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Cell Communication and Signaling : CCS Apr 2023Osteoarthritis (OA) is a multifactorial chronic disease primarily characterized by the degeneration of articular cartilage. Currently, there is a lack of effective... (Review)
Review
Osteoarthritis (OA) is a multifactorial chronic disease primarily characterized by the degeneration of articular cartilage. Currently, there is a lack of effective treatments for OA other than surgery. The exploration of the mechanisms of occurrence is important in exploring other new and effective treatments for OA. The current evidence shows that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a vital role in cytogenesis and is involved in OA progression. The terms "JAK2", "STAT3", and "Osteoarthritis"were used in a comprehensive literature search in PubMed to further investigate the relationship between the JAK2/STAT3 signaling pathway and OA. This review focuses on the role and mechanism of JAK2/STAT3 signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation. In addition, this review summarizes recent evidence of therapeutic approaches to treat OA by targeting the JAK2/STAT3 pathway to accelerate the translation of evidence into the progression of strategies for OA treatment. Video abstract.
Topics: Humans; Chondrocytes; Janus Kinase 2; STAT3 Transcription Factor; Signal Transduction; Cartilage, Articular; Osteoarthritis
PubMed: 37013568
DOI: 10.1186/s12964-023-01094-4 -
Critical Reviews in Oncology/hematology Apr 2021Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are treatments commonly used for lung cancer. The toxicity profile including toxicity incidence,... (Meta-Analysis)
Meta-Analysis Review
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are treatments commonly used for lung cancer. The toxicity profile including toxicity incidence, severity, and spectrum (involving various specific adverse events) of each EGFR-TKI are of particular clinical interest and importance. Data from phase II and III randomized controlled trials comparing treatments among EGFR-TKIs (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib) and chemotherapy for lung cancer were synthesized with Bayesian network meta-analysis. The primary outcome was systemic all-grade and grade ≥3 adverse events. The secondary outcome was specific all-grade adverse events including those of the skin, gastrointestinal tract, lung, etc. 40 trials randomizing 13,352 patients were included. Generally greater toxicity for dacomitinib and afatinib, and safety for icotinib were suggested. Furthermore, we found individual EGFR-TKIs had different toxicity spectrums. These findings provide a compelling safety reference for the individualized use of EGFR-TKIs for patients with lung cancer.
Topics: Bayes Theorem; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Network Meta-Analysis; Protein Kinase Inhibitors
PubMed: 33757838
DOI: 10.1016/j.critrevonc.2021.103305 -
Lung Cancer (Amsterdam, Netherlands) Oct 2023Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of... (Meta-Analysis)
Meta-Analysis Review
Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis.
OBJECTIVE
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making.
MATERIALS AND METHODS
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework.
RESULTS
Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs.
CONCLUSIONS
The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.
Topics: Humans; Anaplastic Lymphoma Kinase; Protein-Tyrosine Kinases; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Crizotinib; Network Meta-Analysis; Lung Neoplasms; Protein Kinase Inhibitors
PubMed: 37597303
DOI: 10.1016/j.lungcan.2023.107319 -
Journal of Chemotherapy (Florence,... Apr 2022Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and... (Meta-Analysis)
Meta-Analysis
Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor-naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis.
Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, = 0.03) and alectinib (Hazard ratio: 0.65, = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free survival than brigatinib (Hazard ratio: 0.57, = 0.03) and alectinib (Hazard ratio: 0.59, = 0.03) for ALK inhibitor-naive patients. Among lorlatinib, alectinib, brigatinib, and crizotinib, lorlatinib had the highest probability to reach the best overall confirmed response rates (probability of 48%) and intracranial confirmed response rates (probability of 44%). No significant difference was found among them in overall survival and adverse events analysis. In terms of progression free survival, our results indicated that lorlatinib was the best treatment choice for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. The future head-to-head trials assessing the relative efficacy of lorlatinib, alectinib and brigatinib were warranted.
Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 34139965
DOI: 10.1080/1120009X.2021.1937782 -
Clinical Lung Cancer Sep 2023MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was... (Review)
Review
INTRODUCTION
MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes.
METHODS
On June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC.
RESULTS
We included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy.
CONCLUSIONS
Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.
Topics: Aged; Humans; Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Exons; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met
PubMed: 37451931
DOI: 10.1016/j.cllc.2023.06.008 -
Current Oncology (Toronto, Ont.) Jan 2022Compound epidermal growth factor receptor () mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon mutations. We... (Review)
Review
Compound epidermal growth factor receptor () mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon mutations. We conducted a systematic review to investigate the available data on this patients' subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4-26% of total mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40-80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20-70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound mutations, taking into account different sensitivity profile of accompanying mutations for selecting the most adequate EGFR TKI for individual patients.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 35049698
DOI: 10.3390/curroncol29010024 -
Cancer Epidemiology Feb 2022Mutations in exons 18-21 of the epidermal growth factor receptor gene (EGFR) can confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with... (Review)
Review
Mutations in exons 18-21 of the epidermal growth factor receptor gene (EGFR) can confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small-cell lung cancer (NSCLC). Deletions in exon 19 or the exon 21 L858R substitution comprise approximately 85% of mutations, but comparatively few data are available on the remaining "uncommon" mutations. We conducted a systematic literature review to identify evidence on uncommon EGFR mutations in locally advanced/metastatic NSCLC (PROSPERO registration number: CRD42019126583). Electronic screening and congress searches identified studies published in 2012-2020 including patients with locally advanced/metastatic NSCLC and uncommon EGFR mutations (excluding T790M). We assessed the prevalence of uncommon mutations (in studies using direct sequencing of exons 18-21), and compared response to treatment and progression-free survival (PFS) in patients with common versus uncommon mutations and in those with exon 20 mutations versus other uncommon mutations. We identified 64 relevant studies. Uncommon mutations constituted 1.0-18.2% of all EGFR mutations, across 10 studies. The most frequently reported uncommon mutations were G719X (0.9-4.8% of all EGFR mutations), exon 20 insertions (Ex20ins; 0.8-4.2%), L861X (0.5-3.5%), and S768I (0.5-2.5%). Patients with common mutations typically experienced better treatment response and longer PFS on EGFR-TKIs than patients with uncommon mutations; Ex20ins mutations were associated with less favourable outcomes than other uncommon mutations. This review shows that uncommon mutations may comprise a clinically significant proportion of the EGFR mutations occurring in NSCLC, and highlights disparities in EGFR-TKI sensitivity between different uncommon mutations.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Prevalence; Protein Kinase Inhibitors
PubMed: 34922050
DOI: 10.1016/j.canep.2021.102080 -
Advanced Drug Delivery Reviews Jan 2020Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main...
Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main driver for diversity of skin pigmentation. Dark melanin acts to protect against the deleterious effects of ultraviolet (UV) radiation, including photo-aging and skin cancer formation. In turn, UV radiation activates skin melanocytes to induce further pigmentation (i.e., "tanning pathway"). The well-characterized MSH/MC1R-cAMP-MITF pathway regulates UV-induced melanization. Pharmacologic activation of this pathway ("sunless tanning") represents a potential strategy for skin cancer prevention, particularly in those with light skin or the "red hair" phenotype who tan poorly after UV exposure due to MC1R inactivating polymorphisms. Skin hyperpigmentation can also occur as a result of inflammatory processes and dermatological disorders such as melasma. While primarily of cosmetic concern, these conditions can dramatically impact quality of life of affected patients. Several topical agents are utilized to treat skin pigmentation disorders. Here, we review melanogenesis induced by UV exposure and the agents that target this pathway.
Topics: Administration, Cutaneous; Cyclic AMP; Dermatologic Agents; Drug Delivery Systems; Humans; Melanins; Pigmentation Disorders; Protein Kinases; Skin Pigmentation; Ultraviolet Rays
PubMed: 32092380
DOI: 10.1016/j.addr.2020.02.002 -
Cancer Apr 2023This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC). (Meta-Analysis)
Meta-Analysis
Efficacy and safety of first-line treatments for patients with advanced anaplastic lymphoma kinase mutated, non-small cell cancer: A systematic review and network meta-analysis.
BACKGROUND
This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC).
METHODS
A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed.
RESULTS
The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20-0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12-0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4-5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0-2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%).
CONCLUSIONS
For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit.
PLAIN LANGUAGE SUMMARY
Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non-small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Crizotinib; Anaplastic Lymphoma Kinase; Network Meta-Analysis; Bayes Theorem; Lactams, Macrocyclic; Protein Kinase Inhibitors
PubMed: 36748799
DOI: 10.1002/cncr.34664 -
ESMO Open Dec 2022Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments'... (Review)
Review
BACKGROUND
Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments' value. HR-QoL has been assessed in trials testing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in breast cancer (BC), using various questionnaires at different timepoints. HR-QoL reports from BC patients treated with CDK4/6i in the real-world setting are also available.
METHODS
We systematically reviewed the literature, searching for full-length articles, and selected conference abstracts reporting data on HR-QoL in BC patients at any stage and of any molecular subtype treated with abemaciclib, palbociclib or ribociclib.
RESULTS
A total of 533 full-length articles and 143 abstracts were retrieved. After screening for eligibility, 38 records were included (31 clinical trials; 7 real-world reports). Assessment methods were heterogeneous across studies in terms of questionnaires, evaluation timepoints and endpoints. Overall, adding CDK4/6i to endocrine therapy did not worsen patients' HR-QoL, with a positive trend towards pain improvement. Gastrointestinal scores (diarrhea, nausea and appetite loss) statistically favored the control arm among metastatic BC patients receiving abemaciclib, whereas they were superimposable in the early setting. The combination of palbociclib and endocrine therapy showed similar HR-QoL outcomes compared with endocrine therapy alone, but determined better scores compared with chemotherapy. HR-QoL was specifically assessed in premenopausal patients treated with ribociclib, showing similar scores compared with postmenopausal patients.
CONCLUSIONS
Despite methodological heterogeneity does not allow a proper comparison, HR-QoL was generally maintained with CDK4/6i. However, differences between abemaciclib, palbociclib and ribociclib exist and mainly rely on the distinct safety profiles of the compounds. These differences should be acknowledged and taken into account in the clinical practice.
Topics: Female; Humans; Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Quality of Life; Cyclin-Dependent Kinase 6; Protein Kinase Inhibitors
PubMed: 36399953
DOI: 10.1016/j.esmoop.2022.100629