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Cancer Medicine May 2023Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.
AIMS
The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.
MATERIALS & METHODS
Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies.
RESULTS
One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02).
DISCUSSION
Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS.
CONCLUSION
These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.
Topics: Humans; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Vinorelbine; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Cyclophosphamide; Chronic Disease
PubMed: 37016270
DOI: 10.1002/cam4.5749 -
Annals of Medicine Dec 2022Extensive application of anti-HER2 targeted therapy improves significantly the HER2-positive advanced breast cancer (BC) prognosis, however, it is still difficult to...
OBJECTIVES
Extensive application of anti-HER2 targeted therapy improves significantly the HER2-positive advanced breast cancer (BC) prognosis, however, it is still difficult to treat brain metastasis. In current study, we explored effective approaches combining pyrotinib to treat brain metastasis in patients with HER2-positive advanced BC based upon clinical data.
MATERIALS AND METHODS
Current study included 61 HER2-positive BC patients with brain metastases (BM) who were treated by pyrotinib-based regimens. The systemic regimens included pyrotinib combined with capecitabine, pyrotinib combined with nab-paclitaxel, and pyrotinib combined with vinorelbine. Patients' progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and objective response rate (ORR), as well as drug-related adverse events (AEs) in regard of each combination regimen were analyzed.
RESULTS
Pyrotinib-based systemic therapy resulted in 8.6 months median PFS (mPFS) and 18.0 months median OS (mOS) among the BM patients. Regarding different regimens, the combination of pyrotinib with nab-paclitaxel was superior to the combination with capecitabine and vinorelbine with respect to PFS and OS. The central nervous system (CNS) ORR did not showcase significant difference among 3 regimens, however, nab-paclitaxel combined regimen obtained the best peripheral ORR (84.6%) ( ≤ .05).
CONCLUSIONS
Pyrotinib-based combination therapy is safe for HER2-positive brain metastasis treatment. Compared with vinorelbine or capecitabine, pyrotinib combined with nab-paclitaxel is more effective with less toxicity, which is the preferable regimen for HER2-positive brain metastasis.KEY MESSAGESPresent investigation investigated effective methods through combining pyrotinib to treat brain metastasis with HER2-positive advanced brain cancer. The outcomes verified that pyrotinib-based combination therapy was safe and efficient to treat HER2-positive brain metastasis. Therefore, it is effective to treat brain metastasis applying anti-HER2 targeted therapies although pyrotinib showcases efficiency regarding its treatments for the metastasis.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Receptor, ErbB-2; Capecitabine; Vinorelbine; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms
PubMed: 36331291
DOI: 10.1080/07853890.2022.2139411 -
Frontiers in Oncology 2022Leptomeningeal metastases (LM) are rare and catastrophic for metastatic breast cancer (MBC). The prognosis of HER2-positive breast cancer (BC) with LM is extremely poor.... (Review)
Review
Leptomeningeal metastases (LM) are rare and catastrophic for metastatic breast cancer (MBC). The prognosis of HER2-positive breast cancer (BC) with LM is extremely poor. There is no high-quality evidence of treatment regimens in HER2-positive BC with LM yet. Here, we present a case of LM in a 50-year-old woman with HER2-positive BC. Immunohistochemistry revealed invasive ductal carcinoma, estrogen receptor negative, progesterone receptor negative, HER2 3+, P53 positive 80%, and Ki-67 positive 35%. Reported for the first time, the patient was given pyrotinib-targeted therapy (400 mg, oral, every day), metronomic vinorelbine (40 mg, oral, three times a week), and intrathecal methotrexate (10 mg, infrequent and irregular use due to poor compliance) synchronously. The patient received and benefited from the treatment regimen for 16 months. And the quality of life, as self-reported, improved significantly. We also comprehensively summarized all the case reports, observational studies, and clinical trials related to HER2-positive BC with LM in the PubMed database and ClinicalTrials.gov. Intrathecal chemotherapy (methotrexate, cytarabine, thiotepa), intrathecal trastuzumab, whole-brain radiotherapy, and systemic therapy are commonly used treatment options according to a review of the literature and research. Pembrolizumab and trastuzumab deruxtecan (DS-8201) as novel drugs are promising in LM. Furthermore, trastuzumab emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs) such as tucatinib and neratinib have exhibited good efficacy in HER2-positive BC with central nervous system (CNS) metastases and deserve further exploration. In our report, combining pyrotinib-targeted therapy with metronomic chemotherapy is a potential regimen, which has presented satisfactory therapeutic efficacy and also warrants additional investigation in HER2-positive BC with LM.
PubMed: 35251981
DOI: 10.3389/fonc.2022.811919 -
International Journal of Molecular... Dec 2023Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of...
Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of rapamycin/sirolimus (mTOR) and microtubules are prominent druggable targets for HCC. In this study, we demonstrated that co-targeting mTOR using mTOR inhibitors (everolimus and sirolimus) along with the microtubule inhibitor vinorelbine yielded results superior to those of the monotherapies in HCC PDX models. Our research showed that the vinorelbine arrests cells at the mitotic phase, induces apoptosis, and normalizes tumor blood vessels but upregulates survivin and activates the mTOR/p70S6K/4EBP1 pathway. The addition of the everolimus significantly improved the tumor response to the vinorelbine, leading to improved overall survival (OS) in most tested orthotopic HCC PDX models. The mechanistic investigation revealed that this marked antitumor effect was accompanied by the downregulations of mTOR targets (p-p70S6K, p-4EBP1, and p-S6K); several key cell-cycle regulators; and the antiapoptotic protein survivin. These effects did not compromise the normalization of the blood vessels observed in response to the vinorelbine in the vinorelbine-sensitive PDX models or to the everolimus in the everolimus-sensitive PDX models. The combination of the everolimus and vinorelbine (everolimus/vinorelbine) also promoted apoptosis with minimal toxicity. Given the cost-effectiveness and established effectiveness of everolimus, and especially sirolimus, this strategy warrants further investigation in early-phase clinical trials.
Topics: Humans; Everolimus; Carcinoma, Hepatocellular; Vinorelbine; Survivin; Ribosomal Protein S6 Kinases, 70-kDa; Liver Neoplasms; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 38203186
DOI: 10.3390/ijms25010017 -
International Journal of Molecular... Jun 2023Drug combinations are increasingly studied in the field of anticancer agents. Mathematical models, such as Loewe, Bliss, and HSA, are used to interpret drug...
Drug combinations are increasingly studied in the field of anticancer agents. Mathematical models, such as Loewe, Bliss, and HSA, are used to interpret drug combinations, while informatics tools help cancer researchers identify the most effective combinations. However, the different algorithms each software uses lead to results that do not always correlate. This study compared the performance of Combenefit (Ver. 2.021) and SynergyFinder (Ver. 3.6) in analyzing drug synergy by studying combinations involving non-steroidal analgesics (celecoxib and indomethacin) and antitumor drugs (carboplatin, gemcitabine, and vinorelbine) on two canine mammary tumor cell lines. The drugs were characterized, their optimal concentration-response ranges were determined, and nine concentrations of each drug were used to make combination matrices. Viability data were analyzed under the HSA, Loewe, and Bliss models. Celecoxib-based combinations showed the most consistent synergistic effect among software and reference models. Combination heatmaps revealed that Combenefit gave stronger synergy signals, while SynergyFinder produced better concentration-response fitting. When the average values of the combination matrices were compared, some combinations shifted from synergistic to antagonistic due to differences in the curve fitting. We also used a simulated dataset to normalize each software's synergy scores, finding that Combenefit tends to increase the distance between synergistic and antagonistic combinations. We conclude that concentration-response data fitting biases the direction of the combination (synergistic or antagonistic). In contrast, the scoring from each software increases the differences among synergistic or antagonistic combinations in Combenefit when compared to SynergyFinder. We strongly recommend using multiple reference models and reporting complete data analysis for synergy claiming in combination studies.
Topics: Animals; Dogs; Celecoxib; Drug Therapy, Combination; Antineoplastic Agents; Software; Drug Combinations; Drug Synergism; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37298656
DOI: 10.3390/ijms24119705 -
Experimental and Therapeutic Medicine Mar 2022Peripherally inserted central catheters (PICCs) are used for the administration of chemotherapy drugs, including vinorelbine. The present study aimed to construct a...
Peripherally inserted central catheters (PICCs) are used for the administration of chemotherapy drugs, including vinorelbine. The present study aimed to construct a rabbit model with vinorelbine administration via PICC, and to dynamically monitor the formation of phlebitis and thrombosis. PICC was inserted into 48 rabbits following specific clinical procedures. The rabbits were randomly divided (n=6 per group) into the following eight groups: i) Control (PICC in place for 1 day); ii) 2nd day of PICC placement (received the first cycle of vinorelbine administration); iii) 3rd day of PICC placement; iv) 7th day of PICC placement; v) 14th day of PICC placement; vi) 21st day of PICC placement; vii) 23rd day of PICC placement (received the second cycle of vinorelbine administration); and viii) 24th day of PICC placement. Hematoxylin and eosin staining was performed on catheter, ear vein and anterior vena specimens. Prothrombin time was measured using an automatic coagulation analyzer, followed by routine blood tests. Serum levels of inflammation- and thrombosis-related factors, including C-reactive protein, D-dimer, interleukin-2, interleukin-6, P-selectin and E-selectin, were measured using ELISAs. X-ray examination confirmed that the rabbit model with vinorelbine administration via PICC was successfully constructed. On the 1st and 23rd day of PICC placement, thrombosis was observed in the catheter. Furthermore, on the 1st day of PICC placement, thrombosis was clearly observed in the ear vein and anterior vena samples. After vinorelbine administration, phlebitis occurred in the ear vein and anterior vena cava samples. With increasing time after vinorelbine administration via PICC, thrombosis and phlebitis were notably ameliorated. Moreover, on the day of vinorelbine administration, prothrombin time was significantly decreased and the serum levels of inflammation- and thrombosis-related factors were significantly increased compared with previous days. Collectively, the present study observed the formation and specific evolution of phlebitis and venous thrombosis after vinorelbine administration, providing a reference for the early prediction, timely prevention and treatment of PICC-related chemotherapy complications.
PubMed: 35126715
DOI: 10.3892/etm.2022.11135 -
Cells Dec 2021Mitochondria move along the microtubule network and produce bioenergy in the cell. However, there is no report of a relationship between bioenergetic activity of...
Mitochondria move along the microtubule network and produce bioenergy in the cell. However, there is no report of a relationship between bioenergetic activity of mitochondria and microtubule stability in mammalian cells. This study aimed to investigate this relationship. We treated HEK293 cells with microtubule stabilizers (Taxol and Epothilone D) or a microtubule disturber (vinorelbine), and performed live-cell imaging to determine whether mitochondrial morphology and bioenergetic activity depend on the microtubule status. Treatment with microtubule stabilizers enhanced the staining intensity of microtubules, significantly increased ATP production and the spare respiratory capacity, dramatically increased mitochondrial fusion, and promoted dynamic movement of mitochondria. By contrast, bioenergetic activity of mitochondria was significantly decreased in cells treated with the microtubule disturber. Our data suggest that microtubule stability promotes mitochondrial functional activity. In conclusion, a microtubule stabilizer can possibly recover mitochondrial functional activity in cells with unstable microtubules.
Topics: Adenosine Triphosphate; Cell Proliferation; Cell Respiration; Cell Shape; Cell Survival; Gene Expression Regulation; HEK293 Cells; Humans; Membrane Potential, Mitochondrial; Microtubules; Mitochondria; Oxygen Consumption; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34944107
DOI: 10.3390/cells10123600 -
The Oncologist Dec 2020Desmoid tumors (DT) are rare collagen-forming tumors that can exhibit locally aggressive patterns of behavior. The aim of this study was to evaluate the efficacy and...
INTRODUCTION
Desmoid tumors (DT) are rare collagen-forming tumors that can exhibit locally aggressive patterns of behavior. The aim of this study was to evaluate the efficacy and safety of treatment of DT with single-agent oral vinorelbine.
MATERIALS AND METHODS
A retrospective review of patients treated with vinorelbine 90 mg orally on days 1, 8, and 15 of a 28-day cycle from January 2004 to July 2019 was performed. Response was assessed using RECIST version 1.1. Descriptive statistics were employed.
RESULTS
A total of 29 patients were included. Response rate was 20.7% (6/29), and clinical benefit rate (response by RECIST 1.1 and/or clinical symptom improvement) was 65.5% (19/29). No patient experienced grade 3 or above toxicity. Common toxicities were grade 1-2 nausea (14/26, 48.3%), fatigue (9/26, 31.0%), and diarrhea (4/26, 13.8%).
CONCLUSION
Single-agent oral vinorelbine is an effective, safe, and well-tolerated treatment for DT. It represents a new oral alternative for management of DT.
Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Fibromatosis, Aggressive; Humans; Retrospective Studies; Treatment Outcome; Vinblastine; Vinorelbine
PubMed: 32918789
DOI: 10.1002/ONCO.13516 -
Frontiers in Oncology 2023Lung adenocarcinoma (LUAD) kills millions of people every year. Recently, FDA and researchers proved the significance of high tumor mutational burden (TMB) in treating...
A tumor mutational burden-derived immune computational framework selects sensitive immunotherapy/chemotherapy for lung adenocarcinoma populations with different prognoses.
BACKGROUND
Lung adenocarcinoma (LUAD) kills millions of people every year. Recently, FDA and researchers proved the significance of high tumor mutational burden (TMB) in treating solid tumors. But no scholar has constructed a TMB-derived computing framework to select sensitive immunotherapy/chemotherapy for the LUAD population with different prognoses.
METHODS
The datasets were collected from TCGA, GTEx, and GEO. We constructed the TMB-derived immune lncRNA prognostic index (TILPI) computing framework based on TMB-related genes identified by weighted gene co-expression network analysis (WGCNA), oncogenes, and immune-related genes. Furthermore, we mapped the immune landscape based on eight algorithms. We explored the immunotherapy sensitivity of different prognostic populations based on immunotherapy response, tumor immune dysfunction and exclusion (TIDE), and tumor inflammation signature (TIS) model. Furthermore, the molecular docking models were constructed for sensitive drugs identified by the pRRophetic package, oncopredict package, and connectivity map (CMap).
RESULTS
The TILPI computing framework was based on the expression of TMB-derived immune lncRNA signature (TILncSig), which consisted of AC091057.1, AC112721.1, AC114763.1, AC129492.1, LINC00592, and TARID. TILPI divided all LUAD patients into two populations with different prognoses. The random grouping verification, survival analysis, 3D PCA, and ROC curve (AUC=0.74) firmly proved the reliability of TILPI. TILPI was associated with clinical characteristics, including smoking and pathological stage. Furthermore, we estimated three types of immune cells threatening the survival of patients based on multiple algorithms. They were macrophage M0, T cell CD4 Th2, and T cell CD4 memory activated. Nevertheless, five immune cells, including B cell, endothelial cell, eosinophil, mast cell, and T cell CD4 memory resting, prolonged the survival. In addition, the immunotherapy response and TIDE model proved the sensitivity of the low-TILPI population to immunotherapy. We also identified seven intersected drugs for the LUAD population with poor prognosis, which included docetaxel, gemcitabine, paclitaxel, palbociclib, pyrimethamine, thapsigargin, and vinorelbine. Their molecular docking models and best binding energy were also constructed and calculated.
CONCLUSIONS
We divided all LUAD patients into two populations with different prognoses. The good prognosis population was sensitive to immunotherapy, while the people with poor prognosis benefitted from 7 drugs.
PubMed: 37456238
DOI: 10.3389/fonc.2023.1104137 -
Cancer Research and Treatment Apr 2024This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2...
PURPOSE
This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice.
MATERIALS AND METHODS
This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety.
RESULTS
A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%).
CONCLUSION
Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.
Topics: Female; Humans; Acrylamides; Aminoquinolines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Prospective Studies; Trastuzumab; Vinorelbine
PubMed: 37846468
DOI: 10.4143/crt.2023.786