Organic solvents-free and ambient-pressure drying melamine formaldehyde resin aerogels with homogeneous structures, outstanding mechanical strength and flame retardancy.

Atmospheric drying method for fabricating aerogels is considered the most promising way for casting aerogels on a large scale. However, the organic solvent exchange, remaining environmental pollution risk, is a crucial step in mitigating the impact of surface tension during the atmospheric drying process, especially for wet gel formed through the alkoxy-derived sol-gel process, such as melamine-formaldehyde resin (MF) aerogel. Herein, a tough polymer-assisted in situ polymerization was proposed to fabricate MF resin aerogel with a combination of mechanical toughness and strength, enabling it to withstand the capillary force during water evaporation. The monolithic MF resin aerogel through the sol-gel method can be directly prepared without additional network strengthening or organic solvent exchange. The resulting MF resin aerogel exhibits a homogeneous as well as hierarchical structure with macropores and mesopores (~6 µm and ~5 nm), high compressive modulus of 31.8 MPa, self-extinguishing property, and high-temperature thermal insulation with 97 % heat decrease for butane flame combustion. This work presents a straightforward and environmentally friendly method for fabricating MF resin aerogels with nanostructures and excellent performance in open conditions, exhibiting various applications.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Cuproptosis: unveiling a new frontier in cancer biology and therapeutics.

Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types.

Unveiling the intratumoral microbiota within cancer landscapes.

Recent advances in cancer research have unveiled a significant yet previously underappreciated aspect of oncology: the presence and role of intratumoral microbiota. These microbial residents, encompassing bacteria, fungi, and viruses within tumor tissues, have been found to exert considerable influence on tumor development, progression, and the efficacy of therapeutic interventions. This review aims to synthesize these groundbreaking discoveries, providing an integrated overview of the identification, characterization, and functional roles of intratumoral microbiota in cancer biology. We focus on elucidating the complex interactions between these microorganisms and the tumor microenvironment, highlighting their potential as novel biomarkers and therapeutic targets. The purpose of this review is to offer a comprehensive understanding of the microbial dimension in cancer, paving the way for innovative approaches in cancer diagnosis and treatment.

Congener-specific fate and impact of microcystins in the soil-earthworm system.

Microcystins (MCs) have a significant influence on aquatic ecosystems, but little is known about their terrestrial fate and impact. Here, we investigated the fate of two MCs (MC-LR and MC-RR) in the soil-earthworm system, with consideration of their congener-specific impact on earthworm health, soil bacteria, and soil metabolome. Although MCs had little acute lethal effect on earthworms, they caused obvious growth inhibition and setae rupture. Relative to MC-RR, MC-LR exhibited higher bioaccumulation and the resulting dermal lesions and deformation of longitudinal muscles. While the incorporation of both MCs into soils stimulated pathogenic bacteria and depressed oxidative stress tolerant bacteria, the response among soil nitrification and glutathione metabolism differed between the two congeners. The dissipation kinetics of MCs obeyed the first-order model. Earthworms stimulated soil N-cycling enzyme activities, increased the abundance of MC-degrading bacteria, and promoted bacterial metabolic functions related to glutathione metabolism, xenobiotics biodegradation, and metabolism of amino acids that comprise MCs, which accelerated the dissipation of MC-LR and MC-RR by 227% and 82%, respectively. These results provide evidence of significant congener differences in the terrestrial fate and impact of MCs, which will enable a better understanding of their role in mediating soil functions and ecosystem services.

CAR T treatment beyond cancer: Hope for immunomodulatory therapy of non-cancerous diseases.

Engineering a patient's own T cells to accurately identify and eliminate cancer cells has effectively cured individuals afflicted with previously incurable hematologic cancers. These findings have stimulated research into employing chimeric antigen receptor (CAR) T therapy across various areas within the field of oncology. However, evidence from both clinical and preclinical investigations emphasize the broader potential of CAR T therapy, extending beyond oncology to address autoimmune disorders, persistent infections, cardiac fibrosis, age-related ailments and other conditions. Concurrently, the advent of novel technologies and platforms presents additional avenues for utilizing CAR T therapy in non-cancerous contexts. This review provides an overview of the rationale behind CAR T therapy, delineates ongoing challenges in its application to cancer treatment, summarizes recent findings in non-cancerous diseases, and engages in discourse regarding emerging technologies that bear relevance. The review delves into prospective applications of this therapeutic approach across a diverse range of scenarios. Lastly, the review underscores concerns related to precision and safety, while also outlining the envisioned trajectory for extending CAR T therapy beyond cancer treatment.

Multiparametric MRI subregion radiomics for preoperative assessment of high-risk subregions in microsatellite instability of rectal cancer patients: A multicenter study.

BACKGROUND: Microsatellite instability (MSI) is associated with treatment response and prognosis in patients with rectal cancer (RC). However, intratumoral heterogeneity limits MSI testing in patients with RC. We developed a subregion radiomics model based on multiparametric magnetic resonance imaging (MRI) to preoperatively assess high-risk subregions with MSI and predict the MSI status of patients with RC. METHODS: This retrospective study included 475 patients (training cohort, 382; external test cohort, 93) with RC from two participating hospitals between April 2017 and June 2023. In the training cohort, subregion radiomic features were extracted from multiparametric MRI, which included T2-weighted, T1-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging. MSI-related subregion radiomic features, classical radiomic features, and clinicoradiological variables were gathered to build five predictive models using logistic regression. Kaplan-Meier survival analysis was conducted to explore the prognostic information. RESULTS: Among the 475 patients (median age, 64 years [interquartile range, IQR: 55-70 years];304 men and 171 women), the prevalence of MSI was 11.16% (53/475). The subregion radiomics model outperformed the classical radiomics and clinicoradiological models in both training (area under the curve [AUC]=0.86, 0.72, and 0.59, respectively) and external test cohorts (AUC=0.83, 0.73, and 0.62, respectively). The subregion-clinicoradiological model combining clinicoradiological variables and subregion radiomic features performed the optimal, with AUCs of 0.87 and 0.85 in the training and external test cohorts, respectively. The 3-year disease-free survival rate of MSI groups predicted based on the model was higher than that of the predicted microsatellite stability (MSS) groups in both patient cohorts (training, P=0.032; external test, P=0.046). CONCLUSIONS: We developed and validated a model based on subregion radiomic features of multiparametric MRI to evaluate high-risk subregions with MSI and predict the MSI status of RC preoperatively, which may assist in individualized treatment decisions and positioning for biopsy.

Erythropoietin-derived peptide ARA290 mediates brain tissue protection through the ß-common receptor in mice with cerebral ischemic stroke.

AIM: To explore the neuroprotective effects of ARA290 and the role of ß-common receptor (ßCR) in a mouse model of middle cerebral artery occlusion (MCAO). METHODS: This study included male C57BL/6J mice that underwent MCAO and reperfusion. The neuroprotective effect of ARA290 on MCAO-induced brain injury was investigated using neurological function tests (Longa and modified neurological severity score). Cerebral infarction was examined by 2, 3, 5-triphenyl tetrazolium chloride staining, neuronal apoptosis was assessed by immunofluorescence staining, blood parameters were measured using a flow cytometry-based automated hematology analyzer, liquid chromatography with tandem mass spectrometry was used to identify the serum metabolomics signature, inflammatory cytokines and liver index were detected by commercially available kits, and the protein levels of the erythropoietin (EPO) receptor and ßCR were measured by western blot. RESULTS: ARA290 exerted a qualitatively similar neuroprotective effect after MCAO as EPO. ARA290 significantly reduced neuronal apoptosis and the level of inflammatory cytokines in the brain tissue. However, ARA290's neuroprotective effect was significantly suppressed following the injection of siRNA against ßCR. CONCLUSION: ARA290 provided a neuroprotective effect via ßCR in cerebral ischemic mice without causing erythropoiesis. This study provides novel insights into the role of ARA290 in ischemic stroke intervention.

A pilot trial of neoadjuvant pyrotinib plus trastuzumab, dalpiciclib, and letrozole for triple-positive breast cancer.

Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II-III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%-84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0-I was 75% (95% CI, 46.8%-91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%-70.5%) at baseline to 17.2% (95% CI, 0.7%-33.7%) after neoadjuvant therapy (p = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.

Deciphering the link: ferroptosis and its role in glioma.

Glioma, as the most frequently occurring primary malignancy in the central nervous system, significantly impacts patients' quality of life and cognitive abilities. Ferroptosis, a newly discovered form of cell death, is characterized by significant iron accumulation and lipid peroxidation. This process is fundamentally dependent on iron. Various factors inducing ferroptosis can either directly or indirectly influence glutathione peroxidase, leading to reduced antioxidant capabilities and an increase in lipid reactive oxygen species (ROS) within cells, culminating in oxidative cell death. Recent research indicates a strong connection between ferroptosis and a range of pathophysiological conditions, including tumors, neurological disorders, ischemia-reperfusion injuries, kidney damage, and hematological diseases. The regulation of ferroptosis to intervene in the progression of these diseases has emerged as a major area of interest in etiological research and therapy. However, the exact functional alterations and molecular mechanisms underlying ferroptosis remain to be extensively studied. The review firstly explores the intricate relationship between ferroptosis and glioma, highlighting how ferroptosis contributes to glioma pathogenesis and how glioma cells may resist this form of cell death. Then, we discuss recent studies that have identified potential ferroptosis inducers and inhibitors, which could serve as novel therapeutic strategies for glioma. We also examine the current challenges in targeting ferroptosis in glioma treatment, including the complexity of its regulation and the need for precise delivery methods. This review aims to provide a comprehensive overview of the current state of research on ferroptosis in glioma, offering insights into future therapeutic strategies and the broader implications of this novel cell death pathway in cancer biology.

Deep learning-assisted ultrasonic diagnosis of cervical lymph node metastasis of thyroid cancer: a retrospective study of 3059 patients.

Objective: This study aimed to develop a deep learning system to identify and differentiate the metastatic cervical lymph nodes (CLNs) of thyroid cancer. Methods: From January 2014 to December 2020, 3059 consecutive patients with suspected with metastatic CLNs of thyroid cancer were retrospectively enrolled in this study. All CLNs were confirmed by fine needle aspiration. The patients were randomly divided into the training (1228 benign and 1284 metastatic CLNs) and test (307 benign and 240 metastatic CLNs) groups. Grayscale ultrasonic images were used to develop and test the performance of the Y-Net deep learning model. We used the Y-Net network model to segment and differentiate the lymph nodes. The Dice coefficient was used to evaluate the segmentation efficiency. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were used to evaluate the classification efficiency. Results: In the test set, the median Dice coefficient was 0.832. The sensitivity, specificity, accuracy, PPV, and NPV were 57.25%, 87.08%, 72.03%, 81.87%, and 66.67%, respectively. We also used the Y-Net classified branch to evaluate the classification efficiency of the LNs ultrasonic images. The classification branch model had sensitivity, specificity, accuracy, PPV, and NPV of 84.78%, 80.23%, 82.45%, 79.35%, and 85.61%, respectively. For the original ultrasonic reports, the sensitivity, specificity, accuracy, PPV, and NPV were 95.14%, 34.3%, 64.66%, 59.02%, 87.71%, respectively. The Y-Net model yielded better accuracy than the original ultrasonic reports. Conclusion: The Y-Net model can be useful in assisting sonographers to improve the accuracy of the classification of ultrasound images of metastatic CLNs.

Radiological characteristics predicting early poor drug response in patients with hemifacial spasm.

OBJECTIVES: Patients with hemifacial spasm (HFS) often resort to botulinum toxin injections or microvascular decompression surgery when medication exhibits limited effectiveness. This study aimed to identify MRI and demographic factors associated with poor drug response at an early stage in patients with HFS. METHODS: We retrospectively included patients with HFS who underwent pre-therapeutic MRI examination. The presence, location, severity, and the offending vessels of neurovascular compression were blindly evaluated using MRI. Drug responses and clinical data were obtained from the medical notes or phone follow-ups. Logistic regression analysis was performed to identify potential factors. RESULTS: A total of 116 patients were included, with an average age at the time of first examination of 50.4 years and a median duration of onset of 18 months. Forty-nine (42.2%) patients reported no symptom relief. Thirty-seven (31.9%) patients reported poor symptom relief. Twenty-two (19.0%) patients reported partial symptom relief. Eight (6.9%) patients achieved complete symptom relief. The factors that were statistically significant associated with poor drug responses were contact in the attach segment of the facial nerve and aged 70 and above, with an odds ratio of 7.772 (p = 0.002) and 0.160 (p = 0.028), respectively. CONCLUSIONS: This study revealed that mild compression in the attach segment of the facial nerve in pre-therapeutic MRI increases the risk of poor drug responses in patients with HFS, while patients aged 70 and above showed a decreased risk. These findings may assist clinician to choose optimal treatment at an early stage.

Current state of immune checkpoints therapy for glioblastoma.

Glioblastoma (GBM), one of the most aggressive forms of brain cancer, has limited treatment options. Recent years have witnessed the remarkable success of checkpoint inhibitor immunotherapy across various cancer types. Against this backdrop, several clinical trials investigating checkpoint inhibitors for GBM are underway in multiple countries. Furthermore, the integration of immunotherapy with traditional treatment approaches is now emerging as a highly promising strategy. This review summarizes the latest advancements in checkpoint inhibitor immunotherapy for GBM treatment. We provide a concise yet comprehensive overview of current GBM immunotherapy options. Additionally, this review underscores combination strategies and potential biomarkers for predicting response and resistance in GBM immunotherapies.

Late-stage gem-difluoroallylation of phenol in bioactive molecules and peptides with 3,3-difluoroallyl sulfonium salts.

An efficient method for the late-stage selective O-fluoroalkylation of tyrosine residues with a stable yet highly reactive fluoroalkylating reagent, 3,3-difluoroallyl sulfonium salts (DFASs), has been developed. The reaction proceeds in a mild basic aqueous buffer (pH = 11.6) with high efficiency, high biocompatibility, and excellent regio- and chemoselectivity. Various oligopeptides and phenol-containing bioactive molecules, including carbohydrates and nucleosides, could be selectively O-fluoroalkylated. The added vinyl and other functional groups from DFASs can be valuable linkers for successive modification, significantly expanding the chemical space for further bioconjugation. The synthetic utility of this protocol has been demonstrated by the fluorescently labeled anti-cancer drug and the synthesis of O-link type 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid-tyrosine3-octreotate (DOTA-TATE), showing the prospect of the method in medicinal chemistry and chemical biology.

Anterior cervical discectomy and fusion with a zero-profile VA spacer device: a clinical and radiological study with two-year follow-up.

STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to compare clinical and radiological outcomes of the anterior cervical discectomy and fusion (ACDF) with a novel zero-profile variable-angle (Zero-P VA) spacer and a traditional poly-ether-ether-ketone (PEEK) cage and plate system in cases pertaining to cervical radiculopathy/myelopathy. There are two conventional types of ACDF procedures aimed at treating symptomatic cervical spondylosis. The first one involves an uninstrumented "stand-alone" approach utilizing bone graft/cage, while the second incorporates bone graft/cage in conjunction with a front plate positioned before the vertebral bodies. Both procedures have their own inherent advantages and disadvantages. The Zero-P VA spacer, however, represents a unique synthesis by amalgamating the advantages of both traditionally typical procedures. Notably, this spacer can potentially circumvent the issue related to prevertebral soft-tissue disturbance and reduce the occurrence of dysphagia. METHODS: Using our surgical database, the authors systematically conducted a retrospective analysis encompassing all patients who underwent single-level ACDF between January 2018 and January 2019, with a minimum two-year follow-up. Patients either received a Zero-P VA implant or PEEK cage coupled with plating. The Japanese Orthopedic Association (JOA) score and Visual Analogue Scale (VAS) for arm and neck pain were documented. Dysphagia was evaluated using the Eating Assessment Tool-10 (ETA-10). Additional parameters such as cervical alignment, fusion rate and the incidence of postoperative complications were assessed. RESULTS: According to the outcomes of the statistical analysis, there was no substantial disparity that emerged in the advancements observed in the JOA and VAS metrics between the two study cohorts. Noteworthy, however, the ETA-10 scores were statistically significantly reduced in the Zero-P VA group compared to the cage and plating group (p < 0.05). At the final follow-up, there were no statistically significant differences in the height of the operated segment, Cobb angle of the fused segment, C2-C7 Cobb angle and fusion rate between the two groups (p > 0.05). However, postoperative complications were slightly lower in patients with the Zero-P VA group (7.69%) as compared to the cage and plating group (16.67%). CONCLUSION: The clinical outcomes observed with the Zero-P VA spacer used for single-level ACDF were found to be satisfactory. The performance of this device is comparable or even superior to the traditional cage and plating method in preventing postoperative dysphagia and mitigating potential complications associated with the use of a plate.

Worldwide research trends on tumor burden and immunotherapy: a bibliometric analysis.

Various immunotherapy has been greatly applied to comprehensive treatment of malignant cancer under different degrees of tumor burden. Scientific researchers have gained considerable progress in the relationship between immunotherapy and tumor burden in recent years. This review aimed to explore the prospect and developing trends in the field of tumor burden and immunotherapy from a bibliometric perspective. Articles about tumor burden and immunotherapy were collected from the Web of Science Core Collection (WoSCC) (retrieved on 3 January 2023). The R package 'Bibliometrix' analyzed the primary bibliometric features and created a three-filed plot to display the relationship between institutions, countries, and keywords. VOSviewer was used for co-authorship analysis, co-occurrence analysis, and their visualization. And CiteSpace calculated the citation burst references and keywords. A total of 1030 publications were retrieved from 35 years of scientific researches. The United States (US) and China published the most articles. The most productive journals were Cancer Immunology Immunotherapy and Journal for ImmunoTherapy of Cancer . The top one institution of the highest output was University of Texas MD Anderson Cancer Center. The hot keywords of strong citation burst strength in recent years were 'nivolumab', 'tumor microenvironment', and 'immune checkpoint inhibitor'. The most popular tumor type is melanoma. This bibliometric analysis mapped a basic knowledge structure. The field of tumor burden and immunotherapy is entering a rapid growing stage and keeping it value for future research.

Rare post-operative intracranial abscess due to Serratia marcescens: what we can learn from it?

BACKGROUND: Nosocomial infections caused by Serratia marcescens mostly occurred in pediatrics and it was very rarely reported after adult surgery. Here, an intracranial abscess caused by Serratia marcescens was reported. We report a rare case of a postoperative intracranial abscess caused by Serratia marcescens in a 63-year-old male patient with a left parietal mass. The patient underwent resection of the mass on June 1, 2022, and the postoperative pathology revealed an angiomatous meningioma, WHO I. He then experienced recurrent worsening of right limb movements, and repeated cranial CT scans showed oozing blood and obvious low-density shadows around the operation area. Delayed wound healing was considered. Subsequently, a large amount of pus was extracted from the wound. The etiological test showed that Serratia marcescens infection occurred before the removal of the artificial titanium mesh. Antibiotics were initiated based on the results of drug susceptibility tests. At present, the patient is recovering well and is still closely monitored during follow-up. CONCLUSION: It is rare for Serratia marcescens to cause brain abscesses without any obvious signs of infection. This report provided in detail our experience of a warning postoperative asymptomatic brain abscess caused by an uncommon pathogen.

Development and validation of web-based nomograms for predicting survival status in patients with intrahepatic cholangiocarcinoma depending on the surgical status: a SEER database analysis.

This study aimed to develop and validate prognostic nomograms that can estimate the probability of 1-, 3- and 5-year overall survival (OS) as well as cancer-specific survival (CSS) for Intrahepatic cholangiocarcinoma (ICCA) patients. Clinical data of 1446 patients diagnosed with ICCA between 2010 and 2017 from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. In both the OS and the CSS group, the training cohort and validation cohort were divided into a 7:3 ratio. Age, sex, AJCC T stage, AJCC N stage, AJCC M stage, surgical status, and tumor grade were selected as independent prognostic risk factors to build the nomograms. To compare the efficacy of predicting 1-, 3-, and 5-year OS and CSS rates of the nomogram with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, we evaluated the Harrell's index of concordance (C-index), area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) in both cohorts. The results showed the nomogram for 1-, 3-, and 5-year OS and CSS prediction performed better than the AJCC staging system. In the subgroup analysis for patients could not receive surgery as the primary treatment. We developed two nomograms for predicting the 1-, and 2-year OS and CSS rates following the same analysis procedure. Results indicate that the performance of both nomograms, which contained sex, AJCC T stage, AJCC M stage, chemotherapy, and tumor grade and prognostic factors, was also superior to the AJCC staging system. Meanwhile, four dynamic network-based nomograms were published. The survival analysis showed the survival rate of patients classified as high-risk based on the nomogram score was significantly lower compared to those categorized as low-risk (P < 0.0001). Finally, accurate and convenient nomograms were established to assist clinicians in making more personalized prognosis predictions for ICCA patients.

Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating diverse tumor microenvironments.

Mounting evidence suggests a strong association between tumor immunity and epigenetic regulation. The histone-lysine N-methyltransferase 2 (KMT2) family plays a crucial role in the methylation of histone H3 at lysine 4. By influencing chromatin structure and DNA accessibility, this modification serves as a key regulator of tumor progression and immune tolerance across various tumors. These findings highlight the potential significance of the KMT2 family in determining response to immune checkpoint inhibitor (ICI) therapy, which warrants further exploration. In this study, we integrated four ICI-treated cohorts (n = 2069) across 10 cancer types and The Cancer Genome Atlas pan-cancer cohort and conducted a comprehensive clinical and bioinformatic analysis. Our study indicated that patients with KMT2 family gene mutations benefited more from ICI therapy in terms of overall survival (P < 0.001, hazard ratio [HR] = 0.733 [95% confidence interval (CI): 0.632-0.850]), progression-free survival (P = 0.002, HR = 0.669 [95% CI: 0.518-0.864]), durable clinical benefit (P < 0.001, 54.1% vs. 32.6%), and objective response rate (P < 0.001, 40.6% vs. 22.0%). Through a comprehensive analysis of the tumor microenvironment across different KMT2 mutation statuses, we observed that tumors harboring the KMT2 mutation exhibited enhanced immunogenicity, increased infiltration of immune cells, and higher levels of immune cell cytotoxicity, suggesting a propensity towards a "hot tumor" phenotype. Therefore, our study indicates a potential association between KMT2 mutations and a more favorable response to ICI therapy and implicates different tumor microenvironments associated with ICI therapy response.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.

BACKGROUND: The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. METHOD: We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. RESULTS: Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. CONCLUSIONS: RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.