Prediction of survival and analysis of prognostic factors for patients with AFP negative hepatocellular carcinoma: a population-based study.

PURPOSE: Hepatocellular carcinoma (HCC) has a poor prognosis, and alpha-fetoprotein (AFP) is widely used to evaluate HCC. However, the proportion of AFP-negative individuals cannot be disregarded. This study aimed to establish a nomogram of risk factors affecting the prognosis of patients with AFP-negative HCC and to evaluate its diagnostic efficiency. PATIENTS AND METHODS: Data from patients with AFP-negative initial diagnosis of HCC (ANHC) between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results database for model establishment and validation. We randomly divided overall cohort into the training or validation cohort (7:3). Univariate and multivariate Cox regression analysis were used to identify the risk factors. We constructed nomograms with overall survival (OS) and cancer-specific survival (CSS) as clinical endpoint events and constructed survival analysis by using Kaplan-Meier curve. Also, we conducted internal validation with Receiver Operating Characteristic (ROC) analysis and Decision curve analysis (DCA) to validate the clinical value of the model. RESULTS: This study included 1811 patients (1409 men; 64.7% were Caucasian; the average age was 64 years; 60.7% were married). In the multivariate analysis, the independent risk factors affecting prognosis were age, ethnicity, year of diagnosis, tumor size, tumor grade, surgery, chemotherapy, and radiotherapy. The nomogram-based model related C-indexes were 0.762 (95% confidence interval (CI): 0.752-0.772) and 0.752 (95% CI: 0.740-0.769) for predicting OS, and 0.785 (95% CI: 0.774-0.795) and 0.779 (95% CI: 0.762-0.795) for predicting CSS. The nomogram model showed that the predicted death was consistent with the actual value. The ROC analysis and DCA showed that the nomogram had good clinical value compared with TNM staging. CONCLUSION: The age(HR:1.012, 95% CI: 1.006-1.018, P-value < 0.001), ethnicity(African-American: HR:0.946, 95% CI: 0.783-1.212, P-value: 0.66; Others: HR:0.737, 95% CI: 0.613-0.887, P-value: 0.001), tumor diameter(HR:1.006, 95% CI: 1.004-1.008, P-value < 0.001), year of diagnosis (HR:0.852, 95% CI: 0.729-0.997, P-value: 0.046), tumor grade(Grade 2: HR:1.124, 95% CI: 0.953-1.326, P-value: 0.164; Grade 3: HR:1.984, 95% CI: 1.574-2.501, P-value < 0.001; Grade 4: HR:2.119, 95% CI: 1.115-4.027, P-value: 0.022), surgery(Liver Resection: HR:0.193, 95% CI: 0.160-0.234, P-value < 0.001; Liver Transplant: HR:0.102, 95% CI: 0.072-0.145, P-value < 0.001), chemotherapy(HR:0.561, 95% CI: 0.471-0.668, P-value < 0.001), and radiotherapy(HR:0.641, 95% CI: 0.463-0.887, P-value:0.007) were independent prognostic factors for patients with ANHC. We developed a nomogram model for predicting the OS and CSS of patients with ANHC, with a good predictive performance.

Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial.

Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

Single-photon emission computed tomography-defined active bone marrow-sparing volumetric-modulated arc therapy reduces the incidence of acute hematologic toxicity in locally advanced cervical cancer patients who receive chemoradiotherapy: A single-center prospective randomized controlled trial.

BACKGROUND: This study aims to test the efficacy of single-photon emission computed tomography (SPECT)-defined active bone marrow-sparing (ABMS) volumetric-modulated arc therapy (VMAT) in reducing grade 3+ acute hematologic toxicity (HT) in locally advanced cervical cancer patients treated with chemoradiotherapy. METHODS: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer patients. Participants were randomized to the 99m Tc sulfur colloid SPECT-defined ABMS VMAT (ABMS group) or control group, who received weekly cisplatin concurrently with VMAT followed by high-dose-rate intracavitary brachytherapy. The ABMS group additionally received SPECT-defined ABM dose constraints. The primary end point was the incidence of grade 3+ acute HT. RESULTS: A total of 192 Federation of Gynaecology and Obstetrics stage IB-IIIB patients were randomly treated (96 each in the ABMS control groups). The median follow-up was 24.0 months. The incidence of grade 3+ acute HT in the ABMS group was significantly lower than that in the control group (32.3% vs. 53.1%, p < .01). The number of patients completing five cycles of cisplatin was 88.5% in the ABMS group and 75% in the control group, and the difference was significant (p = .02). There were no differences in planning target value coverage, organs at risk dosimetric parameters, 2-year progression-free survival, or 2-year overall survival between the two groups. Patients in the control group had nonsignificantly worse 2-year distant metastasis than patients in the ABMS group (17.8% vs. 11.1%, p = .19). CONCLUSIONS: ABMS VMAT significantly reduced grade 3+ acute HT and improved chemotherapy delivery compared with the control treatment. We found weak evidence of the effect of ABMS VMAT on distant metastasis.

Preoperative CA19-9 and GGT ratio as a prognostic indicator in ampullary carcinoma.

BACKGROUND AND AIMS: In recent years, more and more inflammatory indicators have been studied to predict the long-term survival of patients with ampullary carcinoma (AC) after radical resection, but these prognostic indicators are still controversial. Therefore, based on previous inflammation scores, this study established a novel, easily accessible, more feasible and more predictive prognostic marker [Carbohydrate antigen199 to gamma-glutamyltransferase ratio (CA19-9/GGT)] to better assess the prognostic significance in AC patients undergoing radical resection. METHODS: Overall survival (OS) and recurrence-free survival (RFS) were analyzed by Cox regression model. Correlation between CA19-9/GGT and clinicopathological variables were analyzed by Chi-squared test, Fisher ' s exact test, independent sample t test and Mann-Whitney U test. The performance of prognostic indexes is compared by the consistency index (C-index). The prediction accuracy of nomogram is further confirmed by calibration curve and decision curve analysis (DCA). RESULTS: CA19-9/GGT was an independent risk factor affecting OS [P = 0.001, hazard ratio (HR) 2.459, 95% confidence intervals (CI) 1.450-4.167] and RFS (P = 0.002, HR 2.333, 95% CI 1.371-3.971) in multivariate analysis. The optimal cut-off value of CA19-9/GGT was 0.14. In CA19-9/GGT correlation analysis, high risk group (> 0.14) was significantly associated with poor prognosis. The predictive performance of CA19-9/GGT (OS: C-index = 0.753, RFS: C-index = 0.745) was confirmed to be superior to other prognostic indicators according to the C-index. Compared with the simple AJCC staging system, the Nomogram prediction model (OS: C-index = 0.787, RFS: C-index = 0.795) established by the combination of CA19-9/GGT and AJCC 8th TNM staging system has higher prediction accuracy. CONCLUSIONS: CA19-9/GGT was an independent prognostic indicator after radical resection of AC. Incorporating CA19-9/GGT into the AJCC TNM staging system optimized the prediction accuracy of the TNM staging system, and further verified the predictive value of CA19-9/GGT.

PRR34-AS1 promotes exosome secretion of VEGF and TGF-ß via recruiting DDX3X to stabilize Rab27a mRNA in hepatocellular carcinoma.

BACKGROUND: Exosomes are deemed to be an important tool of intercellular communicators in cancer cells. Our study investigated the role of PRR34 long non-coding RNA antisense RNA 1 (PRR34-AS1) in regulating exosome secretion in hepatocellular carcinoma (HCC) cells. METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) analyzed the expression of PRR34-AS1. We assessed the function of PRR34-AS1 on the biological changes of THLE-3 cells and HCC cells. The downstream interaction between RNAS was assessed by mechanistic experiments. RESULTS: PRR34-AS1 expression was upregulated in HCC cells in comparison to THLE-3 cells. PRR34-AS1 depletion repressed HCC cell proliferation, migration and invasion as well as EMT phenotype, while PRR34-AS1 up-regulation accelerated the malignant phenotypes of THLE-3 cells. PRR34-AS1 recruited DDX3X to stabilize the mRNA level of exosomal protein Rab27a. Moreover, PRR34-AS1 facilitated the malignant phenotypes of THLE-3 cells by elevating Rab27a expression to promote the exosome secretion of VEGF and TGF-ß in HCC cells. CONCLUSIONS: The current study revealed a novel function of PRR34-AS1 in accelerating exosome secretion in HCC cells and offered an insight into lncRNA function in the regulation of tumor cell biology.

Rapid titration with oral sustained-release morphine plus subcutaneous morphine in a multi-center, randomized control study of cancer patients with moderate to severe cancer pain.

BACKGROUND: Pain is one of the most common concomitant symptoms among cancer patients. Pharmacologic agents are regarded as a cornerstone of cancer pain management. 'Dose titration' with short-acting morphine is widely accepted. Such a titration method is very complicated. The analgesic background establishment is often delayed. Titration based on sustained-release opioids is also recommended, but the onset of analgesic effect requires hours, whereas the rescue analgesia is always needed. This study evaluated the optimized morphine titration scheme with a simultaneous combination of sustained-release morphine and subcutaneous morphine. METHODS: In a multicenter, 7-day, randomized controlled study, patients with moderate to severe cancer pain were assigned to receive either sustained-release morphine and subcutaneous morphine simultaneously (rapid titration) or only subcutaneous morphine to dose titration. The primary outcome was the safety and the number of times of rescue therapy as needed in the first 24 h. RESULTS: A total of 108 patients with moderate to severe cancer pain were included in the study. The number of times of rescue analgesics in the first 24 h significantly reduced in the rapid titration group (0.4 ± 0.48 vs. 2.3 ± 0.78, P = 0.000). No differences in the intensity of opioid-related symptoms were found between the two groups. CONCLUSIONS: Rapid titration is safe and efficient, which could significantly decrease rescue analgesics in the first 24 h and achieve better analgesic efficacy for cancer pain patients.

Effective method to reduce the normal brain dose in single-isocenter hypofractionated stereotactic radiotherapy for multiple brain metastases.

BACKGROUND AND PURPOSE: Island blocking and dose leakage problems will lead to unnecessary irradiation to normal brain tissue (NBT) in hypofractionated stereotactic radiotherapy (HSRT) for multiple brain metastases (BM) with single-isocenter volumetric modulated arc therapy (VMAT). The present study aimed at investigating whether reducing the number of metastases irradiated by each arc beam could minimize these two problems. MATERIALS AND METHODS: A total of 32 non-small-cell lung cancer (NSCLC) patients with multiple BM received HSRT (24-36 Gy/3 fractions) with single-isocenter VMAT, where each arc beam only irradiated partial metastases (pm-VMAT), were enrolled in this retrospective study. Conventional single-isocenter VMAT plans, where each arc beam irradiated whole metastases (wm-VMAT), was regenerated and compared with pm-VMAT plans. Furthermore, the clinical efficacy and toxicities were evaluated. RESULTS: Pm-VMAT achieved similar target coverage as that with wm-VMAT, with better dose fall-off (P < 0.001) and NBT sparing (P < 0.001). However, pm-VMAT resulted in more monitor units (MU) and longer beam-on time (P < 0.001). The intracranial objective response rate and disease control rate for all patients were 75% and 100%, respectively. The local control rates at 1 year and 2 year were 96.2% and 60.2%, respectively. The median progression-free survival and overall survival were 10.3 months (95% confidence interval [CI] 6.8-13.2) and 18.5 months (95% CI 15.9-20.1), respectively. All treatment-related adverse events were grade 1 or 2, and 3 lesions (2.31%) from 2 patients (6.25%) demonstrated radiation necrosis after HSRT. CONCLUSION: HSRT with pm-VMAT is effective and has limited toxicities for NSCLC patients with multiple BM. Pm-VMAT could provide better NBT sparing while maintaining target dose coverage.

Apatinib-induced Grade 3 hand-foot syndrome in advanced lung adenocarcinoma successful treated with thalidomide: A case report.

Hand-foot syndrome (HFS) is a specific cutaneous toxicity caused by a variety of antitumor drugs. The most common drugs include capecitabine, pegylated liposomal doxorubicin and fluorouracil (PLD), tyrosine kinase inhibitor. It is a dose-limiting cutaneous toxicity of these drugs. We reported an advanced lung adenocarcinoma female patient, who developed a Grade 3 HFS after a third-line treatment with apatinib of 250 mg for 10 days, the patient developed intolerable pain with pruritus. Large erythema on the skin of the hand, with local ulceratio, exudation, and desquamation of cutaneous lesions. After treatment with 100 mg of thalidomide every night for 1 week, the patient's HFS was significantly relieved, and the duration of the remission was about 2 months, which not only significantly improved the patient's quality of life, but also maintained the antitumor strength.

Effect of PAK1 gene silencing on proliferation and apoptosis in hepatocellular carcinoma cell lines MHCC97-H and HepG2 and cells in xenograft tumor.

This study intends to explore the effect of the PAK1 gene silencing on apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H and HepG2 cells and cells in xenograft tumor. MHCC97-H and HepG2 cells and mice with xenograft tumor in vivo were randomly divided into control, empty vector and PAK1 shRNA groups. Morphology and the expression of green fluorescent protein of MHCC97-H and HepG2 cells and cells in xenograft tumor were observed. MTT assay and flow cytometry were used to detect proliferation, cell cycle and apoptosis of MHCC97-H and HepG2 cells and cells in xenograft tumor. The expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2, p21, p53, Bax and Bcl-2 were measured using the quantitative reverse transcription polymerase chain reaction and western blotting. Compared with the control and empty vector groups, number of adherent cells of MHCC97-H and HepG2 cells and cells in xenograft tumor was reduced, and green fluorescent cells became round and reduced in the PAK1 shRNA group. Cell proliferation, the cells at S phase, the mRNA and protein expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2 and Bcl-2 of MHCC97-H and HepG2 cells and cells in xenograft tumor were decreased, while the cells at G1 phase, apoptosis rate, the mRNA and protein expressions of p21, p53 and Bax of MHCC97-H and HepG2 cells and cells in xenograft tumor were increased in the PAK1 shRNA group. PAK1 gene silencing decreases proliferation of MHCC97-H cells, HepG2 cells and cells in xenograft tumor through the p53/p21 pathway.

Inhibition of cyclin-dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis.

Increasing evidence has shown that THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, exhibits therapeutic effects in various tumors. However, the possible effect of THZ1 on hepatocellular carcinoma (HCC) remains unknown. Our study was to investigate the roles of THZ1 in HCC cells and in subcutaneous HCC model and illustrate the molecular mechanisms. The phosphorylation levels of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII) C-terminal domain (CTD) and the expression levels of Ki67, Mcl-1, survivin, XIAP, and p53 in HCC cells under different conditions were examined by Western blot analysis. Cell growth and apoptosis were assessed via 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Tumor volume was assessed in HCC mice with THZ1 or vehicle treatment and immunohistochemical (IHC) analysis was conducted on excised tumors. THZ1 significantly inhibited the phosphorylation of Ser2, Ser5, and Ser7 within RNAPII-CTD in the dose-dependent and irreversible manner. MTT assay and flow cytometry analysis showed that THZ1 inhibited HCC cell proliferation and induced apoptosis, respectively. Western blot analysis indicated THZ1 significantly upregulated p53 expression and downregulated the expressions of Mcl-1, survivin, XIAP, and Ki67. THZ1 suppressed tumor growth in Hep3B xenografted mice in a time-dependent manner. IHC analysis indicated that tumors in THZ1 group had less Ki67+ cells and more cleaved caspase-3+ cells than those in vehicle group. THZ1 exhibited anti-HCC effects through irreversibly inhibiting CDK7 activity, decreasing RNAPII-CTD phosphorylation, inducing p53 expression and inhibiting antiapoptotic gene expressions, which subsequently induced apoptosis and inhibited proliferation of HCC cells.

miR-122-5p Inhibits the Proliferation, Invasion and Growth of Bile Duct Carcinoma Cells by Targeting ALDOA.

BACKGROUND/AIMS: Bile duct cancer, although not among the most common tumors, still accounts for more and more worldwide deaths each year. By attempting to verify an overexpression of ALDOA in cholangiocarcinoma tissues and cells and explore the underlying molecular mechanism regulated by miR-122-5p, this study was designed to provide a potential molecular target in bile duct cancer treatment. METHODS: Western blot and immunohistochemistry were performed to detect the ALDOA protein level in duct carcinoma tissues. The transfection efficiency was confirmed by western blot and/or RT-qPCR assay. The proliferation of bile duct carcinoma cells was determined by MTT and colony formation assay. The invasion ability of bile duct carcinoma cells was evaluated with Transwell invasion assay. Flow cytometry detected cell apoptosis of bile duct carcinoma cells. The miRNAs which modulate ALDOA were filtrated from bioinformatics software and clinical specimens. The target relationship was confirmed by dual luciferase reporter assay. Furthermore, a xenograft model was completed to verify the impact of miRNA on inhibition growth of bile duct carcinoma cells. RESULTS: ALDOA was found up-regulated in bile duct carcinoma tissues and cells. Knockdown of ALDOA promoted the apoptosis of cells and inhibited the proliferation and invasion of bile duct carcinoma cells. Bioinformatics and clinical specimens indicated the negative correlation and targeted regulation between miR-122-5p and ALDOA. By down-regulating ALDOA, overexpression of miR-122-5p appeared to promote cell apoptosis and significantly inhibit cell proliferation, invasion in vitro and suppress the tumor growth in vivo. CONCLUSION: miR-122-5p inhibited proliferation and invasion of bile duct carcinoma cells and promoted cell apoptosis by targeting ALDOA expression.

Development and validation of a machine learning-based early prediction model for massive intraoperative bleeding in patients with primary hepatic malignancies.

BACKGROUND: Surgical resection remains the primary treatment for hepatic malignancies, and intraoperative bleeding is associated with a significantly increased risk of death. Therefore, accurate prediction of intraoperative bleeding risk in patients with hepatic malignancies is essential to preventing bleeding in advance and providing safer and more effective treatment. AIM: To develop a predictive model for intraoperative bleeding in primary hepatic malignancy patients for improving surgical planning and outcomes. METHODS: The retrospective analysis enrolled patients diagnosed with primary hepatic malignancies who underwent surgery at the Hepatobiliary Surgery Department of the Fourth Hospital of Hebei Medical University between 2010 and 2020. Logistic regression analysis was performed to identify potential risk factors for intraoperative bleeding. A prediction model was developed using Python programming language, and its accuracy was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Among 406 primary liver cancer patients, 16.0% (65/406) suffered massive intraoperative bleeding. Logistic regression analysis identified four variables as associated with intraoperative bleeding in these patients: ascites [odds ratio (OR): 22.839; P < 0.05], history of alcohol consumption (OR: 2.950; P < 0.015), TNM staging (OR: 2.441; P < 0.001), and albumin-bilirubin score (OR: 2.361; P < 0.001). These variables were used to construct the prediction model. The 406 patients were randomly assigned to a training set (70%) and a prediction set (30%). The area under the ROC curve values for the model's ability to predict intraoperative bleeding were 0.844 in the training set and 0.80 in the prediction set. CONCLUSION: The developed and validated model predicts significant intraoperative blood loss in primary hepatic malignancies using four preoperative clinical factors by considering four preoperative clinical factors: ascites, history of alcohol consumption, TNM staging, and albumin-bilirubin score. Consequently, this model holds promise for enhancing individualised surgical planning.

Complete remission of reactive cutaneous capillary endothelial proliferation caused by the programmed cell death-1 inhibitor camrelizumab achieved through thalidomide monotherapy: A case report.

Reactive cutaneous capillary endothelial proliferation (RCCEP) is a common adverse effect of the anti-programmed cell death-1 (PD-1) monoclonal antibody camrelizumab and usually occurs on the skin. This condition causes bleeding nodules of varying severity depending on disease grade; these affect a person's appearance and quality of life. The exact mechanism remains elusive and its occurrence in visceral organs has not been previously reported, to the best of our knowledge. Furthermore, there is currently a lack of standard, uniform treatments. The present study reported on a patient who experienced RCCEP during treatment with camrelizumab and benefited greatly from thalidomide, which caused no serious adverse events. An elderly Chinese female initially diagnosed with stage II endometrial cancer had previously undergone surgery, radiotherapy and intravenous chemotherapy but developed multiple metastases in the peritoneum and vaginal remnant. The patient was subsequently prescribed camrelizumab after systemic treatment failed. Soon after commencing treatment with this PD-1 inhibitor, the patient developed RCCEP, whereupon oral low-dose thalidomide monotherapy (100 mg nightly) was prescribed. At two weeks after commencing thalidomide, the RCCEP symptoms were alleviated. Based on this patient's successful treatment, it is suggested that low-dose thalidomide may be an alternative intervention for patients with camrelizumab-induced RCCEP.

Pyroptosis Provides New Strategies for the Treatment of Cancer.

Cancer is an important cause of death worldwide. The main types of cancer treatment are still surgery, chemotherapy and radiotherapy, and immunotherapy is becoming an important cancer treatment. Pyroptosis is a type of programmed cell death that accompanies an inflammatory response. This paper reviews the recent research progress in pyroptosis in tumors. Pyroptosis has been observed since 1986 and until recently has been recognized as programmed cell death mediated by GSDM family proteins. The molecular pathway of pyroptosis depends on the inflammasome-mediated caspase-1/GSDMD pathway, which is the canonical pathway, and the caspase-4/5/11/GSDMD pathway, which is the noncanonical pathway. Other pathways include caspase3/GSDME. Pyroptosis is a double-edged sword that is closely related to the tumor immune microenvironment. On the one hand, pyroptosis produces a chronic inflammatory environment, promotes the transition of normal cells to tumor cells, helps tumor cells achieve immune escape, and promotes tumor growth and metastasis. On the other hand, some tumor cell treatments can induce pyroptosis, which is a nonapoptotic form of cell death. Additionally, pyroptosis releases inflammatory molecules that promote lymphocyte recruitment and enhance the immune system's ability to kill tumor cells. With the advent of immunotherapy, pyroptosis has been shown to enhance the antitumor efficacy of immune checkpoint inhibitors. Some antineoplastic agents, such as chemotherapeutic agents, can also exert antineoplastic effects through the pyroptosis pathway. Pyroptosis, which is a programmed cell death mode, has been the focus of research in recent years, and the relationship between pyroptosis, tumors and tumor immunity has attracted attention, but there are still some questions to be answered regarding the specific mechanism. Further study of pyroptosis would aid in developing new antitumor therapies and has great clinical prospects.

Nuclear receptor coactivator 6 (NCoA6) promotes cell proliferation, migration, and invasion in pancreatic cancer.

BACKGROUND: Nuclear receptor coactivator 6 (NCoA6) is overexpressed in various cancers and considered a multifunctional coactivator of various transcription factors and nuclear receptors. However, the role of NCoA6 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: NCoA6 expression data in PDAC were extracted from TCGA and GTEx databases, and their correlation with survival outcomes were analyzed using the Kaplan-Meier plotter database. NCoA6 protein expression in PDAC tissues was evaluated using immunohistochemistry. RNA-sequencing technology was used to sequence the transcriptome of NCoA6-silenced PANC-1 cells, followed by differential expression, GO/KEGG and GSEA analyses. The effects of NCoA6 on cell proliferation, migration, invasion, cell cycle, and apoptosis were determined in two representative cell lines (PANC-1 and SW1990). Western blotting, qPCR, and co-immunoprecipitation were performed to explore the mechanism of action of NCoA6 in PDAC cells. RESULTS: NCoA6 expression was markedly increased in PDAC tissues, and high NCoA6 expression was associated with poor survival prognosis. However, there was no significant relationship between NCoA6 expression and metastasis in PDAC patients. Our RNA-sequencing data analysis found 1194 significant differentially expressed genes between the control and NCoA6-silenced PANC-1 cells. GO/KEGG analysis results mainly focused on cytokine production, cytokine activity, and cytokine-cytokine receptor interactions. GSEA results showed that the knockdown of NCoA6 affected the expression of histone deacetylase 1 (HDAC1) targeted genes. NCoA6 knockdown suppressed proliferation, migration, and invasion of PDAC cells. Finally, western blotting, qPCR, and co-immunoprecipitation results showed that NCoA6 interacted with HDAC1 and that NCoA6 expression was negatively correlated with F-box and WD repeat domain-containing 7 (FBW7) and caudal-related homeobox transcription factor 2 (CDX2) expression in pancreatic cancer. CONCLUSIONS: NCoA6 has a profound effect on cell proliferation, migration, invasion, and prognosis of PDAC and is potentially related to the expression of HDAC1, FBW7, and CDX2. Our results may provide novel therapeutic strategies for PDAC patients.

Huo Xiang Zheng Qi Oral Liquid Combined with 5-HT3 Receptor Antagonists and Dexamethasone Can Prevent Chemotherapy-Induced Nausea and Vomiting for Patients Receiving Multiday Cisplatin-Based Regimen: A Multicenter Trial.

Background: Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects associated with deterioration in the quality of life. This study aimed to assess the clinical value of Huoxiang Zhengqi (HXZQ) oral liquid, a Chinese patent medicine, in combination with 5-HT3 receptor antagonists (RAs) and dexamethasone, in preventing CINV in patients receiving multiday cisplatin-based chemotherapy. Methods: In this multicenter, exploratory randomized clinical trial, the authors compared the efficacy of HXZQ oral liquid against a control group receiving a placebo, in combination with 5-HT3 RAs and dexamethasone, in preventing CINV in chemotherapy-naive patients receiving a multiday cisplatin-based regimen between January 2021 and September 2021. The primary endpoint was the complete response (CR) rate. The secondary endpoints included days with no CINV, the incidence of CINV, and life function. Results: Sixty patients were randomized into two groups and included in the study. The CR rate was significantly improved by HXZQ oral liquid in acute CINV (63.33% vs. 33.33%, p = 0.020) and CINV beyond the risk phase (96.67% vs. 46.67%, p = 0.000). The number of days with no CINV was significantly more in the HXZQ group compared with the control group in the overall phase (18.10 ± 3.64 vs. 12.13 ± 7.63, p = 0.002). Significantly higher Functional Living Index-Emesis total and domain scores were observed in the HXZQ group. Conclusions: HXZQ oral liquid combined with 5-HT3 RAs and dexamethasone is a feasible and safe approach to prevent CINV in patients receiving multiday cisplatin-based chemotherapy who cannot use neurokinin 1 RAs. Clinical Trial Registration: ChiCTR2000040123.

Successful therapy using high-dose furmonertinib for non-small cell lung cancer with leptomeningeal metastasis: a case report and literature review.

Background: Lung cancer is the second most common form of malignant tumor and has the highest mortality rate worldwide. Among its subtypes, lung adenocarcinoma is the most prevalent. Leptomeningeal metastasis (LM) is rare and is characterized by a dismal prognosis, with overall survival periods typically spanning 4 to 6 weeks without treatment. However, in specific cases, survival can be extended to 4 to 6 months with appropriate therapy. The recent approval of third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, aumolertinib, and furmonertinib, has introduced promising treatment options for individuals with non-small cell lung cancer (NSCLC) who develop LM after developing resistance to first- and second-generation TKIs. These third-generation TKIs exhibit an enhanced ability to penetrate the blood-brain barrier (BBB), opening up new avenues for managing this challenging condition. Case summary: We report the case of a 48-year-old Chinese man diagnosed with advanced NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. Following a pulmonary lobectomy and postoperative adjuvant therapy with gefitinib, the patient was diagnosed with LM, which was confirmed by his neurologic symptoms, cerebrospinal fluid cytologic analysis, and cranial enhancement magnetic resonance imaging. Subsequently, he received oral treatment in the form of 160 mg of furmonertinib daily. After 5 days of furmonertinib therapy, the patient recovered from lethargy, with an obvious improvement in cognitive function. Follow-up visits revealed a 6-month survival period following the LM diagnosis. Patients with NSCLC and LM typically present with severe symptoms, and the efficacy of systemic treatment, intrathecal chemotherapy, and radiotherapy remains unsatisfactory. We hope that this specific case provide valuable insights into the management of patients with EGFR mutation-associated NSCLC with LM. Conclusion: Furmonertinib, a third-generation EGFR TKI with notable BBB penetration, shows promise in LM control and the rapid alleviation of intracranial symptoms. Further investigations into appropriate dosage and toxicity management are imperative.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.