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Archives of Cardiovascular Diseases 2020The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK)... (Meta-Analysis)
Meta-Analysis
Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.
BACKGROUND
The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized.
AIM
To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting.
METHODS
We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data.
RESULTS
MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach.
CONCLUSIONS
In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.
Topics: Adverse Drug Reaction Reporting Systems; Aged; Antineoplastic Agents; Cardiovascular Diseases; Databases, Factual; Female; Fibrosarcoma; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Patient Safety; Pharmacovigilance; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 32418884
DOI: 10.1016/j.acvd.2020.03.014 -
The International Journal of Biological... Jun 2021The study aims to provide a comprehensive account of the association of five gene polymorphisms (rs1380576, rs1563828, rs10900598, rs11801299, and rs4245739) with... (Meta-Analysis)
Meta-Analysis
PURPOSE
The study aims to provide a comprehensive account of the association of five gene polymorphisms (rs1380576, rs1563828, rs10900598, rs11801299, and rs4245739) with susceptibility to cancer.
METHODS
A literature search for eligible candidate gene studies published before 27 February 2021 was conducted in PubMed, Medline and Web of Science. The following combinations of main keywords were used: (MDM4 OR MDMX OR HDMX OR mouse double minute 4 homolog) AND (polymorphism OR mutation OR variation OR SNP OR genotype) AND (cancer OR tumor OR neoplasm OR malignancy OR carcinoma OR adenocarcinoma). Potential sources of heterogeneity were sought out via meta-regression, subgroup and sensitivity analysis.
RESULTS
Overall, a total of 15 articles with 21,365 cases and 29,280 controls for five polymorphisms of the gene were enrolled. In the stratified analysis of rs1380576, we found that Asians might have less susceptibility to cancer. We found that rs4245739 was correlated with a decreased risk of cancer for Asians and breast cancer susceptibility. However, for other polymorphisms, the results showed no significant association with cancer risk.
CONCLUSION
rs1380576 polymorphism is negatively associated with the risk of cancer in the Asian population. rs4245739 polymorphism is inversely associated with cancer risk for Asians and breast cancer susceptibility.
Topics: Animals; Cell Cycle Proteins; Female; Genetic Predisposition to Disease; Humans; Mice; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins
PubMed: 34347554
DOI: 10.1177/17246008211033874 -
Diagnostic Pathology Mar 2023Epithelioid and spindle rhabdomyosarcoma (ES-RMS) with TFCP2 rearrangement is a recently discovered rare variant of rhabdomyosarcoma composed of epithelioid and spindle...
BACKGROUND
Epithelioid and spindle rhabdomyosarcoma (ES-RMS) with TFCP2 rearrangement is a recently discovered rare variant of rhabdomyosarcoma composed of epithelioid and spindle cells, because it shows extraordinarily adverse prognosis and is easily misdiagnosed as other epithelioid or spindle cell tumors.
METHODS
A rare case of ES-RMS with TFCP2 rearrangement was presented and English literatures in Pubmed online up to 01 July 2022 were gathered by two authors for a systematic review according to the inclusion and exclusion criteria.
CASE PRESENTATION/RESULTS
We report a case of ES-RMS in an early 30s-years-old female, the neoplastic cells are remarkably immunoreactive with CK(AE1/AE3), and partially with ALK protein. Unexpectedly, the tumor shows TFCP2 rearrangement with coexistence of increased copy numbers of EWSR1 and ROS1 gene and MET gene mutation. Besides, Next-generation sequencing for genetic mutational profiling revealed frequent MET exon14 mutations in chromosome 7, most of which are C > T nonsynonymous SNV, and exon42 of ROS1 in chromosome 6 showed frequent G > T mutation up to 57.54%. In addition, neither MyoD1 mutation nor gene fusions were detected. Moreover, the patient shows high tumor mutational burden (TMB) up to 14.11 counts/Mb. Finally, as many cases of ES-RMS including our case had local progression or metastasis, we find, similar to epithelioid rhabdomyosarcoma (median survival time is 10 month), ES-RMS shows a more aggressive behavior and adverse prognosis (median survival time is 17 month) than spindle cell/sclerosing rhabdomyosarcoma (median survival time is 65 month) according previous studies.
CONCLUSIONS
ES-RMS with TFCP2 rearrangement is a rare malignant tumor and easily confused with other epithelioid or spindle cell tumors, it may harbor additional gene alteration in addition to TFCP2 rearrangement, such as MET mutation, increased copy numbers of EWSR1 and ROS1 gene, high TMB. Most importantly, it may show very poor outcome with extensive metastasis.
Topics: Humans; Female; Adult; Abdominal Wall; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Transcription Factors; Rhabdomyosarcoma; Prognosis; Biomarkers, Tumor; DNA-Binding Proteins
PubMed: 36998041
DOI: 10.1186/s13000-023-01330-y -
Value in Health : the Journal of the... Jan 2020Monoclonal antibodies against epidermal growth factor receptor (EGFR) have proved beneficial for the treatment of metastatic colorectal cancer (mCRC), particularly when...
BACKGROUND
Monoclonal antibodies against epidermal growth factor receptor (EGFR) have proved beneficial for the treatment of metastatic colorectal cancer (mCRC), particularly when combined with predictive biomarkers of response. International guidelines recommend anti-EGFR therapy only for RAS (NRAS,KRAS) wild-type tumors because tumors with RAS mutations are unlikely to benefit.
OBJECTIVES
We aimed to review the cost-effectiveness of RAS testing in mCRC patients before anti-EGFR therapy and to assess how well economic evaluations adhere to guidelines.
METHODS
A systematic review of full economic evaluations comparing RAS testing with no testing was performed for articles published in English between 2000 and 2018. Study quality was assessed using the Quality of Health Economic Studies scale, and the British Medical Journal and the Philips checklists.
RESULTS
Six economic evaluations (2 cost-effectiveness analyses, 2 cost-utility analyses, and 2 combined cost-effectiveness and cost-utility analyses) were included. All studies were of good quality and adopted the perspective of the healthcare system/payer; accordingly, only direct medical costs were considered. Four studies presented testing strategies with a favorable incremental cost-effectiveness ratio under the National Institute for Clinical Excellence (£20 000-£30 000/QALY) and the US ($50 000-$100 000/QALY) thresholds.
CONCLUSIONS
Testing mCRC patients for RAS status and administering EGFR inhibitors only to patients with RAS wild-type tumors is a more cost-effective strategy than treating all patients without testing. The treatment of mCRC is becoming more personalized, which is essential to avoid inappropriate therapy and unnecessarily high healthcare costs. Future economic assessments should take into account other parameters that reflect the real world (eg, NRAS mutation analysis, toxicity of biological agents, genetic test sensitivity and specificity).
Topics: Antineoplastic Agents, Immunological; Clinical Decision-Making; Colorectal Neoplasms; Cost-Benefit Analysis; DNA Mutational Analysis; Drug Costs; ErbB Receptors; Genes, ras; Genetic Predisposition to Disease; Health Care Costs; Humans; Mutation; Neoplasm Metastasis; Patient Selection; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Precision Medicine; Predictive Value of Tests; Quality-Adjusted Life Years
PubMed: 31952666
DOI: 10.1016/j.jval.2019.07.009 -
Pathobiology : Journal of... 2021The aim of this study was to assess the relationship of cluster of differentiation 117 (CD117) expression with the clinicopathological characteristics and the prognosis... (Meta-Analysis)
Meta-Analysis
The aim of this study was to assess the relationship of cluster of differentiation 117 (CD117) expression with the clinicopathological characteristics and the prognosis in patients with non-small cell lung cancer (NSCLC). No meta-analysis concerning the correlation of CD117 expression with clinical and prognostic values of the patients with NSCLC is reported. A systematic literature search was conducted to achieve eligible studies. The combined odds ratios (ORs) or hazard ratios (HRs: multivariate Cox analysis) with their 95% confidence intervals (CIs) were calculated in this analysis. Final 17 eligible studies with 4,893 NSCLC patients using immunohistochemical detection were included in this meta-analysis. CD117 expression was not correlated with gender (male vs. female), clinical stage (stages 3-4 vs. stages 1-2), tumor grade (grade 3 vs. grades 1-2), T-stage (T-stages 3-4 vs. T-stages 0-2), distal metastasis, and disease-free survival (DFS) of NSCLC (all p values >0.05). CD117 expression was associated with lymph node metastasis (positive vs. negative: OR = 0.74, 95% CI = 0.56-0.97, p = 0.03), histological type (adenocarcinoma (AC) versus squamous cell carcinoma (SCC): OR = 1.74, 95% CI = 1.26-2.39, p = 0.001), and a worse overall survival (OS) (HR = 1.89, 95% CI = 1.22-2.92, p = 0.004). The expression of CD117 was significantly higher in AC than in SCC. CD117 may be an independent prognostic indicator for worse OS in NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Cell Differentiation; Humans; Neoplasm Staging; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins c-kit
PubMed: 34107476
DOI: 10.1159/000514386 -
Medicina (Kaunas, Lithuania) Jun 2020The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein...
The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein and a key modulator of the programmed cell death (PCD) pathways. The current study evaluates the clinical evidence on Bcl-2 and neurological recovery in patients after traumatic brain injury (TBI). All studies in English were queried from the National Library of Medicine PubMed database using the following search terms: (B-cell lymphoma 2/Bcl-2/Bcl2) AND (brain injury/head injury/head trauma/traumatic brain injury) AND (human/patient/subject). There were 10 investigations conducted on Bcl-2 and apoptosis in TBI patients, of which 5 analyzed the pericontutional brain tissue obtained from surgical decompression, 4 studied Bcl-2 expression as a biomarker in the cerebrospinal fluid (CSF), and 1 was a prospective randomized trial. Immunohistochemistry (IHC) in 94 adults with severe TBI showed upregulation of Bcl-2 in the pericontusional tissue. Bcl-2 was detected in 36-75% of TBI patients, while it was generally absent in the non-TBI controls, with Bcl-2 expression increased 2.9- to 17-fold in TBI patients. Terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL) positivity for cell death was detected in 33-73% of TBI patients. CSF analysis in 113 TBI subjects (90 adults, 23 pediatric patients) showed upregulation of Bcl-2 that peaked on post-injury day 3 and subsequently declined after day 5. Increased Bcl-2 in the peritraumatic tissue, rising CSF Bcl-2 levels, and the variant allele of are associated with improved mortality and better outcomes on the Glasgow Outcome Score (GOS). Bcl-2 is upregulated in the pericontusional brain and CSF in the acute period after TBI. Bcl-2 has a neuroprotective role as a pro-survival protein in experimental models, and increased expression in patients can contribute to improvement in clinical outcomes. Its utility as a biomarker and therapeutic target to block neuronal apoptosis after TBI warrants further evaluation.
Topics: Apoptosis; Biomarkers; Brain Injuries, Traumatic; Humans; Lymphoma, B-Cell; Proto-Oncogene Proteins c-bcl-2
PubMed: 32570722
DOI: 10.3390/medicina56060300 -
Medicine Oct 2020Recently, increased expression of TET1 has been shown to inhibit tumor development in many studies. Therefore, a meta-analysis was conducted to assess the prognostic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recently, increased expression of TET1 has been shown to inhibit tumor development in many studies. Therefore, a meta-analysis was conducted to assess the prognostic role of TET1 in solid tumors.
METHODS
PubMed, Embase, and the Web of Science (last updated on June 13, 2019) were searched and 16 eligible studies involving 3100 patients were eventually taken forward into the meta-analysis.
RESULTS
Pooled results indicated that higher TET1 expression in cancer tissues was associated with improved overall survival (OS) [hazard ratio (HR) = 0.736, 95% confidence interval (95% CI) = 0.542-0.998, P = .049]. In the subgroup analysis, higher TET1 expression in respiratory tumors (HR = 0.778, 95% CI = 0.639-0.946, P = .012) and breast cancer in Asian patients (HR = 0.326, 95% CI = 0.199-0.533, P < .001) were significantly associated with better OS. In addition, the association between high TET1 expression and prolonged OS was also statistically significant in the following subgroups; data source from samples (HR = 0.561, 95% CI = 0.384-0.819, P = .003), reported in text (HR = 0.539, 95% CI = 0.312-0.931, P = .027), TET1 protein (HR = 0.635, 95% CI = 0.409-0.984, P = .042), Asians (HR = 0.563, 95% CI = 0.376-0.844, P = .005).
CONCLUSION
This meta-analysis displays that high expression levels of TET1 in tissues is significantly associated with better survival in patients with solid tumors. This finding can be used as evidence to the tone that TET1 may be a useful target for the treatment of patients with solid tumors in the future.
Topics: Biomarkers, Tumor; Disease-Free Survival; Gene Expression; Humans; Mixed Function Oxygenases; Neoplasms; Predictive Value of Tests; Prognosis; Proto-Oncogene Proteins
PubMed: 33126331
DOI: 10.1097/MD.0000000000022863 -
European Journal of Pediatric Surgery :... Oct 2021The prognosis of stage 4S/MS neuroblastoma has traditionally been reported as excellent, yet conflicting treatment protocols exist for this enigmatic disease. To...
INTRODUCTION
The prognosis of stage 4S/MS neuroblastoma has traditionally been reported as excellent, yet conflicting treatment protocols exist for this enigmatic disease. To critically address this question, we have undertaken a systematic review of published studies to accurately determine outcomes for infants with stage 4S/MS neuroblastoma.
MATERIALS AND METHODS
Studies were identified using MEDLINE, Embase, and Cochrane databases using the relevant search terms. Literature reviews, case reports, and adult studies were excluded. Data were extracted independently following article selection by three authors and reviewed by the senior author.
RESULTS
The original search retrieved 2,325 articles. Following application of exclusion criteria and removing duplicate data, 37 studies (1,105 patients) were included for final review. Overall patient survival was 84%. Twelve studies (544 patients) recorded MYCN status. Mortality in MYCN amplified tumors was 56%. Chromosome 1p/11q status was reported in four studies and 1p/11q deletion carried a 40% fatality rate. Management included observation only (201 patients, 8.5% mortality), surgical resection of primary tumor only (153 patients, 6.5% mortality), chemotherapy only (186 patients, 21% mortality), radiotherapy (5 deaths, 33% mortality), chemotherapy with surgery (160 patients, 10% mortality), surgery with radiotherapy (21 patients, 19% mortality), radiotherapy with chemotherapy (42 patients, 29% mortality), and surgery with chemotherapy and radiotherapy (27 patients, 33% mortality).
CONCLUSION
There is a significant mortality observed in stage 4S/MS neuroblastoma infants with a dismal outcome observed in those patients with MYCN amplification and 1p/11q deletion. Those patients suitably amenable for conservative management or surgery to excise the primary tumor carry the best prognosis.
Topics: Humans; Infant; Infant, Newborn; N-Myc Proto-Oncogene Protein; Neoplasm Staging; Neuroblastoma
PubMed: 32932540
DOI: 10.1055/s-0040-1716836 -
PloS One 2022Early-life adversity (ELA) causes long-lasting structural and functional changes to the brain, rendering affected individuals vulnerable to the development of... (Meta-Analysis)
Meta-Analysis
Early-life adversity (ELA) causes long-lasting structural and functional changes to the brain, rendering affected individuals vulnerable to the development of psychopathologies later in life. Immediate-early genes (IEGs) provide a potential marker for the observed alterations, bridging the gap between activity-regulated transcription and long-lasting effects on brain structure and function. Several heterogeneous studies have used IEGs to identify differences in cellular activity after ELA; systematically investigating the literature is therefore crucial for comprehensive conclusions. Here, we performed a systematic review on 39 pre-clinical studies in rodents to study the effects of ELA (alteration of maternal care) on IEG expression. Females and IEGs other than cFos were investigated in only a handful of publications. We meta-analyzed publications investigating specifically cFos expression. ELA increased cFos expression after an acute stressor only if the animals (control and ELA) had experienced additional hits. At rest, ELA increased cFos expression irrespective of other life events, suggesting that ELA creates a phenotype similar to naïve, acutely stressed animals. We present a conceptual theoretical framework to interpret the unexpected results. Overall, ELA likely alters IEG expression across the brain, especially in interaction with other negative life events. The present review highlights current knowledge gaps and provides guidance to aid the design of future studies.
Topics: Animals; Brain; Cytoskeletal Proteins; Early Growth Response Protein 1; Gene Expression; Genes, Immediate-Early; Male; Nerve Tissue Proteins; Proto-Oncogene Proteins c-fos; Rodentia; Stress, Psychological
PubMed: 35025862
DOI: 10.1371/journal.pone.0253406 -
Molecular Diagnosis & Therapy Mar 2021Understanding molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC) has considerably improved in the last decades. As a result, novel therapeutic...
BACKGROUND
Understanding molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC) has considerably improved in the last decades. As a result, novel therapeutic strategies have evolved, amongst which are epidermal growth factor receptor (EGFR)-targeted therapies. With the exception of cetuximab, targeted therapies for HNSCC have not yet been introduced into clinical practice. One important aspect of new treatment regimes in clinical practice is presence of robust biomarkers predictive for therapy response.
METHODS
We performed a systematic search in PubMed, Embase and the Cochrane library. Articles were included if they investigated a biomarker for targeted therapy in the EGFR-PI3K-AKT-mTOR-pathway.
RESULTS
Of 83 included articles, 52 were preclinical and 33 were clinical studies (two studies contained both a preclinical and a clinical part). We classified EGFR pathway inhibitor types and investigated the type of biomarker (biomarker on epigenetic, DNA, mRNA or protein level).
CONCLUSION
Several EGFR-PI3K-AKT-mTOR-pathway inhibitor biomarkers have been researched for HNSCC but few of the investigated biomarkers have been adequately confirmed in clinical trials. A more systematic approach is needed to discover proper biomarkers as stratifying patients is essential to prevent unnecessary costs and side effects.
Topics: Biomarkers, Tumor; Cetuximab; ErbB Receptors; Humans; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases
PubMed: 33686517
DOI: 10.1007/s40291-021-00518-6