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Ivonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer. HARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later. Between Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38–0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1–49% (HR 0·54 [95% CI 0·37–0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29–0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups. Ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer. Akeso Biopharma.

RNA degradation plays a vital role in post-transcriptional regulation of gene expression. RNA stability is changed in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD), but its role and underlying mechanisms in sleeve gastrectomy (SG) effectively remodeling hepatocytes and improving MASLD is unclear. A high-fat diet-induced MASLD model for SG and a hepatocyte-specific Zfp36 knockdown mouse model were established to evaluate the role of zinc finger protein 36 (ZFP36) in MASLD. The expression of ZFP36 and TEA domain transcription factor 4 (TEAD4) was examined in liver tissue samples from MASLD patients. Hepatic ZFP36 expression is downregulated in MASLD but is restored following SG. Hepatocyte-specific Zfp36 knockdown exacerbates high-fat diet-induced liver injury and impairs the therapeutic effect of SG on hepatic steatosis. Mechanistically, ZFP36 binds to TEAD4 mRNA to promote its degradation, thereby modulating the Hippo pathway. Inhibition of TEAD4 transcriptional activity reverses the aggravated MASLD phenotype caused by Zfp36 knockdown. In liver biopsy samples from MASLD patients, ZFP36 expression correlates negatively with TEAD4 expression. Collectively, these findings identify SG-induced upregulation of ZFP36 as a critical mechanism for alleviating MASLD through suppression of TEAD4.

Background Lymph node metastasis (LNM) is an important factor for thyroid cancer patients’ treatment and prognosis. The aim of this study was to explore the clinical value of ultrasound features and radiomics analysis in predicting LNM in thyroid cancer patients before surgery. Methods The characteristics of ultrasound images of 150 thyroid nodules were retrospectively analysed. All nodules were confirmed as thyroid cancer. Among the assessed patients, only one hundred and twenty-six patients underwent lymph node dissection. All patients underwent an ultrasound examination before surgery. In the radiomic analysis, the area of interest was identified from selected ultrasound images by using ITK-SNAP software. The radiomic features were extracted by using Ultrosomics software. Then, the data were classified into a training set and a validation set. Hypothetical tests and bagging were used to build the model. The diagnostic performance of different ultrasound features was assessed, a radiomic analysis was conducted, and a receiver operating characteristic (ROC) curve analysis was performed to explore the diagnostic accuracy. Results Regarding the prediction of LNM, the ROC curves showed that the area under the curve (AUC) values of an irregular shape and microcalcification were 0.591 (P = 0.059) and 0.629 (P = 0.007), respectively. In the radiomics analysis, in the training set, the AUC value of LNM was 0.759, with a sensitivity of 0.90 and a specificity of 0.860. In the verification set, the AUC was 0.803, with a sensitivity of 0.727 and a specificity of 0.800. Conclusions Microcalcification and an irregular shape are predictors of LNM in thyroid carcinoma patients. In addition, radiomics analysis has promising value in screening meaningful ultrasound features in thyroid cancer patients with LNM. Therefore, the prediction of LNM based on ultrasound features and radiomic features is useful for making appropriate decisions regarding surgery and interventions before thyroid carcinoma surgery.

Gastric cancer (GC) is a heterogeneous disease with poor prognosis. Tumor-derived extracellular vesicles (EVs) assume a role in intercellular communication by carrying various molecules, including proteins, RNA, and DNAs, which has been identified to exhibit oncogenic effect in GC. Therefore, this research aimed to figure out whether tumor-derived EVs transmit c-Myc to orchestrate the growth and metastasis of GC. KCNQ1OT1, microRNA (miR)-556-3p and CLIC1 expression of GC tissues was detected through RT-qPCR. EVs were isolated from GC cells, followed by RT-qPCR and Western blot analysis of c-Myc expression in EVs and GC cells. Next, GC cells were incubated with EVs or transfected with a series of mimic, inhibitor, or siRNAs to assess their effects on cell viability, migrative, invasive, and apoptotic potential. Relationship among c-Myc, KCNQ1OT1, miR-556-3p, and CLIC1 was evaluated by dual-luciferase reporter assay. PI3K/AKT pathway-related proteins were assessed through Western blot analysis. KCNQ1OT1 and CLIC1 were highly expressed but miR-556-3p in GC tissues. c-Myc was high-expressed in tumor-derived EVs and GC cells. Mechanistically, c-Myc could induce KCNQ1OT1 expression, and KCNQ1OT1 bound to miR-556-3p that negatively targeted CLIC1 to inactivate PI3K/AKT pathway. Tumor-derived EVs, EVs-c-Myc, KCNQ1OT1 or CLIC1 overexpression, or miR-556-3p inhibition promoted GC cell proliferative, invasive, and migrative capacities but repressed their apoptosis through activating PI3K/AKT pathway. Collectively, tumor-derived EVs carrying c-Myc activated KCNQ1OT1 to downregulate miR-556-3p, thus elevating CLIC1 expression to activate the PI3K/AKT pathway, which facilitated the growth and metastasis of GC.

Background To evaluate the prognostic value of pretreatment lymphocyte counts with respect to clinical outcomes in patients with solid tumors. Methods Systematic literature search of electronic databases (Pubmed, Embase and Web of Science) up to May 1, 2018 was carried out by two independent reviewers. We included Eligible studies assessed the prognostic impact of pretreatment lymphocytes and had reported hazard ratios (HR) with 95% confidence intervals (CIs) for endpoints including overall survival (OS) and progression-free survival (PFS). Only English publications were included. Results A total of 42 studies comprising 13,272 patients were included in this systematic review and meta-analysis. Low pretreatment lymphocyte count was associated with poor OS (HR = 1.27, 95% CI 1.16–1.39, P  < 0.001, I 2  = 58.5%) and PFS (HR = 1.27, 95% CI 1.15–1.40, P  < 0.001, I 2  = 25.7%). Subgroup analysis disaggregated by cancer type indicated that low pretreatment lymphocytes were most closely associated with poor OS in colorectal cancer followed by breast cancer and renal cancer. Conclusions Low pretreatment lymphocyte count may represent an unfavorable prognostic factor for clinical outcomes in patients with solid tumors.

Background Papillary thyroid carcinoma (PTC) is a common endocrine tumor. Increasing evidence has shown that microRNA dysfunction is involved in the occurrence and development of cancer. The expression of MicroRNA-30b-5p (miR-30b-5p) was down-regulated in PTC; however, its role in the development of PTC is not clear. Hence, this study aimed to explore the role and mechanism of miR-30b-5p in the occurrence and development of PTC. Methods The qRT-PCR assay was used to detect the expression of miR-30b-5p in 60 cases of papillary thyroid carcinoma along with their matched non-cancerous tissues. This study explored the biological function of miR-30b-5p by the functional gain and loss experiments in vitro and vivo. The direct target gene of miR-30b-5p and its signaling pathway was identified through bioinformatics analysis, qRT-PCR, western blot, rescue experiments, and double luciferase 3'-UTR report analysis. Results This study demonstrated that the low expression of miR-30b-5p is related to poor clinicopathological features. Functionally, the overexpression of miR-30b-5p inhibited the proliferation, invasion, and migration of PTC cells. Bioinformatics and luciferase analysis showed that GALNT7 is the direct and functional target of miR-30b-5p. Moreover, miR-30b-5p inhibited the proliferation of PTC in vivo by inhibiting the expression of GALNT7. The studies on the mechanism have shown that GALNT7 promotes cell proliferation and invasion by activating EGFR/PI3K/AKT kinase pathway, which can be attenuated by the kinase inhibitors. Conclusions Overall, miR-30b-5p inhibited the progression of papillary thyroid carcinoma by targeting GALNT7 and inhibiting the EGFR/PI3K/AKT pathway.

Several studies have evaluated PD-1 inhibitors plus chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), but comparative data with chemoradiotherapy (CRT) remain limited. This multicenter, randomized, open-label, phase 2 non-inferiority trial (REVO, NCT05007145) assessed the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy (ICT) versus CRT in patients with resectable, locally advanced ESCC. A total of 104 patients were randomized to ICT (camrelizumab, nab-paclitaxel, cisplatin) or CRT (nab-paclitaxel, cisplatin, radiotherapy). The primary endpoint was pathologic complete response (pCR). ICT achieved a pCR rate of 32.7% versus 34.6% with CRT (rate ratio 0.94, 90% CI 0.6–1.49), demonstrating non-inferiority and meeting the pre-specified primary endpoint. Major pathologic response was observed in 42.3% of ICT patients and 57.7% of CRT patients, with R0 resection achieved in 100% of both groups. 1-year disease-free survival was 89.1% versus 78.2%, and 1-year overall survival was 100% versus 92.3% for ICT and CRT, respectively. Grade ≥3 treatment-related adverse events occurred in 19.2% of ICT patients and 33.3% of CRT patients, and surgical complications were reported in 31.1% and 35.9%, respectively. These findings indicate that ICT is a safe and effective neoadjuvant strategy for resectable ESCC with a more favorable safety profile. Neoadjuvant chemoradiotherapy has become the standard of care in patients with resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Here, authors present a randomised phase II trial reporting the non-inferiority of neoadjuvant camrelizumab (anti-PD-1) and chemotherapy (nab-paclitaxel and cisplatin) compared to chemoradiation (nab-paclitaxel, cisplatin, and radiotherapy in patients with resectable LA-ESCC.

Background and Objectives: Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Patients with GC have higher nutritional risk. This study aimed to construct a nomogram model for predicting pre-operative nutritional risk in patients with GC in order to assess preoperative nutritional risk in patients more precisely. Methods and Study Design: Patients diagnosed with GC and undergoing surgical treatment were included in this study. Data was collected through clinical information, laboratory testing, and radiomics-derived characteristics. Least absolute shrinkage selection operator (LASSO) regression analysis and multi-variable logistic regression were employed to construct a clinical prediction model, which takes the form of a logistic nomogram. The effectiveness of the nomogram model was evaluated using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: A total of three predictors, namely body mass index (BMI), hemoglobin (Hb) and radiomics characteristic score (Radscore) were identified by LASSO regression analysis from a total of 21 variables studied. The model constructed using these three predictors displayed medium prediction ability. The area under the ROC curve was 0.895 (95% CI 0.844-0.945) in the training set, with a cutoff value of 0.651, precision of 0.957, and sensitivity of 0.718. In the validation set, it was 0.880 (95% CI 0.806-0.954), with a cutoff value of 0.655, precision of 0.930, and sensitivity of 0.698. DCA also confirmed the clinical benefit of the combined model. Conclusions: This simple and dependable nomogram model for clinical prediction can assist physicians in assessing preoperative nutritional risk in GC patients in a time-efficient and accurate manner to facilitate early identification and diagnosis.

Background Metabolic reprogramming is a hallmark of malignant transformation and supports tumor proliferation and survival. Chloride intracellular channel protein 1 (CLIC1) has been implicated in multiple oncogenic processes; however, its mechanistic role in regulating glycolysis in gastric cancer (GC) remains largely unknown. This study aimed to elucidate how CLIC1 modulates PKM2-dependent glycolytic metabolism and its impact on gastric tumor progression. Methods Bioinformatic analyses were performed using TCGA and GEO datasets to assess correlations between CLIC1 and glycolytic pathways. Immunohistochemistry was used to assess CLIC1 and PKM2 expression and their correlation in GC. Functional assays, including Seahorse extracellular flux analysis, glucose/lactate quantification, and ATP measurement were used to evaluate glycolytic activity. Protein interactions were analyzed by co-immunoprecipitation, GST pull-down, and mass spectrometry. Cellular proliferation, migration, and invasion were assessed by CCK-8, wound healing, and Transwell assays. Xenograft mouse models were established to evaluate in vivo tumorigenic capacity and the therapeutic effects of glycolytic inhibition. Results CLIC1 expression was positively correlated with glycolytic pathway activity in GC. CLIC1 and PKM2 were highly expressed in gastric cancer tissues and showed a positive correlation. CLIC1 knockdown suppressed glycolysis and inhibited GC cell proliferation, migration, and invasion, whereas CLIC1 overexpression exerted the opposite effects. Mechanistically, CLIC1 directly interacted with the C-terminal domain of PKM2, stabilizing its dimeric form, thereby facilitating glycolytic flux and nuclear PKM2 accumulation. Pharmacological inhibition of PKM2 or glycolysis attenuated CLIC1-induced tumor growth both in vitro and in vivo. Conclusions This study identifies CLIC1 as a novel metabolic regulator that drives glycolytic reprogramming through direct interaction with PKM2 in gastric cancer. Targeting the CLIC1–PKM2 axis may provide a promising therapeutic strategy for metabolic intervention in GC and highlights a potential translational target for future clinical application.