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Cancer Investigation Sep 2023RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered... (Review)
Review
RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered tumors. We searched PubMed, Embase, Cochrane, WOS, and Clinicaltrials.gov. Objective-response, complete-response, and partial-response were 60-89%, 0-11%, and 55-89%, respectively, with the use of RET-specific drugs. ≥Grade 3 adverse events were seen in 28-53% of the patients, with hypertension, change in ALT, QT prolongation, neutropenia, and pneumonitis among the common side effects. Hence, selpercatinib and pralsetinib were effective and well tolerated by most of the patients with RET-altered tumors.
Topics: Humans; Neoplasms; Drug-Related Side Effects and Adverse Reactions; Hypertension; Neutropenia; Protein Kinase Inhibitors; Lung Neoplasms; Proto-Oncogene Proteins c-ret
PubMed: 37782113
DOI: 10.1080/07357907.2023.2255655 -
CNS Neuroscience & Therapeutics Aug 2023Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological activities, among which circular RNAs (circRNAs) have been proven to be more tissue-specific and conservative. Many recent studies found the potential of circRNAs as biomarkers for many diseases, including cardiovascular diseases, cancers, and ischemic stroke. This systemic review and meta-analysis aimed to identify circRNAs as potential biomarkers for AIS.
METHODS
This study has been prospectively registered in PROSPERO (Registration No. 11 CRD42021288033). Published literature comparing circRNA expression profiles between AIS and non-AIS in human and animal models were retrieved from the articles published by January 2023 in major databases. We descriptively summarized the included studies, conducted meta-analysis under a random effects model, and did bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.
RESULTS
Totally 23 studies were included, reporting 18 distinctive upregulated and 20 distinctive downregulated circRNAs. Diagnostic meta-analysis indicated discriminative ability of the circRNAs. Furthermore, circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1 were reported with the same regulation trend in more than one study (animal studies included). GO and KEGG enrichment analyses indicated that the target genes of these five circRNAs were enriched in regulating cell proliferation, apoptosis, and oxidative stress.
CONCLUSIONS
This study demonstrates that circRNAs (circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1) generally are promising as potential biomarkers for AIS. However, due to the limited number of studies, diagnostic value of individual circRNA could not be validated. More in vitro and in vivo functional studies are needed.
Topics: Animals; Humans; RNA, Circular; Ischemic Stroke; Stroke; Biomarkers; MicroRNAs; RNA; Gene Expression Profiling; Protein Serine-Threonine Kinases
PubMed: 37186176
DOI: 10.1111/cns.14220 -
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 -
BMC Cancer Nov 2023RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS
We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS
Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS
In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
Topics: Humans; Prognosis; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); ErbB Receptors; Antibodies, Monoclonal; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Mutation; MicroRNAs; Biomarkers, Tumor
PubMed: 37974093
DOI: 10.1186/s12885-023-11600-z -
Radiotherapy and Oncology : Journal of... Sep 2023In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings.
MATERIALS AND METHODS
This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT.
RESULTS
After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low.
CONCLUSION
Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Trastuzumab; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Maytansine; Treatment Outcome; Breast Neoplasms
PubMed: 37437610
DOI: 10.1016/j.radonc.2023.109805 -
International Journal of Molecular... Nov 2023Studying primary melanoma and its corresponding metastasis has twofold benefits. Firstly, to better understand tumor biology, and secondly, to determine which sample... (Meta-Analysis)
Meta-Analysis Review
Studying primary melanoma and its corresponding metastasis has twofold benefits. Firstly, to better understand tumor biology, and secondly, to determine which sample should be examined in assessing drug targets. This study systematically analyzed all the literature on primary melanoma and its matched metastasis. Following PRISMA guidelines, we searched multiple medical databases for relevant publications from January 2000 to December 2022, assessed the quality of the primary-level studies using the QUIPS tool, and summarized the concordance rate of the most reported genes using the random-effects model. Finally, we evaluated the inter-study heterogeneity using the subgroup analysis. Thirty-one studies investigated the concordance of and in 1220 and 629 patients, respectively. The pooled concordance rate was 89.4% [95% CI: 84.5; 93.5] for and 97.8% [95% CI: 95.8; 99.4] for . When high-quality studies were considered, only mutation status consistency increased. Five studies reported the concordance status of c (93%, 44 patients) and promoter (64%, 53 patients). Lastly, three studies analyzed the concordance of cancer genes involved in the signaling pathways, apoptosis, and proliferation, such as (25%, four patients), (44%, nine patients), and (20%, five patients). Our study found that the concordance of known drug targets (mainly ) during melanoma progression is higher than in previous meta-analyses, likely due to advances in molecular techniques. Furthermore, significant heterogeneity exists in the genes involved in the melanoma genetic makeup; although our results are based on small patient samples, more research is necessary for validation.
Topics: Humans; Melanoma; Skin Neoplasms; Proto-Oncogene Proteins B-raf; Mutation; Melanoma, Cutaneous Malignant
PubMed: 38003476
DOI: 10.3390/ijms242216281 -
European Journal of Medical Research Aug 2023The aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
METHODS
We conducted a systematic review and meta-analysis to aggregate the clinical outcomes of patients with LM from EGFR-mutant NSCLC treated with osimertinib. A comprehensive literature search for published and unpublished studies was implemented in April 2021 of PubMed, EMBASE, the Cochrane Library, and several international conference databases, in accordance with the PRISMA guidelines. Meta-analysis of proportions was conducted to calculate the pooled rate of overall response rate (ORR), disease control rate (DCR), one-year overall survival (OS), and adverse events (AEs).
RESULTS
A total of eleven studies (five prospective and six retrospective) including 353 patients were included. The majority of patients (346/353, 98.0%) received osimertinib as ≥ 2nd-line treatment for LM, either at a dosage of 80 mg (161/353, 45.6%) or 160 mg (191/353, 54.1%). The pooled rates of ORR and DCR were 42% (95% CI 24% to 59%) and 93% (95% CI 88% to 97%), respectively. The pooled one-year OS rate was 59% (95% CI 53% to 65%) in 233 patients from five studies. The highest incidence of AEs of all grades was rash (53%), followed by diarrhea (45%), paronychia (35%), decreased appetite (35%), and dry skin (27%), based on data from four studies.
CONCLUSIONS
Our study highlighted and confirmed the meaningful efficacy and a manageable safety profile of osimertinib for the treatment of LM from EGFR-mutant advanced NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Retrospective Studies; Prospective Studies; Antineoplastic Agents; ErbB Receptors; Protein Kinase Inhibitors; Mutation
PubMed: 37542339
DOI: 10.1186/s40001-023-01219-y -
European Journal of Cancer (Oxford,... Sep 2023The recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate the following: i) what is the optimal neoadjuvant regimen and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate the following: i) what is the optimal neoadjuvant regimen and ii) whether anthracyclines could be excluded.
METHODS
A systematic literature search in Medline, Embase and Web of Science databases was performed. Studies had to satisfy the following criteria: i) randomised controlled trials (RCTs), ii) enroled patients treated preoperatively for HER2-positive BC (breast cancer), iii) at least one treatment group received an anti-HER2 agent, iv) available information of any efficacy end-point and v) published in English. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. Pathologic complete response (pCR), event-free survival (EFS) and overall survival (OS) were the efficacy end-points of interest, and selected safety end-points were also analysed.
RESULTS
A total of 11,049 patients with HER2-positive BC (46 RCTs) were included in the network meta-analysis, and 32 different regimens were evaluated. Dual anti-HER2-therapy, with pertuzumab or tyrosine kinase inhibitors, combined with chemotherapy was significantly superior to trastuzumab and chemotherapy in terms of pCR, EFS and OS. However, a higher risk of cardiotoxicity was observed with dual anti-HER2-therapy. Anthracycline-based chemotherapy was not associated with better efficacy outcomes in comparison with non-anthracycline-based chemotherapy. In anthracycline-free regimens, the addition of carboplatin presented numerically better efficacy outcomes.
CONCLUSION
Dual HER2 blockade with chemotherapy is the recommended choice as neoadjuvant therapy for HER2-positive breast cancer, preferably by omitting anthracyclines in favour of carboplatin.
Topics: Humans; Female; Neoadjuvant Therapy; Carboplatin; Network Meta-Analysis; Receptor, ErbB-2; Breast Neoplasms; Trastuzumab; Antibiotics, Antineoplastic; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37142539
DOI: 10.1016/j.ejca.2023.03.042 -
Journal of Clinical PsychopharmacologyThis systematic review aimed to investigate the clinical manifestations and characteristics of venlafaxine-associated rhabdomyolysis.
PURPOSE
This systematic review aimed to investigate the clinical manifestations and characteristics of venlafaxine-associated rhabdomyolysis.
METHODS
A systematic search was conducted in PubMed, Elsevier, Science Direct, Embase, Springer Link, Wiley Online Library, CNKI, and Wanfang databases from the date of database inception to January 2023. Previously reported cases of venlafaxine-associated rhabdomyolysis were identified, and relevant data from these cases were collected for descriptive statistical analysis. Cases that met the inclusion criteria were evaluated to determine the correlation between adverse reactions and venlafaxine.
RESULTS
A total of 12 patients with venlafaxine-associated rhabdomyolysis were included. None of these patients had a history of muscle pain or discomfort. Of the 12 patients, 5 patients received venlafaxine at doses of ≤225 mg/d, whereas the remaining 7 patients received doses exceeding 225 mg/d. The main clinical symptoms included myalgia, muscle weakness, and renal injury. All 12 patients discontinued venlafaxine and received symptomatic care.
CONCLUSIONS
Venlafaxine, used either as a monotherapy or in combination with other drugs, may be associated with rhabdomyolysis. Creatine kinase levels may normalize or significantly decrease after discontinuation of venlafaxine and symptomatic treatment.
Topics: Rhabdomyolysis; Venlafaxine Hydrochloride; Humans; Male; Adult; Female; Middle Aged; Creatine Kinase; Myalgia
PubMed: 38506608
DOI: 10.1097/JCP.0000000000001838 -
Endocrine-related Cancer Aug 2023Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown advantages in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-)... (Meta-Analysis)
Meta-Analysis
Adjuvant and neoadjuvant therapy with cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and meta-analysis.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown advantages in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This study aimed to evaluate the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy (ET) in patients with HR+, HER2- early breast cancer. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials (RCTs) related to CDK4/6 inhibitors combined with ET. Literature conforming to the research content was identified according to the inclusion and exclusion criteria. The efficacy endpoints included invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) with adjuvant therapy. The efficacy endpoint of neoadjuvant therapy was complete cell cycle arrest (CCCA). The safety outcomes included the incidence of adverse events (AEs) and grade 3-4 hematological and non-hematological AEs. Data analysis was performed using Review Manager software (version 5.3). A statistical model (fixed-effects model or random-effects model) was selected based on the level of heterogeneity, and a sensitivity analysis was performed if strong heterogeneity existed. Subgroup analyses were performed based on the baseline patient characteristics. Nine articles (including six RCTs) were included in the study. In adjuvant therapy, compared with the control group, CDK4/6 inhibitors combined with ET showed no statistically significant difference in IDFS (hazard ratio = 0.83, 95% confidence interval (CI) = 0.64-1.08, P = 0.17) and DRFS (hazard ratio = 0.83, 95% CI = 0.52-1.31, P = 0.42). In neoadjuvant therapy, CDK4/6 inhibitors combined with ET significantly improved CCCA compared with the control group (odds ratio = 9.00, 95% CI = 5.42-14.96, P < 0.00001). In terms of safety, the combination treatment group had a significantly increased incidence of grade 3-4 hematological AEs in patients, especially grade 3-4 neutropenia (risk ratio (RR) = 63.90, 95% CI = 15.44-264.41, P < 0.00001) and grade 3-4 leukopenia (RR = 85.89, 95% CI = 19.12-385.77, P < 0.00001), with statistically significant differences. In patients with HR+, HER2- early breast cancer, the addition of CDK4/6 inhibitors may prolong IDFS and DRFS in adjuvant therapy, especially in high-risk patients. Further follow-up is needed to establish whether OS can be improved with CDK4/6 inhibitors plus ET. CDK4/6 inhibitors also showed effective anti-tumor proliferation activity in neoadjuvant therapy. Regular monitoring of routine blood tests in patients using CDK4/6 inhibitors is essential.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Protein Kinase Inhibitors
PubMed: 37283514
DOI: 10.1530/ERC-22-0365