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Journal of Cancer 2024It's a major public health problem of global concern that malignant gliomas tend to grow rapidly and infiltrate surrounding tissues. Accurate grading of the tumor can...
It's a major public health problem of global concern that malignant gliomas tend to grow rapidly and infiltrate surrounding tissues. Accurate grading of the tumor can determine the degree of malignancy to formulate the best treatment plan, which can eliminate the tumor or limit widespread metastasis of the tumor, saving the patient's life and improving their prognosis. To more accurately predict the grading of gliomas, we proposed a novel method of combining the advantages of 2D and 3D Convolutional Neural Networks for tumor grading by multimodality on Magnetic Resonance Imaging. The core of the innovation lies in our combination of tumor 3D information extracted from multimodal data with those obtained from a 2D ResNet50 architecture. It solves both the lack of temporal-spatial information provided by 3D imaging in 2D convolutional neural networks and avoids more noise from too much information in 3D convolutional neural networks, which causes serious overfitting problems. Incorporating explicit tumor 3D information, such as tumor volume and surface area, enhances the grading model's performance and addresses the limitations of both approaches. By fusing information from multiple modalities, the model achieves a more precise and accurate characterization of tumors. The model I s trained and evaluated using two publicly available brain glioma datasets, achieving an AUC of 0.9684 on the validation set. The model's interpretability is enhanced through heatmaps, which highlight the tumor region. The proposed method holds promise for clinical application in tumor grading and contributes to the field of medical diagnostics for prediction.
PubMed: 38947386
DOI: 10.7150/jca.95987 -
Journal of Cancer 2024Bone metastasis (BoM) has been closely associated with increased morbidity and poor survival outcomes in patients with non-small cell lung cancer (NSCLC). Given its...
Bone metastasis (BoM) has been closely associated with increased morbidity and poor survival outcomes in patients with non-small cell lung cancer (NSCLC). Given its significant implications, this study aimed to systematically compare the biological characteristics between advanced NSCLC patients with and without BoM. In this study, the genomic alterations from the tumor tissue DNA of 42 advanced NSCLC patients without BoM and 67 patients with BoM and were analyzed by a next-generation sequencing (NGS) panel. The serum concentrations of 18 heavy metals were detected by inductively coupled plasma emission spectrometry (ICP-MS). A total of 157 somatic mutations across 18 mutated genes and 105 somatic mutations spanning 16 mutant genes were identified in 61 out of 67 (91.05%) patients with BoM and 37 of 42 (88.10%) patients without BoM, respectively. Among these mutated genes, , , , , and stood out exclusively in patients with BoM, whereas , , and manifested solely in those without BoM. Moreover, both co-occurring sets of genes and mutually exclusive sets of genes in patients with BoM were different from those in patients without BoM. In addition, the serum concentrations of Cu and Sr in patients with BoM were significantly higher than in patients without BoM. One of our aims was to explore how these heavy metals associated with BoM interacted with other heavy metals, and significant positive correlations were observed between Cu and Co, between Cu and Cr, between Sr and Ba, and between Sr and Ni in patients with BoM. Given the significant impacts of molecular characteristics on patients' prognosis, we also observed a noteworthy negative correlation between mutations and Co, alongside a significant positive correlation between mutations and Cd. The genomic alterations, somatic interactions, key signaling pathways, functional biological information, and accumulations of serum heavy metals were markedly different between advanced NSCLC patients with and without BoM, and certain heavy metals (e.g., Cu, Sr) might have potentials to identify high-risk patients with BoM.
PubMed: 38947377
DOI: 10.7150/jca.95191 -
Journal of Cancer 2024Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer...
Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer types, their role in pancreatic cancer remains largely unexplored. The mRNA and protein expression of MYB family genes in pancreatic cancer samples was analyzed using TNMplot, HPA, and TISBID online bioinformatics tools, sourced from the TCGA and GETx databases. The relationship between MYB family gene expression and survival time was assessed through Kaplan-Meier analysis, while the prognostic impact of MYB family gene expression was evaluated using the Cox proportional hazards model. Additionally, Spearman's correlation analysis was employed to investigate the correlation between MYB family genes and TMB/MSI. The integration of data from various databases demonstrated that all MYB family genes exhibited dysregulated expression in pancreatic cancer. However, only the expression of the MYBL2 gene displayed a notable association with the grade and stage of pancreatic cancer. Furthermore, the MYBL2 gene exhibited significant variations in both univariate and multivariate factor analyses.Subsequent functional analyses revealed a significant correlation between MYBL2 expression in pancreatic cancers and various biological processes, such as DNA replication, tumor proliferation, G2M checkpoint regulation, pyrimidine metabolism, and the P53 pathway. Additionally, a notable positive association was observed between MYBL2 expression and tumor mutational burden (TMB), a predictive indicator for response to PD1 antibody treatment. MYBL2 may be a double marker for independent diagnosis and PD1 antibody response prediction of pancreatic cancer patients.
PubMed: 38947375
DOI: 10.7150/jca.96320 -
Frontiers in Immunology 2024Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this...
BACKGROUND
Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this study is to establish and validate a radiomics based on enhanced computed tomography (CT) and combined with clinical data to predict the major pathological response to NIT in ESCC patients.
METHODS
This retrospective study included 82 ESCC patients who were randomly divided into the training group (n = 57) and the validation group (n = 25). Radiomic features were derived from the tumor region in enhanced CT images obtained before treatment. After feature reduction and screening, radiomics was established. Logistic regression analysis was conducted to select clinical variables. The predictive model integrating radiomics and clinical data was constructed and presented as a nomogram. Area under curve (AUC) was applied to evaluate the predictive ability of the models, and decision curve analysis (DCA) and calibration curves were performed to test the application of the models.
RESULTS
One clinical data (radiotherapy) and 10 radiomic features were identified and applied for the predictive model. The radiomics integrated with clinical data could achieve excellent predictive performance, with AUC values of 0.93 (95% CI 0.87-0.99) and 0.85 (95% CI 0.69-1.00) in the training group and the validation group, respectively. DCA and calibration curves demonstrated a good clinical feasibility and utility of this model.
CONCLUSION
Enhanced CT image-based radiomics could predict the response of ESCC patients to NIT with high accuracy and robustness. The developed predictive model offers a valuable tool for assessing treatment efficacy prior to initiating therapy, thus providing individualized treatment regimens for patients.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Male; Female; Neoadjuvant Therapy; Tomography, X-Ray Computed; Esophageal Neoplasms; Middle Aged; Machine Learning; Retrospective Studies; Aged; Immunotherapy; Nomograms; Treatment Outcome; Adult; Radiomics
PubMed: 38947338
DOI: 10.3389/fimmu.2024.1405146 -
Frontiers in Immunology 2024Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options...
Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival.
Topics: Humans; Male; Doxorubicin; Hemangioendothelioma, Epithelioid; Nivolumab; Prostatic Neoplasms; Programmed Cell Death 1 Receptor; Antineoplastic Combined Chemotherapy Protocols; Immunotherapy; Immune Checkpoint Inhibitors; Ipilimumab; Treatment Outcome; Polyethylene Glycols; Middle Aged
PubMed: 38947327
DOI: 10.3389/fimmu.2024.1384111 -
Frontiers in Immunology 2024Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC... (Comparative Study)
Comparative Study
INTRODUCTION
Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency.
METHODS
We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m and cyclophosphamide 500 mg/m for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m and cyclophosphamide 500 mg/m for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity.
RESULTS
From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026).
DISCUSSION
As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.
Topics: Humans; Immunotherapy, Adoptive; Male; Middle Aged; Female; Antigens, CD19; Vidarabine; Retrospective Studies; Lymphoma, Non-Hodgkin; Aged; Cyclophosphamide; Adult; Lymphocyte Depletion; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Receptors, Antigen, T-Cell
PubMed: 38947326
DOI: 10.3389/fimmu.2024.1403145 -
Frontiers in Immunology 2024Monocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to...
BACKGROUND
Monocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to identify key monocyte-related genes and elucidate their mechanisms in PRAD.
METHOD
Utilizing the TCGA-PRAD dataset, immune cell infiltration levels were assessed using CIBERSORT, and their correlation with patient prognosis was analyzed. The WGCNA method pinpointed 14 crucial monocyte-related genes. A diagnostic model focused on monocytes was developed using a combination of machine learning algorithms, while a prognostic model was created using the LASSO algorithm, both of which were validated. Random forest and gradient boosting machine singled out CCNA2 as the most significant gene related to prognosis in monocytes, with its function further investigated through gene enrichment analysis. Mendelian randomization analysis of the association of HLA-DR high-expressing monocytes with PRAD. Molecular docking was employed to assess the binding affinity of CCNA2 with targeted drugs for PRAD, and experimental validation confirmed the expression and prognostic value of CCNA2 in PRAD.
RESULT
Based on the identification of 14 monocyte-related genes by WGCNA, we developed a diagnostic model for PRAD using a combination of multiple machine learning algorithms. Additionally, we constructed a prognostic model using the LASSO algorithm, both of which demonstrated excellent predictive capabilities. Analysis with random forest and gradient boosting machine algorithms further supported the potential prognostic value of CCNA2 in PRAD. Gene enrichment analysis revealed the association of CCNA2 with the regulation of cell cycle and cellular senescence in PRAD. Mendelian randomization analysis confirmed that monocytes expressing high levels of HLA-DR may promote PRAD. Molecular docking results suggested a strong affinity of CCNA2 for drugs targeting PRAD. Furthermore, immunohistochemistry experiments validated the upregulation of CCNA2 expression in PRAD and its correlation with patient prognosis.
CONCLUSION
Our findings offer new insights into monocyte heterogeneity and its role in PRAD. Furthermore, CCNA2 holds potential as a novel targeted drug for PRAD.
Topics: Humans; Male; Prostatic Neoplasms; Monocytes; Prognosis; Immunotherapy; Biomarkers, Tumor; Machine Learning; Molecular Docking Simulation; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Computational Biology; Multiomics
PubMed: 38947325
DOI: 10.3389/fimmu.2024.1426474 -
Frontiers in Immunology 2024Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of...
Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of therapeutic protocols, as removal of all visible tumor lesions (cytoreduction) profoundly improves the overall survival. Enhanced predictive tools for assessing cytoreduction are essential to optimize therapeutic precision. Patients' immune status broadly reflects the tumor cell biological behavior and the patient responses to disease and treatment. Serum cytokine profiling is a sensitive measure of immune adaption and deviation, yet its integration into treatment paradigms is underexplored. This study is part of the IMPACT trial (NCT03378297) and aimed to characterize immune responses before and during primary treatment for HGSOC to identify biomarkers for treatment selection and prognosis. Longitudinal serum samples from 22 patients were collected from diagnosis until response evaluation. Patients underwent primary cytoreductive surgery or neoadjuvant chemotherapy (NACT) based on laparoscopy scoring. Twenty-seven serum cytokines analyzed by Bio-Plex 200, revealed two immune phenotypes at diagnosis: Immune High with marked higher serum cytokine levels than Immune Low. The immune phenotypes reflected the laparoscopy scoring and allocation to surgical treatment. The five Immune High patients undergoing primary cytoreductive surgery exhibited immune mobilization and extended progression-free survival, compared to the Immune Low patients undergoing the same treatment. Both laparoscopy and cytoreductive surgery induced substantial and transient changes in serum cytokines, with upregulation of the inflammatory cytokine IL-6 and downregulation of the multifunctional cytokines IP-10, Eotaxin, IL-4, and IL-7. Over the study period, cytokine levels uniformly decreased in all patients, leading to the elimination of the initial immune phenotypes regardless of treatment choice. This study reveals distinct pre-treatment immune phenotypes in HGSOC patients that might be informative for treatment stratification and prognosis. This potential novel biomarker holds promise as a foundation for improved assessment of treatment responses in patients with HGSOC. ClinicalTrials.gov Identifier: NCT03378297.
Topics: Humans; Female; Ovarian Neoplasms; Cystadenocarcinoma, Serous; Cytokines; Middle Aged; Aged; Neoadjuvant Therapy; Phenotype; Cytoreduction Surgical Procedures; Biomarkers, Tumor; Neoplasm Grading; Prognosis; Treatment Outcome; Adult
PubMed: 38947323
DOI: 10.3389/fimmu.2024.1394497 -
Frontiers in Immunology 2024To collect real-world data regarding the attainment of the early-achieved lupus low disease activity state (LLDAS) in systemic lupus erythematosus (SLE) patients... (Observational Study)
Observational Study
Frequency and predictors for early-achieved lupus low disease activity state in systemic lupus erythematosus patients treated with telitacicept or belimumab: A real-life, single-center observational study.
OBJECTIVE
To collect real-world data regarding the attainment of the early-achieved lupus low disease activity state (LLDAS) in systemic lupus erythematosus (SLE) patients receiving telitacicept or belimumab treatment, and identify factors predictive of target achievement.
METHODS
Eighty-seven SLE patients who received telitacicept (N=42) or belimumab (N=45) were retrospectively reviewed in this observational study. Clinical and laboratory data, disease activity assessment, and glucocorticoid dosage were collected for analysis. Achieving LLDAS at least once within 24 weeks post-treatment was considered as early-achieved LLDAS. Multivariate regression was used to assess baseline predictive variables for early-achieved LLDAS. Subgroup analysis and interaction tests were also performed to examine the robustness of the results across different sets of baseline characteristics. Prognostic stratification for early-achieved LLDAS was established based on the identified risk factors.
RESULTS
During the 24-week follow-up period, LLDAS was achieved by at least one time in 49.43% (43/87) of the patients, with sustained achievement through week 24 observed in 36 out of these 43 patients (83.27%). Multivariate analysis revealed that early achievement of LLDAS was particularly observed in patients with higher baseline lymphocyte counts [HR=1.79, 95% CI (1.19-2.67), P=0.005]and serum albumin levels [HR=1.06, 95% CI (1.003-1.12), P=0.039]. Conversely, hematological involvement [HR=0.48, 95% CI (0.24-0.93), P=0.031] predicted lower attainment of early-achieved LLDAS. The use of telitacicept was associated with a reduced risk of failing to attain early achievement of LLDAS [HR=2.55, 95% CI (1.36-4.79), P=0.004]. Subgroup analyses and interaction tests showed a stable relationship between the telitacicept use and LLDAS achievement. The results remained consistent across all subgroup analyses. Significant differences (P<0.001) were observed in the Kaplan-Meier estimates for LLDAS among risk groups based on the number of identified risk factors.
CONCLUSION
The achievement of LLDAS is attainable in the management of SLE patients undergoing treatment with telitacicept or belimumab in real-life clinical practice. Baseline lymphocyte counts, serum albumin levels, hematological involvement and the use of telitacicept serve as robust predictors for early-achieved LLDAS, helping to identify patients who are likely to benefit on the treatment.
Topics: Humans; Lupus Erythematosus, Systemic; Female; Male; Adult; Antibodies, Monoclonal, Humanized; Middle Aged; Retrospective Studies; Treatment Outcome; Immunosuppressive Agents; Severity of Illness Index; Prognosis
PubMed: 38947321
DOI: 10.3389/fimmu.2024.1423035 -
Frontiers in Immunology 2024In spite of its high mortality rate and poor prognosis, the pathogenesis of sepsis is still incompletely understood. This study established a cuproptosis-based risk...
Identification and experimental validation of cuproptosis regulatory program in a sepsis immune microenvironment through a combination of single-cell and bulk RNA sequencing.
BACKGROUND
In spite of its high mortality rate and poor prognosis, the pathogenesis of sepsis is still incompletely understood. This study established a cuproptosis-based risk model to diagnose and predict the risk of sepsis. In addition, the cuproptosis-related genes were identified for targeted therapy.
METHODS
Single-cell sequencing analyses were used to characterize the cuproptosis activity score (CuAS) and intercellular communications in sepsis. Differential cuproptosis-related genes (CRGs) were identified in conjunction with single-cell and bulk RNA sequencing. LASSO and Cox regression analyses were employed to develop a risk model. Three external cohorts were conducted to assess the model's accuracy. Differences in immune infiltration, immune cell subtypes, pathway enrichment, and the expression of immunomodulators were further evaluated in distinct groups. Finally, various experiments, such as flow cytometry, Western blot, and ELISA, were used to explore the role of LST1 in sepsis.
RESULTS
ScRNA-seq analysis demonstrated that CuAS was highly enriched in monocytes and was closely related to the poor prognosis of sepsis patients. Patients with higher CuAS exhibited prominent strength and numbers of cell-cell interactions. A total of five CRGs were identified based on the LASSO and Cox regression analyses, and a CRG-based risk model was established. The lower riskScore cohort exhibited enhanced immune cell infiltration, elevated immune scores, and increased expression of immune modulators, indicating the activation of an antibacterial response. Ultimately, experiments demonstrated that LST1, a key gene in the risk model, was enhanced in the macrophage in response to LPS, which was closely related to the decrease of macrophage survival rate, the enhancement of apoptosis and oxidative stress injury, and the imbalance of the M1/M2 phenotype.
CONCLUSIONS
This study constructed a cuproptosis-related risk model to accurately predict the prognosis of sepsis. We further characterized the cuproptosis-related gene LST1 to provide a theoretical framework for sepsis therapy.
Topics: Sepsis; Humans; Single-Cell Analysis; Male; Female; Middle Aged; Prognosis; Sequence Analysis, RNA; Cellular Microenvironment; Aged
PubMed: 38947313
DOI: 10.3389/fimmu.2024.1336839