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Oncotarget May 2016p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) expression appears to be predictive of prognosis in various solid tumors, though the evidence is not yet conclusive. We... (Meta-Analysis)
Meta-Analysis Review
p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) expression appears to be predictive of prognosis in various solid tumors, though the evidence is not yet conclusive. We therefore performed a meta-analysis to explore the relationship between PAK1 and prognosis in patients with solid tumors. Relevant publications were searched in several widely used databases, and 15 studies (3068 patients) were included in the meta-analysis. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between PAK1 and prognosis. Associations between PAK1 expression and prognosis were observed for overall survival (HR = 2.81, 95% CI = 1.07-7.39) and disease-specific survival (HR = 2.15, 95% CI = 1.47-3.16). No such association was detected for time to tumor progression (HR = 1.78, 95% CI = 0.99-3.21).Our meta-analysis thus indicates that PAK1 expression may be a predictive marker of overall survival and disease-specific survival in patients with solid tumors.
Topics: Biomarkers, Tumor; Disease-Free Survival; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Prognosis; p21-Activated Kinases
PubMed: 27027431
DOI: 10.18632/oncotarget.8320 -
American Journal of Cardiovascular... Jan 2024Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent ventricular dilatation and failure. New therapeutic targets are being investigated for their potential roles in improving PAH patients' symptoms and reversing pulmonary vascular pathology.
METHOD
We aimed to address the available knowledge from the published randomized controlled trials (RCTs) regarding the role of Rho-kinase (ROCK) inhibitors, bone morphogenetic protein 2 (BMP2) inhibitors, estrogen inhibitors, and AMP-activated protein kinase (AMPK) activators on the PAH evaluation parameters. This systematic review (SR) was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CDR42022340658) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS
Overall, 5092 records were screened from different database and registries; 8 RCTs that met our inclusion criteria were included. The marked difference in the study designs and the variability of the selected outcome measurement tools among the studies made performing a meta-analysis impossible. However, the main findings of this SR relate to the powerful potential of the AMPK activator and the imminent antidiabetic drug metformin, and the BMP2 inhibitor sotatercept as promising PAH-modifying therapies. There is a need for long-term studies to evaluate the effect of the ROCK inhibitor fasudil and the estrogen aromatase inhibitor anastrozole in PAH patients. The role of tacrolimus in PAH is questionable. The discrepancy in the hemodynamic and clinical parameters necessitates defining cut values to predict improvement. The differences in the PAH etiologies render the judgment of the therapeutic potential of the tested drugs challenging.
CONCLUSION
Metformin and sotatercept appear as promising therapeutic drugs for PAH.
CLINICAL TRIALS REGISTRATION
This work was registered in PROSPERO (CDR42022340658).
Topics: Humans; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; AMP-Activated Protein Kinases; Familial Primary Pulmonary Hypertension; Estrogens; Metformin
PubMed: 37945977
DOI: 10.1007/s40256-023-00613-5 -
Clinical Rheumatology Oct 2013The aim of the present study was to conduct a meta-analysis of the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, recently approved for the treatment... (Meta-Analysis)
Meta-Analysis Review
The aim of the present study was to conduct a meta-analysis of the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, recently approved for the treatment of active rheumatoid arthritis in patients who have failed previous treatment with methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, and other databases till 3 May 2013. All included studies were analyzed with the use of the Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Nine randomized controlled trials (RCTs) comparing tofacitinib with placebo were identified. Two of them additionally provided the comparison with adalimumab. However, only eight RCTs met the inclusion criteria for the meta-analysis. The overall results of the meta-analysis showed that tofacitinib provided a statistically significant improvement according to the response criteria (ACR20/50/70) after 12 weeks of treatment when compared to placebo (p < 0.00001). Moreover, it was demonstrated that tofacitinib was significantly superior to adalimumab in achieving the ACR50 response criteria at week 12 (p = 0.003). For the safety analysis, there were no statistically significant differences between tofacitinib-, adalimumab-, and placebo-treated patients in respect to the risk of serious adverse events or treatment discontinuation due to adverse reactions (p > 0.05). The findings of this systematic review with meta-analysis indicate that tofacitinib monotherapy or with background methotrexate provides early statistically significant and clinically important improvement in rheumatoid arthritis symptoms and has an acceptable safety profile comparable to that of placebo. The results of the present meta-analysis show that the frequency of serious adverse events was not increased after tofacitinib treatment. In addition, tofacitinib might provide an effective treatment option compared to intravenous or subcutaneous biological DMARDs, as suggested by the result of the comparison made regarding tofacitinib vs. adalimumab ACR50 response rate.
Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Inflammation; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 23877486
DOI: 10.1007/s10067-013-2329-9 -
European Journal of Endocrinology May 2015Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC... (Meta-Analysis)
Meta-Analysis Review
Therapy of endocrine disease: response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis.
CONTEXT
Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients.
METHODS
All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported.
RESULTS
In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity.
CONCLUSION
The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.
Topics: Antineoplastic Agents; Humans; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Thyroid Neoplasms
PubMed: 25572389
DOI: 10.1530/EJE-14-0788 -
Medicina (Kaunas, Lithuania) Nov 2022Background and Objectives: Lung cancer remains the most common malignancy worldwide. As the global population ages, the prevalence of epidermal growth factor receptor... (Review)
Review
Background and Objectives: Lung cancer remains the most common malignancy worldwide. As the global population ages, the prevalence of epidermal growth factor receptor (EGFR)-mutation-positive non-small cell lung cancer (NSCLC) is increasing. Materials and Methods: We performed a meta-analysis and a systematic review of randomized, controlled trials to evaluate the efficacy of EGFR TKIs on progression-free survival (PFS) and overall survival (OS) in older adult patients with advanced EGFR-mutated NSCLC. A total of 1327 patients were included; among these, 662 patients were >65 years of age. Results: A pooled analysis indicated (1) an overall improvement in higher PFS for dacomitinib and osimetinib than that for other drugs (hazard ratio [HR] = 0.654, 95% CI: 0.474 to 0.903; p = 0.01) and (2) and no significant difference in the OS between the EGFR TKIs (HR = 0.989, 95% CI: 0.796 to 1.229; p = 921). Conclusion: Our study found that osimertinib achieved a higher PFS than all other EGFR TKIs did. Osimertinib is the preferred EGFR TKI for treatment of older adult patients with advanced EGFR-mutated NSCLC.
Topics: Humans; Aged; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Protein Kinase Inhibitors
PubMed: 36422186
DOI: 10.3390/medicina58111645 -
Health Technology Assessment... May 2014Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours... (Review)
Review
Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer: a systematic review and cost-effectiveness analysis.
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy. Patients with NSCLC are therefore tested for EGFR-TK tumour gene mutations to inform treatment decisions. There are a variety of tests available to detect these mutations. The different tests vary in the specific mutations that they attempt to detect, the amount of tumour cells needed for the test to work, the time that it takes to give a result, the error rate of the test, and the cost of the test.
OBJECTIVE
To compare the performance and cost-effectiveness of EGFR-TK mutation tests used to identify previously untreated adults with locally advanced or metastatic NSCLC, who may benefit from first-line treatment with TKIs.
DATA SOURCES
Twelve databases to August 2012 [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment database (HTA), Science Citation Index (SCI), Latin American and Caribbean Health Sciences Literature (LILACS), BIOSIS Previews, NIHR Health Technology Assessment programme, PROSPERO (International Prospective Register of Systematic Reviews)], research registers and conference proceedings. A web-based survey gathered data on technical performance of EGFR-TK mutation tests.
METHODS
Randomised controlled trials were assessed for methodological quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using QUADAS-2. There were insufficient data for meta-analysis. For accuracy studies, we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data as relative risks, with 95% CIs. The health-economic analysis considered the long-term costs and quality-adjusted life-years (QALYs) associated with different tests followed by treatment with either standard chemotherapy or a TKI. Direct sequencing was taken as the comparator. The de novo model consisted of a decision tree and a Markov model.
RESULTS
The survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. Six studies provided data on the accuracy of EGFR-TK mutation testing for predicting response to treatment with TKIs. Estimates of accuracy were similar across studies. Six analyses provided data on the clinical effectiveness of TKIs compared with standard chemotherapy. There were no clear differences in the treatment effects reported by different studies, regardless of which EGFR mutation test was used to select patients. Cost-effectiveness analysis using 'Evidence on comparative effectiveness available' and 'Linked evidence' approaches: Therascreen(®) EGFR polymerase chain reaction (PCR) Kit (Qiagen, Venlo, the Netherlands) was both less effective and less costly than direct sequencing of all exon 19-21 mutations at an incremental cost-effectiveness ratio of £32,167 (comparative) and £32,190 (linked) per QALY lost. 'Assumption of equal prognostic value' approach: the lowest total strategy cost was [commercial-in-confidence (CiC) information has been removed] [Sanger sequencing or Roche cobas EGFR Mutation Testing Kit(®) (Roche Molecular Systems, Inc., Branchburg, NJ, USA)] compared with (CiC information has been removed) for the most expensive strategy (fragment length analysis combined with pyrosequencing).
LIMITATIONS
The cost-effectiveness analysis assumed that the differences in outcomes between the results of the trials were solely attributable to the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation.
CONCLUSION
There was no strong evidence that any one EGFR mutation test had greater accuracy than any other test. Re-testing of stored samples from previous studies, where patient outcomes are already known, could be used to provide information on the relative effectiveness of TKIs and standard chemotherapy in patients with EGFR mutation-positive and mutation-negative tumours, where mutation status is determined using tests for which adequate data are currently unavailable.
STUDY REGISTRATION
PROSPERO CRD42012002828.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoplasm Metastasis; Neoplasm Staging; Polymerase Chain Reaction; Protein Kinase Inhibitors; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Reproducibility of Results; Technology Assessment, Biomedical
PubMed: 24827857
DOI: 10.3310/hta18320 -
Expert Opinion on Drug Safety Jan 2017A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an... (Comparative Study)
Comparative Study Meta-Analysis Review
Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis.
BACKGROUND
A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately.
METHODS
The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed.
RESULTS
Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (OR:3.26; 95%CI:1.12 to 9.50), nilotinib (OR: 3.69; 95%CI:2.29 to 5.95) and dasatinib (OR:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (OR:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results.
CONCLUSIONS
Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.
Topics: Antineoplastic Agents; Dasatinib; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Vascular Diseases
PubMed: 27852118
DOI: 10.1080/14740338.2017.1261824 -
PloS One 2013The aim of this study was to assess the role of skin rash in predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the... (Meta-Analysis)
Meta-Analysis Review
Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis.
BACKGROUND
The aim of this study was to assess the role of skin rash in predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the prognosis of patients with non-small cell lung cancer (NSCLC).
METHOD
We systematically searched for eligible articles investigating the association between rash and the efficacy of EGFR-TKIs and the prognosis of patients with NSCLC. The summary risk ratio (RR) and hazard ratio (HR) were calculated using meta-analysis.
RESULTS
We identified 33 eligible trials involving 6,798 patients. We used two different standards to group the patients [standard 1: rash vs. no rash, standard 2: rash (≥ stage 2) vs. rash (stage 0, 1)]. For standard 1, the objective response rate (ORR) and disease control rate (DCR) of the rash group were significantly higher than the no rash group [RR = 3.28; 95% CI: 2.41-4.47(corrected RR = 2.225, 95% CI: 1.658-2.986); RR = 1.96, 95% CI: 1.58-2.43]. The same results were observed for standard 2. For standards 1 and 2, the progression-free survival (PFS) (HR = 0.45, 95% CI: 0.37-0.53; HR = 0.57, 95% CI: 0.50-0.65) and overall survival (OS) (HR = 0.40, 95% CI: 0.28-0.52; HR = 0.53, 95% CI: 0.35-0.71) of the rash group were significantly longer than the control group, and the same results were observed in the subgroup analysis.
CONCLUSIONS
skin rash after EGFR-TKI treatment may be an efficient clinical marker for predicting the response of patients with NSCLC to EGFR-TKIs. Furthermore, skin rash is also the prognostic factor of patients with NSCLC. Patients with skin rash have a longer PFS and OS.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Exanthema; Humans; Lung Neoplasms; Prognosis; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 23383079
DOI: 10.1371/journal.pone.0055128 -
PloS One 2015The Death-Associated Protein Kinase 1 (DAPK1) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The Death-Associated Protein Kinase 1 (DAPK1) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic review and a meta-analysis in order to evaluate DAPK1 promoter methylation as an epigenetic marker for CC risk.
METHODS
A systematic literature search was carried out. The Cochrane software package Review Manager 5.2 was used. The fixed-effects or random-effects models, according to heterogeneity across studies, were used to calculate odds ratios (ORs) and 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by histological type, assays used to evaluate DAPK1 promoter methylation, and control sample source.
RESULTS
A total of 20 papers, published between 2001 and 2014, on 1929 samples, were included in the meta-analysis. DAPK1 promoter methylation was associated with an increased CC risk based on the random effects model (OR: 21.20; 95%CI = 11.14-40.35). Omitting the most heterogeneous study, the between study heterogeneity decreased and the association increased (OR: 24.13; 95% CI = 15.83-36.78). The association was also confirmed in all the subgroups analyses.
CONCLUSIONS
A significant strong association between DAPK1 promoter methylation and CC was shown and confirmed independently by histological tumor type, method used to evaluate methylation and source of control samples. Methylation markers may have value in early detection of CC precursor lesions, provide added reassurances of safety for women who are candidates for less frequent screens, and predict outcomes of women infected with human papilloma virus.
Topics: DNA Methylation; Death-Associated Protein Kinases; Female; Humans; Odds Ratio; Promoter Regions, Genetic; Risk; Uterine Cervical Neoplasms
PubMed: 26267895
DOI: 10.1371/journal.pone.0135078 -
Journal of Cancer Research and Clinical... Jul 2017Most randomized clinical trials evaluating second generation tyrosine kinase inhibitors (TKI) for the first-line treatment of Chronic Myeloid Leukemia used as comparator... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Most randomized clinical trials evaluating second generation tyrosine kinase inhibitors (TKI) for the first-line treatment of Chronic Myeloid Leukemia used as comparator the 'standard' dose of 400 mg imatinib daily. Several studies showed higher rates of major molecular remission (MMR) at 12 months with 800 mg compared to 400 mg, suggesting that high-dose imatinib may be the appropriate comparator rather than 400 mg.
METHODS
We systematically reviewed randomized trials comparing the two dosages, calculated a common estimator and compared the result to a common estimator of trials evaluating a second generation TKI in comparison with 400 mg imatinib daily.
RESULTS
We identified three trials comparing 400-800 mg imatinib resulting in a common relative risk of 1.30 (1.13-1.49) and indicating a significantly higher rate of MMR in patients treated with 800 mg imatinib (p = 0.0003). We identified five trials comparing 400 mg imatinib daily to a second generation TKI. The common relative risk for MMR at 12 months was 1.69 (1.50-1.90, p < 0.0001). Differences in the prognostic profiles precluded a direct comparison of the common efficacy estimates.
CONCLUSIONS
We conclude that imatinib was probably not licensed at the optimal dose initially. We suggest that in the future, new TKIs are compared with a higher dose of imatinib. In addition, high-dose imatinib should be considered more often for routine clinical decisions based on the characteristics of the individual patient.
Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Protein-Tyrosine Kinases
PubMed: 28275866
DOI: 10.1007/s00432-017-2385-7