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Heliyon Nov 2023The high incidence and severe clinical manifestations of phlebitis pose a complex and urgent clinical challenge. The rapid and simple establishment of animal phlebitis...
BACKGROUND
The high incidence and severe clinical manifestations of phlebitis pose a complex and urgent clinical challenge. The rapid and simple establishment of animal phlebitis models and the development of preventive strategies are crucial to resolving this problem.
METHODS
In this study, we established such models by mixing vinorelbine ditartrate (VNR) and carbomer to form a sustained-release gel carrier, and then injected it around the veins rather than inside the vessels. Furthermore, we analyzed the efficacy of the carbomer/VNR gel in inducing phlebitis by monitoring the morphology of the veins using HE staining, immunohistochemical and immunofluorescence staining, and western blotting. Reactive oxygen species (ROS) and lipid peroxidation levels were determined using flow cytometry. Finally, we evaluated the inhibitory effect of N-acetylcysteine (NAC) on VNR-induced phlebitis in rabbits and rats.
RESULTS
Our findings suggested that the carbomer/VNR gel rapidly and easily induced phlebitis due to by retention of the gel in situ, wrapping the veins, and the prolonged release of VNR. NAC alleviated the VNR-induced oxidative stress response and expression of inflammatory cytokines by attenuating mitochondrial damage in venous endothelial cells, thereby preventing the occurrence of phlebitis in rabbits and rats.
CONCLUSION
The in situ carbomer/VNR gel provides a rapid and simple method for establishing an animal model to study the pathogenesis of phlebitis. Furthermore, the observed therapeutic effect of NAC highlights its novel and efficacious role in preventing and treating phlebitis.
PubMed: 37942159
DOI: 10.1016/j.heliyon.2023.e21235 -
International Journal of Molecular... Jan 2024Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its...
Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models. In this study, mice bearing HCC tumors were treated with the vehicle, sorafenib (15 mg/kg), vinorelbine (3 mg/kg), and sorafenib-vinorelbine combination (Sora/Vino). Rigorous monitoring of the tumor growth and side effects coupled with comprehensive histological and molecular analyses was conducted. The overall survival (OS) of mice bearing HCC orthotopic tumors was also assessed. Our data showed a notable 86.4% response rate to Sora/Vino, surpassing rates of 31.8% for sorafenib and 9.1% for vinorelbine monotherapies. Sora/Vino significantly inhibited tumor growth, prolonged OS of mice bearing HCC orthotopic tumors ( < 0.01), attenuated tumor cell proliferation and angiogenesis, and enhanced necrosis and apoptosis. The combination therapy effectively suppressed the focal adhesion kinase (FAK) pathway, which is a pivotal player in cell proliferation, tumor angiogenesis, survival, and metastasis. The noteworthy antitumor activity in 22 HCC PDX models positions Sora/Vino as a promising candidate for early-phase clinical trials, leveraging the established use of sorafenib and vinorelbine in HCC and other cancers.
Topics: Humans; Animals; Mice; Sorafenib; Carcinoma, Hepatocellular; Vinorelbine; Liver Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Xenograft Model Antitumor Assays; Antineoplastic Agents
PubMed: 38338842
DOI: 10.3390/ijms25031563 -
Molecular Oncology Feb 2024The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor...
NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.
The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Gefitinib; Lung Neoplasms; Cyclic AMP Response Element-Binding Protein; Translational Research, Biomedical; ErbB Receptors; Cisplatin; Vinorelbine; Mutation; Protein Kinase Inhibitors; Receptor, Notch1; CREB-Binding Protein
PubMed: 37864465
DOI: 10.1002/1878-0261.13542 -
BMC Cancer Apr 2024This study aimed to systematically analyze the effect of a serine/threonine kinase (STK11) mutation (STK11) on therapeutic efficacy and prognosis in patients with... (Meta-Analysis)
Meta-Analysis
Effect of the STK11 mutation on therapeutic efficacy and prognosis in patients with non-small cell lung cancer: a comprehensive study based on meta-analyses and bioinformatics analyses.
BACKGROUND
This study aimed to systematically analyze the effect of a serine/threonine kinase (STK11) mutation (STK11) on therapeutic efficacy and prognosis in patients with non-small cell lung cancer (NSCLC).
METHODS
Candidate articles were identified through a search of relevant literature published on or before April 1, 2023, in PubMed, Embase, Cochrane Library, CNKI and Wanfang databases. The extracted and analyzed data included the hazard ratios (HRs) of PFS and OS, the objective response rate (ORR) of immune checkpoint inhibitors (ICIs), and the positive rates of PD-L1 expression. The HR of PFS and OS and the merged ratios were calculated using a meta-analysis. The correlation between STK11 and clinical characteristics was further analyzed in NSCLC datasets from public databases.
RESULTS
Fourteen retrospective studies including 4317 patients with NSCLC of whom 605 had STK11 were included. The meta-analysis revealed that the ORR of ICIs in patients with STK11 was 10.1% (95%CI 0.9-25.2), and the positive rate of PD-L1 expression was 41.1% (95%CI 25.3-57.0). STK11 was associated with poor PFS (HR = 1.49, 95%CI 1.28-1.74) and poor OS (HR = 1.44, 95%CI 1.24-1.67). In the bioinformatics analysis, PFS and OS in patients with STK11 alterations were worse than those in patients without alterations (p < 0.001, p = 0.002). Nutlin-3a, 5-fluorouracil, and vinorelbine may have better sensitivity in patients with STK11 than in those with STK11.
CONCLUSIONS
Patients with STK11-mutant NSCLC had low PD-L1 expression and ORR to ICIs, and their PFS and OS were worse than patients with STK11 after comprehensive treatment. In the future, more reasonable systematic treatments should be explored for this subgroup of patients with STK11-mutant NSCLC.
Topics: Humans; AMP-Activated Protein Kinase Kinases; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; Prognosis; Protein Serine-Threonine Kinases; Retrospective Studies
PubMed: 38632512
DOI: 10.1186/s12885-024-12130-y -
Cost Effectiveness and Resource... Mar 2024Triple-negative breast cancer (TNBC) is responsible for 10-20% cases of breast cancer and is resulting in rising healthcare costs. Thus, health-economic evaluations are...
BACKGROUND
Triple-negative breast cancer (TNBC) is responsible for 10-20% cases of breast cancer and is resulting in rising healthcare costs. Thus, health-economic evaluations are needed to relate clinical outcomes and costs of treatment options and to provide recommendations of action from a health-economic perspective.
METHODS
We investigated the cost-benefit-ratio of approved treatment options in metastatic TNBC in Germany by applying the efficiency frontier approach. These included sacituzumab-govitecan (SG), eribulin, vinorelbine, and capecitabine. Clinical benefit was measured as (i) median overall survival (mOS) and (ii) health-related quality of life (HRQoL) in terms of time to symptom worsening (TSW). To assess medical benefits, literature was systematically reviewed in PubMed for (i) and (ii), respectively. Treatment costs were calculated considering annual direct outpatient treatment costs from a statutory healthcare payer perspective. It was intended that both, (i) and (ii), yield an efficiency frontier.
RESULTS
Annual direct outpatient treatment costs amounted to EUR 176,415.21 (SG), EUR 47,414.14 (eribulin), EUR 13,711.35 (vinorelbine), and EUR 3,718.84 (capecitabine). Systematic literature review of (i) and statistical analysis resulted in OS values of 14.3, 9.56, 9.44, and 7.46 months, respectively. Capecitabine, vinorelbine, and SG are part of the efficiency frontier including OS. The highest additional benefit per additional cost was determined for vinorelbine, followed by SG. Systematic review of (ii) revealed that no TSW data of TNBC patients receiving vinorelbine were available, preventing the presentation of an efficiency frontier including HRQoL.
CONCLUSIONS
Vinorelbine is most cost-effective, followed by SG. Health-economic evaluations support decision-makers to assess treatment options within one indication area. In Germany, the efficiency frontier can provide decision support for the pricing of innovative interventions. Results of our analysis may thus guide reimbursement determination.
PubMed: 38459569
DOI: 10.1186/s12962-024-00528-1 -
American Journal of Cancer Research 2023Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic...
Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic astrocytoma (AA) or glioblastoma (GBM) treated with concomitant and adjuvant 20-30 mg/m/dose of vinorelbine and 30 mg/kg/day valproic acid (VA) in combination to consolidated TMZ and focal RT after maximal surgery. We evaluated the feasibility of treating children diagnosed with HGG. The median follow-up time was 51.4 months (range, 6.2-106.6 months). The 5-year OS was 57.9% (CI 95%, 33.2-76.3) and the 5-year PFS was 57.9% (CI 95%, 33.2-76.3). Eight patients (42.1%) have progressed so far, with a median time to progression of 9 months from diagnosis (range, 4.6-34.7 months). All of them died for disease progression. At time of analysis, 11 patients were still alive with no evidence of disease. It is notable that all events occurred within 35 months from the start of therapy. All 19 treated patients reported low-grade drug-related adverse events (AEs). The treatment was well tolerated in our limited cohort of patients without significant toxicity. Further studies of the efficacy and safety of combination of vinorelbine/VA to consolidated RT/TMZ therapy in children with HGG are underway in a clinical trial setting.
PubMed: 37693163
DOI: No ID Found -
Therapeutic Advances in Medical Oncology 2023Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire...
BACKGROUND
Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have platinum-refractory disease.
OBJECTIVES
To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC.
DESIGN AND METHODS
Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either or (, four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and treatment studies were undertaken.
RESULTS
Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary mutations, two -mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the fusion, known to upregulate drug efflux MDR1.
CONCLUSION
The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.
PubMed: 38028140
DOI: 10.1177/17588359231208674 -
Scientific Reports Oct 2023Canine pulmonary adenocarcinoma (PAC) resembles human lung tumors in never-smokers, but it is rarer than human pulmonary adenocarcinoma. Therefore, research on canine...
Canine pulmonary adenocarcinoma (PAC) resembles human lung tumors in never-smokers, but it is rarer than human pulmonary adenocarcinoma. Therefore, research on canine PAC is challenging. In the present study, we successfully established various novel canine PAC cell lines from a single lesion in a dog, including two parent cell lines and fourteen cloned cell lines, and characterized their cellular properties in vitro. Several of these cell lines showed epithelial-mesenchymal transition (EMT)-like and/or cancer stem cell (CSCs)-like phenotypes. We additionally assessed the sensitivity of the cells to vinorelbine in vitro. Three clonal lines, two of which showed EMT- and CSC-like phenotypes, were resistant to vinorelbine. Furthermore, we evaluated the expression and activation status of EGFR, HER2, and Ras signaling factors. The findings indicated that the cell lines we established preserved the expression and activation of these factors to varying extents. These novel canine PAC cell lines can be utilized in future research for understanding the pathogenesis and development of treatments for canine PAC.
Topics: Dogs; Humans; Animals; Vinorelbine; Cell Line, Tumor; Adenocarcinoma of Lung; Lung Neoplasms; Phenotype; Epithelial-Mesenchymal Transition; Neoplastic Stem Cells
PubMed: 37798461
DOI: 10.1038/s41598-023-44062-1 -
Veterinary Sciences Nov 2023Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven...
Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven antineoplastic activity and a low toxicity profile in dogs. Treatment-naïve, client-owned dogs with a cyto/histological diagnosis of advanced pulmonary carcinoma, selected from a laboratory database and previously subjected to imaging, were enrolled in the study. Vinorelbine (15 mg/m) was administered weekly for 4 weeks and then fortnightly until progressive disease was documented. Staging work-up was repeated by means of diagnostic imaging after the fourth VRL (i.e., 28 days) and monthly thereafter; response to treatment was evaluated according to the RECIST. Toxicity was graded following the VCOGC group. Ten dogs met the inclusion criteria. Partial response was documented in eight dogs. Median time to progression was 88 days (range: 7-112) and median survival time for all dogs was 100 days (range 7-635). The most common side effect was neutropenia. The main limitations of the study were the absence of histological diagnosis in eight cases and the limited number of treated dogs. VRL is well tolerated with an adequate toxicity profile and may be useful in the management of advanced lung tumours if used as a first-line treatment strategy.
PubMed: 38133215
DOI: 10.3390/vetsci10120664 -
Cancer Pathogenesis and Therapy Jan 2024Human epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large...
Inetetamab combined with pyrotinib and oral vinorelbine for patients with human epidermal growth factor receptor 2 positive advanced breast cancer: A single-arm phase 2 clinical trial.
BACKGROUND
Human epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large proportion of patients still develop resistance to trastuzumab. In this study, we investigated the efficacy and safety of inetetamab, another anti-HER2 antibody, combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment.
METHODS
In this prospective, single-arm, phase 2 trial, patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited. Patients received a combination of inetetamab (loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks), pyrotinib (400 mg orally once daily), and vinorelbine (60 mg/m orally once weekly) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and safety.
RESULTS
Between February 13, 2022 and December 25, 2022, 30 patients were screened and enrolled in this study. The median age of the patients at enrollment was 54 years, 12 patients (40.0 %) had hormone-receptor-positive disease and 23 patients (76.7 %) had visceral metastasis. The median PFS was 8.63 months (95 % confidence interval [CI] 4.15-13.12 months). The median OS was not reached. The ORR was 53.3 % (16/30) and the DCR was 96.7 % (29/30). The most common Grade III/IV adverse events were leukopenia ( = 5, 16.7 %), neutropenia ( = 4, 13.3 %), and diarrhea ( = 3, 10 %). No treatment-related serious adverse events or deaths occurred.
CONCLUSIONS
The combination regimen of inetetamab, pyrotinib, and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients.
TRIAL REGISTRATION
No.NCT05823623; https://www.clinicaltrials.gov/.
PubMed: 38328709
DOI: 10.1016/j.cpt.2023.10.004