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Chinese Medical Journal Nov 2023The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR -mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR -mutated NSCLC patients with different BM statuses.
METHODS
Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR -mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework.
RESULTS
This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.20, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For patients without BM, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 47.1%. For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively.
CONCLUSION
Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR -mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Bevacizumab; Bayes Theorem; Network Meta-Analysis; Protein Kinase Inhibitors; Pemetrexed; ErbB Receptors; Brain Neoplasms; Mutation
PubMed: 37160733
DOI: 10.1097/CM9.0000000000002468 -
The Journal of International Medical... Apr 2023This meta-analysis aimed to update knowledge about the association between the variant rs4973768 and breast cancer incidence. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This meta-analysis aimed to update knowledge about the association between the variant rs4973768 and breast cancer incidence.
METHODS
Studies were identified from relevant digital databases. Fixed- or random-effects models were used to calculate odds ratios and 95% confidence intervals. Statistical Q and I tests and sensitivity analyses were used to detect interstudy heterogeneity and test the statistical stability of overall estimates, respectively. Egger's tests were applied to detect publication bias among included studies. In silico analysis was used to ascertain increased expression of mRNA in rs4973768 with the mutant allele. Trial sequential analysis was used to calculate the study's sample size.
RESULTS
The overall odds ratios reflected a positive correlation between the rs4973768 polymorphism and susceptibility to breast cancer in five genetic comparisons of alleles T and C, and tests revealed significant heterogeneity in the allele comparison. After stratification by ethnicity, heterogeneity in Asian and White populations substantially decreased (Ph = 0.984, I = 0%) and remained stable (Ph = 0.083, I = 46.3%), respectively. The mutant allele was associated with increased expression of mRNA in rs4973768. The cumulative z curve indicated that our conclusions were robust.
CONCLUSIONS
Our updated consequence shows that the rs4973768 polymorphism is associated with increased breast cancer risk.
Topics: Humans; Female; Breast Neoplasms; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Risk; Alleles; Odds Ratio; Risk Factors; Case-Control Studies; Sodium-Bicarbonate Symporters
PubMed: 37128157
DOI: 10.1177/03000605231166517 -
Clinical and Experimental Medicine Nov 2023Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2... (Meta-Analysis)
Meta-Analysis Review
Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.
Topics: Humans; Female; Trastuzumab; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Neoplasms; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37120775
DOI: 10.1007/s10238-023-01072-7 -
Medical Oncology (Northwood, London,... Apr 2023Ameloblastoma in 66% of the cases harbor a somatic mutation of the "mitogen-activated protein kinase" signaling pathway (BRAF V600E). In V600E mutations, BRAF is in the... (Review)
Review
BACKGROUND
Ameloblastoma in 66% of the cases harbor a somatic mutation of the "mitogen-activated protein kinase" signaling pathway (BRAF V600E). In V600E mutations, BRAF is in the permanent "on" state and relays the growth-promoting signals independently of the EGFR pathway. Therefore, mutant BRAF represents a target for handful of new drugs.
METHODS
We conducted a literature search, with the search terms "Vemurafenib, Dabrafenib, Ameloblastoma, and BRAF." These included seven case reports with nine patients who underwent monotherapy with Dabrafenib or Vemurafenib or combination therapy with Dabrafenib and Trametinib.
RESULTS
The patients age ranges from 10 years up to 86 years. The distribution of women and men is 4:5. Patients with an initial diagnosis of ameloblastoma, as well as recurrences or metastasized ameloblastoma were treated. Indications cover neoadjuvant therapy up to the use in metastasized patients in an irresectable state. Results ranging from "only" tumor size reduction to restitutio ad integrum.
CONCLUSION
We see the use of BRAF Inhibitors to reduce tumor size with consecutive surgical treatment as a reasonable option for therapy. However, we are aware that at present the data are based only on case reports with the longest follow-up of just 38 months. We encourage further clinical trials in the use of BRAF Inhibitors for selecting ameloblastoma patients in a multi-center setting.
Topics: Male; Humans; Female; Child; Vemurafenib; Proto-Oncogene Proteins B-raf; Ameloblastoma; Imidazoles; Protein Kinase Inhibitors; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37115331
DOI: 10.1007/s12032-023-01993-z -
Cells Mar 2023Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall... (Review)
Review
INTRODUCTION
Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of studies investigating the efficacy and safety profile of GSTs in HCAs.
METHODS
A structured PubMed search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article.
RESULTS
The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed.
CONCLUSION
The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype . Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.
Topics: Animals; Cerebellar Ataxia; Trinucleotide Repeats; Spinocerebellar Degenerations; Proteins
PubMed: 37048110
DOI: 10.3390/cells12071037 -
BMC Medical Genomics Apr 2023Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner...
BACKGROUND
Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.
METHODS
We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.
RESULTS
One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.
CONCLUSIONS
We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.
Topics: Humans; Wolfram Syndrome; Cochlear Implants; Cochlear Implantation; Pedigree; Hearing Loss; Deafness
PubMed: 37041640
DOI: 10.1186/s12920-023-01506-x -
Current Pharmaceutical Biotechnology 2023Periodontal diseases and dental caries are the two most common dental diseases caused by the dental plaque.
INTRODUCTION
Periodontal diseases and dental caries are the two most common dental diseases caused by the dental plaque.
OBJECTIVE
The aim of the present study was to review the clinical efficacy of probiotics for oral health in randomized controlled trials.
METHODS
An electronic search was conducted in December 2021 in Embase, Medline, The Cochrane Library, ProQuest, and Google Scholar using the following keywords: "mouthwash" and "probiotics". The titles and abstracts of 3,775 articles were screened and 24 publications that fulfilled the inclusion criteria were included.
RESULTS
A total of 24 clinical trials were reviewed, including 1612 participants receiving either probiotics or mouth treatments. The results of this review indicated that individuals receiving probiotic products have a significant reduction (65% reduction; < 0.05) in the count of in their mouths. It was also found that probiotic products were more effective or equal in effect compared to chlorhexidine in reducing oral pathogens, gingival index, and plaque index scores. On the other hand, the consumption of xylitol mouthwash was shown to cause an improvement in salivary parameters. Considering their safety and effectiveness, the use of probiotic products, such as kefir and mouthwashes, has been recommended against cariogenic bacteria and periodontal diseases.
CONCLUSION
Probiotics are considered a safe alternative to conventional therapies, such as chlorhexidine and fluoride. Co-administration of chlorhexidine, fluoride, and probiotics seems to be a perfect package.
Topics: Humans; Chlorhexidine; Oral Health; Fluorides; Dental Caries; Mouthwashes; Probiotics; Periodontal Diseases; Treatment Outcome
PubMed: 37038663
DOI: 10.2174/1389201024666230405135457 -
Life (Basel, Switzerland) Mar 2023Melanoma continues to represent the most serious skin cancer worldwide. However, few attempts have been made to connect the body of research on advanced melanoma. In... (Review)
Review
Melanoma continues to represent the most serious skin cancer worldwide. However, few attempts have been made to connect the body of research on advanced melanoma. In the present review, we report on strides made in the diagnosis and treatment of intracranial metastatic melanoma. Relevant Cochrane reviews and randomized-controlled trials published by November 2022 were systematically retrieved from the Cochrane Library, EMBASE, and PubMed databases (N = 27). Search and screening methods adhered to the 2020 revision of the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Although the research surrounding the earlier detection of melanoma brain metastasis is scarce, several studies have highlighted specific markers associated with MBM. Such factors include elevated BRAFV600 mutant ctDNA, high LDH concentration, and high IGF-1R. The approach to treating MBM is moving away from surgery and toward nonsurgical management, namely, a combination of stereotactic radiosurgery (SRS) and immunotherapeutic agents. There is an abundance of emerging research seeking to identify and improve both novel and established treatment options and diagnostic approaches for MBM, however, more research is still needed to maximize the clinical efficacy, especially for new immunotherapeutics. Early detection is optimal for the efficacy of treatment and MBM prognosis. Current treatment utilizes chemotherapies and targeted therapies. Emerging approaches emphasize biomarkers and joint treatments. Further exploration toward preliminary identification, the timing of therapies, and methods to ameliorate adverse treatment effects are needed to advance MBM patient care.
PubMed: 36983983
DOI: 10.3390/life13030828 -
Current Oncology (Toronto, Ont.) Mar 2023Small-cell lung cancer (SCLC) transformation from EGFR mutant adenocarcinoma is a rare entity that is considered to be a new phenotype of SCLC. While transformation from...
Small-cell lung cancer (SCLC) transformation from EGFR mutant adenocarcinoma is a rare entity that is considered to be a new phenotype of SCLC. While transformation from adenocarcinoma (ADC) with EGFR exon 19 deletions and exon 21 L858R point mutations has been described, to our knowledge, no cases of transformation to SCLC from exon-18-mutated ADC have been reported. We reported a clinical case of a patient with exon-18-EGFR-transformed SCLC, and we performed a systematic review of the literature.
Topics: Humans; Adenocarcinoma; ErbB Receptors; Exons; Lung Neoplasms; Small Cell Lung Carcinoma
PubMed: 36975478
DOI: 10.3390/curroncol30030265 -
Seminars in Oncology 2023Available evidence suggests that in patients with advanced BRAF V600-mutant melanoma treated with the combination of BRAF and MEK inhibitors, gender could be associated... (Meta-Analysis)
Meta-Analysis Review
Available evidence suggests that in patients with advanced BRAF V600-mutant melanoma treated with the combination of BRAF and MEK inhibitors, gender could be associated with survival outcome. We performed a systematic review and meta-analysis of all randomized clinical trials (RCTs) testing the combination of BRAF and MEK inhibitors, to assess the interaction between treatment effect and patients' gender. We searched PubMed, MEDLINE, Embase, and Scopus, for phase II and III RCTs up to January 30, 2022. We included all RCTs that enrolled patients with BRAF V600-mutant advanced cutaneous melanoma and assessed combinations of BRAF and MEK inhibitors versus BRAF inhibitor monotherapy. Our aim was to assess differences if any in treatment efficacy between men and women, measured in terms of the differences in progression-free survival (PFS) and overall survival (OS) log-hazard ratios (log-HRs). We calculated the pooled PFS- and OS-HRs with 95% confidence intervals (CIs) in men and women using a random-effects model and assessed the heterogeneity between the estimates using an interaction test. Five RCTs that enrolled a total of 2,113 patients were included in the analysis. In women, the combination of BRAF and MEK inhibitors halved the risk of progression or death as compared with BRAF inhibitor monotherapy with a pooled PFS-HR of 0.50 (95%CI 0.41-0.61). In men, the benefit obtained with BRAF and MEK inhibitors was smaller with a pooled PFS-HR of 0.63 (95%CI 0.54-0.74), P-heterogeneity = .05. A similar trend was observed for OS where the pooled OS-HR was 0.62 (95%CI 0.48-0.80) in women and only 0.78, (95%CI 0.67-0.92) in men, P-heterogeneity = 0.11. These results support meaningful gender-based heterogeneity of response to combination of BRAF and MEK inhibitors targeted therapy in patients with advanced BRAF-mutant melanoma, that should be considered in future research to improve treatment effectiveness.
Topics: Male; Female; Humans; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Melanoma; Skin Neoplasms; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36967333
DOI: 10.1053/j.seminoncol.2023.03.003