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Journal of Managed Care & Specialty... Jun 2024Larotrectinib is approved for patients with advanced gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with... (Comparative Study)
Comparative Study
Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.
BACKGROUND
Larotrectinib is approved for patients with advanced gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done.
OBJECTIVE
To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances.
METHODS
We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility.
RESULTS
In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab.
CONCLUSIONS
In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Thyroid Neoplasms; Quality-Adjusted Life Years; Nivolumab; Pyrimidines; Pyrazoles; Male; Female; Antibodies, Monoclonal, Humanized; Middle Aged; Adult; Aged; Treatment Outcome
PubMed: 38824630
DOI: 10.18553/jmcp.2024.30.6.581 -
Journal of Ovarian Research Jun 2024Ovarian clear cell carcinoma (OCCC) is a rare pathological histotype in ovarian cancer, while the survival rate of advanced OCCC (Stage III-IV) is substantially lower...
BACKGROUND
Ovarian clear cell carcinoma (OCCC) is a rare pathological histotype in ovarian cancer, while the survival rate of advanced OCCC (Stage III-IV) is substantially lower than that of the advanced serous ovarian cancer (OSC), which is the most common histotype. The goal of this study was to identify high-risk OCCC by comparing OSC and OCCC, with investigating potential risk and prognosis markers.
METHODS
Patients diagnosed with ovarian cancer from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) Program. Logistic and Cox regression models were used to identify risk and prognostic factors in high-risk OCCC patients. Cancer-specific survival (CSS) and overall survival (OS) were assessed using Kaplan-Meier curves. Furthermore, Cox analysis was employed to build a nomogram model. The performance evaluation results were displayed using the C-index, calibration plots, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Immunohistochemically approach was used to identify the expression of the novel target (GPC3).
RESULTS
In the Cox analysis for advanced OCCC, age (45-65 years), tumor numbers (total number of in situ/malignant tumors for patient), T3-stage, bilateral tumors, and liver metastases could be defined as prognostic variables. Nomogram showed good predictive power and clinical practicality. Compared with OSC, liver metastases had a stronger impact on the prognosis of patients with OCCC. T3-stage, positive distant lymph nodes metastases, and lung metastases were risk factors for developing liver metastases. Chemotherapy was an independent prognostic factor for patient with advanced OCCC, but had no effect on CSS in patients with liver metastases (p = 0.0656), while surgery was significantly related with better CSS in these patients (p < 0.0001) (p = 0.0041). GPC3 expression was detected in all tissue sections, and GPC3 staining was predominantly found in the cytoplasm and membranes.
CONCLUSION
Advanced OCCC and OCCC with liver metastases are two types of high-risk OCCC. The constructed nomogram exhibited a satisfactory survival prediction for patients with advanced OCCC. GPC3 immunohistochemistry is expected to accumulate preclinical evidence to support the inclusion of GPC3 in OCCC targeted therapy.
Topics: Humans; Female; Ovarian Neoplasms; Middle Aged; Prognosis; Aged; Adenocarcinoma, Clear Cell; Cystadenocarcinoma, Serous; SEER Program; Adult; Nomograms; Risk Factors
PubMed: 38824600
DOI: 10.1186/s13048-024-01435-y -
Respiratory Research Jun 2024Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as...
BACKGROUND
Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma.
METHODS
The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor.
RESULTS
Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-β1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression.
CONCLUSIONS
Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.
Topics: Animals; Amino Acid Oxidoreductases; Ovalbumin; Airway Remodeling; Proto-Oncogene Proteins c-akt; Mice; Humans; Asthma; Signal Transduction; Female; Mice, Inbred BALB C; Male; Epithelial-Mesenchymal Transition
PubMed: 38824593
DOI: 10.1186/s12931-024-02811-4 -
Respiratory Research Jun 2024Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including... (Review)
Review
Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.
Topics: Animals; Lung; Humans; Lung Diseases; Drug Discovery; Organ Culture Techniques
PubMed: 38824592
DOI: 10.1186/s12931-024-02855-6 -
European Journal of Medical Research Jun 2024The prevalence of low-dose CT (LDCT) in lung cancer screening has gradually increased, and more and more lung ground glass nodules (GGNs) have been detected. So far, a... (Review)
Review
The prevalence of low-dose CT (LDCT) in lung cancer screening has gradually increased, and more and more lung ground glass nodules (GGNs) have been detected. So far, a consensus has been reached on the treatment of single pulmonary ground glass nodules, and there have been many guidelines that can be widely accepted. However, at present, more than half of the patients have more than one nodule when pulmonary ground glass nodules are found, which means that different treatment methods for nodules may have different effects on the prognosis or quality of life of patients. This article reviews the research progress in the diagnosis and treatment strategies of pulmonary multiple lesions manifested as GGNs.
Topics: Humans; Lung Neoplasms; Multiple Pulmonary Nodules; Tomography, X-Ray Computed; Lung
PubMed: 38824558
DOI: 10.1186/s40001-024-01904-6 -
BMC Cancer Jun 2024An accurate and non-invasive approach is urgently needed to distinguish tuberculosis granulomas from lung adenocarcinomas. This study aimed to develop and validate a...
Development and validation of a preoperative CT‑based radiomics nomogram to differentiate tuberculosis granulomas from lung adenocarcinomas: an external validation study.
BACKGROUND
An accurate and non-invasive approach is urgently needed to distinguish tuberculosis granulomas from lung adenocarcinomas. This study aimed to develop and validate a nomogram based on contrast enhanced-compute tomography (CE-CT) to preoperatively differentiate tuberculosis granuloma from lung adenocarcinoma appearing as solitary pulmonary solid nodules (SPSN).
METHODS
This retrospective study analyzed 143 patients with lung adenocarcinoma (mean age: 62.4 ± 6.5 years; 54.5% female) and 137 patients with tuberculosis granulomas (mean age: 54.7 ± 8.2 years; 29.2% female) from two centers between March 2015 and June 2020. The training and internal validation cohorts included 161 and 69 patients (7:3 ratio) from center No.1, respectively. The external testing cohort included 50 patients from center No.2. Clinical factors and conventional radiological characteristics were analyzed to build independent predictors. Radiomics features were extracted from each CT-volume of interest (VOI). Feature selection was performed using univariate and multivariate logistic regression analysis, as well as the least absolute shrinkage and selection operator (LASSO) method. A clinical model was constructed with clinical factors and radiological findings. Individualized radiomics nomograms incorporating clinical data and radiomics signature were established to validate the clinical usefulness. The diagnostic performance was assessed using the receiver operating characteristic (ROC) curve analysis with the area under the receiver operating characteristic curve (AUC).
RESULTS
One clinical factor (CA125), one radiological characteristic (enhanced-CT value) and nine radiomics features were found to be independent predictors, which were used to establish the radiomics nomogram. The nomogram demonstrated better diagnostic efficacy than any single model, with respective AUC, accuracy, sensitivity, and specificity of 0.903, 0.857, 0.901, and 0.807 in the training cohort; 0.933, 0.884, 0.893, and 0.892 in the internal validation cohort; 0.914, 0.800, 0.937, and 0.735 in the external test cohort. The calibration curve showed a good agreement between prediction probability and actual clinical findings.
CONCLUSION
The nomogram incorporating clinical factors, radiological characteristics and radiomics signature provides additional value in distinguishing tuberculosis granuloma from lung adenocarcinoma in patients with a SPSN, potentially serving as a robust diagnostic strategy in clinical practice.
Topics: Humans; Female; Middle Aged; Nomograms; Male; Tomography, X-Ray Computed; Retrospective Studies; Adenocarcinoma of Lung; Lung Neoplasms; Diagnosis, Differential; Granuloma; Aged; Tuberculosis, Pulmonary; Preoperative Period; Radiomics
PubMed: 38824514
DOI: 10.1186/s12885-024-12422-3 -
Cell Death & Disease Jun 2024Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms...
Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms have not been sufficiently elucidated. Mitochondria modulate the viability, plasticity, proliferative capacity, and differentiation potential of MSCs. We hypothesized that alterations in the 5-hydroxymethylcytosine (5hmC) profile of mitochondria-related genes may mediate obesity-driven dysfunction of human adipose-derived MSCs. MSCs were harvested from abdominal subcutaneous fat of obese and age/sex-matched non-obese subjects (n = 5 each). The 5hmC profile and expression of nuclear-encoded mitochondrial genes were examined by hydroxymethylated DNA immunoprecipitation sequencing (h MeDIP-seq) and mRNA-seq, respectively. MSC mitochondrial structure (electron microscopy) and function, metabolomics, proliferation, and neurogenic differentiation were evaluated in vitro, before and after epigenetic modulation. hMeDIP-seq identified 99 peaks of hyper-hydroxymethylation and 150 peaks of hypo-hydroxymethylation in nuclear-encoded mitochondrial genes from Obese- versus Non-obese-MSCs. Integrated hMeDIP-seq/mRNA-seq analysis identified a select group of overlapping (altered levels of both 5hmC and mRNA) nuclear-encoded mitochondrial genes involved in ATP production, redox activity, cell proliferation, migration, fatty acid metabolism, and neuronal development. Furthermore, Obese-MSCs exhibited decreased mitochondrial matrix density, membrane potential, and levels of fatty acid metabolites, increased superoxide production, and impaired neuronal differentiation, which improved with epigenetic modulation. Obesity elicits epigenetic changes in mitochondria-related genes in human adipose-derived MSCs, accompanied by structural and functional changes in their mitochondria and impaired fatty acid metabolism and neurogenic differentiation capacity. These observations may assist in developing novel therapies to preserve the potential of MSCs for tissue repair and regeneration in obese individuals.
Topics: Humans; Mesenchymal Stem Cells; Obesity; Mitochondria; Epigenesis, Genetic; Adipose Tissue; Cell Differentiation; Female; Male; 5-Methylcytosine; Adult; Middle Aged; Cell Proliferation
PubMed: 38824145
DOI: 10.1038/s41419-024-06774-8 -
Transplantation Proceedings May 2024To assess the principles of qualification and the range of organ transplantation in a patient with diagnosis of system sclerosis with pulmonary manifestation and severe...
OBJECTIVE
To assess the principles of qualification and the range of organ transplantation in a patient with diagnosis of system sclerosis with pulmonary manifestation and severe myocardial insufficiency.
METHODS
We present the case of a 43-year-old patient with confirmed systemic sclerosis with pulmonary manifestations and biventricular heart insufficiency after disease exacerbation and sudden cardiac arrest in the pulseless electrical activity (PEA) mechanism with effective resuscitation, with increasing shortness of breath and the need for inotropes and levosimendan infusion without a significant improvement in his general status. Owing to the diagnosis of a systemic disease with no option for pharmacologic or any other treatment for heart failure, he was reevaluated and put on an urgent waiting list for isolated heart transplantation. After 7 days, heart transplantation was performed. Given the risk of disease progression and the possibility of future lung transplantation, the pleural cavities were untouched. The standard immunosuppression protocol was followed with the use of rabbit antithymocyte globulin.
RESULTS
The patient was extubated at 24 hours after heart transplantation. The results of endomyocardial biopsies performed during the hospital stay and at a 6-month follow-up were negative. The patient was discharged to home after 22 days of an uneventful hospital stay.
CONCLUSIONS
Scleroderma as an autoimmunologic disease remains a challenge for the transplantation team as a possible progressive multiorgan insufficiency requiring qualification for organ transplantation. The course of the disease varies depending on the form of systemic sclerosis. Careful assessment, qualification, and determination of appropriate preprocedure and postprocedure immunosuppressive treatment are essential to an uncomplicated course of treatment.
PubMed: 38824076
DOI: 10.1016/j.transproceed.2024.03.036 -
Cancer Letters May 2024Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from...
Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63-IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.
PubMed: 38823762
DOI: 10.1016/j.canlet.2024.216999 -
International Journal of Pharmaceutics May 2024Camptothecin, a natural alkaloid, was first isolated from the bark and stem of the Camptotheca acuminate tree in China. It, along with its analogs, has demonstrated... (Review)
Review
Camptothecin, a natural alkaloid, was first isolated from the bark and stem of the Camptotheca acuminate tree in China. It, along with its analogs, has demonstrated potent anti-cancer activity in preclinical studies, particularly against solid tumors such as lung, breast, ovarian, and colon cancer. Despite its promising anti-cancer activity, the application of camptothecin is limited due to its poor solubility, toxicity, and limited biodistribution. Nanotechnology-based drug delivery systems have been used to overcome limited bioavailability and ensure greater biodistribution after administration. Additionally, various drug delivery systems, particularly polymeric micelles, have been investigated to enhance the solubility, stability, and efficacy of camptothecin. Polymeric micelles offer a promising approach for the delivery of camptothecin. Polymeric micelles possess a core-shell structure, with a typical hydrophobic core, which exhibits a high capacity to incorporate hydrophobic drugs. The structure of polymeric micelles can be engineered to have a high drug loading capacity, enabling them to carry a large amount of hydrophobic drug within their core. The shell portion of polymeric micelles is composed of hydrophilic polymers Furthermore, the hydrophilic segment of polymeric micelles plays an important role in protecting against the reticuloendothelial system (RES). This review provides a discussion on recent research and developments in the delivery of camptothecin using polymeric micelles for the treatment of cancers.
PubMed: 38823466
DOI: 10.1016/j.ijpharm.2024.124292