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European Urology Aug 2023Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external... (Review)
Review
CONTEXT
Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external and internal factors) contribute significantly to the development of BC. Therefore, establishing a clear understanding of these risk factors is the key to prevention.
OBJECTIVE
To perform an up-to-date systematic review of BC's epidemiology and external risk factors.
EVIDENCE ACQUISITION
Two reviewers (I.J. and S.O.) performed a systematic review using PubMed and Embase in January 2022 and updated it in September 2022. The search was restricted to 4 yr since our previous review in 2018.
EVIDENCE SYNTHESIS
Our search identified 5177 articles and a total of 349 full-text manuscripts. GLOBOCAN data from 2020 revealed an incidence of 573 000 new BC cases and 213 000 deaths worldwide in 2020. The 5-yr prevalence worldwide in 2020 was 1 721 000. Tobacco smoking and occupational exposures (aromatic amines and polycyclic aromatic hydrocarbons) are the most substantial risk factors. In addition, correlative evidence exists for several risk factors, including specific dietary factors, imbalanced microbiome, gene-environment risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy.
CONCLUSIONS
We present a contemporary overview of the epidemiology of BC and the current evidence for BC risk factors. Smoking and specific occupational exposures are the most established risk factors. There is emerging evidence for specific dietary factors, imbalanced microbiome, gene-external risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. Further high-quality evidence is required to confirm initial findings and further understand cancer prevention.
PATIENT SUMMARY
Bladder cancer is common, and the most substantial risk factors are smoking and workplace exposure to suspected carcinogens. On-going research to identify avoidable risk factors could reduce the number of people who get bladder cancer.
Topics: Humans; Vehicle Emissions; Risk Factors; Urinary Bladder Neoplasms; Smoking; Tobacco Smoking; Occupational Exposure
PubMed: 37198015
DOI: 10.1016/j.eururo.2023.03.029 -
Signal Transduction and Targeted Therapy Mar 2023The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription... (Review)
Review
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
Topics: Humans; Tumor Suppressor Protein p53; Apoptosis; Autophagy; Cell Cycle; Ferroptosis
PubMed: 36859359
DOI: 10.1038/s41392-023-01347-1 -
Molecular Diagnosis & Therapy Mar 2022Numerous therapeutic agents specifically targeting the mesenchymal-epithelial transition (MET) oncogene are being developed. (Review)
Review
INTRODUCTION
Numerous therapeutic agents specifically targeting the mesenchymal-epithelial transition (MET) oncogene are being developed.
OBJECTIVE
The aim of the current review was to systematically identify and analyze clinical trials that have evaluated MET inhibitors in various cancer types and to provide an overview of their clinical outcomes.
METHODS
An electronic literature search was carried out in the PubMed and Embase databases to identify published clinical trials related to MET inhibitors. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement was followed for the systematic appraisal of the literature. Data related to clinical outcomes, including progression-free survival, overall survival, objective response rate, and overall tumor response, were extracted.
RESULTS
In total, 49 publications were included. Among these, 51.02% were phase II studies, 14.28% were randomized controlled trials, three were phase III studies, two were prospective observational studies, and the remainder were either phase I or Ib studies. The majority (44.89%) of articles reported the clinical outcomes of MET inhibitors, including small molecules, monoclonal antibodies, and other agents, in patients with non-small-cell lung cancer (NSCLC) harboring MET alterations. MET amplification, overexpression, and MET exon 14 skipping mutations were the major MET alteration types reported across the included studies. Clinical responses/outcomes varied considerably.
CONCLUSION
This systematic literature review provides an overview of the literature available in Embase and PubMed regarding MET-targeted therapies. MET-selective tyrosine kinase inhibitors (TKIs) (capmatinib, tepotinib, and savolitinib) may become a new standard of care in NSCLC, specifically with MET exon 14 skipping mutations. A combination of MET TKIs with epidermal growth factor receptor (EGFR) TKIs (osimertinib + savolitinib, tepotinib + gefitinib) may be a potential solution for MET-driven EGFR TKI resistance. Further, MET alteration (MET amplification/overexpression) may be an actionable target in gastric cancer and papillary renal cell carcinoma.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Observational Studies as Topic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met
PubMed: 35266116
DOI: 10.1007/s40291-021-00568-w -
Cell Communication and Signaling : CCS Feb 2020Breast cancer has grown to be the second leading cause of cancer-related deaths in women. Only a few treatment options are available for breast cancer due to the... (Review)
Review
Breast cancer has grown to be the second leading cause of cancer-related deaths in women. Only a few treatment options are available for breast cancer due to the widespread occurrence of chemoresistance, which emphasizes the need to discover and develop new methods to treat this disease. Signal transducer and activator of transcription 3 (STAT3) is an early tumor diagnostic marker and is known to promote breast cancer malignancy. Recent clinical and preclinical data indicate the involvement of overexpressed and constitutively activated STAT3 in the progression, proliferation, metastasis and chemoresistance of breast cancer. Moreover, new pathways comprised of upstream regulators and downstream targets of STAT3 have been discovered. In addition, small molecule inhibitors targeting STAT3 activation have been found to be efficient for therapeutic treatment of breast cancer. This systematic review discusses the advances in the discovery of the STAT3 pathways and drugs targeting STAT3 in breast cancer. Video abstract.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; STAT3 Transcription Factor; Signal Transduction
PubMed: 32111215
DOI: 10.1186/s12964-020-0527-z -
ESMO Open Jun 2022Frontline immune checkpoint inhibitors (ICI)-based regimens in non-oncogene-addicted non-small-cell lung cancer (NSCLC) have been deeply investigated. To rank the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Frontline immune checkpoint inhibitors (ICI)-based regimens in non-oncogene-addicted non-small-cell lung cancer (NSCLC) have been deeply investigated. To rank the available therapeutic options, we carried out a systematic review and Bayesian meta-analysis.
METHODS
A comprehensive search for randomized controlled trials (RCTs) of ICI regimens, and a pairwise and a network meta-analysis (NMA) with an all-comers and a stratified strategy were conducted. Endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (TRAEs).
RESULTS
Nineteen RCTs involving 17 treatment regimens were included. For the all-comers population, pembrolizumab/chemotherapy (CT) and cemiplimab were most likely the best treatments. For programmed death-ligand 1 (PD-L1) <1% nivolumab/ipilimumab with/without CT, for PD-L1 >1% and 1%-49% pembrolizumab/CT and for PD-L1 >50% cemiplimab ranked first for OS. In non-squamous (NSQ), pembrolizumab with/without CT ranked first for OS; cemiplimab ranked worse than the unselected population. In squamous (SQ), pooled hazard ratio (HR) showed a better chance in improving efficacy for combination strategy, while monotherapy did not, except for cemiplimab that ranked second. Atezolizumab/CT/bevacizumab ranked first in most subgroups for PFS. Direct comparison showed a non-statistically significant benefit of ICI regimens for the liver metastases cohort in OS, with a good ranking for pembrolizumab/CT and atezolizumab/bevacizumab/CT. Regarding brain metastases, all ICI regimens demonstrated an improvement in OS and PFS compared to CT. Nivolumab/ipilimumab/CT ranked better in this subset.
CONCLUSIONS
Our meta-analysis updated on the most recent findings demonstrates that different ICI treatments rank differently in specific NSCLC settings (histology, biomarker and clinical presentation) offering a novel challenging scenario for clinical decision making and research planning.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Humans; Ipilimumab; Lung Neoplasms; Nivolumab
PubMed: 35427835
DOI: 10.1016/j.esmoop.2022.100465 -
Signal Transduction and Targeted Therapy Feb 2021The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and...
The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.
Topics: Alternative Splicing; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA Splicing; RNA Splicing Factors; RNA, Circular
PubMed: 33623018
DOI: 10.1038/s41392-021-00486-7 -
Journal of Thoracic Oncology : Official... Dec 2023Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could influence screening and determine targeted treatment. We aimed to establish prevalence and incidence in these groups, stratified by genomic alterations.
METHODS
A systematic review and meta-analysis compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were conducted (PROSPERO identification CRD42022315915). Articles published in MEDLINE, EMBASE, and Cochrane Library between January 2000 and May 2022 were included. Prevalence at diagnosis and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models.
RESULTS
A total of 64 unique articles were included (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC having incidence data from 40 studies). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% confidence interval [CI]: 26.1-31.0), and highest in patients that are ALK-positive (34.9%) or with RET-translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 0.13 in the wild-type group (14 studies, 95% CI: 0.11-0.16). Incidence was 0.16 in the EGFR group (16 studies, 95% CI: 0.11-0.21), 0.17 in the ALK group (five studies, 95% CI: 0.10-0.27), 0.10 in the KRAS group (four studies, 95% CI: 0.06-0.17), 0.13 in the ROS1 group (three studies, 95% CI: 0.06-0.28), and 0.12 in the RET group (two studies, 95% CI: 0.08-0.17).
CONCLUSIONS
Comprehensive meta-analysis indicates a higher prevalence and incidence of BM in patients with certain targetable genomic alterations. This supports brain imaging at staging and follow-up, and the need for targeted therapies with brain penetrance.
Topics: Humans; Lung Neoplasms; Incidence; Protein-Tyrosine Kinases; Proto-Oncogene Proteins p21(ras); Proto-Oncogene Proteins; Carcinoma, Non-Small-Cell Lung; Genomics; Brain Neoplasms; Receptor Protein-Tyrosine Kinases; ErbB Receptors
PubMed: 37392903
DOI: 10.1016/j.jtho.2023.06.017 -
Brazilian Journal of Otorhinolaryngology 2021The association between uterine cervix and anogenital carcinomas and human papillomavirus, HPV, is well established, however the involvement of this virus in the... (Review)
Review
INTRODUCTION
The association between uterine cervix and anogenital carcinomas and human papillomavirus, HPV, is well established, however the involvement of this virus in the development of oral squamous cell carcinomas remains controversial.
OBJECTIVES
To evaluate the relationship between HPV infection and oral squamous cell carcinomas, and to estimate the incidence of this infection in these patients.
METHODS
Four electronic databases were searched to find studies that met the following inclusion criteria: i) performed in humans; ii) were cohort, case-control or cross-sectional; iii) assessed the HPV oncogenic activity by the E6 and E7 mRNA; iv) included primary oral squamous cell carcinomas which; v) diagnosis had been confirmed by biopsy. Information about the country; study period; sample obtainment; sites of oral squamous cell carcinomas; number, gender and age range of the population; the prevalence of HPV infection and subtypes detected; use of tobacco or alcohol and oral sex practice were extracted. The methodological quality of included articles was assessed using 14 criteria.
RESULTS
The search strategy retrieved 2129 articles. Assessment of the full text was done for 626 articles, but five were included. The total of participants included was 383, most of them male with mean age between 51.0 and 63.5 years old. Seventeen patients were HPV/mRNA-positive, being the subtypes 16 and 18 detected more frequently. Nine of the HPV/mRNA-positive oral squamous cell carcinomas occurred on the tongue. The quality score average of included articles was five points.
CONCLUSIONS
Among the 383 oral squamous cell carcinoma patients included, 17 (4.4%) were HPV/mRNA-positive, nevertheless it was not possible to assess if HPV infection was associated with oral squamous cell carcinomas because none of the studies included was longitudinal and cross-sectional investigations do not have control group.
Topics: Carcinoma, Squamous Cell; Cross-Sectional Studies; DNA, Viral; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mouth Neoplasms; Papillomaviridae; Papillomavirus Infections; Squamous Cell Carcinoma of Head and Neck
PubMed: 33339760
DOI: 10.1016/j.bjorl.2020.10.017 -
European Journal of Cancer (Oxford,... Jul 2023Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma.
METHODS
Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events.
RESULTS
A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab.
CONCLUSION
Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile.
Topics: Humans; Nivolumab; Ipilimumab; Network Meta-Analysis; Proto-Oncogene Proteins B-raf; Antineoplastic Combined Chemotherapy Protocols; Melanoma; Mitogen-Activated Protein Kinase Kinases
PubMed: 37196485
DOI: 10.1016/j.ejca.2023.04.010 -
BioMed Research International 2022Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing... (Review)
Review
BACKGROUND
Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAF mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAF mutation potential of these lesions and new prevention strategies in PTC patients.
METHODS
A total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAF mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021.
RESULTS
The following variables were associated with an increased risk of BRAF mutation in PTC patients: age ≥ 45 years (OR = 1.39, 95%CI = 1.21-1.60, < 0.00001), male gender (OR = 1.13, 95%CI = 0.99-1.28, = 0.06), multifocality (OR = 1.22, 95%CI = 1.07-1.40, = 0.004), lymph node metastasis (OR = 1.33, 95%CI = 0.79-2.23, = 0.28), extrathyroidal extension + (OR = 1.61, 95%CI = 1.06-2.44, = 0.03), vascular invasion + (OR = 2.04, 95%CI = 1.32-3.15, = 0.001), and tumor node metastasis stage (OR = 1.61, 95%CI = 1.38-1.88, < 0.00001). In addition, tumor size (>1 cm) (OR = 0.51, 95%CI = 0.32-0.81, = 0.005) and distant metastasis (OR = 0.69, 95%CI = 0.22-2.21, = 0.54) had no association or risk with BRAF mutation in PTC patients.
CONCLUSION
Our systematic review identified the following significant risk factors of BRAF mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAF mutation in PTC patients.
Topics: Carcinoma, Papillary; Humans; Lymphatic Metastasis; Male; Middle Aged; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 35647194
DOI: 10.1155/2022/9959649