Interleukin-6 on postoperative day three as an early predictor of infections following laparoscopic gastric cancer resection.

BACKGROUND: To investigate the role of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) as early predictors of infectious complications after laparoscopic gastric cancer surgery. METHODS: Patients who underwent laparoscopic gastric cancer surgery between January 2020 and June 2022 were retrospectively enrolled. IL-6, PCT, and CRP levels were assessed before surgery and on postoperative days (PODs) 3 and 5. Differences in serum IL-6, PCT, and CRP levels between the infected and non-infected groups were compared. The diagnostic accuracy was determined using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 206 patients were enrolled, and 21 patients (10.19%) developed postoperative infections. Serum IL-6, PCT, and CRP levels in the infected group were significantly higher than those in the non-infected group on PODs 3 and 5. IL-6 with an optimal cutoff value of 84.00 pg/mL (AUC 0.84), PCT with an optimal cutoff value of 1.39 ng/mL (AUC 0.80), CRP with an optimal cutoff value of 150.00 mg/L (AUC 0.76) on POD 3 had superior diagnostic accuracy in predicting postoperative infections. Multivariate analysis identified PCT and IL-6 levels on POD 3 as independent risk factors, the AUC of the combination of IL-6 and PCT was 0.89. The Delong test showed no difference between the AUC of IL-6 alone and IL-6 combined with PCT prediction (P = 0.07, Z = 1.81). CONCLUSIONS: IL-6 level on POD 3 is an excellent predictor of infectious complications following laparoscopic gastric cancer surgery. Patients with IL-6 levels lower than 84.00 pg/mL on POD 3 can ensure safe early discharge with a low probability of infection.

Development and Validation of a Novel Nomogram Model for Early Diagnosis of Anastomotic Leakage After Laparoscopic Colorectal Cancer Surgery.

Background: This study aimed to investigate the clinical value of inflammatory factors for predicting anastomotic leakage (AL) after laparoscopic colorectal cancer surgery and establish a nomogram model to assess the probability of its occurrence. Patients and Methods: Data of 637 patients who underwent laparoscopic colorectal cancer surgery between June 2019 and June 2022 were collected. Differences in procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) levels before surgery and on postoperative day (POD) 3 and 5 were compared between patients with and without AL (AL and non-AL groups, respectively). The diagnostic accuracy was determined using the area under the receiver operating characteristic curve (AUC), and a nomogram model was developed. Results: Post-operative AL occurred in 46 (7.2%) patients. Procalcitonin, CRP, and WBC levels on POD 3 and 5 were higher in the AL group than in the non-AL group. The AUCs of PCT, CRP, and WBC levels for predicting AL on POD 3 were 0.833, 0.757, and 0.756, respectively, which were better than those on POD 5 (AUC = 0.669, 0.581, and 0.588, respectively). The nomogram model for AL was developed based on five variables (PCT, CRP, WBC, American Society of Anesthesiologists [ASA] grade and comorbidities), and it had an AUC of 0.922. Calibration curves demonstrated that the nomogram had good fit. The Delong test showed that the AUC of the nomogram for predicting the probability of AL was higher than that of PCT alone (z = 2.311, p = 0.02). Conclusions: Procalcitonin measured on POD 3 seems to be a promising negative predictor of AL after laparoscopic colorectal cancer surgery. Furthermore, the nomogram model developed in our study, which utilizes a series of predictors that can be easily accessed, has demonstrated potential to further improve the prediction accuracy.

Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response.

Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1-/- and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD-/- mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD-/- mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis.

Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.

Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs). Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.

Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis.

Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1ß, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.

Prognostic value of post-operative serum procalcitonin in gastric adenocarcinoma patients undergoing radical gastrectomy: propensity score matching analysis of extended cohort from a prospective bi-center study.

BACKGROUND: The aim of this study was to investigate the predictive value of procalcitonin (PCT) on post-operative day (POD) 3 and 5 for the prognosis of gastric adenocarcinoma (GA) patients who underwent radical gastrectomy surgery in extended cohort from a prospective bi-center study. METHODS: Consecutive GA patients who received surgery in the Hunan Cancer Hospital were enrolled as the training cohort, and those from Wuhan Union Hospital were included as external validation cohort. The optimal cutoff concentration of PCT for overall survival (OS) in the training cohort was determined by X-tile. The independent predictive factors for OS were identified using univariate and multivariate Cox regression analyses. Furthermore, the predictive value of elevated PCT was clarified in the validation cohort and propensity score matched cohort, respectively. RESULTS: The optimal cutoff concentrations of PCT for OS were 0.67 ng/mL at POD 3 and 0.39 ng/mL at POD 5 in the training cohort (n = 906). Patients with higher PCT concentrations (≥ 0.39 ng/mL) at POD 5 had a significantly worse prognosis whether developing post-operative infections or not. Moreover, a synergistic influence was confirmed in those with elevated PCT concentration and infections. Multivariate analyses confirmed that PCT concentration ≥ 0.39 ng/mL at POD 5 was significantly associated with poorer survival in training cohort (HR: 1.422, 95% CI 1.041-1.943, P = 0.027), validation cohort (n = 297, HR: 2.136, 95% CI 1.073-4.252, P = 0.031) and matched cohort (n = 901, HR: 1.454, 95% CI 1.104-1.914, P = 0.008), separately. CONCLUSIONS: PCT concentration ≥ 0.39 ng/mL at POD 5 was a reliable predictor for poorer prognosis in GA patients undergoing radical gastrectomy.

4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer.

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas of investigation, particularly in cancers. The present study aimed to explore the role of cuproptosis in colorectal cancer progression. The genetic alterations of cuproptosis in colon cancer were evaluated using a database. MTT assays, colony formation, and flow cytometry were used to examine the effect of elesclomol-Cu and 4-Octyl itaconate (4-OI) on colorectal cancer cell and oxaliplatin-resistant cell viability. The anti-tumor effect of elesclomol with 4-OI was verified in vivo assay. The results showed that FDX1, SDHB, DLAT, and DLST genes were more highly expressed in normal tissues than those in primary tumor tissues. Patients with high expressions of these genes in tumor tissues had a better prognosis. Using MTT assay and colony formation analysis, elesclomol-Cu pulse treatment showed significant inhibition of cell viability in HCT116, LoVo, and HCT116-R cells. In addition, flow cytometry revealed elesclomol-Cu significantly promoted apoptosis. Tetrathiomolybdate, a copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, a glucose metabolism inhibitor, sensitized cuproptosis. Furthermore, galactose further promoted cuproptosis. Interestingly, 4-OI significantly enhanced cuproptosis which was irrelevant to ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis was inhibited by 4-OI through GAPDH, one of the key enzymes of glycolysis, sensitizing cuproptosis. Meanwhile, FDX1 knockdown weakened the ability of 4-OI to promote cuproptosis. In vivo experiments, 4-OI with elesclomol-Cu showed better anti-tumor effects. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.

A Combination of Preoperative Computed Tomography-Defined Sarcopenia and Systemic Inflammation on Survival in Patients with Poorly Differentiated Neuroendocrine Neoplasms Following Radical Resection.

This retrospective study of 122 patients with gastrointestinal poorly differentiated neuroendocrine neoplasms (GI-PDNEN) who underwent radical resection between January 2010 and December 2020 aimed to investigate the usefulness of combined computed tomography (CT)-defined sarcopenia and systemic inflammation to evaluate long-term prognoses for patients who underwent radical surgical resection. Sarcopenia, based on a pre-defined L3 skeletal muscle index cutoff value, was assessed using preoperative abdominal CT images. Patients (neuroendocrine carcinoma, 86 patients; mixed adenoneuroendocrine carcinoma, 36 patients) were divided into low-, intermediate-, and high-risk groups using sarcopenia scores and neutrophil-to-lymphocyte ratios (SNLRs). Higher SNLRs were significantly associated with higher age (P = 0.004), larger tumor size (P = 0.042), lower body mass index (P = 0.042), and lower hemoglobin (P = 0.001) and albumin (P = 0.031) levels. Multivariate analysis indicated that a higher SNLR was an independent risk factor for poor overall survival (OS, P = 0.01) and relapse-free survival (RFS, P = 0.001) in patients with GI-PDNEN postoperatively. Sarcopenia and a higher NLR were significantly associated with poor RFS and OS following radical resection. The SNLR had a definite predictive prognostic value in preoperatively identifying patients with GI-PDNEN and a probable poor long-term prognosis, especially those with neuroendocrine carcinoma.

Necrosulfonamide ameliorates intestinal inflammation via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, while the present therapeutic efficacy is insufficient. In recent years, numerous studies have shown that necrosulfonamide (NSA) played a protective role in many inflammatory diseases by blocking mixed lineage kinase domain-like protein (MLKL) polymerization. However, the protective effect of NSA in dextran sodium sulfate (DSS)-induced colitis has not been reported. In the present study, we used DSS to establish mouse models of acute colitis to explore the proactive effect of NSA. Our study showed that NSA alleviated symptoms of DSS-induced colitis through reducing weight loss and disease activity index (DAI) score. Furthermore, NSA inhibited macrophages and CD4+/CD8 + T-cell accumulation in colon tissue caused by DSS. In addition, we found that NSA had the therapeutic effects on DSS-induced colitis. Mechanistically, we detected the expression level of phosphorylated MLKL, the release of LDH, cytokines, and N-gasdermin D (N-GSDMD) to examine necroptosis and pyroptosis pathways. We found NSA alleviated the severity of DSS-induced colitis by inhibiting the expressions of phosphorylated MLKL and N-GSDMD in vivo. In vitro experiments, we found NSA inhibited the release of inflammatory factors and LDH and the expressions of N-GSDMD in bone marrow-derived macrophages. Furthermore, we found NSA inhibited the expression of phosphorylated MLKL and necroptosis of NCM460 cell through western blot and flow cytometer. In general, this study reveals that NSA inhibits pyroptosis and necroptosis pathways to eventually alleviate intestinal inflammation, which may serve as a potential candidate for IBD therapy.

Diagnostic accuracy of C-reactive protein and procalcitonin in the early diagnosis of infections after laparoscopic rectal cancer surgery.

BACKGROUND: We aimed to examine the diagnostic accuracy of postoperative procalcitonin (PCT) and C-reactive protein (CRP) in the detection of infectious complications in patients after laparoscopic rectal cancer surgery, as opposed to all colorectal surgery. METHODS: Between December 2018 and December 2020, 204 patients who underwent laparoscopic rectal cancer surgery were enrolled retrospectively. The PCT, CRP and white blood cell (WBC) count were measured before surgery and on postoperative days (PODs) 3 and 5. Diagnostic accuracy was determined by the area under the receiver operating characteristic curve (AUC). Net Reclassification Index (NRI) was used to calculate the ability to correct reclassification. RESULTS: Infectious complications occurred in 36 patients (17.6%), including 17 cases of anastomotic leakage (AL) (8.3%). The AUCs of PCT and CRP in predicting infectious complications on POD 3 were 0.690 and 0.731, respectively, which were better than those on POD 5 (AUC 0.666 and 0.697, respectively). PCT with an optimal cutoff value of 1.10 ng/mL (AUC 0.792, specificity 78.6%, negative predictive value [NPV] 96.6%), CRP with an optimal cutoff value of 109.5 mg/L (AUC 0.760, specificity 78.6%, NPV 96.1%) on POD 3 had superior diagnostic accuracy in predicting AL, both better than WBC (AUC 0.627). The AUC of combining PCT and CRP on POD 3 in predicting AL was 0.851, with a specificity of 79.7% and NPV of 97.4%, and the NRI was estimated to be 7.0%. CONCLUSIONS: Both PCT and CRP on POD 3 are excellent negative predictors for early monitoring of infectious complications, especially AL, in patients undergoing laparoscopic rectal cancer surgery.

Safety and feasibility of laparoscopy-assisted surgery for gastrointestinal stromal tumors larger than 5 cm: Results of a retrospective, single-center series of 1,802 consecutive patients.

BACKGROUND: The role of laparoscopy-assisted resection for treating gastrointestinal stromal tumors >5 cm is still disputed. We aimed to assess the advantages of laparoscopy-assisted resection for treating gastrointestinal stromal tumors >5 cm. METHODS: In total, 1,802 patients with primary gastrointestinal stromal tumors who underwent laparoscopy-assisted surgery or open surgery were retrospectively evaluated. Propensity score matching was performed to reduce confounders. RESULTS: In total, 518 patients with tumor size >5 cm were enrolled in this study (males: 292, 56.4%; females: 226, 43.6%; median age: 58 years, range: 23-85 years). One hundred and twenty-three (23.7%) patients underwent laparoscopy-assisted resection, and 395 (76.3%) patients underwent open resection. After propensity score matching, 190 patients were included (95 in each group). The laparoscopy-assisted surgery group was superior to the open surgery group considering the blood loss (>200 mL: 6.3% vs 22.1%, P = .005), length of midline incision (6.0 ± 0.9 cm vs 9.6 ± 2.1 cm, P < .001), time to first flatus (49.7 ± 10.5 hours vs 63.9 ± 7.4 hours, P < .001), and shorter hospital stay (10.3 ± 3.2 days vs 11.9 ± 2.9 days, P < .001). The difference in relapse-free survival or overall survival between the laparoscopy-assisted surgery and open surgery groups after matching was not significant (all P > .05). On subgroup analysis, the relapse-free survival and overall survival of the laparoscopy-assisted surgery group were comparable to those of the open surgery group, irrespective of tumor location (gastric or nongastric locations) (all P > .05). CONCLUSION: When performed by experienced surgeons, laparoscopy-assisted resection is feasible and safe for gastrointestinal stromal tumors >5 cm, which showed improved short-term outcomes and comparable oncological outcomes, regardless of whether the tumor had a gastric or nongastric location.

Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation.

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI can further develop into serious liver diseases such as cirrhosis and liver cancer. Therefore, how to effectively prevent and treat ALI has become the focus of research. Numerous studies have reported Maresin1 (MaR1) has anti-inflammatory effect and protective functions on organs. In the present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) to establish an ALI model, explored the mechanism of liver cells death caused by D-GalN/LPS, and determined the effect of MaR1 on D-GalN/LPS-induced ALI. In vivo experiments, we found that MaR1 and ferrostatin-1 significantly alleviated D-GalN/LPS-induced ALI, reduced serum alanine transaminase and aspartate transaminase levels, and improved the survival rate of mice. Meanwhile, MaR1 inhibited hepatocyte death, inhibited tissue reactive oxygen species (ROS) expression, reduced malondialdehyde (MDA), reduced glutathione (GSH), GSH/oxidized glutathione (GSSG), and iron content induced by D-GalN/LPS in mice. In addition, MaR1 inhibited ferroptosis-induced liver injury through inhibiting the release of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6. Subsequently, western blot showed that MaR1 improved the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). In vitro experiments, we found that MaR1 inhibited LPS-induced and erastin-induced cell viability reduction. Meanwhile, we found that MaR1 increased the MDA and GSH levels in cells. Western blot showed that MaR1 increased the expression level of Nrf2/HO-1/GPX4. Next, the Nrf2 was knocked down in HepG2 cells, and the results showed that the protective effect of MaR1 significantly decreased. Finally, flow cytometry revealed that MaR1 inhibited ROS production and apoptosis. Overall, our study showed MaR1 inhibited ferroptosis-induced liver injury by inhibiting ROS production and Nrf2/HO-1/GPX4 activation.