major pathological response (MPR) rate and pathological complete response (pCR) rate were 44.2% and 21.3%, respectively, in the NICT-MIG group. Patients in the NICT-MIG group had longer operation times (P = 0.005) and postoperative days (P = 0.030) than those in the MIG group. No significant differences were found in intraoperative bleeding, number of retrieved lymph nodes, first flatus day, R0 resection rate, overall postoperative complication (POC) morbidity, severe POC morbidity, 2-year overall, and recurrence-free survival between the MIG and NICT-MIG groups (P > 0.05). Multivariate logistic analysis revealed that an estimated blood loss > 200 mL (P = 0.010) and a lymphocyte-to-monocyte ratio (LMR) ≤ 3.25 (P = 0.006) were independent risk factors for POCs after MIG in older patients. Conclusion The safety, and efficacy of NICT-MIG were comparable to those of upfront MIG in older patients with GC. Patients with an estimated blood loss > 200 mL or an LMR ≤ 3.25 should be carefully evaluated for an increased risk of POCs in older patients who undergo MIG. Trial registration Chinese Clinical Trial Registry (Registration Number: ChiCTR2400086827).

Accumulating evidence has proved the close association between alterations in gut microbiota and resistance to chemotherapeutic drugs. However, the potential roles of gut microbiota in regulating oxaliplatin sensitivity in gastric cancer (GC) have not been investigated before. We first found that antibiotic treatment diminished the therapeutic efficacy of oxaliplatin in a GC mouse model. Importantly, this effect could be transmitted to germ-free mice via fecal microbiota transplantation, indicating a potential role of gut microbiota modulation in oxaliplatin efficacy. Further, metagenomics data showed that Akkermansia muciniphila (A. muciniphila) ranked first among the bacterial species with decreased relative abundances after antibiotic treatment. Metabolically active A. muciniphila promotes oxaliplatin efficacy. As shown by metabolomics analysis, the metabolic pattern of gut microbiota was disrupted with significantly downregulated levels of pentadecanoic acid (PEA), and the use of PEA significantly promoted oxaliplatin efficacy. Mechanistically, FUBP1 positively regulated aerobic glycolysis of GC cells to hinder the therapeutic efficacy of oxaliplatin. A. muciniphila-derived PEA functioned as an inhibitory factor of glycolysis by directly antagonizing the activity of FUBP1, which potentiated GC responses to oxaliplatin. Our research suggested a key role for intestinal A. muciniphila and its metabolite PEA in promoting oxaliplatin efficacy, thus providing a new perspective for probiotic and prebiotic intervention in GC patients during chemotherapy.

Background: Although chemoresistance constitutes a significant barrier to the effectiveness of chemotherapy in colorectal cancer (CRC), its precise mechanisms remain unclear. YAP functions as an oncogene in various malignancies. However, the relationship between YAP and chemoresistance in CRC needs clarification. Methods: The expression level of YAP in CRC tissues was assessed through immunohistochemistry (IHC), and the impact of YAP on CRC cell chemoresistance was evaluated using the Cell Counting Kit-8, EdU, and flow cytometry assays. Meanwhile, tumor proliferation was assessed in vivo by analyzing the expression of PCNA and Ki-67 in subcutaneous tumors via IHC. In addition, the TUNEL assay was employed to evaluate tumor apoptosis levels and western blot was utilized to detect the mTOR/GLUT3 pathway-related protein expression to provide insights into the underlying mechanism. Results: YAP was highly expressed in CRC tissues and correlated with patient prognosis and clinicopathological features. Bioinformatic analysis based on the TCGA database revealed that YAP was associated with DNA replication, glycolysis, and the mTOR pathway. Meanwhile, YAP could enhance chemoresistance and glycolysis in CRC cells both in vitro and in vivo. Additional mechanistic experiments unveiled that YAP promoted CRC cell chemoresistance via the mTOR/GLUT3 axis. Conclusion: This study validated the role of YAP as an oncogene in CRC, as it promoted chemoresistance through the mTOR/GLUT3 axis. These results suggested YAP as a potential target for promoting the efficacy of chemotherapy in patients with CRC.

Background: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). Method: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. The authors examined 367 patients with proximal GC who received NACT followed by PG (n=164) or TG (n=203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. Results: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P>0.05). The TG group had a higher total number of lymph nodes retrieved (P<0.001) and longer operative time (P=0.007) compared to the PG group. The incidence of Clavien-Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (17.5%, 14/80) (P=0.689). The 5-year OS rates were 68.4 for the PG group and 66.0% for the TG group (P=0.881), while the 5-year RFS rates were 64.8 and 61.9%, respectively (P=0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74, 0.67, 1.33, and 1.74%, respectively. Conclusion: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.

Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

Traumatic colon injury (TCI) is a typical injury with high mortality. Prolongation of the intervention time window is a potentially useful approach to improving the outcomes of TCI casualties. This study aimed to identify the pathological mechanisms of TCI and to develop effective strategies to extend the survival time. A semicircular incision was made to prepare a TCI model using C57BL/6 mice. An overview of microbiota dysregulation was achieved by metagenome sequencing. Protein expression reprogramming in the intestinal epithelium was investigated using proteomics profiling. The mice that were subjected to TCI died within a short period of time when not treated. Gut symbiosis showed abrupt turbulence, and specific pathogenic bacteria rapidly proliferated. The protein expression in the intestinal epithelium was also reprogrammed. Among the differentially expressed proteins, SERPINA3N was overexpressed after TCI modeling. Deletion of Serpina3n prolonged the posttraumatic survival time of mice with TCI by improving gut homeostasis in vivo. To promote the translational application of this research, the effects of melatonin (MLT), an oral inhibitor of the SERPINA3N protein, were further investigated. MLT effectively downregulated SERPINA3N expression and mitigated TCI-induced death by suppressing the NF-κB signaling pathway. Our findings prove that preventive administration of MLT serves as an effective regimen to prolong the posttraumatic survival time by restoring gut homeostasis perturbed by TCI. It may become a novel strategy for improving the prognosis of patients suffering from TCI.

Long non-coding RNA colon cancer-associated transcript 2 (lncRNA CCAT2) lncRNA CCAT2 is a type of RNA encoded by human 8q24 chromosomal region and plays diverse mechanisms in oncobiologic behaviors. lncRNA CCAT2, as a tumorigenic factor, participates in the upstream and downstream regulation of multiple signaling pathways. It involves in the process of neoplastic invasion and metastasis through regulating molecular sponge, chromosome modification, and post-transcriptional modification. It interacts with microRNAs to form the competing endogenous RNA and constitutes of complex lncRNA-microRNA interaction regulatory networks. The lncRNA CCAT2 also engages in the regulation of multiple classical signaling pathways such as Wnt/β-catenin pathway, and it interacts with a variety of RNA-binding proteins to promote the invasion and metastasis of tumors. It has been gradually acknowledged that the single nucleotide polymorphism of lncRNA CCAT2 influences the malignant progression of tumors, which may provide evidence for fully demonstrating the genetic structures and molecular functions of lncRNA CCAT2. The research on molecular biological functions of lncRNA CCAT2 may not only facilitate the drawing of a comprehensive regulatory map of lncRNA CCAT2 on invasion and metastasis of tumors but also provide scientific theoretical basis for development of targeted drugs and gene detection based on the regulatory map of lncRNA CCAT2.

ObjectiveGastric cancer (GC) is one of the most malignant tumors worldwide. Thus, it is necessary to explore the underlying mechanisms of GC progression and develop novel therapeutic regimens. Long non-coding RNAs (lncRNAs) have been demonstrated to be abnormally expressed and regulate the malignant behaviors of cancer cells. Our previous research demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) has potential value for GC diagnosis and discrimination. However, the functional mechanisms of lncRNA CCAT2 in GC development remain to be explored.MethodsGC and normal adjacent tissues were collected to detect the expression of lncRNA CCAT2, ESRP1 and CD44 inclinical specimens and their clinical significance for GC patients. Cell counting kit-8, wound healing and transwell assays were conducted to investigate the malignant behaviors in vitro. The generation of nude mouse xenografts by subcutaneous, intraperitoneal and tail vein injection was performed to examine GC growth and metastasis in vivo. Co-immunoprecipitation, RNA-binding protein pull-down assay and fluorescence in situ hybridization were performed to reveal the binding relationships between ESRP1 and CD44.ResultsIn the present study, lncRNA CCAT2 was overexpressed in GC tissues compared to adjacent normal tissues and correlated with short survival time of patients. lncRNA CCAT2 promoted the proliferation, migration and invasion of GC cells. Its overexpression modulates alternative splicing of Cluster of differentiation 44 (CD44) variants and facilitates the conversion from the standard form to variable CD44 isoform 6 (CD44v6). Mechanistically, lncRNA CCAT2 upregulated CD44v6 expression by binding to epithelial splicing regulatory protein 1 (ESRP1), which subsequently mediates CD44 alternative splicing. The oncogenicrole of the lncRNA CCAT2/ESRP1/CD44 axis in the promotion of malignant behaviors was verified by both in vivo and in vitro experiments. ConclusionsOur findings identified a novel mechanism by which lncRNA CCAT2, as a type of protein-binding RNA,regulates alternative splicing of CD44 and promotes GC progression. This axis may become an effective target for clinical diagnosis and treatment.

Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It has been proven as a targeted drug for gastric cancer (GC) therapy. However, long-term treatment with everolimus may cause severe side effects for recipients. Decreasing the dosage and attenuating the associated risks are feasible to promote clinical translation of everolimus. This study aimed to identify the underlying mechanisms of responses to everolimus and develop novel regimens for GC treatment. Our findings proved that there was a significant dose-dependent relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was actively upregulated to counteract the anticancer effects of everolimus. GLUT12 might be overexpressed in GC. High expression of GLUT12 might be correlated with tumor progression and short survival time of GC patients. Bioinformatic analysis suggested that GLUT12 might be involved in regulating cancer development and metabolism. The experiments proved that GLUT12 significantly promoted GC growth, glycolysis and impaired the anticancer effects of everolimus. Androgen receptor (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated the promotive effects on GLUT12 expression. Both in-vitro and in-vivo experiments demonstrated that GLUT12 knockdown augmented anticancer effects of everolimus. Enzalutamide, an AR inhibitor, or AR knockdown was comparable to GLUT12 suppression. This study identified the role of the AR/GLUT12 pathway in the development of poor responses to everolimus. Interference with AR/GLUT12 pathway may serve as a promising approach to promoting the translational application of everolimus in GC therapy.

To the Editor: Retroperitoneal liposarcoma (RLS) pertains to one of the rare malignant tumors originated from the retroperitoneum. It is evaluated as the most common type of retroperitoneal sarcoma. RLS can be divided into four subtypes according to the pathological classification, which includes well-differentiated liposarcoma (WDL), dedifferentiated liposarcoma (DDL), myxoid cell liposarcoma (MLS), and pleomorphic liposarcoma (PLS).[1] Giant RLS refers to the RLS with long diameter two times larger than the specified length of pathologic tumor stage-4 (pT4) category (≥30 cm) according to the eighth version of the American Joint Committee on Cancer (AJCC) Staging Manual.[2] Despite relatively low incidence, it brings great health burdens for patients and the standard therapeutic strategies remain to be explored. There are specific features of giant RLS according to clinical experience. For instance, giant RLS can occupy almost the entire abdominal cavity, close to or even wrapping around the inferior vena cava. Due to its location in the deep abdomen, patients usually have untypical symptoms at the early stage. The obvious signs and symptoms can be perceived only when the tumor becomes giant. These features increase difficulties in achieving complete resection during surgery and satisfactory patient outcomes. In addition, there is a lack of comprehensive research on the characteristics of giant RLS, which hinders the further progress of its diagnosis and targeted therapies. Identification of giant RLS characteristics may have great significance in clinical practice. Herein, we conducted a single-center retrospective study to reveal the clinicopathological features and outcomes of patients with giant RLS. This study was approved by the Protection of Human Subjects Committee of the Chinese People's Liberation Army (PLA) General Hospital (No. S2015-106-01). Informed written consent was provided by all participants included in this study. A total of 61 patients with giant RLS who received treatment at the First Medical Center, PLA General Hospital from January 2000 to December 2015 were enrolled in this study. Those with remote metastasis or perioperative death, or who received chemoradiotherapy were excluded from this study. The complete surgical margin referred to the resected margin without observable tumors. The complete resection was defined as the operation that macroscopically resected RLS without residual tumors. The time point of recurrence was when the recurrent region of RLS was detected. Overall survival (OS) referred to the time from surgical complete resection to the end of 5-year follow-up or death. Recurrence-free survival (RFS) was defined as the time from surgical complete resection to the onset of recurrence or death within 5 years.[3] Univariate analysis was performed for the selection of factors that were correlated with OS or RFS. The candidate factors were next included in the multivariate analysis to determine independent prognostic factors using Cox regression model. The categorical data were expressed as number (percentage); continuous variables were expressed as median (Q1–Q3) since they are not normally distributed. All data were analyzed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp, Armonk, New York, USA). A two-sided P-value < 0.05 was considered statistically significant. In this retrospective study, there were 34 male (56%) and 27 female (44%) patients. The median age of them was 55 (46–63) years. The median size of tumors was 35 (31–40) cm [Supplementary Table 1, https://links.lww.com/CM9/B211], and the giant tumors could occupy the entire abdominal cavity [Supplementary Figure 1, https://links.lww.com/CM9/B211]. Considering the proportions and differentiation status of the four pathological subtypes of giant RLS, the patients were divided into two subgroups: WDL and non-WDL groups. WDL group accounted for the largest proportions among the four subtypes (34/61, 56%); the remaining 27 cases with DDL, MLS, and PLS subtypes were classified as the non-WDL group (44%). A total of 41 patients underwent organ resection (67%) and 17 cases were subjected to the resection of three and more organs (28%) [Supplementary Table 1, https://links.lww.com/CM9/B211]. The colon was the most frequently removed organ [Supplementary Figure 2, https://links.lww.com/CM9/B211]. Postoperative complications were evaluated according to the Clavien–Dindo classification.[4] There were 19 cases scored as Grade I (31%); while 42 cases underwent more serious complications were scored as Grades II–IV (69%) [Supplementary Table 1, https://links.lww.com/CM9/B211]. Subgroup analysis showed that 52% of cases in WDL group who received complete resection suffered from the Grade II–IV complications (13/25), while 81% of cases in non-WDL group who received complete resection had the Grade II–IV complications (13/16) [Supplementary Figure 3, https://links.lww.com/CM9/B211]. The median OS of all patients was 40 months during the 5-year follow up. The 1-, 3-, and 5-year OS rates were 83.8%, 51.7%, and 31.3%, respectively [Figure 1A]. To explore prognostic factors of 5-year OS for patients with giant RLS, univariate analysis was performed and indicated that resection times, resection method, intraoperative bleeding volume, total transfusion volume, postoperative complication, tumor morphology, tumor number, completeness of tumor capsule, pathological subtype, and status of surgical margin had significant correlations with 5-year OS (all P < 0.05) [Supplementary Table 1, https://links.lww.com/CM9/B211]. Variables with statistical significance were further examined using multivariate analysis. The results showed that postoperative complication and status of surgical margin were the prognostic factors of 5-year OS (both P < 0.05) [Supplementary Table 1, https://links.lww.com/CM9/B211].Figure 1: The 5-year OS and RFS analysis of patients with giant RLS. (A) The 5-year OS analysis of all 61 giant RLS patients included in this study. (B and C) The 5-year OS analysis of patients with WDL subtype (B) and non-WDL subtype (C) undergoing complete and incomplete resection. (D and E) The 5-year OS analysis of patients based on postoperative complication grades (D) and surgical margin status (E). (F) The 5-year RFS analysis of all 41 patients who received complete resection. (G and H) The 5-year RFS analysis of patients based on tumor capsule completeness (G) and resection times (H). OS: Overall survival; RFS: Recurrence-free survival; RLS: Retroperitoneal liposarcoma; WDL: Well-differentiated liposarcoma.The patients were next stratified to investigate the 5-year OS of subpopulations. Patients with WDL subtype of giant RLS who received complete resection had significantly better 5-year OS than those who received incomplete resection (P < 0.05) [Figure 1B]; whereas, for those with non-WDL subtypes, the difference between the two groups with complete or incomplete resections was not significant (P > 0.05) [Figure 1C]. In addition, we found that the patients who had milder postoperative complications or negative surgical margins obtained better 5-year OS (P < 0.05) [Figures 1D and 1E]. For the investigations into prognostic factors of RFS, data of 41 of the 61 patients, who received complete resection, were analyzed [Supplementary Table 2, https://links.lww.com/CM9/B211]. A total of 33 patients experienced local recurrence within 5 years. The median RFS was 15 (8–25) months. The 1-, 3-, and 5-year RFS rates of patients were 61.6%, 18.7%, and 13.4%, respectively [Figure 1F]. According to the univariate analysis, resection times, pathological subtype, and completeness of tumor capsule were correlated with 5-year RFS (all P < 0.05). After multivariate analysis, only the pathological subtype (P < 0.05) showed as an independent prognostic factor of 5-year RFS [Supplementary Table 2, https://links.lww.com/CM9/B211]. In addition, we found that the 5-year RFS of patients who had incomplete tumor capsules or multiple surgeries (resection times >3) was worse (both P < 0.05) [Figures 1G and 1H]. Few studies focused on the clinicopathological characteristics and survival outcomes of patients with giant RLS. Our study aimed to investigate the clinical features and risk factors of giant RLS, providing basic evidence for the development of giant RLS therapy. Compared with the survival outcomes of patients with non-giant RLS reported by other studies, those who suffered from giant RLS may have a worse prognosis.[5] Moreover, the processes of giant RLS resection are complicated, which may increase the risks of postoperative complications. In this study, we found that serious postoperative complication was significantly associated with the poor prognosis of patients with giant RLS. The importance of postoperative management of complications should be emphasized for patients with giant RLS. The role of pathological subtype in predicting the survival time of patients with ordinary RLS has been revealed in recent years. In this study, however, the pathological subtype was not proved to be an independent prognostic factor of 5-year OS. This contradiction may be attributable to the progression of giant RLS. The pathological subtype presented in this study was identified during the last surgery before follow-up. Well-differentiated giant RLS may progress to poorly-differentiated subtype, promoting tumor invasion, and attenuating survival benefits of patients. Additionally, the follow-up endpoint for RFS is tumor recurrence or a patient's death. RFS can reflect the effects of detected pathological subtype on survival time, free from potential influences of subsequent progression. Our findings proved that pathological subtype served as an independent factor of 5-year RFS, which further verifies our assumption that giant RLS may have a natural tendency to malignant progression. The completeness of surgical resection has been reported as an independent prognostic factor of patients with RLS. Supported by this evidence, wide application of complete RLS resection has been recommended. However, this opinion may be inappropriate for the treatment of giant RLS. In this study, giant tumors in many cases were found wrapping around abdominal organs and large vessels, which increased difficulties in achieving complete resection. Rigid conduction of complete resection may conversely elevate surgical risks and impair benefits from operations. Hence, a complete resection strategy for a giant RLS requires cautious consideration. Patients with WDL subtype of giant RLS could obtain significant survival benefits from complete resection when compared with those receiving incomplete resection. However, there were no significant differences in survival time between non-WDL patients who received complete and incomplete resections, and they were more likely to have severe postoperative complications. This suggests that pathological subtype may serve as an indicator for surgical decision-making. Radical resection may fit for patients with WDL subtype of giant RLS, while the cases with non-WDL subtype may need staging or palliative operations. Further clinical investigations should be conducted to prove the effectiveness of this strategy. It has to be admitted that there are several limitations. First, the study only included the cases from one center and the sample size is small due to the extremely low incidence of giant RLS. It impairs the representativeness of this research. Second, as a retrospective study, the range of collected information is limited and some potential biases cannot be eliminated. Third, several indicators of pathological examination, such as tumor necrosis and mitotic count, were not reported in some cases. It increases difficulties in more deeply identifying mechanisms underlying giant RLS progression. In conclusion, the status of surgical margins and postoperative complications were independent factors of OS, and the pathological subtype was proved as an independent marker for the recurrence of giant RLS. Complete resection for the WDL subtype of giant RLS contributed to prognosis improvement. However, survival benefits from complete resection were not obtained for the patients with non-WDL subtype of giant RLS. The pathological subtype may serve as an important reference indicator for the surgical decision-making process of giant RLS. Funding This study was supported by the National Natural Science Foundation of China (No. 82073192) and the National Key Research and Development Project of China (No. 2019YFB1311505). Conflicts of interest None.

Background Immune checkpoint inhibitors (ICIs) have shown promising prospects in locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) immunotherapy, but their efficacy in neoadjuvant settings remains unclear. This study aimed to assess the efficacy and safety of integrating programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors into neoadjuvant chemotherapy (NACT) of GC/GEJC treatment. Methods PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and main oncology conference databases were systematically searched up to 19 November 2022, and randomized controlled trials (RCTs) and cohort studies that evaluated the efficacy and safety of PD-1/PD-L1 inhibitors plus NACT were included. The main outcomes were pathological complete response (pCR), major pathological response (MPR), R0 resection rate, and treatment-related adverse events (TRAEs). Results A total of 753 patients from 20 prospective studies were included in this meta-analysis. The pooled pCR and MPR rates from studies reporting were 21.7% [95% confidence interval (CI), 18.1%–25.5%] and 44.0% (95% CI, 34.1%–53.8%), respectively. The pooled incidence rate of total TRAEs was 89.1% (95% CI, 82.7%–94.3%), and the incidence rate of grade 3 to 4 TRAEs was 34.4% (95% CI, 17.8%–66.5%). The pooled R0 resection rate was reported to be 98.9% (95% CI, 97.0%–99.9%). Subgroup analysis has not found significant differences in efficacy and safety among different PD-1/PD-L1 inhibitors. Moreover, the efficacy in patients with positive PD-L1 expression (combined positive score ≥1) was comparable with that in the entire study population [pCR, 22.5% vs. 21.2% (p > 0.05); MPR, 48.6% vs. 43.7% (p > 0.05)]. Conclusion This systematic review and meta-analysis found that PD-1/PD-L1 inhibitors combined with NACT for locally advanced GC/GEJC were well tolerated and may confer therapeutic advantages. The integration of ICIs into NACT has shown the potential for application in any PD-L1 expression population.