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Seizure Mar 2024Wolf-Hirschhorn syndrome (WHS) is araredisorderwithan estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region... (Review)
Review
Wolf-Hirschhorn syndrome (WHS) is araredisorderwithan estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region (Wolf-Hirschhorn Syndrome Critical region- WHSCR) on chromosome 4p16.3. WHS is clinically characterized by pre-and postnatal growth restriction, hypotonia, intellectual disability, craniofacial dysmorphismand congenital fusion anomalies. The clinical aspects are variable due to the deletion size.Consistently, epilepsy is one of the major concerns for parents and professionals caring for children with WHS. Seizures tend to occur in over 90% of patients, with onset within the first 3 years of life, and a peak incidence at around 6-12 months of age. Approximately 20% of patients had the first seizure onset within the first 6 months of age, almost 50% at 6 to 12 months of age and about 25% later than 12 months of age. The main types of epileptic seizures occurring in patients with WHS were generalized tonic-clonic seizures (around 70%). These were followed by tonic spasms (20%); focal seizures with impaired awareness (12%) and clonicseizures in 7% of patients.Seizures are often triggered by fever, followed by infections of various systems. Particularly, half of WHS patients experience status epilepticus in the first years of life, which can be fatal. Due to limited number of reports on the topic of EEG abnormalities in epilepsy among WHS patients, it is difficult to determine whether there are any characteristic deviations for WHS. Although more than 300 persons with WHS have been reported in the literature, there is sparse knowledge about epilepsy and methods of its anti-seizure medication (ASM) management with an assessment of their effectiveness. The purpose of this systematic review is to briefly summarize achievements and advances in the field of epilepsy in Wolf-Hirschhorn syndrome.
Topics: Child; Humans; Infant; Wolf-Hirschhorn Syndrome; Epilepsy; Intellectual Disability; Status Epilepticus; Craniofacial Abnormalities; Chromosome Deletion; Phenotype
PubMed: 36526544
DOI: 10.1016/j.seizure.2022.12.001 -
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 -
Annals of Hematology Aug 2023IKZF1 (IKAROS family Zinc Finger 1) alteration is an essential regulator of both T- and B-cell lineage specification with leukemogenic potential. IKZF1 deletion have... (Meta-Analysis)
Meta-Analysis
IKZF1 (IKAROS family Zinc Finger 1) alteration is an essential regulator of both T- and B-cell lineage specification with leukemogenic potential. IKZF1 deletion have been described in childhood acute lymphoblastic leukemia (ALL) with varying prevalence often influenced by underlying cytogenetics and also shown to have diverse prognostic significance. We aimed to evaluate the prevalence and prognostic significance of IKZF1 deletion among childhood ALL. Electronic databases of MEDLINE, EMBASE and SCOPUS were searched and 32 studies found eligible. Estimated prevalence of IKZF1 deletion among BCR::ABL1 negative and BCR::ABL1 positive ALL patients was 14% (95%CI:13-16%, I = 79%; 26 studies) and 63% (95%CI:59-68% I = 42%; 10 studies) respectively. Most common site of IKZF1 deletion was whole chromosome (exon1-8) deletion in 32.3% (95%CI: 23.8-40.7%) followed by exon 4-7 deletion in 28.6% (95%CI: 19.7-37.5%). A positive minimal residual disease at the end of induction was more common among patients with IKZF1 deletion, odds ratio: 3.09 (95%CI:2.3-4.16, I = 54%; 15 studies). Event-free survival and overall survival were significantly worse for IKZF1 deletion, hazard ratio (HR): 2.10 (95%CI:1.90-2.32, I = 28%; 31 studies) and HR: 2.38 (95%CI:1.93-2.93, I = 40; 15 studies) respectively. In summary, the current meta-analysis highlights the frequency of IKZF1 deletion and its negative impact on survival in childhood ALL. Further studies exploring the influence of IKZF1 deletion in the presence of classical cytogenetic and other copy number alterations would further help in characterising its prognostic role.
Topics: Child; Humans; Prognosis; Prevalence; Ikaros Transcription Factor; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Gene Deletion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37154889
DOI: 10.1007/s00277-023-05250-1 -
Fertility and Sterility Jan 2024To investigate whether Azoospermia Factor c (AZFc) microdeletions affect Assisted Reproductive Technology (ART) outcomes. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To investigate whether Azoospermia Factor c (AZFc) microdeletions affect Assisted Reproductive Technology (ART) outcomes.
DESIGN
Systematic review and meta-analysis.
SETTING
Not applicable.
PATIENTS
Infertile men with and without AZFc microdeletions.
INTERVENTION(S)
Electronic databases were searched for case-control studies reporting sperm retrieval rates and outcomes of ART in infertile men with and without AZFc microdeletions from inception to April 2023. Study quality was assessed using the Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for both categories of infertile men.
MAIN OUTCOME MEASURES
The primary outcome was successful sperm retrieval and the secondary outcomes were outcomes of ART.
RESULTS
Case-control studies reporting sperm retrieval rates and ART outcomes in men with AZFa and AZFb deletions were unavailable. On the basis of the data from 3,807 men, sperm retrieval rates were found to be higher in men with AZFc microdeletions compared to their non-deleted counterparts [OR = 1.82, 95% CI 0.97, 3.41], but the difference was not statistically significant. A significantly lower fertilization rate (OR = 0.61, 95% CI [0.50, 0.74]), clinical pregnancy rate (OR = 0.61, 95% CI [0.42, 0.89]), and live birth rate (OR = 0.54, 95% CI [0.40, 0.72]) were observed in men with AZFc deletions compared with men without deletions. There was no statistically significant difference in rates of embryo cleavage, blastocyst formation, good-quality embryos, implantation, and miscarriage between the two groups. On correcting for female factors, the fertilization rate (OR = 0.76, 95% CI [0.71, 0.82]), cleavage rate (OR = 0.54, 95% CI [0.41, 0.72]), clinical pregnancy rate (OR = 0.39, 95% CI [0.30, 0.52]), and live birth rate (OR = 0.48, 95% CI [0.35, 0.65]) were significantly lower in men with AZFc deletions compared with controls.
CONCLUSIONS
Presence of AZFc microdeletions adversely affects outcomes of ART in infertile men. Further in-depth studies delineating the role of the AZF genes in embryonic development are necessary to understand the full-impact of this finding.
CLINICAL TRIAL REGISTRATION NUMBER
CRD42022311738.
Topics: Pregnancy; Humans; Male; Female; Azoospermia; Oligospermia; Retrospective Studies; Chromosome Deletion; Chromosomes, Human, Y; Semen; Infertility, Male; Sertoli Cell-Only Syndrome
PubMed: 37923163
DOI: 10.1016/j.fertnstert.2023.10.029 -
Journal of Magnetic Resonance Imaging :... Nov 2023As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in... (Review)
Review
As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.
Topics: Humans; Artificial Intelligence; Brain Neoplasms; Reproducibility of Results; Chromosome Deletion; Glioma; Isocitrate Dehydrogenase; Oligodendroglioma; Mutation
PubMed: 37083159
DOI: 10.1002/jmri.28737 -
European Journal of Medical Research Aug 2023Previous studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Previous studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall survival (OS) compared to erlotinib alone (monotherapy) for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Two phase III randomized controlled trials (RCTs) had reported the OS results in 2021. This meta-analysis aimed to include the results of the two RCTs to make a decision.
MATERIALS AND METHODS
We systematically searched relevant databases for RCTs on the use of bevacizumab plus erlotinib in advanced EGFR-mutant NSCLC. The main outcomes of interest were PFS, OS, and the reported hazard ratio (HR). Fixed-effect model was used to estimate pooled HR.
RESULTS
Total 5 RCTs with 935 patients were eligible for this meta-analysis. All studies reached their primary study endpoints including PFS and OS. Compared to monotherapy, combination therapy remarkably prolonged PFS (HR = 0.60, 95% confidence interval CI 0.51-0.70; p < 0.00001); however, OS was similar between the two groups (HR = 0.90, 95% CI 0.76-1.08; p = 0.26). Subgroup analysis demonstrated that in deletion within exon 19 (19del) mutation subgroup, the combination therapy could only prolong PFS (HR = 0.60, 95% CI 0.47-0.76; p < 0.0001) but not OS (HR = 1.00, 95% CI 0.73-1.37; p = 1.00), and also in leucine-to-arginine substitution in exon 21 (L858R) mutation subgroup (HR = 0.59, p < 0.0001 and HR = 0.80, p = 0.18, respectively). For patients with brain metastasis at baseline, the combination therapy achieved a significant better PFS than the monotherapy (HR = 0.60, 95% CI 0.39-0.90; p = 0.01), and a better OS with the difference marginally significant (HR = 0.69, 95% CI 0.46-1.02; p = 0.06).
CONCLUSIONS
Combination of bevacizumab and erlotinib can prolong progression-free survival but not overall survival compared to erlotinib alone in advanced EGFR-mutant non-small cell lung cancer patients. The combination therapy not only can prolong progression-free survival but also has a tendency to prolong overall survival for patients with brain metastasis at baseline.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Bevacizumab; Erlotinib Hydrochloride; Randomized Controlled Trials as Topic; Brain Neoplasms; Lung Neoplasms; ErbB Receptors
PubMed: 37635242
DOI: 10.1186/s40001-023-01272-7 -
Neuropediatrics Oct 2023Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE)....
BACKGROUND
Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype.
METHODS
We searched on PubMed using the search terms "" AND "therapy" and "" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies.
RESULTS
In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%).
CONCLUSION
Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; KCNQ2 Potassium Channel; Epilepsy, Benign Neonatal; Mutation; Seizures; Phenotype; Genotype; Phenobarbital
PubMed: 36948217
DOI: 10.1055/a-2060-4576 -
Amyotrophic Lateral Sclerosis &... Feb 2024Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by... (Review)
Review
OBJECTIVE
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by progressive muscle weakness, atrophy, and paralysis. The mutation-associated ALS has been classified as ALS6. We reported a case of ALS6 with de novo mutation and investigated retrospectively the characteristics of cases with mutation.
METHODS
We reported a male patient with a new heterozygous variant of the gene and comprehensively reviewed 173 ALS cases with mutation. The literature was reviewed from the PubMed MEDLINE electronic database (https://www.ncbi.nlm.nih.gov/pubmed) using "Amyotrophic Lateral Sclerosis and mutation" or " mutation" as key words from 1 January 2009 to 1 January 2022.
RESULTS
We report a case of ALS6 with a new mutation point (c.1225-1227delGGA) and comprehensively review 173 ALS cases with mutation. Though ALS6 is all with mutation, it is still a highly heterogenous subtype. The average onset age of ALS6 is 35.2 ± 1.3 years, which is much lower than the average onset age of ALS (60 years old). Juvenile FUS mutations have an aggressive progression of disease, with an average time from onset to death or tracheostomy of 18.2 ± 0.5 months. gene has the characteristics of early onset, faster progress, and shorter survival, especially in deletion mutation p.G504Wfs *12 and missense mutation of p.P525L.
CONCLUSIONS
ALS6 is a highly heterogenous subtype. Our study could allow clinicians to better understand the non-ALS typical symptoms, phenotypes, and pathophysiology of ALS6.
Topics: Humans; Male; Amyotrophic Lateral Sclerosis; Mutation; Mutation, Missense; Neurodegenerative Diseases; Retrospective Studies; RNA-Binding Protein FUS
PubMed: 37926865
DOI: 10.1080/21678421.2023.2272170 -
Journal of Reproductive Immunology Sep 2023Preeclampsia remains enigmatic and responsible for vast maternal and fetal morbidity and mortality worldwide. Our objective was to assess the strength of the effect of... (Meta-Analysis)
Meta-Analysis Review
Preeclampsia remains enigmatic and responsible for vast maternal and fetal morbidity and mortality worldwide. Our objective was to assess the strength of the effect of the 14 bp deletion/insertion polymorphism in exon 8 of the 3'UTR region of the human leukocyte antigen-G (HLA-G) gene on preeclampsia risk across different populations. A systematic review by a meta-analysis was performed to summarize the scattered epidemiologic evidence, which remains inconclusive and controversial. A systematic literature search according to the PRISMA guidelines was conducted to screen relevant publications. Odds ratio and corresponding 95% confidence interval were estimated to measure the magnitude of the association between this polymorphism and preeclampsia onset. Thirty studies comprising 9402 subjects were eligible. Pooled estimates suggested that both fetal and paternal insertion variants were significantly associated with increased odds of this disease. Nevertheless, the presence of the 14 bp insertion sequence in mothers does not seem to increase the risk of preeclampsia. Moreover, the results of subgroup analysis suggested that the fetal, maternal, and paternal polymorphism has a significant deleterious impact on the preeclampsia risk in the Asian population. In addition, the significant association between the paternal polymorphism and preeclampsia in primigravida was observed in the pooled estimation with a small sample size. By summarizing the amount of significant evidence, our study nominated this polymorphism as a potential biomarker for early risk stratification for Asians. Further large-scale validation is needed to establish fully solid and conclusive evidence for the impact of the insertion polymorphism on preeclampsia risk.
Topics: Female; Humans; Pregnancy; 3' Untranslated Regions; Asian; Fetus; Pre-Eclampsia; HLA-G Antigens
PubMed: 37633154
DOI: 10.1016/j.jri.2023.104135 -
Clinical Lung Cancer Mar 2024The discovery of epidermal growth factor receptor (EGFR) mutations has greatly changed the clinical outlook for patients with advanced non-small-cell lung cancer... (Review)
Review
The discovery of epidermal growth factor receptor (EGFR) mutations has greatly changed the clinical outlook for patients with advanced non-small-cell lung cancer (NSCLC). Unlike the most common EGFR mutations, such as exon 19 deletion (del19) and exon 21 L858R point mutation, EGFR exon 20 insertion mutation (EGFR ex20ins) is a rare mutation of EGFR. Due to its structural specificity, it exhibits primary resistance to traditional epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), leading to poor overall survival prognosis for patients. In recent years, there has been continuous progress in the development of new drugs targeting EGFR ex20ins, bringing new hope for the treatment of this patient population. In this regard, we conducted a systematic review of the molecular characteristics, diagnostic advances, and treatment status of EGFR ex20ins. We summarized the latest data on relevant drug development and clinical research, aiming to provide reference for clinical diagnosis, treatment, and drug development.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutagenesis, Insertional; Protein Kinase Inhibitors; ErbB Receptors; Mutation; Exons
PubMed: 38172024
DOI: 10.1016/j.cllc.2023.11.010