-
Signal Transduction and Targeted Therapy Oct 2023The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent...
The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies. During the dose escalation phase, patients received a single intravenous infusion of sintilimab at varying doses of 1, 3, and 10 mg/kg. The primary endpoints included the identification of dose-limiting toxicities (DLTs) as well as the evaluation of safety and tolerance. Secondary endpoints focused on assessing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 29 patients were enrolled, including 10 individuals diagnosed with Hodgkin lymphoma (HL) and 19 patients with various other tumor categories. Notably, diverse pathological types such as thymoma, choroid plexus carcinoma, and NK/T-cell lymphoma were also included in the study cohort. By the safety data cutoff, most adverse events were grade 1 or 2, with grade 3 or higher treatment-related adverse events (TRAE) occurring in 10% of patients. Among the 27 evaluated subjects, four achieved confirmed complete response (CR) while seven patients exhibited confirmed partial response (PR). Additionally, seven patients maintained disease (SD) during the study period. Notably, sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL. Whole-exome sequencing (WES) was conducted in 15 patients to assess the mutational landscape and copy number variation (CNV) status. The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment. The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.
Topics: Child; Humans; Antibodies, Monoclonal, Humanized; Carcinoma; Chronic Disease; DNA Copy Number Variations; Treatment Outcome; Immune Checkpoint Inhibitors
PubMed: 37828033
DOI: 10.1038/s41392-023-01636-9 -
Chinese Medical Journal Nov 2023Thymic carcinomas (TCs) and thymic neuroendocrine neoplasms (TNENs) are two aggressive subtypes of thymic malignancy. Traditional therapy for advanced TCs and TNENs has...
BACKGROUND
Thymic carcinomas (TCs) and thymic neuroendocrine neoplasms (TNENs) are two aggressive subtypes of thymic malignancy. Traditional therapy for advanced TCs and TNENs has limited outcome. New genomic profiling of TCs and TNENs might provide insights that contribute to the development of new treatment approaches.
METHODS
We used gene panel sequencing technologies to investigate the genetic aberrations of 32 TC patients and 15 TNEN patients who underwent surgery at Shanghai Chest Hospital between 2015 and 2017. Patient samples were sequenced using a 324-gene platform with licensed technologies. In this study, we focused on clinically relevant genomic alterations (CRGAs), which are previously proven to be pathogenic alterations, to identify the pathology-specific mutational patterns, prognostic signatures of TCs and TNENs.
RESULTS
The mutational profiles between TCs and TNENs were diverse. The genetic alterations that ranked highest in TCs were in CDKN2A, TP53, ASXL1, CDKN2B, PIK3C2G, PTCH1, and ROS1 , while those in TNENs were in MEN1, MLL2, APC, RB1 , and TSC2 . Prognostic analysis showed that mutations of ROS1, CDKN2A, CDKN2B, BRAF, and BAP1 were significantly associated with worse outcomes in TC patients, and that mutation of ERBB2 indicated shortened disease-free survival (DFS) and overall survival (OS) in TNEN patients. Further investigation found that the prognosis-related genes were focused on signal pathways of cell cycle control, chromatin remodeling/DNA methylation, phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase (MAPK) signaling.
CONCLUSION
We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors, and identified the pathology-specific mutational patterns, prognostic signatures, and potential therapeutic targets for TCs and TNENs.
Topics: Humans; Thymoma; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; China; Thymus Neoplasms; Prognosis; Neuroendocrine Tumors; Mutation
PubMed: 37749819
DOI: 10.1097/CM9.0000000000002852 -
The Thoracic and Cardiovascular Surgeon Aug 2023Thymoma is the most common tumor of the anterior mediastinum. However, the correlation between thymoma stage and pulmonary function was not assessed. Our objective in...
BACKGROUND
Thymoma is the most common tumor of the anterior mediastinum. However, the correlation between thymoma stage and pulmonary function was not assessed. Our objective in this study was to describe the pulmonary function in thymoma subjects stratified with different staging systems.
METHODS
A total of 143 subjects with a diagnosis of thymoma who underwent extended thymectomy for thymoma between January 2001 and December 2019 were reviewed retrospectively. All the subjects experienced pulmonary function tests (PFTs) using Master Screen PFT system and total respiratory resistance measurement.
RESULTS
We evaluated 143 subjects with a diagnosis of thymoma; the significant differences were observed in mean values of vital capacity, inspiratory volume (IC), total lung capacity (TLC), ratio of residual volume to total lung capacity (RV/TLC), forced vital capacity, forced expiratory volume in 1 second, ratio of forced expiratory volume in 1 second to forced vital capacity, peak expiratory flow, peak inspiratory flow, maximum ventilation volume, total airway resistance, and diffusing capacity for carbon monoxide (DLCO) across upper airway obstruction classification. PFTs of subjects with varying Masaoka stages are different. RV and RV/TLC of subjects in stages III and IV were higher than those of normal level, while DLCO of subjects in stage IV was lower than the normal level, and the mean level of IC showed significant difference between stage II and stage III.
DISCUSSION
The pulmonary function patterns of thymoma subjects significantly correlate with tumor location and size rather than clinical Masaoka stage.
Topics: Humans; Retrospective Studies; Thymoma; Treatment Outcome; Lung; Forced Expiratory Volume; Thymus Neoplasms
PubMed: 35896441
DOI: 10.1055/s-0042-1749320 -
Brain and Nerve = Shinkei Kenkyu No... Jan 2024The pathogenesis of juvenile myasthenia gravis is similar to that of adult-onset cases, but does differ significantly in that it is predominantly ocular type, has a low...
The pathogenesis of juvenile myasthenia gravis is similar to that of adult-onset cases, but does differ significantly in that it is predominantly ocular type, has a low antibody-positive rate, a low thymoma complication rate, and a high remission rate. The evidence for the adult treatment strategy of low-dose steroids and fast-acting treatment is insufficient in children, and the safety of immunosuppressive drugs has not been established. Steroid use in children in particular requires caution due to the risk of growth retardation, and while lower doses are desirable, the efficacy of lower doses has not been as fully investigated as in adults. Conversely, experience has shown that the use of adequate doses of steroids results in high remission rates, and there is currently no rationale for recommending lower doses.
Topics: Adult; Child; Humans; Eye; Immunosuppressive Agents; Myasthenia Gravis; Steroids
PubMed: 38191135
DOI: 10.11477/mf.1416202553 -
Scientific Reports Feb 2024B-cell subsets in peripheral blood (PB) and tumor microenvironment (TME) were evaluated to determine myasthenia gravis (MG) severity in patients with thymoma-associated...
B-cell subsets in peripheral blood (PB) and tumor microenvironment (TME) were evaluated to determine myasthenia gravis (MG) severity in patients with thymoma-associated MG (TMG) and the distribution of B cells in type B TMG. The distribution of mature B cells, including Bm1-Bm5, CD19 and CD20 B cells and non-switched (NSMBCs) and switched (SMBCs) memory B cells, were determined in 79 patients with thymoma or TMG. Quantitative relationships between the T and TMG groups and the TMG-low and TMG-high subgroups were determined. NSMBCs and SMBCs were compared in TME and PB. Type B thymoma was more likely to develop into MG, with types B2 and B3 being especially associated with MG worsening. The percentage of CD19 B cells in PB gradually increased, whereas the percentage of CD20 B cells and the CD19/CD20 ratio were not altered. The (Bm2 + Bm2')/(eBm5 + Bm5) index was significantly higher in the TMG-high than in thymoma group. The difference between SMBC/CD19 and NSMBC/CD19 B cell ratios was significantly lower in the thymoma than TMG group. NSMBCs assembled around tertiary lymphoid tissue in thymomas of patients with TMG. Few NSMBCs were observed in patients with thymoma alone, with these cells being diffusely distributed. MG severity in patients with TMG can be determined by measuring CD19 B cells and Bm1-Bm5 in PB. The CD19/CD20 ratio is a marker of disease severity in TMG patients. Differences between NSMBCs and SMBCs in PB and TME of thymomas can synergistically determine MG severity in patients with TMG.
Topics: Humans; Thymoma; B-Lymphocyte Subsets; Thymus Neoplasms; B-Lymphocytes; Myasthenia Gravis; Tumor Microenvironment
PubMed: 38302676
DOI: 10.1038/s41598-024-53250-6 -
European Journal of Endocrinology Jan 2024The pathogenesis of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis was gradually revealed as cases emerged. Our comprehensive analysis, including...
The pathogenesis of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis was gradually revealed as cases emerged. Our comprehensive analysis, including all reported cases, identified a new instance of anti-PIT-1 hypophysitis postimmune checkpoint inhibitor therapy. All 9 patients exhibited extremely low growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) levels; 2 had a slightly atrophic pituitary gland; 4 had thymoma, and 5 had malignant neoplasms of diffuse large B-cell lymphoma (DLBCL) and other origins. Patients with thymoma showed multiple autoimmune diseases. HLA-A*24:02 and/or A*02:06 were present in six and DR53 in 5 cases analyzed. High anti-PIT-1 antibody titers and ectopic PIT-1 expression in the cytosol and nucleus of the tumor tissues were observed in patients with thymoma or DLBCL, whereas it was exclusively observed in the nuclei of a bladder cancer patient. These findings provide new insights into the pathophysiology of paraneoplastic autoimmune hypophysitis.
Topics: Humans; Autoantibodies; Autoimmune Diseases; Autoimmune Hypophysitis; Hypophysitis; Thymoma; Thymus Neoplasms; Transcription Factor Pit-1; Transcription Factors
PubMed: 38146732
DOI: 10.1093/ejendo/lvad179 -
European Review For Medical and... Nov 2023Thymus is an immune organ in which pathological changes may cause autoimmune diseases, including myasthenia gravis (MG). Recent studies have focused on Toll-like...
OBJECTIVE
Thymus is an immune organ in which pathological changes may cause autoimmune diseases, including myasthenia gravis (MG). Recent studies have focused on Toll-like receptor 4 (TLR4) signaling as the cause of such changes. In our previous study, an imbalance of T helper 17 (Th17) cells and T regulatory (Treg) cells was found in MG thymoma. These results suggest the involvement of TLR4 in the pathogenesis of thymoma MG via an alteration of the Th17/Treg balance. Here, we aimed to assess whether the TLR4-MyD88-NF-κB pathway is upregulated in MG thymoma and its relationship with Th17/Treg cells.
PATIENTS AND METHODS
We collect thymoma samples from 54 patients with or without MG, detecting the expression level of TLR4, MyD88, and NF-κB in thymoma tissues. Next, we established an in vitro experiment of coculturing thymoma cells with CD4+ T cells and detected the differentiation of Th17 cells and Treg cells and their marker protein, retinoid-related orphan receptor gamma t (RORγt) and forkhead transcription factor 3 (Foxp3).
RESULTS
We found TLR4, MyD88, and NF-κB expressed more in MG thymoma compared with simple thymoma. After the transwell coculturing, we observed an imbalance of Th17/Treg cells after TLR4 stimulation.
CONCLUSIONS
TLR4 is stimulated in thymoma, causing an increase of Th17 cells and a decrease of Treg cells, namely an imbalance of Th17/Treg cells, resulting in MG.
Topics: Humans; NF-kappa B; T-Lymphocytes, Regulatory; Thymoma; Myeloid Differentiation Factor 88; Toll-Like Receptor 4; Myasthenia Gravis; Th17 Cells; Thymus Neoplasms; Forkhead Transcription Factors
PubMed: 37975358
DOI: 10.26355/eurrev_202311_34309 -
Portuguese Journal of Cardiac Thoracic... Jul 2023
Topics: Humans; Thymectomy; Immunologic Deficiency Syndromes; Thymus Neoplasms
PubMed: 37418767
DOI: 10.48729/pjctvs.313 -
Internal Medicine (Tokyo, Japan) Sep 2023
Topics: Humans; Cardiac Tamponade; Thymoma; Thymus Neoplasms; Pericardial Effusion
PubMed: 36642518
DOI: 10.2169/internalmedicine.0903-22 -
Academic Radiology Apr 2024This study aims to evaluate the feasibility and effectiveness of deep transfer learning (DTL) and clinical-radiomics in differentiating thymoma from thymic cysts.
Development and Validation of Contrast-Enhanced CT-Based Deep Transfer Learning and Combined Clinical-Radiomics Model to Discriminate Thymomas and Thymic Cysts: A Multicenter Study.
RATIONALE AND OBJECTIVES
This study aims to evaluate the feasibility and effectiveness of deep transfer learning (DTL) and clinical-radiomics in differentiating thymoma from thymic cysts.
MATERIALS AND METHODS
Clinical and imaging data of 196 patients pathologically diagnosed with thymoma and thymic cysts were retrospectively collected from center 1. (training cohort: n = 137; internal validation cohort: n = 59). An independent external validation cohort comprised 68 thymoma and thymic cyst patients from center 2. Region of interest (ROI) delineation was performed on contrast-enhanced chest computed tomography (CT) images, and eight DTL models including Densenet 169, Mobilenet V2, Resnet 101, Resnet 18, Resnet 34, Resnet 50, Vgg 13, Vgg 16 were constructed. Radiomics features were extracted from the ROI on the CT images of thymoma and thymic cyst patients, and feature selection was performed using intra-observer correlation coefficient (ICC), Spearman correlation analysis, and least absolute shrinkage and selection operator (LASSO) algorithm. Univariate analysis and multivariable logistic regression (LR) were used to select clinical-radiological features. Six machine learning classifiers, including LR, support vector machine (SVM), k-nearest neighbors (KNN), Light Gradient Boosting Machine (LightGBM), Adaptive Boosting (AdaBoost), and Multilayer Perceptron (MLP), were used to construct Radiomics and Clinico-radiologic models. The selected features from the Radiomics and Clinico-radiologic models were fused to build a Combined model. Receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) were used to evaluate the discrimination, calibration, and clinical utility of the models, respectively. The Delong test was used to compare the AUC between different models. K-means clustering was used to subdivide the lesions of thymomas or thymic cysts into subregions, and traditional radiomics methods were used to extract features and compare the ability of Radiomics and DTL models to reflect intratumoral heterogeneity using correlation analysis.
RESULTS
The Densenet 169 based on DTL performed the best, with AUC of 0.933 (95% CI: 0.875-0.991) in the internal validation cohort and 0.962 (95% CI: 0.923-1.000) in the external validation cohort. The AdaBoost classifier achieved AUC of 0.965 (95% CI: 0.923-1.000) and 0.959 (95% CI: 0.919-1.000) in the internal and external validation cohorts, respectively, for the Radiomics model. The LightGBM classifier achieved AUC of 0.805 (95% CI: 0.690-0.920) and 0.839 (95% CI: 0.736-0.943) in the Clinico-radiologic model. The AUC of the Combined model in the internal and external validation cohorts was 0.933 (95% CI: 0.866-1.000) and 0.945 (95% CI: 0.897-0.994), respectively. The results of the Delong test showed that the Radiomics model, DTL model, and Combined model outperformed the Clinico-radiologic model in both internal and external validation cohorts (p-values were 0.002, 0.004, and 0.033 in the internal validation cohort, while in the external validation cohort, the p-values were 0.014, 0.006, and 0.015, respectively). But there was no statistical difference in performance among the three models (all p-values <0.05). Correlation analysis showed that radiomics performed better than DTL in quantifying intratumoral heterogeneity differences between thymoma and thymic cysts.
CONCLUSION
The developed DTL model and the Combined model based on radiomics and clinical-radiologic features achieved excellent diagnostic performance in differentiating thymic cysts from thymoma. They can serve as potential tools to assist clinical decision-making, particularly when endoscopic biopsy carries a high risk.
Topics: Humans; Thymoma; Radiomics; Mediastinal Cyst; Retrospective Studies; Tomography, X-Ray Computed; Machine Learning; Thymus Neoplasms
PubMed: 37949702
DOI: 10.1016/j.acra.2023.10.018