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Introduction: Several studies have reported associations between various autoimmune diseases and migraine. Using Mendelian randomization (MR), this study aimed to evaluate the interplay between autoimmune diseases and migraine. Methods: Here, instrumental variables, exposure factors, and outcome factors for 10 common autoimmune diseases and migraine and its subtypes were screened. This screening utilized comprehensive statistics from Europe's largest genome-wide association study and performed reverse MR analysis on positive results. The causality between autoimmune diseases and migraine was comprehensively assessed using multiple analytical methods. Additionally, sensitivity analyses, such as the horizontal diversity heterogeneity and leave-one-out method, were performed. Results: Random-effects inverse variance weighting analysis revealed a causal correlation between autoimmune hyperthyroidism and migraine (p = 0.0002), and this association was consistent across both migraine with aura (MA; p = 0.006) and migraine without aura (MO; p = 0.017). In addition, there was a positive causal association between systemic lupus erythematosus (SLE) and MA (p = 0.001) and between hypothyroidism and MO (p = 0.038). There is insufficient evidence to substantiate a causal link between outcomes and other autoimmune-related disorders, and reverse MR results did not reveal a causal relationship between migraines and these autoimmune disorders. The validity of the results was demonstrated by a sensitivity analysis; horizontal pleiotropy and heterogeneity were not observed. Discussion: This study observed a positive genetic association between autoimmune hyperthyroidism and migraines. In addition, SLE positively affects MA, and hypothyroidism contributes to the incidence of MO. These results have great significance for future research and prevention of migraine.
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AIM: This study aimed to explore the value of ultrasound (US) images in chronic kidney disease (CKD) screening by constructing a CKD screening model based on grey-scale US images. METHODS: According to the CKD diagnostic criteria, 1049 patients from Tongde Hospital of Zhejiang Province were retrospectively enrolled in the study. A total of 4365 renal US images were collected from these patients. Convolutional neural networks were used for feature extractions and a screening model was constructed by fusing ResNet34 and texture features to identify CKD and its stage. A comparative analysis was performed to compare the diagnosis results of the model with physicians. RESULTS: When diagnosing CKD or non-CKD, the receiver operating characteristic curve (AUC) of our model was 0.918 and that of the senior physician group was 0.869 (p < .05). For the diagnosis of CKD stage, the AUC of our model for CKD G1-G3 was 0.781, 0.880, and 0.905, respectively, while the AUC of the senior physician group for CKD G1-G3 was 0.506, 0.586, and 0.796, respectively; all differences were statistically significant (p < .05). The diagnostic efficiency of our model for CKD G4 and G5 reached the level of the senior physicians group. Specifically, the AUC of our model for CKD G4-G5 was 0.867 and 0.931, respectively, while the AUC of the senior physician group for CKD G4-G5 was 0.838 and 0.963, respectively (all p > .05). CONCLUSIONS: Our deep learning radiomics model is more effective than senior physicians in the diagnosis of early CKD.
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Introduction: In recent years, the development of drug-eluting embolization beads that can be imaged has become a hot research topic in regard to meeting clinical needs. In our previous study, we successfully developed nano-assembled microspheres (NAMs) for multimodal imaging purposes. NAMs can not only be visualized under CT/MR/Raman imaging but can also load clinically required doses of doxorubicin. It is important to systematically compare the pharmacokinetics of NAMs with those of commercially available DC Beads and CalliSpheres to evaluate the clinical application potential of NAMs. Methods: In our study, we compared NAMs with two types of drug-eluting beads (DEBs) in terms of irinotecan, drug-loading capacity, release profiles, microsphere diameter variation, and morphological characteristics. Results: Our results indicate that NAMs had an irinotecan loading capacity similar to those of DC Beads and CalliSpheres but exhibited better sustained release in vitro. Conclusion: NAMs have great potential for application in transcatheter arterial chemoembolization for the treatment of colorectal cancer liver metastases.
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Irinotecán , Microesferas , Imagen Multimodal , Irinotecán/administración & dosificación , Irinotecán/farmacología , Humanos , Imagen Multimodal/métodos , Portadores de Fármacos/química , Liberación de Fármacos , Quimioembolización Terapéutica/métodos , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/farmacologíaRESUMEN
The frequency domain characteristics of acoustic emission can reflect issues such as rock structure and stress conditions that are difficult to analyze in time domain parameters. Studying the influence of immersion time on the mechanical properties and acoustic emission frequency domain characteristics of muddy mineral rocks is of great significance for comprehensively analyzing rock changes under water-rock coupling conditions. In this study, uniaxial compression tests and acoustic emission tests were conducted on sandstones containing montmorillonite under dry, saturated, and different immersion time conditions, with a focus on analyzing the effect of immersion time on the dominant frequency of rock acoustic emission. The results indicated that immersion time had varying degrees of influence on compressive strength, the distribution characteristics of dominant acoustic emission frequencies, the frequency range of dominant frequencies, and precursor information of instability failure for sandstones. After initial saturation, the strength of the rock sample decreased from 53.52 MPa in the dry state to 49.51 MPa, and it stabilized after 30 days of immersion. Both dry and initially saturated rock samples exhibited three dominant frequency bands. After different immersion days, a dominant frequency band appeared between 95 kHz and 110 kHz. After 5 days of immersion, the dominant frequency band near 0 kHz gradually disappeared. After 60 days of immersion, the dominant frequency band between 35 kHz and 40 kHz gradually disappeared, and with increasing immersion time, the dominant frequency of the acoustic emission signals increased. During the loading process of dry rock samples, the dominant frequency of acoustic emission signals was mainly concentrated between 0 kHz and 310 kHz, while after saturation, the dominant frequencies were all below 180 kHz. The most significant feature before the rupture of dry rock samples was the frequent occurrence of high frequencies and sudden changes in dominant frequencies. Before rupture, the characteristics of precursor events for initially saturated and immersed samples for 5, 10, and 30 days were the appearance and rapid increase in sudden changes in dominant frequencies, as well as an enlargement of the frequency range of dominant frequencies. After 60 days of immersion, the precursor characteristics of rock sample rupture gradually disappeared, and sudden changes in dominant frequencies frequently occurred at various stages of sample loading, making it difficult to accurately predict the rupture of specimens based on these sudden changes.
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OBJECTIVE: We developed and validated a clinical-radiomics model for preoperative prediction of the short-term efficacy of initial drug-eluting beads transarterial chemoembolization (D-TACE) treatment in patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective cohort study of 113 patients with intermediate and advanced HCC, 5343 features were extracted based on three sequences of the arterial phase (AP), diffusion-weighted imaging, and T2-weighted images based on contrast-enhanced magnetic resonance imaging, and minimum redundancy maximum correlation and least absolute shrinkage and selection operator (LASSO) regression were applied for feature selection and model construction. Multifactor logistic regression was used to build a clinical-imaging model based on clinical factors and a clinical-radiomics model. The area under the curve (AUC) and calibration curves were used to assess model performance, and the clinical value of the model was analyzed using decision curve analysis. The relationship between the actual and predicted short-term efficacy of the combined model and progression-free survival (PFS) was evaluated using Kaplan-Meier survival curves and log-rank tests. RESULTS: A total of 34 radiomics features were selected by LASSO, and the clinical-radiomics model had the best predictive performance (AUC = 0.902 and AUC = 0.845 for the training and testing sets, respectively), and the model based on AP had the best predictive performance among the four radiomics models (AUC = 0.89 for the training set and AUC = 0.85 for the testing set); the multifactorial logistic regression results showed that microsphere type (p = 0.042) and AP Rad-score (p = 0.01) were associated with short-term efficacy. In addition, a difference in PFS was observed in patients with HCC with different short-term efficacies predicted by the combined model. Moreover, prognosis was better in the objective versus non-objective response group. CONCLUSIONS: The combined clinical-radiomics model is an effective predictor of the short-term efficacy of initial D-TACE in patients with HCC, contributing to clinical and economic benefits for patients.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Medios de Contraste , Neoplasias Hepáticas , Imagen por Resonancia Magnética , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Quimioembolización Terapéutica/métodos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Imagen por Resonancia Magnética/métodos , Anciano , Resultado del Tratamiento , Valor Predictivo de las Pruebas , Adulto , Estudios de Cohortes , RadiómicaRESUMEN
Objectives: The lymphotactin receptor X-C motif chemokine receptor 1 (XCR1) is an essential member of the chemokine receptor family and is related to tumor development and progression. Nevertheless, further investigation is required to explore its expression patterns, prognostic values, and functions related to target or immune therapies in patients with hepatocellular carcinoma (HCC). Materials and methods: The differential expression patterns of XCR1 and its prognostic influences were performed through The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Subsequently, immunohistochemistry (IHC) staining and univariate and multivariate Cox regressions were performed to validate the prognostic values in different subgroups. Furthermore, the potential roles of XCR1 in predicting target and immune therapeutic responses were also investigated. Results: Increased expression level of XCR1 was associated with favorable overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis revealed that a high expression level of XCR1 or positive immune cell proportion score (iCPS) were associated with favorable OS in the HCC patients with favorable tumor characteristics. In addition, the enhanced XCR1 expression was associated with the tumor environment scores, immune cell infiltration levels, and the expression levels of immune checkpoint genes. Further analysis revealed that improved expression of XCR1 was linked to better OS and RFS in HCC patients who received sorafenib. Conclusion: This study identified that XCR1 is a valuable prognostic biomarker in the HCC population, especially in those with favorable tumor characteristics. The combination of iCPS status and BCLC status has a synergistic effect on stratifying patients' OS and RFS. Further analyses showed that XCR1 has the potential ability to predict treatment responses to sorafenib and immune-based therapies.
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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.
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OBJECTIVES: To observe the curative efficacy of auricular comprehensive therapy on menstrual migraine(MM) and its effect on serum prostaglandin F2α(PGF2α), prostaglandin E2(PGE2) contents and ratio, so as to explore its possible mechanism. METHODS: A total of 66 patients with MM of liver-fire syndrome were randomly divided into observation group (33 cases, 2 cases dropped off) and control group (33 cases, 2 cases dropped off), and 20 healthy women were included in the normal group. Patients in the control group were given flunarizine hydrochloride capsules orally, twice a day, for 3 consecutive weeks. Patients in the observation group were treated with auricular comprehensive therapy, starting 2-5 days before menstrual cramps, once a week, for a total of 3 weeks. The visual analogue scale (VAS) and migraine score were evaluated before and after treatment, and follow-up for 1 and 2 menstrual cycles. Serum PGF2α and PGE2 contents were measured before and after treatment, and the PGF2α/PGE2 ratio was calculated. The clinical effective rates in the two groups were calculated. RESULTS: After treatment and follow-up for 1 and 2 menstrual cycles, the VAS scores, headache degree, the frequency and duration of headache attacks, as well as accompanying symptoms of the observation and control groups were lower than those before treatment(P<0.05), and those of the observation group was lower than those of the control group(P<0.05). Before treatment, the PGF2α contents in the observation and control group were significantly higher(P<0.05), while the PGE2 contents lower(P<0.05) and PGF2α/PGE2 ratio higher(P<0.05) than those in the normal group. After treatment, the serum PGF2α contents in the observation and control group were significantly reduced compared with which before treatment(P<0.05), and were lower in the observation group than that in the control group (P<0.05). The serum PGE2 contents in the observation and control groups were significantly increased after treatment compared with which before treatment(P<0.05), with the contents in the observation group higher than that in the control group(P<0.05). The serum PGF2α/PGE2 ratio in the observation and control group was significantly reduced after treatment compared with which before treatment(P<0.05), with the control group higher than the normal group(P<0.05), and the observation group lower than the control group(P<0.05). The clinical effective rate of the observation group was 93.5% (29/31), and that of the control group was 77.4% (24/31). The effective rate of the observation group was significantly higher than that of the control group(P<0.05). CONCLUSIONS: The curative efficacy of auricular comprehensive therapy on MM with liver-fire syndrome is significantly better than that of oral flunarizine hydrochloride capsules, especially in relieving hea-daches, reducing the frequency and duration of headache attacks, as well as accompanying symptoms. Its mechanism may be related to regulating the abnormal PGF2α and PGE2 contents of patients and reducing the ratio of PGF2α/PGE2.
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Trastornos Migrañosos , Prostaglandinas , Humanos , Femenino , Flunarizina , Dinoprostona , Trastornos Migrañosos/tratamiento farmacológico , Cefalea/terapia , SíndromeRESUMEN
PURPOSE: While the role of drug-eluting beads transarterial chemoembolization (DEB-TACE) for hepatocellular carcinoma (HCC) is established, questions regarding appropriate bead size for use in patients remain. This trial evaluated the effectiveness and safety of DEB-TACE using small-size (≤ 100 µm) microspheres loaded with epirubicin. MATERIALS AND METHODS: This prospective, single-arm, multicenter study enrolled patients diagnosed with HCC who underwent DEB-TACE using 40 (range, 30-50), 75 (range, 60-90), or 100 (range, 75-125) µm epirubicin-loaded microspheres (TANDEM microspheres, Varian Medical). Bead size was at the discretion of treating physicians and based on tumor size and/or vascular structure. The primary outcome measure was 6-month objective response rate (ORR). Secondary outcome measures were 30-day and 3-month ORR, time to tumor progression and extrahepatic spread, proportion of progression-free survival and overall survival (OS) at one year, and incidence of treatment-associated adverse events. RESULTS: Data from 108 patients from ten centers was analyzed. Six-month ORR was 73.3 and 71.3% based on European association for the study of the liver (EASL) and modified response evaluation criteria in solid tumors (mRECIST) criteria, respectively. Thirty-day ORR was 79.6% for both EASL and mRECIST criteria with 3-month ORR being 80.0 and 81.0%, respectively, for each criteria. One-year PPF and OS rate were 60.3 and 94.3%. There was a total of 30 SAEs reported to be likely to definitely associated with microsphere (n = 9), epirubicin (n = 9), or procedure (n = 12) with none resulting in death. CONCLUSION: DEB-TACE using epirubicin-loaded small-sized (≤ 100 µm) microspheres demonstrates promising local tumor control and acceptable safety in patients with HCC. TRIAL REGISTRATION: Clinicaltrials.gov NCT03113955; registered April 14, 2017. Trial Registration Clinicaltrials.gov NCT03113955; registered April 14, 2017. LEVEL OF EVIDENCE: 2, Prospective, Non-randomized, Single-arm, study.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Epirrubicina , Neoplasias Hepáticas/patología , Microesferas , Estudios Prospectivos , Resultado del Tratamiento , Quimioembolización Terapéutica/métodos , Doxorrubicina , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: We aimed to develop a Transformer-based deep learning (DL) network for prognostic stratification in hepatocellular carcinoma (HCC) patients undergoing RFA. METHODS: A Swin Transformer DL network was trained to establish associations between magnetic resonance imaging (MRI) datasets and the ground truth of microvascular invasion (MVI) based on 696 surgical resection (SR) patients with solitary HCC ≤3 cm, and was validated in an external cohort (n = 180). The multiphase MRI-based DL risk outputs using an optimal threshold of .5 was employed as a MVI classifier for prognosis stratification in the RFA cohort (n = 180). RESULTS: Over 90% of all enrolled patients exhibited hepatitis B virus infection. Liver cirrhosis was significantly more prevalent in the RFA cohort compared to the SR cohort (72.2% vs. 44.1%, p < .001). The MVI risk outputs exhibited good performance (area under the curve values = .938 and .883) for predicting MVI in the training and validation cohort, respectively. The RFA patients at high risk of MVI classified by the MVI classifier demonstrated significantly lower recurrence-free survival (RFS) and overall survival rates at 1, 3 and 5 years compared to those classified as low risk (p < .001). Multivariate cox regression modelling of a-fetoprotein > 20 ng/mL [hazard ratio (HR) = 1.53; 95% confidence interval (95% CI): 1.02-2.33, p = .047], high risk of MVI (HR = 3.76; 95% CI: 2.40-5.88, p < .001) and unfavourable tumour location (HR = 2.15; 95% CI: 1.40-3.29, p = .001) yielded a c-index of .731 (bootstrapped 95% CI: .667-.778) for evaluating RFS after RFA. Among the three risk factors, MVI was the most powerful predictor for intrahepatic distance recurrence. CONCLUSIONS: The proposed MVI classifier can serve as a valuable imaging biomarker for prognostic stratification in early-stage HCC patients undergoing RFA.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ablación por Radiofrecuencia , Humanos , Pronóstico , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Invasividad NeoplásicaRESUMEN
RATIONALE AND OBJECTIVES: To identify CT features for distinguishing grade 1 (G1)/grade 2 (G2) from grade 3 (G3) pancreatic neuroendocrine tumors (PNETs) using different machine learning (ML) methods. MATERIALS AND METHODS: A total of 147 patients with 155 lesions confirmed by pathology were retrospectively included. Clinical-demographic and radiological CT features was collected. The entire cohort was separated into training and validation groups at a 7:3 ratio. Least absolute shrinkage and selection operator (LASSO) algorithm and principal component analysis (PCA) were used to select features. Three ML methods, namely logistic regression (LR), support vector machine (SVM), and K-nearest neighbor (KNN) were used to build a differential model. Receiver operating characteristic (ROC) curves and precision-recall curves for each ML method were generated. The area under the curve (AUC), accuracy rate, sensitivity, and specificity were calculated. RESULTS: G3 PNETs were more likely to present with invasive behaviors and lower enhancement than G1/G2 PNETs. The LR classifier yielded the highest AUC of 0.964 (95% confidence interval [CI]: 0.930, 0.972), with 95.4% accuracy rate, 95.7% sensitivity, and 92.9% specificity, followed by SVM (AUC: 0.957) and KNN (AUC: 0.893) in the training group. In the validation group, the SVM classier reached the highest AUC of 0.952 (95% CI: 0.860, 0.981), with 91.5% accuracy rate, 97.3% sensitivity, and 70% specificity, followed by LR (AUC: 0.949) and KNN (AUC: 0.923). CONCLUSIONS: The LR and SVM classifiers had the best performance in the training group and validation group, respectively. ML method could be helpful in differentiating between G1/G2 and G3 PNETs.
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Purpose: This multicenter, open-label, phase Ib/II study aimed to assess the efficacy and safety of cadonilimab, a humanized, tetravalent, bispecific antibody plus lenvatinib in first-line treatment of advanced hepatocellular carcinoma (aHCC). Methods: Patients with histologically confirmed aHCC were included to receive either 6 mg/kg cadonilimab every 2 weeks plus lenvatinib (cohort A) or 15 mg/kg cadonilimab every 3 weeks plus lenvatinib (cohort B). The primary endpoint was objective response rate (ORR) by RECIST v1.1, while the secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and time to response (TTR). Results: A total of 59 patients were enrolled (31 in cohort A and 28 in cohort B). The median follow-up time was 27.4 months as of the data cutoff date (July 28, 2023). The ORR in cohort A was 35.5% (95% CI: 19.2, 54.6) and that in cohort B was 35.7% (95% CI: 18.6, 55.9), and the median DoR was 13.6 months (95% CI: 4.14, NE) and 13.67 months (95% CI: 3.52, NE), respectively. The median PFS was 8.6 months (95% CI: 5.2, 15.2) and 9.8 months (95% CI: 6.9, 15.2), respectively. The median OS was 27.1 months (95% C: 15.7, NE) for cohort A, while it was not reached for cohort B. Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 66.1% of patients, with serious TRAEs occurring in 39.0% of cases. Decreased platelet count (47.5%), proteinuria (45.8%), hypertension (44.1%), and white blood cell count (44.1%) were the most common TRAEs. Conclusion: This novel combination therapy showed promising efficacy and manageable toxicity that could provide an option in first-line setting of aHCC. Clinical Trial Registration: [www.ClinicalTrials.gov], NCT04444167.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Terapia Combinada , Empatía , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Non-specific adsorption of bioprobes based on surface-enhanced Raman spectroscopy (SERS) technology inevitably endows white blood cells (WBC) in the peripheral blood with Raman signals, which greatly interfere the identification accuracy of circulating tumor cells (CTCs). In this study, an innovative strategy was proposed to effectively identify CTCs by using SERS technology assisted by a receiver operating characteristic (ROC) curve. Firstly, a magnetic Fe3O4-Au complex SERS bioprobe was developed, which could effectively capture the triple negative breast cancer (TNBC) cells and endow the tumor cells with distinct SERS signals. Then, the ROC curve obtained based on the comparison of SERS intensity of TNBC cells and WBC was used to construct a tumor cell identification model. The merit of the model was that the detection sensitivity and specificity could be intelligently switched according to different identification purposes such as accurate diagnosis or preliminary screening of tumor cells. Finally, the difunctional recognition ability of the model for accurate diagnosis and preliminary screening of tumor cells was further validated by using the healthy human blood added with TNBC cells and blood samples of real tumor patients. This novel difunctional identification strategy provides a new perspective for identification of CTCs based on the SERS technology.
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Técnicas Biosensibles , Células Neoplásicas Circulantes , Neoplasias de la Mama Triple Negativas , Humanos , Células Neoplásicas Circulantes/patología , Neoplasias de la Mama Triple Negativas/diagnóstico , Espectrometría Raman/métodos , Plata/químicaRESUMEN
Supramolecular self-assembly has gained increasing attention to construct multicomponent drug delivery systems for cancer diagnosis and therapy. Despite that these self-assembled nanosystems present surprising properties beyond that of each subcomponent, the spontaneous nature of co-self-assembly causes significant difficulties in control of the synthesis process and consequently leads to unsatisfactory influences in downstream applications. Hence, we utlized an in situ dynamic covalent reaction based on thiol-disulfide exchange to slowly produce disulfide macrocycles, which subsequently triggered the co-self-assembly of an anticancer drug (doxorubicin, DOX) and a magnetic resonance imaging (MRI) contrast agent of ultrasmall iron oxide nanoparticles (IO NPs). It showed concentration regulation of macrocyclic disulfides, DOX, and IO NPs by a dynamic covalent self-assembly (DCS) strategy, resulting in a stable codelivery nanosystem with high drug loading efficiency of 37.36%. More importantly, disulfide macrocycles in the codelivery system could be reduced and broken by glutathione (GSH) in tumor cells, thus leading to disassembly of nanostructures and intellgent release of drugs. These stimuli-responsive performances have been investigated via morphologies and molecular structures, revealing greatly enhanced dual-modal MRI abilities and smart drug release under the trigger of GSH. Moreover, the codelivery system conjugated with a targeting molecule of cyclic Arg-Gly-Asp (cRGD) exhibited significant biocompatibility, MR imaging, and chemotherapeutic anticancer effect in vitro and in vivo. These results indicated that in situ dynamic covalent chemistry enhanced the control over co-self-assembly and paved the way to develop more potential drug delivery systems.
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Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Disulfuros/química , Nanopartículas/química , Antineoplásicos/química , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Imagen por Resonancia Magnética , Glutatión , Medios de Contraste/uso terapéuticoRESUMEN
Objectives: To investigate the potential mechanisms of 125I seed implantation therapeutic treatment on inactivating the VEGFR2/PI3K/AKT pathway in cholangiocarcinoma. Methods: The human cholangiocarcinoma cell lines HCCC-9810 and HuCCT1 were purchased for in vitro studies. The BALB/c nude mice were obtained for in vivo studies. The proliferation of cells was detected by CCK-8, colony formation, and BrdU staining. The migration and invasion of cells were determined by wound healing assay and Transwell assay, respectively. Hematoxylin and eosin staining was utilized for histological evaluation. Protein expression was determined by western blotting and immunohistochemistry. Results: Compared with the control group, .6 mCi group and .8 mCi group inhibited cholangiocarcinoma cells proliferation, invasion, migration, and promoted apoptosis, the protein expression of p-VEGFR2, VEGFR2, PI3K, p-AKT/AKT, cyclin B1, cyclin A, CDK1, and Bcl-2 was decreased. Similar results were obtained from in vitro experiments. However, when VEGF is overexpressed, the inhibitory effect of .8 mCi was partially significantly reversed on cholangiocarcinoma cells. The in vivo studies further confirmed the inhibitory effects of .6 mCi group and .8 mCi group on cholangiocarcinoma. Conclusion: 125I seed irradiation could inhibit cholangiocarcinoma cells proliferation, migration, and invasion and promote apoptosis through inactivation of the VEGFR2/PI3K/AKT signaling pathway.
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Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.
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Vesículas Extracelulares , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Esfingomielina Fosfodiesterasa , Compuestos de Anilina , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Esterasas , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Introduction: Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. Methods: In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. Results: As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9-54.3) in group A and 14.3% (95% CI, 3.0-36.3) in group B. Median duration of response was not reached (95% CI, 3.3-not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9-NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4-5.5) and 4.1 months (95% CI, 1.5-NE), and median overall survival was 11.6 months (95% CI, 6.4-NE) and 14.3 months (95% CI, 8.2-NE) in groups A and B, respectively. Conclusion: Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.
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Most hepatocellular carcinomas (HCC) treated by transcatheter arterial chemoembolization with drug-eluting beads (DEB-TACE) are characterized by coagulation necrosis; therefore, it is often difficult to distinguish enhancement in the arterial phase that would lead to false negative evaluation. This study aimed to evaluate the specificity and sensitivity of the difference value of multiphase contrast-enhanced computed tomography (CECT) in predicting residual tumor activity in HCC lesions after DEB-TACE. This retrospective diagnostic study analyzed CECT images of 73 HCC lesions in 57 patients 20 to 40 days (average 28 days) after DEB-TACE treatment at our Hospital from January to December 2019. Postoperative pathology or digital subtraction angiography images were used as references. Residual tumor activity after the first intervention was determined based on the presence of tumor staining in digital subtraction angiography or the postoperative pathological discovery of HCC tumor cells. A significant difference was observed between the active and inactive residual groups in ∆ HU difference between CT values of arterial phase and non-contrast scans (AN, P = .000), difference between CT values of venous phase and non-contrast scans (VN, P = .000), difference between CT values of delay phase and non-contrast scans (DN, P = .000), (difference between CT values of venous and arterial phase scans, P = .001), and (difference between CT values of delay and arterial phase scans, P = .005). No statistically significant difference was observed between the delayed and venous phases (difference between CT values of delay and venous phase scans, P = .361). The area under the curve (AUC) of the ROC curve showed that the diagnostic efficacies in difference in CT value of AN (AUC = 0.976), VN (AUC = 0.927), and DN (AUC = 0.924) were higher, and their cutoff values were 4.86, 12.065, 20.19 HU with their sensitivities of 93.3%, 84.4%, 77.8% and specificities of 100%, 96.4%, and 100%, respectively. difference in CT value values of AN, VN, DN, difference between CT values of venous and arterial phase scans and difference between CT values of delay and arterial phase scans can sensitively detect residual tumor activity 20-40 days after DEB-TACE. Thus, more sensitive active residual foci were detected using all 3 enhanced phases rather than only the arterial phase. Quantitative analysis of multiphase CECT can detect residual tumor activity in an early and noninvasive manner, which can provide time for patients to receive early follow-up treatment.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasia Residual/diagnóstico por imagen , Neoplasia Residual/terapia , Estudios Retrospectivos , Quimioembolización Terapéutica/métodos , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
The efficiency of immunotherapy for triple-negative breast cancer (TNBC) is relatively low due to the difficulty in accurately detecting immune checkpoints. The detection of TNBC-related programmed cell death ligand-1 (PD-L1) expression is important to guide immunotherapy and improve treatment efficiency. Surface-enhanced Raman spectroscopy (SERS) and magnetic resonance (MR) imaging exhibit great potential for early TNBC diagnosis. SERS, an optical imaging mode, has the advantages of high detection sensitivity, good spatial resolution, and "fingerprint" spectral characteristics; however, the shallow detection penetration of SERS bioprobes limits its application in vivo. MR has the advantages of allowing deep penetration with no radiation; however, its spatial resolution needs to be improved. SERS and MR have complementary imaging features for tumor marker detection. In this study, gold nanorod and ultrasmall iron oxide nanoparticle composites were developed as dual-modal bioprobes for SERS-MRI to detect PD-L1 expression. Anti-PD-L1 (aPD-L1) was utilized to improve the targeting ability and specificity of PD-L1 expression detection. TNBC cells expressing PD-L1 were accurately detected via the SERS imaging mode in vitro, which can image at the single-cell level. In addition, bioprobe accumulation in PD-L1 expression-related tumor-bearing mice was simply and dynamically monitored and analyzed in vivo using MR and SERS. To the best of our knowledge, this is the first time a SERS-MRI dual-modal bioprobe combined with a PD-L1 antibody has been successfully used to detect PD-L1 expression in TNBC. This work paves the way for the design of high-performance bioprobe-based contrast agents for the clinical immunotherapy of TNBC.
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Combining photodynamic therapy (PDT) and chemotherapy (CHT) by loading an anti-cancer drug and a photosensitizer (PS) into the same delivery nanosystem has been proposed as an effective approach to achieve synergistic effects for a safe cancer treatment. However, exploring an ideal delivery nanosystem has been challenging, because the noncovalent interactions must be maintained between the multiple components to produce a stable yet responsive nanostructure that takes into account the encapsulation of drug molecules. We addressed this issue by engineering the interfacial interaction between Ag2S quantum dots (QDs) using a pillararene derivative to direct the co-self-assembly of the entire system. The high surface area-to-volume ratio of the Ag2S QDs provided ample hydrophobic space to accommodate the anti-drug molecule doxrubicine. Moreover, Ag2S QDs served as PSs triggered by 808 nm near-infrared (NIR) light and also as carriers for high-efficiency delivery of drug molecules to the tumor site. Drug release experiments showed smart drug release under the acidic microenvironments (pH 5.5) in tumor cells. Additionally, the Ag2S QDs demonstrated outstanding PDT ability under NIR light, as confirmed by extracellular and intracellular reactive oxygen species generation. Significant treatment efficacy of the chemo-photodynamic synergistic therapy for cancer using the co-delivery system was demonstrated via in vitro and in vivo studies. These findings suggest that our system offers intelligent control of CHT and PDT, which will provide a promising strategy for constructing hybrid systems with synergistic effects for advanced applications in biomedicine, catalysis, and optoelectronics.