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Clinical Lymphoma, Myeloma & Leukemia Apr 2021Available targeted agents (TAs) for the upfront therapy of chronic lymphocytic leukemia (ie, ibrutinib, acalabrutinib, venetoclax) have rarely been compared in... (Comparative Study)
Comparative Study Meta-Analysis
Comparison Between Venetoclax-based and Bruton Tyrosine Kinase Inhibitor-based Therapy as Upfront Treatment of Chronic Lymphocytic Leukemia (CLL): A Systematic Review and Network Meta-analysis.
BACKGROUND
Available targeted agents (TAs) for the upfront therapy of chronic lymphocytic leukemia (ie, ibrutinib, acalabrutinib, venetoclax) have rarely been compared in head-to-head clinical trials. In search of data for evidence-based treatment decisions, a systematic literature review and network meta-analysis was performed.
MATERIALS AND METHODS
The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA).
RESULTS
Only 3 trials were suitable for the base-case network analysis (ILLUMINATE, ELEVATE-TN, and CLL14). Regarding progression-free survival (PFS), fixed-effect analyses comparing ibrutinib-obinutuzumab (IO) with venetoclax-obinutuzumab (VO) (relative risk [RR], 1.52; 95% confidence interval [CI], 0.82-2.81), acalabrutinib (A) with IO (RR, 0.87; 95% CI, 0.47-1.61), and A with VO (RR, 0.57; 95% CI, 0.32-1.01) revealed that the upper limit of the 95% CI for RR did exceed the 1.0 value. This indicates a lack of significant difference in PFS for IO, VO, and A. In contrast, acalabrutinib plus obinutuzumab (AO) improved PFS in comparison with IO (RR, 0.43; 95% CI, 0.22-0.87) and VO (RR, 0.29; 95% CI, 0.15-0.56). No differences in the frequency of adverse events was observed across different TAs. Also, the analysis of PFS in relationship with high-risk genetic features (ie, TP53 aberrations, IGHV unmutated, 11q deletion) showed similar results for different TAs. However, patients with unmutated IGHV status fared better with AO than with VO in terms of PFS.
CONCLUSIONS
This systematic review and network meta-analysis indicated that upfront AO prolongs PFS in comparison with IO and VO, whereas no differences are observed between IO, VO, and single-agent A. Hopefully, ongoing studies will further delineate the position of different TAs in chronic lymphocytic leukemia therapy based on effectiveness, availability, safety, cost, and treatment objectives.
Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Mutation; Network Meta-Analysis; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Randomized Controlled Trials as Topic; Sulfonamides; Tumor Suppressor Protein p53
PubMed: 33199185
DOI: 10.1016/j.clml.2020.10.012 -
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 -
Clinical & Translational Oncology :... May 2020The specific association between PTEN deletion or ERG rearrangement and the recurrence of prostate cancer (PC) treated with radical prostatectomy (RP) or brachytherapy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The specific association between PTEN deletion or ERG rearrangement and the recurrence of prostate cancer (PC) treated with radical prostatectomy (RP) or brachytherapy is still unelaborated. Therefore, we performed a comprehensive meta‑analysis to understand the impact of these factors on cancer recurrence.
METHODS
A comprehensive literature search was performed in November 2018 based on PUBMED, EMBASE and Web of science database. Hazard ratio (HR) for biochemical recurrence free (BRF) which was defined as a PSA greater than or equal to 0.4 ng/mL after RP or another therapy for any detectable PSA and recurrence-free survival (RFS) which defined the time from the beginning of treatment to the earliest occurrence of local recurrence, distant metastasis or death. Which were extracted from eligible studies. I value was used to assess the pooled heterogeneity.
RESULT
A total of 6744 patients from 17 studies were included in this analysis Overall, The pooled results showed that PTEN loss predict pooled BRF (HR 1.79, 95% CI 1.49-2.16, P < 0.001) and RFS (HR 1.71, 95% CI 1.50-1.95, P < 0.001) in patients after radical prostatectomy or brachytherapy for prostate cancer. Subgroup analysis revealed that PTEN deletion significantly predicted poor BRF or RFS in heterozygous studies group (HR 1.70, 95% CI 1.31-2.21, P < 0.001). The PTEN deletion also significantly predicted poor BRF or PFS in homozygous studies (HR 2.54, 95% CI 1.89-3.17, P < 0.001). And we had found that there was no significant association between ERG rearrangement and cancer recurrence regardless of PTEN loss or not. In addition, we concluded that Gleason score > 6 significantly predicted the poor BRF or RFS in studies, especially in Gleason score = 4 + 3 (HR 3.16, 95% CI 2.08-4.80, P < 0.01).
CONCLUSION
This study presented that PTEN deletion significantly reduce time of BRF or RFS, especially based on homozygous deletion. And we also found ERG rearrangement in tumor cell could not significantly predict BRF or RFS.
Topics: Gene Rearrangement; Humans; Male; Neoplasm Recurrence, Local; PTEN Phosphohydrolase; Prognosis; Prostatectomy; Prostatic Neoplasms; Sequence Deletion; Transcriptional Regulator ERG
PubMed: 31359337
DOI: 10.1007/s12094-019-02170-3 -
Clinical Gastroenterology and... Aug 2020Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer... (Review)
Review
BACKGROUND & AIMS
Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer (CRC) and polyposis syndromes. We performed a systematic review to provide a comprehensive overview of somatic mosaicism in patients with CRC and polyposis syndromes.
METHODS
We searched PubMed through March 2018 to identify reports of mosaicism in patients with CRC or polyposis syndromes. We divided the final set of studies into 3 subgroups describing APC mosaicism, mosaicism in other CRC susceptibility genes, and epigenetic mosaicism.
RESULTS
Of the 232 articles identified in our systematic search, 46 met the criteria for further analysis. Of these, 35 studies described mosaic variants or epimutations in patients with CRC or polyposis syndromes. Nineteen studies described APC mosaicism, comprising a total of 57 patients. Six described mosaicism in genes associated with familial CRC syndromes, such as Lynch and Cowden syndromes. Ten studies described epigenetic mosaicism, sometimes resulting from a germline variant (such as deletion of EPCAM).
CONCLUSIONS
We found that somatic mosaicism is underdiagnosed but critical for determining the clinical management of patients with de novo polyposis who possibly carry mosaic APC variants, and present a decision tree for the clinical management of these patients. Mosaicism in genes associated with susceptibility to CRC contributes to development of other familial CRC syndromes. Heritable epigenetic mosaicism is likely underestimated and could have a dominant pattern of inheritance. However, the inheritance of primary mosaic epimutations, without an underlying genetic cause, is complex and not fully understood.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Genetic Predisposition to Disease; Humans; Mosaicism; Neoplastic Syndromes, Hereditary
PubMed: 32147591
DOI: 10.1016/j.cgh.2020.02.049 -
Cancers Aug 2019Some commonly available patient or disease characteristics may be associated with progression-free survival (PFS) and overall survival (OS) in EGFR-mutant non-small cell... (Review)
Review
Some commonly available patient or disease characteristics may be associated with progression-free survival (PFS) and overall survival (OS) in EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors). We performed a systematic review and meta-analysis of randomized control trials (RCTs) to explore differences in outcomes associated with EGFR-TKIs among subgroups of EGFR-mutant NSCLC patients. Pooled HRs for progression or death (PFS-HRs) and pooled HRs for death (OS-HRs) were compared among sub-groups defined according to baseline clinical and demographic variables as well as type of EGFR mutation. In the entire assessable population of 4465 EGFR-mutant NSCLC patients, significant interactions with PFS were found for gender (males vs. females; pooled ratio of the PFS-HRs = 1.2; 95% CI 1.12-1.56), smoking history (smokers vs. non-smokers; pooled ratio of the PFS-HRs = 1.26; 95% CI 1.05-1.51), and type of EGFR mutation (patients with exon 21 L858R mutation vs. exon 19 deletion; pooled ratio of the PFS-HRs = 1.39; 95% CI 1.18-1.63). Male patients, smokers and patients with EGFR exon 21 L858R mutation may derive less benefit from EGFR-TKIs compared to female patients, non-smokers and patients with EGFR exon 19 deletion.
PubMed: 31466227
DOI: 10.3390/cancers11091259 -
American Journal of Medical Genetics.... Dec 2021MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability,... (Review)
Review
MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability, developmental delay, lack of speech, limited walking, and seizures. Despite these findings, the disorder is not easily recognized clinically. We performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assemble the most comprehensive list of patients and their phenotypes. Through searching PubMed, Web of Science, and MEDLINE, 43 articles met the inclusion criteria and were fully reviewed. One hundred and seventeen patients were identified from these publications with most having a phenotype of intellectual disability, developmental delay, seizures, hypotonia, absent speech, inability to walk, stereotypic movements, and MRI abnormalities. Nonclassical findings included one patient with a question mark ear, two patients with a jugular pit, one patient with a unique neuroendocrine finding, and nine patients that did not have MEF2C deletions or disruptions but may be affected due to a positional effect on MEF2C. This systematic review characterizes the phenotype of MEF2C-related disorders, documents the severity of this condition, and will help providers to better diagnose and care for patients and their families. Additionally, this compiled information provides a comprehensive resource for investigators interested in pursuing specific genotype-phenotype correlations.
Topics: Chromosome Deletion; Epilepsy; Genetic Predisposition to Disease; Haploinsufficiency; Humans; Intellectual Disability; MEF2 Transcription Factors; Muscle Hypotonia
PubMed: 34184825
DOI: 10.1002/ajmg.a.62412 -
American Journal of Medical Genetics.... Feb 2022Variants in the pleckstrin homology domain-interacting protein (PHIP) gene are implicated in the clinical phenotype of Chung-Jansen syndrome, which includes dysmorphic...
Variants in the pleckstrin homology domain-interacting protein (PHIP) gene are implicated in the clinical phenotype of Chung-Jansen syndrome, which includes dysmorphic features, cognitive dysfunction, aberrant behavior, and childhood onset obesity. Following a systematic literature review, 35 patients are reported to have unique PHIP variants impacting the encoded protein product. We summarize the status and frequency of these variants and relationship to clinical presentation. We also describe an additional patient with a rare, pathogenic variant due to a five base pair deletion leading to an altered codon at I307 but with a stop codon at 22 codons downstream; notably, a variant was identified at the same location as seen previously at protein position I307 in one other subject and a frameshift change at that protein position. We compare the clinical characteristics between the two patients and analyze whether certain types of gene defects impact clinical presentation in previously reported individuals. In addition, we predict structural protein models, which yielded unique differences between the wild-type and I307P-related mutant truncated proteins. Protein-protein interactions indicate involvement of POMC and related proteins with potential contribution to obesity, congenital, neuromuscular, and lipid disorders with heart, gastrointestinal, and rheumatoid diseases. With its surrounding proline-rich region, the I307P point mutation increases susceptibility to conformational rigidity and thermodynamic stability, ultimately impacting function as well as a stop codon downstream. Furthermore, the frameshift mutation seen in our patient may result in a truncated protein with a short abnormal region prior to the stop codon due to a five base pair deletion at I307 or target the protein for nonsense-mediated mRNA decay.
Topics: Child; Frameshift Mutation; Humans; Nonsense Mediated mRNA Decay; Phenotype
PubMed: 34773373
DOI: 10.1002/ajmg.a.62557 -
Nephron 2023Genetic testing is recommended for accurate diagnosis of Bartter syndrome (BS) and serves as a basis for implementing specific target therapies. However, populations...
BACKGROUND
Genetic testing is recommended for accurate diagnosis of Bartter syndrome (BS) and serves as a basis for implementing specific target therapies. However, populations other than Europeans and North Americans are underrepresented in most databases and there are uncertainties in the genotype-phenotype correlation. We studied Brazilian BS patients, an admixed population with diverse ancestry.
METHODS
We evaluated the clinical and mutational profile of this cohort and performed a systematic review of BS mutations from worldwide cohorts.
RESULTS
Twenty-two patients were included; Gitelman syndrome was diagnosed in 2 siblings with antenatal BS and congenital chloride diarrhea in 1 girl. BS was confirmed in 19 patients: BS type 1 in 1 boy (antenatal BS); BS type 4a in 1 girl and BS type 4b in 1 girl, both of them with antenatal BS and neurosensorial deafness; BS type 3 (CLCNKB mutations): 16 cases. The deletion of the entire CLCNKB (1-20 del) was the most frequent variant. Patients carrying the 1-20 del presented earlier manifestations than those with other CLCNKB-mutations and the presence of homozygous 1-20 del was correlated with progressive chronic kidney disease. The prevalence of the 1-20 del in this BS Brazilian cohort was similar to that of Chinese cohorts and individuals of African and Middle Eastern descent from other cohorts.
CONCLUSION
This study expands the genetic spectrum of BS patients with different ethnics, reveals some genotype/phenotype correlations, compares the findings with other cohorts, and provides a systematic review of the literature on the distribution of BS-related variants worldwide.
Topics: Pregnancy; Female; Humans; Bartter Syndrome; Brazil; Phenotype; Mutation; Solute Carrier Family 12, Member 1; Chloride Channels
PubMed: 36882007
DOI: 10.1159/000528557 -
Clinica Chimica Acta; International... Mar 2022Fetalhyperechogenickidneys (HEK)are associated with a wide range of etiologies and prognoses. Prenatal counselling and management can be extremely challenging,...
BACKGROUND
Fetalhyperechogenickidneys (HEK)are associated with a wide range of etiologies and prognoses. Prenatal counselling and management can be extremely challenging, especially for isolated HEK.
METHODS
A total of 28 pregnancies were screened by ultrasonography with HEK from March 1, 2016 to December 31, 2020. Genetic testings for aneuploidy and copy number variations (CNVs) are routine during the investigation for etiologies of fetal HEK in our unit. Trio-whole exome sequencing(WES) was offered to the family when karyotyping and microarray were not diagnostic.A systematic review (SR) was conducted to use the authoritative literature retrieval databases describing genetic testings' results in prenatal HEK cases.
RESULTS
In the 28 HEK fetuses, 2 (7.14%) cases were identified with chromosome abnormalities and 6 (21.43%) cases were detected with pathogenic CNVs. Through trio-WES analysis, pathogenic or likely pathogenic variations were detected in the following genes: PKD1, BBS2, BBS9, HNF1B, PKHD1 and ETFA in another 10 (35.71%) fetuses. And the remaining 10 (35.71%) cases were undiagnosed. The pooled data from all reviewed studies indicate that HNF1B gene heterozygous deletion or mutation are the most common genetic causes associated with HEK.
CONCLUSION
This is the first study to accurately describe the genotype ratio at different levels of genetic testing associated with fetal HEK. Our study has suggested that trio-WES could improve the detection rate and efficiency ofidentification genetic pathologies in fetuseswith isolated HEK. The WES results provide new evidences to guide prenatal counseling and management.
Topics: DNA Copy Number Variations; Female; Fetus; Humans; Kidney; Kidney Diseases; Pregnancy; Prenatal Diagnosis
PubMed: 35065907
DOI: 10.1016/j.cca.2022.01.012 -
Pediatric Cardiology Jan 2021Cardiac involvement of Duchenne and Becker muscular dystrophies (DMD/BMD) is the most common cause of fatal outcomes. It is still unclear whether some DMD/BMD gene... (Meta-Analysis)
Meta-Analysis
Cardiac involvement of Duchenne and Becker muscular dystrophies (DMD/BMD) is the most common cause of fatal outcomes. It is still unclear whether some DMD/BMD gene mutations might be predictive of cardiac involvement. In this study, we provide a comprehensive overview on genotypes of cardiac disease in DMD/BMD. We systematically searched the PubMed/Medline, EMBASE and Cochrane electronic databases. Search results were filtered to include only human studies, English language and all dates up to August 2019. We summarized and extensively reviewed all studies that passed the selection criteria and performed a meta-analysis on key genotype parameters of cardiac disease in DMD/BMD. Of 3450 articles scanned, we included 18 studies from 9 regions in the meta-analysis. The pooled studies included 2661 DMD/BMD patients and 1324 DMD/BMD patients with cardiac disease. The most common mutation type was exon deletion, with a pooled frequency of 90% (P < 0.01). In DMD/BMD patients with cardiac dysfunction, a higher frequency of involvement of exons 45 and 46 was found in DMD/BMD patients with cardiac dysfunction. This might be predictive of cardiac involvement in patients with DMD/BMD.
Topics: Cardiovascular Diseases; Exons; Genotype; Humans; Male; Muscular Dystrophy, Duchenne; Mutation; Phenotype
PubMed: 33037470
DOI: 10.1007/s00246-020-02470-4