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Journal of Gastrointestinal and Liver... Mar 2022Several studies have suggested that mutations in MEFV, the gene responsible for familial Mediterranean fever (FMF), are frequently detected in inflammatory bowel disease... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Several studies have suggested that mutations in MEFV, the gene responsible for familial Mediterranean fever (FMF), are frequently detected in inflammatory bowel disease (IBD) patients. We aimed to provide further evidence regarding a potential correlation between MEFV gene mutations and IBD by identifying all relevant studies and analyzing their results.
METHODS
EMBASE, PubMed/MEDLINE, and Google Scholar were used to identify all studies that published until January 2021 and reported MEFV mutation patterns in patients with ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC) with or without a control group. The Newcastle-Ottawa quality assessment scale was used to appraise the quality of the included studies.
RESULTS
Thirteen observational studies, including 937 patients and 977 controls, were analyzed. MEFV mutation rate in IBD patients was 0.238 (95%CI: 0.209-0.270; I 2 =95%); MEFV mutated alleles were more frequent in IBD patients when compared with controls (p=0.03 for UC, p=0.01 for CD and IC). Subgroup analysis indicated that MEFV mutations were increased in patients with IC when compared with UC and CD (I 2 =91%, p<0.001). Patients with extra-intestinal manifestations and pancolitis had 2.57 (95%CI 1.07-6.14; p=0.03) and 2.02 (95%CI: 1.01-4.04, P=0.049) odds ratios to carry MEFV mutant genotypes, respectively. Exon 10 mutations had the most serious impact. No source of heterogeneity was detected.
CONCLUSIONS
MEFV mutations are common in IBD and are linked with the presence of extra-intestinal manifestations and pancolitis. Further research to assess the clinical significance and evolutionary significance of MEFV mutations in IBD patients is warranted.
Topics: Chronic Disease; Colitis, Ulcerative; Crohn Disease; Familial Mediterranean Fever; Humans; Inflammatory Bowel Diseases; Mutation; Pyrin
PubMed: 35306551
DOI: 10.15403/jgld-4070 -
Clinical Genitourinary Cancer Apr 2024Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). The aim of the present... (Meta-Analysis)
Meta-Analysis Review
Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olaparib, Rucaparib) and investigational (Talazoparib, Niraparib, Veliparib) PARPi in mCRPC patients. Three databases were queried for studies analyzing oncological outcomes and adverse events of mCRPC patients receiving PARPi. Primary outcome was a PSA decline ≥ 50% from baseline. Secondary outcomes were objective response rate, progression-free survival (PFS), radiological PFS, overall survival (OS), conversion of circulating tumor cell count, and time to PSA progression. The number and rate of any grade adverse events (AEs), grade ≥ 3 AEs, and most common grade ≥ 3 AEs were registered. A subanalysis of outcomes per mutation type, prospective trials, and studies adopting combination therapies was performed. Overall, 31 studies were included in this systematic review, 28 of which are available for meta-analysis. The most frequently investigated drug was Olaparib. The most frequent mutation was BRCA2. A PSA decline rate of 43% (95% CI 0.32-0.54) was observed in the overall population. Mean OS was 15.9 (95% CI 12.9-19.0) months. In BRCA2 patients, PSA decline rate was 66% (95% CI 0.57-0.7) and OS 23.4 months (95% CI 22.8-24.1). Half of the patients suffered from grade 3 and 4 AEs (0.50 [95% CI 0.39-0.60]). Most common AEs were hematological, the most frequent being anemia (21.5%). PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Prostate-Specific Antigen; Prospective Studies; Mutation
PubMed: 38281877
DOI: 10.1016/j.clgc.2023.12.011 -
Biochimica Et Biophysica Acta. Reviews... Dec 2019Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which... (Meta-Analysis)
Meta-Analysis Review
The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: A systematic review and meta-analysis of randomized and non-randomized trials.
BACKGROUND
Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy.
OBJECTIVE
The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer.
METHODS
A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors.
RESULTS
The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%-31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28-26.62, P ≤.001).
CONCLUSION
ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Fulvestrant; Humans; Mutation; Non-Randomized Controlled Trials as Topic; Randomized Controlled Trials as Topic; Tamoxifen
PubMed: 31647985
DOI: 10.1016/j.bbcan.2019.188315 -
BMC Pediatrics Oct 2023Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic...
BACKGROUND
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS.
METHODS
We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included.
RESULTS
The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years.
CONCLUSIONS
Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.
Topics: Female; Humans; Infant; Male; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Mutation; Phenotype; Shwachman-Diamond Syndrome; Signal Recognition Particle
PubMed: 37803383
DOI: 10.1186/s12887-023-04324-3 -
Mutation Research. Reviews in Mutation... 2022Whole-exome sequencing (WES) is useful for molecular diagnosis, family genetic counseling, and prognosis of intellectual disability (ID). However, ID molecular diagnosis... (Meta-Analysis)
Meta-Analysis Review
Whole-exome sequencing (WES) is useful for molecular diagnosis, family genetic counseling, and prognosis of intellectual disability (ID). However, ID molecular diagnosis ascertainment based on WES is highly dependent on de novo mutations (DNMs) and variants of uncertain significance (VUS). The quantification of DNM frequency in ID molecular diagnosis ascertainment and the biological mechanisms common to genes with VUS may provide objective information about WES use in ID diagnosis and etiology. We aimed to investigate and estimate the rate of ID molecular diagnostic assessment by WES, quantify the contribution of DNMs to this rate, and biologically and functionally characterize the genes whose mutations were identified through WES. A PubMed/Medline, Web of Science, Scopus, Science Direct, BIREME, and PsycINFO systematic review and meta-analysis was performed, including studies published between 2010 and 2022. Thirty-seven articles with data on ID molecular diagnostic yield using the WES approach were included in the review. WES testing accounted for an overall diagnostic rate of 42% (Confidence interval (CI): 35-50%), while the estimate restricted to DNMs was 11% (CI: 6-18%). Genetic information on mutations and genes was extracted and split into two groups: (1) genes whose mutation was used for positive molecular diagnosis, and (2) genes whose mutation led to uncertain molecular diagnosis. After functional enrichment analysis, in addition to their expected roles in neurodevelopment, genes from the first group were enriched in epigenetic regulatory mechanisms, immune system regulation, and circadian rhythm control. Genes from uncertain diagnosis cases were enriched in the renin angiotensin pathway. Taken together, our results support WES as an important approach to the molecular diagnosis of ID. The results also indicated relevant pathways that may underlie the pathogenesis of ID with the renin-angiotensin pathway being suggested to be a potential pathway underlying the pathogenesis of ID.
Topics: Humans; Exome; Exome Sequencing; Intellectual Disability; Renin-Angiotensin System
PubMed: 35905832
DOI: 10.1016/j.mrrev.2022.108428 -
Clinical & Translational Oncology :... Feb 2024The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available.
METHODS
The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs).
RESULTS
There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events.
CONCLUSION
TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable.
Topics: Humans; Trifluridine; Uracil; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); Colonic Neoplasms; Rectal Neoplasms; Drug Combinations; Antineoplastic Combined Chemotherapy Protocols; Pyrrolidines; Thymine
PubMed: 37414979
DOI: 10.1007/s12094-023-03268-5 -
Dermatologic Therapy Aug 2020The current systematic review aimed to evaluate the efficacy and safety of dabrafenib plus trametinib (dabrafenib-trametinib) with those of other therapeutic... (Review)
Review
Efficacy and safety of dabrafenib-trametinib in the treatment of unresectable or metastatic melanoma with BRAF V600 mutation: A systematic review and network meta-analysis.
The current systematic review aimed to evaluate the efficacy and safety of dabrafenib plus trametinib (dabrafenib-trametinib) with those of other therapeutic alternatives in the treatment of patients with BRAF V600 mutation unresectable or metastatic melanoma. The search was carried out on four databases up to July-2018. Two separate network meta-analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF V600 mutation (NMA-pBRAFV600) and another with a mixed population (with or without the mutation: NMA-pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA-pMixed was assessed via sensitivity analysis. Five clinical trials were included in the NMA-pBRAFV600. In the NMA-pBRAFV600 population, dabrafenib-trametinib had a favorable effect on overall survival (OS) and progression-free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine, and on partial response rate (PRR) and overall response rate (ORR) compared with dacarbazine and vemurafenib. In the NMA-pMixed population, dabrafenib-trametinib had a positive effect on OS vs ipilimumab 3 mg/kg and on PFS and PRR vs ipilimumab (3 and 10 mg/kg), nivolumab, and pembrolizumab. However, dabrafenib-trametinib, and vemurafenib-cobimetinib were comparable in terms of clinical efficacy. In addition, dabrafenib-trametinib was associated with less grades 3 and 4 adverse events.
PubMed: 32761749
DOI: 10.1111/dth.14135 -
Advances in Therapy Jan 2022The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH-mutated gliomas. Non-canonical IDH1 mutations or IDH2... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH-mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear.
METHODS
We performed a systematic review and meta-analysis to assess the clinical role of IDH non-canonical mutations.
RESULTS
Overall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 glioma including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4-10.7%) in patients with IDH-mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference 31%, 95% CI 23-38%) and presented a significantly prolonged survival (pooled HR 0.47, 95% CI 0.28-0.81) as compared to those with IDH1 R132H mutation.
CONCLUSION
Non-canonical IDH1 mutations occur in 7.9% of IDH-mutated gliomas and identify a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for improved stratification and selection of patients.
Topics: Brain Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Mutation
PubMed: 34853984
DOI: 10.1007/s12325-021-01977-3 -
Positive Correlation of Thyroid Nodule Cytology with Molecular Profiling-a Single-Center Experience.Endocrine Pathology Dec 2021Despite several reports on the association between molecular profiling, aggressive histology, and clinical outcomes, the association between mutation expression and...
Despite several reports on the association between molecular profiling, aggressive histology, and clinical outcomes, the association between mutation expression and pre-operative cytology is yet to be demonstrated. Therefore, we performed a retrospective, single-center study, including all patients who underwent molecular profiling of thyroid nodules in Bethesda System for Reporting Thyroid Cytopathology (BSRTC) categories III to VI, between 2018 and 2019. Medical records were reviewed to collect demographics, cytology results according to BSRTC, final pathology (presence of malignancy and its type, as well as presence of aggressive features, including extrathyroidal extension, positive neck lymph nodes, and multifocality), and the identified genetic variants stratified by risk levels, according to the 2015 ATA guidelines. We supplemented this analysis with a systematic review to identify the variant distributions across the literature. We included data on 55 nodules from 48 patients for the final analysis. A significant positive correlation was found between BSRTC categories and the mutation risk level, shown by an increase in the intermediate to high-risk mutation rate in the higher BSRTC categories (Rs = 0.660, p ≤ 0.001). A significant positive correlation was also found between mutation risk levels and the presence of malignancy and aggressive tumor features (Rs = 0.637, p < 0.001 and Rs = 0.459, p = 0.006, respectively). This novel positive and significant correlation between BSRTC categories and the mutation risk level provides additional insight to aid clinicians in the interpretation of BSRTC results and may contribute to the discussion of appropriate management of thyroid nodule with patients.
Topics: Adult; Aged; Biopsy, Fine-Needle; Cytodiagnosis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Israel; Male; Middle Aged; Retrospective Studies; Sequence Analysis, DNA; Thyroid Neoplasms; Thyroid Nodule; Transcriptome
PubMed: 34086262
DOI: 10.1007/s12022-021-09680-3 -
Pharmacological Research Feb 2024To assess the efficacy and safety of FDA-approved KRAS inhibitors in patients with KRAS-mutated solid tumors. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess the efficacy and safety of FDA-approved KRAS inhibitors in patients with KRAS-mutated solid tumors.
METHODS
We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest.
RESULTS
18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRAS-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77).
CONCLUSIONS
This study provided a comprehensive understanding of the efficacy and safety of KRAS inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRAS inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRAS inhibitor treatment.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; Proto-Oncogene Proteins p21(ras); NF-E2-Related Factor 2; Carcinoma, Non-Small-Cell Lung; Mutation; Lung Neoplasms
PubMed: 38185210
DOI: 10.1016/j.phrs.2024.107060