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Caspian Journal of Internal Medicine 2020Mutations in the EGFR signaling pathway play an important role in the development of colorectal cancer (CRC). Mutations in these genes, like KRAS and BRAF, affect the... (Review)
Review
BACKGROUND
Mutations in the EGFR signaling pathway play an important role in the development of colorectal cancer (CRC). Mutations in these genes, like KRAS and BRAF, affect the treatment strategies and associated with poor prognosis and relative resistance to anti-EGFR therapies. Our aim was to conduct a systematic and meta-analysis on all studies that have been conducted on the prevalence of these gene mutations in Iranian CRC patients.
METHODS
Four science citation index databases (MEDLINE, EMBASE, Web of Science and Cochrane library) and local databases were searched up to March 2018 with related keywords. Two reviewers independently screened and extracted the data. Quality of all included studies was assessed using an adapted checklist from STROBE. A random-effect model was used to calculate the total prevalence of KRAS and BRAF mutations in CRC subjects by the event rate (ER). Meta-regression was utilized to explore heterogeneity causes.
RESULTS
In total, from 573 records, 23 eligible studies (2662 patients) were included for data extraction and analysis. In 18 of 23 included studies, the prevalence of KRAS mutations was 33.9% (95% CI=30.1-37.9) with I2=65.17 (p<0.001). The occurrence of KRAS mutations in codon 12 and 13 was 76.9% (95% CI = 70.4-82.3%) with I2=84.88 (p<0.001) and 23.5% (95% CI=17.9-30.3) with I2=85.85 (p<0.001), respectively. In 9 of 23 studies, the BRAF mutation rate was 3.2% (95% CI=0.003-13.6) with I2=88.61 (p<0.001).
CONCLUSION
The prevalence of these mutations in CRC patients shows a significant difference in the different regions of Iran, which is probably due to environmental and racial factors.
PubMed: 33680376
DOI: 10.22088/cjim.11.4.355 -
BioMed Research International 2023LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and meta-analysis are aimed at summarizing epidemiology, disease onset and progression, visual recovery, risk factors, and treatment options of Leber's hereditary optic neuropathy (LHON) with mitochondrial DNA mutation G11778A from current evidence.
METHODS
The PubMed database was examined from its inception date to November 2021. Data from included studies were pooled with either a fixed-effects model or a random-effects model, depending on the results of heterogeneity tests. Sensitivity analysis was conducted to test the robustness of results.
RESULTS
A total of 41 articles were included in the systematic review for qualitative analysis, and 34 articles were included for quantitative meta-analysis. The pooled estimate of proportion of G11778A mutation among the three primary mutations of mitochondrial DNA (G11778A, G3460A, and T14484C) for LHON was 73% (95% CI: 67% and 79%), and the LHON patients with G11778A mutation included the pooled male ratio estimate of 77% (76% and 79%), the pooled age estimate of 35.3 years (33.2 years and 37.3 years), the pooled onset age estimate of 22.1 years (19.7 years and 24.6 years), the pooled visual acuity estimate of 1.4 LogMAR (1.2 LogMAR and 1.6 LogMAR), and the pooled estimate of spontaneous visual recovery rate (in either 1 eye) of 20% (15% and 27%).
CONCLUSIONS
The G11778A mutation is a prevalent mitochondrial DNA mutation accounting for over half of LHON cases with three primary mutations. Spontaneous visual recovery is rare, and no effective treatment is currently available.
Topics: Adult; Female; Humans; Male; Young Adult; DNA, Mitochondrial; Mitochondria; Mutation; Optic Atrophy, Hereditary, Leber; Pedigree
PubMed: 36743514
DOI: 10.1155/2023/1107866 -
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 -
Ecancermedicalscience 2021Cervical Cancer (CC) is a significantly prevalent disease in developing countries. Currently, targeted therapies are not a primary standard of care in CC. This... (Review)
Review
Cervical Cancer (CC) is a significantly prevalent disease in developing countries. Currently, targeted therapies are not a primary standard of care in CC. This information could be crucial for developing directed therapies and patient screening for biomarkers that would allow personalised treatment of CC. This systematic review aimed to estimate the prevalence of potential therapeutic targets such as the epidermal growth factor receptor (EGFR) and the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways in patients with CC, identified through genomic and non-genomic testing. Studies were identified through an ad-hoc search strategy from the available on MEDLINE (Ovid), CENTRAL, LILACS, SCOPUS, through the Clinical Trial registry on Clinicaltrials.gov, International Clinical Trials Registry Platform, RENIS (Argentine National Registry of Health Research) and grey literature sources. We included 74 studies which represented a total pool of 7,862 participants. Forty-five studies informed mutations of EGFR, with a combined positivity rate of 53% (95%CI: 45%-60%; I = 95%). Twenty studies informed the presence of mutations in PIK3CA with a combined positivity rate of 30% (95%CI: 21%-39%; I = 96%). Twenty-three studies reported a mutation in Ras, with a combined positivity rate of 14% (95%CI: 8%-21%; I = 95%). Raf mutations were informed in six studies. Six studies informed the presence of Akt mutations, two studies informed mTOR mutations and only one study reported mutations of MAPK. The most frequently described therapeutic targets were EGFR, and the PIK3CA and Ras pathways, though inconsistency in positivity rates was significant. Our study did not allow the identification of any specific clinical characteristics that might explain the observed heterogeneity. Despite the overall good quality of the included studies, the applicability of these results to patients' general population with CC is still unclear.
PubMed: 33889209
DOI: 10.3332/ecancer.2021.1200 -
Breast Cancer Research and Treatment Sep 2023In light of the clinically meaningful results of the PI3K inhibitors in PIK3CA-mutated metastatic breast cancer (BC) patients, the reliable identification of PIK3CA... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
In light of the clinically meaningful results of the PI3K inhibitors in PIK3CA-mutated metastatic breast cancer (BC) patients, the reliable identification of PIK3CA mutations is of outmost importance. However, lack of evidence on the optimal site and timing of assessment, presence of temporal heterogeneity and analytical factors pose several challenges in clinical routine. We aimed to study the discordance rates of PIK3CA mutational status between primary and matched metastatic tumors.
METHODS
A systematic literature search was performed in three different databases (Embase, Pubmed, Web of Science) and-upon screening-a total of 25 studies reporting PIK3CA mutational status both on primary breast tumors and their matched metastases were included in this meta-analysis. The random-effects model was used for pooled analyses of discordance of PIK3CA mutational status.
RESULTS
The overall discordance rate of PIK3CA mutational status was 9.8% (95% CI, 7.0-13.0; n = 1425) and did not significantly differ within BC subtypes or metastatic sites. The change was bi-directional, more commonly observed from PIK3CA mutated to wild-type status (14.9%, 95% CI 11.8-18.2; n tumor pairs = 453) rather than the opposite direction (8.9%, 95% CI 6.1-12.1; n tumor pairs = 943).
CONCLUSIONS
Our results indicate the need of obtaining metastatic biopsies for PIK3CA-mutation analysis and the possibility of testing of the primary tumor, in case a re-biopsy deemed non-feasible.
Topics: Humans; Female; Breast Neoplasms; Phosphatidylinositol 3-Kinases; Class I Phosphatidylinositol 3-Kinases; Mutation
PubMed: 37392328
DOI: 10.1007/s10549-023-07010-1 -
Virus Genes Apr 2022African swine fever virus (ASFV) is the causative agent of African swine fever (ASF). The virus causes an acute highly hemorrhagic disease in domestic pigs, with high... (Review)
Review
African swine fever virus (ASFV) is the causative agent of African swine fever (ASF). The virus causes an acute highly hemorrhagic disease in domestic pigs, with high mortality. Although the overall genome mutation rate of ASFV, a large DNA virus, is relatively low, ASFV exhibits genetic and antigenic diversity. ASFV can be classified into 24 genotypes on the basis of the B646L gene. Cross-protected ASFV strains can be divided into eight serogroups on the basis of antibody-mediated hemadsorption inhibition. Here, we review research progress on ASFV genotyping and serogrouping, and explain how this information assists in the rapid identification of virus origin during ASF outbreaks and will aid in the development of ASF vaccines.
Topics: African Swine Fever; African Swine Fever Virus; Animals; Genotype; Phylogeny; Serogroup; Sus scrofa; Swine
PubMed: 35061204
DOI: 10.1007/s11262-021-01879-0 -
Annals of Oncology : Official Journal... Aug 2022'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and...
BACKGROUND
'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research.
PATIENTS AND METHODS
A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts.
RESULTS
Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated.
CONCLUSIONS
RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.
Topics: Antineoplastic Agents, Immunological; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms
PubMed: 35533926
DOI: 10.1016/j.annonc.2022.04.450 -
Kidney International Reports Feb 2023Posttransplant disease recurrence is a feared and severe complication in children with steroid resistant nephrotic syndrome (SRNS), but little is known about its...
INTRODUCTION
Posttransplant disease recurrence is a feared and severe complication in children with steroid resistant nephrotic syndrome (SRNS), but little is known about its incidence. Recent data suggest relapse is exceptional in patients with genetic SRNS, and initial steroid sensitivity may represent a risk factor for recurrence.
METHODS
Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to describe the post-transplant relapse rate among children with SRNS; as well as the association between recurrence and all potential risk factors, including the presence of causative genetic mutations, initial steroid sensitivity, underlying histology, and gender. The inclusion criteria were as follows: (i) children with SRNS who are undergoing kidney transplant, (ii) available data on post-transplant recurrence, (iii) no patient selection according to the underlying histology, (iv) available data on genetic testing, and (v) prospective or retrospective cohort design.
RESULTS
Of the 5818 records identified, 8 studies including 581 children with SRNS met the inclusion criteria. Overall posttransplant recurrence rate was 39% (95% confidence interval [CI] 34%-44%). No genetic patient relapsed, whereas the recurrence rate in patients with no causative genetic mutation identified was 61% (95% CI 53%-69%). Children with initial steroid sensitivity were at a higher risk for recurrence with a 1.91 relative risk (RR) (95% CI 1.48-2.46) compared with those with primary SRNS (PSRNS). Gender and histology did not significantly affect relapse rate.
CONCLUSION
Post-transplant recurrence is a common event in children with idiopathic non-genetic SRNS, complicating the clinical course in over 60% of patients. The presence of a causative genetic mutation virtually excludes a recurrence. Initial steroid sensitivity is the only other significant risk factor, doubling the risk of relapse.
PubMed: 36815113
DOI: 10.1016/j.ekir.2022.10.030 -
Microbiological Research Jun 2023Innumerable pathogens including RNA viruses have catastrophic pandemic propensity, in turn, SARS-CoV-2 infection is highly contagious. Emergence of SARS-CoV-2 variants... (Review)
Review
Innumerable pathogens including RNA viruses have catastrophic pandemic propensity, in turn, SARS-CoV-2 infection is highly contagious. Emergence of SARS-CoV-2 variants with high mutation rate additionally codifies infectious ability of virus and arisen clinical imputations to human health. Although, our knowledge of mechanism of virus infection and its impact on host system has been substantially demystified, uncertainties about the emergence of virus are still not fully understood. To date, there are no potentially curative drugs are identified against the viral infection. Even though, drugs are repurposed in the initial period of infection, many are significantly negative in clinical trials. Moreover, the infection is dependent on organ status, co-morbid conditions, variant of virus and geographic region. This review article aims to comprehensively describe the SARS-CoV-2 infection and the impacts in the host cellular system. This review also briefly provides an overview of genome, proteome and metabolome associated risk to infection and the advancement of therapeutics in SARS-CoV-2 infection management.
Topics: Humans; COVID-19; SARS-CoV-2; Antiviral Agents; Mutation Rate
PubMed: 36989761
DOI: 10.1016/j.micres.2023.127364 -
Cureus Jun 2022Erdheim Chester disease (ECD) is a type of histiocytosis characterized by a variable clinical presentation. The treatment of ECD is complex and mainly unknown. We aim to... (Review)
Review
Erdheim Chester disease (ECD) is a type of histiocytosis characterized by a variable clinical presentation. The treatment of ECD is complex and mainly unknown. We aim to conduct a literature review of the treatment of ECD and consolidate the knowledge about the most recent and updated treatment for ECD. To conduct the systematic review, we used the preferred reporting items for systematic reviews and meta-analysis (PRISMA) protocol. To analyze the bias, we used the Cochrane collaboration risk-of-bias tool to assess the bias. We included observational studies and clinical trials on humans, which were written in English. Papers not fulfilling the objective of our study were excluded. Overall, the drug showed efficacy in the clinical trials, showing prolonged improvement and high rates of response rate. Overall, the drug was not well tolerated, and patients had a long list of side effects. Nevertheless, the drug seems to be a good option for second-line treatment for patients with ECD and BRAFV600 mutation.
PubMed: 35844342
DOI: 10.7759/cureus.25935